温度及pH敏感水凝胶的制备与溶胀性能研究

用顺丁烯二酸酐(MAH)对β-环糊精(β-CD)进行化学改性,合成出了一种新型功能性单体MAH-β-CD。以N,N'-亚甲基双丙烯酰胺(BIS)为交联剂,过硫酸铵(APS)为引发剂,通过氧化还原自由基引发单体MAH-β-CD、N-异丙基丙烯酰胺(NIPA)及阴离子单体丙烯酸钠(SA)共聚,合成出一种新型水凝胶。用核磁共振、红外光谱对水凝胶进行了表征。溶胀研究结果表明,该水凝胶具有较好的pH及温度敏感性。     

Synthesis and drug-release properties of biodegradable hydrogels having β-cyclodextrin

A new β-cyclodextrin (β-CD) methacrylated monomer was synthesized from the reaction of β-CD, glycidyl methacrylate. Based on inclusion character of β-CD, a series of hydrogels were prepared by irradiating the mixtures of β-CD methacrylate monomer (β-CD-Met), poly(ethylene glycol) monoacrylate, poly(ethylene glycol)diacrylate, fumaric acid monoethyl ester-functionalized poly(lactic-co-glycolic) acid, 1-vinyl-2-pyrrolidone, N,N′-methylene bisacrylamide, and the photoinitiator. Gel percentages and equilibrium swelling ratios (%) of hydrogels were investigated. It was observed that equilibrium-swelling ratio increased with increasing β-CD-Met content in the hydrogel composition. SEM images demonstrated that β-CD-Met-based hydrogel have lots of voids on the fractured surface. In this study, ibuprofen (IBU) which is capable of forming inclusion complex with β-CD was chosen. For the hydrogel with maximum CD content, the IBU drug loading was found as 9 mg/g dry gel. It can be concluded that the inclusion complex-formation capability of β-CD moiety increases the drug release by improving the aqueous solubility of hydrophilic drugs.     

带β-环糊精侧基水凝胶的制备与性能研究

用顺丁烯二酸酐（MAH）对β-环糊精（β-CD）进行化学改性制备丁烯二酸单酯化β-环糊精单体（MAH-β-CD）。用氧化还原自由基引发单体MAH-β-CD、丙烯酰胺（AM）以及丙烯磺酸钠（SAS）共聚,合成水凝胶,用红外光谱对产物结构表征。溶胀研究结果表明该水凝胶具有良好的温度、pH敏感性。     

Preparation and characterization of nanosized P(NIPAM-MBA) hydrogel particles and adsorption of bovine serum albumin on their surface

Thermosensitive polymer hydrogel particles with size varying from 480 to 620 nm were prepared through precipitation copolymerization of N-isopropylacrylamide with N,N′-methylenebisacrylamide (MBA) in water with ammonium persulfate as the initiator. Only polymer hydrogels without any coagula were obtained when MBA concentration in the monomer mixture was kept between 2.5 and 10.0 wt%; with increased MBA concentration, the monomer conversion was enhanced, the size of the hydrogels was increased, and their shrinking was lessened when heated from 25°C to 40°C. Bovine serum albumin adsorption on the surface of the hydrogels of different MBA content was measured at different pH levels and under different temperatures. The results demonstrated that the adsorption of the protein on the hydrogels could be controlled by adjusting the pH, the temperature of adsorption, and the crosslinking in the hydrogels. The results were interpreted, and the mechanisms of the polymerization were proposed.     

Synthesis and characterization of thermoresponsive N-isopropylacrylamide/methacrylated pullulan hydrogels

Thermosensitive hydrogels were prepared by free radical polymerization starting from a methacrylated pullulan derivative (acting as the cross-linker) and using N-isopropylacrylamide (NIPAAM) as the monomer. Several hydrogels were obtained by changing the monomer to cross-linker ratio. A significant thermosensitivity was observed only when the molar amount of NIPAAM incorporated in the network was at least eight times higher that of methacrylate groups on pullulan. The hydrogel with high amount of NIPAAM deswells more than 80% after the T-jump. The lower critical solution temperature of thermosensitive hydrogels decreases with increasing amount of NIPAAM. The mechanical properties of the hydrogels are strongly affected by the percentage of incorporated NIPAAM and by the temperature.     

Determination of reactivity ratios and swelling characteristics of ‘stimuli’ responsive copolymers of N-acryloyl-N′-ethyl piperazine and MMA

‘Stimuli’ responsive copolymers of N-acryloyl-N′-ethyl piperazine (AcrNEP) and methyl methacrylate (MMA) were synthesized by free radical solution polymerization. The copolymers were analyzed as thin films by FTIR spectroscopy. The monomer reactivity ratios were determined by linearization methods of Fineman-Ross (F-R) and Kelen-Tüdös (K-T) giving the results r₁ (AcrNEP)=0.58 and r₂ (MMA)=0.91 by the F-R method and r₁=0.72 and r₂=1.08 by the K-T method. The latter r values in turn yielded Q=0.59 and e=−0.12 for AcrNEP. Crosslinked copolymer hydrogels of AcrNEP and MMA with various compositions were prepared in bulk and solution by photo-initiated free-radical polymerization. The gels were dual responsive to pH and temperature. The response to pH was reversible with a response time of 100 min with good reversibility and with no loss in swelling capacity. Water sorption of the gels was investigated gravimetrically and the collective diffusion coefficients were determined at 10, 25, and 50 °C. The water sorption of the gels in water was Fickian. The temperature dependence of the equilibrium water content was studied by the Gibbs-Helmholtz equation. The enthalpy of mixing decreased with an increase in the hydrophilic content (AcrNEP) of the gel. Other parameters such as type and amount of crosslinker, preparative conditions, nature of buffers, and salts were found to influence the swelling behavior.     

On the water swelling behaviour of poly(N-isopropylacrylamide) [P(N-iPAAm)], poly(methacrylic acid) [P(MAA)], their random copolymers and sequential interpenetrating polymer networks (IPNs)

Thermo- and pH-responsive stimuli hydrogels based on N-isopropylacrylamide (N-iPAAm) and methacrylic acid (MAA) have been synthesized and their swelling behaviour studied as a function of composition, pH and temperature. Copolymers varying in composition have been obtained by copolymerizing these two monomers and interpenetrating polymer networks (IPNs) of P(MAA) and P(N-iPAAm) by the sequential method. Temperature and pH have been changed in the ranges from 25 to 40 °C and from 2 to 9, respectively. The swelling behaviour of the hydrogels depends on the nature of the polymer and the environmental conditions, namely pH and temperature. Copolymer gels under basic conditions exhibit higher degree of swelling than the homopolymer ones. The disruption of the complexes dominates the kinetic swelling of MAA enriched gels under basic conditions. The hydrogen bond formation between carboxyl and amide groups has been made clear through the dynamic swelling behaviour of copolymers under acidic conditions. IPNs reduce their ability to swell in water with increasing P(N-iPAAm) content because of the formation of hydrophobic interpolymer complexes through hydrogen bonding. Lower critical solution temperature occurs only in the enriched N-iPAAm copolymers under acidic conditions when the MAA carboxyl groups are unionized.     

Temperature sensitive poly(N-t-butylacrylamide-co-acrylamide) hydrogels: synthesis and swelling behavior

A series of temperature sensitive hydrogels was prepared by free-radical crosslinking copolymerization of N-t-butylacrylamide (TBA) and acrylamide in methanol. N,N′-methylenebis(acrylamide) was used as the crosslinker. It was shown that the swelling behavior of the hydrogels can be controlled by changing the amount of TBA units in the network chains. Hydrogels immersed in dimethylsulfoxide (DMSO)-water mixtures exhibited reentrant swelling behavior, in which the gels first deswell then reswell if the DMSO content of the solvent mixture is continuously increased. In water over the temperature range of 2-64 °C, hydrogels with less than 40[percnt] TBA by mole were in a swollen state while those with TBA contents higher than 60[percnt] were in a collapsed state. Hydrogels with 40-60[percnt] TBA exhibited swelling-deswelling transition in water depending on the temperature. The temperature interval for the deswelling transition of 60[percnt] TBA gel was found to be in the range from 10 to 28 °C, while for the 40[percnt] TBA gel, the deswelling started at about 20 °C and continued until the onset of the hydrolysis of the network chains at around 64 °C. It was shown that the Flory-Rehner theory of swelling equilibrium provides a satisfactory agreement to the experimental swelling data of the hydrogels, provided that the sensitive dependence of the χ parameter on both temperature and polymer concentration is taken into account.     

Enantioselective separation of R,S-phenylsuccinic acid by biphasic recognition chiral extraction

A new process has been developed to separate phenylsuccinic acid (H₂A) enantiomers, based on the oppositely preferential recognition of hydrophobic and hydrophilic chiral selectors in organic and aqueous phases, respectively, which is named as biphasic recognition chiral extraction (BRCE). BRCE system is established by adding hydrophobic l-iso-butyl tartrate in organic phase and hydrophilic β-cyclodextrin (β-CD) derivative in aqueous phase, which preferentially recognize S-H₂A and R-H₂A, respectively. The studies performed involve two enantioselective extractions in a biphasic system, where H₂A enantiomers form four complexes with β-CD derivative in aqueous phase and l-iso-butyl tartrate in organic phase, respectively. Here it is shown that the efficiency of the extraction depends, often strongly, on a number of process variables, including the types of organic solvents and β-CD derivatives, iso-butyl tartrate configurations, the concentrations of the extractants and H₂A enantiomers, pH and temperature. Phase-equilibria in BRCE systems is governed by the complex chemical equilibria in both the organic and aqueous phases. By changing the monophasic recognition chiral extraction (MRCE) system into BRCE system, the enantioselectivity increases from 1.501 to 2.862. The maximum enantioselectivity for H₂A enantiomers is obtained at pH≤2.5 and the ratio of 2:1 of [l-(+)-iso-butyl tartrate] to [HP-β-CD]. The experimental results show that BRCE is of much stronger chiral separation ability than MRCE, which is due to utilization of the separation abilities of both tartrate and β-CD derivative. It may be very helpful to optimize the extraction systems and realize the large-scale production of pure enantiomers.     

Cyclodextrin based hydrogels: Inclusion complex formation and micellization of adamantane and cholesterol grafted polymers

Inclusion complex formation between β-cyclodextrin (β-CD) and suitable guest molecules has frequently been exploited to design self-assembled polymer networks. In this paper, we report on hydrogels composed of eight-armed poly(ethylene glycol) (PEG) grafted with β-CD (8armPEG20k-CD), adamantane (8armPEG20k-ad) or cholesterol (8armPEG20k-chol). Mixtures of 8armPEG20k-CD and 8armPEG20k-ad showed viscous behavior (G″ > G′); 8armPEG20k-CD and 8armPEG20k-chol formed elastic hydrogels (G′ > G″). To study the interaction of adamantane and cholesterol grafted PEG with β-CD, linear model compounds (mPEG5k-ad and mPEG5k-chol) were synthesized. Isothermal titration calorimetry (ITC) experiments showed a higher association constant for inclusion complexes formed with mPEG5k-chol (47,000 ± 1650) than for those formed with mPEG5k-ad (30,000 ± 900). Fluorescence spectroscopy and dynamic light scattering (DLS) measurements further showed the ability of mPEG5k-chol to self-assemble into micelles. Self-assembly of 8armPEG20k-chol further increased the strength of the formed hydrogels. Altogether, this study contributes to a better understanding of cyclodextrin based biomaterials.     

Influence of the swelling history on the swelling kinetics of stimuli-responsive poly[(N-isopropylacrylamide)-co-(methacrylic acid)] hydrogels

The influence of the swelling history on the swelling behavior of poly[(N-isopropylacrylamide)-co-(methacrylic acid)] P[(N-iPAAm)-co-(MAA)] random copolymers hydrogels synthesized by free radical polymerization in solution of N-iPAAm and MAA comonomers crosslinked with tetraethylene glycol dimethyl acrylate (TEGDMA) has been studied. The swelling behavior under pH 7 at 18, 29, 39 and 49 °C of this series of copolymers, previously soaked either at pH 2 or 7 has been investigated. The swelling kinetics of these two series of samples displays different behavior as function of the composition and temperature. However, the equilibrium swelling values only show slight dependences on the previous soaking pH and temperature. When samples are soaked at pH 7, then the swelling at pH 7 follows a first order kinetics, irrespective of the copolymer composition or the temperature at which the experiment has been carried out. In this case, the swelling process is very fast and depends only slightly on temperature. The first order rate constant increases with the MAA content in the hydrogel. Furthermore, the swelling rate of copolymer hydrogels soaked at pH 2, show strong dependence on composition and temperature. They follow an autocatalytic swelling kinetics due to the disruption of hydrogen bond arrangements. An initial slow water uptake is followed by an acceleration process, in which water molecules inside the gel help the next water molecules to come in. Two rate constants, a first-order rate constant and an autocatalytic one have been obtained from the kinetics analysis. They have revealed different temperature dependence which may be due to a balance between hydrophobic and hydrogen bond interactions. The temperature dependence of the swelling kinetics is stronger and more complex for copolymers treated under pH 2 than for copolymers soaked under pH 7.     

Synthesis and properties of thermosensitive, crown ether incorporated poly(N-isopropylacrylamide) hydrogel

A crown ether derivative (4′-allyldibenzo-18-crown-6, CE) was covalently incorporated into the network of temperature sensitive poly(N-isopropylacrylamide) (PNIPA) hydrogels by copolymerization in a mixed solvent of water and tetrahydrofuran (H₂O/THF). The poly(N-isopropylacrylamide-co-4′-allyldibenzo-18-crown-6) (poly(NIPA-co-CE)) hydrogels exhibited dramatically faster deswelling rates than normal PNIPA hydrogels at a temperature (50 °C) above their lower critical solution temperatures. The effect of the solvent component ratio in the mixed solvent during the copolymerization on the swelling properties of the poly(NIPA-co-CE) hydrogel was investigated. The thermosensitive poly(NIPA-co-CE) hydrogels have potential applications in the extraction of cations and separation of chiral drugs.     

Structure and dynamics of a vinylidene fluoride oligomer and its cyclodextrin inclusion compounds as studied by solid-state F MAS and H → F CP/MAS NMR spectroscopy

The molecular structure and dynamics of a vinylidene fluoride oligomer telomerized by carbon tetrachloride (Cl-OVDF) and its inclusion compound (IC) with β-cyclodextrin (β-CD) have been investigated using solid-state ¹⁹F magic angle spinning (MAS) and ¹H → ¹⁹F cross-polarization (CP)/MAS NMR spectroscopy. The preferential IC formation of the lower-molecular-weight components with β-CD was used to refine as-received Cl-OVDF. The refined Cl-OVDF with larger molecular weight readily takes γ-form (tttg⁺tttg⁻) conformation, and it also forms ICs with β-CD (Cl-OVDF/β-CD IC) under a certain condition. ¹⁹F MAS NMR indicates that Cl-OVDF chains virtually isolated in the β-CD cavities take no specific conformations even at −40 °C. The temperature dependence of the magnetic relaxation times (T₁^F, T_1ρ^F) indicates that the Cl-OVDF chains in ICs undergo molecular motions similar to the amorphous phase in the bulk, although the intramolecular spin diffusion among ¹⁹F nuclei is more significant in the former because of the one-dimensional confinement.     

Copolymer hydrogels based on N-isopropylacrylamide and itaconic acid

In this study, the swelling behaviour of copolymer hydrogels of N-isopropylacrylamide (NIPAM) and itaconic acid (IA) in response to temperature and pH value of the external media was studied. The equilibrium degree of swelling for PNIPAM and PNIPAM/IA copolymers was greater at 25 °C than at 37 °C. The degree of swelling was low at low pH values. As the degree of ionization increased above the nominal pK_a values of IA, the increased hydrophilicity resulted in larger degrees of swelling. At 37 °C, the PNIPAM hydrogel and some copolymers show anomalous swelling behaviour, i.e. the overshooting effect, in buffered solutions of certain pH values. A swelling-deswelling study showed that the deswelling process of the hydrogels was faster then the swelling process. According to dynamic swelling studies, the diffusion exponent and the diffusion coefficient both increase with increasing content of IA.     

Dynamic swelling of hydrogels based on random terpolymers of N-isopropylacrylamide, methacrylic acid and poly(ethylene glycol) macromonomer

A series of pH-responsive hydrogels based on N-isopropylacrylamide (N-iPAAm), methacrylic acid (MAA) and poly(ethylene glycol) monomethyl ether monomethacrylate macromonomer (PEGMEMA), P(N-iPAAm-co-MAA-co-PEGMEMA) random terpolymers, were synthesized and their swelling behaviour studied as a function of both monomer composition and previous swelling treatment. The swelling kinetic curves were followed using gravimetric, photographic and magnetic resonance imaging (MRI) techniques, which provide spatial and temporal resolution. The swelling behaviour was non-Fickian at pH 7, being this fact more relevant when the samples were pre-soaked in pH 2 solution. Low pH promotes hydrogen bond arrangements that disrupt at pH 7, where sigmoidal swelling curves were observed. The sigmoidal shape of the curves increases as well as the swelling time with increasing N-iPAAm/PEGMEMA ratio. This indicates that hydrogen bond arrangements between MAA and N-iPAAm are stronger that those formed by MAA and PEGMEMA. The influence of the polymer composition on the hydrogen bond arrangements was also studied from the swelling kinetics curves at different pH media, observing that the swelling rate, the swelling curve shape and the whole amount of water absorbed were clearly dependent on this parameter.     

Rapid pH/temperature-responsive cationic hydrogels with dual stimuli-sensitive grafted side chains

Dual temperature- and pH-sensitive comb-type grafted cationic hydrogels are successfully synthesized by grafting polymeric chains with freely mobile ends, which are composed of both N-isopropylacrylamide (NIPAM) segments and N,N-dimethylamino ethyl methacrylate (DMAEMA) segments, onto the backbone of crosslinked poly(NIPAM-co-DMAEMA) networks. Equilibrium and dynamic swelling/deswelling properties of the prepared hydrogels responding to pH and/or temperature are investigated. The prepared hydrogels demonstrate a lower critical solution temperature (LCST) at about 34 °C and a pK_a value at about pH 7.3. At lower pH and lower temperature, both the swelling degree and the swelling rate of the comb-type grafted hydrogel are larger than those of the normal-type crosslinked hydrogel. The comb-type grafted poly(NIPAM-co-DMAEMA) hydrogel exhibits a more rapid deswelling rate than that of the normal-type hydrogel in response to a pH jump from 2.0 to 11.0 at a fixed temperature. The volume changes of the poly(NIPAM-co-DMAEMA) hydrogels are acute in a series of fixed buffer solutions with an abrupt increase of environmental temperature from 18 °C to a temperature higher than the LCST. The comb-type grafted poly(NIPAM-co-DMAEMA) hydrogels show quite fast shrinking behaviors in response to simultaneous dual temperature and pH stimuli. Drug-release in vitro from the prepared poly(NIPAM-co-DMAEMA) hydrogels is carried out when the environmental temperature and pH are changed synchronously. The results show that the model drug Vitamin B₁₂ is released much more rapidly from the comb-type grafted hydrogel than that from the normal-type hydrogel. The proposed dual temperature/pH-sensitive comb-type grafted cationic poly(NIPAM-co-DMAEMA) hydrogel in this study may find various potential applications, e.g., for fabricating rapid-response smart sensors, actuators, and chemical/drug carriers and so on.     

Self-assembly, drug-delivery behavior, and cytotoxicity evaluation of amphiphilic chitosan-graft-poly(1,4-dioxan-2-one) copolymers

Allyl glycidyl ether (AGE)-functionalized chitosan (CS-AGE), a macromolecular crosslinker, was synthesized and then copolymerized with N-isopropylacrylamide (NIPAAm) monomer under UV irradiation to produce hydrogels. The allylated chitosan and the resulting hydrogels were characterized by ¹?H NMR and FT IR, respectively. The interior morphologies of the hydrogels were investigated by scanning electron microscopy (SEM) after freeze drying them in the equilibrium state in buffer solution at pH 2.0. Their swelling kinetics were found to be sensitive to both temperature and pH, so it was possible to modulate the swelling by adjusting the pH or the temperature of the medium containing the hydrogel and the proportion of the CS derivative with respect to the NIPAAm monomer. Rheological measurements were utilized to investigate the mechanical properties of the hydrogels. The in vitro release profiles of the model drugs methyl orange (MO) and bovine serum albumin (BSA) from the hydrogels were also examined. The results revealed that the drug release rate could be tuned by adjusting the pH of the medium and the hydrogel composition.     

β-环糊精／丙烯酰胺水凝胶的合成与表征

采用顺丁烯二酸酐（MAH）对具有分子包结能力的β-环糊精（B—CD）进行化学改性,合成得到丁烯二酸单酯化β-CD单体（MAH—β—CD）,再以N,N’-亚甲基双丙烯酰胺作交联剂,亚硫酸氢钠、过硫酸铵为引发剂使MAH—β—CD与丙烯酰胺发生聚合,制备含有β—CD结构单元的新型水凝胶。该水凝胶具有较好的pH值和温度敏感性。     

Poly(N-isopropylacrylamide) hydrogels with improved shrinking kinetics by RAFT polymerization

Functional poly(N-isopropylacrylamide) (PNIPAM) hydrogels were prepared by reversible addition fragmentation chain transfer (RAFT) polymerization of N-isopropylacrylamide (NIPAM) in the presence of N,N-methylenebisacylamide (BIS) as a cross-linker and 4-cyanopentanoic acid dithiobenzoate as chain transfer reagent (CTA). The swelling behaviors were investigated and the hydrogels by RAFT polymerization (RAFT gels) showed accelerated shrinking kinetics and higher swelling ratio comparing with conventional hydrogel (CG). It could be attributed to the presence of dangling chains mainly caused by CTA, which could retard the crosslinking reaction rate greatly. Another CTA, 3-(trithiocarbonyl) propanoic acid, was adopted to further investigate the effect of CTA. It showed the similar effect except the different accelerated degree to the shrinking kinetics. Furthermore, the living character of the RAFT process was used to polymerize a new batch of monomer (NIPAM) from functional RAFT gels to introduce grafted structure. The PNIPAM-g-PNIPAM hydrogels indicted further accelerated shrinking kinetics than functional backbone hydrogels.     

Preparation,characterization, and drug release properties of poly(2-hydroxyethyl methacrylate) hydrogels having β-cyclodextrin functionality

A new β-cyclodextrin urethane-methacrylate monomer was synthesized from the reaction of toluene-2,4-diisocyanate, 2-hydroxyethyl methacrylate (HEMA), and β-cyclodextrin (β-CD). Based on inclusion character of β-CD, a series of hydrogels were prepared by irradiating the mixtures of β-cyclodextrin urethane-methacrylate monomer (β-CD-UM), poly(ethylene glycol) diacrylate (PEG-DA), HEMA, and the photoinitator. Gel percentages and equilibrium swelling ratios (%) of hydrogels were investigated. It was observed that the equilibrium-swelling ratio increased with increasing β-CD-UM content in the hydrogel composition. SEM images demonstrated that β-CD-UM based hydrogel have porous fractured surface. In this study four different drug molecules, salicylic acid, sulfathiazole, rifampicin, and methyl orange as model drug, which are capable of forming inclusion complexes withβ-CD were chosen. For sulfathiazole and rifampicin, the drug loadings are very low (0.04 and 0.008 mmol/g dry gel), whereas methyl orange and salicylic acid drug uptakes are found as 0.15 and 0.18 mmol/g dry gel, respectively. The incorporation of β-CD-UM comonomer into the gel slightly reduces the methyl orange and salicylic acid releases. However, a significant enhancement was achieved in the case of sulfathiazole delivery. It can be concluded that the inclusion complex formation capability of β-CD moiety increases the drug release by improving the aqueous solubility of hydrophobic drugs. On the other hand, in the case of hydrophilic drugs, the drug release retards by forming strong drug-β-CD complex and reducing the drug diffusivity. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008