多重靶向双药纳米载药纤维的抗肿瘤效果研究及机制分析

肿瘤细胞药物抵抗的关键因素为乏氧细胞的存在以及NF-kB通路的激活。申请人前期证实基于“聚集诱导发光”效应的光敏剂TPE-Py能够有效激发线粒体内的ROS。此外，姜黄素的抗肿瘤活性依赖于抑制NF-kB通路的活性。因此，我们猜想激发ROS的TPE-Py与NF-kB通路抑制剂姜黄素的联合应用可获得更佳的抑瘤效果。为了解决水溶性以及靶向性差的问题，我们构建具有主动靶向EphA2受体的负载姜黄素与光敏剂TPE-Py-FFGYSA的双药纳米载药纤维。首先，在TPE-Py上偶联能够靶向胃癌组织高表达EphA2的小肽YSA使得该光敏剂获得肿瘤主动靶向性。其次，基于“Carrier free”的概念构建具有极高载药量的姜黄素自组装纳米纤维。最后，采用姜黄素纳米纤维负载TPE-Py-FFGYSA来获得一种EphA2及线粒体多重靶向效应的纳米纤维递药体系。在体内外胃癌模型上考察该载药体系的抑瘤效果及机制。

The key factors of drug resistance in cancer cells include the existence of hypoxic cells and the activation of NF-kB pathway. The applicant demonstrated that a novel kind of photosensitizer “TPE-Py” can effectively induce the generation of ROS in mitochondria. In addition, the antitumor effect of curcumin dependents on the inhibition of NF-kB activation. Therefore, we hypothesize that the combinational administration of TPE-Py and curcumin may achieve synergistic antitumor efficacy. To overcome the limitation of poor solubility and lack of targetability of free drugs, we construct a kind of novel co-loaded drug delivery system with the active targeting of EphA2. First, a small peptide YSA with EphA2 targeting ability is conjugated with TPE-Py. Second, a novel kind of curcumin loaded nanofiber delivery system is prepared based on the concept of “Carrier free” with the application of a self-assembled peptide. At last, TPE-Py-FFGYSA is encapsulated into curcumin loaded nanofibers to acquire dual drug-loaded nanofibers with active EphA2 and mitochondria targeting ability. The antitumor effect will be evaluated in in vitro and in vivo cancer models.