Comparison of poly(aspartic acid) hydrogel and poly(aspartic acid)/gelatin complex for entrapment and pH‐sensitive release of protein drugs

Biodegradable poly(aspartic acid) (PASP) hydrogel and PASP/gelatin complex were prepared to evaluate their potential application as pH‐sensitive matrices for controlled protein release. Entrapment of myoglobin (Mb) and its release were compared between the two types of carriers. It was found that incorporation of Mb into PASP hydrogel strongly depended on the medium pH and NaCl concentration, and was time‐consuming. However, complete entrapment of Mb into PASP/gelatin complex was found within pH ranged from 2.5 to 4.0, which was concomitant with the formation of PASP/gelatin complex. By adjusting Mb feed ratio, Mb entrapment in the complex can be up to 31.54% (by weight) with high loading efficiency (96.2%). Gradual release of Mb from PASP hydrogel was observed within pH 2.0–7.4, while Mb release from PASP/gelatin complex was negligible within pH 2.0–4.2 for 4 days. In addition, pulsatile Mb release can be achieved by combining polyanhydride with pH‐sensitive PASP/gelatin complex, while the device composed of polyanhydride and PASP hydrogel is mechanically unstable. PASP/gelatin complex formed by electrostatic interactions is superior to the single‐component PASP hydrogel synthesized by chemical cross‐linking as pH‐sensitive matrices for controlled protein release when entrapment of proteins and pH‐sensitivity of protein release are concerned. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci, 2006     

Synthesis and characterization of chitosan/poly(acrylic acid) polyelectrolyte complex

Polyelectrolyte complex based on chitosan and acrylic acid monomer by photoinitiated free‐radical polymerization in the absence of crosslinker showed a large transition in swelling in response to changes in pH of surrounding medium. Their ability to swell arises from polyelectrolyte interactions and molecular structure of the complex. The main properties of interest that related to the molecular structure, swelling volumes, glass transition temperature, and elastic modulus of the complex were investigated. The effect of water content, the only variable in the sample component, played an important role in molecular structure of the complex and as a consequence, the extent of intermolecular linkage, especially amide bonds which in turn governed the degree of swelling of the polyelectrolyte complex in this study. The decreased degree of swelling and higher temperature shift of glass transition temperature was found with increased water content, whereas increased modulus of elasticity of dry complex was found in lower water content of synthesis component. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 83: 1025–1035, 2002     

Thermo‐ and pH‐responsive microgels for controlled release of insulin

Microgel particles were prepared, made of hydroxypropylcellulose‐graft‐(acrylic acid) (HPC‐g‐AA) and acrylic acid(AA). The particles undergo reversible volume phase transitions in response to both pH and temperature changes while keeping the inherent properties of PAA and HPC‐g‐AA. Dynamic light scattering measurements reveal that the average hydrodynamic radius and hydrodynamic radius distributions of the microgel particles depend on temperature and pH. The microgels exhibit excellent pH sensitivity and a higher swelling ratio at higher pH in aqueous solution. In vitro release study shows that the amount of insulin released from the microgels is less at pH = 1.2 than at pH = 6.8. The results indicate that the resultant microgels seem to be of great potential for intelligent oral drug delivery. Copyright © 2012 Society of Chemical Industry     

pH‐responsive hydrogels with dispersed hydrophobic nanoparticles for the delivery of hydrophobic therapeutic agents

To investigate the delivery of hydrophobic therapeutic agents, a new class of polymer carriers was synthesized. These carriers are composed of two components: (i) a pH‐responsive hydrogel composed of methacrylic acid grafted with poly(ethylene glycol) tethers, P(MAA‐g‐EG), and (ii) hydrophobic poly(methyl methacrylate) (PMMA) nanoparticles. Before the P(MAA‐g‐EG) hydrogel was crosslinked, PMMA nanoparticles were added to the solution and upon exposure to UV light they were photoencapsulated throughout the P(MAA‐g‐EG) hydrogel structure. The pH‐responsive behavior of P(MAA‐g‐EG) is capable of triggered release of a loaded therapeutic agent, such as a low molecular weight drug or protein, when it passes from the stomach (low pH) to upper small intestine (neutral pH). The introduction of PMMA nanoparticles into the hydrogel structure affected the swelling behavior, therapeutic agent loading efficiency, and solute release profiles. In equilibrium swelling conditions the swelling ratio of nanoparticle‐containing hydrogels decreased with increasing nanoparticle content. Loading efficiencies of the model therapeutic agent fluorescein ranged from 38% to 51% and increased with increasing hydrophobic content. Release studies from neat P(MAA‐g‐EG) and the ensuing P(MAA‐g‐EG) hydrogels containing nanoparticles indicated that the transition from low pH (2.0) to neutral pH (7.0) triggered fluorescein release. Maximum fluorescein release depended on the structure and hydrophobicity of the carriers used in these studies. Copyright © 2012 Society of Chemical Industry     

Temperature‐dependent permeability of polyelectrolyte complex capsule membranes having N‐isopropylacrylamide domains

As a microcapsule with temperature sensitivity, poly(methacrylic acid)–polyethylenimine complex capsules containing N‐isopropylacrylamide units were designed. Two kinds of copolymers of methacrylic acid and N‐isopropylacrylamide were synthesized by free‐radical copolymerization. Partly crosslinked poly(methacrylic acid)–polyethylenimine complex capsules containing the methacrylic acid–N‐isopropylacrylamide copolymers were prepared at 40 or 25°C. The permeation of phenylethylene glycol through the capsule membranes was investigated. Permeability of the capsules prepared at 25°C increased monotonously with increasing temperature from 10 to 50°C. Permeability of the capsules prepared at 40°C also increased with increasing temperature up to 25°C but decreased above 30°C. Also, the degree of swelling of the membranes prepared at 40°C decreased above 30°C. Differential scanning calorimetry measurement showed that N‐isopropylacrylamide units underwent more efficient transition in the capsule membranes prepared at 40°C than in the membranes prepared at 25°C. The capsule membranes prepared at 40°C might have domains in which N‐isopropylacrylamide units are concentrated, whereas these units should distribute uniformly in the capsule membranes made at 25°C. Such a difference in distribution of N‐isopropylacrylamide units might result in the different permeation property of the capsule membranes. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 2703–2710, 2000     

Polyanion/gelatin complexes as pH‐sensitive gels for controlled protein release

Polyanion/gelatin complexes including poly(methacrylic acid) (PMAA)/gelatin, poly(acrylic acid) (PAA)/gelatin, and heparin/gelatin are investigated as pH‐sensitive gels for controlled protein release. Polyanions can interact with gelatin and form amorphous precipitates within a certain pH range, which is affected by the polyanion nature. The entrapment efficiency of model proteins (myoglobin, cytochrome c, and pepsin) into the complexes is rather high (>80%). By using a modified colloid titration that mixes a solution of gelatin and model proteins titrated with polyanion solution, myoglobin and cytochrome c are found to interact with polyanions by electrostatic forces at low pH, while pepsin either interacts with the polyanion when the pH is below its isoelectric point (IEP) or complexes with gelatin at a pH above IEP_pepsin. At pH 7.4 all the complexes dissociate and proteins are rapidly released within a few hours. The complexes are stable and the proteins are retained within a certain pH range, which is related to the polyanion type (e.g., 5.0–2.0 for PMAA, 4.6–1.2 for PAA, and <4.3 for heparin). The three processes of complex formation, dissociation, and protein release have a good correlation. In addition, the protein release transition takes place within a rather narrow pH range (ca. 0.5 units) and the protein nature has little effect on the protein release profile. The high protein entrapment efficiency and good pH sensitivity of the protein release can be mainly attributed to the electrostatic attractive interactions between proteins and polyanion or gelatin. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 80: 1416–1425, 2001     

Preparation of pH‐responsive crosslinked materials from natural rubber and poly(4‐vinylpyridine)

Stimuli‐responsive elastomers are smart materials for sensing applications. Natural rubber (NR) is a renewable elastomer with excellent elasticity and fatigue resistance. In this work, a straightforward method for the preparation of pH‐responsive crosslinked materials from NR and poly(4‐vinylpyridine) (P4VP) via free radical crosslinking reaction using benzoyl peroxide (BPO) as an initiator is described. The effects of P4VP and BPO concentrations, reaction time and reaction temperature on immobilization percentage were investigated. It was found that the immobilization percentage reached 90% when using a P4VP concentration of 150 phr and a BPO concentration of 10 phr for 24 h at 90 °C. The pH responsiveness of the crosslinked materials was studied via water swelling, water contact angle and dye release measurements. Unlike unmodified rubber, the P4VP‐crosslinked NR was found to be pH‐responsive in acidic solution. Indigo carmine adsorption studies showed the Langmuir isotherm suggesting monolayer coverage of dye on the rubber surface. The dye could also be released upon increasing the pH of solution above 4. Based on these results, the introduction of pH responsiveness to NR will lead to novel responsive rubber‐based materials that can be used in biomedical and sensing applications. © 2016 Society of Chemical Industry     

pH‐sensitive shrinking of a dextran sulfate/chitosan complex gel and its promotion effect on the release of polymeric substances

A pH‐sensitive gel was prepared by polyelectrolyte complex formation between dextran sulfate and chitosan. When the complex gel contained more amino groups than sulfate groups, it shrank pronouncedly at around pH 7 in NaCl solutions of various concentrations, probably because of the deionization of protonated amino groups remaining free from electrostatic interaction with the sulfate groups. Using the complex gel loaded with dextran by absorption, releasing behaviors were studied under various conditions. It was shown that shrinking of the complex gel had a promotion effect on the release of dextran. In 170 mM NaCl solution, the complex gel released dextran more rapidly at pH 8 than at pH 2, because the degree of shrinking was greater at pH 8. Thus, the promotion effect of the complex gel on the release of dextran was pH dependent, though the release rates at the two pHs became closer as the average molecular weight of dextran loaded was lowered. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 81: 667–674, 2001     

Synthesis,characterization, and dilute solution properties of pH‐responsive polyacyloylethylpiperazinium polymers

Four different pH‐ and electrolyte‐responsive polymers were synthesized from ethyl piperazine with four different counter ions viz., chloride, bromide, sulfate, and nitrate. IR and NMR spectroscopic techniques confirmed the structure of monomers and polymers. Thermal properties of these polymers were investigated by TGA and DSC analysis. The dilute solution properties in pure water, in inorganic simple salt solutions, and pH‐responsive behavior of these polymers were studied by the measurement of viscosity by Ubbelohde viscometer. Flocculation behavior of these polymers was investigated by turbidity studies with bentonite suspension. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 3174–3186, 2006     

Synthesis and characterization of fast responsive thermo‐ and pH‐sensitive poly[(N,N‐diethylacrylamide)‐co‐(acrylic acid)] hydrogels

BACKGROUND: A considerable amount of research has been focused on smart hydrogels that can respond to external environmental stimuli, especially temperature and pH. In this study, fast responsive thermo‐ and pH‐sensitive poly[(N,N‐diethylacrylamide)‐co‐(acrylic acid)] hydrogels were prepared by free radical copolymerization in aqueous solution using poly(ethylene glycol) (PEG) as a pore‐forming agent. RESULTS: Swelling studies showed that the hydrogels produced had both temperature and pH sensitivity. The deswelling kinetics at high temperature demonstrated that the shrinking rates were influenced by the addition of the pore‐forming agent and the amount of acrylic acid in the initial total monomers. The deswelling curves in low‐buffer solutions had two stages. Pulsatile swelling studies indicated that the PEG‐modified hydrogels were superior to the normal ones. These different swelling properties were further confirmed by the results of scanning electron microscopy. CONCLUSION: Such fast responsive thermo‐ and pH‐sensitive hydrogels are expected to be useful in biomedical fields for stimuli‐responsive drug delivery systems. Copyright © 2008 Society of Chemical Industry     

Controlled heparinase‐catalyzed degradation of polyelectrolyte multilayer capsules with heparin as responsive layer

This work describes the enzymatic degradation of combined hollow capsules via layer‐by‐layer (LbL) self‐assembly technique. They previously showed the build‐up and characterization of capsules composed of synthetic [Poly(sodium 4‐styrene‐sulfonate)/Poly(allylamine hydrochloride)] and biodegradable (Heparin/Chitosan) polyelectrolytes. Biocatalytic response of assembled multilayer capsules provides a more functional and oriented approach in controlled release of encapsulated molecules: in this case multilayer capsule was disassembled by heparinase. Morphological change of individual capsule was assessed with Atomic Force Microscopy and Confocal Laser Scanning Microscopy. The sustained release of encapsulated FITC‐Dextran model was realized under enzymatic degradation of the capsule shells by heparinase. The release profile of FITC‐Dextran indicated the successful control in a concentration‐dependent manner, which shows the applicability as smart drug delivery system. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 44916.     

Preparation of fast pH‐responsive ferric carboxymethylcellulose/poly(vinyl alcohol) double‐network microparticles

BACKGROUND: Carboxymethylcellulose (CMC) and poly(vinyl alcohol) (PVA) are biocompatible, and their complex hydrogel shows pH responsiveness. Thus, they are chosen as starting materials to prepare physically dual‐crosslinked Fe‐CMC/PVA microparticles with improved properties. RESULTS: Fe‐CMC/PVA double‐network microparticles were obtained via a facile process under mild conditions. Sodium carboxymethylcellulose was crosslinked with ferric ions to form particles that contained aqueous PVA solution in an emulsion system. The hydrogel particles were then subjected to a freezing–thawing cycle to achieve further crosslinking; the size of the particles formed was in the range 0.2–1.2 µm. The microparticles were capable of maintaining the stability of proteins such as hemoglobin in an acidic environment and exhibited pH‐responsive release behavior. CONCLUSION: The pH responsivity of the Fe‐CMC/PVA physical double‐network microparticles is fast, which is helpful for effectively protecting a loaded bioactive substance. Thus, they may be potential candidates for pH‐sensitive applications. Copyright © 2008 Society of Chemical Industry     

Effect of membrane pore size on the pH‐sensitivity of polyethersulfone hollow fiber ultrafiltration membrane

In our recent study, pH‐sensitive polyethersulfone (PES) hollow fiber membranes were prepared by blending poly (acrylonitrile‐co‐acrylic acid) (PANAA), and the electroviscous effect had great effect on the water flux change. While the question remains: is the water flux change caused by the electroviscous effect for all the membranes with different pore sizes? Herein, pH‐sensitive hollow fiber membranes with different pore sizes were prepared. The pore size and the theoretic water flux were calculated through the ultrafiltration of polyethylene glycol (PEG) solution. Comparing the calculated fluxes and the experimental ones, we found that the water flux change was mainly caused by the pore size change at the pH value larger than pKa, while that was caused by both the pore size change and the electroviscous effect when pH value was smaller than the pKa, and the pore size change was caused by the ionization of the ? COOH in the copolymer. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Characterization of polyelectrolyte effect in poly(acrylic acid) solutions

The viscometric behavior of poly(acrylic acid) solutions, as well as their ion transport properties, were monitored as a function of polymer concentration and the addition of KOH in nonisoionic conditions. Polyelectrolyte effect was studied and characterized by conductivimetry as well as viscometric properties at the infinite dilution limit. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 191–196, 2003     

Dual pH‐ and thermal‐responsive nanocomposite hydrogels for controllable delivery of hydrophobic drug baicalein

Hydrogels have been widely used as mild biomaterials due to their bio‐affinity, high drug loading capability and controllable release profiles. However, hydrogel‐based carriers are greatly limited for the delivery of hydrophobic payloads due to the lack of hydrophobic binding sites. Herein, nano‐liposome micelles were embedded in semi‐interpenetrating poly[(N‐isopropylacrylamide)‐co‐chitosan] (PNIPAAm‐co‐CS) and poly[(N‐isopropylacrylamide)‐co‐(sodium alginate)] (PNIPAAm‐co‐SA) hydrogels which were responsive to both temperature and pH, thereby establishing tunable nanocomposite hydrogel delivery systems. Nano‐micelles formed via the self‐assembly of phospholipid could serve as the link between hydrophobic drug and hydrophilic hydrogel due to their special amphiphilic structure. The results of transmission and scanning electron microscopies and infrared spectroscopy showed that the porous hydrogels were successfully fabricated and the liposomes encapsulated with baicalein could be well contained in the network. In addition, the experimental results of response release in vitro revealed that the smart hydrogels showed different degree of sensitiveness under different pH and temperature stimuli. The results of the study demonstrate that combining PNIPAAm‐co‐SA and PNIPAAm‐co‐CS hydrogels with liposomes encapsulated with hydrophobic drugs is a feasible method for hydrophobic drug delivery and have potential application prospects in the medical field. © 2018 Society of Chemical Industry     

pH‐ and temperature‐induced release of doxorubicin from multilayers of poly(2‐isopropyl‐2‐oxazoline) and tannic acid

We present a simple strategy to prepare doxorubicin (DOX) containing hydrogen‐bonded films of poly(2‐isopropyl‐2‐oxazoline) (PIPOX) and tannic acid (TA) which release DOX in acidic conditions while releasing a minimal amount of DOX at physiological pH. Water soluble complexes of TA and DOX (TA ? DOX) were prepared prior to film construction. PIPOX and TA ? DOX were deposited at the surface at pH 6.5 using the layer‐by‐layer (LbL) technique. We found that multilayers released a minimal amount of DOX at physiological pH due to further ionization of TA with increasing pH and enhanced electrostatic interactions between TA and DOX. In contrast, pH‐induced release of DOX was observed in moderately acidic conditions due to protonation of TA as the acidity increased and electrostatic interactions between TA and DOX decreased. Moreover, we found that raising the temperature from 25 °C to 37.5 °C increased the amount of DOX released from the surface. This can be rationalized with the conformational changes within the multilayers correlated with the lower critical solution temperature behaviour of PIPOX and increased kinetic energy of DOX molecules. Considering the acidic nature of tumour tissues and important biological properties of PIPOX and TA, these multilayers are promising for pH‐ and temperature‐triggered release of DOX from surfaces. © 2017 Society of Chemical Industry     

Fabrication of pH‐responsive molecularly imprinted polyethersulfone particles for bisphenol‐A uptake

pH‐responsive molecularly imprinted particles were successfully fabricated by pore‐filling poly (acrylic acid) (PAA) gels into bisphenol‐A (BPA)‐imprinted polyethersulfone particles. The adsorbed BPA amount (or rate) decreased after filling the PAA gels both for the imprinted and nonimprinted particles. However, it was confirmed that changing the acidity of the solution reversibly controls the rebinding ability toward BPA and that the BPA uptake of the pore‐filled particles exhibited chemical valve behavior at a pH between 3 and 6. This finding can be attributed to the swelling of the PAA gels in the particles. The present methodology provides a simple way to prepare pH‐responsive molecularly imprinted materials and is expandable to the imprinting of other hydrophobic molecules, such as dibenzofuran. Also, the results of this work demonstrate the potential of stimuli‐responsive molecularly imprinted polymer materials as smart chemicals and as drug‐delivery systems. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Synthesis,characteristics, and phase behavior of a thermosensitive and pH‐sensitive polyelectrolyte

A series of poly(N‐isopropylacrylamide‐co‐methacrylic acid‐co‐octadecyl acrylate) (poly(NIPAM‐co‐MAA‐co‐ODA)) with different monomer molar ratios was synthesized. Critical micelle concentration (CMC) of the polyelectrolyte solution was determined and the CMC increase with methacrylic acid content in the polyelectrolyte. The phase behaviors of the polyelectrolyte solution were studied, and the effects of various factors on the phase transition were discussed. The experimental results indicate that the lower critical solution temperature and the phase transition pH depend on the monomer molar ratio in the polyelectrolyte. Effect of polyelectrolyte concentration on phase transition pH was studied, and results shown that the phase‐transition pH is independent of the polyelectrolyte concentration. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Homogeneous complex solution formed through interactions of poly(acrylamide‐co‐acrylic acid)/poly(acrylamide‐co‐dimethyldiallylammonium chloride) complex with M n+ hydration metal ions in aqueous media

A homogeneous complex solution, formed through inter‐polyelectrolyte complexation of poly(acrylamide‐co‐acrylic acid) (P(AM‐AA)) with poly(acrylamide‐co‐dimethyldiallylammonium chloride) (P(AM‐DMDAAC)) and interaction of the P(AM‐AA)/P(AM‐DMDAAC) complex with M ⁿ⁺ hydrated metal ion, was prepared and the structure and properties of the P(AM‐AA)/P(AM‐DMDAAC)/M ⁿ⁺ homogeneous complex solution were studied by UV spectrometry, dynamic light scattering and viscometry. The experimental results show that the homogeneous complex solution can be obtained by controlling the composition of the P(AM‐AA)/P(AM‐DMDAAC) complex and the M ⁿ⁺ metal ion content. Compared to the constituents, ie the P(AM‐AA) solution, the P(AM‐DMDAAC) solution and the P(AM‐AA)/P(AM‐DMDAAC) complex solution, the P(AM‐AA)/P(AM‐DMDAAC)/M ⁿ⁺ complex solution has a new peak at 270 nm in its UV spectrum, a larger hydrodynamic radius, and hence a higher solution viscosity, all of which indicate that there exist specific interactions between polymers and M ⁿ⁺ metal ions. These interactions lead to the formation of a network structure and hence an obvious increase not only in solution viscosity but also in resistance of the polymer solution to simple salts, to temperature changes and to shearing. © 2001 Society of Chemical Industry     

Chitosan–polyelectrolyte complexation for the preparation of gel beads and controlled release of anticancer drug. II. Effect of pH‐dependent ionic crosslinking or interpolymer complex using tripolyphosphate or polyphosphate as reagent

Chitosangel beads were prepared using an in‐liquid curing method by ionotropic crosslinking or interpolymer linkage with tripolyphosphate (TPP) or polyphosphate (PP). The ionic interaction of chitosan with TPP or PP is pH‐dependent due to the transition of “ladder‐loop” complex structures. Chitosan gel beads cured in a pH value lower than 6 of a TPP solution was a controlled homogeneous ionic‐crosslinking reaction, whereas chitosan gel beads cured in a lower pH PP solution was a nonhomogeneous interpolymer complex reaction due to the mass‐transfer resistance for the diffusion of macromolecular PP. According to the results of FTIR and EDS studies, it was suggested that significantly increasing the ionic‐crosslinking density or interpolymer linkage of a chitosan–TPP or chitosan–PP complex could be achieved by transferring the pH value of curing agent, TPP or PP, from basic to acidic. The swelling behavior of various chitosan beads in acid medium appeared to depend on the ionic‐crosslinking density or interpolymer linkage of the chitosan–TPP or chitosan–PP complex, which were deeply affected by the in‐liquid curing mechanism of the chitosan gel beads. By the transition of the in‐liquid curing mechanism, the swelling degree of chitosan–TPP or chitosan–PP beads was depressed and the disintegration of chitosan–TPP or chitosan–PP beads did not occur in strong acid. The drug‐release patterns of the modified chitosan gel beads in simulated intestinal and gastric juices were sustained for 20 h. These results indicate that the sustained release of anticancer drugs could be achieved due to the variation of the reaction mechanism of a chitosan–polyelectrolyte pH‐dependent ionic interaction. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 1093–1107, 1999