胞内外阶梯式触发的钙磷复合脂质药物基因共递送系统对三阴性乳腺癌的治疗研究

项目名称： 胞内外阶梯式触发的钙磷复合脂质药物基因共递送系统对三阴性乳腺癌的治疗研究

项目编号： No.81502692

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 沈鸣

作者单位： 上海交通大学

项目金额： 18.5万元

中文摘要： 针对三阴性乳腺癌易耐药和术后复发、转移的现状，本项目设计一种胞内外阶梯式触发的药物基因共载系统，多机制联合作用提高纳米制剂的靶向性，抑制肿瘤生长和转移。合成mPEG-腙键-透明质酸(HA)-二硫键-磷脂，制备长循环脂质体，包裹抗肿瘤药物紫杉醇(PTX)；同时钙磷与miR-124静电结合，包裹在脂质体内，形成钙磷复合的可裂解长循环脂质给药系统。.给药系统在血循环中依赖于PEG的长循环效应和钙磷对脂质体的稳定作用；到达肿瘤部位时，经由EPR效应进入肿瘤部位，在酸性环境下腙键断裂，PEG脱落，克服PEG的摄取抑制缺点；暴露出的寡聚HA靶向于肿瘤细胞表面的CD44而被摄取；在肿瘤细胞内谷胱甘肽的作用下，二硫键断裂，寡聚HA脱落，拮抗内源性HA，与耐药相关蛋白结合从而克服耐药性；并增加肿瘤细胞粘附性，抑制其转移；钙磷复合脂质纳米粒在溶酶体内解离，释放出PTX和miR-124，发挥抗肿瘤协同作用。

中文关键词： C21_乳腺肿瘤；肿瘤微环境响应；克服肿瘤耐药性；药物基因共递送；肿瘤靶向

英文摘要： The project aims to resolve recurrence, metastasis and drug resistance of triple negative breast cancer, as well as the “PEG dilemma” in long-circulating nano-drug delivery system. A PTX-miR-124 co-delivery nano system of multi-level tumor targeting and anti-tumor capability was designed. A material of mPEG-Hydrazone bond-HA- Disulfide bond-Phospholipids was designed and synthesized. The material was prepared into stepped cleavable long-circulating calcium phosphate composed lipid delivery system response to tumor microenvironment loading PTX in the lipid layer and miR-124 composed with calcium phosphate by electric charge..The NPs depends on the long-circulating capacity of PEG and stabilizing effect of calcium phosphate in the cycle. The hydrazone bond is broken and PEG layer get off in the acidic environment after the NPs get into tumor tissue through EPR effect. Oligo-HA is exposed to target to CD44 on the surface of tumor cells and mediated endocytosis. The disulfide bond is broken by the glutathione in tumor cells and oligo-HA is released to bind with resistance-associated proteins antagonizing endogenous HA. The oligo-HA also increases tumor cell adhesion and inhibits metastasis. At last, the calcium phosphate composed lipid NPs collapse, releasing PTX and miR-124 to produce synergistic antitumor effect.

英文关键词： Breast cancer;Tumor microenvironment response;Overcome drug resistance;Drug & gene co-delivery;Tumor targeting