基于脂蛋白的双级脑靶向纳米载体的构建及其抗脑神经胶质瘤功效研究

The present work will concern the development of discoidal reconstituted HDL (disc rHDL) modified with apoA-I and apoE to serve as a novel delivery vehicle for anti-gliomas drugs like gemcitabine and paclitaxel due to the attractive attributes of HDL including unique existing form and physiological function in the brain, the specific distribution of LDLR, LRP1 and SR-BI on the blood-brain barrier and glioma cell, and the need of anticancer treatment .The compositions of disc rHDL will be recombined and optimized as a new brain targeting system. In addition, the delivery system will be targeted functional molecular modification, and expected to have better transmission characteristics to glioma lesion regional as well as excellent therapeutic effect. The stability problems for disc rHDL will be solved through chemical modification of enzymatic reaction group, inhibition remodelling activity of enzymes and rearrangement of apolipoprotein on the surface of rHDL to stabilize the carrier and improve the targeting efficiency. In this subject, the reconstituted drug-HDL complex will be prepared and studied from several aspects such as pharmaceutics, biopharmaceutics, pharmacokinetics (PK), pharmacodynamics (PD) and so on. The contents refer to the combination of apolipoprotein and delivery system, stability of the reconstituted carrier, chemical modification of the target molecules, selection and optimization of formulation and preparation technique, investigation and evaluation of tissue distribution in animals and new target effect for brain glioma, PK and PD experiments. This subject would be an exploration to develop HDL as a novel drug delivery system, discover its new target point on brain glioma, overcome the stability problems of biomimetic drug carries in vivo and optimize the structure of carrier. It will provide detailed and accurate scientific test method and data.

根据高密度脂蛋白（HDL）在脑内的存在形式和生理功能，以及血脑屏障与胶质瘤细胞特异分布的HDL相关受体LDLR、LRP1、SR-BI，结合抗癌治疗需求，选择apoA-I、apoE修饰盘状重组HDL（rHDL）并对其组成成份进行重组优化，作为一种新型脑靶向载体包载吉西他滨和紫杉醇，并予以靶向功能分子修饰期待在体内具有更好的脑胶质瘤病灶区域传输特性及治疗作用。针对盘状rHDL载体亟待解决的稳定性问题，通过化学修饰酶促反应基团和改变载体表面载脂蛋白排列方式，达到稳定载体提高靶向效率的目的。本课题将对这一新载体系统的相关特性进行研究完善，内容涉及载脂蛋白与载体的结合、靶向分子修饰、制剂处方和工艺调整优化、体内外趋靶性测评、药动学及药效学试验等。本项目研究的成果将为进一步了解rHDL作为新型载药系统的应用价值，拓展其脑胶质瘤新靶区，以及优化载体结构等关键问题的解决，提供详实有力的科学试验方法与数据。

本课题针对盘状rHDL载体亟待解决的稳定性问题，选择正丁醛修饰胆固醇羟基，有效解决了稳定重组HDL在血液输送过程中的稳定性问题，达到了提高靶向效率的目的。根据高密度脂蛋白（HDL）在脑内的存在形式和生理功能，以及血脑屏障与胶质瘤细胞特异分布的HDL相关受体LDLR、LRP1、SR-BI，结合抗癌治疗需求，选择apoA-I、apoE修饰盘状重组HDL（rHDL）并对其组成成份进行重组优化，作为一种新型脑靶向载体包载紫杉醇，体内外靶向性考察结果表明rHDL具有优良的脑靶向特性以及良好的脑胶质瘤病灶区域传输及治疗作用。本项目研究的成果将为进一步了解rHDL作为新型载药系统的应用价值，拓展其脑胶质瘤新靶区，以及优化载体结构等关键问题的解决，提供详实有力的科学试验方法与数据。