Novel thermosensitive hydrogel composites based on poly(d,l‐lactide‐co‐glycolide) nanoparticles embedded in poly(n‐isopropyl acrylamide) with sustained drug‐release behavior

To reach sustained drug release, a new composite drug‐delivery system consisting of poly(d,l ‐lactide‐co‐glycolide) (PLGA) nanoparticles (NPs) embedded in thermosensitive poly(N‐isopropyl acrylamide) (PNIPAAm) hydrogels was developed. The PNIPAAm hydrogels were synthesized by free‐radical polymerization and were crosslinked with poly(ethylene glycol) diacrylate, and the PLGA NPs were prepared by a water‐in‐oil‐in‐water double‐emulsion solvent‐evaporation method. The release behavior of the composite hydrogels loaded with albumin–fluorescein isothiocyanate conjugate was studied and compared with that of the drug‐loaded neat hydrogel and PLGA NPs. The results indicate that we could best control the release rate of the drug by loading it to the PLGA NPs and then embedding the whole system in the PNIPAAm hydrogels. The developed composite hydrogel systems showed near zero‐order drug‐release kinetics along with a reduction or omission of initial burst release. The differential scanning calorimetry results reveal that the lower critical solution temperature of the developed composite systems remained almost unchanged (<1°C increase only). Such a characteristic indicated that the thermosensitivity of the PNIPAAm hydrogel was not distinctively affected by the addition of PLGA NPs. In conclusion, an approach was demonstrated for the successful preparation of a new hybrid hydrogel system having improved drug‐release behavior with retained thermosensitivity. The developed systems have enormous potential for many biotechnological applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40625.     

Poly(N‐isopropylacrylamide‐co‐sodium acrylate) hydrogels: Interactions with surfactants

Poly(N‐isopropylacrylamide‐co‐sodium acrylate) [poly(NIPAM‐co‐SA)] hydrogels were modified with three different kind of surfactants (cationic, anionic, and nonionic) to study the effect on the swelling properties. The structural variation of the surfactant‐modified hydrogels was investigated in detail. The interaction between the surfactants and the hydrogel varies and strictly depends on the surfactant type. The variation in thermal stability of the modified surfactant hydrogels was investigated and compared with unmodified hydrogel. Further, the hydrogel swelling/diffusion kinetic parameters were investigated and diffusion of water into hydrogel was found to be of the non‐Fickian transport mechanism. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 3423–3430, 2007     

Temperature‐responsiveness and sustained delivery properties of macroporous PEG‐co‐PNIPAAm‐co‐PCL hydrogels

A series of novel thermosensitive macroporous poly (ethylene glycol) (PEG)‐co‐poly(N‐isopropylacrylamide) (PNIPAAm)‐co‐poly (ε‐caprolactone) (PCL) hydrogels were synthesized via in situ free radical polymerization. Poly(ethylene glycol diacrylate) (PEGDAc) and poly(ε‐caprolactone diacrylate) (PCLDAc) were prepared as macrocrosslinkers. All compounds were investigated by Nuclear Magnetic Resonance (NMR) and Fourier transform‐infrared spectroscopy (FT‐IR). Differential Scanning Calorimetry (DSC) results showed the lower critical solution temperatures (LCSTs) of the gels were at around 31°C. The macroporous gels not only had considerable swelling ratios, but also exhibited rapid swelling kinetics and response sensitivity. Above mentioned hydrogels showed a remarkable oscillatory swelling–deswelling transition, making them have potential application in long‐term drug delivery. POLYM. ENG. SCI., 55:223–230, 2015. © 2014 Society of Plastics Engineers     

Preparation and characterization of pH‐ and temperature‐responsive semi–interpenetrating polymer network hydrogels based on linear sodium alginate and crosslinked poly(N‐isopropylacrylamide)

In this study, pH‐ and temperature‐responsive hydrogels based on linear sodium alginate (SA) and crosslinked poly(N‐isopropylacrylamide) (PNIPAAm) were prepared by semi‐interpenetrating network (semi‐IPN) technique. The dually responsive hydrogels were characterized by FTIR, DSC, and SEM, and their temperature‐ and pH‐responsive behaviors were investigated by measuring equilibrium swelling ratios and pulsatile swelling experiments. The results showed that these hydrogels underwent volume phase transition at around 33°C irrespective of the pH value of the medium, but their pH sensitivity was evident only below their volume phase transition temperature. Under basic conditions, the swelling ratios of SA/PNIPAAm semi‐IPN hydrogels were greater than that of pure PNIPAAm hydrogel and increased with increasing SA content incorporated into the hydrogels, but the case was inverse under acidic conditions. The pulsatile swelling experiments indicated that the higher the SA content in SA/PNIPAAm semi‐IPN hydrogels, the faster the response rate to both pH and temperature change. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 97: 1931–1940, 2005     

Syntheses,characterization, and antibacterial activity of chitosan grafted hydrogels and associated mica‐containing nanocomposite hydrogels

Chitosan (CS) grafted poly[(acrylic acid)‐co‐(2‐hydroxyethyl methacrylate)] (CS‐g‐poly(AA‐co‐HEMA)) at different molar ratios of AA and HEMA, and the associated nanocomposite hydrogels of CS‐g‐poly(AA‐co‐HEMA)/mica were synthesized by radical copolymerization. The grafting positions at the amino or hydroxyl groups in the CS were identified by Fourier transform infrared spectroscopy. CS‐g‐poly(AA‐co‐HEMA) hydrogels were intercalated in the mica and the amount of hydrogel insertion did not affect the spacing of the silicate layers in mica. The higher mica loadings produced a rougher surface of the nanocomposite hydrogel. The water absorbency of the CS‐g‐poly(AA‐co‐HEMA)/mica nanocomposite hydrogels decreased with increasing levels of mica loading to a lower level than those of the CS‐g‐poly(AA‐co‐HEMA) hydrogels. Both CS‐g‐poly(AA) and CS‐g‐poly(AA‐co‐HEMA)/mica nanocomposite hydrogels exhibited a higher antiproliferative activity against Staphylococcus aureus than did the neat CS hydrogel with CS‐g‐poly(AA) revealing a very pronounced minimum inhibition concentration (MIC) of 1.56 mg mL^?1. The extent of mica loading in the CS‐g‐poly(AA‐co‐HEMA) nanocomposite hydrogels did not affect the MIC (12.5 mg mL^?1). © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Preparation,characterization, and drug‐release properties of pH/temperature‐responsive poly(N‐isopropylacrylamide)/chitosan semi‐IPN hydrogel particles

Novel poly(N‐isopropylacrylamide) (PNIPAAm)/chitosan (CS) semi‐interpenetrating polymer network hydrogel particles were prepared by inverse suspension polymerization. The prepared particles were sensitive to both temperature and pH, and they had good reversibility in solution at different temperatures and pH values. The swelling ratios of PNIPAAm/CS hydrogel particles decreased slightly with the addition of CS, which did not shift the lower critical solution temperature. The drug‐release behavior of the particles was investigated using cyclic adenosine 3′,5′‐monophosphate (cAMP) as a model drug. The release of cAMP from the hydrogel particles was affected by temperature, pH, and the CS content in the particles. These results showed that semi‐IPN hydrogel particles appeared to be of great promise in pH‐ and temperature‐sensitive oral drug release. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Dual‐responsive semi‐interpenetrating network beads based on calcium alginate/poly(N‐isopropylacrylamide)/poly(sodium acrylate) for sustained drug release

To improve the mechanical strength of natural hydrogels and to obtain a sustained drug‐delivery device, temperature‐/pH‐sensitive hydrogel beads composed of calcium alginate (Ca‐alginate) and poly(N‐isopropylacrylamide) (PNIPAAm) were prepared in the presence of poly(sodium acrylate) (PAANa) with ultrahigh molecular weight (M_η ≥ 1.0 × 10⁷) as a strengthening agent. The influence of PAANa content on the properties, including the beads stability, swelling, and drug‐release behaviors, of the hydrogels was evaluated. Scanning electron microscopy and oscillation experiments were used to analyze the structure and mechanical stability of the hydrogel beads, respectively. The results show that stability of the obtained Ca‐alginate/PNIPAAm hydrogel beads strengthened by PAANa the alginate/poly(N‐isopropyl acrylamide) hydrogel bead (SANBs) was significantly improved compared to that of the beads without PAANa (NANBs) at pH 7.4. The swelling behavior and drug‐release capability of the SANBs were markedly dependent on the PAANa content and on the environmental temperature and pH. The bead sample with a higher percentage of PAANa exhibited a lower swelling rate and slower drug release. The drug release profiles from SANBs were further studied in simulated intestinal fluid, and the results demonstrated here suggest that SANBs could serve as a potential candidate for controlled drug delivery in vivo. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Hollow poly(N‐isopropylacrylamide)‐co‐poly(acrylic acid) microgels with high loading capacity for drugs

A convenient approach has been developed for the preparation of microsize hydrogels composed of crosslinked poly(acrylic acid) (PAA) and poly(N‐isopropylacrylamide) (PNIPAm). First, semi‐interpenetration polymer networks of hydropropylcellulose (HPC) and PNIPAm‐co‐PAA copolymer are formed through the copolymerization and crosslinking of monomer acrylic acid and N‐isopropylacrylamide in HPC aqueous solution. After the selective removal of HPC from networks due to ionization of PAA units and disruption of hydrogen bonding with increasing pH, PNIPAm‐co‐PAA microgels are obtained, whose volume is confirmed to be responsive to both temperature and pH. Doxorubicin hydrochloride (Dox) can be encapsulated in PNIPAm‐co‐PAA microgels with high drug loading driven by the electrostatic interaction, and a sustained‐release characteristic of Dox from the microgels is observed under physiological pH value and temperature. In vitro cell experiments, the drug‐loaded microgels can be taken up by LoVo cells and release their payload in cell cytoplasm without loss of drug efficacy. This indicates that PNIPAm‐co‐PAA microgels might be a potential drug delivery carriers especially for water‐soluble or polypeptide drugs. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Synthesis and swelling behavior of thermosensitive IPN hydrogels based on sodium acrylate and N‐isopropyl acrylamide by a two‐step method

A series of interpenetrating polymer network (IPN) hydrogels having higher swelling ratio (SR) and thermosensitivity were synthesized from sodium acrylate (SA) and N‐isopropyl acrylamide (NIPAAm) by a two‐step method. A series of the porous poly(sodium acrylate ‐co‐1‐vinyl–2‐pyrrolidone) [poly(SA‐co‐VP)], (SV), hydrogels were prepared from acrylic acid having 90% degree of neutralization and VP monomer in the first step. The second step is to immerse the SV dried gels into the NIPAAm solution containing initiator, accelerator, and crosslinker to absorb NIPAAm solution and then polymerized to form the poly(SA‐co‐VP)/poly(NIPAAm) IPN hydrogels (SVN). The effect of the different molar ratios of SA/VP and the content of NIPAAm on the swelling behavior and physical properties of the SVN hydrogels was investigated. Results showed that the SVN hydrogels displayed an obviously thermoreversible behavior when the temperature turns across the critical gel transition temperature (CGTT) of poly(NIPAAm) hydrogel. The pore diameter distributions inside the hydrogel also indicated that the pore sizes inside the SVN hydrogels were smaller than those inside the SV hydrogels. At the same time, the more proportion of SA was added into the hydrogel, the larger pore diameter of the SV hydrogel was formed. The results also showed that the SR decreased with an increase of the VP content in the SV hydrogel and more obviously decreased in the SVN hydrogels. The SVN networks also showed stronger shear moduli than SV hydrogels. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Synthesis of thermoresponsive polymeric micelles of PNIPAAm‐b‐OMMA as a drug carrier for loading and controlled release of prednisolone

We synthesized a drug delivery system of poly(N‐isopropylacrylamide)‐b‐oligo(methyl methacrylate) (PNIPAAm‐b‐OMMA) via polycondensation of two homopolymers in 1,4‐dioxane. The products are characterized by FT‐IR and ¹H‐NMR spectra and TEM. The PNIPAAm‐b‐OMMA copolymer micelles in aqueous solution present the same lower critical solution temperature (LCST) as the unmodified PNIPAAm, owing to the formation of a core–shell micellar structure that the hydrophilic shell shields the hydrophobic inner OMMA core from interacting with water. The micelle carriers exhibit two heterogeneous microdomains: a hydrophobic inner core capable of highly solubilizing hydrophobic prednisolone molecules, plus a hydrated outer shell that stabilizes this micellar structure below its LCST. Moreover, the micelle carriers show reversible thermoresponsive aggregation/dispersion in response to temperature cycles through the LCST. By using the antiinflammation drug prednisolone as model drug, it is found that the PNIPAAm‐b‐OMMA drug carrier could prolong the release time and control the release amount by changing the temperature. Accordingly, this copolymer micelle may provide as an effective drug carrier for drug control and release. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Swelling and hydrolytic degradation behaviour of pH‐responsive hydrogels of poly[(N‐isopropylacrylamide)‐co‐(methacrylic acid)] crosslinked by biodegradable polycaprolactone chains

BACKGROUND: Stimuli‐responsive hydrogels are typically obtained from non‐biodegradable monomers. The use of biodegradable crosslinkers can overcome this limitation. In this context, the main aim of this work was to use modified polycaprolactone as a crosslinker in the preparation of pH‐responsive hydrogels based on N‐isopropylacrylamide and methacrylic acid to give poly[(N‐isopropylacrylamide)‐co‐(methacrylic acid)] (P(N‐iPAAm‐co‐MAA)). RESULTS: Poly(caprolactone) dimethacrylate macromonomer was synthesized and successfully employed as crosslinker with various ratios in the synthesis of well‐known pH‐responsive hydrogels of P(N‐iPAAm‐co‐MAA). The swelling properties of these degradable hydrogels were investigated. They practically do not swell at pH = 2, but exhibit a very high swelling capacity in distilled water and in solutions of pH = 7. In addition, degradation studies at pH = 12 showed that the hydrolysis of the ester groups in the polycaprolactone chains produces, after a relatively short time, the total solubilization of the polymer chains. CONCLUSION: The hydrogels under study have certain characteristics that could make them good candidates for use as matrices in controlled drug delivery. On the one hand, they do not swell in acid pH solution (stomach conditions) but they swell extensively at neutral pH. On the other hand, they became rapidly water soluble following degradation. Copyright © 2009 Society of Chemical Industry     

Thermo‐responsive injectable hydrogel system based on poly(N‐isopropylacrylamide‐co‐vinylphosphonic acid). I. Biomineralization and protein delivery

To achieve the injectable hydrogel system in order to improve bone regeneration by locally delivering a protein drug including bone morphogenetic proteins, thermo‐responsive injectable hydrogels composed of N‐isopropylacrylamide (NIPAAm) and vinyl phosphonic acid (VPAc) were prepared. The P(NIPAAm‐co‐VPAc) hydrogels were also biomineralized by urea‐mediation method to create functional polymer hydrogels that deliver the protein drug and mimic the bone extracellular matrix. The loosely cross‐linked P(NIPAAm‐co‐VPAc) hydrogels were pliable and fluid‐like at room temperature and could be injected through a small‐diameter aperture. The lower critical solution temperature (LCST) of P(NIPAAm‐co‐VPAc) hydrogel was influenced by the monomer ratio of NIPAAm/VPAc and the hydrogel with a 96/4 molar ratio of NIPAAm/VPAc exhibited an LCST of ～34.5°C. Water content was influenced by temperature, NIPAAm/VPAc monomer ratio, and biomineralization; however, all hydrogels maintained more than about 77% of the water content even at 37°C. In a cytotoxicity study, the P(NIPAAm‐co‐VPAc) and biomineralized P(NIPAAm‐co‐VPAc) hydrogels did not significantly affect cell viability. The loading content of bovine serum albumin in hydrogel, which was used as a model drug, gradually increased with the amount of VPAc in the hydrogel owing to the ionic interaction between VPAc groups and BSA molecules. In addition, the release behavior of BSA from the P(NIPAAm‐co‐VPAc) hydrogels was mainly influenced by the drug loading content, water content, and biomineralization of the hydrogels. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Temperature‐induced volume change and glucose sensitivity of poly[(N‐isopropylacry‐ lamide)‐co‐acrylamide‐co‐(phenylboronic acid)] microgels

Nearly monodisperse glucose‐sensitive poly[(N‐isopropylacrylamide)‐co‐acrylamide‐co‐(phenylboronic acid)] microgels were synthesized in aqueous media by the functionalization of poly[(N‐isopropylacrylamide)‐co‐acrylamide‐co‐(acrylic acid)] microgels with 3‐aminophenylboronic acid via carbodiimide coupling. The glucose‐sensitive and thermosensitive behaviour of the microgels was investigated using a dynamic light scattering technique. The introduction of the hydrophobic phenylboronic acid (PBA) group significantly decreases the temperature at which maximum volume change of the resultant microgel particles is observed. The glucose sensitivity of the PBA‐containing microgels relies on the stabilization of the charged phenylborate ions by binding with glucose, which can convert more hydrophobic PBA groups to the hydrophilic phenylborate ions. The effect of pH, ionic strength and PBA content on temperature‐induced volume change and glucose sensitivity was systemically studied. The effect of NaCl on the glucose sensitivity was also investigated at physiological pH and ionic strength. Copyright © 2011 Society of Chemical Industry     

Effect of the SA content of a novel thermo‐sensitive P(NIPAM‐co‐SA) copolymer on denatured lysozyme refolding in vitro

A novel hydrogel of P(NIPAM‐co‐SA) copolymer was synthesized by inverse suspension polymerization by adding sodium acrylate (SA) to improve the phase transition properties of poly(N‐isopropylacrylamide) (PNIPAM). The morphologies, size distribution and thermosensitive characteristics of gel particles were studied and the maximal swelling ratio and LCST (Lower Critical Solution Temperature) of gel particles increased obviously with the addition of SA comonomer. When the protein concentration was 250 μg/mL, the optimized refolding conditions of denatured lysozyme with P(NIPAM‐co‐SA) hydrogel were that operating at the temperature of 35°C and a urea concentration of 2M, in which the mass ratio of P(NIPAM‐co‐SA) hydrogel with 4% SA copolymerized to lysozyme was 10 : 1. Under the optimized conditions, the activity recovery of lysozyme increased to 76.5% assisted by P(NIPAM‐co‐SA) gel particles compared with 55.6% by simple dilution. When refolding finished, the gel particles could be removed and recovered easily and the activity recovery of lysozyme was still as high as 61.5% after reused for 5 batches. With the addition of different amounts of SA comonomer, the hydrophobicity of the copolymer could be varied. Then the copolymerized hydrogel inhibits protein molecules aggregation more effectively through the moderate hydrophobic interactions between copolymers and protein molecules in the course of lysozyme refolding compared with the presence of PNIPAM polymer. All results above demonstrate that the P(NIPAM‐co‐SA) is a cost effective additive with tunable hydrophobicity for application in the refolding of recombinant proteins expressed as inclusion bodies in vitro. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Micelles formed by self‐assembly of hyperbranched poly[(amine‐ester)‐co‐(D,L‐lactide)] (HPAE‐co‐PLA) copolymers for protein drug delivery

BACKGROUND: The aim of the work presented was to synthesize a series of amphiphilic hyperbranched poly[(amine‐ester)‐co‐(D ,L ‐lactide)] (HPAE‐co‐PLA) copolymers and study the formation of copolymeric micelles. These copolymeric micelle systems are expected to be potential candidates for applications in protein drug delivery. RESULTS: The chemical structures of the copolymers were confirmed by Fourier transform infrared spectroscopy, ¹³C NMR and thermogravimetric analysis. Fluorescence spectroscopy and dynamic light scattering confirmed the formation of copolymeric micelles of the HPAE‐co‐PLA copolymers. The maintenance of stability of bovine serum albumin (BSA) during release from micelles in vitro was also measured using circular dichroism and fluorescence spectrometry. CONCLUSION: Novel hyperbranched HPAE‐co‐PLA copolymers have been synthesized. Conjugation of PLA to HPAE was proved to be an available method for the preparation of micelles for protein delivery. The BSA‐loaded micelles showed enhanced encapsulation efficiency and the structural stability of BSA was retained during the release process. The hyperbranched polymeric micelles could be useful as drug carriers for protein drug delivery systems. Copyright © 2008 Society of Chemical Industry     

Poly(N‐isopropylacrylamide‐co‐hydroxyethyl methacrylate) graft copolymers and their application as carriers for drug delivery system

Poly(N‐isopropylacrylamide‐co‐hydroxyethyl methacrylate) [P(NIPAM‐co‐HEMA)] copolymer was synthesized by controlled radical polymerization from respective N‐isopropylacrylamide (NIPAM) and hydroxyethyl methacrylate (HEMA) monomers with a predetermined ratio. To prepare the thermosensitive and biodegradable nanoparticles, new thermosensitive graft copolymer, poly(L ‐lactide)‐graft‐poly(N‐isoporylacrylamide‐co‐hydroxyethyl methacrylate) [PLLA‐g‐P(NIPAM‐co‐HEMA)], with the lower critical solution temperature (LCST) near the normal body temperature, was synthesized by ring opening polymerization of L ‐lactide in the presence of P(NIPAM‐co‐HEMA). The amphiphilic property of the graft copolymers was formed by the grafting of the PLLA hydrophobic chains onto the PNIPAM based hydrophilic backbone. Therefore, the graft copolymers can self‐assemble into uniformly spherical micelles ò about 150–240 nm in diameter as observed by the field emission scanning electron microscope and dynamic light scattering. Dexamethasone can be loaded into these nanostructures during dialysis with a relative high loading capacity and its in vitro release depends on temperature. Above the LCST, most of the drugs were released from the drug‐loaded micelles, whereas a large amount of drugs still remains in the micelles after 48 h below the LCST. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Thermodynamic investigation of thermoresponsive xanthan‐poly (N‐isopropylacrylamide) hydrogels

Polysaccharide‐based hydrogels, such as xanthan maleate/poly(N‐isopropylacrylamide) (PNIPAAm) interpenetrated polymer networks, are thermostimulable materials of interest for the controlled release of biologically active components due to conformation changes at the low critical‐solution temperature (LCST) PNIPAAm phase transition. The phase transition of these interpenetrated polymer network hydrogels, where PNIPAAm is in a ‘confined’ environment, was examined by high resolution magic angle spinning nuclear magnetic resonance and differential scanning calorimetry. High resolution magic angle spinning nuclear magnetic resonance spectroscopy allows the accurate determination of LCST and an evaluation of the corresponding thermodynamic data. More particularly, the evolution of these data as a function of the composition of the hydrogel, and of the external parameters such as pH and ionic strength, was considered. LCST shows a minimal value with increasing xanthan content. Moreover, it was possible to calculate, as a function of temperature, the fraction of NIPAAm which remains uncollapsed. The data obtained for pure PNIPAAm hydrogels are in good agreement with recently published results. The phase transition of PNIPAAm in a diphasic hydrogel is broader when PNIPAAm is ‘confined’ within an interpenetrated polymer network than in a pure PNIPAAm crosslinked network. The widening of the transition with increasing xanthan content indicates a reduction of the PNIPAAm interchain aggregation in a network structure. Copyright © 2011 Society of Chemical Industry     

Temperature/pH‐sensitive comb‐type graft hydrogels composed of chitosan and poly(N‐isopropylacrylamide)

Comb‐type graft hydrogels, composed of chitosan and poly(N‐isopropylacrylamide) (PNIPAAm), were prepared to manifest rapid temperature and pH sensitivity. Instead of directly grafting the NIPAAm monomer onto the chitosan chain, semitelechelic PNIPAAm with carboxyl end group was synthesized by radical polymerization using 3‐mercaptopropionic acid as the chain‐transfer agent, and was grafted onto chitosan having amino groups. The comb‐type hydrogels were prepared with two different graft yields and grafting regions, such as surface‐ and bulk‐grafting, and then compared with a chitosan hydrogel. The synthesis of telechelic PNIPAAm and the formation of amide group were confirmed by using FTIR spectroscopy and gel permeation chromatography. Results from the water state and thermal stability revealed that the introduction of the PNIPAAm side chain disturbed the ordered arrangement of the chitosan molecule, resulting in an increase in the equilibrium water content. Comb‐type graft hydrogels showed rapid temperature and pH sensitivity because of the free‐ended PNIPAAm attached to the chitosan main chain and the chitosan amino group itself, respectively. In particular, the surface graft hydrogel maintained its dimension at low pH, although the chitosan main chain was not crosslinked, whereas chitosan and bulk graft hydrogel were dissolved as a result of the coating effect of pH‐independent PNIPAAm. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 2612–2620, 2004     

Synthesis and characterization of a novel stimuli‐responsive magnetite nanohydrogel based on poly(ethylene glycol) and poly(N‐isopropylacrylamide) as drug carrier

A novel stimuli‐responsive magnetite nanohydrogel (MNHG), namely [poly(ethylene glycol)‐block‐poly(N‐isopropylacrylamide‐co‐maleic anhydride)₂]‐graft‐poly(ethylene glycol)/Fe₃O₄ [PEG‐b‐(PNIPAAm‐co‐PMA)₂]‐g‐PEG/Fe₃O₄, was successfully developed. For this purpose, NIPAAm and MA monomers were block copolymerized onto PEG‐based macroinitiator through atom transfer radical polymerization technique to produce PEG‐b‐(PNIPAAm‐co‐PMA)₂. The synthesized Y‐shaped terpolymer was crosslinked through the esterification of maleic anhydride units using PEG chains to afford a hydrogel. Afterward, magnetite nanoparticles were incorporated into the synthesized hydrogel through the physical interactions. The chemical structures of all synthesized samples were characterized using Fourier transform infrared and proton nuclear magnetic resonance spectroscopies. Morphology, thermal stability, size, and magnetic properties of the synthesized MNHG were investigated. In addition, the doxorubicin hydrochloride loading and encapsulation efficiencies as well as stimuli‐responsive drug release ability of the synthesized MNHG were also evaluated. The drug‐loaded MNHG at physiological condition exhibited negligible drug release values. In contrast, at acidic (pH 5.3) condition and a little bit higher temperature (41 °C) the developed MNHG showed higher drug release values, which qualified it for cancer chemotherapy due to especial physiology of cancerous tissue in comparison with the surrounding normal tissue. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46657.     

Compressive moduli and network parameters of N‐isopropylacrylamide hydrogels copolymerized by monoesters of itaconic acid and crosslinked with tetraallylammonium bromide

The present study focuses on the mechanical properties of hydrophilically or hydrophobically modified poly(N‐isopropylacrylamide) (PNIPAAm) hydrogels, and all discussions on their improved mechanical strengths are based on the conformational effects of hydrophobic side chains attached to the comonomers and the structural differences between the crosslinkers. Three different types of monoalkyl itaconates, bearing octyl (Oc), cetyl (Ce), and cyclohexyl (CH) groups as comonomers, were used to prepare the copolymeric PNIPAAm hydrogels crosslinked with N,N′‐methylenebisacrylamide (BIS) and tetraallylammonium bromide (TAB) as neutral tetrafunctional and ionic octafunctional crosslinkers, respectively. The most striking result is the compressive E modulus of TAB‐crosslinked PNIPAAm hydrogel containing 10 mol % of mOcI. It reaches nearly 1.0 MPa and is independent of the temperature and pH of the swelling/shrinking medium. The result was discussed in terms of the inter/intramolecular interactions between hydrophobic octyl groups adopting a rod‐like conformation in the case of 25 °C/distilled deionized water (DDW) and 37 °C/DDW combinations. Further, it was observed that the electrostatic repulsive forces between the carboxylate groups on mOcI units could be suppressed even at 37 °C and pH 9 due to the rod‐like conformations of C₈H₁₇ groups. Its micrographs under bright‐field and polarized light supported the presence of an ordered anisotropic phase and multiple associations of extended, hydrophobic side chains. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45039.