乳腺癌耐药蛋白 （BCRP）是近年来新发现的转运蛋白，其表达水平与肿瘤耐药呈正相关。因此，利用治疗性siRNA沉默肿瘤中BCRP的表达，可阻断肿瘤耐药。本课题拟在前期研发的PEG-胆酸纳米胶束基础上，设计可共载siRNA、药物，并能克服递送过程中多级生物学障碍的新型纳米载体。纳米胶束内引入的聚乙烯亚胺（PEI）既可通过静电相互作用包裹siRNA，又可通过“质子海绵效应”协助内含体逃逸。双硫键交联可提高纳米胶束的体内稳定性和基于EPR效应的肿瘤富集。50%以上临床乳腺癌过度表达促黄体激素释放激素（LHRH）受体，LHRH多肽修饰可增加纳米胶束的乳腺癌细胞靶向特异性和胞内摄取。pH/还原双重响应性有利于纳米胶束在细胞内“两阶段”释放基因、药物，最大限度实现协同治疗效应。共载BCRP-siRNA/阿霉素纳米胶束抗乳腺癌疗效如能在动物模型（尤其是PDX模型）获得成功，将具有重要临床转化意义。

Breast cancer resistance protein (BCRP) is a newly discovered transporter protein, and its expression is positively correlated with cancer drug resistance. Therefore, the use of therapeutic siRNA silencing BCRP expression can overcome cancer drug resistance. Based on our previously developed PEG-oligocholic acid polymeric micelles, we propose to design and develop a new class of nano-carrier, which is able to co-load therapeutic siRNA and drugs, and overcome the multi-stage biological barriers for gene and drug delivery. The introduction of polyethyleneimine (PEI) into micelles will help wrap siRNA through electrostatic interactions, and facilitate the endosome escape of micelles through "proton sponge effect". Disulfide cross-linkage will improve in vivo stability of micelles and increase the EPR effect-based tumor accumulation. It has been reported that more than 50% of breast cancer patients over-express luteinizing hormone-releasing hormone (LHRH) receptors. The decoration of nanocarrier with LHRH peptide will facilitate the breast cancer cell targeting and receptor-mediated intracellular uptake. pH/redox dual response will achieve controlled "two-stage" intracellular gene/drug release to produce a maximum synergistic effect. If successfully proven in animal models (particularly PDX model), this novel nano-micelle system for co-delivery of BCRP-siRNA and doxorubicin will have great translational potential in clinic.