环γ-聚谷氨酸涂层的双重响应性载阿霉素纳米胶束及其抗肿瘤效应

常用肿瘤化疗药物水溶性低、稳定性差、体内循环时间短、缺乏肿瘤靶向性，影响治疗效果，甚至引起严重毒副作用。纳米载体可以增强药物的肿瘤靶向性，提升药物稳定性并延缓药物释放。我们从水母刺丝囊分离鉴定了一组全新小分子环γ-聚谷氨酸(cyclo-γ-PGA)，与链状γ-聚谷氨酸同属聚阴离子类多肽分子，但又具有环肽结构，性能更加稳定；还以光敏剂原卟啉和含二硫键的硫辛酸为疏水基团，聚乙二醇单甲醚为亲水基团，设计制备了双重响应性纳米胶束mPEG-LA-PpIX。本项目拟进一步制备cyclo-γ-PGA涂层的载阿霉素纳米胶束mPEG-LA-PpIX-DOX@cyclo-γ-PGA，阐明cyclo-γ-PGA作为生物涂层在提升纳米胶束稳定性及利用γ-谷氨酰转肽酶介导的内吞途径增加细胞对胶束摄取等方面的优势；同时明确该纳米胶束的还原/光刺激双重响应性能及其体内外抗肿瘤效应，为肿瘤化疗药物输送体系研究提供新思路。

Common cancer chemotherapeutic agents have poor water-solubility, chemical instability and short blood circulation time, and lack tumor specificity, thus limiting their therapeutic effects and even causing serious side effects. Fortunately, the fast development of nanoscale transport systems for chemotherapeutic drugs based on carrier materials could help to enhance the targeting capability and stability of the drugs and prolong their release time. We have recently isolated and identified a novel group of small cyclopolypeptides, cyclo-gamma-polyglutamic acid (cyclo-γ-PGA), from the jellyfish nematocysts, which belong to polyanionic polypeptides just like the normal gamma-polyglutamic acid peptide chains but with a stabler cyclic peptide backbone. And we have also developed the dual-responsive nanomicelles – mPEG-LA-PpIX, using photosensitizer protoporphyrin (PpIX) and disulfide bond-containing lipoic acid (LA) as the hydrophobic groups and polyethylene glycol methyl ether (mPEG) as the hydrophilic groups. Furthermore, this study aims to synthesize cyclo-γ-polyglutamic acid-coated nanomicelles loaded doxorubicin – mPEG-LA-PpIX-DOX@cyclo-γ-PGA for elucidating the superiority of cyclo-γ-PGA as coating material in improving the stability of nanomicelles and enhancing the uptake of micelles by cells through gamma-glutamyl transpeptidase mediated endocytosis pathway, and it is expected to confirm the reduction/light dual-responsive properties of these nanomicelles and prove their antitumor effects in vitro and in vivo. The results will shed new light on the research of drug delivery systems for cancer chemotherapy.