抗EGFRvⅢ抗体介导的聚合物胶束肿瘤靶向性及机理研究

建立肿瘤特异性受体介导的靶向给药载体可能是提高抗肿瘤药物疗效并降低毒副作用的关键。表皮生长因子受体Ⅲ型变异体（EGFRvⅢ）是表皮生长因子受体（EGFR）在肿瘤中最常见的突变形式，未表达于任何正常组织，是一个肿瘤特异性靶点。高分子聚合物胶束以自组装携带抗肿瘤药物，可通过高通透性和滞留效应（EPR）被动积聚于肿瘤部位，但缺乏主动靶向性。因此，将聚合物胶束通过抗EGFRvⅢ抗体或抗体片断（包括单链抗体和Fab）修饰，研究不同修饰配体和不同修饰量与聚合物胶束理化性质、体内外肿瘤细胞靶向性、组织分布、药物代谢动力学、聚合物胶束在肿瘤细胞内亚结构的鉴定与识别以及肿瘤抑制效果等体内外构效关系，探索其实现主动靶向递药的构建规律，阐明抗体修饰聚合物胶束特异性主动靶向递送的机制，建立高靶向性，高肿瘤抑制率，低毒副作用的抗体修饰聚合物胶束mAb-PGG-PTX，并为其他配体修饰药物载体提供借鉴和依据。

In order to specially targeting deliver anti-tumor drugs, decrease side effects on normal tissues and improve the therapeutic effects, the mechanism of active targeting in solid tumors with antibody conjugated polymeric micells will be studied. Epidermal growth factor receptor variant Ⅲ (EGFRvⅢ) is the most common variant of epidermal growth factor receptor (EGFR) in tumor, which does not express in any regular organs and could be a special targeted site for anti-tumor drug delivery. High molecular weight polymeric micells could self-assemble in aqueous as nanoparticles to passively targeting deliver drug to tumor by enhanced permeability and retention effect (EPR). However, it is not an active targeting delivery. Therefore, in this project Poly(Poly(L-γ-glutamyl -glutamine))-Paclitaxel will be conjugated with the specially targeting anti-EGFRvⅢ antibody to be polymeric micells mAb-PGG-PTX. The effects of ligans, monoclone antibody, single-chain antibody, fragments of antibody and contents on the tumor targeting will be investigated both in EGFRvIII positive cells and mice bearing tumors.The endocytosis will be visualized in EGFRvIII positive cells. Furthermore, the content of this mAb-PGG-PTX polymeric micell in plasma and tissues will be determined and the pharmacokinetic parameters will be calculated to bulid up the relationship between the structure and the efficacy. The tumor inhibition and survival rate will be evaluated and compared between the active and passive targeting polymeric micells. Consequently, this project will build up a basic research to know how to actively targeting deliver anti-tumor drug to tumore by antibody-conjugated polymeric micells.