Intracellular pH‐sensitive dextran‐based micelles as efficient drug delivery platforms

As drug delivery systems, stimuli‐responsive polymer micelles hold great potential in cancer chemotherapeutics to improve therapeutic efficiency and eliminate organism adverse effects. Here, pH‐sensitive polymeric micelles based on dextran‐g‐benzimidazole were designed and used for intracellular anticancer drug delivery. The anticancer drug doxorubicin (DOX) was effectively loaded into the micelles via hydrophobic interactions. In vitro release studies demonstrated that the release of loaded DOX was greater and faster under acid conditions such as in carcinomatous areas (pH < 6.8) than in physiological conditions (pH 7.4). MTT assays and flow cytometric analyses showed that DOX‐loaded micelles had higher cellular proliferation inhibition towards HeLa and HepG2 cells than pH‐insensitive controls. These pH‐sensitive micelles with significant efficiency for intracellular drug release will be beneficial to the future of in vivo biomedical applications. © 2014 Society of Chemical Industry     

PEGylated polylysine derived copolymers with reduction‐responsive side chains for anticancer drug delivery

Reduction‐responsive drug delivery systems have recently gained intense attention in intracellular delivery of anticancer drugs. In this study, we developed a PEGylated polypeptide, poly(ethylene glycol)‐block‐poly(?‐propargyloxycarbonyl‐l ‐lysine) (PEG₁₁₃‐b‐PPAL), as a novel clickable substrate for conjugation of reduction‐responsive side chains for antineoplastic drug delivery. PEG₁₁₃‐b‐PPAL was synthesized through ring‐opening polymerization of alkyne‐containing N‐carboxyanhydride monomers. A designed disulfide‐containing side chain was introduced onto the PEGylated polypeptide by click reaction. The obtained copolymer PEG₁₁₃‐b‐P(Lys‐DSA) formed micelles by self‐assembly, which exhibited reduction‐responsive behavior under the stimulus of 10 mmol L^–1 glutathione (GSH) in water. A small molecule intermediate, compound 2 , was used as a model to investigate the thiol reduction mechanism of PEG₁₁₃‐b‐P(Lys‐DSA) copolymers. The anticancer drug doxorubicin (DOX) was then loaded into the micelles with a drug loading content of 6.73 wt% and a loading efficiency of 40.3%. Both the blank and the drug‐loaded micelles (DOX‐loaded polylysine derived polymeric micelles (LMs/DOX)) adopted a spherical morphology, with average diameters of 48.0 ± 13.1 and 63.8 ± 20.0 nm, respectively. The in vitro drug release results indicated that DOX could be released faster from the micelles by the trigger of GSH in phosphate buffered saline. Confocal laser scanning microscopy and flow cytometer analysis further proved the intracellular delivery of DOX by LMs/DOX and their GSH‐sensitive release behavior. A 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay showed that the polymers exhibited negligible cytotoxicity towards normal L929 cells or cancer MCF‐7 cells with a treated concentration up to 1.0 mg mL^–1. In conclusion, our synthesized biocompatible and biodegradable PEGylated polypeptides hold great promise for intracellular antineoplastic drug delivery. © 2019 Society of Chemical Industry     

Synthesis and characterization of PEG–PCL–PEG triblock copolymers as carriers of doxorubicin for the treatment of breast cancer

Triblock copolymers of monomethoxy poly(ethylene glycol) (mPEG) and ε‐caprolactone (CL) were prepared with varying lengths of poly(ε‐caprolactone) (PCL) compositions and a fixed length of mPEG segment. The molecular characteristics of triblock copolymers were characterized by ¹H NMR, gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FT‐IR), X‐ray diffraction (XRD), and differential scanning calorimetry (DSC). These amphiphilic linear copolymers based on PCL hydrophobic chain and hydrophilic mPEG ending, which can self‐assemble into nanoscopic micelles with their hydrophobic cores, encapsulated doxorubicin (DOX) in an aqueous solution. The particle size of prepared micelles was around 40–92 nm. The DOX loading content and DOX loading efficiency were from 3.7–7.4% to 26–49%, respectively. DOX‐released profile was pH‐dependent and faster at pH 5.4 than pH 7.4. Additionally, the cytotoxicity of DOX‐loaded micelles was found to be similar with free DOX in drug‐resistant cells (MCF‐7/adr). The great amounts of DOX and fast uptake accumulated into the MCF‐7/adr cells from DOX‐loaded micelles suggest a potential application in cancer chemotherapy. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Graphene Oxide Hybrid Supramolecular Hydrogels with Self‐Healable,Bioadhesive and Stimuli‐Responsive Properties and Drug Delivery Application

Self‐healable hydrogels are promising soft materials with great potential in biomedical applications due to their autonomous self‐repairing capability. Although many attempts are made to develop new hydrogels with good self‐healing performance, to integrate this characteristic along with other responsive multifunctions into one hydrogel still remains difficult. Here, a self‐healable hybrid supramolecular hydrogel (HSH) with tunable bioadhesive and stimuli‐responsive properties is reported. The strategy is imparting graphene oxide (GO) nanosheets and quadruple hydrogen bonding ureido‐pyrimidinone (UPy) moieties into a thermoresponsive poly(N‐isopropylacrylamide) (PNIPAM) polymer matrix. The obtained GO–HSH hydrogel shows rapid self‐healing behavior and good adhesion to various surfaces from synthetic materials to biological tissue. In addition, doxorubicin hydrochloride (DOX) release profiles reveal the dual thermo‐ and pH‐responsiveness of the GO–HSH hydrogel. The DOX‐loaded hydrogel can further directly adhere to titanium substrate, and the released DOX from this thin hydrogel coating remains biologically active and has high capability to kill tumor cells.     

Acid‐sensitive reactive oxygen species triggered dual‐drug delivery systems for chemo‐photodynamic therapy to overcome multidrug resistance

In clinical treatment, multidrug resistance (MDR) is one of the major obstacles resulting in the failure of chemotherapy. It is still a challenge to overcome MDR. Herein, we fabricated intelligent dextran‐based dual‐drug delivery systems histidine modified dextran conjugated doxorubicin/zinc porphyrin/paclitaxel (DHTD/Zn‐TPP/PTX) via supramolecular metallo‐coordination for synergistic chemo‐photodynamic therapy to overcome cancer drug resistance. In this designed DHTD/Zn‐TPP/PTX, one anticancer drug (doxorubicin, DOX) was conjugated on the dextran backbone through a reactive oxygen species sensitive linker and the other drug PTX was encapsulated into the acid responsive supramolecular micelles formed by the photosensitizer Zn‐TPP and histidine grafted on dextran. DHTD/Zn‐TPP/PTX with excellent stability could be effectively internalized by tumour cells. In the acidic tumour environment, the loaded PTX and Zn‐TPP as photosensitizer could be released; moreover, when irradiated with light the conjugated DOX could be specifically released because the linker broke. As the obtained data indicate, DHTD/Zn‐TPP/PTX exhibited not only an enhanced anticancer therapeutic effect but also significant growth inhibition for drug‐resistant MCF‐7/ADR cells to reverse MDR, having great potential for synergistic treatments of cancer to overcome MDR. © 2020 Society of Chemical Industry     

An in vitro focus on doxorubicin hydrochloride delivery of novel pH‐responsive poly(2‐succinyloxyethylmethacrylate) and poly[(N‐4‐vinylbenzyl),N,N‐diethylamine] diblock copolymers

Novel pH‐responsive poly(2‐succinyloxyethylmethacrylate)‐b‐poly[(N‐4‐vinylbenzyl),N,N‐diethylamine] [poly(SEMA‐b‐VEA)] diblock copolymers were synthesized via reversible addition fragmentation transfer (RAFT) polymerization to investigate their self‐assembly micellar behavior. The self‐assembly behaviors of synthesized diblock copolymers with distinct molecular weights (labeled (1) to) were confirmed by ¹H NMR spectroscopy, TEM and dynamic light scattering measurements. Doxorubicin hydrochloride (DOX) loading capacity was evaluated, and the in vitro cytotoxicity effect of DOX‐loaded diblock copolymer was also studied by assessing the survival rate of the breast cancer cell line MCF‐7 with 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The results exhibited remarkable controlled release in the MTT assay. The DOX encapsulation efficiency was calculated to be 96.4%. The size and zeta potential of DOX‐loaded poly(SEMA‐b‐VEA) diblock copolymers were 204 nm and +5.7 mV at a pH of 7.4. DOX release values after 440 h at pH 7.4, 5.4 and 4 were 22.15%, 31.43% and 47.06%, respectively. The released values of DOX‐loaded poly(SEMA‐b‐VEA) and at pH 7.4 were 22.15%, 20.5% and 17.5%, respectively. Cell survival ratios were 18.9%, 23.16% and 16.92% after 72 h. Poly(SEMA‐b‐VEA) copolymers can be considered in nanomedicine applications due to their excellent pH‐responsive micellar behavior. © 2017 Society of Chemical Industry     

Synthesis of hollow maghemite (-Fe2O3) particles for magnetic field and pH-responsive drug delivery and lung cancer treatment

The development of smart stimuli-responsive materials for drug delivery offers new opportunities for precise drug release and cancer chemotherapy. A combination of more than one stimuli is highly desirable to further maximize the therapy by taking the advantages of various unique merits. Herein, we employed polyethylene glycol (PEG) functionalized γ-Fe₂O₃ particles (γ-Fe₂O₃/PEG) as a novel magnetic drug carrier for doxorubicin (DOX) delivery. The results showed that the γ-Fe₂O₃/PEG exhibited excellent thermal effects under alternating magnetic field (AMF), high magneto-thermal stability, and large DOX loading capacity. Furthermore, the effects of pH and AMF on the DOX drug release were studied. It was discovered that DOX loaded γ-Fe₂O₃/PEG carriers were highly responsive to both AMF and pH, resulting in significantly improved cancer cell killing capability over a single stimulus. The magnetic and pH responsive drug delivery system provided a new opportunity to minimize the side effects and maximize the therapeutic efficiency of lung cancer treatment.     

Core/shell pH‐sensitive micelles self‐assembled from cholesterol conjugated oligopeptides for anticancer drug delivery

A doxorubicin (DOX) delivery system of pH‐sensitive micelles self‐assembled from cholesterol conjugated His₅Arg₁₀ (HR15‐Chol) and His₁₀Arg₁₀ (HR20‐Chol) has been described in this article. The amphiphilic molecules have low critical micelle concentrations of 17.8 and 28.2 μg/mL for HR15‐Chol and HR20‐Chol, respectively, even at a low pH of 5.0. The pH‐sensitive histidine segment of the polypeptide block is insoluble at pH 7.4 but becomes positively charged and soluble via protonation at pH lower than 6.0. The size and zeta potential of DOX‐loaded micelles increases with the decrease in pH. Coarse‐grained simulations were performed to verify the structure of DOX‐loaded micelles and pH sensitivity of HR15/20‐Chol. The in vitro DOX release from the micelles is significantly accelerated by decreasing pH from 7.4 to 5.0. Furthermore, DOX release from the micelles is controlled by a Fickian diffusion mechanism. These micelles have great potential applications in delivering hydrophobic anticancer drugs for improved cancer therapy. © 2009 American Institute of Chemical Engineers AIChE J, 2010     

PEGylated hollow pH‐responsive polymeric nanocapsules for controlled drug delivery

Novel pH‐responsive PEGylated hollow nanocapsules (HNCaps) were fabricated through a combination of distillation–precipitation copolymerization and surface thiol–ene ‘click’ grafting reaction. For this purpose, SiO₂ nanoparticles were synthesized using the Stöber approach, and then modified using 3‐(trimethoxysilyl)propyl methacrylate (MPS). Afterward, a mixture of triethyleneglycol dimethacrylate (as crosslinker), acrylic acid (AA; as pH‐responsive monomer) and MPS‐modified SiO₂ nanoparticles (as sacrificial template) was copolymerized using the distillation–precipitation approach to afford SiO₂@PAA core–shell nanoparticles. The SiO₂ core was etched from SiO₂@PAA using HF solution, and the obtained PAA HNCaps were grafted with a thiol‐end‐capped poly(ethylene glycol) (PEG) through a thiol–ene ‘click’ reaction to produce PAA‐g‐PEG HNCaps. The fabricated HNCaps were loaded with doxorubicin hydrochloride (DOX) as a model anticancer drug, and their drug loading and encapsulation efficiencies as well as pH‐dependent drug release behavior were investigated. The anticancer activity of the drug‐loaded HNCaps was extensively evaluated using MTT assay against human breast cancer cells (MCF7). The cytotoxicity assay results as well as superior physicochemical and biological features of the fabricated HNCaps mean that the developed DOX‐loaded HNCaps have excellent potential for cancer chemotherapy. © 2020 Society of Chemical Industry     

Temperature,pH, and reduction triple‐stimuli‐responsive inner‐layer crosslinked micelles as nanocarriers for controlled release

Temperature, pH, and reduction triple‐stimuli‐responsive inner‐layer crosslinked micelles as nanocarriers for drug delivery and release are designed. The well‐defined tetrablock copolymer poly(polyethylene glycol methacrylate)–poly[2‐(dimethylamino) ethyl methacrylate]–poly(N‐isopropylacrylamide)–poly(methylacrylic acid) (PPEGMA‐PDMAEMA‐PNIPAM‐PMAA) is synthesized via atom transfer radical polymerization, click chemistry, and esterolysis reaction. The tetrablock copolymer self‐assembles into noncrosslinked micelles in acidic aqueous solution. The core‐crosslinked micelles, shell‐crosslinked micelles, and shell–core dilayer‐crosslinked micelles are prepared via quaternization reaction or carbodiimide chemistry reaction. The crosslinked micelles are used as drug carriers to load doxorubicin (DOX), and the drug encapsulation efficiency with 20% feed ratio reached 59.2%, 73.1%, and 86.1%, respectively. The cumulative release rate of DOX is accelerated by single or combined stimulations. The MTT (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay verifies that the inner‐layer crosslinked micelles show excellent cytocompatibility, and DOX‐loaded micelles exhibit significantly higher inhibition for HepG2 cell proliferation. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46714.     

Rheological properties of poly(ethylene glycol)/poly(N‐isopropylacrylamide‐co‐2‐acrylamido‐2‐methylpropanesulphonic acid) semi‐interpenetrating networks

For the increasing demands of multifunctional materials in applications such as drug delivery system, a pH‐ and temperature‐responsive polyelectrolyte copolymer gel system was studied using rheometry. Rheological properties, determined by plate–plate rheometry in oscillatory shear, of hydrogels formed by free radical initiated copolymerization of N‐isopropylacrylamide (NIPA) and 2‐acrylamido‐2‐methylpropanesulphonic acid (AMPS) in the presence of methylene bisacrylamide (MBAA) as crosslinker are compared with the properties of semi‐interpenetrating network (SIPN) polyelectrolyte gels made by incorporation of poly(ethylene glycol) with molar mass 6000 g mol^?1 (PEG6000). Based on our systematic studies for this PEG/SIPN system, the effects of initiator and crosslinker concentration, relative proportions of comonomer units in the main chains, PEG6000 content and temperature on viscoelastic properties, unusual high storage moduli at small strain for the SIPN were discussed. The SIPN gel with characteristics of PEG molecules as well as pH and temperature responsiveness from AMPS and NIPA units has potential application in drug delivery system design. Ice‐like rheological behavior of the PEG/AMPS‐NIPA SIPN gels at low temperature was first time reported and water remains homogeneous without phase separation in PEG/AMPS‐NIPA SIPN hydrogels at low temperature may be considered as an ideal candidate for water storage material. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Multifunctional,pH‐responsive graft copolymer prepared from deproteinized natural rubber and 4‐vinylpyridine via emulsion polymerization

We investigated the synthesis of a pH‐responsive graft copolymer of natural rubber and 4‐vinylpyridine. The grafting reaction was carried out using deproteinized natural rubber (DPNR) latex, with potassium persulfate as a free radical initiator. The pH responsiveness of the graft copolymer was investigated using water swelling and contact angle measurements, and was compared with that of pure DPNR. The graft copolymer was found to become responsive in solution at a pH of around 4. Indigo carmine adsorption studies identified the Langmuir isotherm, suggesting monolayer coverage. The adsorbed indigo carmine, a model anionic drug, and carbon dots, an emerging nanosized fluorophore, could be released from the graft copolymer by lowering the pH of the solution. The graft copolymer was tested as a heavy metal adsorbent, and demonstrated selectivity to copper(II) ions. The graft copolymer of 4‐vinylpyridine and DPNR developed in this study is therefore a multifunctional, pH‐responsive material with a wide range of potential applications, including sensing and catalysis, as a biomedical material and as an adsorbent. © 2017 Society of Chemical Industry     

Multiresponsive polyanionic microgels with inverse pH responsive behavior by encapsulation of polycationic nanogels

Intelligent, stimuli‐responsive hydrogels have great utility in various fields spanning biomedical technology, separations, and catalysis. Their overall response to surrounding fluids may be further tailored to a specific application by incorporation of one or more intelligent responses within one material, known as multiresponsive hydrogels. This is a report on the facile synthesis and characterization of poly(methacrylic acid‐co‐N‐vinylpyrrolidone) microgels encapsulating polycationic nanogels (70 – 100 nm) to incorporate inverse pH responsive behavior within a single hydrogel. Potentiometric titration and pH swelling studies reveal a swelling response dependent on both pH and crosslinking agent. Additionally, a protein and a small molecule are loaded and released to evaluate the pH‐dependent binding affinity. Such a material could exhibit unique protein ‐ binding capacity and pH‐responsive behavior for use in separation or drug delivery applications. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40098.     

Dually Responsive Nanoparticles for Drug Delivery Based on Quaternized Chitosan

In this work, we report the fabrication and functional demonstration of a kind of dually responsive nanoparticles (NPs) as a potential drug delivery vector. The pH value, corresponding to the acidic microenvironment at the tumor site, and mannitol, to the extracellular trigger agent, were employed as the dually responsive factors. The function of dual responses was achieved by breaking the dynamic covalent bonds between phenylboronic acid (PBA) groups and diols at low pH value (pH 5.0) and/or under the administration of mannitol, which triggered the decomposition of the complex NPs and the concomitant release of anticancer drug of doxorubicin (DOX) loaded inside the NPs. The NPs were composed of modified chitosan (PQCS) with quaternary ammonium and PBA groups on the side chains, heparin (Hep), and poly(vinyl alcohol) (PVA), in which quaternary ammonium groups offer the positive charge for the cell-internalization of NPs, PBA groups serve for the formation of dynamic bonds in responding to pH change and mannitol addition, PVA furnishes the NPs with diol groups for the interaction with PBA groups and the formation of dynamic NPS, and Hep plays the roles of reducing the cytotoxicity of highly positively-charged chitosan and forming of complex NPs for DOX up-loading. A three-step fabrication process of drug-loaded NPs was described, and the characterization results were comprehensively demonstrated. The sustained drug release from the drug-loaded NPs displayed obvious pH and mannitol dependence. More specifically, the cumulative DOX release was increased more than 1.5-fold at pH 5.0 with 20 mg mL⁻¹ mannitol. Furthermore, the nanoparticles were manifested with effective antitumor efficient and apparently enhanced cytotoxicity in response to the acidic pH value and/or mannitol.     

γ‐Irradiation preparation of poly(acrylic acid)–chitosan hydrogels for in vitro drug release

Biocompatible and biodegradable pH‐responsive hydrogels based on poly(acrylic acid) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a γ‐irradiation polymerization technique. The degree of gelation was over 96% and increased as the chitosan or acrylic acid (AAc) content increased. The equilibrium swelling studies of hydrogels prepared under various conditions were carried out in an aqueous solution, and the pH sensitivity in a range of pH 1–12 was investigated. The AAc/chitosan hydrogels showed the highest water content when 30 vol % AAc and 0.1 wt % chitosan were irradiated with a 30 kGy dose of radiation. In addition, an increase of the degree of swelling with an increase in the pH was noticed and it had the highest value at pH 12. The drug 5‐fluorouracil was loaded into these hydrogels and the release studies were carried out in simulated gastric and intestinal fluids. The in vitro release profiles of the drugs showed that more than 90% of the loaded drugs were released in the first 1 h at intestinal pH and the rest of the drug was released slowly. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 3270–3277, 2003     

Self‐assembled nanoparticles from folate‐decorated maleilated pullulan–doxorubicin conjugate for improved drug delivery to cancer cells

The goal of this study was to develop doxorubicin conjugate nanoparticles with increased antitumor effects, reduced side effects and the ability to overcome multidrug resistance (MDR). In this regard, folate‐decorated maleilated pullulan–doxorubicin conjugate nanoparticles were developed as carriers for co‐delivery of pyrrolidinedithiocarbamate and doxorubicin (FA‐MP‐DOX/PDTC + DOX NPs). The resultant nanoparticles showed spherical geometry, with an average diameter of 152 nm. The two drugs were released from the nanoparticles in a slow, pH‐dependent sustained release. To test the efficacy of these nanoparticles, in vitro tests including cell viability and folate receptor‐mediated endocytosis were conducted against both A2780 cells and A2780/DOX^R cells. Compared to free DOX, the FA‐MP‐DOX/PDTC + DOX NPs showed effective but less potent cytotoxicity against A2780 cells. For A2780/DOX^R cells, they showed enhanced cellular uptake, increased targeting capacity and cytotoxicity. These results suggest that co‐delivery of PDTC and DOX may further overcome MDR by transporting an increased amount of DOX within cells in addition to the folate receptor‐mediated endocytosis process. © 2012 Society of Chemical Industry     

Facile fabrication of double‐walled polymeric hollow spheres with independent temperature and pH dual‐responsiveness for synergetic drug delivery

A dual‐responsive double‐walled polymeric hollow sphere (PHS) serving as a candidate for synergetic drug delivery platform is prepared by a simple and green template polymerization in aqueous medium. The PHS, comprised of thermo‐responsive crosslinked poly(N‐isopropylacrylamide) (PNIPAM) as the inner shell and pH‐responsive crosslinked poly(methacrylic acid) (PMAAc) as the outer shell, is assembled through self‐removal of the thermo‐responsive template from a core‐triple shell structure by free radical polymerization with sequential addition of reactants. The discrete double‐shell structure renders the PHS independent temperature and pH‐controlled swelling/shrinking capability. Taking the advantage of two compartmentalized internal spaces (the core and the interlayer spaces) with independent temperature‐ and pH‐dependent behaviors, two model drugs representing the small molecule and the macromolecule are loaded in selective locations of the PHS. Two drugs show dramatically different release profiles according to environmental temperature and pH, due to the localization of drugs and the stimuli‐dependent property of its protective shells. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44335.     

Efficient pH Dependent Drug Delivery to Target Cancer Cells by Gold Nanoparticles Capped with Carboxymethyl Chitosan

Doxorubicin (DOX) was immobilized on gold nanoparticles (AuNPs) capped with carboxymethyl chitosan (CMC) for effective delivery to cancer cells. The carboxylic group of carboxymethyl chitosan interacts with the amino group of the doxorubicin (DOX) forming stable, non-covalent interactions on the surface of AuNPs. The carboxylic group ionizes at acidic pH, thereby releasing the drug effectively at acidic pH suitable to target cancer cells. The DOX loaded gold nanoparticles were effectively absorbed by cervical cancer cells compared to free DOX and their uptake was further increased at acidic conditions induced by nigericin, an ionophore that causes intracellular acidification. These results suggest that DOX loaded AuNPs with pH-triggered drug releasing properties is a novel nanotheraputic approach to overcome drug resistance in cancer.     

pH‐sensitive hydroxyethyl starch–doxorubicin conjugates as antitumor prodrugs with enhanced anticancer efficacy

Doxorubicin (DOX) is a widely used chemotherapeutic drug for the treatment of several types of cancers, which has limitation in clinical applications because of severe heart toxicity. Herein, to reduce the fast clearance from the blood system and the severe systemic toxicity caused by the nonspecific protein adsorption, a pH‐sensitive drug delivery system with higher drug conjugated content was prepared by conjugating DOX onto hydroxyethyl starch (HES) with a pH‐sensitive hydrazone bond. In normal physiological environment, the release of DOX conjugated onto HES was slight which could be neglected without any side effect. However, in an acidic environment mimicking the tumor microenvironment, this pH‐sensitive hydrazone linkage provided a controlled and sustained release of DOX over a period of more than 3 days. The conjugates had good biocompatibility, long circulation, and lower cytotoxicity, which could efficiently be transferred into HeLa and HepG2 cells and release the conjugated drug. Based on these promising properties, these HES–DOX conjugates outline the significant potential for future biomedical application in the controlled release of antitumor drugs. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42778.     

Preparation of poly(acrylic acid)–chitosan hydrogels by gamma irradiation and in vitro drug release

Biocompatible and biodegradable pH‐responsive hydrogels based on poly(acrylic acid) (AAc) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a gamma irradiation polymerization technique. The degree of gelation was over 96% and increased as the chitosan or acrylic acid content increased. The equilibrium swelling studies of hydrogels prepared in various conditions were carried out in an aqueous solution, and the pH sensitivity in the range of pH 1–12 was investigated. The AAc/chitosan hydrogels showed the highest water content when the 30 vol % AAc and 0.1 wt % chitosan were irradiated with a 30‐kGy radiation dose. Also, an increase of swelling degree with an increase in the pH was noticed and showed the highest value at pH 12. The drug, 5‐fluorouracil, was loaded into these hydrogels and the release studies were carried out in simulated gastric and intestinal fluids. The in vitro release profiles of the drugs showed that more than 90% of the loaded drugs were released in the first 1 h at the intestinal pH and the rest of the drug had been released slowly. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 3660–3667, 2003