细胞内还原环境响应性层层自组装纳米载药系统抗肿瘤转移的药效与机理研究

Reducible sensitive self-assembled nanocomposites (RLN) was developed to reduce the tumor metastasis of breast cancer. shRNA of NF-κB/Snail and curcumin was encapsulated into the RLN by by layer by layer assembly technique. Curcumin was conjugated with the Octarginine with a reducible sensitive disulfide bond, which could be degraded in the reducible intracellular microenviroment. Effect of RLN on the invasion and migration of higher metastatic breast cancer cells was investigated. Moreover, the cellular uptake,cytosolic transfer and retardation of RLN was investigated to clarify the possible mechanism . Furthermore, the in vivo pharmacokinetics, distribution,its metabolism of RLN in various organs and its activity on reducing the tumor metastasis was determined in an orthotopic model of metastatic breast cancer.

本项目拟针对恶性肿瘤转移的关键问题，采用自组装层层包载技术，根据肿瘤细胞内还原环境的生理学特性，同时包载干扰RNA和小分子药物姜黄素，设计构建对肿瘤细胞内还原环境响应性的纳米载体系统（RLN），选择高转移性乳腺癌细胞（4T1或MDA-MB-231）和稳定表达虫荧光素酶的乳腺癌原位转移模型，研究纳米载体系统在肿瘤细胞及肿瘤动物模型体内的行为过程，从细胞水平和整体动物水平评价其抑制肿瘤转移的效果，揭示RLN降解特性及其抗肿瘤转移的作用机理。

本研究主要开展细胞内还原环境响应性层层自组装纳米载药系统抗肿瘤转移的药效与机理研究，设计合成了对细胞内还原环境响应性功能性材料DOPE-S-S-r9，采用层层自组装技术，通过模拟蛋白花冠的特性制备了白蛋白仿生的纳米花冠载体DRI-S@HSA，同时包载Twist的siRNA和光热治疗剂IR-780，用于抗乳腺癌生长和转移的研究。结果表明DRI-S@HAS为团簇状纳米颗粒，在高转移乳腺癌细胞4T1中能够被大量摄取，并且显著抑制肿瘤细胞的迁移和增殖能力。在乳腺癌原位转移模型中，DRI-S@HAS能够显著提高在肿瘤部位的蓄积和深部穿透，而且在肿瘤部位具有良好的光热效应。药效评价结果表明DRI-S@HAS能够使乳腺癌原位肿瘤的生长抑制83.6%，肺转移的发生降低92.2%，显著抑制乳腺癌的生长和转移，从而为乳腺癌转移提供了一种有效策略，这种白蛋白仿生纳米花冠为靶向肿瘤的药物输送提供一种具有广泛应用前景的药物输送平台。相关研究在Adv Fucnt Mater、ACS Nano等国际权威期刊发表SCI论文6篇（IF>10的3篇），申请发明专利2项，获得2015年中国科学院王宽诚人才奖等奖励与荣誉4项。