多重肝靶向抗肿瘤自组装前药纳米给药系统

The morbidity rate of liver cancer in China is the highest in the world. Toxicity and side effect of nucleoside antitumor drugs are great. Targeting to liver cancer cells is the key piont to achieve high efficacy and safty. A novel step-by-step liver-targeted antitumor prodrug self-assembled nanoscale system is designed in this study, which is an integrated technique based on self-assembled drug delivery system (SADDS), targeting to hepatic parenchymal cells, and the HepDirect molecular targeting. The new system passively targets to liver cancer tissue based on the enhanced permeability and retention (EPR) effect of tumor. It then actively targets to hepatic parenchymal cells through the galactoside molecules coated on the surface. After entering cells, the drug is transferred to its active form monophhosphate to achieve molecular targeting through the highly expressed CYP3A4 enzyme in heptic parenchymal cells. The marked advantage of this system includes high drug loads and strong stability. Gemcitabine, cytarabine and fludarabine are selected as the model drugs. The HepDirect prodrugs are synthesized followed by lipid derivation to get the amphiphilic prodrugs. The targeted nanoscale self-assembled drug delivery system are prepared from the amphiphilic prodrugs and the long-circulating liver-targeted molecule galactoside. The physical and chemical properties, degradation in vitro/vivo, biodistribution, and antitumor pharmacodynamics in vitro/vivo are explored. This research provides a new targeted drug delivery technology and solves the important problems of parent drugs including bad stability, no targeting and high dose.

我国是全球肝癌发病率最高的国家。核苷类抗肝癌药物毒副作用大，如何将其靶向至肝癌细胞是实现高效、安全治疗的关键。本项目结合自组装药物传递系统、肝实质细胞靶向技术、HepDirect分子靶向技术，设计了一种新型多重肝靶向抗肿瘤自组装前药纳米给药系统。该系统基于肿瘤EPR效应被动靶向到肝癌组织，由表面的半乳糖苷分子主动靶向到肝实质细胞，被肝实质细胞中高表达的CYP3A4酶代谢活化为单磷酸核苷实现分子靶向。该系统载药量大、稳定性好。本项目吉西他滨、阿糖胞苷、氟达拉滨为模型药物，合成HepDirect前药，再脂质衍生化得到两亲前药，与长循环肝靶向分子半乳糖苷构成纳米自组装体，考察理化性质、体内外降解和分布规律、体内外抗肝癌药效。本研究为肝癌治疗提供了一种新的靶向给药技术，并且解决了原药不稳定、靶向性差、剂量大的问题。

该系统基于肿瘤EPR效应被动靶向到肝癌组织，由表面的半乳糖苷分子主动靶向到肝实质细胞，被肝实质细胞中高表达的CYP3A4酶代谢活化为单磷酸核苷实现分子靶向。该系统载药量大、稳定性好。本项目以吉西他滨为模型药物，合成HepDirect 前药，再脂质衍生化得到两亲前药，与长循环肝靶向分子半乳糖苷构成纳米自组装体，考察理化性质、体内外降解和分布规律、体内外抗肝癌药效。本研究为肝癌治疗提供了一种新的靶向给药技术，并且解决了原药不稳定、靶向性差、剂量大的问题。已基本完成原申请计划。出版专著1部，发表SCI论文3篇(累计影响因子10.55)、中文核心期刊论文1篇，1篇SCI论文正在投稿中。申请发明专利1项。培养硕士生1名。