快速响应的温敏性PNIPAAm／粘土复合水凝胶的合成及性能研究

以碳酸钠为制孔剂合成了快速响应的温敏性PNIPAAm／粘土复合水凝胶(NNC水凝胶),DSC分析表明,其体积相转变温度在33℃左右,与传统的PNIPAAm水凝胶没有很大的偏差。动力学研究表明,该水凝胶在温敏膨胀或收缩时,具有快速的响应速率,在5 min内的失水率达90％以上,这与扫描电镜观察到水凝胶具有大而连贯的孔洞结构相一致。     

Novel polyurethane‐based thermosensitive hydrogels as drug release and tissue engineering platforms: design and in vitro characterization

Poloxamer P407 (P407) is a Food and Drug Administration approved triblock copolymer; its hydrogels show fast dissolution in aqueous environment and weak mechanical strength, limiting their in vivo application. In this work, an amphiphilic poly(ether urethane) (NHP407) was synthesized from P407, an aliphatic diisocyanate (1,6‐hexanediisocyanate) and an amino acid derived diol (N‐Boc serinol). NHP407 solutions in water‐based media were able to form biocompatible injectable thermosensitive hydrogels with a lower critical gelation temperature behavior, having lower critical gelation concentration (6% w/v versus 18% w/v), superior gel strength (G′ at 37 °C about 40 000 Pa versus 10 000 Pa), faster gelation kinetics (<5 min versus 15–30 min) and higher stability in physiological conditions (28 days versus 5 days) compared to P407 hydrogels. Gel strength and PBS absorption at 37 °C increased whereas dissolution rate (in phosphate‐buffered saline (PBS) at 37 °C) and permeability to nutrients (studied using fluorescein isothiocyanate–dextran model molecule) decreased as a function of NHP407 hydrogel concentration from 10% to 20% w/v. By varying the concentration, NHP407 hydrogels were thus prepared with different properties which could suit specific applications, such as in situ drug/cell delivery or bioprinting of scaffolds. Moreover, deprotected amino groups in NHP407 could be exploited for the grafting of bioactive molecules obtaining biomimetic hydrogels. © 2016 Society of Chemical Industry     

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

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

药物控释用智能水凝胶研究进展

智能水凝胶在药物控释方面具有智能化、效率高和安全方便等优点.近年来,研究开发药物控释用智能水凝胶非常活跃,展示了广阔的应用前景.本文综述了药物控释用温度、pH值、葡萄糖、电场、磁场及光敏感水凝胶的最新研究进展.     

Dual responsive block copolymer coated hollow mesoporous silica nanoparticles for glucose-mediated transcutaneous drug delivery

A self-regulated anti-diabetic drug release device mimicking pancreatic cells is highly desirable for the therapy of diabetes. Herein, a glucose-mediated dual-responsive drug delivery system, which combines pH- and H₂O₂-responsive block copolymer grafted hollow mesoporous silica nanoparticles (HMSNs) with microneedle (MN) array patch, has been developed to achieve self-regulated administration. The poly[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate]-b-poly[2-(dimethylamino)ethyl methacrylate] (PPBEM-b-PDM) polymer serves as gate keeper to prevent drug release from the cavity of HMSNs at normoglycemic level. In contrast, the drug release rate is significantly enhanced upon H₂O₂ and pH stimuli due to the chemical change of H₂O₂ sensitive PPBEM block and acid responsive PDM block. Therefore, incorporation of anti-diabetic drug and glucose oxidase (GOx, which can oxidize glucose to gluconic acid and in-situ produce H₂O₂) into stimulus polymer coated HMSNs results in a glucose-mediated MN device after depositing the drug-loaded nanoparticles into MN array patch. Both in vitro and in vivo results show this MN device presents a glucose mediated self-regulated drug release characteristic, which possesses a rapid drug release at hyperglycemic level but retarded drug release at normoglycemic level. The result indicates that the fabricated smart drug delivery system is a good candidate for the therapy of diabetes.     

Thermosensitive hydrogels for modified release of ellagic acid obtained from Alchemilla vulgaris L. extract

Stimulus-sensitive hydrogels are used as carriers for modified release of pharmaceuticals. The synthesis of thermosensitive hydrogels poly(N-isopropylacrylamide), p(NIPAM), and poly(N-isopropylacrylamide-co-2-hydroxypropyl methacrylate), p(NIPAM-HPMet), is performed. The synthesized hydrogels are characterized using FTIR and scanning electron microscope methods and swelling properties, and applied for modified release of ellagic acid (EA). This work presents the selective extraction of EA, as a natural antioxidant, from the aerial parts of Alchemilla vulgaris L. EA and A. vulgaris extract are incorporated into p(NIPAM) and p(NIPAM-HPMet) hydrogels and characterized by FTIR method. The EA content in the extract by the UHPLC–DAD–HESI–MS/MS method is determined (0.64?mg?cm^?3). The total flavonoids content in the A. vulgaris extract was determined by the spectrophotometric method. Antioxidant activity of the A. vulgaris extract and EA is examined using the 2,2-diphenyl-1-picrylhydrazyl assay. The p(NIPAM-HPMet) shows a better incorporation and release at 37°C of EA standard and A. vulgaris extract (98.87 and 96.45% respectively), compared with p(NIPAM).     

Dual-responsive hydrogels based on maleilated curdlan-graft-poly(N-isopropylacrylamide)

The esterification reaction between curdlan and maleic anhydride was performed to provide polymerizable double bonds and pH-sensitive carboxylic groups for the curdlan chains. The new derivative was used as macromolecular cross-linker in the polymerization of N-isopropylacrylamide, when thermo and pH-sensitive networks were obtained in the form of microparticles. The loading and releasing profiles of a model macromolecular drug, lysozyme, were evaluated. The protein release rate was influenced by the pH and temperature. The pulsatile release of the lysozyme was also observed, the pulse being the swelling of the microparticles due to the decrease of the temperature under the volume phase transition temperature.     

温敏聚N-异丙基丙烯酰胺的载药和释药性能研究

以对乙酰氨基酚为模型药物分子,温敏水凝胶聚N-异丙基丙烯酰胺(PNIPAAm)为载体,研究了药物在凝胶上的负载和在不同温度(25和37℃)下磷酸盐缓冲溶液(pH 7.4)中的释放行为.结果表明,对乙酰氨基酚的负载量约为35wt％,并且与载体PNIPAAm存在氢键作用.药物在磷酸盐缓冲溶液中的体外模拟释放结果显示,当温度(37℃)高于凝胶的LCST时,对乙酰氨基酚释放的较慢;当温度(25℃)低于其LCST时,释放的较快.因此,可通过环境温度的改变达到APAP在载体PNIPAAm上控制释放的目的.     

温敏印迹硅胶微球对薯蓣皂素的吸附及控制释放

研究分子印迹聚合物对特定药物的吸附及控制释放具有重要理论和应用价值。本文以硅胶为载体,先对其进行硅烷化修饰,再以薯蓣皂素为模板分子,以甲基丙烯酸（MAA）和N-异丙基丙烯酰胺（NIPAm）为共同功能单体、乙二醇二甲基丙烯酸酯（EGDMA）为交联剂、偶氮二异丁腈（AIBN）为引发剂,通过表面接枝分子印迹聚合物制备了薯蓣皂素温敏印迹硅胶微球。用傅里叶红外光谱及扫描电镜对聚合物表面化学基团及颗粒形貌进行表征。测试了分子印迹硅胶微球的载药性及在不同环境条件下的药物释放行为。结果表明,温敏印迹硅胶微球对薯蓣皂素具有良好吸附性能,其饱和吸附量为21.6mg/g,也具有较高的控制缓释性能。释放动力学表明,其在12h内控制薯蓣皂素释放率为81.9%,而非印迹硅胶微球不具备缓释性。环境条件对温敏印迹硅胶微球的控制释放具有重要影响。当温度为30℃、溶剂为甲醇、NaCl离子强度为1.5×10^-4mol/L时,印迹微球具有最高释放率,达99.28%。     

温敏性聚(N-异丙基丙烯酰胺)/聚丙烯酰胺互穿网络水凝胶

采用紫外引发法制备了物理交联的聚(N-异丙基丙烯酰胺)和化学交联聚丙烯酰胺为组分的互穿网络水凝胶。利用FFIR对所得的凝胶进行了结构分析;测定了该水凝胶在20℃时的溶胀率和50℃时的水保持率;利用DMA和DSC分别研究了水凝胶的储能模量随温度的变化及相转变行为。结果表明:与聚(N-异丙基丙烯酰胺)水凝胶相比,该水凝胶有较好的溶胀率;且具有超快的响应速率,如10 min内失去90%的水;其储能模量增加;虽然其相转变行为变弱,但临界溶解温度(LCST)有所提高。     

介孔羟基磷灰石的合成及药物释放性能研究

本文采用水热合成法,制备出介孔羟基磷灰石,该材料具有较高比表面积和较大的孔容,药物缓释性能测试表明,材料具有较高的药物组装率和较好药物缓释性能,因此,可以作为药物缓释载体,从而更好地实现对骨组织的修复。     

Synthesis of hollow mesoporous silica (HMS) nanoparticles as a candidate for sulfasalazine drug loading

Hollow mesoporous silica nanoparticles have emerged as attractive drug delivery carriers. In this work, we report successful synthesis of hollow mesoporous silica nanoparticles (HMSNs) using poly tert-butyl acrylate (PtBA) nanospheres as hard templates and CTAB as structure directing agent for loading sulfasalazine into its porous structure. The samples were synthesized using PtBA; sodium dodecyl sulfate (SDS) - in an aqueous solution of CTAB and tetraethylorthosilicate (TEOS) as the inorganic precursor. Two different methods were utilized to remove organic phases including calcination, and acidic/basic ethanolic solvent extraction approach. For the latter, microstructural studies using SEM and N₂ porosimetery revealed the formation of highly uniform mono-dispersed particles of sphere morphology (~ 130 nm) with the high specific surface area (1501 m²/g) and mean pore size of ~ 2.6 nm. However, rather deformed and aggregated sphere-like particles were obtained for the calcined samples. TEM examinations also confirmed the formation of 20–30 nm thick walls for the prepared HMSNs particles. Further, HMSN samples treated by solvent extraction method were functionalized by 3-aminopropyl triethoxysilane (APTS) compound for drug delivery. DTA/TG analysis showed that the total amount of loaded sulfasalazine drug was 5.1 wt%.     

Injectable and thermosensitive poly(organophosphazene) hydrogels for a 5‐fluorouracil delivery

The drug solubility and its release profiles of an anticancer drug from an injectable thermosensitive poly(organophosphazene) hydrogel bearing hydrophobic L ‐isoleucine ethyl ester and hydrophilic α‐amino‐ω‐methoxy‐poly(ethylene glycol) with and without hydrolysis‐sensitive glycyl lactate ethyl ester or functional glycyl glycine have been investigated. 5‐Fluorouracil (5‐FU) was used as a model anticancer drug. The aqueous solutions of 5‐FU incorporated poly(organophosphazenes) were an injectable fluid state at room temperature and formed a transparent gel at body temperature. The poly(organophosphazene) solution could enhance the solubility of 5‐FU and its solubility (34.26 mg/mL) was increased up to 10‐fold compared to that in phosphate‐buffered saline (3.39 mg/mL, pH 7.4, 4°C). The in vitro drug release profiles from poly(organophosphazene) hydrogels were established in phosphate‐buffered saline at pH 7.4 at 37°C and the release of 5‐FU was significantly affected by the diffusion‐controlled stage. The results suggest that the injectable and thermosensitive poly(organophosphazene) hydrogel is a potential carrier for 5‐FU to increase its solubility, control a relatively sustained and localized release at target sites and thus decrease systemic side effects. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Development of polyampholyte hydrogels based on laponite for electrically stimulated drug release

Polyampholyte hydrogels (PAHs) composed of laponite, polyacrylamide and poly(3‐acrylamidopropyl)trimethylammonium chloride crosslinked with ethylene glycol dimethacrylate were synthesized and characterized for their sensitivity to external conditions and their ability to control the release of the active drug agent paracetamol. Three PAHs were synthesized by taking the weight ratio of laponite to total monomer as 7, 15 and 29%. PAHs were characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis and swelling measurements carried out in various media. Equilibrium and pulsatile swelling studies were performed on all hydrogels to determine to what extent the hydrogels would respond to changes in environmental pH, ionic strength and electric field, and how fast that response would be. Paracetamol was loaded into the hydrogels, and was released into buffered solutions as a function of pulsatile changes in pH and electric field. © 2014 Society of Chemical Industry     

Interpenetrating polymeric network hydrogels for potential gastrointestinal drug release

New interpenetrating polymeric network (IPN) hydrogels based on chitosan (C), poly(N‐vinyl pyrrolidone) (PVP) and poly(acrylic acid) (PAAc), crosslinked with glutaraldehyde (G) and N,N‘‐methylenebisacrylamide (MBA), were prepared and investigated for potential gastrointestinal drug delivery vehicles utilizing a model drug, amoxicillin. IPN hydrogels were synthesized by simultaneous polymerization/crosslinking of acrylic acid monomer in the presence of another polymer (C) and crosslinker (G, MBA). Three different concentrations of glutaraldehyde were used (0.5, 1.0 and 2.0 w/w) to control the overall porosity of the hydrogels, named C‐P‐AAc/0.5, C‐P‐AAc/1.0 and C‐P‐AAc/2.0, respectively. Spectroscopic and thermal analyses such as Fourier transform infrared spectroscopy, thermogravimetric analysis and thermomechanical analysis were performed for IPN characterization. Equilibrium swelling studies were conducted for pH and temperature response behavior. Swelling studies were also carried out in simulated gastric fluid of pH = 1.1 and simulated intestinal fluid of pH = 7.4 to investigate possible site‐specific drug delivery. It was found that the release behavior of the drug from these IPN hydrogels was dependent on the pH of the medium and the proportion of crosslinker in the IPN. It was observed that amoxicillin release at pH = 7.4 was higher than at pH = 1.1. The analysis of the drug release showed that amoxicillin was released from these hydrogels through a non‐Fickian diffusion mechanism. Copyright © 2007 Society of Chemical Industry     

Stepwise surface modification of mesoporous silica and its use in poly(urethane-urea) composite films

The compatibility between polymer matrix and filler is a vital issue in the fabrication of composites with desirable properties. To enhance the interfacial adhesion between matrix and filler, various surface modification treatments are applied. The objective of this study was to increase the affinity of silica and poly(urethane-urea)s (PUUs), thereby improving the mechanical properties of the resulting composites. Stepwise surface modification of mesoporous silica with amine-containing dendrimers was done. Various techniques were used to confirm the surface-modified structure during the stepwise reaction. Additionally, the N₂ adsorption–desorption method indicated a gradual reduction in surface area, pore diameter and pore volume of the particles, which warrants the gradual propagation of the dendrimers on the surface and also inside the pores. A type IV isotherm was obtained in this analysis. Two types of pre-synthesized PUUs were chosen for composite preparation containing the surface-modified silica with 0.5, 1, 2.5 and 5 wt% concentrations. Due to the high affinity of the dendrimers containing amine moieties on the particles with polyurethane, a proper dispersion of particles in the matrix was achieved based on scanning electron micrographs. Tensile measurements showed an increased Young's modulus and strength of polyurethane films as a result of addition of the particles. However, no significant improvement in the tensile performance of the composites was seen above 2.5 wt% particle loading due to some particle aggregations. © 2021 Society of Industrial Chemistry.     

Effect of fluorinated hydrophobic monomer on the drug release behavior for the thermosensitive hydrogels

Three series of copolymeric gels based on N‐isopropylacrylamide (NIPAAm) and perfluoroalkyl methacrylate such as 2,2,3,3,4,4,5,5‐octafluoropentyl methacrylate (OFPMA), 4,4,5,5,6,7,7,7‐octafluoro‐2‐hydroxy‐6‐(trifluoromethyl)heptyl methacrylate (OFHHMA), and 3,3,4,4,5,6,6,6‐octafluoro‐5‐(trifluoromethyl)hexyl methacrylate (OFHMA), were prepared by emulsion polymerization. The effect of perfluoroalkyl methacrylate and sodium lauryl sulfate (SLS), which can act as a surfactant and a pore‐forming agent, on the equilibrium swelling ratio and mechanical properties of the present hydrogels was investigated. Results show that hydrophobic monomers made the swelling ratio of the gel decrease and the mechanical property of the gel increase; however, SLS exhibits a contrary result. In addition, the effect of perfluoroalkyl methacrylate on the drug release behavior was also investigated. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 4661–4667, 2006     

Investigation of loading and release in PVA‐based hydrogels

We used Methylene Blue (MB) and Methyl Orange (MO) as model drugs to investigate the controlled release behavior of hydrogels from poly(vinyl alcohol) crosslinked with ethylenediaminetetraacetic dianhydride. The cationic or anionic character of these compounds and the molecular weight between crosslinks of the hydrogel and the concentration of ionizable groups in the hydrogel greatly affected the loading and release of the drugs. MB loading was favored, therefore, by a higher content of negative charges in the hydrogel, although this implied a greater degree of crosslinking and, therefore, a lower mesh size. On the other hand, the overall loading of negative MO, favored by a higher mesh size, was very low because of unfavorable interactions with the electrolyte charges. Release studies showed that one of the parameters that most affected the drug release behavior of these hydrogels was the pH of the solution. MB and MO were not completely released, even at pH 1. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 85: 1644– 1651, 2002.     

Effect of hydrophobicity of a drug on its release from hydrogels with different topological structures

The effect of the topological structure; that is, the network heterogeneity, of hydrophobically modified, slightly acidic hydrogels on the binding and release of low molar mass drugs has been studied using ibuprofen and ephedrine as model compounds with varying water solubility. The difference in the heterogeneity of the gels has been produced by the choice of the hydrophobe copolymerized into the polymer network. The effect of the drug loading on the release kinetics has been investigated as well. The release of hydrophobic ibuprofen was slower from a strongly aggregated heterogeneous gel than from a more homogeneous one, because of the strong hydrophobic interaction between ibuprofen and the heterogeneous hydrogel. The release of hydrophilic ephedrine from the homogeneous gel with an initial drug content of 30 wt % of dry polymer showed negative time dependence, indicating that during and after the swelling of the gel, ephedrine started to bind to the polymer. However, the release of ephedrine from a heterogeneous hydrogel increased with time. This shows that the heterogeneous, aggregated polymer binds the hydrophobic substance more strongly than the homogeneous one does, and that the homogeneous network has higher affinity for the basic hydrophilic substance than the heterogeneous one does. The loading contents of ibuprofen and ephedrine affect the release rates in different ways because of the different binding and release mechanisms. The number of binding sites accessible for ephedrine inside the polymer network is assumed to change upon the swelling of the gel. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 73: 1031–1039, 1999     

聚乙撑二氧噻吩/二氧化硅复合材料制备及导电性研究

以表面含磺酸基团的改性二氧化硅纳米微球为填料,以三氯化铁(FeCl3)为氧化剂,对甲苯磺酸钠(TSANa)为掺杂剂,氧化聚合乙撑二氧噻吩(EDOT),制备了具有良好导电性的PEDOT/SiO2复合材料。并利用X射线光电子能谱(XPS)、扫描电子显微镜(SEM)和四探针等手段进行了表征。结果表明:当FeCl3与EDOT的摩尔比为0.8,TSANa的质量分数为10%,反应时间为4 h,得到的复合材料具有较高的电导率。