聚乙二醇化纳米药物的制备及抗肿瘤性能研究

发布时间：2018-01-20 17:39

本文关键词： 聚乙二醇化纳米药物自组装超分子交联小分子前药　出处：《浙江大学》2017年博士论文　论文类型：学位论文

【摘要】：传统小分子化疗药物治疗选择性差,毒副作用大,在新研发的化疗药物中,聚乙二醇化修饰的纳米药物最有希望替代现有化疗药物。通过聚乙二醇化修饰,纳米药物表面水溶性增加,且可以有效防止免疫系统的追踪,延长了纳米药物的体内循环时间。然而,通过自组装形成的纳米药物在血液循环中易解组装,引发药物到达肿瘤部位前提前释放。本文设计制备了三种新型交联固定纳米结构的还原响应聚乙二醇化纳米药物,为聚乙二醇化纳米药物的潜在临床应用提供了新思路。嵌段聚合物的自组装是制备聚合物纳米药物的主要方法之一,本文提出了一种简易制备还原响应核交联聚乙二醇化纳米药物的新方法。采用免官能团保护的“一锅”缩聚法合成了疏水段含有多巯基的聚乙二醇化脂肪族聚酯,在自组装形成负载紫杉醇胶束的同时,通过对巯基的氧化交联或原位巯—烯“点击”交联制备了核交联载药胶束。该聚乙二醇化纳米药物可以在还原环境下快速解交联,释放紫杉醇,并表现出良好的抑制肿瘤细胞生长的能力。有望作为一种可降解纳米药物实现规模化制备和应用。简单明确的化学组成更利于纳米药物的理化性能分析及临床审批。本文设计合成了一种仅含两组分的核交联聚乙二醇化纳米药物。含有两官能度金刚烷修饰的喜树碱前药与疏水段含有多个环糊精的聚乙二醇嵌段聚合物自组装形成胶束时发生主客体包合,实现药物稳定负载的同时实现了纳米药物的核交联。与传统化学交联的纳米药物相比,该以主客体包合物为物理交联点的纳米药物制备方式更加简便,化学组成更加明确,更有利于实现纳米药物的临床应用。对于寡聚乙二醇与药物化学键合形成的纳米药物,往往具有较高的临界胶束浓度,纳米药物容易解组装,而对其进行化学交联将使纳米药物化学构成复杂化,很难通过药监部门的审批。本文设计制备了一种基于主客体作用的超分子聚乙二醇化纳米药物:通过二硫键连接金刚烷与喜树碱,合成了结构明确的还原敏感小分子前药;通过对环糊精的聚乙二醇化修饰,制备了含多个仲氨基团的聚乙二醇—环糊精键合物;以上两者通过主客体包合即可形成两亲性超分子聚乙二醇化前药,在水中自组装得到纳米药物;对聚乙二醇—环糊精部分进行化学交联可进一步提高纳米药物的稳定性。该方法可同时实现聚乙二醇化纳米药物在低浓度下纳米结构的稳定以及药物分子的单一化学组成。该聚乙二醇化纳米药物在肿瘤微环境中可通过二硫键的响应性断裂迅速释放出喜树碱分子,小鼠抑瘤实验表明其具有优异的抗肿瘤性能,且毒副作用很小。该研究为聚乙二醇化纳米药物的设计提供了新思路。
[Abstract]:Traditional small molecular chemotherapeutic drugs have poor selectivity and toxic side effects. Among the newly developed chemotherapeutic drugs, polyethylene glycol modified nanopharmaceuticals are the most promising alternatives to existing chemotherapeutic drugs. The surface water solubility of nanopharmaceuticals is increased, and it can effectively prevent the tracking of immune system, prolonging the circulating time of nanopharmaceuticals in vivo. However, the nanopharmaceuticals formed by self-assembly are easy to be unassembled in the blood circulation. Three novel reduction-responsive polyethylene glycol nanopharmaceuticals with cross-linked fixed nanostructures were designed and prepared before the initiation drug reached the tumor site. The self-assembly of block polymers is one of the main methods to prepare polymer nanopharmaceuticals. In this paper, a new simple method for preparation of reductive nuclear cross-linked polyethylene glycol nanopharmaceuticals is proposed. The "one pot" protected by functional groups is used. Poly (ethylene glycol) aliphatic polyester containing many sulfhydryl groups in hydrophobic segment was synthesized by condensation. At the same time of self-assembly to form paclitaxel micelles. The nucleated drug carrier micelles were prepared by oxidative crosslinking of sulfhydryl groups or in situ "click-click" crosslinking of mercaptopenes. The polyethylene glycol nanoparticles could be rapidly uncrosslinked and released paclitaxel in a reduced environment. It is expected to be a biodegradable nano-drug for large-scale preparation and application. Simple and clear chemical composition is more conducive to the physical and chemical performance analysis and clinical review of nanopharmaceuticals. In this paper, we designed and synthesized a nuclear crosslinked polyethylene glycol nanopharmaceuticals containing only two components. The two functional amantadine modified camptothecin prodrugs and hydrophobic segments containing multiple cyclodextrins were self-assembled. The inclusion of the host and the object occurs when the micelles are assembled. Compared with the traditional chemically crosslinked nanopharmaceuticals, the method of preparing nanopharmaceuticals with host and guest inclusion compounds as physical crosslinking point is more convenient than that of traditional chemically crosslinked nanopharmaceuticals. Chemical composition is more clear, more conducive to the clinical application of nanopharmaceuticals. For nano-drugs formed by chemical bonding of polyethylene glycol with drugs, there is often a higher critical micelle concentration. Nanopharmaceuticals are easy to be unassembled and chemically crosslinked will complicate the chemical composition of nanopharmaceuticals. In this paper, a supramolecular polyethyleneglycol nanopharmaceuticals based on host and guest interaction were designed and prepared, which were connected with camptothecin and adamantane by disulfide bond. The reductive sensitive small molecule prodrug with clear structure was synthesized. The polyglycol-cyclodextrin bond containing several secondary amino groups was prepared by the modification of cyclodextrin. The above two can form amphiphilic supramolecular polyethylene glycol pre-drug by host and guest inclusion and self-assemble in water to obtain nano-drug. The stability of nanopharmaceuticals can be further improved by chemical crosslinking of PEG-cyclodextrin. This method can simultaneously stabilize the nanostructure of PEG-cyclodextrin at low concentration and the single drug molecule. Chemical composition. The polyethylene glycol nanopharmaceuticals can rapidly release camptothecin molecules in tumor microenvironment by disulfide bond responsive breakage. The anti-tumor test in mice showed that it had excellent anti-tumor properties and had little side effects. This study provided a new idea for the design of polyethylene glycol nanoparticles.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：TQ460.1

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