基于温敏凝胶的靶向HIV-1 gp41融合肽与免疫细胞辅助受体CCR5的杀微生物剂研究

In recent years, sexual transmission has become the major route of HIV infection in China, therefore, HIV pre-exposure prophylaxis by medications is particularly important. As the “cocktail therapy” has been commonly used in AIDS treatment, there comes the demands of multi-drug combined delivery for vaginal/rectal mucosa drug delivery system, especially the efficient controlled release of both hydrophobic and hydrophilic drugs. This research plans to develop polycation thermo-sensitive hydrogels which are suitable for vaginal/rectal mucosa drug delivery, meanwhile loading theaflavin-3,3'-digallate(TF-3) for blocking envelope glycoprotein gp41 of HIV-1 virus and nifeviroc as CCR5 receptor antagonist. By adjusting the hydrophilic/hydrophobic microdomains and charge density of these polycation thermo-sensitive hydrogels, the controlled release of hydrophilic TF-3 and hydrophobic nifeviroc in vagina/rectum is promisingly achieved. Thus bioavailability of both two drugs is enhanced and mucosal irritation can be avoided, in addition, hydrogel can form a protective layer on the surface of vaginal/rectal mucosa, prevent virus adsorption, and reduce the risk of sexually transmitted HIV infection. By research on stuctural performance, mucosal drug delivery ability, bio-safety and HIV blocking efficency of these polycation thermo-sensitive hydrogels, this project aims to provide feasible methods of microbicides development for HIV pre-exposure prophylaxis.

近年来性传播已成为我国新发HIV感染的主要传播途径，通过药物实现HIV病毒暴露前预防显得尤为重要，其中多靶点联合用药的“鸡尾酒疗法”是艾滋病治疗中常用手段，这就对多药联合递送的阴道/直肠黏膜给药系统提出了需求，尤其需要解决亲、疏水性药物的有效控释问题。本课题拟构建适宜于阴道/直肠黏膜环境的聚阳离子温敏水凝胶，同时负载HIV-1病毒膜蛋白gp41融合肽抑制剂茶黄素双没食子酸酯TF-3和靶细胞辅助受体CCR5拮抗剂尼非韦罗，通过调控凝胶亲疏水微区和电荷密度，实现对亲水性药物TF-3和疏水性药物尼非韦罗的局部控制释放，提高药物的生物利用度并避免药物突释造成黏膜刺激；同时温敏凝胶对黏膜破损形成保护层，阻碍病毒与黏膜吸附，降低性传播感染HIV的风险。本项目通过对阳离子温敏水凝胶的结构性能与其黏膜给药功能性、生物安全性和阻断HIV感染效率的研究，为阻断HIV经性途径传播的杀微生物剂的开发提供可行途径。

近年来性传播已成为我国新发HIV感染的主要传播途径，通过药物实现HIV病毒暴露前预防显得尤为重要，其中包括杀微生物剂在内的新型预防策略成为研究热点，这就对多药联合递送的阴道/直肠黏膜给药系统提出了需求，尤其需要解决亲、疏水性药物的有效控释问题。本课题拟构建适宜于阴道/直肠黏膜环境的聚阳离子温敏水凝胶，同时负载HIV-1病毒膜蛋白gp41融合肽抑制剂茶黄素双没食子酸酯(TF-3）和靶细胞辅助受体CCR5拮抗剂尼非韦罗，通过调控凝胶亲疏水微区和电荷密度，实现对亲水性药物TF-3和疏水性药物尼非韦罗的共同控制释放，提高药物的生物利用度并且避免药物突释造成的黏膜刺激性；同时利用温敏凝胶对黏膜破损形成保护层，阻碍病毒与黏膜吸附，降低性传播感染HIV的风险。本项目通过对阳离子温敏水凝胶的结构性能与其粘膜给药功能性的研究，为阻断HIV经性途径传播的杀微生物剂的开发提供可行途径。.本课题成功构建了可同时递送亲/疏水药物的纳米温敏水凝胶P407-LDH NPs，动物实验结果表明该凝胶对雌性白兔阴道刺激性较小，并可同时递送亲水性药物和疏水性药物经阴道粘膜进入兔子血液，实现了亲水性不同的药物的局部协同控制释放，提供了经粘膜局部给药的给药平台。