索拉非尼/BEZ235双载靶向纳米递送系统抗肝癌的协同效应与机制研究

The drug resistance to Sorafenib (SFB) produced by HCC cells is primarily brought about by the Crosstalk signal effect, in which abnormally activated PI3K/Akt/mTOR signal pathway inhibits the apoptosis of HCC cells and accordingly induces the SFB drug resistance. Dactolisib(BEZ235), the dual inhibitor of PI3K/mTOR, can inhibit the PI3K/Akt/mTOR pathway activation, and the combination of SFB with BEZ235 would prevent HCC from developing drug resistance to SFB. Based on our previous work about Anti-GPC3-SFB-NP carriers, this study would focus on how to develop structure-controllable targeted dual-drug nano-delivery system with loaded Sorafenib and BEZ235 (Anti-GPC3-SFB/BEZ235-NP, Ab-SFB/BEZ235-NP), and on how to achieve stable delivery and precise release in the complex microenvironment. The study would further explore the mechanisms of the system and its effect on the proliferation, invasion, and apoptosis of HCC cells, and would evaluate the system's efficiency on drug resistance of HCC cells to SFB and its effect on preclinical therapy. Additionally, the system's stability and biosafety would also be evaluated, with the hope for providing the experimental basis for clinical application in the future. The preliminary achievements of this study would help to promote the application of SFB in HCC therapy, and to provide new insight and technologies for the development of targeted drugs with the safety and efficiency.

肝细胞癌(HCC)对索拉非尼(SFB)耐药主要是由于信号通路串扰效应，异常活化PI3K/Akt/mTOR通路，抑制HCC细胞凋亡，诱导SFB耐药。PI3K与mTOR双重抑制剂BEZ235有效抑制PI3K/Akt/mTOR通路活化，SFB与BEZ235组合将可解除HCC对SFB的获得性耐药。本研究在已制备的Anti-GPC3-SFB-NP(Ab-SFB-NP)纳米递药系统的研究基础上，通过结构优化，组合荷载SFB与BEZ235，获得双药递送系统(Ab-SFB/BEZ235-NP)，实现了药物稳定递送与靶向控释。研究将进一步揭示该系统对HCC细胞的增殖、侵袭、凋亡等过程的影响与分子机制；检测该系统负调HCC对SFB耐药性的效能；评价对HCC的临床前疗效；探讨该系统的稳定性与安全性，为临床应用研究奠定实验基础。课题成果有望提高SFB治疗肝癌的疗效，为开发安全、高效的肝癌靶向药物提供新技术和思路。

获得性耐药限制索拉非尼(SFB)治疗肝细胞癌的疗效，有待发展新的治疗方案以抑制肝癌进展，延长患者生存期。本项目通过对耐SFB肝癌细胞株研究证实，异常活化的PI3K/AKT/mTOR信号途径与自噬是肝细胞癌耐药的主要因素，抑制主要信号通路异化与自噬可显著提高SFB抑制肝癌细胞增殖与诱导肝癌细胞凋亡的能力，协同增强肝细胞癌对SFB的敏感性，进一步通过动物肝细胞癌模型证实了PI3K/AKT/mTOR信号抑制剂BEZ235能协同增强SFB抗肝癌疗效。项目组设计并制备了一种能够同时抑制PI3K/AKT/mTOR通路活化和诱导自噬的肝癌靶向递送系统，研究了载体材料的组成、结构与药物递送功能相关性及其稳定性与生物相容性；制备了能够同时抑制PI3K/AKT/mTOR通路活化与调节肿瘤自噬的肝癌靶向双药递送系统(Ab-SFB/BEZ235-NP)，其以纳米粒的形式提高了磷脂酰肌醇蛋白聚糖3(GPC3)阳性肝癌细胞的亲和力，抑制肝癌细胞中主要异化信号通路与自噬，提高了药物的靶向性，协同增强了抗耐药性肝癌疗效；且制备的纳米药物在异种移植肝癌组织内能够有效富集，降低药物对正常组织的毒性，显著抑制了肝癌生长，协同增强索拉非尼抗肝癌的疗效。本项目所获新型功能型纳米载药系统为治疗索拉非尼耐药肝癌提供了新思路和实验基础。完成了项目计划书的研究目标。培养博士生3名，硕士生8名；发表论文15篇，申请专利4项，其中1项获得授权；项目组成员与暨南大学生物医学工程学院建立了合作关系，并有1人获得基金委面上项目。