Injectable thermosensitive hydrogels for intra‐articular delivery of methotrexate

Intra‐articular drug delivery is the preferred approach for targeting pharmacologic treatment directly at the joints to reduce undesirable side effects associated with systemic drug delivery. In this study, a controlled delivery system of methotrexate (MTX) based on injectable thermosensitive poly(ε‐caprolactone)‐poly(ethylene glycol)‐poly(ε‐caprolactone) (PCL‐PEG‐PCL, PEP) hydrogels was developed for the intra‐articular drug delivery. The thermosensitive PEP copolymers were prepared by ring‐opening polymerization. The synthesized PEP copolymers were characterized for their structure, composition, and the sol‐to‐gel transition. The in vitro MTX release from the PEP hydrogels was studied. MTX plasma concentration following intra‐articular injection into healthy rats was determined by HPLC. Biocompatibility was confirmed by histology analysis after the intra‐articular injection. The synthesized PEP copolymers aqueous solutions formed in situ gel rapidly after the injection. PEP hydrogels showed the ability to control the release of incorporated MTX. Following intra‐articular injection, the PEP hydrogels decreased the clearance rate of MTX in the joint cavity. The maximum plasma concentrations of MTX in rats injected with free MTX were threefold higher than that of the groups injected with MTX hydrogels. These results suggest that the intra‐articular delivery of the PEP hydrogels may be a viable strategy for the controlled release of drugs for treating arthritis diseases. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Preparation of chitosan‐based thermosensitive hydrogels for drug delivery

The thermosensitive material that could be transformed into gel at 37°C was prepared from chitosan (dissolved in acetic acid/sodium acetate buffer solution) and a mixture of α‐ and β‐glycerophosphate (αβ‐GP). The thermosensitive characteristics, appearance, and structure of the hydrogel were all affected by the pH, ionic strength, and CS/αβ‐GP ratio. The optimal conditions for the preparation of a transparent CS‐αβ‐GP thermosensitive hydrogel were pH 4.6, ionic strength 0.15 mol/L, and a CS/αβ‐GP ratio of 8.8/1.2 (v/v). The hydrogel was stable for at least 3 months at 4°C. We believe that hydrogen bonding interactions between the N? H (and C?O) groups of chitosan and the O? H groups of αβ‐GP play an important role during the process of sol‐to‐gel transition. The cumulative release of adriamycin from the CS‐αβ‐GP hydrogel, measured in PBS at pH 7.4, reached only 60 to 70% over 24 h, indicating that this material could be potentially used in a sustained drug delivery system. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

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 micelles prepared from poly(ɛ‐caprolactone)–poly(ethylene glycol) and poly(ɛ‐caprolactone/glycolide)–poly(ethylene glycol) block copolymers for sustained drug delivery

A series of poly(?‐caprolactone)–poly(ethylene glycol) (PCL‐PEG) and poly(?‐caprolactone/glycolide)–poly(ethylene glycol) [P(CL/GA)‐PEG] diblock copolymers were prepared by ring‐opening polymerization of ?‐caprolactone or a mixture of ?‐caprolactone and glycolide using monomethoxy PEG (mPEG) as macroinitiator and Sn(Oct)₂ as catalyst. The resulting copolymers were characterized using ¹H‐NMR, gel permeation chromatography, differential scanning calorimetry, and wide‐angle X‐ray diffraction. Copolymer micelles were prepared using the nanoprecipitation method. The morphology of the micelles was spherical or worm‐like as revealed by transmission electron microscopy, depending on the copolymer composition and the length of the hydrophobic block. Introduction of the glycolide component, even in small amounts (CL/GA = 10), disrupted the chain structure and led to the formation of spherical micelles. Interestingly, the micelle size decreased with the encapsulation of paclitaxel. Micelles prepared from mPEG5000‐derived copolymers exhibited better drug loading properties and slower drug release than those from mPEG2000‐derived copolymers. Drug release was faster for copolymers with shorter PCL blocks than for those with longer PCL chains. The introduction of glycolide moieties enhanced drug release, but the overall release rate did not exceed 10% in 30 days. In contrast, drug release was enhanced in acidic media. Therefore, these bioresorbable micelles and especially P(CL/GA)‐PEG micelles with excellent stability, high drug loading content, and prolonged drug release could be promising for applications as drug carriers. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 45732.     

Thermosensitive PCL‐PEG‐PCL hydrogels: Synthesis,characterization, and delivery of proteins

In this work, a biodegradable and injectable in situ gel‐forming controlled drug delivery system based on thermosensitive poly(ε‐caprolactone)‐poly(ethylene glycol)‐poly(ε‐caprolactone) (PCL‐PEG‐PCL) hydrogels was studied. A series of PCL‐PEG‐PCL triblock copolymers were synthesized and characterized by ¹H‐NMR and gel permeation chromatography (GPC). Thermosensitivity of the PCL‐PEG‐PCL triblock copolymers was tested using the tube inversion method. The in vitro release behaviors of two model proteins, including bovine serum albumin (BSA) and horseradish peroxidase (HRP), from PCL‐PEG‐PCL hydrogels were studied in detail. The in vivo gel formation and degradation of the PCL‐PEG‐PCL triblock copolymers were also investigated in this study. The results showed that aqueous solutions of the synthesized PCL‐PEG‐PCL copolymers can form in situ gel rapidly after injection under physiological conditions. The PCL‐PEG‐PCL hydrogels showed the ability to control the release of incorporated BSA and HRP. The released HRP was confirmed to conserve its biological activity by specific enzymatic activity assay. The in vivo gel formation and degradation studies indicated that PCL‐PEG‐PCL copolymers hydrogels can sustain at least 45 days by subcutaneous injection. Therefore, owing to great thermosensitivity and biodegradability of these copolymers, PCL‐PEG‐PCL copolymers hydrogels show promise as an in situ gel‐forming controlled drug delivery system for therapeutic proteins. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Horseradish peroxidase‐mediated in situ forming hydrogels from degradable tyramine‐based poly(amido amine)s

Horseradish peroxidase (HRP)‐mediated crosslinking of poly(amido amine) (PAA) copolymers was successfully applied in the preparation of in situ forming degradable hydrogels under physiological conditions. PAA copolymers containing different amounts of tyramine residues (termed as pAEEOL/TA) could be synthesized through Michael‐type addition between methylenebisacryamide and amine mixture of 2‐(2‐aminoethoxy) ethanol and tyramine (TA). Depending on the amount of TA residue, the HRP, and H₂O₂ concentration, the gelation times could be varied from about 50 to 350 s. The swelling and degradation experiments indicated under physiological conditions the pAEEOL/TA‐based hydrogels are completely degradable within 6–8 days. Rheological analysis revealed that storage modulus of the hydrogels increased from 2500 to 4100 Pa when increasing HRP concentrations. Importantly, pAEEOL/TA copolymers have low cytotoxicity. Moreover, NIH 3T3 (mouse embryonic fibroblast) cells exposed in the degradation products of pAEEOL/TA‐based hydrogels retained high cell viability, implying that the hydrogels are cyto‐biocompatible. In vitro release of methylene blue and IgG protein from pAEEOL/TA‐based hydrogels could be effectively sustained by encapsulation of the drug in the hydrogels. The results indicate that HRP‐crosslinked, degradable pAEEOL/TA‐based hydrogels are promising for biomedical applications. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Development and characterization of thermosensitive hydrogels based on poly(N‐isopropylacrylamide) and calcium alginate

This work refers to the synthesis and characterization of thermosensitive hydrogels based on interpenetrating polymer networks (IPNs) of poly(N‐isopropylacrylamide) (PNIPAAm) and calcium alginate in the form of films. The influence of the crosslinking degree of PNIPAAm and alginate content on thermal, swelling, mechanical, and morphological properties of hydrogels is investigated in detail. Characterization of pure PNIPAAm hydrogels and IPN hydrogels was performed by FTIR, DSC, DMA, and SEM. In addition, the studies of equilibrium swelling behavior as well as swelling, deswelling, and reswelling kinetics are performed. The results obtained imply the benefits of synthesizing IPNs based on PNIPAAm and calcium alginate over pure PNIPAAm hydrogels. The presence of calcium alginate contributes to the improvement of mechanical properties, the deswelling rate of hydrogels, and the network porosity, without altering the thermosensitivity of PNIPAAm significantly. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Synthesis and characterization of novel biodegradable polymeric prodrugs containing 5‐fluorouracil and 4‐amino‐N‐(2‐pyrimidinyl) benzene sulfonamide terminal groups

To develop novel biodegradable polymeric prodrugs with target‐directing and drug‐active functional groups, a series of polymeric antitumor prodrugs containing sulfadiazine and 5‐fluorouracil terminal groups were prepared via the two‐step reaction of chlorinated poly(lactic acid) or chlorinated poly(lactic acid‐co‐glycolic acid) with potassium sulfadiazine (SF‐K) and 1,3‐dihydroxymethyl‐5‐fluorouracil. The synthesized polymers were characterized by means of infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, gel permeation chromatography, viscosity measurements, differential scanning calorimetry, and ultraviolet (UV) spectroscopy. The GA/LA value was varied, so that the effects of the comonomer content on the solubility, thermal properties, and degradable behaviors were examined respectively. It was found that introducing the GA units could increase the melting temperature (T_m), the hydrolytic degradation, and the hydrophilicity, while it decreased the glass transition temperature (T_g). The drug content of 5‐FU measured by UV spectra is 56.3 in maximum. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007     

Design of a drug delivery system based on poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels

To obtain biodegradable materials for biomedical applications, new biopolymeric hydrogels based on blends of polyacrylamide nanoparticles and chitosan have been prepared. In this work, we have studied the behavior of the diffusion of ascorbic acid (V‐C) from poly(acrylamide‐co‐acrylic acid)/chitosan nanostructured hydrogels. The process involves the synthesis of nanoparticles of polyacrylamide by inverse microemulsion polymerization and their complexation with chitosan dissolved in an acrylic acid aqueous solution. We have studied the effect of the concentration of the polyacrylamide nanoparticles, which are crosslinked with N,N′‐methylenebisacrylamide, in the delivery of V‐C. The results indicate that the drug delivery operates by a non‐Fickian mechanism. Also, we have obtained the diffusion coefficient for V‐C in gels for different nanoparticle concentrations, using a modified form of Fick's second law that takes into account dimensional changes in the hydrogels during drug release. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Fabrication and drug release properties of poly(5‐benzyloxy‐trimethylene‐co‐glycolide) microspheres

Poly(5‐benzyloxy‐trimethylene carbonate‐co‐glycolide) random copolymers were synthesized through the ring‐opening polymerization of 5‐benzyloxy‐trimethylene carbonate and glycolide (GA). The copolymers with different compositions, PBG‐1 with 17% GA units and PBG‐2 with 45% GA units, were obtained. Using these copolymers, microsphere drug delivery systems with submicron sizes were fabricated using an “ultrasonic assisted precipitation method.” The in‐vitro drug release from these microspheres was investigated. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Hydrolysis‐improved thermosensitive polyorganophosphazenes with α‐amino‐ω‐methoxy‐poly(ethylene glycol) and amino acid esters as side groups

A series of hydrolysis‐improved thermosensitive polyorganophosphazenes with α‐amino‐ω‐methoxy‐poly(ethylene glycol) (AMPEG) and amino acid esters (AAEs) of ‘N,N‐systems’ was synthesized, and their properties were evaluated in comparison with the thermosensitive polyorganophosphazenes with methoxy‐poly(ethylene glycol) (MPEG) and AAEs of ‘O,N‐systems’, by means of ³¹P NMR spectroscopy, gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). Most of the present polymers showed a lower critical solution temperature (LCST) in the range 32.0–79.0 °C, depending on the kinds of AAE, length of AMPEG and the mol ratio of the two substituents. These polymers exhibited higher LCSTs and faster degradation rates than the MPEG‐based polymers. The aqueous solution of poly(ethyl glycinate phosphazene)‐graft‐poly(ethylene glycol) [NP(GlyEt)_0.94(AMPEG350)_1.06]_n did not show an LCST, which is presumed to be due to its high hydrophilicity, in contrast to [NP(GlyEt)_1.01(MPEG350)_0.99]_n which showing an LCST at 77.5 °C. On the other hand, the polymers with a high content of AAE or with hydrophobic amino acids such as L ‐aspartic acid and L ‐glutamic acid, have shown a similar LCST to those of the MPEG‐based polymers. The half‐lives (t_1/2) for hydrolysis of [NP(AMPEG350)_1.06(GlyEt)_0.94]_n at pH 5, 7.4 and 10 were 9, 16, and 5 days, respectively, which are almost 2.5 to 4 times faster than that of the MPEG‐based polymers. The LCST of the present N,N‐polymers has been shown to be more influenced by salts such as NaCl (‘salting‐out’ effect) and tetrapropylammonium bromide (TPAB) (‘salting‐in’ effect) compared with the ‘O,N‐system’. Such differences of the ‘N,N‐systems’ from the ‘O,N‐systems’ in thermosensitivity, hydrolysis behavior and salt effect seem to be due to the higher hydrophilicity of the amino group in AMPEG. Copyright © 2005 Society of Chemical Industry     

Cephazoline sodium release from poly(N‐isopropyl acrylamide‐co‐N,N‐dimethylacrylamide) hydrogels

Hydrogels are hydrophilic polymers that swell to an equilibrium volume in the presence of water, preserving their shape. The dynamic swelling behavior of poly(N‐isopropylacrylamide‐co‐N,N‐dimethylacrylamide) [poly(NIPA‐co‐DMA)] copolymers at 37°C was investigated. It was observed that the swelling degree in the copolymers decreases with the N‐isopropylacrylamide content. In addition, the liberation mechanism was found to be Fickian. Diffusion coefficients according to Fick′s law as a function of the N‐isopropylacrylamide concentration and results of the release process are reported. The kinetics of cephazoline sodium release from poly(NIPA‐co‐DMA) hydrogels with different compositions was studied. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 91: 3433–3437, 2004     

Non‐catalyst synthesis and in vitro drug release property of poly(5,5‐dimethyl‐1,3‐dioxan‐2‐one)‐block‐methoxy poly(ethylene glycol) copolymers

A series of poly(5,5‐dimethyl‐1,3‐dioxan‐2‐one)‐block‐methoxy poly(ethylene glycol) (PDTC‐b‐mPEG) copolymers were synthesized by the ring‐opening polymerization of 5,5‐dimethyl‐1,3‐dioxan‐2‐one (DTC) in bulk, using methoxy poly(ethylene glycol) (mPEG) as initiator without adding any catalysts. The resulting copolymers were characterized by Fourier transform infrared spectra, ¹H NMR and gel permeation chromatography. The influences of some factors such as the DTC/mPEG molar feed ratio, reaction time and reaction temperature on the copolymerization were investigated. The experimental results showed that mPEG could effectively initiate the ring‐opening polymerization of DTC in the absence of catalyst, and that the copolymerization conditions had a significant effect on the molecular weight of PDTC‐b‐mPEG copolymer. In vitro drug release study demonstrated that the amount of indomethacin released from PDTC‐b‐mPEG copolymer decreased with increase in the DTC content in the copolymer. © 2013 Society of Chemical Industry     

Mechanical properties of poly(N‐isopropyl‐acrylamide‐co‐itaconic acid) hydrogels

Hydrogels of N‐isopropylacrylamide and itaconic acid were synthesized with different monomer ratios and with two crosslinking agent concentrations. The different xerogels were immersed in water and the swelling process was conducted up to equilibrium conditions at two temperatures (22 and 37°C). These temperatures are lower and higher than the transition temperature shown by PNIPA hydrogels. The mechanical properties of the different solvated hydrogels were examined by oscillatory shear measurements at 22 and 37°C. The copolymer volume fraction and the elastic storage modulus of the hydrogels decreased as the itaconic acid percentage in the copolymer increased. This behavior was attributed to the higher hydrophilic character of the itaconic acid comonomer. Effective crosslinking density, molar mass between crosslinks, and the polymer–solvent interaction parameter were determined from the experimental values of the elastic storage moduli and the copolymer volume fractions. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 85: 2540–2545, 2002     

Synthesis,self‐assembly,and drug release behavior of star‐shaped poly(ε‐caprolactone)‐b‐poly(ethylene oxide) block copolymer with porphyrin core

A serial of star‐shaped poly(ε‐caprolactone)‐b‐poly(ethylene oxide) (SPPCL‐b‐PEO) block copolymers with porphyrin core were successfully synthesized from ring‐opening polymerization (ROP) of ε‐caprolactone (CL) initiated with porphyrin core, followed by coupling reaction with a hydrophilic polymer poly(ethylene oxide) (PEO) shell. The structure of this novel copolymer were synthesized and thoroughly characterized by Nuclear Magnetic Resonance (NMR), Gel Permeation Chromatography (GPC), Fourier Transform Infrared Spectroscopy (FTIR). Notably, the as‐prepared porphyrin‐cored star‐shaped copolymer could self‐assembly into different structures determined by transmission electron microscopy (TEM) and dynamic lighting scattering (DLS), which provides the great potential of using this well‐defined photodynamic therapy material for drug delivery system. Particularly, the doxorubicin‐loaded SPPCL‐b‐PEO nanosphere exhibits property of pH‐induced drug release. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40996.     

Thermoreversible hydrogels. XVIII. Synthesis,swelling characteristics,and diffusion behaviors of porous,ionic, thermosensitive hydrogels

Porous, ionic, thermosensitive hydrogels were prepared from N‐isopropylacrylamide, a cationic monomer [trimethyl (acrylamido propyl) ammonium iodide (TMAAI)], an anionic monomer [acrylic acid (AA)], a zwitterionic monomer [N′,N′‐dimethyl (acrylamido propyl) ammonium propane sulfonate], or a nonionic monomer [poly(ethylene glycol) methyl ether acrylate], and a pore‐forming agent [poly(ethylene glycol) (PEG)] of different molecular weights. Some fundamental properties and dynamic swelling kinetic parameters and solute permeation for these porous gels were investigated. The results showed that the gel containing the cationic monomer TMAAI had a higher equilibrium swelling ratio. The diffusion coefficients showed that the swelling rates for the gels with the anionic monomer AA and PEG with a higher molecular weight (20,000) were faster. The results showed that the fast swelling–deswelling behavior for the porous structure gels was due to them being more available than the gels with long hydrophilic side chains. In addition, the interactive force between the solutes and gels and the solute permeation through the porous gels were investigated. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 2214–2223, 2003     

Thermosensitive and hydrolysis‐sensitive poly(organophosphazenes)

The lower critical solution temperature (LCST) properties and hydrolytic behaviour of thermosensitive biodegradable polyphosphazenes with monomethoxy‐poly(ethylene glycol), glycine ethyl ester and depsipeptide ethyl esters substituents have been studied. All the polymers synthesized show LCST properties. The LCSTs of the polymers are affected by the composition of the polymers and increase with the degradation of the polymers in aqueous solution. The higher content of depsipeptide ethyl esters in the polymers accelerates the LCST change and the degradation of the polymers in aqueous solution. Most polymers synthesized have half‐lives of less than 10 days in neutral solution. © 2002 Society of Chemical Industry     

Poly(N-isopropylacrylamide)/mesoporous silica thermosensitive composite hydrogels for drug loading and release

Temperature-sensitive hydrogels are attracting increasing attention for controlled drug delivery. However, achieving high drug loadings and sustained drug release remains challenging. Herein, we describe the successful synthesis of a series of novel temperature-sensitive poly(N-isopropylacrylamide) (PNIPA)/mesoporous silica nanoparticles (MSN) hydrogels by physical crosslinking of NIPA with MSN. The external and internal structures, temperature sensitivity, drug-loading capacity, and blood compatibility of the PNIPA/MSN composite hydrogels are studied. Results show that MSN addition improved the network structure and adjusted the size of the hole, MSN could also act as drug carrier, thereby enhancing the drug loading capacity. The composite hydrogels underwent a phase transition at 33.7 °C (at the lower critical solution temperature). The hemolysis rate of the composite hydrogels was less than 1%, thus they can be classified as a nonhemolytic materials with good biocompatibility. The composite hydrogels reported here thus have great potential in drug transport and temperature-activated drug release. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48391.     

Thermally crosslinked anionic hydrogels composed of poly(vinyl alcohol) and poly(γ‐glutamic acid): Preparation,characterization, and drug permeation behavior

pH‐sensitive anionic hydrogels composed of poly(vinyl alcohol) (PVA) and poly(γ‐glutamic acid) (γ‐PGA) were prepared by the freeze drying method and thermally crosslinked to suppress hydrogel deformation in water. The physical properties, swelling, and drug‐diffusion behaviors were characterized for the hydrogels. In the equilibrium swelling study, PVA/γ‐PGA hydrogels shrunk in pH regions below the pK_a (2.27) of γ‐PGA, whereas they swelled above the pK_a. In the drug‐diffusion study, the drug permeation rates of the PVA/γ‐PGA hydrogels were directly proportional to their swelling behaviors. The cytocompatibility test showed no cytotoxicity of the PVA/γ‐PGA hydrogels for the 3T3 fibroblast cell lines. The results of these studies suggest that hydrogels prepared from PVA and γ‐PGA could be used as orally administrable drug‐delivery systems. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Dynamic swelling behavior of pH‐sensitive anionic hydrogels used for protein delivery

There have been many attempts to use anionic hydrogels as oral protein delivery carriers because of their pH‐responsive swelling behavior. The dynamic swelling behavior of poly(methacrylic acid‐co‐methacryloxyethyl glucoside) and poly(methacrylic acid‐g‐ethylene glycol) hydrogels was investigated to determine the mechanism of water transport through these anionic hydrogels. The exponential relation M_t/M_∞ = ktⁿ (where M_t is the mass of water absorbed at time t and M_∞ is the mass of water absorbed at equilibrium) was used to calculate the exponent (n) describing the Fickian or non‐Fickian behavior of swelling polymer networks. The mechanism of water transport through these gels was significantly affected by the pH of the swelling medium. The mechanism of water transport became more relaxation‐controlled in a swelling medium of pH 7.0, which was higher than pK_a of the gels. The experimental results of the time‐dependent swelling behaviors of the gels were analyzed with several mathematical models. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 1606–1613, 2003