“协同靶向”策略构建两性寡肽脂质体介导三氧化二砷前药脑胶质瘤胞内递药及机理研究

中药砒霜有效成分三氧化二砷（As2O3）对脑胶质瘤有良好疗效，但因其分布无特异性，毒性大、治疗窗窄等原因限制其临床应用。经文献及前期研究发现，靶向递药系统受多重机体屏障阻碍仍难以将As2O3准确递送至脑胶质瘤细胞内，因此本项目提出整体考虑As2O3理化性质、机体屏障及脑胶质瘤微环境特点的新型靶向策略，构建兼具“协同靶向”和释药监测的脑胶质瘤递药系统，使As2O3前药、两性寡肽修饰脂质体与Angiopep-2靶头在递药系统透血脑屏障，多级pH响应靶向脑胶质瘤细胞以及前药溶酶体逃逸全过程协同作用实现肿瘤细胞内定位释药与释药监测。本项目将构建患者来源脑胶质瘤移植瘤模型、体外血脑屏障-三维脑胶质瘤细胞模型与CRISPR/cas9技术构建转基因细胞模型，从动物-细胞-分子三个水平研究载体协同靶向、胞内释药及转运机理。本项目的实施将为实现中药的脑胶质瘤胞内递送和释药监测提供新策略与新方法。

Arsenic trioxide (As2O3), an active ingredient of Traditional Chinese Medicine White Arsenic, is a potential agent for anti-glioma therapy for long time. However, its clinical application is limited largely because of the poor tumor distribution, high toxicity and narrow therapeutic windows. Otherwise, although delivered by targeted drug delivery system, As2O3 is still difficult to be targeted accurately and precisely due to the multiple physiological and pathological barrier. In this study, we will construct a multifunctional glioma active targeting drug delivery system embedding the characters of “synergistic targeting” and drug release monitoring. The property of As2O3, the biological characteristics of gliomas and the tumor microenvironment will be considered comprehensively through the combination of As2O3 prodrug, Angiopep-2 and zwitterionic oligopeptide to structure the synergy-targeted liposomes. Our synergistic targeting strategy will effectively assistant As2O3 to overcome multiple barriers, actively target glioma and precisely release in the cytoplasm of cancer cells as well as quantitative monitor the drug release. In addition, we will build patient derived glioma xenografts model and further using in vitro blood-brain barrier and glioma model and gene knockout model to study the transport mechanisms and evaluate the drug delivery system in vivo and in vitro from the molecular, cellular and animal levels. Our project will provide initial strategy and methods for the precise targeting and drug release monitoring Traditional Chinese Medicine in brain glioma.