功能性聚合物微球的设计及其在肿瘤微环境触发释放药物递送体系中的应用

发布时间：2018-05-20 08:40

本文选题：药物传输系统 + 乳液聚合　；参考：《兰州大学》2017年硕士论文

【摘要】：目前,化疗仍然是癌症治疗的主要手段。然而,抗癌药物的毒副作用一直是传统化学疗法亟待解决的难题,药物在抑制癌变细胞增殖的同时也容易杀死正常细胞。研究人员着力于制造具有良好的生物可降解性和生物相容性的细胞环境刺激响应性的药物递送系统,如果实现了药物在癌变细胞的靶向释放,那么药物在正常细胞的泄漏将得到解决。抗癌药物的非特异性等诸多问题影响了它的抗癌活性,于是具备多重刺激响应性的药物传输体系成为研究的热点。因此,本论文针对上述的问题,首先合成了醛基功能化的小分子疏水单体4-甲酰基苯基丙烯酸酯(FPA),然后分别与聚乙二醇二甲基丙烯酸酯(PEGMA),甲基丙烯酸(MAA),丙烯酰-β-环糊精(ACD)通过乳液聚合制备了载药性能良好,具有良好生物降解性的刺激响应性的聚合物微球。然后对不同药物负载方式下形成的药物载体微球的药物释放行为进行了研究。本论文的工作有以下三个部分:1.通过乳液聚合制备得到了pH/氧化还原双刺激响应性前药微球P(FPA-co-PEGMA)。其中可生物降解的二硫键会在还原性介质中发生断裂。作为药物载药,它利用通过FPA中的醛基和阿霉素的氨基形成亚胺结构,以共价键的形式完成药物的负载。1H NMR谱图表征了小分子单体FPA的结构,纳米微球的形貌和粒径分别是由TEM和DLS观察的。通过观察该纳米粒子降解后的粒径研究了其降解性能。因为亚胺结构在中性条件下相对稳定,因此该药物载体在肿瘤微环境中能够可控释放阿霉素,从而避免了对正常组织的损害。良好的降解性能、pH/氧化还原双重响应性使其具有成为智能药物递送体系的巨大潜力。2.通过乳液聚合制备了P(FPA-co-PEGMA-co-MAA)纳米粒子。通过TEM,DLS表征了该纳米粒子的形貌和粒径。在相同条件下研究了该微球的降解行为。该纳米药物载体可以通过化学键合和静电吸附吸负载阿霉素。于是通过三种不同的负载方式完成了抗癌药物阿霉素的吸附。在体外模拟药物释放实验中三种微球的药物释放行为表明了该纳米粒子具备pH和Redox双重刺激响应性。所以,该纳米粒子在癌症治疗领域有广大的应用价值。3.通过丙烯酰氯和β-环糊精合成丙烯酰-β-环糊精(ACD),利用乳液聚合制备了纳米粒子P(ACD-co-FPA)。该药物载体可以通过FPA的醛基进行化学键合载药,也可以通过环糊精的疏水作用进行载药。通过DLS和TEM观察该纳米粒的粒径和形貌。通过观察该微球在不同时间段的降解行为研究了其降解性能。药物的释放研究表明了该纳米粒子具备pH/氧化还原双重刺激响应性,因而该药物传输体系可实现药物在肿瘤组织或癌细胞中的智能可控释放。
[Abstract]:At present, chemotherapy is still the main means of cancer treatment. However, the toxicity and side effects of anticancer drugs have always been a difficult problem to be solved in traditional chemotherapy. Drugs can inhibit the proliferation of cancerous cells and kill normal cells at the same time. The researchers are working on a drug delivery system with good biodegradability and biocompatibility that stimulates the response of cells to environmental stimuli, if the targeted release of drugs in cancerous cells is achieved. Then the release of the drug in normal cells will be resolved. The nonspecificity of anticancer drugs has affected its anticancer activity, so the drug delivery system with multiple stimuli response has become a hot topic. Therefore, this paper aims at the above problems, A small hydrophobic monomer, 4-formylphenyl acrylate (FPAA), was first synthesized, and then it was prepared by emulsion polymerization with polyethylene glycol dimethacrylate (PEGMAA), methacrylate (MAA), and acryl- 尾 -cyclodextrin (ACD). Polymer microspheres with good biodegradability and irritability. Then the drug release behavior of drug carrier microspheres under different drug loading modes was studied. The work of this thesis has the following three parts: 1. PH/ redox double stimulative prodrug microspheres (PFPA-co-PEGMAA) were prepared by emulsion polymerization. The biodegradable disulfide bond breaks in reducing medium. As a drug carrier, it forms an imine structure through the aldehyde group in FPA and the amino group of adriamycin. The structure of the small molecular monomer FPA is characterized by covalent bonding. The morphology and particle size of the nanoparticles were observed by TEM and DLS, respectively. The degradation performance of the nanoparticles was studied by observing the particle size after degradation. Because the imine structure is relatively stable under neutral conditions, the drug carrier can release adriamycin in tumor microenvironment, thus avoiding damage to normal tissue. The high biodegradability (pH / redox dual response) makes it have great potential as an intelligent drug delivery system. PfPA-co-PEGMA-co-MAA nanoparticles were prepared by emulsion polymerization. The morphology and particle size of the nanoparticles were characterized by Tem DLS. The degradation behavior of the microspheres was studied under the same conditions. The nano-drug carrier can adsorb adriamycin by chemical bonding and electrostatic adsorption. Thus, the adriamycin adsorption of the anticancer drug was completed by three different loading modes. The drug release behavior of three kinds of microspheres in vitro simulated drug release experiments showed that the nanoparticles were both responsive to pH and Redox stimuli. Therefore, the nanoparticles have a wide range of application value in the field of cancer treatment. Acryl- 尾 -cyclodextrin (ACD) was synthesized by acrylyl chloride and 尾 -cyclodextrin. The drug carrier can be chemically bonded by the aldehyde group of FPA or by hydrophobic action of cyclodextrin. The size and morphology of the nanoparticles were observed by DLS and TEM. The degradation properties of the microspheres were studied by observing the degradation behavior of the microspheres at different time periods. The drug release studies show that the nanoparticles have pH/ redox double stimuli response, so the drug delivery system can realize the intelligent and controllable release of drugs in tumor tissues or cancer cells.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O631;TQ460.1

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