hGC33修饰、Sorafenib负载纳米递药系统的GPC3+肝癌靶向及协同抗癌机制研究

Sorafenib approved by FDA for the treatment of advanced hepatocellular carcinoma (HCC) is a multi-kinase inhibitor on multi-target. Attributed to the inadequate concentration and targeting effect, its efficacy is limited. The sorafenib-loaded nanoparticles we previously developed with a controlled drug release rate can reduce drug administration frequency via intravenous administration; however the drug targeting effect is still limited. The therapeutic antibody (hGC33) against glypican 3 specifically expressed on HCC cells has specific targeting and therapeutic effect on HCC cells. In this project, based on the optimized NPs，hGC33 modified and sorafenib loaded PCL-TPGS/Pluronic P123 nanoparticles (hGC33-Sorafenib-NPs) targeted to HCC, which have such characteristics as controlled drug release in tumor body and enhanced anti-HCC efficacy through synergistic inhibitory effect of hGC33 and sorafenib on HCC cells, will be constructed. And the construction process will be systematically studied to obtain the hGC33-Sorafenib-NPs with controlled compositional structure. Moreover, the influence of hGC33 modification on drug targeting will also be studied to clarify the transportation mechanism of hGC33-Sorafenib-NPs. Furthermore, the inner relationship between the compositional structure and the synergistic anticancer effect will be researched to make the mechanism of the synergistic anticancer effect clear on molecular level. The construction of the HCC-specific drug delivery system with synergistic inhibitory effect will present a new approach and idea for the treatment of HCC.

索拉非尼（Sorafenib）是FDA批准用于晚期肝癌的多靶点多激酶抑制剂，由于浓度和靶向性不足限制疗效。申请人前期用纳米粒（NPs）负载索拉非尼，静脉给药可降低给药频率与控制释药速率，但靶向性依然不够。针对肝癌相对特异表达分子磷脂酰肌醇蛋白聚糖3的治疗性抗体(hGC33)对肝癌细胞具有特异靶向性和治疗作用，本项目拟在优化纳米粒基础上，联合应用索拉非尼和hGC33，获得具有肝癌靶向、瘤内可控释药以及hGC33与索拉非尼协同增加抗肝癌活性的hGC33-Sorafenib-NPs。研究hGC33-Sorafenib-NPs制备工艺，获得结构可控的hGC33-Sorafenib-NPs；研究hGC33修饰对靶向性的影响，明确靶向联控递药系统的转运机制；阐明该系统结构与协同抗癌效应的内在关系，揭示其协同抗肝癌分子机制。该肝癌靶向协同递药系统的建立将为肝癌治疗提供新途径和思路。

索拉非尼(SFB)为小分子多酶抑制剂，主要为口服剂型，不但存在胃肠道刺激等不良反应，更重要的是在非肿瘤组织的分布降低了生物利用率。本项目利用PCL-TPGS/Pluronic P123载药量大、荷载药物可控释、易修饰、粒经可控等特点，构建新型GPC3 抗体（Ab）修饰肝癌靶向纳米递药系统(Ab-SFB-NP)，实验结果证实该纳米递药系统可稳定与控释所载药物索拉非尼，提高索拉非尼靶向性与生物利用度、降低治疗的毒副作用。与索拉非尼单药治疗相比，hGC33-SFB-NP增强对HCC反应，促使反应持续时间更长，抗癌效果更佳。这主要是hGC33-SFB-NP通过抑制Ras/Raf/MEK与Wnt/β-catenin信号通路，协同抑制HCC细胞的EMT化；阻滞细胞周期于G0/G1期；提高了协同抑制肿瘤生长的效率，并显著增强了诱导肿瘤死亡效率，实现了有效控制肝癌转移，延缓肝癌生长与延长肝癌荷瘤鼠的生存期，达到了协同抗肝癌效应的目标。