靶向肿瘤微环境的功能蛋白、microRNA和阿霉素联合投递纳米微囊设计及肿瘤抑制研究

项目名称： 靶向肿瘤微环境的功能蛋白、microRNA和阿霉素联合投递纳米微囊设计及肿瘤抑制研究

项目编号： No.51473119

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 一般工业技术

项目作者： 原续波

作者单位： 天津大学

项目金额： 85万元

中文摘要： 肿瘤微环境在肿瘤发生发展中发挥着重要作用，靶向肿瘤微环境需要多靶点协同治疗和可克服肿瘤屏障的药物载体。本课题以单蛋白纳米微囊技术为基础，制备包载VHL-GC/DOX-反义miR结合体的纳米微囊，通过微囊表面修饰磷脂酰胆碱壳层促进纳米微囊体内长循环、肿瘤被动靶向和肿瘤内渗透，进一步利用肿瘤微环境高表达酶或弱酸环境使间隔臂断链并脱去表面壳层，形成表面带靶向因子或呈正电性纳米微囊，利于肿瘤细胞吞噬，并释放VHL调控肿瘤缺氧，释放DOX抑制肿瘤细胞增殖，释放miR抑制VEGF和LOX表达促进血管和细胞外基质正常化，同时协同VHL调控缺氧并增敏DOX化疗，解决肿瘤信号通路的冗余性问题。课题将系统研究纳米载体结构设计与其克服肿瘤屏障在肿瘤内渗透、药物释放、肿瘤微环境调控与肿瘤抑制的关系，同时深入探讨肿瘤微环境调控对纳米载体靶向肿瘤微环境的影响，为开发新型药物载体和靶向肿瘤微环境治疗提供理论依据。

中文关键词： 纳米微囊；靶向输送；肿瘤微环境；协同；肿瘤治疗

英文摘要： Tumor microenvironment plays fundamental roles in tumor growth and metastasis. The tumor infiltrate composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, cancer-associated fibroblastic cells and the hypoxia and acidity environment contributes actively to cancer progression. Thus in the clinical setting the targeting of the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become mandatory. However, the varieties of stromal cells, the complexity of the molecular components of the tumor stroma, and the hypoxia and abnormal vasculature which present huge challenges for the delivery of therapeutants targeting the tumor microenvironment by nanoparticles need synergetic multi-target therapy. MicroRNAs (miRs) have recently emerged as important players involved in regulating multiple aspects of cancer biology and the tumor microenvironment. And von Hippel-Lindau (VHL) protein has been proved to be an efficient suppressor for tumor hypoxia by degrading of hypoxia-inducible factor (HIF), which is a transcription factor that plays a central role in the regulation of tumor hypoxia. In present proposal, we design a microenvironment-responsive nanocapsule for co-delivery of VHL, miR and DOX based on single-protein nanocapsules technology. The nanocapsules were prepared through in-site radical polymerization. Phosphatidylcholine (PC) groups were conjugated to the surface of nanocapsules via enzyme-cleavable peptide or acid-degradable spacer, facilitating the long-circulation in vivo and passive-targeting and penetration of nanocapsules in tumor. After the detachment of PC shell triggered by microenvironment, the expose of target ligand or positive-charges promote the internalization of nanocapsules by intratumoral cells, releasing VHL, miR and DOX to synergistically regulate hypoxia, normalize of tumor vasculature and extracellular matrix, and inhibit tumor. The influence of nanocapsule structure on their intratumoral penetration and drug distribution, and the mechanism of synergetic therapy will be investigated systematically.

英文关键词： Nanocapsules;Targeting delivery;Tumor microenvironment;Synergy;Tumor therapy