肿瘤新生血管靶向微泡-双配体修饰的载药纳米粒复合物体系构建及其抗肿瘤性能评价

微泡爆破能增加内皮间隙和胞膜通透性，而纳米粒具有较好的生物相容性、载药量高、性能稳定，故将两种体系优势组合，构建微泡-载药纳米粒复合物，较具应用前景。但体内环境下如何促进纳米粒被肿瘤组织有效摄取并减少网状内皮系统(RES)吞噬等非特异性聚集，是亟待解决的问题。前期研究中利用叶酸受体的内吞作用及穿膜肽主动穿膜的协同效应，我们已制备出叶酸、穿膜肽双配体载紫杉醇纳米粒，并证实双配体修饰对肿瘤细胞内纳米粒摄取有增效作用。本课题拟将靶向肿瘤新生血管的微泡通过生物素-亲和素桥与双配体纳米粒偶联构建复合物，该体系借助靶向微泡引导首先聚集于肿瘤血管，并通过超声定向爆破和双配体作用实现药物靶向输送，最终促进肿瘤血管内皮细胞及肿瘤细胞有效药物摄取。微泡成膜材料中DSPE-PEG2000-COOH的加入有利于体系逃逸RES同时为配体化学连接提供了功能基团。靶向微泡引入体系有助于减少非特异聚集，且兼具分子探针潜能

Ultrasound targeted microbubble destruction (UTMD) could increase endothelial gap and membrane permeability and drug loaded nanoparticles (NP) are of efficient payload capacity, therefore by combining advantages of the two systems, the complexes of microbubbles and nanoparticles will have a promising application prospect in drug delivery. However, there is an urgent problem needs to be studied whether the NP could be effectively uptaken by cancer cells in vivo and avoid the uptake by reticuloendothelial systems (RES). In previous studies, by utilizing folate targeting effect and Tat transmembrane ability we have designed folate and cell penetrating peptide modified paclitaxel loaded NP successfully and confirmed higher cellular uptake efficiency in tumor tissue. Herein, we aimed to develop a novel drug delivery and imaging system by conjugating to tumor-neovascular targeted microbubbles to NP through avidin-biotin chemistry. This system could accumulate in tumor vascular and achieve targeted drug delivery by utilizing dual ligand effects and US effect, hence enhance targeted celluar uptake in tumor endothelial cells and tumor cells. The conjugation of targeted microbubbles to NP can attribute to reduce unspecific accumulation of nanoparticles , increase enhance specific intracellular drug delivery and perform molecular imaging at the same time. DSPE-PEG2000-COOH, one of film materials chosen to prepare microbubbles, is able to reject NP uptake in RES and provide functional group for ligand link chemistry.