Luminescent N-isopropylacrylamide–surfmer copolymer hydrogels prepared upon electrostatic self-assembly of 1-pyrenesulfonate

The preparation of luminescent hydrogels based on the electrostatic self-assembly of 1-pyrenesulfonate (PyS) anions in a positively charged N-isopropylacrylamide (NiPAAm)/surfmer copolymer gel is described. The hydrogels were prepared from a micellar aqueous solution of 11-acryloyloxyundecyltrimethylammonium bromide and NiPAAm upon ⁶⁰Co-gamma irradiation. For assembly of PyS, the gel was shrunken at 50 °C and re-swollen at 20 °C in an aqueous solution of sodium 1-pyrenesulfonate. Re-swelling was accompanied by electrostatic assembly of PyS anions within the gel. Subsequently, the excess non-bound PyS ions were removed by repeatedly swelling and shrinking the gel in pure water at 20 °C and 50 °C, respectively. Incorporation of PyS ions in the hydrogel was studied using UV/Vis spectroscopy and energy dispersive x-ray (EDX) measurements. The amount of electrostatically adsorbed PyS was found to be proportional to the amount of copolymerized surfmer. EDX studies indicated that 20% of the bromide counterions were replaced for PyS. The PyS counterions could be released again if the functionalized hydrogel was immersed in acidified water. At a pH of 1, an almost complete release of PyS was found after 250 h. The preparation method can be used to introduce a variety of functional properties in thermoresponsive charged copolymer gels.     

Novel crosslinked thermoresponsive hydrogels with controlled poly(ethylene glycol)—poly(propylene glycol) multiblock copolymer structure

New thermoresponsive crosslinked hydrogels with controlled multiblock copolymer structure were prepared from equimolar amounts of α,ω-diamino poly(propylene glycol)s with molecular weights (MW) 230, 400, and 2,000 g mol^?1 and diepoxy-terminated poly(ethylene glycol)s of approximate MW 1,000; 2,000; and 4,000 g mol^?1. Their thermoresponsive character was investigated on the 10–70 °C interval, while the swelling behavior was tested at 21, 37, and 50 °C. All hydrogels displayed temperature sensitivity, but a volume phase transition was noticed only in the case of poly(propylene glycol) (PPG)₂₀₀₀-containing hydrogels. The volume phase transition temperature (T _VPT ) depended on the MW of the hydrophilic poly(ethylene glycol) (PEG) chains attached to the PPG₂₀₀₀ block, as well as on the added salts. Longer PEG blocks determined a shift of T _VPT towards higher values, while the influence of the salt added was in agreement with the Hofmeister series, except for NaH₂PO₄ which determined the destruction of the hydrogel network. The equilibrium swelling degree depended on the MW of both PEG and PPG blocks, as well as on temperature. The analysis of the swelling process indicated a modification of the gel characteristics with temperature and second-order kinetics for the water penetration into the hydrogel.     

Synthesis of 3‐(tert‐Butoxycarbonylmethyl)‐N‐vinyl‐2‐caprolactam and Homologous Copolymerization Toward Biocompatible Carboxylated Poly(N‐vinyl‐2‐caprolactam) Responsive to pH and Temperature

A new monomer derivative of N‐vinyl‐2‐caprolactam (VCL), namely 3‐(tert‐butoxycarbonylmethyl)‐N‐vinyl‐2‐caprolactam (TBMVCL), was synthesized via nucleophilic substitution at the α‐carbon to the lactam carbonyl group. The monomer was copolymerized radically with VCL and the copolymer compositions were controlled through varying the molar feeding percentages of TBMVCL. The resulting copolymers exhibited temperature‐responsive properties in water, with cloud points decreasing from 33 °C to 13 °C when the TBMVCL composition increased from 2.2 mol % to 18.6 mol %. Removal of the tert‐butyl protecting groups via acid hydrolysis exposed the carboxyl groups, which conferred pH sensitivity to the thermoresponsive properties of the resulting deprotected copolymers. The cloud point was found to increase with the increase of solution pH from 2.0 to 7.4, due to the ionization of the carboxyl groups. The influence of pH was most drastic for the 18.6 mol % copolymer composition. Furthermore, the phase transition temperature of the deprotected copolymers was found to be dependent on the polymer solution concentration, exemplifying classical Flory–Huggins miscibility behavior. Comparison of responsiveness was also made with another type of carboxyl functionalized poly(N‐vinyl‐2‐caprolactam) copolymer reported in our prior study, to examine the influence of the chemical structure of the carboxyl substitution group. Finally, the deprotected copolymer was demonstrated to be biocompatible using a fibroblast cell culture. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 112–120     

Hybrid alginate beads with thermal‐responsive gates for smart drug delivery

Polysaccharide‐based thermo‐responsive material was prepared by grafting PNIPAAm onto hybrid alginate beads, in which a biomineralized polyelectrolyte layer was constructed aiming to enhance the mechanical strength and ensure higher graft efficiency. XPS results demonstrated that the incorporation of PNIPAAm to the hybrid beads was successful, and the PNIPAAm‐grafted beads were more hydrophilic than the ungrafted ones as indicated by their swelling behavior. The drug release behaviors revealed that the grafted beads were both thermo‐ and pH‐sensitive, and the PNIPAAm existed in the pores of the alginate beads acted as the “on–off” gates: the pores of the beads were covered by the stretched PNIPAAm to delay the drug release at 25°C and opened to accelerate the drug release at 37°C because of the shrinking of PNIPAAm molecules. This paper would be a useful example of grafting thermo‐responsive polymers onto biodegradable natural polymer substrate. The obtained beads provide a new mode of behavior for thermo‐responsive “smart” polysaccharide materials, which is highly attractive for targeting drug delivery system and chemical separation. Copyright © 2010 John Wiley & Sons, Ltd.     

Kappa-Carrageenan/PVA Filmswith Antibacterial Properties: Part 1. Optimization of Preparation Conditions and Preliminary Drug Release Studies

In this work, kappa carrageenan (KC) and poly(vinyl alcohol) are crosslinked with glutaraldehyde (GTA) to produce films without using catalyst HCL. The optimum conditions for the formation of film have been established based on their water absorption property. The crosslinking reaction was confirmed by FTIR analysis.The films were also characterized by scanning electron microscopy(SEM) and X-ray diffraction (XRD) analysis.The equilibrium swelling of films showed fair dependency on the presence of salt in the swelling medium.However, pH dependent swelling behavior was not prominent. Finally, a representative film sample was loaded with antibacterial drug Gentamicin sulphate and release was monitored kinetically in the physiological fluid (PF) at 37°C. The film showed fair antibacterial action against model bacteria E.Coli.     

Dynamic Release of Riboflavin from Ethyl Cellulose Coated Barium Alginate Beads for Gastrointestinal Drug Delivery: An in vitro Study

The present work describes the dynamic release of model drug riboflavin form uncoated and ethyl cellulose coated barium alginate beads in the media of continuous varying pH at the physiological temperature 37°C. The drug release behavior has been studied in the simulating gastric fluid (SGF, pH 1.2) for 0–2 h and then in the simulating intestinal fluid (SIF pH 6.8) for 2–48 h. In addition to the traditional dissolution test (TDT, the dynamic release has also been studied by a newly developed method, called ‘flow through diffusion cell’ (FTDC). The release profiles, obtained by using these two methods have been found to differ appreciably from each other. Moreover, the nature of the solid mass surrounding the beads in the FTDC method also influences the release behavior of beads. The uncoated beads demonstrated faster drug release of drug in the medium of lower pH (i.e., 1.2) as compared to that in the medium of pH 6.8 and the release process was found to be diffusion controlled.     

Tailoring thermoresponsive nanostructured poly(N-isopropylacrylamide) hydrogels made with poly(acrylamide) nanoparticles

The thermoresponsive behavior and mechanical properties of nanostructured hydrogels, which consist of poly(acrylamide) nanoparticles embedded in a cross-linked poly(N-isopropylacrylamide) hydrogel matrix, are reported here. Nanostructured hydrogels exhibit a tuned volume phase transition temperature (T _VPT), which varies with nanoparticle content in the range from 32 up to 39–40 °C. Moreover, larger equilibrium water uptake, faster swelling and de-swelling rates, and larger equilibrium swelling at 25 °C were obtained with nanostructured hydrogels compared with those of conventional ones. Elastic and Young’s moduli were larger than those of conventional hydrogels at similar swelling ratios. The tuned T _VPT and the de-swelling rate were predicted with a modified Flory–Rehner equation coupled with a mixing rule that considers the contribution of both polymers. These behaviors are explained by a combination of hydrophilic/hydrophobic interactions and by the controlled inhomogeneities (nanoparticles) introduced by the method of synthesis.     

Synthesis and characterization of novel thermoresponsive‐co‐biodegradable hydrogels composed of N‐isopropylacrylamide,poly(L‐lactic acid), and dextran

A series of novel multifunctional hydrogels that combined the merits of both thermoresponsive and biodegradable polymeric materials were designed, synthesized, and characterized. The hydrogels were copolymeric networks composed of N‐isopropylacrylamide (NIPAAM) as a thermoresponsive component, poly(L‐lactic acid) (PLLA) as a hydrolytically degradable and hydrophobic component, and dextran as an enzymatically degradable and hydrophilic component. The chemical structures of the hydrogels were characterized by an attenuated total reflection–Fourier transform infrared spectroscopy (ATR–FTIR) technique. The hydrogels were thermoresponsive, showing a lower critical solution temperature (LCST) at approximately 32 °C, and their swelling properties strongly depended on temperature changes, the balance of the hydrophilic/hydrophobic components, and the degradation of the PLLA component. The degradation of the hydrogels caused by hydrolytic cleavage of ester bonds in the PLLA component was faster at 25 °C below the LCST than at 37 °C above the LCST, determined by the ATR–FTIR technique. Due to their multifunctional properties, the designed hydrogels show great potential for biomedical applications, including drug delivery and tissue engineering. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 5054–5066, 2004     

Self-assembled liposomes from electrosprayed polymer-based microparticles

Composite poly(N-isopropylacrylamide) (PNIPAAm)/phosphatidylcholine (PC) microparticles were prepared by electrospraying. PC-based liposomes were subsequently generated upon the addition of water. The microparticles have an average diameter of ca. 1 μm, while the liposomes produced were found to have much smaller diameters of ca. 225–280 nm. The liposomes had zeta potentials of ?44 to ?50 mV, consistent with the formation of a stable suspension. Upon heat treatment, the liposomes exhibit phase transitions due to the influence of PNIPAAm. The liposomes containing 33 % PC have a phase transition temperature of approximately 36 °C, close to physiological conditions. The model drug ketoprofen could be loaded into electrosprayed microparticles and subsequently incorporated into self-assembled liposomes, with an entrapment efficiency for the latter process of ca. 75 %. Sustained drug release regulated by temperature was observed from these drug-loaded materials. At 25 °C, only 45 % of the total drug loading was released after 110 hours, while at 37 °C drug release approached 90 % over the same time period. The self-assembled liposomes reported here, therefore, have great potential as drug delivery devices.     

Dynamic Release of Propranolol HCl from Cationic Ion–Exchanger–Loaded Calcium Alginate Beads

The dynamic release of drug propranolol HCl from the propranolol HCl–resin complex (PRC) loaded calcium alginate beads has been studied in the buffer media of pH 1.2 at the physiological temperature 37°C. The PRC encapsulated beads demonstrated nearly 58.04% release while naked PRC particles released 98.00% drug in 24 h in the gastric fluid. The amount of drug released was found to increase with and decrease in the amount of sodium alginate in the beads. Similarly, with the increase in the amount of entrapped PRC particles within the beads, the quantity of drug released was also observed to increase. The degree of crosslinking of beads also affected the release kinetics. Interestingly, the release from naked PRC particles followed ‘first‐order’ kinetics while PRC particles, entrapped in calcium–alginate beads, exhibited ‘diffusion controlled’ release behavior as indicated by liner nature of fractional release vs. √t plot.     

Swelling and water transport in temperature-sensitive hydrogels based on 2-methoxyethylacrylate

A series of thermoresponsive hydrogels based on copolymers of 2-methoxyethylacrylate with acrylamide or N,N-dimethylacrylamide were prepared by radiation-induced polymerization in dimethylformamide solution in the presence of a crosslinking agent. The swelling behaviour of the hydrogels was studied by immersing the polymer samples in water at 5°C, 10°C and 37°C. The data were found to satisfactorily fit Fick's law with a constant diffusion coefficient. The results indicate that the swelling ratio increases with increasing the content of the hydrophilic monomers in the hydrogels and at the same time the equilibrium swelling time decreases. The effect of temperature on water transport mechanism was observed.     

Preparation and release profiles of pH/temperature-responsive carboxymethyl chitosan/P(2-(dimethylamino) ethyl methacrylate) semi-IPN amphoteric hydrogel

Thermo- and pH-responsive semi-IPN polyampholyte hydrogels were prepared by using carboxymethyl chitosan and P(2-(dimethylamino) ethyl methacrylate) with N N'-Methylenebisacrylamide (BIS) as crosslinking agent. It was found that the semi-IPN hydrogel shrunk most at the isoelectric point (IEP) and swelled when pH deviated from the IEP. Its swelling ratio dramatically decreased between 30 and 50 °C at pH 6.8 buffer solution. It also showed good reversibility. The UV results showed that when the pH values of drug release medium were 3.7, 6.8, and 9 at 25 °C, the cumulative release rates reached 83.1, 51.5, and 72.2%, respectively. The release rate of coenzyme A (CoA) was higher at 50 °C than 37 and 25 °C at pH 6.8 solution. The release rate decreased with increasing the content of carboxymethyl chitosan at 25 °C in pH 6.8 solution. The results showed that semi-IPN hydrogel seems to be of great promise in pH/temperature drug delivery systems.     

Novel thermoresponsive water-soluble oligomers based on amphiphilic calixresorcinarenes

Novel water-soluble thermoresponsive oligomers TO1 and TO2 were obtained by reaction of amidoamine tetramethylcalixresorcinarenes (C1) and tetrapentylcalixresorcinarenes (C5) with ethylene glycol diglycidyl ether. The compounds were characterised by ¹H and FT-PGSE NMR, FTIR, static light scattering and elemental analysis. The thermoresponsive properties of oligomers were investigated by spectrophotometry, DLS, FT-PGSE NMR and TEM. The cloud points of oligomers (43 °C for TO1 (5 mg/ml) and 41 °C for TO2 (1.2 mg/ml), respectively) were determined. The influence of salts effect on TO2 cloud points was investigated. The binding of anti-inflammatory drug naproxen (Nap) at 20 °C by TO1 and TO2 and its partial release at cloud points of oligomers in aqueous solution are observed using fluorescence and FT-PGSE NMR methods. New example of creating of thermoresponsive macrocyclic systems on the basis of amidoamine calixresorcinarenes with possibility of substrate binding and release under the influence of termo-stimuli in an aqueous solution was shown.     

Novel supramolecular block copolymer containing organic–inorganic pentablock copolymer by ATRP of styrene and vinyl acetate using polydimethylsiloxane/cyclodextrin inclusion complexes as macroinitiator

Organic–inorganic pentablock copolymers have been synthesized via atom transfer radical polymerization (ATRP) of styrene (St) and vinyl acetate (VAc) monomers at 60 °C using CuCl/N,N,N′,N″,N″-pentamethyldiethylenetriamine as a catalyst system initiated from boromoalkyl-terminated poly(dimethylsiloxane) (PDMS)/cyclodextrins macroinitiator (Br-PDMS/γ-CD). Br-PDMS-Br was reacted with γ-CD in different conditions with inclusion complexes being characterized through hydrogen nuclear magnetic resonance (¹H NMR) and differential scanning calorimetry (DSC). Resulting Br-PDMS-Br/γ-CD inclusion complexes were taken as macroinitiators for ATRP of St and VAc. Well-defined poly(styrene)-b-poly(vinyl acetate)-b-poly(dimethylsiloxane/γ-cyclodextrin)-b-poly(vinyl acetate)-b-poly(styrene) (PSt-b-PVAc-b-PDMS/γ-CD-b-PVAc-b-PSt) pentablock copolymer was characterized by ¹H NMR, gel permeation chromatograph (GPC) and DSC. There was a good agreement between the number-average molecular weight calculated from ¹H NMR spectra and that of theoretically calculated. Pentablock copolymers consisting of Br-PDMS-Br/γ-CD inclusion complex as central blocks (inorganic block) and PVAc and PSt as terminal blocks were synthesized by this technique. PSt-b-PVAc-b-PDMS/γ-CD-b-PVAc-b-PSt pentablock copolymer can undergo a temperature-induced reversible transition upon heating of the copolymer complex from white complex at 22 °C to green complex in 55 °C which characterized with XRD and ¹H NMR. XRD showed a change in crystallinity percent of St peak with changing the temperature which calculated by Origin75 software.     

Controlled release of 5-fluorouracil or mitomycin-c from polymer matrix: Preparation by radiation polymerization and in vivo evaluation of the anticancer drug/polymer composites

Polymer tablets containing anticancer drugs such as 5-fluorouracil (5-FU) and mitomycin-C (MMC) have been prepared to evaluate the drug-release characteristics in vitro and the effect on local control of mouse solid tumors in vivo. Radiation-induced polymerization of hydrophilic monomers (2-hydroxyethyl methacrylate and related monomers) at low temperature (-80°C) was performed to immobilize 5-FU or MMC in the polymer matrix. The drug was dispersed as microcrystallines within the polymer matrix. The rate of drug release in vitro in buffer solution (pH7.0, 37°C) increased with increase in hydrophilicity of polymer matrix. Appropriate amount of crosslinks within the polymer matrix, as formed by ethylene glycol dimethacrylate (2G) added in the polymerization system, was effective to control the rate of drug release. The drug release became faster upon the addition of increasing amount of water in the radiation-induced polymerization. The tablet consisting of drug/polymer was buried surgically near solid tumors of striate muscle sarcoma (S180) transplanted to Kunming mice and the therapeutic effect of slow releasing drugs was evaluated in vivo by reference to intraperitoneal (i.p.) injection of the corresponding drugs. The slow releasing drugs led to high chemotherapeutic gain for local control of solid tumors with remarkable reduction of toxic side effect of the drugs.     

Release Property of Alginate Beads Coated with Poly(N-isopropylacrylamide-co-dimethylaminoethylmethacrylate)

Alginate beads were coated with copolymers of N-isopropylacrylamide and dimethylaminoethylmethacrylate (P(NIPAM-co-DMAEMA)s) by taking advantage of electrostatic interaction between alginate and the copolymer. The copolymers, of which DMAEMA contents in the feed for the copolymerization were 5.0% (PND 5) and 15.0% (PND 15), were employed for the coatings of alginate beads. The adsorption curve of PND 5 and PND 15 on the surface of alginate beads seemed to be Langmuir isotherm. The beads were coated in the PND solutions (2%, pH 5.0 or pH 7.0) and the amounts of adsorption (g PND/g alginate) were about 1.3 with PND 5 solution (pH 5.0), 1.2 with PND 15 solution (pH 5.0), and 0.75 with PND 15 (pH 7.0). The release from the beads coated with PNDs were observed at 30°C, 37°C, and 45°C using amaranth or FITC-dextran as a dye. The degrees of release were significantly suppressed due to the coating layers of PNDs. However, the coating layers could hardly act as a controller for the temperature-sensitive release.     

Thermoresponsive and bioactive poly(vinyl ether)-based hydrogels synthesized by radiation copolymerization and photochemical immobilization

A thermoresponsive hydrogel was synthesized by radiation copolymerization of ethylene glycol vinyl ether (EGVE) and butyl vinyl ether (BVE) in the presence of cross-linking agent diethylene glycol divinyl ether. The gel was modified by a cell adhesion factor RGD by photochemical immobilization technique. While the unmodified hydrogel shows fully hydrated form at low temperatures (+4 °C) and it extensively dehydrates at 37 °C, the biomodified hydrogel still kept its thermoresponsive character after immobilization. The effectiveness of immobilization was checked with FTIR-ATR and XPS. The use of bioactive thermoresponsive hydrogels in cell culture applications was investigated. For this purpose, cell culture experiments were realized by L929 mouse fibroblasts. Cell attachment experiments revealed the effect of immobilized RGD with higher values of cell attachment (∼85%), which were obtained especially in the absence of serum. The thermoresponsive character of the hydrogel was useful for the application of low-temperature treatment in order to recover the attached viable cells from the surface of the hydrogel without using trypsin. When the culture temperature was decreased from 37 to 10 °C for 30 min ∼80% of the cells were detached from the hydrogel surface.     

Dual crosslinked pH‐ and temperature‐sensitive hydrogel beads for intestine‐targeted controlled release

Novel drug‐loaded hydrogel beads for intestine‐targeted controlled release were developed by using pH‐ and temperature‐sensitive carboxymethyl chitosan‐graft‐poly(N,N‐diethylacrylamide) (CMCTS‐g‐PDEA) hydrogel as carriers and vitamin B₂ (VB₂) as a model drug. The hydrogel beads were prepared based on Ca²⁺ ionic crosslinking in acidic solution and formed dual crosslinked network structure. The structure of hydrogel and morphology of drug‐loaded beads were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). The study about swelling characteristics of hydrogel beads indicated that the beads had obvious pH‐ and temperature‐sensitivity. In vitro release studies of drug‐loaded beads were carried out in pH 1.2 HCl buffer solution and pH 7.4 phosphate buffer solution at 37°C, respectively. The results indicated that the dual crosslinked method could effectively control the drug release rate under gastrointestinal tract (GIT) conditions, which was superior to traditional single crosslinked beads. In addition, the effects of grafting percentage, pH value, and temperature on the release behavior of the VB₂ were investigated. The drug release mechanism of CMCTS‐g‐PDEA drug‐loaded beads was analyzed by Peppa's potential equation. According to this study, the dual crosslinked hydrogel beads based on CMCTS‐g‐PDEA could serve as suitable candidate for drug site‐specific carrier in intestine. Copyright © 2009 John Wiley & Sons, Ltd.     

Preparation, characterization, swelling and in vitro drug release behaviour of poly[N-acryloylglycine-chitosan] interpolymeric pH and thermally-responsive hydrogels

Novel biodegradable pH- and thermal-responsive interpenetrating polymer network (IPN) hydrogels were prepared for controlled drug delivery studies. The IPN hydrogels were obtained in mild aqueous acid media by irradiation of solutions of N-acryloylglycine (NAGly) mixed with chitosan, in the presence of glutaraldehyde as a crosslinking agent and using 2,2-dimethoxy-2-phenyl acetophenone as photoinitiator. These hydrogels were subjected to equilibrium swelling studies at different temperatures (25 °C, 37 °C and 45 °C) in buffer solutions of pH 2.1 and 7.4 (similar to that of gastric and intestinal fluids respectively). 5-Fluorouracil (5-FU) was entrapped in the hydrogels, and drug release studies carried out at 37 °C in buffer solutions at pH 2.1 and 7.4.     

“One‐step” Preparation of Thiol‐Ene Clickable PEG‐Based Thermoresponsive Hyperbranched Copolymer for In Situ Crosslinking Hybrid Hydrogel

A well‐defined poly(ethylene glycol) based hyperbranched thermoresponsive copolymer with high content of acrylate vinyl groups was synthesized via a “one‐pot and one‐step” deactivation enhanced atom transfer radical polymerization approach, which provided an injectable and in situ crosslinkable system via Michael‐type thiol‐ene reaction with a thiol‐modified hyaluronan biopolymer. The hyperbranched structure, molecular weight, and percentage of vinyl content of the copolymer were characterized by gel permeation chromatography and ¹H NMR. The lower critical solution temperature of this copolymer is close to body temperature, which can result in a rapid thermal gelation at 37 °C. The scanning electron microscopy analysis of crosslinked hydrogel showed the network formation with porous structure, and 3D cell culture study demonstrated the good cell viability after the cells were embedded inside the hydrogel. This injectable and in situ crosslinking hybrid hydrogel system offers great promise as a new class of hybrid biomaterials for tissue engineering.