基于红细胞膜的靶向纳米释药系统抗乳腺癌的肺转移研究

Lung metastasis is the leading cause of death for patients with breast cancer. In this project, poly(ε-caprolactone) (PCL) nanoparticles as core, loading with taxanes alone or together with anti-metastasis drugs (Ator and DSF.) that target key players (MMPs, Snail and Twist) in the EMT process during the lung metastasis of breast cancer, will be coated with red blood cell (RBC) membranes containing photosensitizers (such as DiR or Ce6) and targeting ligands (RGD or MMP-9-responsive ACCP) to construct RBC membrane-based breast cancer targeting and chemotherapeutics/photosensitizers co-delivery system (PN@tDRV). Highly metastatic breast cancer 4T1 cells, et al. will be chosen as models, and techniques such as cryo-TEM and Western blot, et al. will be applied to reveal the relationship between the structures, physicochemical properties of PN@tDRV and their anti-metastasis effects or cytotoxicity, explore the intracellular and in vivo performance of PN@tDRNs, demonstrate the mechanisms that PN@tDRV inhibit the lung metastasis of breast cancer, achieve synergistic effect between anti-metastasis drugs and chemotherapeutic agents, and evaluate the activity in suppressing the growth of primary tumors, the lung metastasis and the preliminary biological safety. The idea of this project is new, and it is hopeful to obtain a major breakthrough in the study on anti-cancer drugs based on nanotechnology and provide valuable references for improving the therapeutic efficacy against metastatic breast cancer.

肺转移是导致乳腺癌死亡的主要原因，本项目拟选择聚（ε-己内酯）（PCL）等包载紫杉烷类药物或共载以肿瘤转移EMT中所涉及的MMPs、Snail及Twist等为靶点的抗转移药物（Ator或DSF等）的纳米粒为内核，将光敏剂DiR或Ce6包入红细胞膜中，并采用RGD或MMP-9酶敏感的ACPP多肽等对其进行靶向性修饰，设计构建基于红细胞膜的靶向共输送乳腺癌化疗药物和光疗剂的新型功能化纳米载药系统（PN@tDRV）。选择乳腺癌高转移性4T1和MDA-MB-231细胞等，采用冷冻电镜、Western Blot等技术揭示PN@tDRV的结构、理化特性与抗转移效果和细胞毒性关系，阐明PN@tDRV的细胞内和体内转运过程，抗乳腺癌肺转移机理及抗转移药与化疗药协同增效的机制，并评价其抗原位瘤生长和抗乳腺癌肺转移的效果及初步生物安全性。项目思路新颖，有望在新型药物靶向控释系统抗乳腺癌肺转移方面取得重大突破。

肺转移是导致乳腺癌死亡的主要原因，发展易被肿瘤细胞摄取、药物释放可控的红细胞膜包覆的纳米载药系统有望在抗乳腺癌肺转移方面取得突破。本项目构建了4种基于红细胞膜的新型纳米递药系统，显著延长了紫杉醇、阿霉素、多西他赛和顺铂等药物的血液循环时间，增加了瘤内药物蓄积，显著抑制了乳腺癌原发灶肿瘤生长和肺转移。证明了红细胞膜包覆与光敏剂的光热和光动力效应结合，能够增强药物的瘤内渗透性和控制药物释放；证明乙酰肝素酶敏感性药物释放机制可实现肿瘤特异性细胞毒性；证明基于红细胞膜的化疗药-光敏剂联合递药系统能够实现化疗和光热、光动力疗法的协同增效。相关研究在国际重要学术刊物上发表高质量论文21篇，其中SCI论文19篇，IF>30的3篇，20<IF<30的1篇，10<IF<20的12篇。申请相关专利3项，获授权2项。培养博士研究生9人，硕士研究生6人。获2020年国家自然科学二等奖1项，获2020年中国药学会科学技术一等奖1项。该研究成果为利用新型纳米载药系统治疗转移性乳腺癌提供了新的思路和手段，对有效提高乳腺癌治疗效果、降低乳腺癌的死亡率具有重要参考意义。