Quinone propionic acid‐based redox‐triggered polymer nanoparticles for drug delivery: Computational analysis and in vitro evaluation

Redox‐responsive polymers with pendant quinone propionic acid groups as a redox trigger were optimized by computational modeling to prepare efficient redox‐triggered polymer nanoparticles (NPs) for drug delivery. Lipophilicities at complete reduction of redox‐responsive polymers (<5000 Da) constructed with adipic acid and glutaric acid were remarkably reduced to range from ?6.29 to ?0.39 compared with nonreduced state (18.87–32.46), suggesting substantial polymer solubility reversal in water. Based on this hypothesis, redox‐responsive NPs were prepared from the synthesized polymers with paclitaxel as model cancer drug. The average size of paclitaxel‐loaded NPs was 249.8 nm and their reconstitutions were stable over eight weeks. In vitro drug release profiles demonstrated the NPs to release >80% of paclitaxel over 24 h at a simulated redox‐state compared with 26.5 to 41.2% release from the control. Cell viability studies revealed that the polymer was nontoxic and the NPs could release paclitaxel to suppress breast cancer cell growth. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40461.     

Reversible cross-linking reactions of alkoxyamine-appended polymers under bulk conditions for transition between flow and rubber-like states

Reversible cross-linking reactions of alkoxyamine-appended polymers with low glass transition temperature (T_g) were successfully carried out under bulk conditions. The low-T_g polymers with alkoxyamine units in the side chains were synthesised by radical copolymerisation of 2-ethylhexyl acrylate and two kinds of alkoxyamine-containing acrylate monomers. By heating the low-T_g polymers under bulk conditions at 100 °C, cross-linked polymers were formed by radical exchange reactions between alkoxyamine units, and a transition from a liquid-like flowable polymer state to a rubber-like polymer state was confirmed. A de-cross-linking reaction was also accomplished by radical exchange reactions between the cross-linked polymers and an added alkoxyamine-containing small molecule or stable nitroxyl radical, which resulted in transition to the flowable state again. The structural transition between low-T_g linear polymers and cross-linked polymers were characterised by ¹H and ¹³C NMR spectroscopy, Fourier transform infrared spectroscopy, rheology measurement, swelling experiment, and gel permeation chromatography measurement.     

Biocompatible hydrogels for the controlled delivery of anti-hypertensive agent: development,characterization and in vitro evaluation

The aim of the present exploration was to develop novel pH-sensitive cross-linked Gelatin/Polyvinyl pyrrolidone hydrogels using different ratios of both the polymers and to investigate the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and invitro release pattern of the model drug (captopril). Grafting polymerization technique was used for the preparation of these hydrogels using glutaraldehyde as crosslinking agent. These polymeric materials were then used as model systems to envisage various important characterizations like FTIR (Fourier transform infrared spectroscopy), XRD (X-ray diffraction) and scanning electron microscopy (SEM). Phosphate buffers of pH 1.2, 6.5 and 7.5 were used for swelling and invitro drug release profile investigation. Different parameters like swelling analysis, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), solvent interaction parameter (χ), volume fraction of polymer (V_2,s) and diffusion coefficient that affects the drug release behavior were also determined. Higher swelling and release was observed at lower pH values. FTIR spectra showed interaction between gelatin and polyvinyl pyrrolidone and successful formation of cross-linked structure. Pulsatile drug release study showed the controlled delivery of model drug. The release of drug occurred through non-fickian diffusion or anomalous mechanism. Aforementioned characterizations reveal successful formation of copolymer. pH sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and the rate of drug diffusion from these hydrogels are comparable which also predicts their possible use for site specific captopril delivery.     

Stimuli-accelerated polymeric drug delivery systems

The controlled delivery of active pharmaceutical ingredients to the site of disease represents a major challenge in drug therapy. Particularly when drugs have to be transported across biological barriers, suitable drug delivery systems are of importance. In recent years responsive delivery systems have been developed which enable a controlled drug release depending on internal or external stimuli such as changes in pH, redox environment or light and temperature. In some studies delivery systems with reactivity against two different stimuli were established either to enhance the response by synergies of the stimuli or to broaden the window of possible trigger events. In the present review numerous exciting developments of pH-, light- and redox-cleavable polymers suitable for the preparation of smart delivery systems are described. The review discusses the different stimuli that can be used for a controlled drug release of polymer-based delivery systems. It puts a focus on the different polymers described for the preparation of stimuli-sensitive systems, their preparation techniques as well as their stimuli-responsive degradation. © 2022 The Authors. Polymer International published by John Wiley & Sons Ltd on behalf of Society of Industrial Chemistry.     

Light-induced release of molecules from polymers

The release of molecules from polymers upon light stimulus has been investigated for a range of applications in particular for drug delivery. In this review, the concept of light-induced release processes from polymers is summarized. Light-triggered processes can be divided into two approaches, the light induced degradation of polymers and the light-induced polarity change of the polymers. Functional groups that can enable the breakdown of the polymer or the cleavage of a linker between polymer and small molecule encompass coumarine and o-nitrobenzyl groups while azobenze and spyropyrane undergo reversible changes. Although the literature is dominated by these four compound classes, functional groups such as anthracene, pyrene, perylene, 2-diazo-1,2-naphthoquinone, and BODIPY can undergo similar changes. Degradation of polymers or simple polarity changes can trigger the release of small molecules such as drugs, but also gas molecules such as nitric oxide and macromolecules including DNA and proteins can be liberated upon light-trigger.     

Cumulative release of cefotaxim from interpenetrating networks of poly(vinyl alcohol-g-acrylamide) and chitosan-g-polyacrylamide chains

In this study, novel interpenetrating networks comprising of poly(vinyl alcohol-g-acrylamide) and chitosan-g-polyacrylamide chains were designed by redox polymerization method and their potential for controlled release of an antibiotic drug cefotaxim, and antibacterial and cytotoxic behaviors were evaluated. The polymer matrix hydrogel was loaded with cefotaxim drug by allowing it to swell in the drug solution reservoirs of concentrations varying in the range 0.1–0.5 mg/mL. The polymer network was examined by FTIR, SEM and DSC techniques for structural, morphological and thermal characterization. The FTIR spectra clearly confirmed the presence of functional groups of constituent polymers; the SEM image suggested a mesh-type morphology with approximate mesh dimensions of 10 μm × 20 μm. The DSC studies revealed a fall in glass transition temperature (Tg) of both chitosan and poly(vinyl alcohol) to 50 and 70 °C, respectively, from their native values. The release studies were performed in PBS (pH 7.4) under in vitro conditions and the drug release kinetics was investigated. It was found that the amount of drug released increases from 5.4 to 8.4 mg when the drug loading increases from 5.0 to 16.0 %. It was also found that when the pH rises from 1.8 to 7.4, an increase in drug release was noticed, while a further increase in pH to 8.6 resulted in a fall in the amount of released drug. The polymer matrix also showed fair antibacterial properties against E. coli and no cytotoxicity for L-929 mouse fibroblast cells.     

Synthesis and properties of degradable hydrogels of konjac glucomannan grafted acrylic acid for colon-specific drug delivery

In this paper, we reported the synthesis and properties of novel hydrogel systems designed for colon targeted drug delivery. The gels were composed of konjac glucomannan (KGM), copolymerized with acrylic acid (AA) and cross-linked by N,N-methylene-bis-(acrylamide) (MBAAm). The influence of various parameters on the equilibrium swelling ratios of the hydrogels was investigated. The swelling ratio was inversely proportional to the content of MBAAm. It was possible to modulate the degree of swelling of the gels by changing cross-linking density of the polymer. The gels' swelling ratio has sensitive respondence to the environmental pH value variation. The results of degradation test show that the hydrogels retain the enzymatic degradation character of KGM and they can be degraded for 52.5% in 5 days by Cellulase E0240. In vitro release of model drug 5-aminosalicylic acid (5-ASA) was studied in the presence of Cellulase E0240 in pH 7.4 phosphate buffer at 37 °C. The accumulative release percent of 5-ASA reached 95.19% after 36 h and the drug release was controlled by the swelling and degradation of the hydrogels.     

Development and characterization of photopolymerizable biodegradable materials from PEG-PLA-PEG block macromonomers

As tissue engineering and drug delivery applications increase in both number and complexity, the demand for new synthetic biocompatible polymers with precisely tailored properties grows accordingly. Block copolymers are a particularly promising biomaterial as the physical and physiological properties of these polymers can be closely controlled through manipulation of the type and organization of the blocks in the polymer's backbone. In this work, poly(ethylene glycol) (PEG) and poly(lactic acid) (PLA) were incorporated into PEG-PLA-PEG block macromonomers with (meth)acrylate functionality to form photopolymerizable, highly cross-linked polymers for potential use in a variety of biomedical applications. Simply by directing the PLA:PEG ratio in these macromonomers, the hydrophobicity, physical behavior, degradation, and biocompatibility of the resulting polymer were controlled. Specifically, it was found that by increasing the PLA:PEG ratio, the degree of water uptake and the mechanical strength of the material is significantly decreased, while the glass transition temperature and degradation of the PEG-PLA polymers are delayed. Additionally, the biocompatibility of the PEG-PLA polymers is significantly influenced by the chemical composition of the material as increased PLA generally yields greater cell compatibility. By demonstrating the versatility of the photopolymerizable PEG-PLA polymers, the results of this study indicate that these materials have the potential to serve as a synthetic biomaterial platform, in which the properties of the polymer can be tailored to a variety of tissue engineering or drug delivery applications.     

Characterization of novel soybean‐oil‐based thermosensitive amphiphilic polymers for drug delivery applications

Hydrolyzed polymers of soybean oil (HPSO) and of epoxidized soybean oil (HPESO) were developed previously. Owing to their natural food origin and biocompatibility, we exploited further their potential as a drug delivery system and pharmaceutical excipients. This work aimed to investigate self‐assembly, thermal transition, interaction with various drugs and surface activity of these novel amphiphilic polymers. The critical micelle concentration of HPSO and HPESO was determined by the surface tension method. The molecular interaction between HPESO and anticancer drug doxorubicin HCl was examined. The effect of the polymers on the solution contact angle and surface energy of compressed tablets of hydrophobic drugs ibuprofen and nifedipine was measured. The thermal transition temperatures T_tr (cloud points) of the polymers in aqueous solutions increased with increasing polymer concentration. HPSO exhibited lower T_tr than HPESO. The critical micelle concentration was found to be 0.05 mg mL^?1 for HPSO and 0.08 mg mL^?1 for HPESO. Strong molecular interactions between HPESO and doxorubicin were observed. Both polymers reduced the interfacial energy and contact angles of drug tablets with more effect on ibuprofen tablets with the use of HPSO. These results suggest that the novel soybean‐oil‐based amphiphilic polymers have great potential for drug delivery and pharmaceutical formulations. Copyright © 2012 Society of Chemical Industry     

Fabrication and Characterization of Matrix-Type Transdermal Patches Loaded with Ramipril and Repaglinide Through Cellulose-based Hydrophilic and Hydrophobic Polymers: In Vitro and Ex Vivo Permeation Studies

Transdermal patches loaded with ramipril and repaglinide were prepared with the ambition to develop matrix-type transdermal drug delivery system for enhanced permeability and hence improved bioavailability. Different formulations were designed by intermittent concentrations of hydroxypropyl methylcellulose K4M as hydrophilic polymer and ethyl cellulose as hydrophobic polymer. Solvent casting method was used for the fabrication of transdermal patches. Oleic acid and propylene glycol were used to enhance permeability along with polyethylene glycol 400 as plasticizer. Newly designed patches were then evaluated for various physicochemical and mechanical properties. Compatibility studies were performed by Fourier transformed infrared spectroscopy which did not reveal any interaction between drug and polymers. Crystalline nature of drugs was confirmed when they were subjected to X-ray diffraction study and surface morphological studies using scanning electron microscopy. Transdermal patches were of good mechanical strength with folding endurance of more than 300-fold and 100% flatness. Percent drug contents of ramipril and repaglinide ranged from 90 to 105%, i.e., analogous to official limits. In vitro and ex vivo permeation studies were executed using franz diffusion cell. The cumulative amount of drug permeated through skin was 55.22–112.72% for repaglinide and 73.14–91.46% for ramipril. The release behavior of the permeated drug was analyzed by the application of model-dependent approaches. The results showed that Korsmeyer–Peppas model was found to be dominating in most of the formulations and drugs followed diffusion mechanism. It could be concluded that hydroxypropyl methylcellulose K4M and ethyl cellulose has great potential for ramipril and repaglinide as a vector for transdermal drug delivery effectively because of the formation of smooth surfaces of patches, high folding endurance, and entrapment efficiency with the ability to release the drugs in sustained manner.     

Preparation of pH-sensitive amphiphilic block star polymers,their self-assembling characteristics and release behavior on encapsulated molecules

Poly(ethylene glycol) (PEG), a polymer with excellent biocompatibility, was widely used to form nanoparticles for drug delivery applications. In this paper, based on PEG, a series of pH-sensitive amphiphilic block star polymers of poly(ethylene glycol)-block-poly(ethoxy ethyl glycidyl ether) (PEG-b-PEEGE) with different hydrophobic length were synthesized by living anionic ring-opening polymerization method. The products were characterized using ¹H NMR and gel permeation chromatography. These copolymers could self-assemble in aqueous solution to form micellar structure with controlled morphologies. Transmission electron microscopy showed that the nanoparticles are spherical or rodlike with different hydrophilic mass fractions. The pH response of polymeric aggregates from PEG-b-PEEGE was detected by fluorescence probe technique at different pH. A pH-dependent release behavior was observed and pH-responsiveness of PEG-b-PEEGE was affected by the hydrophobic block length. These results demonstrated that star-shaped polymers (PEG-b-PEEGE) are attractive candidates as anticancer drug delivery carriers.     

Ultrafine ibuprofen‐loaded polyvinylpyrrolidone fiber mats using electrospinning

BACKGROUND: Drug‐loaded electrospun ultrafine fibers have the advantages of both nanoscale drug delivery systems and conventional solid dosage forms. To improve the control of drug release, the combined use of electrospinning and pharmaceutical polymers has attracted increasing interest recently. RESULTS: Ultrafine drug‐loaded polyvinylpyrrolidone fibers were successfully prepared using an electrospinning process with ibuprofen as the active pharmaceutical ingredient and polyvinylpyrrolidone K30 as the filament‐forming polymer. The analytical results from scanning electron microscopy, differential scanning calorimetry and Fourier transform infrared spectroscopy indicated that the drug had good compatibility with the polymer and that the drug was well distributed in the ultrafine fibers as an amorphous physical form. In vitro dissolution tests showed that the fiber mats were able to dissolve within 10 s through a polymer‐controlled mechanism. CONCLUSION: The fast dissolution of drug‐loaded fibers may lead to applications that improve dissolution rates of poorly water‐soluble drugs, or that involve the preparation of oral fast‐dissolving drug delivery systems. Copyright © 2009 Society of Chemical Industry     

Polymers for use in drug delivery—property and structure requirements

The purpose of this paper is to discuss some of the requirements placed on materials needed for improved administration of drugs. Emphasis is placed on macromolecules that need to be designed and prepared to perform specific pharmacological functions, particularly to act as vehicles for delivering drugs to specific locations within the body. After introducing the reasons for more selective drug delivery, and explaining the rationale for using macromolecules, practical examples of results with linking drugs to polymers, modifying polymers to increase their biological compatibility, attachment to polymers of groups that could mediate their specific recognition, modification of proteins with polymers, and the use of polymer complexes will be given to indicate the areas of need for further development of pharmaceutically useful macromolecules.     

Synthesis and biodegradation of copolyesters from citric acid and glycerol

Summary Seven samples of cross-linked co-polyesters of citric acid and glycerol from seven different mole ratios of the reactants have been synthesised as initially insoluble amorphous solids which become soluble in water within 8–10 days due to partial hydrolysis of the cross-links. They have been characterised by their IR spectra, glass transition temperature and swelling behaviour. The acid to glycerol mole ratios 0.83 and 0.88 produce maximum cross-link density. Microbial degradation of the polymer samples in aqueous suspension has been studied using the fungus Aspergillus niger and the bacterium E. coli. All the polymer samples are degraded by Aspergillus niger and E. coli and the more cross-linked products have been found to be more degradable. The possible use of these cross-linked co-polyesters as matrices for controlled release of drugs has been illustrated.     

Compatibility,mechanical and thermal properties of GAP/P(EO-<Emphasis Type="Italic">co</Emphasis>-THF) blends obtained upon a urethane-curing reaction

A series of cross-linked glycidyl azide polymer with poly(ethylene oxide-co-tetrahydrofuran) (GAP/P(EO-co-THF)) blends were prepared by varying the relative weight ratios of GAP to P(EO-co-THF) using poly-isocyanate mixed curing system (N100/TDI), and by varying the [NCO]/[OH] ratios to find the effects of curing agents on mechanical properties. The compatibility, thermal features and morphological studies of GAP/P(EO-co-THF) polymer networks were described by equilibrium phase diagram, differential scanning calorimeters (DSC) together with thermogravimetric analysis (TGA), scanning electron microscopy (SEM), respectively. The equilibrium phase figure of the partial miscibility system for GAP/P(EO-co-THF) shows that the system has a lower critical solution temperature (LCST). In addition, the DSC and TGA results indicate that the content of two components is gradually approaching, and the glass transition temperatures of GAP/P(EO-co-THF) blends are less than those of the pure GAP and P(EO-co-THF) polymers, and the initial decomposition temperature and the maximum decomposition rate temperature have greatly increased. Furthermore, the thermal decomposition behavior indicates that the thermal stabilities are improved and the physical entangled networks are strengthened. Moreover, the scanning electron microscopy (SEM) images show the GAP/P(EO-co-THF) blends form a certain polymer alloy structure, which is the reason for the improved thermal stabilities and the strengthened networks.     

可降解高分子纳米纤维药物控释系统的研究进展

可降解高分子药物控释系统通过对药物剂量的有效控制,能够降低药物的毒副作用,提高药物的稳定性和利用率。近年来,静电纺丝纳米纤维因其具有比表面积大等特点,作为新型药物控制释放载体受到研究者的广泛关注。本文综述了可降解高分子纳米纤维药物控释系统的研究进展,对可降解高分子纳米纤维的制备及其在药物控释方面的研究进行介绍,并讨论了影响可降解高分子纳米纤维药物释放的因素。     

Preparation of ethyl cellulose microcapsules containing perphenazine and polymeric perphenazine based on acryloyl chloride for physical and chemical studies of drug release control

The preparation of microcapsules containing perphenazine by solvent evaporation using ethyl cellulose is described. The microparticles are formed after solvent evaporation and polymer precipitation. The drug was dissolved in a polymer solution and emulsified into an aqueous phase to form microcapsules. To study the effects on particle size, encapsulation efficiency and morphology, three different molecular weights of ethyl cellulose (M_w=47000, 71000 and 99000) were used. Covalent bonding of drugs to polymers via hydrolytically or enzymatically cleavable covalent bond was achieved for sustained drug delivery. The release rate of perphenazine from these systems was investigated. © 1998 Society of Chemical Industry     

Effect of pH on the drug release rate from a new polymer–drug conjugate system

The corresponding N‐hydroximide and N‐methyl‐N‐hydroximide of poly[ethylene‐alt‐(maleic anhydride)] (weight average molecular weight (M_w) of 100–500 g mol^?1) were prepared as a new oral drug delivery system. Syntheses of N‐hydroximide and N‐methylhydroxamic acid of poly[ethylene‐alt‐(maleic anhydride)] were carried out by chemical modification of polymer with hydroxylamine and N‐methylhydroxylamine, respectively, to give water‐soluble polymers. These activated polymers were immobilized with ketoprofen in the presence of dicyclohexylcarbodiimide to give the corresponding water‐insoluble ketoprofen conjugates. All products were characterized by elemental analysis as well as Fourier transform infrared and ¹H NMR spectra. In vitro release of ketoprofen was studied by measuring UV absorption at λ_max = 260 nm as a function of time. This study demonstrated the potential use of N‐hydroximide and N‐methyl‐N‐hydroxamic acid of poly[ethylene‐alt‐(maleic anhydride)] as a drug delivery system. Controlled release was studied at different pH values and at different temperatures. At physiological temperature, the amount of drug released increased with increasing pH. The copolymer‐drug adducts released the drug very slowly at the low pH found in the stomach thus protecting the drug from the action of high acid conditions and resident digestive enzymes. These N‐hydroxamic acid polymer‐drug conjugates were found to be potentially useful in the delivery of macromolecular drugs to targeted sites in the lower gastrointestinal tract and the colon area. Copyright © 2007 Society of Chemical Industry     

Novel metronidazole-loaded hydrogel as a gastroretentive drug delivery system

A metronidazole-loaded hydrogel was synthesized by free radical polymerization using dimethylaminoethyl methacrylate (DMAEMA) monomer and triethyleneglycol dimethacrylate (TEGDA) and methylene bisacrylamide (MBA) as cross-linkers. The DMAEMA hydrogels were cross-linked with 5 and 10% MBA or with 0.1, 0.5, 1 and 4% TEGDA as cross-linking agents. Ammonium persulfate and tetramethyl ethylene diamine were used as initiator and catalyst, respectively. The prepared hydrogels were characterized, and the effect of cross-linking agent content on the swelling behavior and in vitro drug release of hydrogels was investigated. The results of X-ray diffractometry, differential scanning calorimetry and Fourier transform infrared spectroscopy studies indicated that the prepared hydrogels possessed an amorphous morphology and there was not any interaction between the hydrogel polymers and metronidazole as drug, which resulted in the dependence of drug release on the physicochemical characteristics of hydrogel such as swelling, polymer erosion, and surface morphology. According to the results, the hydrogel containing 0.5% TEGDA which was prepared by freeze-drying method exhibited a porous structure with a high swelling ratio and displayed a sustained and complete drug release. It could be concluded that the hydrogel developed by this facile method is a good candidate with a potential for use in gastroretentive drug delivery systems.     

Bioreducible polymers for gene silencing and delivery

Polymeric gene delivery vectors show great potential for the construction of the ideal gene delivery system. These systems harness their ability to incorporate versatile functional traits to overcome most impediments encountered in gene delivery: from the initial complexation to their target-specific release of the therapeutic nucleic acids at the cytosol. Among the numerous multifunctional polymers that have been designed and evaluated as gene delivery vectors, polymers with redox-sensitive (or bioreducible) functional domains have gained great attention in terms of their structural and functional traits. The redox environment plays a pivotal role in sustaining cellular homeostasis and natural redox potential gradients exist between extra- and intracellular space and between the exterior and interior of subcellular organelles. In some cases, researchers have designed the polymeric delivery vectors to exploit these gradients. For example, researchers have taken advantage of the high redox potential gradient between oxidizing extracellular space and the reducing environment of cytosolic compartments by integrating disulfide bonds into the polymer structure. Such polymers retain their cargo in the extracellular space but selectively release the therapeutic nucleic acids in the reducing space within the cytosol. Furthermore, bioreducible polymers form stable complex with nucleic acids, and researchers can fabricate these structures to impart several important features such as site-, timing-, and duration period-specific gene expression. Additionally, the introduction of disulfide bonds within these polymers promotes their biodegradability and limits their cytotoxicity. Many approaches have demonstrated the versatility of bioreducible gene delivery, but the underlying biological rationale of these systems remains poorly understood. The process of disulfide reduction depends on multiple variables in the cellular redox environment. Therefore, the quest to unravel various issues such as the site and time of disulfide bond reduction during the cellular uptake and trafficking have stimulated a number of interesting studies which have employed disulfide compounds with a variety of reducible linkers. Such studies help researchers understand not only how modifications made to disulfides can alter their thiol-disulfide exchange characteristics but also to decipher the effect of the induced changes on the dynamics of the redox environment. This Account discusses current research trends and recent progress in the disulfide chemistry enabling novel and versatile designs of reducible polymeric gene delivery systems. We present strategies for the introduction of disulfide bonds into polymers. These representative examples and their respective outcomes elaborate the benefit and efficiency of disulfides at the individual stages of gene delivery.