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。

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.