基于声控脑靶向相变纳米粒跨BBB机制及对胶质瘤的靶向化疗

The existence of the blood-brain barrier (BBB) seriously affects the therapeutic efficacy of the central nervous system (CNS) diseases, therefore how to explorer a new drug carrier which can overcome the systemic circulation, BBB and meanwhile has higher efficiency, safety and targeting into the brain tissues is becoming the pursuit of researchers. Ultrasound combined with microbubbles, as a new method for targeting BBB disruption, has been extensively studied and show the promising future. With the progress of biomaterials and nano-medicine, according to the theory of acoustic droplet vaporization (ADV) and specific modification of carrier, we intend to design a kind of intelligent and ADV-induced nano-scale brain-targeted drug delivery system. On this basis, we plan to construct a new acoustic-activated brain-targeted nanoparticles consisting of amphiphilic molecules block copolymer as the shell material, perfluorocarbon cores, the anticancer drug doxorubicin and transferrin (Tf) targeting ligand; then through the research on BBB/C6 glioma model in vitro and tumor-bearing mice model under the sonication, we will mainly observe and verify the biological characteristics of the acoustic-activated brain-targeted drug-loaded nanoparticles, the ability of across BBB and the therapeutic efficacy of glioma, in addition, make a deeper exploration on the relative mechanism by means of molecular biology, morphology, imaging and other detection methods, looking forward to achieve some new breakthroughs for the treatment of CNS disorders.

血脑屏障（BBB）的存在严重影响中枢神经系统（CNS）疾病的疗效，探索一种即能通过体循环、跨越BBB，又能有效、安全、靶向进入脑组织的载药体系一直是业界追寻目标。超声介导微泡作为靶向开放BBB策略已初见成效。随着生物材料和纳米医学的进步，根据"声致相变"学说和对载体进行特定修饰，针对BBB，设计一种具有相变性、智能化的脑靶向纳米药物传递系统。研究是在前期工作基础上，通过构建由两性分子嵌段共聚物为膜材料、声致相变的全氟化碳为核心气体、多柔比星为抗肿瘤药物、转铁蛋白（Tf）等为靶向配体组成的声控脑靶向相变载药纳米粒，使其在超声作用下，以体外肿瘤细胞、BBB/C6胶质瘤和载瘤小鼠模型为研究对象, 采用分子生物学，形态学和影像学等方法，重点观察和验证受控于聚焦超声的新型声控脑靶向纳米粒的相变规律、生物学特性、跨BBB能力和靶向抑瘤效果，并对其机制进行探讨，期待对CNS疾病的治疗有所突破。

血脑屏障（BBB）的存在严重影响中枢神经系统（CNS）疾病的疗效，探索一种即能通过体循环、跨越BBB，又能有效、安全、靶向进入脑组织的载药体系一直是业界追寻目标。超声介导微泡作为靶向开放BBB策略已初见成效。根据“声致相变”学说和对载体进行特定修饰，我们针对BBB设计了一种具有相变性、智能化的脑靶向纳米药物传递系统。我们首先通过双乳化法和碳二亚胺法成功制备了以转铁蛋白为靶向配体、以紫杉醇为装载治疗药物、以液态全氟戊烷为内核的相变型聚乳酸羟基乙酸纳米粒(Tf-PTX-PFP-PLGA), 其具备热致相变及声致相变能力，体外靶向鼠C6胶质瘤细胞的能力良好，并能特异性杀伤胶质瘤细胞。其次，成功实现相变型纳米粒联合FUS(1 MHz)开放SD大鼠脑BBB，在满足安全有效的前提下，1.0 MPa为最优声压值。所制备的Tf-PTX-PFP-PLGA相变型纳米粒具有良好的体内靶向能力，联合FUS能有效抑制SD大鼠颅内原位C6胶质瘤的增殖，促进其坏死、凋亡，延长荷瘤鼠中位生存时间。相信通过本项目的研究能为未来中枢神经系统疾病治疗提供一种新的思路。