化疗是治疗因受体缺失而无法进行靶向治疗的三阴性乳腺癌的主要手段之一。但对化疗药物的耐药不仅可导致癌细胞的转移和癌症复发亦是三阴性乳腺癌预后不良和5年存活率低的主要原因之一。因此，如何克服其耐药和转移是提高三阴性乳腺癌治疗的关键。miR-205和miR-34a是具有较好抑制乳腺癌活性的内源性分子。本课题将利用纳米技术构建分别携带miR-205 和miR-34a与化疗药物阿霉素的共递送体系，重点研究microRNA和化疗药物在纳米载体包载和递送条件下的联合用药是否可以抑制三阴性乳腺癌的耐药和转移及联合给药的抑癌效果是否增强和增强机制。在纳米载体制备方面，将采用聚离子自组装技术构建纳米胶束颗粒并同时包载化疗药物阿霉素和具有抑癌功能的microRNA，探讨最佳药物和基因包载条件，检测其共递送进入三阴性乳腺癌细胞的效率和富集与定位，研究其体内外生物学功能及机制，探索三阴性乳腺癌治疗的新方法新策略。

Chemotherapy is one of the major strategies in the treatment of triple-negative breast cancer (TNBC) in which negative expression of receptors results in the failure of receptor-targeted treatment. Drug resistance is one of the major obstacles which subsequently lead to cancer metastasis, the failure of therapy, tumor relapse and poor 5-year survival rate. Thus, overcoming of drug resistance and metastasis inhibition are currently both critical challenges in efficient breast cancer treatment. MiR-205 and miR-34a are RNA molecules that act as endogenous tumor suppressors. In the present study, miR-205 and miR-34a will be encapsulated into nanoparticles with doxorubicin (DOX), respectively, for intracellular codelivery to investigate the synergistic effects of DOX and microRNA (miRNA) on drug resistance and metastasis of breast cancer and disclose the mechanisms. In our experiments, nanocarriers will be generated through electrostatic interaction-mediated self-assembly approach, which can simultaneously encapsulate DOX and miRNA. The encapsulation efficiency, intracellular delivery and localization, the anticancer effects and mechanisms will be characterized by in vitro and in vivo models. The study will provide novel therapeutic approach against triple-nagative breast cancer.

乳腺癌是女性最常见的恶性肿瘤之一。大约15%-20%的乳腺癌由于缺少雌激素受体（ER），孕激素受体（PR） 和HER-2 受体表达而被命名为三阴性乳腺癌（triple negative breast cancer，TNBC）。TNBC具有发病年龄轻，肿瘤细胞分化差，恶性程度高,复发和转移早，病死率高等特点。因缺乏内分泌治疗的受体，对内分泌治疗不敏感。因此，开发有效治疗TNBC的技术是乳腺癌治疗领域亟待解决的挑战。化疗是因无法进行靶向治疗的三阴性乳腺癌的主要手段之一。但对化疗药物的耐药不仅可导致癌细胞的转移和癌症复发亦是三阴性乳腺癌预后不良和5年存活率低的主要原因之一。因此，如何克服其耐药和转移是提高三阴性乳腺癌治疗的关键。miR-34a是具有较好抑制乳腺癌活性的内源性分子。本课题将利用纳米技术构建携带miR-34a与化疗药物阿霉素的共递送体系，重点研究microRNA和化疗药物在纳米载体包载和递送条件下的联合用药是否可以抑制三阴性乳腺癌的耐药和转移及联合给药的抑癌效果是否增强和增强机制。在纳米载体制备方面，将采用聚离子自组装技术构建纳米胶束颗粒并同时包载化疗药物阿霉素和具有抑癌功能的microRNA，探讨最佳药物和基因包载条件，研究其体内外生物学功能及机制，探索三阴性乳腺癌治疗的新方法新策略。