新型纳米粒子共递送anti-miR-221和顺铂在三阴性乳腺癌中的协同作用及机制研究

The triple-negative breast cancer (TNBC) high mortality rate. Chemotherapy is the most important part of a comprehensive treatment of TNBC. However, the cisplatin is the cornerstone chemotherapy drugs in TNBC. But, due to low efficacy, toxic side effects limit cisplatin’s efficacy. The previous studies of our project found that nanoliposome cisplatin had the low side effects than traditional cisplatin , and the high drug concentrations in tumor tissue, and more effectively inhibit tumor growth. The anti-miR-221 can sensitizing cisplatin therapy effect by down-regulating STAT3 protein in TNBC. And when combined with the two drugs can be more significantly reduced STAT3 downstream BCL-xl protein, upregulation the apoptotic molecule BAX.We Speculate that the co-delivery anti-miR-221 and cisplatin nanoparticles may play a synergistic role by STAT3 pathway in TNBC.This project aims to study and synthesis the targeted delivery, stable controlled release, low side effects and synergistic effect new nano anti-cancer drugs. Cisplatin is bonded to the lipid PGPC with short acid tail preparing liposomes cisplatin conjugate PGPC-cisPt, then with anti-miR-221 co-assemble into nanoparticles.To use TNBC cell lines and animal models to deep study the drug synergism in vivo and vitro level. And describes the collaborative mechanisms of the drug by STAT3 pathway suppress cancer at the molecular level.

三阴性乳腺癌（TNBC）病死率极高。化疗是TNBC综合治疗最重要部分，而顺铂是TNBC化疗的基石，但因靶向性低、毒副作用大限制了疗效。前期研究发现纳米脂质顺铂副作用小、肿瘤组织药物浓度高，能更有效抑制肿瘤。Anti-miR-221在TNBC中可通过下调STAT3通路增加顺铂敏感性，且两药联用时能更明显下调STAT3下游BCL-xl，上调促凋亡分子BAX。推测纳米粒子共递送anti-miR-221和顺铂可能经STAT3通路对TNBC治疗起协同作用。本课题拟合成一种靶向输送、稳定控释、副作用小并起协同作用的新颖纳米抗癌药物：将顺铂键合到带短羧酸尾的脂质PGPC上制备脂质顺铂共轭物PGPC-cisPt，再与anti-miR-221共组装成纳米粒子，利用TNBC细胞株及动物模型在体内外水平深入研究其对TNBC的协同作用，并从分子水平阐述其经STAT3通路抑癌的协同机制，为TNBC的治疗提供新策略。

三阴性乳腺癌（TNBC）病死率极高。化疗是TNBC综合治疗最重要部分，而顺铂是TNBC化疗的基石，但因靶向性低、毒副作用大限制了疗效。我们前期研究发现纳米脂质顺铂副作用小、肿瘤组织药物浓度高，能更有效抑制肿瘤。同时，我们的前期研究也证实Anti-miR-221在TNBC中可通过下调STAT3通路增加顺铂敏感性，且两药联用时能更明显下调STAT3下游BCL-xl，上调促凋亡分子BAX。故我们推测纳米粒子共递送anti-miR-221和顺铂可能经STAT3通路对TNBC治疗起协同作用。该课题立项之后，我们利用经 PGPC 修饰的新型脂质体纳米材料为载体，构建出同时包载化疗药物顺铂和具有肿瘤抑制功能 anti-miR-221 的纳米复合物（CANPs）。该CANPs 纳米颗粒能够靶向共运输顺铂和 anti-miR-221 到三阴性乳腺癌MDA-MB-231 细胞，并增强了对TNBC的协同增效的杀伤作用。该CANPs 纳米颗粒显著降低了靶基因STAT3和 Bcl-2 的表达水平，从分子水平阐述其经STAT3通路抑癌的协同机制，为TNBC的治疗提供了新策略。

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