新型NOTCH1抗体-多壁碳纳米管- γ分泌酶抑制剂复合物抗急性T淋巴细胞白血病的研究

项目名称： 新型NOTCH1抗体-多壁碳纳米管- γ分泌酶抑制剂复合物抗急性T淋巴细胞白血病的研究

项目编号： No.81200381

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 刘胡丹

作者单位： 华中科技大学

项目金额： 23万元

中文摘要： 急性T淋巴细胞白血病(T-ALL)是一种常见的儿童恶性肿瘤，严重威胁青少年健康。文献报道，NOTCH1信号通路异常激活对T-ALL的发生发展至关重要，T-ALL细胞高度依赖NOTCH1的活性生长增殖，故以γ-分泌酶抑制剂（GSI）为代表的NOTCH1抑制剂是目前最有前景的分子靶向药物，然而其组织非专一性引起的毒副作用不容忽视。为克服现有的局限性，本课题提出一种纳米复合物给药系统的策略: 以聚乙二醇功能化的多壁碳纳米管运载GSI分子，同时结合 NOTCH1单克隆抗体以提供靶向。拟采用纳米生物学，分子生物学，细胞生物学以及模式动物等学科交叉的研究方法，1)构建、表征上述载药系统;2)分析复合物抑制NOTCH1活性和T-ALL细胞系的生长情况;3)考察复合物在小鼠模型体内的分布和抗白血病活性。该项目将为探索一个新型、高效、专一、低毒并具有实用前景的T-ALL治疗方案提供新思路。

中文关键词： 靶向治疗；多壁碳纳米管；NOTCH 信号通路；Wnt 信号通路；天然产物

英文摘要： Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive and life-threatening cancer, commonly diagosed in children and adolescents. More and more evidence suggest aberrant NOTCH1 signaling plays a pivotal role in the pathogenesis of acute T-cell lymphoblastic leukemia (T-ALL). As NOTCH1-induced T-ALL cells depend on NOTCH1 signaling for their proliferation, growth and survival, the γ-secretase inhibitor(GSI), one common NOTCH1 inhibitor, is viewed as the most promising agent to treat T-ALL. However, GSI manifested intolerable toxicity in human patients due to its nonspecific targeting. To extenuate the adverse effect, we propose a novel nano-composit drug delivery system: GSI molecules will be loaded onto polyethylene glycol (PEG)-coated multi-wall carbon nanotubes (MWCNTs), to which anti-NOTCH1 monoclonal antibody will be also conjugated. Combining approaches of nanobiology, molecular biology, cell biology and animal modeling, we plan to (1) synthesize and characaterize the NOTCH1 antibody-MWCNT-GSI composit;(2) analyze its inhibitory function of NOTCH1 signaling and T-ALL cell proliferation;(3) study the anti-leukemic activity and in vivo distribution in T-ALL murine models. Our study aims to build the foundation for ultimately achieving a better therapeutic strategy of improved targeting,optimized activi

英文关键词： Targeted therapy；Multi-wall carbon nanotubes；NOTCH signaling；Wnt signaling；Natural product