仿高密度脂蛋白的纳米载药系统抗肝癌研究

Most hepatocellular carcinoma (HCC) are diagnosed at their late stage. Transarterial chemoembolization and sorafenib are the two approved treatments for the disease, but suffer from poor response and high hepatotoxicity. In this project, a series of novel amphiphilic peptides will be designed and synthesized based on apoprotein A-1 (ApoA-1) mimetic peptide to encapsulate chemotherapeutics (such as DM1) through self-assembly, and to construct synthetic high-density-lipoprotein (sHDL) with phagocytosis evasion and hepatocellular carcinoma cell targeting capability for HCC targeted delivery of chemotherapeutics. The physiochemical properties of the formed sHDL including stability, morphology, molecular stacking and drug loading/releasing behavior will be thoroughly determined, and the principles through which these properties are determined by the sequence of peptide and drug loading method will be revealed. The ability of sHDL in evading phagocytosis, promoting intratumoral drug accumulation, increasing HCC cell targeting, decreasing hepatic drug metabolism, improving anti-cancer activity, and decreasing hepatic toxicity will be evaluated. This study will reveal the mechanisms of action of sHDL in protein, cell and animal levels, and will help the further development of effective and safe nanomedicine against HCC. The project proposes a novel strategy to create biomimetic nano-sized drug delivery system for the treatment of HCC, and will deepen our understanding in the mechanism of peptide sequence- and drug loading method-based biological function determination.

大部分肝癌在确诊时即为中晚期，临床仅可采用动脉栓塞微球和索拉菲尼治疗，但治疗效果不佳，肝毒性大。本项目拟设计合成一系列基于载脂蛋白ApoA-1模拟肽的两亲性多肽，通过自组装包载化疗药物（DM1等），构建具有逃避单核细胞清除和肝癌细胞靶向特性的合成高密度脂蛋白（sHDL）纳米载药系统，实现肝癌靶向的药物输送。通过考察不同sHDL的稳定性、形貌、分子堆叠和载释药行为，揭示多肽序列和载药方式决定sHDL理化特性的规律；通过评价不同sHDL逃避单核细胞清除、促进肝肿瘤蓄积、增加肝癌细胞靶向、减少药物肝代谢、提高抗肝癌效果和降低药物肝毒性的能力，在蛋白、细胞和动物水平阐明sHDL纳米载药系统的作用机制；为高效低毒的抗中晚期肝癌纳米药物研发提供理论依据。本项目思路新颖，创新性强，对加深多肽序列和载药方式与sHDL生物学效应间关系的理解，对构建新型抗中晚期肝癌sHDL和其他仿生纳米药物均具有重要意义。

提高肝癌特别是中晚期肝癌的治疗效果和安全性是临床亟待解决的关键问题，如何合理设计递药系统实现肿瘤靶向和瘤内细胞特异性调控时其核心问题之一。本项目以肝癌细胞相比正常肝细胞高表达SR-B1受体的病理性特征为切入点，构建了一系列基于载脂蛋白ApoA-1模拟肽的仿高密度脂蛋白载体，考察了ApoA-1模拟肽分子设计、载药方式、药物组合等设计因素对仿高密度脂蛋白颗粒理化特性、体内行为和生物效应的影响。研究发现：通过引入不同的氨基酸残基可以调控颗粒的电荷等理化特性；仿高密度脂蛋白可有效蓄积到肝癌肿瘤内，并在SR-B1介导下实现瘤内细胞特异性调控；仿高密度脂蛋白的药物包载方式对其毒性有影响；通过优化药物组合可实现单次给药后激活抗肿瘤免疫反应、诱导原位肿瘤消退并产生抗肿瘤免疫记忆，最终抑制肿瘤生长和复发。相关研究在国内外重要学术期刊上发表高质量论文10篇，包括Nat Nanotechnol（IF=40.52）、Adv Mater（IF=32.08）、Nano Today（IF=18.96）、Acta Pharma Sin B（IF=14.90）、Nano Lett（IF=12.26）、J Control Release（IF=11.46）等，培养博士研究生2人，硕士研究生2人，项目负责人获得了包括国家自然科学奖二等奖在内的4项奖励。该项研究揭示了合成高密度脂蛋白设计原理和体内生物相互作用和生物效应机制，筛选获得了具有良好抗肝癌效果和安全性的合成高密度脂蛋白递药系统，为仿生递药系统的设计提供了理论基础，促进了其进一步临床转化。