GLUT1介导的脑靶向细胞微环境敏感聚合物胶束的构建及其抗颅内真菌感染研究

Transport of small molecules, macromolecular drugs into the brain is restricted by the blood-brain barrier tightly. The fungus infection of central nervous system is one of diseases due to the high death rate, difficult treatment. Brain targeting drug delivery system is a powerful means of drug delivery into the brain. The glucose transporter ( GLUT1 ) expressed highly on the surface of the blood-brain barrier and nerve cells is selected as a target site in this project. A brain targeting, cell microenvironment sensitive polymer micelle drug delivery system will be constructed. The chemical bonding cross-linked polymer improves the stability of polymeric micelles. And these micelles can carry the antifungal drugs and improve drug concentration in brain. Based on the existing experience, targeting to GLUT1 on the surface of brain capillary endothelial cells and nerve cells in the brain, small molecule compound will be screened as targeting functional molecular with the BBB crossing and brain nerve cells targeting. A targeting micelle drug delivery system will be constructed. And in order to improve the stability of micelle drug delivery system, the microenvironment sensitive polymer micelle drug delivery system will be designed to reduce drug leakage in the circulation system and improve the brain drug concentration. Finally this drug delivery system is researched to improve therapy effect of central infection.

血脑屏障严密限制小分子、大分子药物向脑内的转运，由真菌引起的中枢神经系统感染性疾病是致死率极高、治疗困难的疾病之一。脑靶向纳米给药系统是药物向脑内递释的强有力的手段。本项目选用血脑屏障、神经细胞表面有较高表达的葡萄糖转运体（GLUT1）为靶点，构建脑靶向、细胞微环境敏感的聚合物胶束给药系统。采用高分子、化学键交联等技术，提高聚合物胶束的稳定性，实现抗真菌药物的脑内靶向浓集。本课题在现有工作经验的基础上，针对脑毛细血管内皮细胞和脑内神经细胞的表面的GLUT1，筛选具有跨越BBB、脑内神经细胞双重功能的小分子化合物作为脑靶向功能分子，进而构建具有跨越BBB、靶向脑内神经细胞特征的靶向纳米胶束给药系统；同时为了提高胶束给药系统的稳定性，设计了细胞内微环境敏感的聚合物胶束给药系统，减少药物在循环系统的泄漏，提高药物脑内浓集效率，可望提高中枢感染的靶向治疗效。

由于血脑屏障（blood-brain barrier，BBB）等相关机制的影响，药物的脑内递送需要高效的脑靶向和稳定的递药系统。利用脱氢抗坏血酸（DHA）作为靶向功能分子我们研究了脑靶向纳米给药系统。 DHA与BBB上的GLUT1具有高亲和力。更重要的是，DHA的GLUT1转运表现为优先从血液到脑部的“单向”累积。纳米胶束由二硫键连接而成，形成一个具有生物反应的内部屏障，能够保持胶束在循环中的高度稳定性，并在到达靶细胞之前屏蔽包埋药物防止泄漏。设计的胶束可以穿过BBB并被脑细胞进一步内化。一旦进入细胞内，可以被细胞内高水平的谷胱甘肽（GSH）触发药物的释放。伊曲康唑（ITZ）因其脑内渗透性差，血液稳定性差而被选作模型药物。结果表明功能化的纳米胶束可以实现高效的直接药物输送到脑内的靶向部位。基于DHA血液循环稳定性显着提高和ITZ脑内递送效率提高的特点，DHA修饰的胶束在抗颅内感染方面效果显着。因此，这种智能纳米器件在脑部疾病治疗中具有很好的应用前景。