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Журнальные статьи

1. Abd Ellah N.H., Abouelmagd S.A. Surface functionalization of polymeric nanoparticles for tumor drug delivery: approaches and challenges // Expert Opin. Drug Deliv. 2017. Vol. 14, № 2. P. 201–214.

Introduction: For years, injectable polymeric nanoparticles (NPs) have been developed for delivering therapeutic agents to the tumors. Frequently, NPs surface have been modified with different moieties and/or ligands to impart stealth effect and/or elicit specific cellular interactions, both known to dramatically affect the in vivo fate and efficacy of these NPs. Areas covered: We discuss different types of ligands and molecules used for surface functionalization of polymeric NPs for tumor drug delivery. First, we summarize methods used through the literature for surface modification of polymeric NPs, then discuss challenges that face researchers either in decorating NPs with desired surface functionalities, characterizing functionalized surfaces or achieving intended cellular interactions and in vivo effects. Expert opinion: Modification of NP surfaces dramatically alters their behavior and favorably enhances their therapeutic efficacy. Choice of surface ligand/functionality should be based on intended therapeutic outcomes, taking into consideration the potential of clinical translation and scale up of the developed systems.

http://dx.doi.org/10.1080%2F17425247.2016.1213238

2. Ahmed O.A., Hussein A.K., Mady F.M. Optimisation of microstructured biodegradable finasteride formulation for depot parenteral application // J. Microencapsul. 2016. Vol. 33, № 3. P. 229–238.

This study aimed to use the biocompatibility features of the biodegradable polymers to prepare depot injectable finasteride (FIN) microspheres for the treatment of benign prostatic hyperplasia. FIN microspheres were prepared utilising an emulsion-solvent evaporation/extraction technique. The Box-Behnken experimental design was adopted to optimise the preparation process. FIN plasma levels in albino rabbits were determined after injection with optimised FIN microspheres formula and compared with oral FIN suspension. Results revealed that the optimum microspheres displayed an amended sustained release pattern with lower initial burst. The cumulative FIN % released after 25 days was in the range 27.83-73.18% for F-4 and F-1, respectively. The optimised formula, with 50.0% (X-1), and 22.316% (X-2) and 1.38% (X-3) showed 6.503m, 93.213%, 14.574%, and 64.838% for Y-1, Y-2, Y-3, and Y-4, respectively. In vivo studies displayed a sustained release pattern with minimal initial burst release when injected into rabbits.

http://dx.doi.org/10.3109%2F02652048.2016.1144821

3. Aho J. et al. Rheology as a tool for evaluation of melt processability of innovative dosage forms // Int. J. Pharm. 2015. Vol. 494, № 2. P. 623–642.

Future manufacturing of pharmaceuticals will involve innovative use of polymeric excipients. Hot melt extrusion (HME) is an already established manufacturing technique and several products based on HME are on the market. Additionally, processing based on, e.g., HME or three dimensional (3D) printing, will have an increasingly important role when designing products for flexible dosing, since dosage forms based on compacting of a given powder mixture do not enable manufacturing of optimal pharmaceutical products for personalized treatments. The melt processability of polymers and API-polymer mixtures is highly dependent on the rheological properties of these systems, and rheological measurements should be considered as a more central part of the material characterization tool box when selecting suitable candidates for melt processing by, e.g., HME or 3D printing. The polymer processing industry offers established platforms, methods, and models for rheological characterization, and they can often be readily applied in the field of pharmaceutical manufacturing. Thoroughly measured and calculated rheological parameters together with thermal and mechanical material data are needed for the process simulations which are also becoming increasingly important. The authors aim to give an overview to the basics of rheology and summarize examples of the studies where rheology has been utilized in setting up or evaluating extrusion processes. Furthermore, examples of different experimental set-ups available for rheological measurements are presented, discussing each of their typical application area, advantages and limitations.

http://dx.doi.org/10.1016%2Fj.ijpharm.2015.02.009

4. Alhijjaj M., Belton P., Qi S. An investigation into the use of polymer blends to improve the printability of and regulate drug release from pharmaceutical solid dispersions prepared via fused deposition modeling (FDM) 3D printing // Eur. J. Pharm. Biopharm. 2016. Vol. 108. P. 111–125.

FDM 3D printing has been recently attracted increasing research efforts towards the production of personalized solid oral formulations. However, commercially available FDM printers are extremely limited with regards to the materials that can be processed to few types of thermoplastic polymers, which often may not be pharmaceutically approved materials nor ideal for optimizing dosage form performance of poor soluble compounds. This study explored the use of polymer blends as a formulation strategy to overcome this processability issue and to provide adjustable drug release rates from the printed dispersions. Solid dispersions of felodipine, the model drug, were successfully fabricated using FDM 3D printing with polymer blends of PEG, PEO and Tween 80 with either Eudragit E PO or Soluplus. As PVA is one of most widely used polymers in FDM 3D printing, a PVA based solid dispersion was used as a benchmark to compare the polymer blend systems to in terms of processability. The polymer blends exhibited excellent printability and were suitable for processing using a commercially available FDM 3D printer. With 10% drug loading, all characterization data indicated that the model drug was molecularly dispersed in the matrices. During in vitro dissolution testing, it was dear that the disintegration behavior of the formulations significantly influenced the rates of drug release. Eudragit EPO based blend dispersions showed bulk disintegration; whereas the Soluplus based blends showed the 'peeling' style disintegration of strip-by strip. The results indicated that interplay of the miscibility between excipients in the blends, the solubility of the materials in the dissolution media and the degree of fusion between the printed strips during FDM process can be used to manipulate the drug release rate of the dispersions. This brings new insight into the design principles of controlled release formulations using FDM 3D printing.

http://dx.doi.org/10.1016%2Fj.ejpb.2016.08.016

5. Alshetaili A.S. et al. Optimization of hot melt extrusion parameters for sphericity and hardness of polymeric face-cut pellets // Drug Dev. Ind. Pharm. 2016. Vol. 42, № 11. P. 1833–1841.

The aim of this study was to formulate face-cut, melt-extruded pellets, and to optimize hot melt process parameters to obtain maximized sphericity and hardness by utilizing Soluplus VR as a polymeric carrier and carbamazepine (CBZ) as a model drug. Thermal gravimetric analysis (TGA) was used to detect thermal stability of CBZ. The Box-Behnken design for response surface methodology was developed using three factors, processing temperature (degrees C), feeding rate (%), and screw speed (rpm), which resulted in 17 experimental runs. The influence of these factors on pellet sphericity and mechanical characteristics was assessed and evaluated for each experimental run. Pellets with optimal sphericity and mechanical properties were chosen for further characterization. This included differential scanning calorimetry, drug release, hardness friability index (HFI), flowability, bulk density, tapped density, Carr's index, and fourier transform infrared radiation (FTIR) spectroscopy. TGA data showed no drug degradation upon heating to 190 degrees C. Hot melt extrusion processing conditions were found to have a significant effect on the pellet shape and hardness profile. Pellets with maximum sphericity and hardness exhibited no crystalline peak after extrusion. The rate of drug release was affected mainly by pellet size, where smaller pellets released the drug faster. All optimized formulations were found to be of superior hardness and not friable. The flow properties of optimized pellets were excellent with high bulk and tapped density.

http://dx.doi.org/10.1080%2F03639045.2016.1178769

6. Aminabhavi T.M. et al. Controlled release of therapeutics using interpenetrating polymeric networks // Expert Opin. Drug Deliv. 2015. Vol. 12, № 4. P. 669–688.

Introduction: The ever-increasing developments in pharmaceutical formulations have led to the widespread use of biodegradable polymers in various forms and configurations. In particular, interpenetrating network (IPN) and semi-IPN polymer structures that are capable of releasing drugs in a controlled manner have gained much wider importance in recent years. Areas covered: Recently, IPNs and semi-IPNs have emerged as innovative materials of choice in controlled release (CR) of drugs as the release from these systems depends on pH of the media and temperature in addition to the nature of the system. These networks can be prepared as smart hydrogels following chemical or physical crosslinking methods to show remarkable drug release patterns compared to single polymer systems. Expert opinion: A large number of IPNs and semi-IPNs have been reported in the literature. The present review is focused on the preparation methods and their CR properties with reference to anticancer, anti-asthmatic, antibiotic, anti-inflammatory, anti-tuberculosis and antihypertensive drugs, as majority of these drugs have been reported to be the ideal choices for using IPNs and semi-IPNs.

http://dx.doi.org/10.1517%2F17425247.2014.974871

7. Amint M.C.I.M. et al. Recent advances in the role of supramolecular hydrogels in drug delivery // Expert Opin. Drug Deliv. 2015. Vol. 12, № 7. P. 1149–1161.

Introduction: Supramolecular hydrogels, formed by noncovalent crosslinking of polymeric chains in water, constitute an interesting class of materials that can be developed specifically for drug delivery and biomedical applications. The biocompatibility, stimuli responsiveness to various external factors, and powerful functionalization capacity of these polymeric networks make them attractive candidates for novel advanced dosage form design. Areas covered: This review summarizes the significance of supramolecular hydrogels in various biomedical and drug delivery applications. The recent advancement of these hydrogels as potential advanced drug delivery systems (for gene, protein, anticancer and other drugs) is discussed. The importance of these hydrogels in biomedical applications, particularly in tissue engineering, biosensing, cell-culture research and wound treatment is briefly described. Expert opinion: The use of supramolecular hydrogels in drug delivery is still in very early stages. However, the potential of such a system is undeniably important and very promising. A number of recent studies have been conducted, which mainly focus on the use of cyclodextrin-based host-guest complex as well as other supramolecular motifs to form supramolecular hydrogels for delivery of various classes of drugs, therapeutic agents, proteins and genes. However, there are still plenty of opportunities for further development in this area for drug delivery and other biomedical applications.

http://dx.doi.org/10.1517%2F17425247.2015.997707

8. Anselmo A.C., Mitragotri S. Impact of particle elasticity on particle-based drug delivery systems // Adv. Drug Deliv. Rev. 2017. Vol. 108. P. 51–67.

Modification of nano/micro-particle physical parameters (e.g. size, shape, surface charge) has proven to be an effective method to enhance their delivery abilities. Recently, advances in particle synthesis have facilitated investigations into the role that particle elasticity plays in modulating drug delivery processes. This review will highlight: (i) methods to tune particle elasticity, (ii) the role particle elasticity plays in cellular internalization, (iii) the role of particle elasticity in modulating circulation times, (iv) the effect of particle elasticity on altering biodistribution and tissue targeting, and (v) the application of computational methods to explain the differences in cellular internalization of particles of different elasticities. Overall, literature reports suggest a complex relationship between particle elasticity and drug delivery processes. Despite this complex relationship, it is clear from numerous in vitro and in vivo studies that particle elasticity is an important parameter that can be leveraged to improve blood circulation, tissue targeting, and specific interactions with cells.

http://dx.doi.org/10.1016%2Fj.addr.2016.01.007

9. Arya A. et al. Design and evaluation of acrylate polymeric carriers for fabrication of pH-sensitive microparticles // Drug Dev. Ind. Pharm. 2017. Vol. 43, № 2. P. 305–318.

Colon-targeted microparticles loaded with a model anti-inflammatory drug were fabricated using especially designed acrylic acid-butyl methacrylate copolymers. Microparticles were prepared by oil-in-oil solvent evaporation method using Span 80 as emulsifier. Microparticles were found to be spherical in shape, hemocompatible and anionic with zeta potential of -27.4 and -29.0mV. Entrapment of drug in the microparticles was confirmed by Fourier transform infrared (FTIR) spectroscopy. However, X-ray diffraction (XRD) and differential scanning calorimetry (DSC) revealed amorphous nature of microparticles due to the dilution effect of amorphous polymer. The microparticles released less than 5% drug at pH 1.2, while more than 90% of the drug load was released at pH 7.4. This suggested the colon targeting nature of the formulations. In experimentally developed colitis in Wistar rats, the microparticle formulation showed significant reduction (p < .05) in the disease activity score (disease symptoms), the colon-to-body weight ratio (tissue edema) and the myeloperoxidase, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta activities.

http://dx.doi.org/10.1080%2F03639045.2016.1239629

10. Baghel S., Cathcart H., O’Reilly N.J. Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class // J. Pharm. Sci. 2016. Vol. 105, № 9. P. 2527–2544.

Poor water solubility of many drugs has emerged as one of the major challenges in the pharmaceutical world. Polymer-based amorphous solid dispersions have been considered as the major advancement in overcoming limited aqueous solubility and oral absorption issues. The principle drawback of this approach is that they can lack necessary stability and revert to the crystalline form on storage. Significant upfront development is, therefore, required to generate stable amorphous formulations. A thorough understanding of the processes occurring at a molecular level is imperative for the rational design of amorphous solid dispersion products. This review attempts to address the critical molecular and thermodynamic aspects governing the physicochemical properties of such systems. A brief introduction to Biopharmaceutical Classification System, solid dispersions, glass transition, and solubility advantage of amorphous drugs is provided. The objective of this review is to weigh the current understanding of solid dispersion chemistry and to critically review the theoretical, technical, and molecular aspects of solid dispersions (amorphization and crystallization) and potential advantage of polymers (stabilization and solubilization) as inert, hydrophilic, pharmaceutical carrier matrices. In addition, different preformulation tools for the rational selection of polymers, state-of-the-art techniques for preparation and characterization of polymeric amorphous solid dispersions, and drug supersaturation in gastric media are also discussed.

http://dx.doi.org/10.1016%2Fj.xphs.2015.10.008

11. Baghel S., Cathcart H., O’Reilly N.J. Theoretical and experimental investigation of drug-polymer interaction and miscibility and its impact on drug supersaturation in aqueous medium // Eur. J. Pharm. Biopharm. 2016. Vol. 107. P. 16–31.

Amorphous solid dispersions (ASDs) have the potential to offer higher apparent solubility and bioavailability of BCS class II drugs. Knowledge of the solid state drug-polymer solubility/miscibility and their mutual interaction are fundamental requirements for the effective design and development of such systems. To this end, we have carried out a comprehensive investigation of various ASD systems of dipyridamole and cinnarizine in polyvinylpyrrolidone (PVP) and polyacrylic acid (PAA) at different drug loadings. Theoretical and experimental examinations (by implementing binary and ternary Flory-Huggins (F-H) theory) related to drug-polymer interaction/miscibility including solubility parameter approach, melting point depression method, phase diagram, drug-polymer interaction in the presence of moisture and the effect of drug loading on interaction parameter were performed. The information obtained from this study was used to predict the stability of ASDs at different drug loadings and under different thermal and moisture conditions. Thermal and moisture sorption analysis not only provided the composition-dependent interaction parameter but also predicted the composition dependent miscibility. DPM-PVP, DPM-PAA and CNZ-PAA systems have shown molecular level mixing over the complete range of drug loading. For CNZ-PVP, the presence of a single T-g at lower drug loadings (10, 20 and 35% w/w) indicates the formation of solid solution. However, drug recrystallization was observed for samples with higher drug weight fractions (50 and 65% w/w). Finally, the role of polymer in maintaining drug supersaturation has also been explored. It has been found that drug-polymer combinations capable of hydrogen-bonding in the solution state (DPM-PVP, DPM-PAA and CNZ-PAA) are more effective in preventing drug crystallization compared to the drug-polymer systems without such interaction (CNZ-PVP). The DPM-PAA system outperformed all other ASDs in various stability conditions (dry-state, in the presence of moisture and in solution state), which was attributed to the drug's low crystallization tendency, the strong DPM-PAA interaction, the robustness of this interaction against moisture or water and the ability of PAA in maintaining DPM supersaturation.

http://dx.doi.org/10.1016%2Fj.ejpb.2016.06.024

12. Bagherifam S. et al. Poly(sebacic anhydride) nanocapsules as carriers: effects of preparation parameters on properties and release of doxorubicin // J. Microencapsul. 2015. Vol. 32, № 2. P. 166–174.

Poly(sebacic anhydride) (PSA) is a promising polymer for the production of drug delivery vehicles. The aim of this work is to study the effect of preparation parameters on the quality of the nanoparticles. In this study, doxorubicin (DOX)-loaded PSA nanocapsules were prepared by an emulsion method. Effects of factors such as type of organic solvent, co-solute (surfactant) and its concentration on drug-loading efficiency, particle size and size distribution, morphology and release profile were examined to gain insight in the preparation and stability of nanostructures. Particles with sizes in the range of 218-1198 nm were prepared. The smallest particles with a narrow size distribution were prepared by using polyvinyl alcohol as a co-solute and dichloromethane as a solvent. Efficiency and intracellular release of doxorubicin from the formulated particles were studied on MDA-MB-231 cells. It was observed that DOX-loaded PSA particles can diffuse into the cells and intracellular antitumour activity is directly related to the released amount of drug from the PSA nanocapsules.

http://dx.doi.org/10.3109%2F02652048.2014.973073

13. Balk M. et al. Recent advances in degradable lactide-based shape-memory polymers // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 136–152.

Biodegradable polymers are versatile polymeric materials that have a high potential in biomedical applications avoiding subsequent surgeries to remove, for example, an implanted device. In the past decade, significant advances have been achieved with poly(lactide acid) (PLA)-based materials, as they can be equipped with an additional functionality, that is, a shape-memory effect (SME). Shape-memory polymers (SMPs) can switch their shape in a predefined manner upon application of a specific external stimulus. Accordingly, SMPs have a high potential for applications ranging from electronic engineering, textiles, aerospace, and energy to biomedical and drug delivery fields based on the perspectives of new capabilities arising with such materials in biomedicine. This study summarizes the progress in SMPs with a particular focus on PLA, illustrates the design of suitable homo- and copolymer structures as well as the link between the (co)polymer structure and switching functionality, and describes recent advantages in the implementation of novel switching phenomena into SMP technology.

http://dx.doi.org/10.1016%2Fj.addr.2016.05.012

14. Basu A. et al. Poly(alpha-hydroxy acid)s and poly(alpha-hydroxy acid-co-alpha-amino acid)s derived from amino acid // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 82–96.

Polyesters derived from the a-hydroxy acids, lactic acid, and glycolic acid, are the most common biodegradable polymers in clinical use. These polymers have been tailored for a range of applications that require a physical material possessing. The physical and mechanical properties of these polymers fit the specific application and also safely biodegrade. These polymers are hydrophobic and do not possess functional side groups. This does not allow hydrophilic or hydrophobic manipulation, conjugation of active agents along the polymer chain, etc. These manipulations have partly been achieved by block copolymerization with, for example, poly(ethylene glycol), to obtain an amphiphilic copolymer. The objective of this review is to survey PLA functional copolymers in which functional a-hydroxy acids derived from amino acids are introduced along the polymer chain, allowing endless manipulation of PLA. Biodegradable functional polyesters are one of the most versatile biomaterials available to biomedical scientists. Amino acids with their variable side chains are ideal candidates for synthesizing such structural as well as stereochemically diverse polymers. They render control over functionalization, conjugation, crosslinking, stimulus responsiveness, and tunable mechanical/thermal properties. Functionalized amino acid derived polyesters are widely used, mainly due to advancement in ring opening polymerization (primarily O-carboxyanhydride mediated). The reaction proceeds under milder conditions and yields high molecular weight polymers. We reviewed on advances in the synthetic methodologies for poly-a-hydroxy esters derived from amino acids with appropriate recent examples.

http://dx.doi.org/10.1016%2Fj.addr.2016.08.003

15. Basu A. et al. Poly(lactic acid) based hydrogels // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 192–205.

Polylactide (PLA) and its copolymers are hydrophobic polyesters used for biomedical applications. Hydrogel medicinal implants have been used as drug delivery vehicles and scaffolds for tissue engineering, tissue augmentation and more. Since lactides are non-functional, they are copolymerized with hydrophilic monomers or conjugated to a hydrophilic moiety to form hydrogels. Copolymers of lactic and glycolic acids with poly(ethylene glycol) (PEG) provide thermo-responsive hydrogels. Physical crosslinking mechanisms of PEG-PLA or PLA-polysaccharides include: lactic acid segment hydrophobic interactions, stereocomplexation of D and L-lactic acid segments, ionic interactions, and chemical bond formation by radical or photo crosslinking. These hydrogels may also be tailored as stimulus responsive (pH, photo, or redox). PLA and its copolymers have also been polymerized to include urethane bonds to fabricate shape memory hydrogels. This review focuses on the synthesis, characterization, and applications of PIA containing hydrogels.

http://dx.doi.org/10.1016%2Fj.addr.2016.07.004

16. Beck-Broichsitter M., Nicolas J., Couvreur P. Design attributes of long-circulating polymeric drug delivery vehicles // Eur. J. Pharm. Biopharm. 2015. Vol. 97. P. 304–317.

Following systemic administration polymeric drug delivery vehicles allow for a controlled and targeted release of the encapsulated medication at the desired site of action. For an elevated and organ specific accumulation of their cargo, nanocarriers need to avoid opsonization, activation of the complement system and uptake by macrophages of the mononuclear phagocyte system. In this respect, camouflaged vehicles revealed a delayed elimination from systemic circulation and an improved target organ deposition. For instance, a steric shielding of the carrier surface by poly(ethylene glycol) substantially decreased interactions with the biological environment. However, recent studies disclosed possible deficits of this approach, where most notably, poly(ethylene glycol)-modified drug delivery vehicles caused significant immune responses. At present, identification of novel potential carrier coating strategies facilitating negligible immune reactions is an emerging field of interest in drug delivery research. Moreover, physical carrier properties including geometry and elasticity seem to be very promising design attributes to surpass numerous biological barriers, in order to improve the efficacy of the delivered medication.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.03.033

17. Beloqui A., des Rieux A., Preat V. Mechanisms of transport of polymeric and lipidic nanoparticles across the intestinal barrier // Adv. Drug Deliv. Rev. 2016. Vol. 106. P. 242–255.

Unraveling the mechanisms of nanoparticle transport across the intestinal barrier is essential for designing more efficient nanoparticles for oral administration. The physicochemical parameters of the nanoparticles (e.g., size, surface charge, chemical composition) dictate nanoparticle fate across the intestinal barrier. This review aims to address the most important findings regarding polymeric and lipidic nanoparticle transport across the intestinal barrier, including the evaluation of critical physicochemical parameters of nanoparticles that affect nanocarrier interactions with the intestinal barrier.

http://dx.doi.org/10.1016%2Fj.addr.2016.04.014

18. Biswas S. et al. Recent advances in polymeric micelles for anti-cancer drug delivery // Eur. J. Pharm. Sci. 2016. Vol. 83. P. 184–202.

Block co-polymeric micelles receive increased attention due to their ability to load therapeutics, deliver the cargo to the site of action, improve the pharmacokinetic of the loaded drug and reduce off-target cytotoxicity. While polymeric micelles can be developed with improved drug loading capabilities by modulating hydrophobicity and hydrophilicity of the micelle forming block co-polymers, they can also be successfully cancer targeted by surface modifying with tumor-homing ligands. However, maintenance of the integrity of the self-assembled system in the circulation and disassembly for drug release at the site of drug action remain a challenge. Therefore, stimuli-responsive polymeric micelles for on demand drug delivery with minimal off-target effect has been developed and extensively investigated to assess their sensitivity. This review focuses on discussing various polymeric micelles currently utilized for the delivery of chemotherapeutic drugs. Designs of various stimuli-sensitive micelles that are able to control drug release in response to specific stimuli, either endogenous or exogenous have been delineated.

http://dx.doi.org/10.1016%2Fj.ejps.2015.12.031

19. Bochmann E.S. et al. Micro-scale prediction method for API-solubility in polymeric matrices and process model for forming amorphous solid dispersion by hot-melt extrusion // Eur. J. Pharm. Biopharm. 2016. Vol. 107. P. 40–48.

A new predictive micro-scale solubility and process model for amorphous solid dispersions (ASDs) by hot-melt extrusion (HME) is presented. It is based on DSC measurements consisting of an annealing step and a subsequent analysis of the glass transition temperature (T-g). The application of a complex mathematical model (BCKV-equation) to describe the dependency of T-g on the active pharmaceutical ingredient (API)/polymer ratio, enables the prediction of API solubility at ambient conditions (25 degrees C). Furthermore, estimation of the minimal processing temperature for forming ASDs during HME trials could be defined and was additionally confirmed by X-ray powder diffraction data. The suitability of the DSC method was confirmed with melt rheological trials (small amplitude oscillatory system). As an example, ball milled physical mixtures of dipyridamole, indomethacin, itraconazole and nifedipine in poly(vinylpyrroli done-co-vinylacetate) (copovidone) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus((R))) were used.

http://dx.doi.org/10.1016%2Fj.ejpb.2016.06.015

20. Borges A.F. et al. Oral films: Current status and future perspectives I - Galenical development and quality attributes // J. Control. Release. 2015. Vol. 206. P. 1–19.

Polymers are the most common excipients used in pharmaceutical dosage forms, and often new applications and innovative polymers appear aiming to overcome unmet needs in the drug formulation field. Orodispersible dosage forms based on polymeric matrices have currently demonstrated their prominence in accordance with the actual market requirements and patients' demands. The versatility of the polymeric oral films had proven their high value as suitable technological platforms for extension and adjustment to different delivery routes and promising markets. These are the main reasons for the increasing investment of several companies in this technology and their applicability in different therapeutic segments. This pharmaceutical form with a blustering beginning as a breath freshener had an emergent entrance in the Rx market proving its reliable value. This review describes and explores the oral film technology from its main component, the polymeric matrices, to the new and possible market applications, highlighting all the critical and important points of its development.

http://dx.doi.org/10.1016%2Fj.jconrel.2015.03.006

21. Cadinoiu A.N. et al. Microparticulated systems based on chitosan and poly(vinyl alcohol) with potential ophthalmic applications // J. Microencapsul. 2015. Vol. 32, № 4. P. 381–389.

Spherical microparticles for encapsulation of drugs for the treatment of diseases, with a diameter ranging between 2 and 4 mu m, were obtained by double crosslinking (ionic and covalent) of chitosan and poly(vinyl alcohol) blend in a water-in-oil emulsion. Microparticles characterisation was carried out in terms of structural, morphological and swelling properties in aqueous media. The presence of chitosan in particles composition confers them a pH-sensitive character. Toxicity and hemocompatibility tests prove the biocompatible character of microparticles. The pilocarpine loading capacity is high as well as the release efficiency which increases up to 72 and 82% after 6 h. The obtained results recommend the microparticles as sustained release drug carriers for the treatment of eye diseases.

http://dx.doi.org/10.3109%2F02652048.2015.1035682

22. Calixto G. et al. Polyacrylic acid polymers hydrogels intended to topical drug delivery: preparation and characterization // Pharm. Dev. Technol. 2015. Vol. 20, № 4. P. 490–496.

Context: Bioadhesiviness of polyacrylic acid polymers make them promising hydrogels to design topical drug delivery systems, allowing a close contact with biological substrate as well as an enhanced local concentration gradient, both factors that may improve the biological performance of the drugs. Aim: Texture and bioadhesive properties of hydrogels were assessed by using texture analyzer and they were correlated with their rheological behavior and performance as drug delivery systems. Methods: Aqueous dispersions of both polymers were prepared at 0.5%, 1.0% and 1.5% w/v. Hardness, compressibility, adhesiveness, cohesiveness, bioadhesion, continuous flow, oscillatory dynamic test and in vitro drug release were evaluated. Results: Rheological and texture parameters were dependent on polymer concentration and C974P polymer built the strongest structures. Both 1.5% hydrogels presented high bioadhesion values. About 50% of the metronidazole (MTZ) was sustained released from hydrogels within 2 h with an initial burst release at early stage. After, the release rates were decreased and 10% of the MTZ was released in the next 10 h. The drug release process was driven by Fickian diffusion and complex mechanism for PP and C974P hydrogels, respectively. Conclusion: The set of results demonstrated that these hydrogels are promising to be used as topical controlled drug delivery system.

http://dx.doi.org/10.3109%2F10837450.2014.882941

23. Carlos Rodriguez-Cabello J. et al. Elastin-like polypeptides in drug delivery // Adv. Drug Deliv. Rev. 2016. Vol. 97. P. 85–100.

The use of recombinant elastin-like materials, or elastin-like recombinamers (ELRs), in drug-delivery applications is reviewed in this work. Although ELRs were initially used in similar ways to other, more conventional kinds of polymeric carriers, their unique properties soon gave rise to systems of unparalleled functionality and efficiency, with the stimuli responsiveness of ELRs and their ability to self-assemble readily allowing the creation of advanced systems. However, their recombinant nature is likely the most important factor that has driven the current breakthrough properties of ELR-based delivery systems. Recombinant technology allows an unprecedented degree of complexity in macromolecular design and synthesis. In addition, recombinant materials easily incorporate any functional domain present in natural proteins. Therefore, ELR-based delivery systems can exhibit complex interactions with both their drug load and the tissues and cells towards which this load is directed. Selected examples, ranging from highly functional nanocarriers to macrodepots, will be presented.

http://dx.doi.org/10.1016%2Fj.addr.2015.12.007

24. Castro-Aguirre E. et al. Poly(lactic acid)-Mass production, processing, industrial applications, and end of life // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 333–366.

Global awareness of material sustainability has increased the demand for bio-based polymers like poly(lactic acid) (PLA), which are seen as a desirable alternative to fossil-based polymers because they have less environmental impact. PLA is an aliphatic polyester, primarily produced by industrial polycondensation of lactic acid and/or ring-opening polymerization of lactide. Melt processing is the main technique used for mass production of PLA products for the medical, textile, plasticulture, and packaging industries. To fulfill additional desirable product properties and extend product use, PLA has been blended with other resins or compounded with different fillers such as fibers, and micro- and nanoparticles. This paper presents a review of the current status of PLA mass production, processing techniques and current applications, and also covers the methods to tailor PLA properties, the main PLA degradation reactions, PLA products' end-of-life scenarios and the environmental footprint of this unique polymer.

http://dx.doi.org/10.1016%2Fj.addr.2016.03.010

25. Chang M. et al. Smart linkers in polymer-drug conjugates for tumor-targeted delivery // J. Drug Target. 2016. Vol. 24, № 6. P. 475–491.

To achieve effective chemotherapy, many types of drug delivery systems have been developed for the specific environments in tumor tissues. Polymer-drug conjugates are increasingly used in tumor therapy due to several significant advantages over traditional delivery systems. In the fabrication of polymer-drug conjugates, a smart linker is an important component that joins two fragments or molecules together and can be cleared by a specific stimulus, which results in targeted drug delivery and controlled release. By regulating the conjugation between the drug and the nanocarriers, stimulus-sensitive systems based on smart linkers can offer high payloads, certified stability, controlled release and targeted delivery. In this review, we summarize the current state of smart linkers (e.g. disulfide, hydrazone, peptide, azo) used recently in various polymer-drug conjugate-based delivery systems with a primary focus on their sophisticated design principles and drug delivery mechanisms as well as in vivo processes.

http://dx.doi.org/10.3109%2F1061186X.2015.1108324

26. Chen Y.L. et al. Characterization of solid dispersions of Patchouli alcohol with different polymers: effects on the inhibition of reprecipitation and the improvement of dissolution rate // Drug Dev. Ind. Pharm. 2015. Vol. 41, № 3. P. 436–444.

Solid dispersion technique is known to be an effective approach for the polymer to keep drugs stable in the solid state, thereby improving the dissolution rate and oral bioavailability through inhibiting reprecipitation in supersaturated solution. In this study, to evaluate the inhibitory effect of polyethylene glycol-6000 (PEG), Polyvinylpyrrolidone K30 (PVP) and Aminoalkyl methacrylate copolymer (Eudragit), the reprecipitation profiles were observed from supersaturated solutions of Patchouli alcohol (PA) in the presence and absence of the polymers. Furthermore, the dissolution profiles of PA solid dispersions formulated with PEG, PVP or Eudragit were compared for investigating the effect on improving dissolution of each polymer. Solid dispersions formulated with Eudragit were found to result in solution with the highest extent of supersaturation. By contrast, PEG and PVP were less effective. At equivalent supersaturation, all three polymers are capable of mitigating reprecipitation relative to that of PA alone. In addition, in the PA solid dispersion with Eudragit (E-SD (1/3)), the highest concentration of supersaturation of PA was maintained for prolonged time. These results unambiguously indicate that it is imperative to select the appropriate polymer and drug/polymer ratio in addition to considering the stability of the supersaturated solution, which was generated following dissolution of amorphous solid dispersion.

http://dx.doi.org/10.3109%2F03639045.2013.877482

27. Chiriac A.P. et al. POLY(N, N-DIMETHYLACRYLAMIDE-co-3, 9-DIVINYL-2, 4, 8, 10-TETRAOXASPIRO (5.5) UNDECANE) SYNTHESIS AS MATRIX ENSURING INTRAMOLECULAR STRATEGIES FOR FURTHER COUPLING APPLICATIONS // Rev. Roum. Chim. 2013. Vol. 58, № 2–3. P. 129–136.

The preparation of the copolymer based on N,N-dimethylacrylamide and 3, 9-divinyl-2, 4, 8, 10-tetraoxaspiro (5.5) undecane (U) synthesized through radical polymerization process in N, N dimethyl acetamide solution and in the presence of peroxide benzoil (PBO) as radical initiator, it is presented. The new system can be included into the "smart" polymer class owing to the gel formation capacity, binding properties, amphilicity, good oxidative and thermal stability, biocompatibility, good films forming, pH sensitive response which is able for. The stereochemistry of the copolymer network ensures as well intramolecular strategies for further coupling processes of various molecular compounds as the polymer matrix to become for example a multi-sensitive structure or a drug delivery system.

http://revroum.lew.ro/wp-content/uploads/2013/2/Art%2004.pdf

28. Chonkar A.D. et al. Development of fast dissolving oral films containing lercanidipine HCl nanoparticles in semicrystalline polymeric matrix for enhanced dissolution and ex vivo permeation // Eur. J. Pharm. Biopharm. 2016. Vol. 103. P. 179–191.

Lercanidipine is a vasoselective dihydropyridine calcium antagonist, mainly used for the treatment of hypertension and angina pectoris. However, it suffers from food dependent absorption, poor solubility, low permeability and considerable first pass metabolism, resulting in highly variable and low bioavailability of 10%. Nanoparticles of lercanidipine were incorporated in fast dissolving oral films (FDO) via preparation of nanosuspension by evaporative antisolvent precipitation method. Prepared nanosuspensions were incorporated in FDO without lyophilizing or spray drying. Two nanosuspensions containing PEG 400 and TPGS 1000 as stabilizers, were selected further for incorporation in FDO. Physicochemical and mechanical properties of the optimized films were observed to be within acceptance criteria. SEM images as well as FTIR chemical images of oral films show uniform distribution of nanoparticles in polymeric matrix. The DSC and XRD results proved the poorly crystalline nature of lercanidipine. However thermal processing of film induces crystallinity in hypromellose which results in embedding of amorphous drug nanoparticles in semicrystalline polymeric matrix. Superior dissolution and permeability properties of nanoparticles were confirmed by in vitro dissolution studies and about 4.5-folds higher ex vivo drug permeation was observed from formulation through porcine buccal mucosa. This may give the clue for enhancement of bioavailability in vivo via improving orotransmucosal absorption.

http://dx.doi.org/10.1016%2Fj.ejpb.2016.04.001

29. Chountoulesi M. et al. y The modulation of physicochemical characterization of innovative liposomal platforms: the role of the grafted thermoresponsive polymers // Pharm. Dev. Technol. 2017. Vol. 22, № 3. P. 330–335.

This study is focused on chimeric advanced drug delivery systems and specifically on thermosensitive liposomes, combining lipids and thermoresponsive polymers. In this investigation, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) chimeric liposomal systems were prepared, incorporating the homopolymer C12H25-poly(N-isopropylacrylamide)-COOH (C12H25-PNIPAM-COOH) and the block copolymer poly(n-butylacrylate-b-N-isoropylacrylamide) (PnBA-PNIPAM), at six different molar ratios. Both of these polymers contain the thermoresponsive PNIPAM block, which exhibits lower critical solution temperature (LCST) at 32 degrees C in aqueous solutions, changing its nature from hydrophilic to hydrophobic above LCST. During the preparation of liposomes, the dispersions were observed visually, while after the preparation we studied the alterations of the physicochemical characteristics, by measuring the size, size distribution and zeta-potential of prepared liposomes. The presence of polymer, either C12H25-PNIPAM-COOH or PnBA-PNIPAM, resulted in liposomes exhibiting different physicochemical characteristics in comparison to conventional DPPC liposomes. At the highest percentage of the polymeric guest, chimeric liposomes were found to retain their size during the stability studies. The incorporation of the appropriate amount of these novel thermoresponsive polymers yields liposomal stabilization and imparts thermoresponsiveness, due to the functional PNIPAM block.

http://dx.doi.org/10.3109%2F10837450.2015.1121497

30. Chudecka-Glaz A. et al. New poly(ester-amide) copolymers modified with polyether (PEAE) for anticancer drug encapsulation // J. Microencapsul. 2016. Vol. 33, № 8. P. 702–711.

New poly(ester-amide) copolymers modified with polyethers were developed for carboplatin encapsulation. These new copolymers contain hydrophobic blocks made of tyrosine derivative and dimer fatty acid, and poly(ethylene glycol) (PEG) as hydrophilic blocks. Short-term hydrolytic degradation revealed high water absorption, slight increase of pH of simulated body fluid and change of sample shape, which indicated the erosive mechanism of polymers degradation. Poly(ester-amide)-PEG copolymers were used for microspheres preparation and carboplatin encapsulation. A double emulsification process was used to produce microspheres with an average diameter of 20-30 mu m. It was found that the amount of drug released was controlled by the molecular mass of PEG used for microspheres preparation. Mathematical models were used to elucidate the release mechanism of the carboplatin from the microspheres. The results demonstrate that poly(ester-amide)-PEG copolymers may be used for targeted carboplatin encapsulation and release.

http://dx.doi.org/10.1080%2F02652048.2016.1228708

31. d’Arcy R., Burke J., Tirelli N. Branched polyesters: Preparative strategies and applications // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 60–81.

In the last 20 years, the availability of precision chemical tools (e.g. controlled/living polymerizations, 'click' reactions) has determined a step change in the complexity of both the macromolecular architecture and the chemical functionality of biodegradable polyesters. A major part in this evolution has been played by the possibilities that controlled macromolecular branching offers in terms of tailored physical/biological performance. This review paper aims to provide an updated overview of preparative techniques that derive hyperbranched, dendritic, comb, grafted polyesters through polycondensation or ring-opening polymerization mechanisms.

http://dx.doi.org/10.1016%2Fj.addr.2016.05.005

32. D’souza A.A., Shegokar R. Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications // Expert Opin. Drug Deliv. 2016. Vol. 13, № 9. P. 1257–1275.

Introduction: Polyethylene glycol (PEG) is a polymer of choice in drug delivery systems. This USFDA-approved polymer is popular due to its tunable properties and well-established safety profile: prime requisites considered during the selection of any excipient in formulation development. Areas covered: The unique properties and applications of PEG have been discussed at length in the existing literature. However, a proper guidance on selection of PEG grade to cater to one's purpose is lacking. This article provides preliminary guidelines to formulators on selection of appropriate PEG grade, typically based on its physico-chemical properties and role-based functional application in pharmaceuticals. It should be noted that the aim article is not to deep dive in each application area. Expert opinion: Guidance on PEG application and grade of choice is lacking in the available literature. The authors have discussed and provided guidance to formulators on the appropriate PEG grade selection for particular application based on the available in vitro and in vivo literature data. In this review a State-of-the-art use of PEG in therapeutic applications, its clinical status and commercial use is also summarized. Nevertheless, toxicities related to different PEG grades and related impurities are discussed in this review.

http://dx.doi.org/10.1080%2F17425247.2016.1182485

33. De Robertis S. et al. Advances in oral controlled drug delivery: the role of drug-polymer and interpolymer non-covalent interactions // Expert Opin. Drug Deliv. 2015. Vol. 12, № 3. P. 441–453

Introduction: After more than four decades of intense research, oral controlled drug delivery systems (DDSs) still represent a topic of major interest for pharmaceutical scientist and formulators. This can be explained in part by considering the economic value of oral DDSs whose market accounts for more than half of the overall drug delivery market. Polymeric systems based on drug-polymer non-covalent interaction represent a limited, but growing part of the field. Despite the large amount of literature and published reviews covering specific aspects, there is still need for a review of the relevant literature providing a general picture of the topic. Areas covered: The present review aims at presenting the latest findings in drug-polymer and interpolymer non-covalent interactions in oral controlled delivery while providing a specific perspective and a critical point of view, particularly on the tools and methods used for the study of these DDSs. Four main sections are considered: i) ionic interactions between drugs and polymers; ii) interpolymer complexes; iii) hydrogen bond; and iv) hydrophobic interactions. Expert opinion: The largest part of the scientific literature deals with systems based on drug-polymer ionic interactions while hydrogen bonding and hydrophobic interaction though, very promising, are more difficult to exploit, and therefore less studied. An accurate and exhaustive representation of the specific role of the chemical functions in establishing predictable interactions between drug and polymers is still required.

http://dx.doi.org/10.1517%2F17425247.2015.966685

34. Demuth B. et al. Downstream processing of polymer-based amorphous solid dispersions to generate tablet formulations // Int. J. Pharm. 2015. Vol. 486, № 1–2. P. 268–286.

Application of amorphous solid dispersions (ASDs) is considered one of the most promising approaches to increase the dissolution rate and extent of bioavailability of poorly water soluble drugs. Such intervention is often required for new drug candidates in that enablement, bioavailability is not sufficient to generate a useful product. Importantly, tableting of ASDs is often complicated by a number of pharmaceutical and technological challenges including poor flowability and compressibility of the powders, compression-induced phase changes or phase separation and slow disintegration due to the formation of a gelling polymer network (GPN). The design principles of an ASD-based system include its ability to generate supersaturated systems of the drug of interest during dissolution. These metastable solutions can be prone to precipitation and crystallization reducing the biopharmaceutical performance of the dosage form. The main aim of the research in this area is to maintain the supersaturated state and optimally enhance bioavailability, meaning that crystallization should be delayed or inhibited during dissolution, as well as in solid phase (e.g., during manufacturing and storage). Based on the expanding use of ASD technology as well as their downstream processing, there is an acute need to summarize the results achieved to this point to better understand progress and future risks. The aim of this review is to focus on the conversion of ASDs into tablets highlighting results from various viewpoints.

http://dx.doi.org/10.1016%2Fj.ijpharm.2015.03.053

35. Dimchevska S. et al. SN-38 loading capacity of hydrophobic polymer blend nanoparticles: formulation, optimization and efficacy evaluation // Drug Dev. Ind. Pharm. 2017. Vol. 43, № 3. P. 502–510.

One of the most important problems in nanoencapsulation of extremely hydrophobic drugs is poor drug loading due to rapid drug crystallization outside the polymer core. The effort to use nanoprecipitation, as a simple one-step procedure with good reproducibility and FDA approved polymers like Poly(lactic-coglycolic acid) (PLGA) and Polycaprolactone (PCL), will only potentiate this issue. Considering that drug loading is one of the key defining characteristics, in this study we attempted to examine whether the nanoparticle (NP) core composed of two hydrophobic polymers will provide increased drug loading for 7-Ethyl-10-hydroxy-camptothecin (SN-38), relative to NPs prepared using individual polymers. D-optimal design was applied to optimize PLGA/PCL ratio in the polymer blend and the mode of addition of the amphiphilic copolymer Lutrol (R) F127 in order to maximize SN-38 loading and obtain NPs with acceptable size for passive tumor targeting. Drug/polymer and polymer/polymer interaction analysis pointed to high degree of compatibility and miscibility among both hydrophobic polymers, providing core configuration with higher drug loading capacity. Toxicity studies outlined the biocompatibility of the blank NPs. Increased in vitro efficacy of drug-loaded NPs compared to the free drug was confirmed by growth inhibition studies using SW-480 cell line. Additionally, the optimized NP formulation showed very promising blood circulation profile with elimination half-time of 7.4 h.

http://dx.doi.org/10.1080%2F03639045.2016.1268151

36. Dong X. et al. Thermosensitive porphyrin-incorporated hydrogel with four-arm PEG-PCL copolymer (II): doxorubicin loaded hydrogel as a dual fluorescent drug delivery system for simultaneous imaging tracking in vivo // Drug Delivery. 2017. Vol. 24, № 1. P. 641–650.

Visualization of a drug delivery system could reveal the pharmacokinetic properties, which is essential for the design of a novel drug delivery system. In vivo optical imaging offers an advanced tool to monitor the drug release process and the therapeutic effect by the combination of fluorescence imaging and bioluminescence imaging. Multispectral fluorescence imaging can separate the drug and the carrier without interference. Herein, a dual fluorescent anti-tumor drug delivery system was monitored with the doxorubicin-loaded hydrogel to further explore the application of the porphyrin-incorporated hydrogel with four-arm PEG-PCL copolymer as a drug carrier, based on the beneficial fluorescence and good biocompatibility of the porphyrin incorporated hydrogel. Using nude mice bearing luciferase expressed hepatic tumor as models, the whole process from the drug delivery to the tumor therapeutic effects were real time visualized simultaneously after administration at interval from 0 to 18 d. The imaging results suggest that the fluorescence signals of the drug and the carrier can be separated and unmixed from the drug-loaded hydrogel successfully, avoiding the interference of the fluorescence signals. The tumor growth or inhibition can be real time tracked and analyzed quantitatively by bioluminescence imaging. Noninvasive continuous tracking the in vivo drug delivery process simultaneously is a potential trend for the precise drug delivery and treatment.

http://dx.doi.org/10.1080%2F10717544.2017.1289570

37. Dubey R.D. et al. Recent advances in drug delivery strategies for improved therapeutic efficacy of gemcitabine // Eur. J. Pharm. Sci. 2016. Vol. 93. P. 147–162.

Gemcitabine (2',2'-difluoro-2'-deoxycytidine; dFdC) is an efficacious anticancer agent acting against a wide range of solid tumors, including pancreatic, non-small cell lung, bladder, breast, ovarian, thyroid and multiple myelomas. However, short plasma half-life due to metabolism by cytidine deaminase necessitates administration of high dose, which limits its medical applicability. Further, due to its hydrophilic nature, it cannot traverse cell membranes by passive diffusion and, therefore, enters via nucleoside transporters that may lead to drug resistance. To circumvent these limitations, macromolecular prodrugs and nanocarrier-based formulations of Gemcitabine are gaining wide recognition. The nanoformulations based approaches by virtue of their controlled release and targeted delivery have proved to improve bioavailability, increase therapeutic efficacy and reduce adverse effects of the drug. Furthermore, the combination of Gemcitabine with other anticancer agents as well as siRNAs using nanocarriers has also been investigated in order to enhance its therapeutic potential. This review deals with challenges and recent advances in the delivery of Gemcitabine with particular emphasis on macromolecular prodrugs and nanomedicines.

http://dx.doi.org/10.1016%2Fj.ejps.2016.08.021

38. Duro-Castano A., Movellan J., Vicent M.J. Smart branched polymer drug conjugates as nano-sized drug delivery systems // Biomater. Sci. 2015. Vol. 3, № 10. P. 1321–1334.

Polymer-drug conjugates represent excellent nanopharmaceutical candidates, as they offer multiple advantages related to their intrinsic characteristics. Many of the said characteristics are provided by the covalent bonding between the drug and the polymer. However, their clinical development has been slow and only one polymer-drug conjugate has reached the market, thus there remains an urgent need for the development of new and smart polymeric systems. Desirable characteristics of these new systems include higher molecular weight and degree of homogeneity, predictable conformations in solution, multivalency, and increased drug loading capacity, amongst others. With these aims in mind, branched polymers are ideal candidates due to their unique rheological, mechanical, and biomedical properties derived from their structure, inaccessible for linear polymers. Within this review, the synthetic strategies developed and the main efforts towards branched polymer implementation as carriers for polymer-drug conjugates will be addressed.

http://dx.doi.org/10.1039%2Fc5bm00166h

39. Fairbanks B.D., Gunatillake P.A., Meagher L. Biomedical applications of polymers derived by reversible addition - fragmentation chain-transfer (RAFT) // Adv. Drug Deliv. Rev. 2015. Vol. 91. P. 141–152.

RAFT - mediated polymerization, providing control over polymer length and architecture as well as facilitating post polymerization modification of end groups, has been applied to virtually every facet of biomedical materials research. RAFT polymers have seen particularly extensive use in drug delivery research. Facile generation of functional and telechelic polymers permits straightforward conjugation to many therapeutic compounds while synthesis of amphiphilic block copolymers via RAFT allows for the generation of self-assembled structures capable of carrying therapeutic payloads. With the large and growing body of literature employing RAFT polymers as drug delivery aids and vehicles, concern over the potential toxicity of RAFT derived polymers has been raised. While literature exploring this complication is relatively limited, the emerging consensus may be summed up in three parts: toxicity of polymers generated with dithiobenzoate RAFT agents is observed at high concentrations but not with polymers generated with trithiocarbonate RAFT agents; even for polymers generated with dithiobenzoate RAFT agents, most reported applications call for concentrations well below the toxicity threshold; and RAFT end-groups may be easily removed via any of a variety of techniques that leave the polymer with no intrinsic toxicity attributable to the mechanism of polymerization. The low toxicity of RAFT-derived polymers and the ability to remove end groups via straightforward and scalable processes make RAFT technology a valuable tool for practically any application in which a polymer of defined molecular weight and architecture is desired.

http://dx.doi.org/10.1016%2Fj.addr.2015.05.016

40. Fang J. et al. Styrene-maleic acid-copolymer conjugated zinc protoporphyrin as a candidate drug for tumor-targeted therapy and imaging // J. Drug Target. 2016. Vol. 24, № 5. P. 399–407.

Previous studies indicated the potential of zinc protoporphyrin (ZnPP) as an antitumor agent targeting to the tumor survival factor heme oxygenase-1, and/or for photodynamic therapy (PDT). In this study, to achieve tumor-targeted delivery, styrene-maleic acid-copolymer conjugated ZnPP (SMA-ZnPP) was synthesized via amide bond, which showed good water solubility, having ZnPP loading of 15%. More importantly, it forms micelles in aqueous solution with a mean particle size of 111.6 nm, whereas it has an apparent Mw of 65 kDa. This micelle formation was not detracted by serum albumin, suggesting it is stable in circulation. Further SMA-ZnPP conjugate will behave as an albumin complex in blood with much larger size (235 kDa) by virtue of the albumin binding property of SMA. Consequently, SMA-ZnPP conjugate exhibited prolonged circulating retention and preferential tumor accumulation by taking advantage of enhanced permeability and retention (EPR) effect. Clear tumor imaging was thus achieved by detecting the fluorescence of ZnPP. In addition, the cytotoxicity and PDT effect of SMA-ZnPP conjugate was confirmed in human cervical cancer HeLa cells. Light irradiation remarkably increased the cytotoxicity (IC50, from 33 to 5 mu M). These findings may provide new options and knowledge for developing ZnPP based anticancer theranostic drugs.

http://dx.doi.org/10.3109%2F1061186X.2015.1077851

41. Fang Y. et al. Polymeric lipid vesicles with pH-responsive turning on–off membrane for programed delivery of insulin in GI tract // Drug Delivery. 2016. Vol. 23, № 9. P. 3582–3593.

A kind of polymeric lipid vesicles (PLVs) with pH-responsive turning on–off membrane for programed delivery of insulin in gastrointestinal (GI) tract was developed, which was self-assembled from the grafted amphipathic polymer of N-tocopheryl-N?-succinyl-?-poly-l-lysine (TP/SC-g-PLL). By controlling the grafting ratio of hydrophobic alkane and ionizable carboxyl branches, the permeability of membrane was adjustable and thus allowing insulin release in a GI-pH dependent manner. The effects of grafting degree of substitution (DS) on the pH-responsive behavior of the formed vesicles were confirmed by critical aggregation concentration determination, morphology and size characterization. Their transepithelial permeability across the GI tract was proved by both confocal visualization in vitro model of Caco-2 cellular monolayer and in vivo hypoglycemic study in diabetic rats. Accordingly, the work described here indicated that the self-assembled PLVs could be a promising candidate for improving the GI delivery of hydrophilic biomacromolecule agents.

http://dx.doi.org/10.1080%2F10717544.2016.1212440

42. Farah S., Anderson D.G., Langer R. Physical and mechanical properties of PLA, and their functions in widespread applications - A comprehensive review // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 367–392.

Poly(lactic acid) (PLA), so far, is the most extensively researched and utilized biodegradable aliphatic polyester in human history. Due to its merits, PIA is a leading biomaterial for numerous applications in medicine as well as in industry replacing conventional petrochemical-based polymers. The main purpose of this review is to elaborate the mechanical and physical properties that affect its stability, processability, degradation, PIA-other polymers immiscibility, aging and recyclability, and therefore its potential suitability to fulfill specific application requirements. This review also summarizes variations in these properties during PLA processing (i.e. thermal degradation and recyclability), biodegradation, packaging and sterilization, and aging (i.e. weathering and hygrothermal). In addition, we discuss up-to-date strategies for PLA properties improvements including components and plasticizer blending, nucleation agent addition, and PIA modifications and nanoformulations. Incorporating better understanding of the role of these properties with available improvement strategies is the key for successful utilization of PLA and its copolymers/composites/blends to maximize their fit with worldwide application needs.

http://dx.doi.org/10.1016%2Fj.addr.2016.06.012

43. Feng S. et al. Drug-loaded PLGA-mPEG microparticles as treatment for atopic dermatitis-like skin lesions in BALB/c mice model // J. Microencapsul. 2015. Vol. 32, № 2. P. 201–209.

This study evaluated the feasibility of mizolastine-loaded microparticles as therapy for atopic dermatitis. Microparticles have been researched for decades as a controlled-release drug delivery system, but seldom been used as treatment for skin disease. In this research, we induced dermatitis in BALB/c mice model by repeated topical application of dinitrofluorobenzene and compared the mizolastine microparticles injection and daily mizolastine injection treatment. The results showed that the mizolastine microparticles treatments significantly inhibited ear thickness and dermatitis index in dermatitis model compared with the dermatitis mice without treatment, showing a similar curative effect compared with daily mizolastine injection treatment, and the improvement continued for several days. Inflammatory cells infiltration into the ears and the plasma level of immunoglobulin E were also suppressed by mizolastine microparticles according to the histopathology analysis. In conclusion, the results suggested that drug-loaded microparticles could be a proper candidate for the treatment of skin diseases.

http://dx.doi.org/10.3109%2F02652048.2014.995727

44. Frederiksen K., Guy R.H., Petersson K. Formulation considerations in the design of topical, polymeric film-forming systems for sustained drug delivery to the skin // Eur. J. Pharm. Biopharm. 2015. Vol. 91. P. 9–15.

Polymeric film-forming systems (FFSs) are potential drug delivery systems for topical application to the skin. The FFSs form thin and transparent polymeric films in situ upon solvent evaporation. Their application convenience and cosmetic attributes, superior to conventional semi-solids, may offer improved patient compliance. This study represents the first phase of an investigation into the use of FFSs for prolonged dermal drug delivery. FFS formulations were distinguished based on their ability to sustain the release of betamethasone 17-valerate (BMV) in vitro over 72 h. The effect of film-forming polymer (hydrophilic: hydroxypropyl cellulose (Klucel (TM) LF); hydrophobic: polymethacrylate copolymers (Eudragit (R) NE and Eudragit (R) RS), and polyacrylate copolymer (Dermacryl (R) 79) was first determined, and then the impact of incorporation of plasticisers (triethyl citrate, tributyl citrate, and dibutyl sebacate) was examined. The Klucel film released a significantly higher amount of BMV than the hydrophobic FFS, 42 versus 4 mu g/cm(2), respectively. The release was increased when a plasticiser was incorporated, and with higher enhancement ratios achieved with the more lipophilic plasticisers. In conclusion, the results show that FFSs can sustain drug release (hence representing useful systems for prolonged dermal therapy) and emphasise the importance of the formulation on drug delivery, with the type of polymer being of greatest significance.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.01.002

45. Frederiksen K., Guy R.H., Petersson K. The potential of polymeric film-forming systems as sustained delivery platforms for topical drugs // Expert Opin. Drug Deliv. 2016. Vol. 13, № 3. P. 349–360.

Introduction: Dosing regimens requiring multiple daily applications frequently result in poor patient compliance, especially in the treatment of chronic skin diseases. Consequently, development of sustained delivery systems for topical drugs permitting less frequent dosing is of continuing interest for dermatological therapy. Areas covered: This potential of polymeric film-forming systems (FFS), created in situ on the skin, as sustained delivery platforms for topical drug delivery is reviewed. Key formulation parameters that determine delivery efficiency are considered focussing on those that permit a drug reservoir to be established in the upper layers of the skin and/or on the skin surface from which release can be sustained over a prolonged period. The advantageous and superior cosmetic attributes of FFS (compared to conventional semi-solid formulations) that offer significantly improved patient compliance are also addressed. Expert opinion: The promise of polymeric FFS as convenient and aesthetic platforms for sustained topical drug delivery is clear. Manipulation of the formulation allows the delivery profile to be customized and optimized to take advantage of both a rapid, initial input of drug into the skin (likely due to a transient period of supersaturation) and a slower, controlled release over an extended time from the residual film created thereafter.

http://dx.doi.org/10.1517%2F17425247.2016.1124412

46. Gao S. et al. Polybutylcyanoacrylate nanocarriers as promising targeted drug delivery systems // J. Drug Target. 2015. Vol. 23, № 6. P. 481–496.

Among the materials for preparing the polymeric nanocarriers, poly(n-butylcyanoacrylate) (PBCA), a polymer with medium length alkyl side chain, is of lower toxicity and proper degradation time. Therefore, PBCA has recently been regarded as a kind of widely used, biocompatible, biodegradable, low-toxic drug carrier. This review highlights the use of PBCA-based nanocarriers (PBCA-NCs) as targeting drug delivery systems and presents the methods of preparation, the surface modification and the advantages and limitations of PBCA-NCs. The drugs loaded in PBCA-NCs are summarized according to the treatment of diseases, and the different therapeutic applications and the most recent developments of PBCA-NCs are also discussed, which provides useful guidance on the targeting research of PBCA-NCs.

http://dx.doi.org/10.3109%2F1061186X.2015.1020426

47. Gill K.K., Kaddoumi A., Nazzal S. PEG-lipid micelles as drug carriers: physiochemical attributes, formulation principles and biological implication // J. Drug Target. 2015. Vol. 23, № 3. P. 222–231.

PEG-lipid micelles, primarily conjugates of polyethylene glycol (PEG) and distearyl phosphatidylethanolamine (DSPE) or PEG-DSPE, have emerged as promising drug-delivery carriers to address the shortcomings associated with new molecular entities with suboptimal biopharmaceutical attributes. The flexibility in PEG-DSPE design coupled with the simplicity of physical drug entrapment have distinguished PEG-lipid micelles as versatile and effective drug carriers for cancer therapy. They were shown to overcome several limitations of poorly soluble drugs such as non-specific biodistribution and targeting, lack of water solubility and poor oral bioavailability. Therefore, considerable efforts have been made to exploit the full potential of these delivery systems; to entrap poorly soluble drugs and target pathological sites both passively through the enhanced permeability and retention (EPR) effect and actively by linking the terminal PEG groups with targeting ligands, which were shown to increase delivery efficiency and tissue specificity. This article reviews the current state of PEG-lipid micelles as delivery carriers for poorly soluble drugs, their biological implications and recent developments in exploring their active targeting potential. In addition, this review sheds light on the physical properties of PEG-lipid micelles and their relevance to the inherent advantages and applications of PEG-lipid micelles for drug delivery.

http://dx.doi.org/10.3109%2F1061186X.2014.997735

48. Gilmore K.A. et al. Matrices for combined delivery of proteins and synthetic molecules // Adv. Drug Deliv. Rev. 2016. Vol. 98. P. 77–85.

With the increasing advancement of synergistic, multimodal approaches to influence the treatment of infectious and non-infectious diseases, we witness the development of enabling techniques merging necessary complexity with leaner designs and effectiveness. Systems-and polypharmacology ask for multi-potent drug combinations with many targets to engage with the biological system. These demand drug delivery designs for one single drug, dual drug release systems and multiple release matrices in which the macromolecular structure allows for higher solubilization, protection and sequential or combined release profiles. As a result, nano- and micromaterials have been evolved from mono- to dual drug carriers but are also an essential part to establish multimodality in polymeric matrices. Surface dynamics of particles creating interfaces between polymer chains and hydrogels inspired the development not only of biomedical adhesives but also of injectable hydrogels in which the nanoscale material is both, adhesive and delivery tool. These complex delivery systems are segmented into two delivery subunits, a polymer matrix and nanocarrier, to allow for an even higher tolerance of the incorporated drugs without adding further synthetic demands to the nanocarrier alone. The opportunities in these quite novel approaches for the delivery of small and biological therapeutics are remarkable and selected examples for applications in cancer and bone treatments are discussed.

http://dx.doi.org/10.1016%2Fj.addr.2015.11.018

49. Goonoo N. et al. Polydioxanone-based bio-materials for tissue engineering and drug/gene delivery applications // European Journal of Pharmaceutics and Biopharmaceutics. 2015. Vol. 97, Part B. P. 371–391.

Since the commercialization of polydioxanone (PDX) as a biodegradable monofilament suture by Ethicon in 1981, the polymer has received only limited interest until recently. The limitations of polylactide-co-glycolide (PLGA) coupled with the growing need for materials with enhanced features and the advent of new fabrication techniques such as electrospinning have revived interest for PDX in medical devices, tissue engineering and drug delivery applications. Electrospun PDX mats show comparable mechanical properties as the major structural components of native vascular extracellular matrix (ECM) i.e. collagen and elastin. In addition, PDX’s unique shape memory property provides rebound and kink resistance when fabricated into vascular conduits. The synthesis of methyl dioxanone (MeDX) monomer and copolymers of dioxanone (DX) and MeDX have opened up new perspectives for poly(ester-ether)s, enabling the design of the next generation of tissue engineering scaffolds for application in regenerating such tissues as arteries, peripheral nerve and bone. Tailoring of polymer properties and their formulation as nanoparticles, nanomicelles or nanofibers have brought along important developments in the area of controlled drug or gene delivery. This paper reviews the synthesis of PDX and its copolymers and provides for the first time an exhaustive account of its applications in the (bio)medical field with focus on tissue engineering and drug/gene delivery.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.05.024

50. Gregoritza M., Brandl F.P. The Diels–Alder reaction: A powerful tool for the design of drug delivery systems and biomaterials // European Journal of Pharmaceutics and Biopharmaceutics. 2015. Vol. 97, Part B. P. 438–453

Click reactions have the potential to greatly facilitate the development of drug delivery systems and biomaterials. These reactions proceed under mild conditions, give high yields, and form only inoffensive by-products. The Diels–Alder cycloaddition is one of the click reactions that do not require any metal catalyst; it is one of the most useful reactions in synthetic organic chemistry and material design. Herein, we highlight possible applications of the Diels–Alder reaction in pharmaceutics and biomedical engineering. Particular focus is placed on the synthesis of polymers and dendrimers for drug delivery, the preparation of functionalized surfaces, bioconjugation techniques, and applications of the Diels–Alder reaction in nanotechnology. Moreover, applications of the reaction for the preparation of hydrogels for drug delivery and tissue engineering are reviewed. A general introduction to the Diels–Alder reaction is presented, along with a discussion of potential pitfalls and challenges. At the end of the article, we provide a set of tools that may facilitate the application of the Diels–Alder reaction to solve important pharmaceutical or biomedical problems.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.06.007

51. Griessinger J.A. et al. Thiolated polymers: evaluation of their potential as dermoadhesive excipients // Drug Dev. Ind. Pharm. 2017. Vol. 43, № 2. P. 204–212.

The objective of this study was to evaluate and compare four different thiolated polymers regarding their dermoadhesive potential. Therefore, three hydrophilic polymers (poly(acrylic acid), Carbopol 971 and carboxymethylcellulose) and a lipophilic polymer (silicone oil) were chosen to generate thiolated polymers followed by characterization. The total work of adhesion (TWA) and the maximum detachment force (MDF) of formulations containing modified and unmodified polymers were investigated on skin obtained from pig ears using a tensile sandwich technique. The synthesis of thiolated polymers provided 564 mu mol, 1079 mu mol, 482 mu mol and 217 mu mol thiol groups per gram poly(acrylic acid), Carbopol 971, carboxymethylcellulose and silicone oil, respectively. Hydrogels containing poly(acrylic acid)-cysteine, Carbopol 971-cysteine, and carboxymethylcellulose-cysteamine exhibited a 6-fold, 25-fold and 9-fold prolonged adhesion on porcine skin than the hydrogel formulations prepared from the corresponding unmodified polymers, respectively. Furthermore, thiolation of silicone oil with thioglycolic acid led to a 5-fold improvement in adhesion compared to the unmodified silicone oil. A comparison between the four thiolated polymer formulations showed a clear correlation between the amount of coupled thiol groups and the TWA. According to these results thiomers might also be useful excipients to provide a prolonged dermal resistance time of various formulations.

http://dx.doi.org/10.1080%2F03639045.2016.1231809

52. Groynom R. et al. Controlled release of photoswitch drugs by degradable polymer microspheres // J. Drug Target. 2015. Vol. 23, № 7–8. P. 710–715.

Background: QAQ (quaternary ammonium-azobenzene-quaternary ammonium) and DENAQ (diethylamine-azobenzene-quaternary ammonium) are synthetic photoswitch compounds that change conformation in response to light, altering current flow through voltage-gated ion channels in neurons. These compounds are drug candidates for restoring light sensitivity in degenerative blinding diseases, such as age-related macular degeneration (AMD). Purpose: However, these photoswitch compounds are cleared from the eye within several days, they must be administered through repeated intravitreal injections. Therefore, we are investigating local, sustained delivery formulations to constantly replenish these molecules and have the potential to restore sight. Methods: Here, we encapsulate QAQ and DENAQ into several molecular weights of poly(lactic-co-glycolic) acid (PLGA) through an emulsion technique to assess the viability of delivering the compounds in their therapeutic window over many weeks. We characterize the loading efficiency, release profile and bioactivity of the compounds after encapsulation. Results: A very small burst release was observed for all of the formulations with the majority being delivered over the following two months. The lowest molecular weight PLGA led to the highest loading and most linear delivery for both QAQ and DENAQ. Bioactivity was retained for both compounds across the polymers. Conclusion: These results present encapsulation into polymers by emulsion as a viable option for controlled release of QAQ and DENAQ.

http://dx.doi.org/10.3109%2F1061186X.2015.1060978

53. Gue E. et al. Accelerated ketoprofen release from spray-dried polymeric particles: importance of phase transitions and excipient distribution // Drug Dev. Ind. Pharm. 2015. Vol. 41, № 5. P. 838–850.

HPMC-, PVPVA- and PVP-based microparticles loaded with 30% ketoprofen were prepared by spray drying suspensions or solutions in various water:ethanol blends. The inlet temperature, drying gas and feed flow rates were varied. The resulting differences in the ketoprofen release rates in 0.1 M HCl could be explained based on X-ray diffraction, mDSC, SEM and particle size analysis. Importantly, long term stable drug release could be provided, being much faster than: (i) drug release from a commercial reference product, (ii) the respective physical drug: polymer mixtures, as well as (iii) the dissolution of ketoprofen powder as received. In addition, highly supersaturated release media were obtained, which did not show any sign for re-crystallization during the observation period. Surprisingly, spraying suspensions resulted in larger microparticles exhibiting faster drug release compared to spraying solutions, which resulted in smaller particles exhibiting slower drug release. These effects could be explained based on the physico-chemical characteristics of the systems.

http://dx.doi.org/10.3109%2F03639045.2014.908902

54. Gullapalli R.P., Mazzitelli C.L. Polyethylene glycols in oral and parenteral formulations-A critical review // Int. J. Pharm. 2015. Vol. 496, № 2. P. 219–239.

Polyethylene glycols (PEGs) are frequently employed as vehicles in oral and parenteral dosage forms. PEGs have low toxicity, are miscible with aqueous fluids in all proportions, and dissolve many poorly aqueous soluble compounds. Compounds with poor aqueous solubility and resulting poor bioavailability and considerable individual variability in the absorption were shown to provide exceptionally high bioavailability and reduced inter-subject variability in plasma concentrations when dosed as solutions or suspensions in PEGs. The advantages offered by PEGs, however, are not without potential challenges that must also be considered and which are the focus of this review. First, PEGs often may have high solubilizing power for some poorly aqueous soluble compounds, the high affinity of these vehicles for water can potentially lead to precipitation of the dissolved compounds when the formulations encounter an aqueous environment in vitro or in vivo, resulting in reduced bioavailability of the compounds. Second, PEGs, due to the presence of hydroxyl groups in their structures, are reactive with compounds dissolved within, resulting in the formation of degradation products. Third, PEGs, due to the presence of recurring ether groups in their polymer chains, are also inherently susceptible to autooxidative reactions, resulting in the formation of highly reactive products, which degrade several compounds formulated with PEGs. The objective is to review the applications and limitations of PEGs in pharmaceutical dosage forms and discuss solutions to mitigate challenges that may potentially arise from their use.

http://dx.doi.org/10.1016%2Fj.ijpharm.2015.11.015

55. Guo X. et al. Polymer-Based Drug Delivery Systems for Cancer Treatment // J. Polym. Sci. Pol. Chem. 2016. Vol. 54, № 22. P. 3525–3550.

This review is focused on the chemical design and synthesis of polymer-based drug delivery systems, in particular with stimuli-responsive nanoplatforms for cancer treatment. We provide a brief description of the properties, synthesis and advantages of amphiphilic block copolymers, including polyether-polyester and polyether-polyanhydride. As for stimuli-responsive polymers, we detail the recent innovative techniques for constructing smarter, more precise and optimally tuned nanocarriers that release drug in the disease site. This review is presented in the context of polymer science research, with special attention focused on the tailor-made polymers containing specific chemical functionalities.

http://dx.doi.org/10.1002%2Fpola.28252

56. Hanna L.A., Basalious E.B., ELGazayerly O.N. Respirable controlled release polymeric colloid (RCRPC) of bosentan for the management of pulmonary hypertension: in vitro aerosolization, histological examination and in vivo pulmonary absorption // Drug Delivery. 2017. Vol. 24, № 1. P. 188–198.

Bosentan is an endothelin receptor antagonist (ERA) prescribed for patients with pulmonary arterial hypertension (PAH). The oral delivery of bosentan possesses several drawbacks such as low bioavailability (about 50%), short duration of action, frequent administration, hepatotoxicity and systemic hypotension. The pulmonary administration would circumvent the pre-systemic metabolism thus improving the bioavailability and avoids the systemic adverse effects of oral bosentan. However, the short duration of action and the frequent administration are the major drawbacks of inhalation therapy. Thus, the aim of this work is to explore the potential of respirable controlled release polymeric colloid (RCRPC) for effective, safe and sustained pulmonary delivery of bosentan. Central composite design was adopted to study the influence of formulation and process variables on nanoparticles properties. The particle size, polydispersity index (PDI), entrapment efficiency (EE) and in vitro bosentan released were selected as dependent variables. The optimized RCRPC showed particle size of 420?nm, PDI of 0.39, EE of 60.5% and sustained release pattern where only 31.0% was released after 16?h. The in vitro nebulization of RCRPC indicated that PLGA nanoparticles could be incorporated into respirable nebulized droplets better than drug solution. Pharmacokinetics and histopathological examination were determined after intratracheal administration of the developed RCRPC to male albino rats compared to the oral bosentan suspension. Results revealed the great improvement of bioavailability (12.71 folds) and sustained vasodilation effect on the pulmonary blood vessels (more than 12?h). Bosentan-loaded RCRPC administered via the pulmonary route may therefore constitute an advance in the management of PAH.

http://dx.doi.org/10.1080%2F10717544.2016.1239661

57. Hu X. et al. Electrospinning of polymeric nanofibers for drug delivery applications // J. Control. Release. 2014. Vol. 185. P. 12–21.

Electrospinning has been recognized as a simple and versatile method for fabrication of polymer nanofibers. Various polymers that include synthetic, natural, and hybrid materials have been successfully electrospun into ultrafine fibers. The inherently high surface to volume ratio of electrospun fibers can enhance cell attachment, drug loading, and mass transfer properties. Drugs ranging from antibiotics and anticancer agents to proteins, DNA, RNA, living cells, and various growth factors have been incorporated into electrospun fibers. This article presents an overview of electrospinning techniques and their application in drug delivery.

http://dx.doi.org/10.1016%2Fj.jconrel.2014.04.018

58. Hunter A.C., Moghimi S.M. Smart polymers in drug delivery: a biological perspective // Polym. Chem. 2017. Vol. 8, № 1. P. 41–51.

Key to the widespread application of smart polymers in drug delivery is understanding the mechanistic interplay, as well as consequence, of the presence of these macromolecules within living systems. This review looks at these interactions in terms of host response to macromolecular structure and subsequent clinical implications. In order to highlight this, three distinct routes of drug delivery are discussed, enabling a journey from the outside of the body in to the cell. This is used to contrast the need for different scientific approaches replete to successful drug delivery in these physiologically diverse areas. The discussion initiates with the application of smart polymers to the oral route of drug delivery, followed by macromolecular fate within the systemic circulation and finally intracellular delivery. The advantages, in terms of biological performance, as well as the challenges of using smart polymers within this multifaceted arena are delineated.

http://dx.doi.org/10.1039%2Fc6py00676k

59. Huo M. et al. Redox-responsive polymers for drug delivery: from molecular design to applications // Polym. Chem. 2014. Vol. 5, № 5. P. 1519–1528.

Glutathione has been regarded as a significant signal for distinguishing between tumor and normal tissue. Recently, reactive oxygen species have attracted much attention for their close connection with many diseases. Taking advantage of the physiological signals, redox-responsive polymeric drug carriers constitute a significant research area in the various stimuli-responsive polymers for biomedical applications. During the rapid development of redox-responsive polymers, molecular design and related synthetic methodology plays a crucial role. In this review, we discuss the reduction- and oxidation-responsive polymeric drug carriers from the view of functional groups, as well as their applications in controlled release.

http://dx.doi.org/10.1039%2Fc3py01192e

60. Ibrahim H.K., Salah S. Formulation of venlafaxine for once daily administration using polymeric material hybrids // J. Microencapsul. 2016. Vol. 33, № 4. P. 299–306.

Objective: Controlled release venlafaxine for once daily administration.Methods: Drug resin complexation followed by polymer encapsulation. A 4(1).2(1) factorial design was used to study the effect of polymer type and core: coat ratio on the release profile and kinetics. Polymer combinations were tried for optimisation adapting the desIMNCility function. The optimised formula was tested in rabbits against commercial extended release capsules.Results: Poly-epsilon-caprolactone, poly(d, l-lactide-co-glycolide) ester and poly(d, l-lactide) ester polymers were more efficient in lowering the release rate and the initial burst release than Eudragit((R))RS100. Encapsulation at 1:1 ratio ensured complete coats and drug release sustainment. Formula prepared using 50:50 PLA/Eudragit at 1:1 ratio sustained the drug release up to 24h with low burst release. This formula had higher venlafaxine absorption in rabbits compared to the commercial capsules.Conclusions: The optimised formula is superior to the available once-daily trials regarding enhanced bioavailability, dosage form versatility and ease of scaling up.

http://dx.doi.org/10.1080%2F02652048.2016.1178351

61. Ijaz M., Bernkop-Schnuerch A. Preactivated thiomers: their role in drug delivery // Expert Opin. Drug Deliv. 2015. Vol. 12, № 8. P. 1269–1281.

Introduction: Since thiolated polymers - known as thiomers - have entered the pharmaceutical arena in the late 1990s, more and more academic and industrial research groups have started to work with these promising polymeric excipients. Meanwhile, various thiomers are the subject of clinical trials and the first product based on thiolated chitosan will reach the market in 2015. Due to the formation of disulfide bonds with mercaptopyridine substructures, thiol groups of thiomers are on the one hand more reactive and on the other hand are protected toward oxidation. These so-called preactivated thionners representing the second generation of thionners are subject of this review. Areas covered: Within this review, preactivated thiomers are classified and their mode of action is described. Furthermore, different synthetic pathways, purification and chemical characterization methods of preactivated thiomers are explained. Their properties including mucoadhesive, permeation-enhancing, efflux pump inhibitory and in situ gelling properties are described. In addition, various formulations based on preactivated thionners are introduced. Expert opinion: The first-generation thiomers have already shown great potential resulting in various product developments. Preactivated thiomers representing the second generation of thiomers - offer the additional advantage of even comparatively more reactive sulfhydryl ligands and of stability toward oxidation. According to this, they are promising novel polymeric excipients for various applications.

http://dx.doi.org/10.1517%2F17425247.2015.1005598

62. Irwan A.W., Berania J.E., Liu X. A comparative study on the effects of amphiphilic and hydrophilic polymers on the release profiles of a poorly water-soluble drug // Pharm. Dev. Technol. 2016. Vol. 21, № 2. P. 231–238.

This paper reports the use of two crystalline polymers, an amphiphilic Pluronic (R) F-127 (PF-127) and a hydrophilic poly(ethylene glycol) (PEG6000) as drug delivery carriers for improving the drug release of a poorly water-soluble drug, fenofibrate (FEN), via micelle formation and formation of a solid dispersion (SD). In 10% PF-127 (aq.), FEN showed an equilibrium solubility of ca. 0.6mg/mL, due to micelle formation. In contrast, in 10% PEG6000 (aq.), FEN only exhibited an equilibrium solubility of 0.0037mg/mL. FEN-loaded micelles in PF-127 were prepared by direct dissolution and membrane dialysis. Both methods only yielded a highest drug loading (DL) of 0.5%. SDs of FEN in PF-127 and PEG6000, at DLs of 5-80%, were prepared by solvent evaporation. In-vitro dissolution testing showed that both micelles and SDs significantly improved FEN's release rate. The SDs of FEN in PF-127 showed significantly faster release than crystalline FEN, when the DL was as high as 50%, whereas SDs of PEG6000 showed similar enhancement in the release rate when the DL was not more than 20%. The DSC thermograms of SDs of PF-127 exhibited a single phase transition peak at ca. 55-57 degrees C when the DL was not more than 50%, whereas those in PEG6000 exhibited a similar peak at ca. 61-63 degrees C when the DL was not more than 35%. When the DL exceeded 50% for SDs of PF-127 and 35% for SDs of PEG6000, DSC thermograms showed two melting peaks for the carrier polymer and FEN, respectively. FT-IR studies revealed that PF-127 has a stronger hydrophobic-hydrophobic interaction with FEN than PEG6000. It is likely that both dispersion and micelle formation contributed to the stronger effect of PF-127 on enhancing the release rate of FEN in its SDs.

http://dx.doi.org/10.3109%2F10837450.2014.991877

63. Ito A. et al. Effect of polymer species and concentration on the production of mefenamic acid nanoparticles by media milling // Eur. J. Pharm. Biopharm. 2016. Vol. 98. P. 98–107.

The effect of four structurally different polymer species (hydroxypropylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and polyvinyl alcohol) on the production of mefenamic acid nanoparticles during media milling has been studied. It was found that product particle sizes are strongly determined by the type of polymeric stabiliser as well as by its concentration at constant process conditions. With respect to small product particle sizes an optimum excipient concentration was identified and adjusted for colloidal stability of the drug nanosuspensions. Furthermore, it was found that overdosing of excipients must be omitted to suppress ripening due to enhanced solubilisation phenomena. Hence, the smallest product particle sizes were obtained using a polymeric stabiliser which exhibits a high affinity to the model drug compound and a low solubilisation capacity. Affinities of each polymer species to mefenamic acid and corresponding surface concentrations were determined using straightforward and simple viscosity measurements of the supernatant. A relationship between polymer affinity, solubilisation capacity and limiting product particle size has been observed, which supports the hypothesis that final product particle sizes are rather determined by the solid-liquid equilibrium than by pure mechanical fracture.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.11.011

64. Jakki S.L. et al. Novel anionic polymer as a carrier for CNS delivery of anti-Alzheimer drug // Drug Delivery. 2016. Vol. 23, № 9. P. 3471–3479.

Natural and plant-based polymers could be used for control release of drugs and also helps in targeting drug to the site of action. The main objective of present work was to check the feasibility of plant-based, namely, mango gum polymeric nanoparticles (NPs) as a carrier for central nervous system (CNS) delivery using model drug donepezil (DZP). The NPs were prepared by modified ionic gelation method and emulsion cross-linking method. Zeta sizer results showed that the diameter of NPs was about 90–130?nm. The polymeric DZP-loaded NPs were almost spherical in shape, as revealed by transmission electron microscopy (TEM). On increasing concentration of NPs suspension from 50??g/ml to 5000??g/ml there was no significant increase in % hemolysis. In vivo studies showed that brain targeting was achieved. So on the basis of above results, the extracted water soluble fraction of mango gum is a suitable candidate for brain delivery in the form of nanoformulations.

http://dx.doi.org/10.1080%2F10717544.2016.1196767

65. Karavasili C., Fatouros D.G. Smart materials: in situ gel-forming systems for nasal delivery // Drug Discov. Today. 2016. Vol. 21, № 1. P. 157–166.

In the last decade in situ gelling systems have emerged as a novel approach in intranasal delivery of therapeutics, capturing the interest of scientific community. Considerable advances have been currently made in the development of novel formulations containing both natural and synthetic polymers. In this paper we present recent developments on in situ gelling systems for nasal delivery, highlighting the mechanisms that govern their formation.

http://dx.doi.org/10.1016%2Fj.drudis.2015.10.016

66. Kaur P. et al. Brain delivery of intranasal in situ gel of nanoparticulated polymeric carriers containing antidepressant drug: behavioral and biochemical assessment // J. Drug Target. 2015. Vol. 23, № 3. P. 275–286.

This study was aimed for brain delivery of Tramadol HCl (centrally acting synthetic opioid) following intranasal administration for treatment of depression. Chitosan nanoparticles (NPs) were prepared by ionic gelation method followed by the addition of developed NPs with in the Pluronic and HPMC-based mucoadhesive thermo-reversible gel. Developed formulation optimized based on the various parameters such as particle size, entrapment efficiency, in vitro release study. Depression induction was done by forced swim test and evaluated by various behavioral and biochemical parameters. Furthermore, results showed significantly increased in locomotors activity, body weight as compared to control group. It also showed alteration in biochemical parameters such glutathione level and catalase levels significantly increased other than lipid peroxidation and nitrite level was found to be decreased after intranasal administration of formulation. Thus, intranasal TRM HCl NP-loaded in situ gel was found to be a promising formulation for the treatment of depression.

http://dx.doi.org/10.3109%2F1061186X.2014.994097

67. Kirimlioglu G.Y. et al. In vitro/in vivo evaluation of gamma-aminobutyric acid-loaded N,N-dimethylacrylamide-based pegylated polymeric nanoparticles for brain delivery to treat epilepsy // J. Microencapsul. 2016. Vol. 33, № 7. P. 625–635.

Objectives of this study were the delivery of gamma aminobutyric acid (GABA) into the brain by means of developing brain targeted, nanosized, non-toxic and biocompatible polymeric nanoparticles, and investigating their effectiveness in epilepsy. For this purpose, GABA conjugated N,N-dimethylacrylamide-based pegylated nanoparticles were designed and characterised for particle size, zeta potential, pH, morphology, DSC, XRD, FTIR, GABA quantification and in vitro release. Formulations showed smaller particle size, cationic zeta potential characteristic, possible GABA polymeric matrix interaction and prolonged release pattern. Brain responses were examined using epileptic rats. Both formulations prepared were found to increase latency of seizure, decrease ending time of convulsion, duration of severe convulsion and mortality rate significantly compared with GABA solution. When GABA concentration was measured in Stratum corsatum, there was no statistical difference between GABA solution and formulations. All findings suggested enhancement in all phases of seizures indicating efficient delivery of GABA into the brain via formulations.

http://dx.doi.org/10.1080%2F02652048.2016.1234515

68. Klouda L. Thermoresponsive hydrogels in biomedical applications: A seven-year update // European Journal of Pharmaceutics and Biopharmaceutics. 2015. Vol. 97, Part B. P. 338–349.

Thermally responsive hydrogels modulate their gelation behavior upon temperature change. Aqueous solutions solidify into hydrogels when a critical temperature is reached. In biomedical applications, the change from ambient temperature to physiological temperature can be employed. Their potential as in situ forming biomaterials has rendered these hydrogels very attractive. Advances in drug delivery, tissue engineering and cell sheet engineering have been made in recent years with the use of thermoresponsive hydrogels. The scope of this article is to review the literature on thermosensitive hydrogels published over the past seven years. The article concentrates on natural polymers as well as synthetic polymers, including systems based on N-isopropylacrylamide (NIPAAm), poly(ethylene oxide)–b-poly(propylene oxide)–b-poly(ethylene oxide) (PEO–PPO–PEO), poly(ethylene glycol) (PEG)-biodegradable polyester copolymers, poly(organophosphazenes) and 2-(dimethylamino) ethyl methacrylate (DMAEMA).

http://dx.doi.org/10.1016%2Fj.ejpb.2015.05.017

69. Knopp M.M. et al. Effect of polymer type and drug dose on the in vitro and in vivo behavior of amorphous solid dispersions // Eur. J. Pharm. Biopharm. 2016. Vol. 105. P. 106–114.

This study investigated the non-sink in vitro dissolution behavior and in vivo performance in rats of celecoxib (CCX) amorphous solid dispersions with polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) at different drug doses. Both in vitro and in vivo, the amorphous solid dispersions with the hydrophilic polymers PVP and HPMC led to higher areas under both, the in vitro dissolution and the plasma concentration-time curves (AUC) compared to crystalline and amorphous CCX for all doses. In contrast, the amorphous solid dispersion with the hydrophobic polymer PVA showed a lower AUC both in vitro and in vivo than crystalline CCX. For crystalline CCX and CCX:PVA, the in vitro AUC was limited by the low solubility of the drug and the slow release of the drug from the hydrophobic polymer, respectively. For the supersaturating formulations, amorphous CCX, CCX:PVP and CCX:HPMC, the in vitro performance was mainly dependent on the dissolution rate and precipitation/crystallization inhibition of the polymer. As expected, the crystallization tendency increased with increasing dose, and therefore the in vitro AUCs did not increase proportionally with dose. Even though the in vivo AUC for all formulations increased with increasing dose, the relative bioavailability decreased significantly, indicating that the supersaturating formulations also crystallized in vivo and that the absorption of CCX was solubility-limited. These findings underline the importance of evaluating relevant in vitro doses, in order to rationally assess the performance of amorphous solid dispersions and avoid confusion in early in vivo studies.

http://dx.doi.org/10.1016%2Fj.ejpb.2016.05.017

70. Kolate A. et al. Polymer assisted entrapment of netilmicin in PLGA nanoparticles for sustained antibacterial activity // J. Microencapsul. 2015. Vol. 32, № 1. P. 61–74.

This study was aimed to develop poly(DL-lactide-co-glycolide) (PLGA) nanoparticle of highly water soluble antibiotic drug, netilmicin sulfate (NS) with improved entrapment efficiency (EE) and antibacterial activity. Dextran sulfate was introduced as helper polymer to form electrostatic complex with NS. Nanoparticles were prepared by double emulsification method and optimized using 2(5-1) fractional factorial design. EE was mainly influenced by dextran sulfate: NS charge ratio and PLGA concentration, whereas particle size (PS) was affected by all factors examined. The optimized NS-loaded-NPs had EE and PS of 93.23 +/- 2.7% and 140.83 +/- 2.4 nm respectively. NS-loaded-NPs effectively inhibited bacterial growth compared to free NS. Sustained release protected its inactivation and reduced the decline in its killing activity over time even in presence of bronchial cells. A MIC value of 18 mu g/mL was observed for NPs on P. aeruginosa. Therefore, NPs with sustained bactericidal efficiency against P. aeruginosa may provide therapeutic benefit in chronic pulmonary infection, like cystic fibrosis.

http://dx.doi.org/10.3109%2F02652048.2014.944951

71. Korzhikov V. et al. Polyester-based microparticles of different hydrophobicity: the patterns of lipophilic drug entrapment and release // J. Microencapsul. 2016. Vol. 33, № 3. P. 199–208.

The paper is devoted to the investigation of the effect of polyester hydrophobicity and ability for crystallisation on lipophilic drug loading and release from microparticles fabricated on the base of these polymers. Poly(l-lactic acid), poly(d, l-lactic acid) and poly (lactic acid-co-glycolic acid) were synthesised by ring-opening polymerisation using stannous octoate as catalyst, while poly(caprolactone) (PCL) and poly(-pentadecalactone) (PPDL) formation was catalysed by lipase. The particles were formed via single emulsion evaporation/diffusion method. The particles obtained were studied using SEM, XRD and DSC methods. The degradation of particles based on different polyesters, entrapment and release of a model hydrophobic drug (risperidone (R)) were thoroughly studied. The effect of particles hydrophobicity and crystallinity on these parameters was of most interest. The drug entrapment is greater for the hydrophobic polymers. Drug release was more rapid from crystalline particles (PLLA, PCL, PPDL), than from amorphous PDLLA and PLGA ones.

http://dx.doi.org/10.3109%2F02652048.2016.1144818

72. Kreuter J. Drug delivery to the central nervous system by polymeric nanoparticles: What do we know? // Adv. Drug Deliv. Rev. 2014. Vol. 71. P. 2–14.

Nanoparticles enable the delivery of a great variety of drugs including anticancer drugs, analgesics, anti-Alzheimer's drugs, cardiovascular drugs, protease inhibitors, and several macromolecules into the brain after intravenous injection of animals. The mechanism of the nanoparticle-mediated drug transport across the BBB appears to be receptor-mediated endocytosis followed by transcytosis into the brain or by drug release within the endothelial cells. Modification of the nanoparticle surface with covalently attached targeting ligands or by coating with certain surfactants that lead to the adsorption of specific plasma proteins after injection is necessary for this receptor-mediated uptake. A very critical and important requirement for nanoparticulate brain delivery is that the employed nanoparticles are biocompatible and, moreover, rapidly biodegradable, i.e. over a time frame of a few days. In addition to enabling drug delivery to the brain, nanoparticles, as with doxorubicin, may importantly reduce the drug's toxicity and adverse effects due to an alteration of the body distribution. Because of the possibility to treat severe CNS diseases such as brain tumours and to even transport proteins and other macromolecules across the blood-brain barrier, this technology holds great promise for a non-invasive therapy of these diseases.

http://dx.doi.org/10.1016%2Fj.addr.2013.08.008

73. Laffleur F. Mucoadhesive polymers for buccal drug delivery // Drug Dev. Ind. Pharm. 2014. Vol. 40, № 5. P. 591–598.

Raising the concept of mucoadhesion in the 1980s, the use of mucoadhesive polymers for buccal drug delivery has been the subject of interest. Buccal route is one of the non-invasive routes comprising several advantages such as targeting the specific tissue (I), bypassing the first-pass effect (II) as well as higher patient compliance (III) and higher bioavailability (IV) have rendered administration route feasible for a variety of drugs. This review highlights the use of mucoadhesive polymers in buccal drug delivery. An overview of the oral mucosa's anatomy, theories of mucoadhesion as well as mucoadhesive polymers is given within this review. Furthermore, recent advantages in mucoadhesive polymers according to the variety of drug delivery forms are presented.

http://dx.doi.org/10.3109%2F03639045.2014.892959

74. Lai P. et al. Overview of the preparation of organic polymeric nanoparticles for drug delivery based on gelatine, chitosan, poly(D,L-lactide-co-glycolic acid) and polyalkylcyanoacrylate // Colloid Surf. B-Biointerfaces. 2014. Vol. 118. P. 154–163.

Polymeric nanoparticles are greatly advancing the field of nanomedicine due to their ability for targeted and controlled drug release. There are two types of materials which form polymeric nanoparticles; natural or synthetic. In this review article, natural polymeric nanoparticles including; gelatine and chitosan and synthetic polymeric nanoparticles such as poly(lactide-co-glycolic acid) and poly-n-alkyl(cyano)acrylate will be discussed. The various preparation methods of these nanoparticles and the impact of critical parameters such as molecular weight, charge or choice of stabilizer will be described, as these control the overall mean size and surface of the nanoparticle which is a critical factor for drug delivery.

http://dx.doi.org/10.1016%2Fj.colsurfb.2014.03.017

75. Lakkireddy H.R., Bazile D. Building the design, translation and development principles of polymeric nanomedicines using the case of clinically advanced poly(lactide(glycolide))-poly(ethylene glycol) nanotechnology as a model: An industrial viewpoint // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 289–332.

The design of the first polymeric nanoparticles could be traced back to the 1970s, and has thereafter received considerable attention, as evidenced by the significant increase of the number of articles and patents in this area. This review article is an attempt to take advantage of the existing literature on the clinically tested and commercialized biodegradable PLA(G)A-PEG nanotechnology as a model to propose quality building and outline translation and development principles for polymeric nano-medicines. We built such an approach from various building blocks including material design, nano-assembly - i.e. physicochemistry of drug/nano-object association in the pharmaceutical process, and release in relevant biological environment - characterization and identification of the quality attributes related to the biopharmaceutical properties. More specifically, as envisaged in a translational approach, the reported data on PLA(G)A-PEG nanotechnology have been structured into packages to evidence the links between the structure, physicochemical properties, and the in vitro and in vivo performances of the nanoparticles. The integration of these bodies of knowledge to build the CMC (Chemistry Manufacturing and Controls) quality management strategy and finally support the translation to proof of concept in human, and anticipation of the industrialization takes into account the specific requirements and biopharmaceutical features attached to the administration route. From this approach, some gaps are identified for the industrial development of such nanotechnology-based products, and the expected improvements are discussed. The viewpoint provided in this article is expected to shed light on design, translation and pharmaceutical development to realize their full potential for future clinical applications.

http://dx.doi.org/10.1016%2Fj.addr.2016.08.012

76. Leyva-Gomez G. et al. Nanoparticle technology for treatment of Parkinson’s disease: the role of surface phenomena in reaching the brain // Drug Discov. Today. 2015. Vol. 20, № 7. P. 824–837

The absence of a definitive treatment for Parkinson's disease has driven the emerging investigation in the search for novel therapeutic alternatives. At present, the formulation of different drugs on nanoparticles has represented several advantages over conventional treatments. This type of multifunctional carrier, owing to its size and composition, has different interactions in biological systems that can lead to a decrease in ability to cross the blood-brain barrier. Therefore, this review focuses on the latest advances in obtaining nanoparticles for Parkinson's disease and provides an overview of technical aspects in the design of brain drug delivery of nanoparticles and an analysis of surface phenomena, a key aspect in the development of functional nanoparticles for Parkinson's disease.

http://dx.doi.org/10.1016%2Fj.drudis.2015.02.009

77. Li Y., Yang L. Driving forces for drug loading in drug carriers // J. Microencapsul. 2015. Vol. 32, № 3. P. 255–272.

The loading capacity of a drug carrier is determined essentially by intermolecular interactions between drugs and carrier materials. In this review, the process of drug loading is described in detail based on the differences in the driving force for drug incorporation, including hydrophobic interaction, electrostatic interaction, hydrogen bonding, Pi-Pi stacking and van der Waals force. Modifying drug-loading sites of carrier materials with interacting groups aiming at tailoring drug-carrier interactions is reviewed by highlighting its importance for improving in vitro properties such as the loading capacity, release behaviour and stability. Other factors affecting drug loading, methods employed to predict the encapsulation capacity and the techniques to verify intermolecular interactions are also discussed to inform the readers of all-sided information on drug-loading processes and theories. The drug carriers can be designed more reasonably with the better understanding of the nature and interacting mechanism of intermolecular interactions.

http://dx.doi.org/10.3109%2F02652048.2015.1010459

78. Liras M. et al. Versatile thiolated thermosensitive polymers synthesized by ATRP of MEO(2)MA and AcSEMA, a new methacrylic monomer with a protected thiol group // Polym. Chem. 2013. Vol. 4, № 24. P. 5751–5759.

Herein, the synthesis of a new monomer containing a protected thiol group, 2-(acetylthio) ethyl methacrylate (AcSEMA), is introduced. The monomer has been copolymerized via atom transfer radical polymerization (ATRP) with 2-(2-methoxyethoxy) ethyl methacrylate (MEO(2)MA) to obtain a series of well-defined hidden-thiol functionalized thermosensitive polymers. The new system exhibits a sharp lower critical solubility temperature (LCST) and after hydrolysis of the acetyl group, the thiolated copolymers exhibit pH responsiveness. Moreover, to show the versatility of AcSEMA, P(MEO(2)MA-co-AcSEMA) copolymers were in situ hydrolyzed and modified by thiol-ene Michael addition with some acrylate compounds. The click reaction was successfully performed as revealed by NMR and the change in the LCST. We finally demonstrate that the addition of these polymer coatings onto gold nanoparticles (AuNPs) results in the formation of stable, colloidal thermosensitive polymer@AuNP complexes due to bridge formation between the thiol groups of AcSEMA and the metallic NP surfaces. The formation of temperature responsive polymer coated plasmonic nanoparticles shows the promise of P(MEO(2)MA-co-AcSEMA) copolymers for building multifunctional nanostructures for drug-delivery, diagnosis, tagging, catalysis and organic electronics systems.

http://dx.doi.org/10.1039%2Fc3py00773a

79. Liu G., Liu W., Dong C.-M. UV- and NIR-responsive polymeric nanomedicines for on-demand drug delivery // Polym. Chem. 2013. Vol. 4, № 12. P. 3431–3443.

Ultraviolet (UV) and near infrared (NIR) light-responsive polymeric nanomedicines (e.g., cargo-loaded micelles and vesicles) have increasingly received much attention for their applications in the spatiotemporal and on-demand drug delivery and disease therapy. This UV/NIR-sensitivity is activated via a one-photon and/or two-photon absorption process. The phototriggered micellar disruption and drug release have three mechanisms: (1) the hydrophobicity-hydrophilicity transition, (2) the photocleavage reaction, and (3) the cascade depolymerization reaction (e.g., self-immolative polymers). As NIR light can penetrate deeply into tissues (up to several inches) with less damage and scattering compared with UV and visible light, the polymeric nanomedicines simultaneously exhibiting both UV- and NIR-sensitivity hold great potential in clinical medicine and are especially discussed in this review.

http://dx.doi.org/10.1039%2Fc3py21121e

80. Louzao I. et al. Cationic polymer mediated bacterial clustering: Cell-adhesive properties of homo- and copolymers // Eur. J. Pharm. Biopharm. 2015. Vol. 95. P. 47–62.

New anti-infective materials are needed urgently as alternatives to conventional biocides. It has recently been established that polymer materials designed to bind to the surface of bacteria can induce the formation of cell clusters which enhance the expression of quorum sensing controlled phenotypes. These materials are relevant for anti-infective strategies as they have the potential to inhibit adhesion while at the same time modulating Quorum Sensing (QS) controlled virulence. Here we carefully evaluate the role that charge and catechol moieties in these polymers play on the binding. We investigate the ability of the cationic polymers poly(N-[3-(dimethylamino)propyl] methacrylamide) (pDMAPMAm, P1), poly(N-dopamine methacrylamide-co-N-[3-(dimethylamino)propyl] methamylamide) (pDMAm-co-pDMAPMAm, P2) and p(3,4-dihydroxy-L-phenylalanine methacrylamide), p(L-DMAm, P3) to cluster a range of bacteria, such as Staphylococcus aureus (Gram-positive), Vibrio harveyi, Escherichia coli and Pseudomonas aeruginosa (Gram-negative) under conditions of varying pH (6, 7 and 8) and polymer concentration (0.1 and 0.5 mg/mL). We identify that clustering ability is strongly dependent on the balance between charge and hydrophobicity. Moreover, our results suggest that catechol moieties have a positive effect on adhesive properties, but only in the presence of cationic residues such as for P2. Overall, our results highlight the subtle interplay between dynamic natural surfaces and synthetic materials, as well as the need to consider synergistic structure-property relationship when designing antimicrobial polymers.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.05.026

81. Luo Y.Y. et al. A review of biodegradable polymeric systems for oral insulin delivery // Drug Deliv. 2016. Vol. 23, № 6. P. 1882–1891.

Currently, repeated routine subcutaneous injections of insulin are the standard treatment for insulin-dependent diabetic patients. However, patients' poor compliance for injections often fails to achieve the stable concentration of blood glucose. As a protein drug, the oral bioavailability of insulin is low due to many physiological reasons. Several carriers, such as macromolecules and liposomes have been used to deliver drugs in vivo. In this review article, the gastrointestinal barriers of oral insulin administration are described. Strategies for increasing the bioavailability of oral insulin, such absorption enhancers, enzyme inhibitors, enteric coatings are also introduced. The potential absorption mechanisms of insulin-loaded nanoparticles across the intestinal epithelium, including intestinal lymphatic route, transcellular route and paracellular route are discussed in this review. Natural polymers, such as chitosan and its derivates, alginate derivatives, gamma-PGA-based materials and starch-based nanoparticles have been exploited for oral insulin delivery; synthetic polymers, such as PLGA, PLA, PCL and PEA have also been developed for oral administration of insulin. This review focuses on recent advances in using biodegradable natural and synthetic polymers for oral insulin delivery along with their future prospects.

http://dx.doi.org/10.3109%2F10717544.2015.1052863

82. Ma R., Shi L. Phenylboronic acid-based glucose-responsive polymeric nanoparticles: synthesis and applications in drug delivery // Polym. Chem. 2014. Vol. 5, № 5. P. 1503–1518.

Glucose-responsive materials have attracted great intention in recent Years due to their potential application in drug delivery. Phenylboronic acid-containing materials have been most widely studied and used in construction of glucose-responsive system for insulin delivery. This review covers the recent advances in synthesis of phenylboronic acid-based glucose-responsive materials, especially in forms of nanogels (microgels), micelles, vesicles, and mesoporous silica nanoparticles. Applications of these nanomaterials in drug delivery are discussed.

http://dx.doi.org/10.1039%2Fc3py01202f

83. Mahattanadul N. et al. Chitosan-functionalised poly(2-hydroxyethyl methacrylate) core-shell microgels as drug delivery carriers: salicylic acid loading and release // J. Microencapsul. 2016. Vol. 33, № 6. P. 563–568.

This work presents the evaluation of chitosan-functionalised poly(2-hydroxyethyl methacrylate) (CS/PHEMA) core-shell microgels as drug delivery carriers. CS/PHEMA microgels were prepared by emulsifier-free emulsion polymerisation with N,N-methylenebisacrylamide (MBA) as a crosslinker. The study on drug loading, using salicylic acid (SA) as a model drug, was performed. The results showed that the encapsulation efficiency (EE) increased as drug-to-microgel ratio was increased. Higher EE can be achieved with the increase in degree of crosslinking, by increasing the amount of MBA from 0.01g to 0.03g. In addition, the highest EE (61.1%) was observed at pH 3. The highest release of SA (60%) was noticed at pH 2.4, while the lowest one (49.4%) was obtained at pH 7.4. Moreover, the highest release of SA was enhanced by the presence of 0.2 M NaCl. The pH- and ionic-sensitivity of CS/PHEMA could be useful as a sustained release delivery device, especially for oral delivery.

http://dx.doi.org/10.1080%2F02652048.2016.1225844

84. Mahmood A. et al. Can thiolation render a low molecular weight polymer of just 20-kDa mucoadhesive? // Drug Dev. Ind. Pharm. 2016. Vol. 42, № 5. P. 686–693.

The objective was to investigate whether even low-molecular weight polymers (LMWPs) can be rendered mucoadhesive due to thiolation. Interceded by the double catalytic system carbodiimide/N-hydroxysuccinimide, cysteamine was covalently attached to a copolymer, poly(4-styrenesulfonic acid-co-maleic acid) (PSSA-MA) exhibiting a molecular weight of just 20 kDa. Depending on the amount of added N-hydroxysuccinimide and cysteamine, the resulting PSSA-MA-cysteamine (PC) conjugates exhibited increasing degree of thiolation, highest being "PC 2300" exhibiting 2300.16 +/- 149.86 mu mol thiol groups per gram of polymer (mean +/- SD; n = 3). This newly developed thiolated polymer was evaluated regarding mucoadhesive, rheological and drug release properties as well from the toxicological point of view. Swelling behavior in 100 mM phosphate buffer pH 6.8 was improved up to 180-fold. Furthermore, due to thiolation, the mucoadhesive properties of the polymer were 240-fold improved. Rheological measurements of polymer/mucus mixtures confirmed results obtained by mucoadhesion studies. In comparison to unmodified polymer, PC 2300 showed 2.3-, 2.3- and 2.4-fold increase in dynamic viscosity, elastic modulus and viscous modulus, respectively. Sustained release of the model drug codeine HCl out of the thiomer was provided for 2.5 h (p < 0.05), whereas the drug was immediately released from the unmodified polymer. Moreover, the thiomer was found non-toxic over Caco-2 cells for a period of 6- and 24-h exposure. Findings of the present study provide evidence that due to thiolation LMWPs can be rendered highly mucoadhesive as well as cohesive and that a controlled drug release out of such polymers can be provided.

http://dx.doi.org/10.3109%2F03639045.2015.1061538

85. Malik R. et al. Polymeric nanofibers: targeted gastro-retentive drug delivery systems // J. Drug Target. 2015. Vol. 23, № 2. P. 109–124.

Background: Conventional oral dosage forms exhibit poor/low bioavailability due to incomplete release of drug and short residence time at the absorption site. Gastro-retentive drug delivery system (GRDDS) is particularly used to improve bioavailability of the drugs, which have narrow absorption window down in the levels of gastrointestinal tract and also to treat local disorders. Purpose: The purpose of this review is to describe the utility of the nanofibers as gastro-retentive dosage form. From last few decades, formulation scientists have put extensive efforts to develop suitable gastro-retentive drug delivery system, which is appropriate for commercialization. Current approaches used for preparation of gastro-retentive drug delivery system offers limited functional features to control the floating behavior. Recently, an extensive research has been developed to improve the gastric residence time by using nanofibers, which ultimately leads to the increased bioavailability of the drug. Multiple functional features and unique properties of nanofibers improve its gastro retention. Conclusion: Nanofiber system provides stomach-specific drug release for longer duration; moreover, increased local action of the drug due to prolonged contact time with the gastric mucosa. Thus, the nanofiber system promises to be the potential approach for gastric retention drug delivery system.

http://dx.doi.org/10.3109%2F1061186X.2014.965715

86. Mandal A. et al. Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies // J. Control. Release. 2017. Vol. 248. P. 96–116.

Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiological barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age-related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclinical efficacy results from both in-vitro and in-vivo animal studies have led to their steady progression through clinical trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water soluble, these polymeric micelles generate clear aqueous solutions which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non-toxicity, ease of surface modification and controlled drug release are additional advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of preparation, physicochemical properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclinical studies.

http://dx.doi.org/10.1016%2Fj.jconrel.2017.01.012

87. Mason L.M. et al. The influence of polymer content on early gel-layer formation in HPMC matrices: The use of CLSM visualisation to identify the percolation threshold // Eur. J. Pharm. Biopharm. 2015. Vol. 94. P. 485–492.

Percolation theory has been used for several years in the design of HPMC hydrophilic matrices. This theory predicts that a minimum threshold content of polymer is required to provide extended release of drug, and that matrices with a lower polymer content will exhibit more rapid drug release as a result of percolation pathways facilitating the faster penetration of the aqueous medium. At present, percolation thresholds in HPMC matrices have been estimated solely through the mathematical modelling of dissolution data. This paper examines whether they can be also identified in a novel way: through the use of confocal laser scanning fluorescence microscopy (CLSM) to observe the morphology of the emerging gel layer during the initial period of polymer hydration and early gel formation at the matrix surface. In this study, matrices have been prepared with a polymer content of 5-30% w/w HPMC 2208 (Methocel K4M), with a mix of other excipients (a soluble drug (caffeine), lactose, microcrystalline cellulose and magnesium stearate) to provide a typical industrially realistic formulation. Dissolution studies, undertaken in water using USP apparatus 2 (paddle) at 50 rpm, provided data for the calculation of the percolation threshold through relating dissolution kinetic parameters to the excipient volumetric fraction of the dry matrix. The HPMC percolation threshold estimated this way was found to be 12.8% v/v, which was equivalent to a matrix polymer content of 11.5% w/w. The pattern of polymer hydration and gel layer growth during early gel layer formation was examined by confocal laser scanning fluorescence microscopy (CLSM). Clear differences in gel layer formation were observed. At polymer contents above the estimated threshold a continuous gel layer was formed within 15 min, whereas matrices with polymer contents below the threshold were characterised by irregular gel layer formation with little evidence of HPMC particle coalescence. According to percolation theory, this implies that a continuous cluster of HPMC particles was not formed. The images provide the first direct evidence of how the percolation threshold may be related to the success or failure of early gel layer development in HPMC matrices. It also shows how extended release characteristics are founded on the successful coalescence of hydrated polymer particles to form a continuous coherent diffusion barrier, which can then inhibit further percolation of the hydration medium. The correlation between percolation thresholds estimated from dissolution and imaging techniques suggests that confocal imaging may provide a more rapid method for estimating the percolation thresholds, facilitating the rational design of HPMC extended release matrices at lower polymer contents with minimal risk of dose dumping.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.06.019

88. McLaughlin C.K., Logie J., Shoichet M.S. Core and Corona Modifications for the Design of Polymeric Micelle Drug-Delivery Systems // Isr. J. Chem. 2013. Vol. 53, № 9–10. P. 670–679.

Polymeric nanoparticle micelles are formed from amphiphilic polymers with a hydrophobic core and a hydrophilic corona. Often comprised of a biodegradable, biocompatible polymer core and a poly(ethylene glycol) corona, these nanoparticle micelles encapsulate a hydrophobic drug and enable surface modification with targeting ligands. Strategies to enhance hydrophobic drug encapsulation are described as chemistries that facilitate covalent modification with antibodies using water-based click chemistry.

http://dx.doi.org/10.1002%2Fijch.201300085

89. Meng F., Dave V., Chauhan H. Qualitative and quantitative methods to determine miscibility in amorphous drug-polymer systems // Eur. J. Pharm. Sci. 2015. Vol. 77. P. 106–111.

Amorphous drug-polymer systems or amorphous solid dispersions are commonly used in pharmaceutical industry to enhance the solubility of compounds with poor aqueous solubility. The degree of miscibility between drug and polymer is important both for solubility enhancement as well as for the formation of a physically stable amorphous system. Calculation of solubility parameters, Computational data mining, T-g measurements by DSC and Raman mapping are established traditional methods used to qualitatively detect the drug-polymer miscibility. Calculation of Flory-Huggins interaction parameter, computational analysis of X-Ray Diffraction (XRD) data, solid state Nuclear Magnetic Resonance (NMR) spectroscopy and Atomic Forced Microscopy (AFM) have been recently developed to quantitatively determine the miscibility in amorphous drug-polymer systems. This brief review introduces and compiles these qualitative and quantitative methods employed in the evaluation of drug-polymer miscibility. Combination of these techniques can provide deeper insights into the true miscibility of the drug-polymer systems.

http://dx.doi.org/10.1016%2Fj.ejps.2015.05.018

90. Merkle H.P. Drug delivery’s quest for polymers: Where are the frontiers? // Eur. J. Pharm. Biopharm. 2015. Vol. 97. P. 293–303.

Since the legendary 1964 article of Folkman and Long entitled "The use of silicone rubber as a carrier for prolonged drug therapy" the role of polymers in controlled drug delivery has come a long way. Today it is evident that polymers play a crucial if not the prime role in this field. The latest boost owes to the interest in drug delivery for the purpose of tissue engineering in regenerative medicine. The focus of this commentary is on a selection of general and personal observations that are characteristic for the current state of polymer therapeutics and carriers. It briefly highlights selected examples for the long march of synthetic polymer drug conjugates from bench to bedside, comments on the ambivalence of selected polymers as inert excipients versus biological response modifiers, and on the yet unsolved dilemma of cationic polymers for the delivery of nucleic acid therapeutics. Further subjects are the complex design of multifunctional polymeric carriers including recent concepts towards functional supramolecular polymers, as well as observations on stimuli-sensitive polymers and the currently ongoing trend towards natural and naturally-derived biopolymers. The final topic is the discovery and early development of a novel type of biodegradable polyesters for parenteral use. Altogether, it is not the basic and applied research in polymer therapeutics and carriers, but the translational process that is the key hurdle to proceed towards an authoritative approval of new polymer therapeutics and carriers.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.04.038

91. Miladi K. et al. Particles from Preformed Polymers as Carriers for Drug Delivery // EXCLI J. 2014. Vol. 13. P. 28–57.

Biodegradable and biocompatible polymers are widely used for the encapsulation of drug molecules. Various particulate carriers with different sizes and characteristics have been prepared by miscellaneous techniques. In this review, we reported the commonly used preformed polymer based techniques for the preparation of micro and nano-structured materials intended for drug encapsulation. A description of polymer-solvent interaction was provided. The most widely used polymers were reported and described and their related research studies were mentioned. Moreover, principles of each technique and its crucial operating conditions were described and discussed. Recent applications of all the reported techniques in drug delivery were also reviewed.

http://www.excli.de/vol13/Elaissaria_03022014_proof.pdf

92. Mishra D.K. et al. Amorphous solid dispersion technique for improved drug delivery: basics to clinical applications // Drug Deliv. Transl. Res. 2015. Vol. 5, № 6. P. 552–565.

Solid dispersion has emerged as a method of choice and has been extensively investigated to ascertain the in vivo improved performance of many drug formulations. It generally involves dispersion of drug in amorphous particles (clusters) or in crystalline particles. Comparatively, in the last decade, amorphous drug-polymer solid dispersion has evolved into a platform technology for delivering poorly water-soluble small molecules. However, the success of this technique in the pharmaceutical industry mainly relies on different drug-polymer attributes like physico-chemical stability, bioavailability and manufacturability. The present review showcases the efficacy of amorphous solid dispersion technique in the research and evolution of different drug formulations particularly for those with poor water soluble properties. Apart from the numerous mechanisms of action involved, a comprehensive summary of different key parameters required for the solubility enhancement and their translational efficacy to clinics is also emphasized.

http://dx.doi.org/10.1007%2Fs13346-015-0256-9

93. Moghanjoughi A.A., Khoshnevis D., Zarrabi A. A concise review on smart polymers for controlled drug release // Drug Deliv. Transl. Res. 2016. Vol. 6, № 3. P. 333–340.

Design and synthesis of efficient drug delivery systems are of critical importance in health care management. Innovations in materials chemistry especially in polymer field allows introduction of advanced drug delivery systems since polymers could provide controlled release of drugs in predetermined doses over long periods, cyclic and tunable dosages. To this end, researchers have taken advantages of smart polymers since they can undergo large reversible, chemical, or physical fluctuations as responses to small changes in environmental conditions, for instance, in pH, temperature, light, and phase transition. The present review aims to highlight various kinds of smart polymers, which are used in controlled drug delivery systems as well as mechanisms of action and their applications.

http://dx.doi.org/10.1007%2Fs13346-015-0274-7

94. Murariu M., Dubois P. PLA composites: From production to properties // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 17–46.

Poly(lactic acid) or polylactide (PLA), a biodegradable polyester produced from renewable resources, is used for various applications (biomedical, packaging, textile fibers and technical items). Due to its inherent properties, PLA has a key-position in the market of biopolymers, being one of the most promising candidates for further developments. Unfortunately, PLA suffers from some shortcomings, whereas for the different applications specific end-use properties are required. Therefore, the addition of reinforcing fibers, micro- and/or nanofillers, and selected additives within PIA matrix is considered as a powerful method for obtaining specific end-use characteristics and major improvements of properties. This review highlights recent developments, current results and trends in the field of composites based on PLA. It presents the main advances in PIA properties and reports selected results in relation to the preparation and characterization of the most representative PLA composites. To illustrate the possibility to design the properties of composites, a section is devoted to the production and characterization of innovative PLA-based products filled with thermally-treated calcium sulfate, a by-product from the lactic acid production process. Moreover, are emphasized the last tendencies strongly evidenced in the case of PIA, i.e., the high interest to diversify its uses by moving from biomedical and packaging (biodegradation properties, "disposables") to technical applications ("durables").

http://dx.doi.org/10.1016%2Fj.addr.2016.04.003

95. Nasr F.H., Khoee S. Design, characterization and in vitro evaluation of novel shell crosslinked poly(butylene adipate)-co-N-succinyl chitosan nanogels containing loteprednol etabonate: A new system for therapeutic effect enhancement via controlled drug delivery // Eur. J. Med. Chem. 2015. Vol. 102. P. 132–142.

This study reports on the development of a novel mucoadhesive and biocompatible shell-crosslinked nanogel system based on poly(butylene adipate) (PBA) and N-succinyl chitosan (S-Cs) by coupling reaction with a new formulation method. For this purpose, two different molecular weights of dendri-merized PBA with amine terminated functional groups were synthesized separately and characterized well by FT-IR, (HNMR)-H-1 and GPC. The PBA nanoparticles containing loteprednol etabonate (LPE) prepared by O/W emulsion technique were reacted immediately with modified carboxylated chitosan via carbodiimide chemistry. TEM photographs of the nanoparticles and crosslinked nanoparticles displayed a spherical morphology closely corresponding to the results obtained by DLS. On The other hand, biodegradability, biocompatibility and bioadhesiveness of the prepared nanoparticles were also studied. It is concluded that the core-shell structured nanogels can be used as novel ocular drug delivery systems with appropriate loading capacity for slightly water soluble LPE as an anti-inflammatory drug.

http://dx.doi.org/10.1016%2Fj.ejmech.2015.07.045

96. Nicolas J. et al. Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery // Chem. Soc. Rev. 2013. Vol. 42, № 3. P. 1147–1235.

Design and functionalization strategies for multifunctional nanocarriers (e.g., nanoparticles, micelles, polymersomes) based on biodegradable/biocompatible polymers intended to be employed for active targeting and drug delivery are reviewed. This review will focus on the nature of the polymers involved in the preparation of targeted nanocarriers, the synthesis methods to achieve the desired macromolecular architecture, the selected coupling strategy, the choice of the homing molecules (vitamins, hormones, peptides, proteins, etc.), as well as the various strategies to display them at the surface of nanocarriers. The resulting morphologies and the main colloidal features will be given as well as an overview of the biological activities, with a special focus on the main in vivo achievements.

http://dx.doi.org/10.1039%2Fc2cs35265f

97. Nigmatullin R. et al. Polyhydroxyalkanoates, a family of natural polymers, and their applications in drug delivery // J. Chem. Technol. Biotechnol. 2015. Vol. 90, № 7. P. 1209–1221.

Polyhydroxyalkanoates (PHAs) are natural biopolymers produced by various microorganisms as a reserve of carbon and energy. PHA synthesis generally occurs during fermentation under nutrient limiting conditions with excess carbon. There are two main types of PHAs, short chain length PHAs (scl-PHAs) and medium chain length PHAs (mcl-PHAs). The mechanical and thermal properties of PHAs depend mainly on the number of carbons in the monomer unit and its molecular weight. PHAs are promising materials for biomedical applications because they are biodegradable, non-toxic and biocompatible. The large range of PHAs, along with their varying physical properties and high biocompatibility, make them highly attractive biomaterials for use in drug delivery. They can be used to produce tablets, micro- and nanoparticles as well as drug eluting scaffolds. A large range of different PHAs have been explored and the results obtained suggest that PHAs are excellent candidates for controlled and targeted drug delivery systems.

http://dx.doi.org/10.1002%2Fjctb.4685

98. Nottelet B., Darcos V., Coudane J. Aliphatic polyesters for medical imaging and theranostic applications // European Journal of Pharmaceutics and Biopharmaceutics. 2015. Vol. 97, Part B. P. 350–370.

Medical imaging is a cornerstone of modern medicine. In that context the development of innovative imaging systems combining biomaterials and contrast agents (CAs)/imaging probes (IPs) for improved diagnostic and theranostic applications focuses intense research efforts. In particular, the classical aliphatic (co)polyesters poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA) and poly(?-caprolactone) (PCL), attract much attention due to their long track record in the medical field. This review aims therefore at providing a state-of-the-art of polyester-based imaging systems. In a first section a rapid description of the various imaging modalities, including magnetic resonance imaging (MRI), optical imaging, computed tomography (CT), ultrasound (US) and radionuclide imaging (SPECT, PET) will be given. Then, the two main strategies used to combine the CAs/IPs and the polyesters will be discussed. In more detail we will first present the strategies relying on CAs/IPs encapsulation in nanoparticles, micelles, dendrimers or capsules. We will then present chemical modifications of polyesters backbones and/or polyester surfaces to yield macromolecular imaging agents. Finally, opportunities offered by these innovative systems will be illustrated with some recent examples in the fields of cell labeling, diagnostic or theranostic applications and medical devices.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.06.023

99. Nour S.A. et al. Intranasal brain-targeted clonazepam polymeric micelles for immediate control of status epilepticus: in vitro optimization, ex vivo determination of cytotoxicity, in vivo biodistribution and pharmacodynamics studies // Drug Delivery. 2016. Vol. 23, № 9. P. 3681–3695.

Clonazepam (CZ) is an anti-epileptic drug used mainly in status epilepticus (SE). The drug belongs to Class II according to BCS classification with very limited solubility and high permeability and it suffers from extensive first-pass metabolism. The aim of the present study was to develop CZ-loaded polymeric micelles (PM) for direct brain delivery allowing immediate control of SE. PM were prepared via thin film hydration (TFH) technique adopting a central composite face-centered design (CCFD). The seventeen developed formulae were evaluated in terms of entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and in vitro release. For evaluating the in vivo behavior of the optimized formula, both biodistrbution using 99mTc-radiolabeled CZ and pharmacodynamics studies were done in addition to ex vivo cytotoxicty. At a drug:Pluronic® P123:Pluronic® L121 ratio of 1:20:20 (PM7), a high EE, ZP, Q8h, and a low PDI was achieved. The biodistribution studies revealed that the optimized formula had significantly higher drug targeting efficiency (DTE?=?242.3%), drug targeting index (DTI?=?144.25), and nose-to-brain direct transport percentage (DTP?=?99.30%) and a significant prolongation of protection from seizures in comparison to the intranasally administered solution with minor histopathological changes. The declared results reveal the ability of the developed PM to be a strong potential candidate for the emergency treatment of SE.

http://dx.doi.org/10.1080%2F10717544.2016.1223216

100. Omolo C.A. et al. Pegylated oleic acid: A promising amphiphilic polymer for nano antibiotic delivery // Eur. J. Pharm. Biopharm. 2017. Vol. 112. P. 96–108.

Vancomycin (VM), a last resort to control methicillin-resistant S. aureus (MRSA) infections, is on the verge of becoming ineffective. Novel nano delivery systems of VM have the potential to combat MRSA. The search for novel materials for nanoantibiotic development is therefore an active research area. In this study, oleic acid (OA) was coupled with monomethoxy polyethylene glycol (mPEG) to obtain a novel bio-safe amphiphilic polymer, mPEG-OA. The critical micelle concentration of mPEG-OA, was found to be 4.5 x 10(-8) m/L. VM-loaded polymersomes were prepared from mPEG-OA and evaluated for size, polydispersity index (PDI), zeta potential (ZP), surface morphology, drug release, in vitro and in vivo antibacterial activity. The size, PDI and ZP of VM-loaded polymersomes were 142.9 +/- 7.5 nm, 0.228 +/- 0.03 and 18.3 +/- 3.55 mV respectively. Transmission electron microscopy images revealed the spherical shape of polymersomes. The encapsulation efficiency was 53.64 +/- 1.86%. The drug release from polymersomes was sustained and in vitro antibacterial activity was 42- and 5-fold more against S. aureus and MRSA, compared with plain VM. An in vivo BALB/c mice, skin infection models revealed that treatment with VM-loaded polymersomes significantly reduced the MRSA burden compared with plain VM and blank polymersomes. There was a 183 and a 25-fold reduction in the MRSA colony finding units load in mice skin treated with VM-loaded polymersomes compared to that treated with blank polymersomes and bare VM respectively. In summary, the developed VM-loaded polymersomes from novel mPEG-OA polymer were found to be a promising nanoantibiotic against MRSA.

http://dx.doi.org/10.1016%2Fj.ejpb.2016.11.022

101. Pandita D., Kumar S., Lather V. Hybrid poly(lactic-co-glycolic acid) nanoparticles: design and delivery prospectives // Drug Discov. Today. 2015. Vol. 20, № 1. P. 95–104.

Poly(lactic-co-glycolic acid) (PLGA), a US Food and Drug Administration (FDA) -approved copolymer, has been exploited widely in the design of nanoparticles because it is biodegradable, biocompatible, protects the drug molecules from degradation, and aids in producing sustained and targeted delivery. However, certain constraints associated with PLGA nanoparticles, such as poor drug encapsulation, polymer degradation, and scale-up issues, have led to the development of emerging hybrid PLGA delivery systems. These hybrid nanoparticles are core-shell nanostructures comprising either a PLGA core or a PLGA shell combining multiple functionalities within one system and, thus, exhibiting the complementary characteristics of two different platforms used for the delivery of a wide range of therapeutics and imaging.

http://dx.doi.org/10.1016%2Fj.drudis.2014.09.018

102. Paramjot et al. Role of polymer-drug conjugates in organ-specific delivery systems // J. Drug Target. 2015. Vol. 23, № 5. P. 387–416.

Polymers have been utilized to deliver the drug to targeted site in controlled manner, achieving the high-therapeutic efficacy. Polymeric drug conjugates having variable ligands as attachments have been proved to be biodegradable, stimuli sensitive and targeted systems. Numerous polymeric drug conjugates having linkers degraded by acidity or intracellular enzymes or sensitive to over expressed groups of diseased organ/tissue have been synthesized during last decade to develop targeted delivery systems. Most of these organs have number of receptors attached with different cells such as Kupffer cells of liver have mannose-binding receptors while hepatocytes have asialoglycoprotein receptors on their surface which mainly bind with the galactose derivatives. Such ligands can be used for achieving high targeting and intracellular delivery of the drug. This review presents detailed aspects of receptors found in different cells of specific organ and ligands with binding efficiency to these specific receptors. This review highlights the need of further studies on organ-specific polymer-drug conjugates by providing detailed account of polymeric conjugates synthesized till date having organ-specific targeting.

http://dx.doi.org/10.3109%2F1061186X.2015.1016436

103. Partenhauser A., Bernkop-Schnuerch A. Mucoadhesive polymers in the treatment of dry X syndrome // Drug Discov. Today. 2016. Vol. 21, № 7. P. 1051–1062.

Mucoadhesive polymers are an essential tool in the treatment of diseases where dry mucosal surfaces are involved. In this review, we focus on the application of mucoadhesive polymers in the context of dry eye, dry mouth, and dry vagina syndrome, collectively named 'dry X syndrome'. With a prolonged residence time on mucosal membranes, mucoadhesive materials are as targeted treatment option, with the mucosa as an intended site of action. Thus, mucoadhesive polymers are able to ease local irritation or itching, alleviate chewing difficulties, improve tear-film break-up time, and help to restore physiological conditions. Here, we discuss the different classes of mucoadhesive material and their performance in the treatment of dry X syndrome.

http://dx.doi.org/10.1016%2Fj.drudis.2016.02.013

104. Pillay V. et al. A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications // J. Biomed. Mater. Res. Part A. 2014. Vol. 102, № 6. P. 2039–2054.

Electroactive polymers (EAPs) are promising candidate materials for the design of drug delivery technologies, especially in conditions where an on-off drug release mechanism is required. To achieve this, EAPs such as polyaniline, polypyrrole, polythiophene, ethylene vinyl acetate, and polyethylene may be blended into responsive hydrogels in conjunction with the desired drug to obtain a patient-controlled drug release system. The on-off drug release mechanism can be achieved through the environmental-responsive nature of the interpenetrating hydrogel-EAP complex via (i) charged ions initiated diffusion of drug molecules; (ii) conformational changes that occur during redox switching of EAPs; or (iii) electroerosion. These release mechanisms are not exhaustive and new release mechanisms are still under investigation. Therefore, this review seeks to provide a concise incursion and critical overview of EAPs and responsive hydrogels as a strategy for advanced drug delivery, for example, controlled release of neurotransmitters, sulfosalicyclic acid from cross-linked hydrogel, and vaccine delivery. The review further discusses techniques such as linear sweep voltammetry, cyclic voltammetry, impedance spectroscopy, and chronoamperometry for the determination of the redox capability of EAPs. The future implications of the hydrogel-EAP composites include, but not limited to, application toward biosensors, DNA hybridizations, microsurgical tools, and miniature bioreactors and may be utilized to their full potential in the form of injectable devices as nanorobots or nanobiosensors.

http://dx.doi.org/10.1002%2Fjbm.a.34869

105. Pillay V. et al. A Review of Polymeric Refabrication Techniques to Modify Polymer Properties for Biomedical and Drug Delivery Applications // AAPS PharmSciTech. 2013. Vol. 14, № 2. P. 692–711.

Polymers are extensively used in the pharmaceutical and medical field because of their unique and phenomenal properties that they display. They are capable of demonstrating drug delivery properties that are smart and novel, such properties that are not achievable by employing the conventional excipients. Appropriately, polymeric refabrication remains at the forefront of process technology development in an endeavor to produce more useful pharmaceutical and medical products because of the multitudes of smart properties that can be attained through the alteration of polymers. Small alterations to a polymer by either addition, subtraction, self-reaction, or cross reaction with other entities have the capability of generating polymers with properties that are at the level to enable the creation of novel pharmaceutical and medical products. Properties such as stimuli-responsiveness, site targeting, and chronotherapeutics are no longer figures of imaginations but have become a reality through utilizing processes of polymer refabrication. This article has sought to review the different techniques that have been employed in polymeric refabrication to produce superior products in the pharmaceutical and medical disciplines. Techniques such as grafting, blending, interpenetrating polymers networks, and synthesis of polymer complexes will be viewed from a pharmaceutical and medical perspective along with their synthetic process required to attain these products. In addition to this, each process will be evaluated according to its salient features, impeding features, and the role they play in improving current medical devices and procedures.

http://dx.doi.org/10.1208%2Fs12249-013-9955-z

106. Piotrowska U., Sobczak M. Enzymatic Polymerization of Cyclic Monomers in Ionic Liquids as a Prospective Synthesis Method for Polyesters Used in Drug Delivery Systems // Molecules. 2015. Vol. 20, № 1. P. 1–23.

Biodegradable or bioresorbable polymers are commonly used in various pharmaceutical fields (e.g., as drug delivery systems, therapeutic systems or macromolecular drug conjugates). Polyesters are an important class of polymers widely utilized in pharmacy due to their biodegradability and biocompatibility features. In recent years, there has been increased interest in enzyme-catalyzed ring-opening polymerization (e-ROP) of cyclic esters as an alternative method of preparation of biodegradable or bioresorbable polymers. Ionic liquids (ILs) have been presented as green solvents in enzymatic ring-opening polymerization. The activity, stability, selectivity of enzymes in ILs and the ability to catalyze polyester synthesis under these conditions are discussed. Overall, the review demonstrates that e-ROP of lactones or lactides could be an effective method for the synthesis of useful biomedical polymers.

http://dx.doi.org/10.3390%2Fmolecules20010001

107. Policianova O. et al. In vitro dissolution study of acetylsalicylic acid solid dispersions. Tunable drug release allowed by the choice of polymer matrix // Pharm. Dev. Technol. 2015. Vol. 20, № 8. P. 935–940.

Due to their high versatility and diverse excipient options, solid dispersions (SDs) are an elegant choice for the formulation of active pharmaceutical ingredients with inconvenient solubility. Four distinct types of polymers with different physicochemical properties [polyvinylpyrrolidone, poly[N-(2-hydroxypropyl)-metacrylamide], poly(2-ethyl-2-oxazoline), and polyethylene glycol] and variable molecular weights were compared to investigate the influence of the polymer matrix on drug release. To probe the extent of intercomponent interactions, acetylsalicylic acid (ASA) was used as a model active substance. Controlled drug release was demonstrated for all four types of polymer-ASA SDs created by the freeze-drying method. While the polyethylene glycol-ASA SD exhibited an increased dissolution rate, the other polymer-ASA systems exhibited significantly reduced drug dissolution kinetics compared to free ASA. Furthermore, in contrast to physical mixtures, the prepared SDs all exhibited zero-order dissolution kinetics for ASA. The dissolution rate was strongly dependent on the molecular weight of the polymer. These results demonstrate that the type of SD may be controlled by the chemical constitutions of the polymers and that appropriate selection of the molecular weight of the polymer matrix enables finely tuned drug release over a wide range of dissolution rates.

http://dx.doi.org/10.3109%2F10837450.2014.943407

108. Prasad L.K., McGinity J.W., Williams R.O. Electrostatic powder coating: Principles and pharmaceutical applications // Int. J. Pharm. 2016. Vol. 505, № 1–2. P. 289–302.

A majority of pharmaceutical powders are insulating materials that have a tendency to accumulate charge. This phenomenon has contributed to safety hazards and issues during powder handling and processing. However, increased understanding of this occurrence has led to greater understanding and control of processing and product performance. More recently, the charging of pharmaceutical powders has been employed to adopt electrostatic powder coating as a pharmaceutical process. Electrostatic powder coating is a mature technology used in the finishing industry and much of that knowledge applies to its use in pharmaceutical applications. This review will serve to summarize the principles of electrostatic powder coating and highlight some of the research conducted on its use for the preparation of pharmaceutical dosage forms.

http://dx.doi.org/10.1016%2Fj.jpharm.2016.04.016

109. Pretula J., Slomkowski S., Penczek S. Polylactides-Methods of synthesis and characterization // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 3–16.

Polylactides with various molar masses, microstructures and crystallinities are used as degradable and biocompatible polymers suitable for preparation of drug carriers and temporary medical implants. This paper presents state of current knowledge on synthesis of lactic acids, high purity lactide monomers and their polymerization. Syntheses of high molar mass polylactides by polycondensation of lactic acid and by ring-opening polymerization of lactides are described and their advantages and disadvantages are discussed. Mechanisms of lactide polymerization initiated by metal alkoxides are described. There are presented also results of more recent studies of polymerization initiated with the so-called "no metal" organocatalysts; both anionic and cationic. Presented are advantages and limitations of synthesis of PLA by all the major polymerization processes until now. Some properties of PLA and most important methods used for PLA characterization are also described.

http://dx.doi.org/10.1016%2Fj.addr.2016.05.002

110. Quinn J.F., Whittaker M.R., Davis T.P. Glutathione responsive polymers and their application in drug delivery systems // Polym. Chem. 2017. Vol. 8, № 1. P. 97–126.

Materials which respond to biological cues are the subject of intense research interest due to their possible application in smart drug delivery vehicles. In particular, novel polymers which respond to biochemical differences between the extra-and intracellular environments may be useful for preparing particles which can chaperone a therapeutic agent in the extracellular environment, and release said agent only when the particle is internalised by a target cell. To that end, polymers that exploit the elevated glutathione (GSH) concentration in the intracellular compartment are attracting substantial research effort. In this review we describe a number of different strategies for the preparation of glutathione responsive materials. In particular, we examine the use of GSH responsive linkers to prepare polymers that degrade upon exposure to millimolar concentrations of GSH, and the use of these polymers to prepare particles that disassemble at these concentrations. We also describe the use of such GSH responsive polymers in the controlled delivery of both chemotherapeutic agents and genetic material, and highlight a number of strategies employed to trigger release of an encapsulated drug using GSH. Additionally, we highlight some of the more novel GSH responsive systems which have recently been reported, and suggest further areas where GSH responsive materials are likely to see continued and highly focused research effort.

http://dx.doi.org/10.1039%2Fc6py01365a

111. Rabanel J.-M. et al. Effect of polymer architecture on curcumin encapsulation and release from PEGylated polymer nanoparticles: Toward a drug delivery nanoplatform to the CNS // Eur. J. Pharm. Biopharm. 2015. Vol. 96. P. 409–420.

We developed a nanoparticles (NPs) library from poly(ethylene glycol) poly lactic acid comb-like polymers with variable amount of PEG. Curcumin was encapsulated in the NPs with a view to develop a delivery platform to treat diseases involving oxidative stress affecting the CNS. We observed a sharp decrease in size between 15 and 20% w/w of PEG which corresponds to a transition from a large solid particle structure to a "micelle-like" or "polymer nano-aggregate" structure. Drug loading, loading efficacy and release kinetics were determined. The diffusion coefficients of curcumin in NPs were determined using a mathematical modeling. The higher diffusion was observed for solid particles compared to "polymer nano-aggregate" particles. NPs did not present any significant toxicity when tested in vitro on a neuronal cell line. Moreover, the ability of NPs carrying curcumin to prevent oxidative stress was evidenced and linked to polymer architecture and NPs organization. Our study showed the intimate relationship between the polymer architecture and the biophysical properties of the resulting NPs and sheds light on new approaches to design efficient NP-based drug carriers.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.09.004

112. Rai V.K. et al. Novel drug delivery system: an immense hope for diabetics // Drug Deliv. 2016. Vol. 23, № 7. P. 2371–2390.

Context: Existing medication systems for the treatment of diabetes mellitus (DM) are inconvenient and troublesome for effective and safe delivery of drugs to the specific site. Therefore, investigations are desired to deliver antidiabetics using novel delivery approaches followed by their commercialization.Objective: The present review aims to provide a compilation on the latest development in the field of novel drug delivery systems (NDDSs) for antidiabetics with special emphasis on particulate, vesicular and miscellaneous systems.Methods: Review of literature (restricted to English language only) was done using electronic databases like Pubmed (R) and Scirus, i.e. published during 2005-2013. The CIMS/MIMS India Medical Drug Information eBook was used regarding available marketed formulation of antidiabetic drugs. Keywords used were nanoparticle, microparticle, liposomes, niosomes, transdermal systems, insulin, antidiabetic drugs and novel drug delivery systems. Single inclusion was made for one article. If in vivo study was not done then article was seldom included in the manuscript.Results: The curiosity to develop NDDSs of antidiabetic drugs with special attention to the nanoparticulate system followed by microparticulate and lipid-based system is found to emerge gradually to overcome the problems associated with the conventional dosage forms and to win the confidence of end users towards the higher acceptability.Conclusion: In the current scientific panorama when the area of novel drug delivery system has been recognized for its palpable benefits, unique potential of providing physical stability, sustained and site-specific drug delivery for a scheduled period of time can open new vistas for precise, safe and quality treatment of DM.

http://dx.doi.org/10.3109%2F10717544.2014.991001

113. Rajesh A.M., Popat K.M. Taste masking of azithromycin by resin complex and sustained release through interpenetrating polymer network with functionalized biopolymers // Drug Dev. Ind. Pharm. 2017. Vol. 43, № 5. P. 732–741.

Objective:The objective was to evaluate taste masking of azithromycin (AZI) by ion exchange resins (IERs) and the formation of covalent semi interpenetrating polymer network (IPN) beads using chitosan (CS) and sodium carboxylated agarose (SCAG) for sustained release of drug. Methods:Methacrylic acid (MAA)-based IERs were prepared by suspension polymerization method. Drug release complexes (DRCs) were prepared by different drug:resin ratios i. e. 1:1, 1:2 and 1:4. The resultant DRCs were characterized using DSC, FTIR, PXRD, in vivo and in vitro taste masking, and in vitro drug release at gastric pH. IPN beads were prepared by entrapping DRCs with bio polymers and cross linked with trisodium citrate (NaCIT), and further cross-linked with glutaraldehyde (GA) for sustained release of AZI. Results:In vitro and in vivo taste masking studies showed that MD1:4 DRC formulation was optimal. The release of AZI from DRC was found to be very fast at gastric pH i. e. 97.37 +/- 1.02% within 45 min. The formation of IPN beads was confirmed by FTIR. The release of drug from IPN beads at gastric and intestinal pH was found to be "<28% and <60%", respectively. The release kinetics showed Fickian diffusion profile for ionically cross-linked beads and zero-order release mechanism for GA cross-linking beads. Conclusions:DRCs can be effectively used for taste masking and newly formulated IPN beads demonstrated sustained release of AZI.

http://dx.doi.org/10.1080%2F03639045.2016.1224894

114. Ramazani F. et al. Locoregional cancer therapy using polymer-based drug depots // Drug Discov. Today. 2016. Vol. 21, № 4. P. 640–647.

Locoregional delivery of anticancer drugs is an attractive approach to minimize adverse effects associated with intravenous chemotherapy. Polymer-based drug depots injected or implanted intratumorally or adjacent to the tumor can provide long-term local drug exposure. This review highlights studies in which drug-eluting depots have been applied locally in the treatment of cancer. In many cases such drug depots are used for prevention of tumor recurrence after surgery to eradicate remaining tumor cells. Clinical success has been reported for the treatment of brain cancer and liver cancer, and preclinical studies showed proof-of-concept for inhaled drug depots in lung cancer and intraperitoneally injected depots for the treatment of abdominal cancer.

http://dx.doi.org/10.1016%2Fj.drudis.2016.02.014

115. Ramazani F. et al. Strategies for encapsulation of small hydrophilic and amphiphilic drugs in PLGA microspheres: State-of-the-art and challenges // Int. J. Pharm. 2016. Vol. 499, № 1–2. P. 358–367.

Poly(lactide-co-glycolide) (PLGA) microspheres are efficient delivery systems for controlled release of low molecular weight drugs as well as therapeutic macromolecules. The most common microencapsulation methods are based on emulsification procedures, in which emulsified droplets of polymer and drug solidify into microspheres when the solvent is extracted from the polymeric phase. Although high encapsulation efficiencies have been reported for hydrophobic small molecules, encapsulation of hydrophilic and/or amphiphilic small molecules is challenging due to the partitioning of drug from the polymeric phase into the external phase before solidification of the particles. This review addresses formulation-related aspects for efficient encapsulation of small hydrophilic/amphiphilic molecules into PLGA microspheres using conventional emulsification methods (e.g., oil/water, water/oil/water, solid/oil/ water, water/oil/oil) and highlights novel emulsification technologies such as microfluidics, membrane emulsification and other techniques including spray drying and inkjet printing. Collectively, these novel microencapsulation technologies afford production of this type of drug loaded microspheres in a robust and well controlled manner.

http://dx.doi.org/10.1016%2Fj.ijpharm.2016.01.020

116. Ramot Y. et al. Biocompatibility and safety of PLA and its copolymers // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 153–162.

PLA and its copolymers are commonly used for a wide variety of applications. While they are considered to be biocompatible, side effects resulting from their implantation have been reported. The implantation of biomaterials always results in a foreign body reaction. Such a reaction has also been reported following PLA and its copolymers. This article reviews the process of inflammatory reaction that is to be expected following implantation of PLA, and it highlights specific cases in which the inflammatory reaction can result in safety concerns. The authors also review selected cases from different medical fields to demonstrate possible clinical side effects resulting from its use.

http://dx.doi.org/10.1016%2Fj.addr.2016.03.012

117. Rao S., Prestidge C.A. Polymer-lipid hybrid systems: merging the benefits of polymeric and lipid-based nanocarriers to improve oral drug delivery // Expert Opin. Drug Deliv. 2016. Vol. 13, № 5. P. 691–707.

Introduction: A number of biobarriers limit efficient oral drug absorption; both polymer-based and lipid-based nanocarriers have demonstrated properties and delivery mechanisms to overcome these biobarriers in preclinical settings. Moreover, in order to address the multifaceted oral drug delivery challenges, polymer-lipid hybrid systems are now being designed to merge the beneficial features of both polymeric and lipid-based nanocarriers.Areas covered: Recent advances in the development of polymer-lipid hybrids with a specific focus on their viability in oral delivery are reviewed. Three classes of polymer-lipid hybrids have been identified, i.e. lipid-core polymer-shell systems, polymer-core lipid-shell systems, and matrix-type polymer-lipid hybrids. We focus on their application to overcome the various biological barriers to oral drug absorption, as exemplified by selected preclinical studies.Expert opinion: Numerous studies have demonstrated the superiority of polymer-lipid hybrid systems to their non-hybrid counterparts in providing improved drug encapsulation, modulated drug release, and improved cellular uptake. These features have encouraged their applications in the delivery of chemotherapeutics, proteins, peptides, and vaccines. With further research expected to optimize the manufacturing and scaling up processes and in-depth pre-clinical pharmacological and toxicological assessments, these multifaceted drug delivery systems will have significant clinical impact on the oral delivery of pharmaceuticals and biopharmaceuticals.

http://dx.doi.org/10.1517%2F17425247.2016.1151872

118. Repanas A., Andriopoulou S., Glasmacher B. The significance of electrospinning as a method to create fibrous scaffolds for biomedical engineering and drug delivery applications // J. Drug Deliv. Sci. Technol. 2016. Vol. 31. P. 137–146.

The unique properties of fibers have received great attention from the scientific community as suitable candidates for biomedical engineering and drug delivery applications. Their properties include, high surface-to-volume ratio, high porosity, adjustable pore size and morphological similarity to the extra cellular matrix. Polymeric fibrous structures have been recognized as drug-delivery system candidates and various techniques have been employed to tailor-made their characteristics, such as the electrohydrodynamic techniques (EHD). The latter methods exploit the electrostatic forces in order to create particles or fibers of tunable microstructure. One of the most important EHD is electrospinning, which is a cost-efficient method to fabricate fibers, either in the laboratory or in the industrial scale. Electrospinning realizes the direct encapsulation of pharmaceutical agents or biomolecules in the fibers, protecting them from the surrounding environment while at the same time controlling their release. Coaxial electrospinning is a modification of the process, which enables the creation of structures with core-shell fiber morphology. Numerous scientific studies have indicated the capability of electrospun fibers to be used as drug delivery systems (DDSs). The main aim of this review is to summarize the basic principles of electrospinning as well as the most recent developments regarding biomedical engineering, focusing on drug delivery.

http://dx.doi.org/10.1016%2Fj.jddst.2015.12.007

119. Rother M. et al. Protein cages and synthetic polymers: a fruitful symbiosis for drug delivery applications, bionanotechnology and materials science // Chem. Soc. Rev. 2016. Vol. 45, № 22. P. 6213–6249.

Protein cages are hollow protein nanoparticles, such as viral capsids, virus-like particles, ferritin, heat-shock proteins and chaperonins. They have well-defined capsule-like structures with a monodisperse size. Their protein subunits can be modified by genetic engineering at predetermined positions, allowing for example site-selective introduction of attachment points for functional groups, catalysts or targeting ligands on their outer surface, in their interior and between subunits. Therefore, protein cages have been extensively explored as functional entities in bionanotechnology, as drug-delivery or gene-delivery vehicles, as nanoreactors or as templates for the synthesis of organic and inorganic nanomaterials. The scope of functionalities and applications of protein cages can be significantly broadened if they are combined with synthetic polymers on their surface or within their interior. For example, PEGylation reduces the immunogenicity of protein cage-based delivery systems and active targeting ligands can be attached via polymer chains to favour their accumulation in diseased tissue. Polymers within protein cages offer the possibility of increasing the loading density of drug molecules, nucleic acids, magnetic resonance imaging contrast agents or catalysts. Moreover, the interaction of protein cages and polymers can be used to modulate the size and shape of some viral capsids to generate structures that do not occur with native viruses. Another possibility is to use the interior of polymer cages as a confined reaction space for polymerization reactions such as atom transfer radical polymerization or rhodium-catalysed polymerization of phenylacetylene. The protein nanoreactors facilitate a higher degree of control over polymer synthesis. This review will summarize the hybrid structures that have been synthesized by polymerizing from protein cage-bound initiators, by conjugating polymers to protein cages, by embedding protein cages into bulk polymeric materials, by forming two-and three-dimensional crystals of protein cages and dendrimers, by adsorbing proteins to the surface of materials, by layer-bylayer deposition of proteins and polyelectrolytes and by encapsulating polymers into protein cages. The application of these hybrid materials in the biomedical context or as tools and building blocks for bionanotechnology, biosensing, memory devices and the synthesis of materials will be highlighted. The review aims to showcase recent developments in this field and to suggest possible future directions and opportunities for the symbiosis of protein cages and polymers.

http://dx.doi.org/10.1039%2Fc6cs00177g

120. Saini P., Arora M., Kumar M.N.V.R. Poly(lactic acid) blends in biomedical applications // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 47–59.

Poly(lactic acid) (PLA) has become a "material of choice" in biomedical applications for its ability to fulfill complex needs that typically include properties such as biocompatibility, biodegradability, mechanical strength, and processability. Despite the advantages of pure PLA in a wider spectrum of applications, it is limited by its hydrophobicity, low impact toughness, and slow degradation rate. Blending PLA with other polymers offers a convenient option to enhance its properties or generate novel properties for target applications without the need to develop new materials. PLA blends with different natural and synthetic polymers have been developed by solvent and melt blending techniques and further processed based on end-use applications. A variety of PLA blends has been explored for biomedical applications such as drug delivery, implants, sutures, and tissue engineering. This review discusses the opportunities for PLA blends in the biomedical arena, including the overview of blending and postblend processing techniques and the applications of PLA blends currently in use and under development.

http://dx.doi.org/10.1016%2Fj.addr.2016.06.014

121. Sakai-Kato K. et al. General considerations regarding the in vitro and in vivo properties of block copolymer micelle products and their evaluation // J. Control. Release. 2015. Vol. 210. P. 76–83.

Block copolymer micelles are nanoparticles formed from block copolymers that comprise a hydrophilic polymer such as poly(ethylene glycol) and a poorly soluble polymer such as poly(amino acids). The design of block copolymer micelles is intended to regulate the in vivo pharmacokinetics, stability, and distribution profiles of an entrapped or block copolymer-linked active substance. Several block copolymer micelle products are currently undergoing clinical development; however, a major challenge in the development and evaluation of such products is identification of the physicochemical properties that affect the properties of the drug product in vivo. Here we review the overall in vitro and in vivo characteristics of block copolymer micelle products with a focus on the products currently under clinical investigation. We present examples of methods suitable for the evaluation of the physicochemical properties, non-clinical pharmacokinetics, and safety of block copolymer micelle products.

http://dx.doi.org/10.1016%2Fj.jconrel.2015.05.259

122. Saucier-Sawyer J.K. et al. Systemic delivery of blood-brain barrier-targeted polymeric nanoparticles enhances delivery to brain tissue // J. Drug Target. 2015. Vol. 23, № 7–8. P. 736–749.

Delivery of therapeutic agents to the central nervous system is a significant challenge, hindering progress in the treatment of diseases such as glioblastoma. Due to the presence of the blood-brain barrier (BBB), therapeutic agents do not readily transverse the brain endothelium to enter the parenchyma. Previous reports suggest that surface modification of polymer nanoparticles (NPs) can improve their ability to cross the BBB, but it is unclear whether the observed enhancements in transport are large enough to enhance therapy. In this study, we synthesized two degradable polymer NP systems surface-modified with ligands previously suggested to improve BBB transport, and tested their ability to cross the BBB after intravenous injection in mice. All the NP preparations were able to cross the BBB, although generally in low amounts (50.5% of the injected dose), which was consistent with prior reports. One NP produced significantly higher brain uptake (similar to 0.8% of the injected dose): a block copolymer of polylactic acid and hyperbranched polyglycerol, surface modified with adenosine (PLA-HPG-Ad). PLA-HPG-Ad NPs provided controlled release of camptothecin, killing U87 glioma cells in culture. When administered intravenously in mice with intracranial U87 tumors, they failed to increase survival. These results suggest that enhancing NP transport across the BBB does not necessarily yield proportional pharmacological effects.

http://dx.doi.org/10.3109%2F1061186X.2015.1065833

123. Shaikh M. et al. Effect of polymer microstructure on the docetaxel release and stability of polyurethane formulation // Eur. J. Pharm. Biopharm. 2016. Vol. 101. P. 82–89.

PurSil (R) AL20 (PUS), a copolymer of 4,4'-dicyclohexylmethane diisocyanate (HMDI), 1,4-butane diol (BD), poly-tetramethylene oxide (PTMO) and poly-dimethyl siloxane (PDMS) was investigated for stability as a vehicle for Docetaxel (DTX) delivery through oesophageal drug eluting stent (DES). On exposure to stability test conditions, it was found that DTX release rate declined at 4 and 40 degrees C. In order to divulge reasons underlying this, changes in DTX solid state as well as PUS microstructure were followed. It was found that re-crystallization of DTX in PDMS rich regions was reducing the drug release at both 4 degrees C and 40 degrees C samples. So far microstructural features have not been correlated with stability and drug release, and in this study we found that at 40 degrees C increase in microstructural domain sizes and the inter-domain distances (from 85 A to 129 A) were responsible for hindering the DTX release in addition to DTX re-crystallization.

http://dx.doi.org/10.1016%2Fj.ejpb.2016.01.015

124. Siegel R.A. Stimuli sensitive polymers and self regulated drug delivery systems: A very partial review // J. Control. Release. 2014. Vol. 190. P. 337–351.

Since the early days of the Journal of Controlled Release, there has been considerable interest in materials that can release drug on an "on-demand" basis. So called "stimuli-responsive" and "intelligent" systems have been designed to deliver drug at various times or at various sites in the body, according to a stimulus that is either endogenous or externally applied. In the past three decades, research along these lines has taken numerous directions, and each new generation of investigators has discovered new physicochemical principles and chemical schemes by which the release properties of materials can be altered. No single review could possibly do justice to all of these approaches. In this article, some general observations are made, and a partial history of the field is presented. Both open loop and closed loop systems are discussed. Special emphasis is placed on stimuli-responsive hydrogels, and on systems that can respond repeatedly. It is argued that the most success at present and in the foreseeable future is with systems in which biosensing and actuation (i.e. drug delivery) are separated, with a human and/or cybernetic operator linking the two.

http://dx.doi.org/10.1016%2Fj.jconrel.2014.06.035

125. Simoes S.M.N. et al. Polymeric micelles for oral drug administration enabling locoregional and systemic treatments // Expert Opin. Drug Deliv. 2015. Vol. 12, № 2. P. 297–318.

Introduction: Amphiphilic block copolymers are recognized components of parenteral drug nanocarriers. However, their performance in oral administration has barely been evaluated to any great extent. Areas covered: This review provides an overview of the methods used to prepare drug-loaded polymeric micelles and to evaluate their stability in gastrointestinal (GI) fluids, and then analyzes in detail recent in vitro and in vivo results about their performance in oral drug delivery. Oral administration of polymeric micelles has been tested for a variety of therapeutic purposes, namely, to increase apparent drug solubility in the GI fluids and facilitate absorption, to penetrate in pathological regions of the GI tract for locoregional treatment, to carry the drug directly toward the blood stream minimizing presystemic loses, and to target the drug after oral absorption to specific tissue or cells in the body. Expert opinion: Each therapeutic purpose demands micelles with different performance regarding stability in the GI tract, ability to overcome physiological barriers and drug release patterns. Depending on the block copolymer composition and structure, a wealth of self-assembled micelles with different morphologies and stability can be prepared. Moreover, copolymer unimers can play a role in improving drug absorption through the GI mucosa, either by increasing membrane permeability to the drug and/or the carrier or by inhibiting drug efflux transporters or first-pass metabolism. Therefore, polymeric micelles can be pointed out as versatile vehicles to increase oral bioavailability of drugs that exhibit poor solubility or permeability and may even be an alternative to parenteral carriers when targeting is pursued.

http://dx.doi.org/10.1517%2F17425247.2015.960841

126. Sonam et al. Effect of Physicochemical Properties of Biodegradable Polymers on Nano Drug Delivery // Polym. Rev. 2013. Vol. 53, № 4. P. 546–567.

This review article is to explore the utilization of biodegradable polymers and their associated physicochemical properties in nano drug delivery (NDD). The main hub of the pharma industry is involved in the development of innovative biodegradable and biocompatible polymers which have targeting ability and a predictable release profile of an incorporated active pharmaceutical ingredient (API) or therapeutic agents. Moreover, the pharmaceutical and biological efficiency of the nano drug delivery system varies with the inherent properties of the polymer. The foremost, important physicochemical properties of biodegradable polymers include molecular weight, hydrophobicity, surface charge, crystallinity, composition of the co-polymer, glass transition temperature, and the nature of coating material. Nevertheless, these properties can be manipulated to modify the kinetics of the delivery system by selecting an optimum polymer (based on physicochemical properties) for a specific purpose.

http://dx.doi.org/10.1080%2F15583724.2013.828751

127. Songsurang K., Siraleartmukul K., Muangsin N. Mucoadhesive drug carrier based on functional-modified cellulose as poorly water-soluble drug delivery system // J. Microencapsul. 2015. Vol. 32, № 5. P. 450–459.

The purpose of this study was to design and characterise an oral mucoadhesive micellar drug carrier. In this regard, a mucoadhesive hydrophobic cationic aminocellulose was easily synthesised under mild homogeneous conditions with high yield. The cellulose derivative resulted in strongly improved mucoadhesive properties but was pH dependent. Furthermore, the hydrophobic anticancer drug camptothecin was successfully encapsulated into the mucoadhesive cellulose derivative micelles with spherical shape stability of 233 nm in diameter and low particle size distribution. The CPT-loaded nanocarriers provided high encapsulation efficiency about 86.4%. In vitro release, CPT-loaded cellulose derivative micelles showed a reduction in release rate compared with physically pure CPT solution. The release results also indicated that a sustained release of CPT to > 80% over 4 d for pH 6.8 and 7.4. Therefore, mucoadhesive hydrophobic cationic aminocellulose micelles seem to be a promising carrier for various pharmaceutical applications especially for poorly water-soluble drug delivery system.

http://dx.doi.org/10.3109%2F02652048.2015.1046516

128. Sood N. et al. Stimuli-responsive hydrogels in drug delivery and tissue engineering // Drug Deliv. 2016. Vol. 23, № 3. P. 758–780.

Hydrogels are the three-dimensional network structures obtained from a class of synthetic or natural polymers which can absorb and retain a significant amount of water. Hydrogels are one of the most studied classes of polymer-based controlled drug release. These have attracted considerable attention in biochemical and biomedical fields because of their characteristics, such as swelling in aqueous medium, biocompatibility, pH and temperature sensitivity or sensitivity towards other stimuli, which can be utilized for their controlled zero-order release. The hydrogels are expected to explore new generation of self-regulated delivery system having a wide array of desirable properties. This review highlights the exciting opportunities and challenges in the area of hydrogels. Here, we review different literatures on stimuli-sensitive hydrogels, such as role of temperature, electric potential, pH and ionic strength to control the release of drug from hydrogels.

http://dx.doi.org/10.3109%2F10717544.2014.940091

129. Sosnik A., Raskin M.M. Polymeric micelles in mucosal drug delivery: Challenges towards clinical translation // Biotechnol. Adv. 2015. Vol. 33, № 6. P. 1380–1392.

Polymeric micelles are nanostructures formed by the self-aggregation of copolymeric amphiphiles above the critical micellar concentration. Due to the flexibility to tailor different molecular features, they have been exploited to encapsulate motley poorly-water soluble therapeutic agents. Moreover, the possibility to combine different amphiphiles in one single aggregate and produce mixed micelles that capitalize on the features of the different components substantially expands the therapeutic potential of these nanocarriers. Despite their proven versatility, polymeric micelles remain elusive to the market and only a few products are currently undergoing advanced clinical trials or reached clinical application, all of them for the therapy of different types of cancer and administration by the intravenous route. At the same time, they emerge as a nanotechnology platform with great potential for non-parenteral mucosal administration. However, for this, the interaction of polymeric micelles with mucus needs to be strengthened. The present review describes the different attempts to develop mucoadhesive polymeric micelles and discusses the challenges faced in the near future for a successful bench-to-bedside translation.

http://dx.doi.org/10.1016%2Fj.biotechadv.2015.01.003

130. Sperling L.E. et al. Advantages and challenges offered by biofunctional core-shell fiber systems for tissue engineering and drug delivery // Drug Discov. Today. 2016. Vol. 21, № 8. P. 1243–1256

Whereas highly porous scaffolds composed of electrospun nanofibers can mimick major features of the extracellular matrix in tissue engineering, they lack the ability to incorporate and release biocompounds (drugs, growth factors) safely in a controlled way. Here, electrospun core-shell fibers (core made from water and aqueous solutions of hydrophilic polymers and the shell from materials with well-defined release mechanisms) offer unique advantages in comparison with those that have helped make porous nanofibrillar scaffolds highly successful in tissue engineering. This review considers the preparation and biofunctionalization of such core-shell fibers as well as applications in various areas, including neural, vascular, cardiac, cartilage and bone tissue engineering, and touches on the topic of clinical trials.

http://dx.doi.org/10.1016%2Fj.drudis.2016.04.024

131. Stankovic M., Frijlink H.W., Hinrichs W.L.J. Polymeric formulations for drug release prepared by hot melt extrusion: application and characterization // Drug Discov. Today. 2015. Vol. 20, № 7. P. 812–823.

Over the past few decades hot melt extrusion (HME) has emerged as a powerful processing technology for the production of pharmaceutical solid dosage forms in which an active pharmaceutical ingredient (API) is dispersed into polymer matrices. It has been shown that formulations using HME can provide time-controlled, sustained and targeted drug delivery, and improved bioavailability of poorly soluble drugs. In this review, the basic principles of the HME process are described together with an overview of some of the most common biodegradable and nonbiodegradable polymers used for the preparation of different formulations using this method. Further, the applications of HME in drug delivery and analytical techniques employed to characterize HME products are addressed.

http://dx.doi.org/10.1016%2Fj.drudis.2015.01.012

132. Stebbins N.D., Ouimet M.A., Uhrich K.E. Antibiotic-containing polymers for localized, sustained drug delivery // Adv. Drug Deliv. Rev. 2014. Vol. 78. P. 77–87.

Many currently used antibiotics suffer from issues such as systemic toxicity, short half-life, and increased susceptibility to bacterial resistance. Although most antibiotic classes are administered systemically through oral or intravenous routes, a more efficient delivery system is needed. This review discusses the chemical conjugation of antibiotics to polymers, achieved by forming covalent bonds between antibiotics and a pre-existing polymer or by developing novel antibiotic-containing polymers. Through conjugating antibiotics to polymers, unique polymer properties can be taken advantage of. These polymeric antibiotics display controlled, sustained drug release and vary in antibiotic class type, synthetic method, polymer composition, bond lability, and antibacterial activity. The polymer synthesis, characterization, drug release, and antibacterial activities, if applicable, will be presented to offer a detailed overview of each system.

http://dx.doi.org/10.1016%2Fj.addr.2014.04.006

133. Tavares M.R. et al. Polymeric nanoparticles assembled with microfluidics for drug delivery across the blood-brain barrier // Eur. Phys. J.-Spec. Top. 2016. Vol. 225, № 4. P. 779–795.

The blood-brain barrier (BBB) is a challenge in the treatment of some diseases, since it prevents many drugs from reaching therapeutic concentrations in the brain. In this context, there is a growing interest in nanoparticles for drug delivery, since they are able to cross this barrier and target the brain. The use of polymeric materials in the development of these nanoparticles has been extensively studied. It has already been demonstrated that these nanosystems have the ability to cross the BBB, which allows effective drug release into the brain. Biodegradable polymers provide a great advantage in the development of nanosystems, but modifications of the nanoparticles' surface is essential. The traditional batch methods lack precise control over the processes of nucleation and growth, resulting in poor control over final properties of the nanoparticles. Therefore, microfluidics could be used to achieve a better production environment for the fabrication of nano- structured drug delivery systems. This study provides a brief review of: the BBB, the polymeric nanoparticles with the ability to overcome the barrier, the properties of the most used polymeric matrices, and the nanostructured drug delivery systems assembled with microfluidics.

http://dx.doi.org/10.1140%2Fepjst%2Fe2015-50266-2

134. Thonggoom O. et al. In vitro controlled release of clove essential oil in self-assembly of amphiphilic polyethylene glycol-block-polycaprolactone // J. Microencapsul. 2016. Vol. 33, № 3. P. 239–248.

In this study, a micellar delivery system with an amphiphilic diblock copolymer of poly (ethylene glycol) and poly (-caprolactone) was synthesised and used to incorporate hydrophobic clove essential oil (CEO). To determine an optimal delivery system, the effects of the copolymer's hydrophobic block length and the CEO-loading content on the encapsulation of CEO were investigated. Percentages of entrapment efficiency (%EE), CEO loading (%CEO), and in vitro release profiles were determined. The size, size distribution, zeta potential, and morphology of the obtained micelles were determined by DLS, FE-SEM, and TEM. The %EE, %CEO, and in vitro release profiles of CEO incorporated in micelles were analysed by HPLC. The study revealed a sustained release profile of CEO from CEO-loaded micelles. The results indicate the successful formulation of CEO-loaded PEG-b-PCL micelle nanoparticles. It is suggested that this micelle system has considerably potential applications in the sustained release of CEO in intravascular drug delivery.

http://dx.doi.org/10.3109%2F02652048.2016.1156173

135. Tsuji H. Poly(lactic acid) stereocomplexes: A decade of progress // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 97–135.

Upon blending enantiomeric poly(L-lactide) [i.e., poly(L-lactic acid) (PLLA)] and poly(D-lactide) (PDLA) [i.e., poly(D-lactic acid) (PDLA)] or synthesis of stereo block poly(lactide) [i.e., poly(lactic acid) (PLA)], a stereocomplex (SC) is formed. PLA SC has a higher melting temperature (or heat resistance), mechanical performance, and hydrolysis-resistance compared to those of neat PLLA and PDLA. Because of such effects, PLA SC has been extensively studied in terms of biomedical and pharmaceutical applications as well as commodity, industrial, and environmental applications. Stereocomplexation stabilizes and strengthens PLA-based hydrogel or nano particles for biomedical applications. Stereocomplexation increases the barrier property of PLA-based materials and thereby prolongs drug release from PLA based materials. In addition, PLA SC is attracting significant attention because it can act as a nucleating agent for the widely used biobased polymer PLLA and thereby the heat resistance of PLLA-based materials can be enhanced. Interestingly, a wide variety of SCs other than PLA SC are found to have been formed in the enantiomeric substituted PIA blends and stereo block substituted PIA polymers. In the present review article, a decade of progress in investigation of PIA SCs is summarized.

http://dx.doi.org/10.1016%2Fj.addr.2016.04.017

136. Tyler B. et al. Polylactic acid (PLA) controlled delivery carriers for biomedical applications // Adv. Drug Deliv. Rev. 2016. Vol. 107. P. 163–175.

Polylactic acid (PLA) and its copolymers have a long history of safety in humans and an extensive range of applications. PLA is biocompatible, biodegradable by hydrolysis and enzymatic activity, has a large range of mechanical and physical properties that can be engineered appropriately to suit multiple applications, and has low immunogenicity. Formulations containing PLA have also been Food and Drug Administration (FDA)-approved for multiple applications making PIA suitable for expedited clinical translatability. These biomaterials can be fashioned into sutures, scaffolds, cell carriers, drug delivery systems, and a myriad of fabrications. PLA has been the focus of a multitude of preclinical and clinical testing. Three-dimensional printing has expanded the possibilities of biomedical engineering and has enabled the fabrication of a myriad of platforms for an extensive variety of applications. PIA has been widely used as temporary extracellular matrices in tissue engineering. At the other end of the spectrum, PLA's application as drug-loaded nanoparticle drug carriers, such as liposomes, polymeric nanoparticles, dendrimers, and micelles, can encapsulate otherwise toxic hydrophobic anti-tumor drugs and evade systemic toxicities. The clinical translation of these technologies from preclinical experimental settings is an ever-evolving field with incremental advancements. In this review, some of the biomedical applications of PIA and its copolymers are highlighted and briefly summarized.

http://dx.doi.org/10.1016%2Fj.addr.2016.06.018

137. Ulbrich K. et al. Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies // Chem. Rev. 2016. Vol. 116, № 9. P. 5338–5431.

Targeted delivery combined with controlled drug release has a pivotal role in the future of personalized medicine. This review covets the principles, advantages, and drawbacks of passive and active targeting based on various polymer and magnetic iron oxide nanoparticle carriers with drug attached by both covalent and noncovalent pathways. Attention is devoted to the tailored conjugation of targeting ligands (e.g., enzymes, antibodies, peptides) to drug carrier systems. Similarly, the approaches toward controlled drug release are discussed. Various polymer-drug conjugates based, for example, on polyethylene glycol (PEG), N-(2-hydroxypropyl)methacrylamide (HPMA), polymeric micelles, and nanoparticle carriers are explored with respect to absorption, distribution, metabolism, and excretion (ADME scheme) of administrated drug. Design and structure of superparamagnetic iron oxide nanoparticles (SPION) and condensed magnetic clusters are classified according to the mechanism of noncovalent drug loading involving hydrophobic and electrostatic interactions, coordination chemistry, and encapsulation in porous materials. Principles of covalent conjugation of drugs with SPIONs including thermo- and pH-degradable bonds, amide linkage, redox-cleavable bonds, and enzymatically-cleavable bonds are also thoroughly described. Finally, results of clinical trials obtained with polymeric and magnetic carriers are analyzed highlighting the potential advantages and future directions in targeted anticancer therapy.

http://dx.doi.org/10.1021%2Facs.chemrev.5b00589

138. van Dongen M.A., Dougherty C.A., Holl M.M.B. Multivalent Polymers for Drug Delivery and Imaging: The Challenges of Conjugation // Biomacromolecules. 2014. Vol. 15, № 9. P. 3215–3234.

Multivalent polymers offer a powerful opportunity to develop theranostic materials on the size scale of proteins that can provide targeting, imaging, and therapeutic functionality. Achieving this goal requires the presence of multiple targeting molecules, dyes, and/or drugs on the polymer scaffold. This critical review examines the synthetic, analytical, and functional challenges associated with the heterogeneity introduced by conjugation reactions as well as polymer scaffold design. First, approaches to making multivalent polymer conjugations are discussed followed by an analysis of materials that have shown particular promise biologically. Challenges in characterizing the mixed ligand distributions and the impact of these distributions on biological applications are then discussed. Where possible, molecular-level interpretations are provided for the structures that give rise to the functional ligand and molecular weight distributions present in the polymer scaffolds. Lastly, recent strategies employed for overcoming or minimizing the presence of ligand distributions are discussed. This review focuses on multivalent polymer scaffolds where average stoichiometry and/or the distribution of products have been characterized by at least one experimental technique. Key illustrative examples are provided for scaffolds that have been carried forward to in vitro and in vivo testing with significant biological results.

http://dx.doi.org/10.1021%2Fbm500921q

139. U15453
Vaz S.H. et al. Brain-derived Neurotrophic Factor (BDNF) Enhances GABA Transport by Modulating the Trafficking of GABA Transporter-1 (GAT-1) from the Plasma Membrane of Rat Cortical Astrocytes // J. Biol. Chem. 2011. Vol. 286, № 47. P. 40464–40476.

The gamma-aminobutyric acid (GABA) transporters (GATs) are located in the plasma membrane of neurons and astrocytes and are responsible for termination of GABAergic transmission. It has previously been shown that brain derived neurotrophic factor (BDNF) modulates GAT-1-mediated GABA transport in nerve terminals and neuronal cultures. We now report that BDNF enhances GAT-1-mediated GABA transport in cultured astrocytes, an effect mostly due to an increase in the V(max) kinetic constant. This action involves the truncated form of the TrkB receptor (TrkB-t) coupled to a non-classic PLC-gamma/PKC-delta and ERK/MAPIK pathway and requires active adenosine A(2A) receptors. Transport through GAT-3 is not affected by BDNF. To elucidate if BDNF affects trafficking of GAT-1 in astrocytes, we generated and infected astrocytes with a functional mutant of the rat GAT-1 (rGAT-1) in which the hemagglutinin (HA) epitope was incorporated into the second extracellular loop. An increase in plasma membrane of HA-rGAT-1 as well as of rGAT-1 was observed when both HA-GAT-1-transduced astrocytes and rGAT-1-overexpressing astrocytes were treated with BDNF. The effect of BDNF results from inhibition of dynamin/dathrin-dependent constitutive internalization of GAT-1 rather than from facilitation of the monensin-sensitive recycling of GAT-1 molecules back to the plasma membrane. We therefore conclude that BDNF enhances the time span of GAT-1 molecules at the plasma membrane of astrocytes. BDNF may thus play an active role in the clearance of GABA from synaptic and extrasynaptic sites and in this way influence neuronal excitability.

http://dx.doi.org/10.1074/jbc.M111.232009

140. Vittorio O. et al. Polyphenols delivery by polymeric materials: challenges in cancer treatment // Drug Delivery. 2017. Vol. 24, № 1. P. 162–180.

Nanotechnology can offer different solutions for enhancing the therapeutic efficiency of polyphenols, a class of natural products widely explored for a potential applicability for the treatment of different diseases including cancer. While possessing interesting anticancer properties, polyphenols suffer from low stability and unfavorable pharmacokinetics, and thus suitable carriers are required when planning a therapeutic protocol. In the present review, an overview of the different strategies based on polymeric materials is presented, with the aim to highlight the strengths and the weaknesses of each approach and offer a platform of ideas for researchers working in the field.

http://dx.doi.org/10.1080%2F10717544.2016.1236846

141. Wang M. et al. Poly(ester amine) constructed from polyethylenimine and pluronic for gene delivery in vitro and in vivo // Drug Delivery. 2016. Vol. 23, № 9. P. 3224–3233.

A series of poly (ester amines) (PEAs) constructed from low molecular weight polyethyleneimine (LPEI, Mw: 0.8k, 1.2k Da) and Pluronic (different molecular weight (Mw) and hydrophilic-lipophilic-balance (HLB)) components were synthesized, and evaluated in vitro and in vivo as gene delivery carriers. Most PEA polymers were able to bind and condense plasmid DNA effectively into particles of approximately 150?nm in solution at the polymer/DNA ratio of 5 and above. Transfection efficiency of the PEA polymers depends on particle size of the polymer/DNA complex, molecular weight and HLB of the Pluronics and the size of PEI within PEA composition, as well as the cell type. Significant improvement in gene delivery efficacy was achieved with PEA01/04/05 composed of Pluronic size (Mw: 3000–5000?Da), and HLB (12–18) in CHO, C2C12 and HSkM cell lines; and the effective transfection was reflected with PEA 01/04/07 composed of Pluronics with size (2000–5000?Da) and HLB (12–23) in mdx mice. The best formulation for pDNA delivery was obtained with PEA 01 producing transgene expression efficiency 5, 19-folds of that of PEI 25k in vitro and in vivo, respectively. These results potent some of these PEA polymers as attractive vehicles for gene or oligonucleotide delivery.

http://dx.doi.org/10.3109%2F10717544.2016.1162877

142. Wang Z., Niu G., Chen X. Polymeric Materials for Theranostic Applications // Pharm. Res. 2014. Vol. 31, № 6. P. 1358–1376.

Nanotechnology has continuously contributed to the fast development of diagnostic and therapeutic agents. Theranostic nanomedicine has encompassed the ongoing efforts on concurrent molecular imaging of biomarkers, delivery of therapeutic agents, and monitoring of therapy response. Among these formulations, polymer-based theranostic agents hold great promise for the construction of multifunctional agents for translational medicine. In this article, we reviewed the state-of-the-art polymeric nanoparticles, from preparation to application, as potential theranostic agents for diagnosis and therapy. We summarized several major polymer formulas, including polymeric conjugate complexes, nanospheres, micelles, and dendrimers for integrated molecular imaging and therapeutic applications.

http://dx.doi.org/10.1007%2Fs11095-013-1103-7

143. Woertz C., Kleinebudde P. Development of orodispersible polymer films with focus on the solid state characterization of crystalline loperamide // Eur. J. Pharm. Biopharm. 2015. Vol. 94. P. 52–63.

The formulation of active pharmaceutical ingredients (API) as orodispersible films is gaining interest among novel oral drug delivery systems due to their small size, enhanced flexibility and improved patient compliance. The aim of this work was the preparation and characterization of orodispersible films containing loperamide hydrochloride (LPH) as model drug. As loperamide hydrochloride is poorly soluble in water it was used in crystalline form with a loading of 2 mg/6 cm(2) film. Hydroxypropyl methylcellulose (HPMC) and different types of hydroxypropyl cellulose (HPC) in different concentrations were used as film forming polymers whereas arabic gum, xanthan gum and tragacanth served as thickening agents. Films were characterized with respect to the content uniformity, morphology, thermal behavior and crystallinity. Suspensions were investigated regarding their viscosity using a rotational rheometer and the crystal structure of the Active Pharmaceutical Ingredient (API) was analyzed using polarized light microscopy. The development of flexible, non-brittle and homogeneous films of LPH was feasible. Two polymorphic forms of LPH appeared in the film formulations dependent on the utilized polymer. While in presence of HPMC the original polymorphic form I remained stable in suspension and films, the polymorphic form II occurred in presence of HPC. Both polymorphic forms were prepared separately and a solid state characterization was performed. Polymorph I showed isometric crystals whereas polymorph II showed needle shaped crystals. Tragacanth was able to prevent the transformation to polymorph II, if it was dissolved first before HPC. When HPC was added first to the suspension, the conversion to form II occurred irreversibly also after further addition of tragacanth.

http://dx.doi.org/10.1016%2Fj.ejpb.2015.04.036

144. Wong P.C.H., Heng P.W.S., Chan L.W. Spray congealing as a microencapsulation technique to develop modified-release ibuprofen solid lipid microparticles: the effect of matrix type, polymeric additives and drug-matrix miscibility // J. Microencapsul. 2015. Vol. 32, № 8. P. 725–736

This study aimed to achieve modified-release of ibuprofen (IBU) by encapsulation within lipid-based matrix materials [cetyl alcohol (CA), stearic acid (SA) and glyceryl dibehenate (GB)] using spray congealing to produce solid lipid microparticles (SLMs). Polymeric additives, polyvinyl-2-pyrrolidone-vinyl-acetate and ethylcellulose, were employed as release-modifying agents. Spray-congealed SLMs yield, scanning electron microscopy (SEM)-based morphology, particle size, drug content and entrapment efficiency were investigated. The influence of matrix type, additive type and concentration and drug-matrix miscibility on release of IBU was elucidated. Yields (81.4-96.4%) and drug encapsulation efficiencies (88.4-100%) of SLMs were high for all formulations. SLMs were generally discrete, spherical and dense. Increasing additives concentration led to not only larger median size SLMs but also faster drug release due to increased hydrophilicity conferred by the additives. Solid solution systems (SA-IBU, GB-IBU) sustained the release of IBU better than solid dispersion system (CA-IBU). CA-and GB-based SLMs closely adhered to the Weibull model of drug release, while SA counterparts followed the Korsmeyer-Peppas model.

http://dx.doi.org/10.3109%2F02652048.2015.1073387

145. Xing J.-F., Zheng M.-L., Duan X.-M. Two-photon polymerization microfabrication of hydrogels: an advanced 3D printing technology for tissue engineering and drug delivery // Chem. Soc. Rev. 2015. Vol. 44, № 15. P. 5031–5039.

3D printing technology has attracted much attention due to its high potential in scientific and industrial applications. As an outstanding 3D printing technology, two-photon polymerization (TPP) microfabrication has been applied in the fields of micro/nanophotonics, micro-electromechanical systems, microfluidics, biomedical implants and microdevices. In particular, TPP microfabrication is very useful in tissue engineering and drug delivery due to its powerful fabrication capability for precise microstructures with high spatial resolution on both the microscopic and the nanometric scale. The design and fabrication of 3D hydrogels widely used in tissue engineering and drug delivery has been an important research area of TPP microfabrication. The resolution is a key parameter for 3D hydrogels to simulate the native 3D environment in which the cells reside and the drug is controlled to release with optimal temporal and spatial distribution in vitro and in vivo. The resolution of 3D hydrogels largely depends on the efficiency of TPP initiators. In this paper, we will review the widely used photoresists, the development of TPP photoinitiators, the strategies for improving the resolution and the microfabrication of 3D hydrogels.

http://dx.doi.org/10.1039%2Fc5cs00278h

146. Xiong G.M. et al. Materials technology in drug eluting balloons: Current and future perspectives // J. Control. Release. 2016. Vol. 239. P. 92–106.

The coating material technology is important for the delivery of anti-proliferative drugs from the surface of drug-eluting balloons (DEBs), which are emerging as alternatives to drug-eluting stents (DES) in the field of interventional cardiology. Currently, several shortcomings limit their competition with DES, including low drug transfer efficiency to the arterial tissues and undesirable particulate generation from the coating matrix. In this review, we provide a survey of the materials used in existing DEBs, and discussed the mechanisms of actions of both the drugs and coating materials. The type of drug and the influence of the coating material characteristics on the drug uptake, distribution and retention in arterial tissues are described. We also summarize the novel coating excipients under development and provide our perspective on the possible use of nano-scale carriers to address the shortcomings of current coating technology. The scope of this review includes only materials that have been approved for biomedical applications or are generally recognized as safe (GRAS) for drug delivery.

http://dx.doi.org/10.1016%2Fj.jconrel.2016.08.018

147. Xu H. et al. Amphiphilic block copolymers-based mixed micelles for noninvasive drug delivery // Drug Delivery. 2016. Vol. 23, № 8. P. 3063–3071.

Amphiphilic block copolymers-based mixed micelles established as new drug-loading system showed superior characteristics in delivering drug such as improved solubility, enhanced stability, multifunctional carrier materials, targeting ability, and high bioavailability. Recently, there are increasing focuses on exploration and study of noninvasive routes, and the results present perfect feasibility, improved compliance and fewer aches and pains. The aim to apply mixed micelles to noninvasive alternative routes has driven massive pharmaceutical attention. Recently, various studies of micelles strategy for noninvasive routes have been conducted to overcome the inherent barriers for uptake across the gastrointestinal tract, mucosal membranes and other in vivo noninvasive barriers, and the result argues well. The objective of this article is to summary these studies and developments of mixed micelles used on noninvasive drug delivery and provide a reference for further research.

http://dx.doi.org/10.3109%2F10717544.2016.1149743

148. Yang Y., Bugno J., Hong S. Nanoscale polymeric penetration enhancers in topical drug delivery // Polym. Chem. 2013. Vol. 4, № 9. P. 2651–2657.

Although recent advances in polymeric nanomaterials hold promise to develop effective transdermal delivery systems, the lack of fundamental understanding of polymer-skin interactions has hindered their fast translation. In this review, we provide a comprehensive overview, focusing on the chemistry aspects of the polymeric nanomaterials, such as surface modification, hydrophilic-hydrophobic grafting, and conjugation with biodegradable polymers or links. These chemical modifications to the nanomaterials have been reported to significantly affect their interactions with skin and delivery of drugs across the skin layers. This review highlights recently developed polymeric systems based on polyester nanoparticles, polymeric micelles, dendrimers, and chitosan, which opens a new avenue through which transdermal drug delivery with high efficiency and low toxicity can be potentially achieved.

http://dx.doi.org/10.1039%2Fc3py00049d

149. Yoncheva K. et al. Triblock polymeric micelles as carriers for anti-inflammatory drug delivery // J. Microencapsul. 2015. Vol. 32, № 3. P. 224–230.

This study evaluated the properties of poly(ethylene oxide)-b-poly(n-butyl acrylate)-b-poly (acrylic acid) (PEO-PnBA-PAA) polymeric micelles as carriers for anti-inflammatory drugs (prednisolone and budesonide). The micelles comprising a hydrophobic PnBA core and a PEO/PAA corona showed average diameter less than 40 nm. The size of the drug-loaded micelles did not change during eight hours into media that mimic physiological fluids indicating high colloidal stability. The calculation of Flory-Huggins parameter showed greater compatibility between budesonide and micellar core suggesting its location in the micellar core, whereas prednisolone was located also into the interface layer. This observation correlated further with slower release of budesonide, especially in acid medium (pH = 1.2). The inclusion of budesonide into micelles showed significant protective effect against the cytotoxic damage induced by the co-cultivation of differentiated human EOL-1 and HT-29 cells. This study revealed the capacity of PEO-PnBA-PAA terpolymer as carrier of nanosized micelles suitable for oral delivery of anti-inflammatory drugs.

http://dx.doi.org/10.3109%2F02652048.2014.995729

150. Zaidi S.A. Molecular imprinted polymers as drug delivery vehicles // Drug Deliv. 2016. Vol. 23, № 7. P. 2262–2271.

This review is aimed to discuss the molecular imprinted polymer (MIP)-based drug delivery systems (DDS). Molecular imprinted polymers have proved to possess the potential and also as a suitable material in several areas over a long period of time. However, only recently it has been employed for pharmaceuticals and biomedical applications, particularly as drug delivery vehicles due to properties including selective recognition generated from imprinting the desired analyte, favorable in harsh experimental conditions, and feedback-controlled recognitive drug release. Hence, this review will discuss their synthesis, the reason they are selected as drug delivery vehicles and for their applications in several drug administration routes (i.e. transdermal, ocular and gastrointestinal or stimuli-reactive routes).

http://dx.doi.org/10.3109%2F10717544.2014.970297

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