基于肿瘤干细胞的始动性与可塑性构建时序性联合给药微纳体系及其抗肿瘤效应的研究

项目名称： 基于肿瘤干细胞的始动性与可塑性构建时序性联合给药微纳体系及其抗肿瘤效应的研究

项目编号： No.31200713

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 生物物理、生化与生物分子学、生物力学与组织工程

项目作者： 王亚洲

作者单位： 重庆大学

项目金额： 22万元

中文摘要： 肿瘤干细胞（CSCs）是肿瘤恶性生物学行为的关键扮演者，是肿瘤发生、转移和治疗抵抗的"种子细胞"。 传统化疗方案虽然能够短期内杀死大量快速增殖的分化型肿瘤细胞，但因缺乏CSCs针对性治疗而无法避免肿瘤的复发与转移。因此本课题基于CSCs在肿瘤演进过程中的始动作用，及其在肿瘤组织微环境诱导下的可塑性，提出将主动靶向CSCs的ADCs和广谱杀伤Non-CSCs的药物联用进行肿瘤给药的新策略。采用同轴静电电喷微纳技术构建时序性多药给药（（AC133-vcMMAF/聚合物A）核层）/（（DOX/聚合物B）壳层）微纳粒，并通过调控电喷系统参数、核壳材料性质实现药物的时序性控释；通过流式细胞仪、免疫组化、移植瘤建模等进行体内外研究分析并评价该多药给药系统对肿瘤生长和细胞亚群分型的影响。项目实施不仅能为肿瘤治疗提供一种全新的给药系统设计策略，还能为针对肿瘤细胞不同分化型态的治疗提供实验和理论依据。

中文关键词： 肿瘤干细胞；抗体偶联药物；静电电喷；核壳结构纳微粒；抗肿瘤

英文摘要： Recent research had revealed that cancer stem cells (CSCs) played an important role in biological properties of malignant tumor cells, and was correlated with carcinogensis, development and drug resistance of cancer as the "seed cells". At present, although cancer chemotherapy modalities can induce death of rapidly growing tumor cell, tumor recurrence and metastasis are still a critical problem to overcome due to lack of selectively or targeted killing can stem cells. In this study, we proposed a new anti-tumor strategy that combination of ADCs targeted killing CSCs with another cytotoxic drug killing Non-CSCs subpopulation based on the initiating and plasticity of CSCs. The (AC133-vcMMAF/Polymer A)/(DOX/Polymer B) Micro-/Nano-particles with core/shell structures will be prepared by use of coaxial electrospray, and making these two drugs could be sequentially released from this drug delivery system via the regulation of electrospray parameters and loading materials' properties; Inhibition on growth of xenograft and effects on proportion of CSCs and Non-CSCs will be studied and investigated by FACS, immunohistochemistry, model of xenograft in vitro and in vivo. This study will give a new strategy for design and preparation a drug delivery system against tumor, and provide an experimental and theoretic basis for s

英文关键词： Cancer stem cell；Antibody–drug conjugate；Electrospray；Nano-Micro particles with core-shell structure；Anti cancer