精准操控脂质体蛋白冠中载脂蛋白结构和功能的新型脑靶向递药系统

The development of therapeutics for brain diseases is one of the key challenges in the related fields, which is due, at least partially to the existence blood-brain barrier (BBB). It is reported that more than 98% small molecules and almost all macromolecules are not able to cross BBB. Peptides have been widely studied to facilitate brain targeted drug delivery via receptor-mediated transcytosis. However, the previous reports mainly focus on the development and optimization of peptide ligands exhibiting high binding affinities. The interaction of biomolecules in blood with brain targeted drug delivery systems (such as protein absorption and detachment, degradation by proteinase, complement activation, reaction with other cells) has been ignored. In the present study, we aim to design a novel peptide to absorb the functional apolipoproteins in plasma in an active and specific manner. The formed protein corona is expected to exhibit brain targeting function and extend circulation time of liposomes in vivo. It is the first time that the adverse factors of passive protein absorb are changed to active manipulation of protein corona. We anticipate that the present study would provide a novel direction for the development of brain targeted drug delivery systems.

目前针对脑部疾病的药物研发进展远远落后于其他疾病，其重要原因之一是药物分子难以通过全身给药方式穿透血－脑屏障的阻碍进入脑内发挥疗效。设计多肽靶分子，通过受体介导的方式实现药物制剂的脑靶向递送是目前的研究热点，但脑靶向制剂研发面临的重大问题是侧重于靶分子与受体的结合作用，而忽略了给药系统的阻力造成的影响（包括循环系统中蛋白的吸附与解离，水解酶的降解，补体系统应激，与其他细胞的相互作用等）。因此，本项目设计了一种新型的多肽靶分子，通过主动和特异性的吸附血浆中的功能性载脂蛋白，形成相对稳定的制剂－蛋白复合物，精准操控制剂表面形成的蛋白冠，达到增强脑靶向功能，延长药物循环时间，改善多肽稳定性，减少体内免疫原性等目的。本项目首次利用制剂在血液中被动吸附的不利因素，转化为主动调控和利用蛋白冠，优化靶分子设计，为开发新型的脑靶向制剂提供了全新的思路和方向。

针对脑部疾病的药物研发进展远远落后于其他疾病，最大的重要障碍之一是药物分子难以穿透血－脑屏障。设计多肽靶分子，通过受体介导的方式实现药物制剂的脑靶向递送是目前的研究热点，但脑靶向制剂研发面临的重大问题是侧重于靶分子与受体的结合作用，而忽略了给药系统的阻力造成的影响（包括循环系统中蛋白的吸附与解离，水解酶的降解，补体系统应激，与其他细胞的相互作用等）。本课题通过仿生淀粉样蛋白β入脑的方式，成功设计了一种新型的多肽靶分子SP，修饰在脂质体上形成SP-sLip，通过主动和特异性的吸附血浆中的功能性载脂蛋白，形成相对稳定的制剂－蛋白复合物，精准操控制剂表面形成的蛋白冠，达到增强脑靶向功能和延长药物循环时间，同时改善多肽稳定性，并减少体内免疫原性等目的。本项目发明了SP-sLip脂质体，首次利用制剂在血液中被动吸附的不利因素，转化为主动调控和利用蛋白冠，优化靶分子设计，开发了一种新型的脑靶向制剂。