酸敏感的聚合物胶束的制备以及生物功能研究

发布时间：2018-08-13 12:09

【摘要】：在影响人类健康的主要疾病中,癌症已经是最主要的威胁之一。越来越多的人因为癌症难以得到治愈而被夺去生命。治疗癌症的常规手段包括化疗,放疗以及手术治疗。虽然普通的放化疗能够很大程度的杀死癌细胞但是同时也会对正常细胞有较大的副作用。所以如何提高药物的肿瘤靶向性以及控制释放同时减小对正常组织的损伤已经成为人们关注的焦点。具有生物响应性的纳米粒子已经被应用于疾病诊断以及提高治疗效果当中。在这些生物响应中,酸响应研究最为广泛。基于肿瘤部位偏酸性的这样一个性质,我们开展了两部分研究工作。第一部分工作我们设计了一个从小分子开始合成经过多步反应而成的三臂聚合物。该聚合物主要包括三个部分:疏水链段PEG,酸响应性的链段以及一个疏水的内核。由于结构的特殊性以及酸响应性单体C7A的存在,我们制备的胶束有以下的特点:胶束的大小将从从95 nm增加到157 nm;当环境中的pH从中性转变为酸性的时候,zeta电位将从电中性转变为带正电(0 mV到20 mV)。在肿瘤的微环境中,癌细胞具有“翻转”的pH梯度并且胞外的pH值较低(pHe=6.5-6.9) 。正是这些特殊的性质,我们制备的胶束能够增加细胞摄取,提高药物在肿瘤的富集程度。第二部分工作我们对天然高分子材料壳聚糖进行化学修饰,从而引入具有组织蛋白酶B响应,且在酸性条件下会断裂的多肽GFLG。以VE-PTX作为前药,通过物理包埋的方法加载到壳聚糖中制备成纳米粒子,并通过静电吸附的方式将靶向肿瘤CD44受体的HA附着在粒子表面以提高靶向性能。一系列的细胞层面实验表明,HA的引入确实能够提高纳米粒子的靶向作用。同时该纳米粒子在促进药物释放以及克服多药耐药性方面也发挥了重要作用。
[Abstract]:Cancer is already one of the major threats to human health. More and more people have been killed because cancer is difficult to cure. Conventional treatments for cancer include chemotherapy, radiotherapy, and surgery. Although regular radiotherapy and chemotherapy can kill cancer cells to a large extent, they can also have significant side effects on normal cells. Therefore, how to improve the tumor targeting of drugs and control release while reducing the damage to normal tissue has become the focus of attention. Bioresponsive nanoparticles have been used in disease diagnosis and treatment. Among these biological responses, acid response is the most widely studied. Based on this property of partial acidity of tumor site, we have carried out two parts of research work. In the first part, we designed a three-arm polymer which was synthesized by multi-step reaction. The polymer consists of three parts: hydrophobic segment PEG, acid-responsive segment and a hydrophobic core. Due to the special structure and the presence of acid responsive monomer C7A, The micelles we prepared have the following characteristics: the size of micelles will increase from 95 nm to 157 nm, and the Zeta potential will change from neutral to positive (0 MV to 20 mV).) when pH changes from neutral to acidic in the environment. In the microenvironment of the tumor, cancer cells have a "inverted" pH gradient and lower extracellular pH (pHe=6.5-6.9). It is precisely these special properties that we have prepared micelles that increase cellular uptake and increase the concentration of drugs in tumors. In the second part, we introduce a polypeptide GFLG, which is cathepsin B responsive and breaks under acidic conditions, by chemical modification of natural polymer chitosan. VE-PTX was used as prodrug and loaded into chitosan by physical entrapment. The HA of tumor CD44 receptor was attached to the surface of the nanoparticles by electrostatic adsorption to improve the targeting performance. A series of cell-level experiments have shown that the introduction of HA can improve the targeting of nanoparticles. The nanoparticles also play an important role in promoting drug release and overcoming multidrug resistance.
【学位授予单位】：北京化工大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O631;TQ460.1

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