PSCA靶向纳米粒携带新型“联合靶向化学药物”治疗HRPC的生物学效应及其机制

项目名称： PSCA靶向纳米粒携带新型“联合靶向化学药物”治疗HRPC的生物学效应及其机制

项目编号： No.81202012

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 方友强

作者单位： 中山大学

项目金额： 23万元

中文摘要： 药物抵抗及缺乏靶向性是HRPC治疗的难点，目前靶向药物主要针对单一靶点设计，抗癌效果有限。我们研究发现，合成的联合靶向化学药物JDF12能产生比单一功能药物更强的抗PCa能力，该药自身能靶向结合PCa高表达的EGFR，阻断EGFR信号通路，并能进一步水解成另一EGFR TK抑制分子和一个DNA烷基化分子，发挥串联级释放协同抗癌分子治疗HRPC的作用，但该药在体液中稳定性较差，容易水解或结合其它高表达EGFR的器官，产生毒副作用。本研究基于这种新型"联合靶向化学药物"，利用纳米技术合成PSCA单克隆抗体修饰载药纳米粒，包裹药物以提高药物水溶性和稳定性，靶向运输JDF12至特异表达PSCA的PCa细胞，增强药物肿瘤靶向性，减少其毒副作用。体内外检测载药靶向纳米粒抗HRPC的生物学效应，研究其阻断EGFR信号通路并烷基化损伤DNA后细胞DNA修复通路的改变，为临床治疗HRPC提供新的手段和依据。

中文关键词： 前列腺癌；纳米粒；化学药物；表皮生长因子受体；DNA损伤

英文摘要： Drug resistance and target deficiency are the challenges in the treatment of hormone refractory prostate cancer(HRPC). Currently, drugs are usually designed to single target, which may have less anti-tumor effectiveness. Our previous studies revealed that the combi-targeting molecule (JDF12) could achieve more potent anti-tumor effect on prostate cancer(PCa) than monotargeted drugs. JDF12 can specifically bind to epidermal growth factor receptor(EGFR) which is highly expressed in PCa and block EGFR-mediated signaling pathway, further decompose into another EGFR tyrosine kinase(TK) inhibitor plus a DNA alkylating moiety. The later two exert synergistic anti-tumor effect with direct blocking of EGFR signaling pathway on HRPC. However, the stability of JDF12 is poor in liquid and it is susceptible to hydrolysis and easily binds to organs with high EGFR expression resulting in side effects. In the present study, this new drug would be employed to synthesize prostate stem cell antigen(PSCA) monoclonal antibody modified nanoparticle by using nanotechnological technique. This modified nanoparticle has favorable soluability and stability and can specifically transport JDF12 to PSCA expressing PCa cells, which increases the targeting effect and reduces the side effect. In vitro and in vivo detection will be performed to

英文关键词： prostate cancer；nanoparticle；chemicals；epidermal growth factor；DNA damage