【作者】 黄怡；

【导师】 范晓东；

【作者基本信息】 西北工业大学 ， 材料物理与化学， 2004， 博士

【摘要】 环糊精高分子以及环境响应性高分子在生物医用材料领域中正得到广泛的研究和应用,结合两者各自独特的功能,用作药物控制释放载体预示着潜在的应用前景。本文通过查阅大量文献,总结前人的研究工作,设计并合成出了不同结构和类型的新型环境响应性环糊精高分子。并对其结构与性能的关系以及作为药物控制释放载体的应用进行了较深入的探讨。 反应性环糊精单体是合成环糊精高分子的重要中间体,本文合成了两大类反应性环糊精单体:一类是环糊精分子中具有可与高分子接枝的活性基团[单6-碘代β-环糊精(β-CD-6-I)、单6-甲酰基β-环糊精(β-CD-6-CHO)],另一类是具有可与乙烯基单体共聚的双键的环糊精单体[单6-丙烯酰乙二胺β-环糊精(β-CD-6-EA)和丙烯酰化β-环糊精]。实验表明,利用缩合剂1,3-二环己基碳化二亚胺合成β-CD-6-EA的反应,其反应条件温和,产率较高,控制反应物摩尔比是反应的关键。采用三种不同的丙烯酰化剂(丙烯酸间硝基苯酯、丙烯酰氯和丙烯酸)在碱性水溶液中或有机溶剂中能够得到不同结构和不同取代度的丙烯酰化β-环糊精。 将所合成的带有乙烯基的单取代(β-CD-6-EA)和多取代环糊精单体(β-CD-3-A和β-CD-6-A)与两种功能性单体甲基丙烯酸-N,N-二甲氨基乙酯(DMA)和丙烯酸(AAc),分别合成了两种线性和两种交联的具有环境敏性感的环糊精高分子。此外,又将单β-CD-6-I和β-CD-6-CHO与可反应性的高分子聚甲基丙烯酸-N,N-二甲氨基乙酯(PDMA)和聚乙烯醇(PVA)以固载的方式合成了另外两种线性环糊精高分子。对于以两种不同结构的β-CD-3-A和β-CD-6-A为单体,分别与DMA和AAc通过氧化还原自由基引发共聚得到的两类含β-环糊精结构单元的新型水凝胶(β-CD-DMA和β-CD-AAc),经红外光谱(IR)及元素分析表征了共聚物的结构和组成。溶胀实验结果表明,两类水凝胶均具有较好的pH、温度及离子强度敏感性。新型线性β-环糊精高分子(PDMA-β-CD)是采用季铵化反应将β-CD-6-I固载到PDMA高分子链上。聚合物的水溶性研究结果表明,环糊精含量为30.43(wt)%时该聚合物仍具有较好的pH、温度及离子强度敏感性。利用PVA与β-CD-CHO之间的缩醛化反应合成出的聚乙烯醇固载β-环糊精(PVA-β-CD)线性环糊精高分子,其最佳反应条件是:反应时间2h,温度70℃,β-CD-6-CHO与PVA的质量比小于等于4∶1。 为了了解和掌握环糊精与药物包合作用的规律和机理,本文从研究环糊精母体分子与所选模型药物的包合作用入手,进一步研究环糊精高分子与药物的相互更多还原

【Abstract】 Cyclodextrin polymers and environmental sensitive polymers have been studied and applied extensively in the field of the biomedical materials. The combination with these two polymers possesses a potential application in controlled drug delivery system. In this paper, the novel cyclodextrin polymers were synthesized based on macromolecular design. The relationship between their molecular structure and physical properties was researched in detail. The mechanisms of controlled drug release were investigated by using two anti-cancer drugs, chlorambucil （CHL） and camptothecin （CPT）, as the model medicines.In order to obtain novel cyclodextrin polymers, two kinds of cyclodextrin-containing reactive monomers were synthesized. Monomers were first synthesized including iodide substituted and carrying reactive group of β-CD-6-I and β-CD-6-CHO which can react with some functional polymers. Mono-[6-（2-acryloylaminoethyl） amino]-6-β-CD （β-CD-6-EA） and acryloyl-β-CD both carrying vinyl groups which can be polymerized with other functional monomers were also synthesized. The results indicated β-CD-6-EA can be obtained by using dicyclohexylcarbodiimide （DCC） as condensation agent with a higher yield. By using different reaction conditions and acylation agents including m-nitrophenyl esters, acrylyl chloride and acrylic acid, the different molecular structure with different substitution . degree of acryloyl-β-CD were synthesized. Two kinds of β-CD-containing acrylic monomers, β-CD-3-A and β-CD-6-A carrying the same vinyl groups, were prepared relying on their reactivity of different hydroxyl groups in cyclodextrin. Nuclear magnetic resonance (¹³C NMR) data indicated that, for β-CD-3-A, acylation occurs at C-2 and C-3 position of β-CD, and for β-CD-6-A, the acylation occurs at its C-2 and C-6 position, respectively.Two functional hydrogels, β-CD-DMA and β-CD-AAc, were synthesized by copolymerization of β-CD-3-A and β-CD-6-A with N,N-dimethylaminoethyl methacrylate （DMA） and acrylic acid （AAc） using a redox initiator system in aqueous solutions. The hydrogels were characterized by Infrared spectroscopy （IR） and element analysis. The equilibrium swelling experiments showed that the hydrogels possess pH-, ionic strength and thermo-sensitivities. However, due to the difference of monomer structures, the physical properties of hydrogels, especially their swellingbehavior in response to the external stimuli, exhibited certain difference. It can also be observed that the transition regions for both hydrogels decrease with the increase in contents of /2-CD-3-A or /2-CD-6-A. A novel /?-CD containing linear polymer （PDMA-/2-CD） which has both thermo- and pH-sensitives was synthesized by quatemization of poly-AfjV -dimethylaminoethyl methacrylate （PDMA） using iodide substituted fi-CD as quaternizing agent. The polymer was characterized by IR, ’H-NMR and element analysis. The aqueous solubility experiments showed that the polymer with 30.43（wt）%/?-CD still exhibited pH-, ionic strength and thermo-sensitivities. However, due to the introduction of hydroxyl groups in /?-CD and quaternizing tertiary amine groups, the solubility of novel polymer synthesized, in response to the external stimuli, was much weaker than that of PDMA. Moreover, the other yff-CD containing linear polymer was synthesized by immobilizing /3-CY) onto the linear chain of PVA through acetalization reaction. The optimum reaction condition was determined in which the feed weight ratio of /2-CD-6-CHO with PVA is 4:1 and reaction temperature is at 70°C for two hours. The macromolecular structures of PVA-/2-CD were characterized by IR and NMR.To understand the molecular interaction mechanism of inclusion complex between /?-CD and the medicine, the supra molecular interaction between parent /?-CD with varying drugs such as nicotine, CHL and CPT in aqueous solutions was studied by UV-vis spectrophotometric, ’H-NMR, fluorescence measurement, phase and solubility method. It was found that the inclusion complexes between fi-CD and drugs were indeed formed. The results were further demonstrated by a competitive inclusion process using phenolphthalein as a molecular probe. UV-vis spectrophotometric titration was used to calculate the stability constants of an inclusion complex between /3-CD and CHL in different pH buffer solutions at 10°C. It was found that the inclusion complexes with stoichiometry were formed with a ratio of 1:1 for the fi-CD and CHL under various experimental conditions. Besides, there exists a greater stability constant in pH=4 buffer solution at 10°C. For the system of /2-CD/CPT, the phase solubility method and fluorescence measurements showed that fi-CD and CPT can form inclusion complexes with a ratio of 1:1 under pH values of 2 and 11. The corresponding inclusion constants are 1.19 x 102 L/mol and 4.48 xlO3 L/mol, respectively. The solid inclusion complexes of /?-CD/nicotine, /2-CD/CHL and /2-CD/CPT were also prepared, and the results of IR, DSC and powder X-ray diffraction data indicated that there existnovel crystalline structures for inclusion complex. Then, the inclusion effects of PDMA-/2-CD were obtained by the method of UV-vis spectrophotometric titration using phenothalin as molecular probe, and the inclusion constant of PVA-/3-CD with CPT was also determined.The mechanisms of controlled release were studied by using the cyclodextrin polymer at different medium. The drug release behavior in different polymer matrixes presented marked difference in accordance with release media and the structure of polymers. For hydrogels /J-CD-DMA system, it was observed that due to the inclusion of /?-CD with the CHL, the release rate was lower than in PDMA. However, for the hydrogels /?-CD-AAc, the release rate for CHL was higher than in PAAc. The release rate at pH=6.8 was also higher than of at pH=2.0. In addition, The release of CPT from PVA-/J-CD films showed that due to the formation of inclusion complex of PVA-/2-CD with the drug, the solubility of the CPT increases greatly. And the cumulative release rate and extent can be effectively improved with the increase in P-CD content. A chitosan film containing /3-CD （/3-CD-SUS/CTS） was obtained by sodium succinate /?-cyclodextrin ester （/^CD-SUS） cross-linked with chitosan （CTS） via electrostatic.interaction. Turbidimetric titration revealed that there are electrostatic interactions between /2-CD-SUSO and CTS. The film showed pH value sensitivity depending on degree of ionzation as well as its the swelling ratio. The release behavior of CPT from the inclusion complex film indicated that the release ratio of CPT is affected by inclusion of /2-CD-SUS with CPT as well as ionic interaction of /KD-SUS with CTS.更多还原