靶向纳米载体共递送c-Met抑制剂PHA-665752，提高索拉非尼抗肝癌疗效与机制研究

治疗肝癌一线药物索拉非尼(SFB)易诱导肝癌细胞产生肝细胞生长因子(HGF)，过表达间质-上皮转换因子(c-Met)激酶及其磷酸化形式并通过衔接蛋白激活RAS/RAF/MAPK与PI3K/AKT等途径，激活PD-L1/PD-1途径来抑制肿瘤免疫，驱动肝癌进展与SFB耐药。我们在Ab-SFB-NP纳米药基础上，组合荷载SFB与选择性c-Met抑制剂(PHA-665752)，获得纳米载体(Ab-SFB/PHA-NP)，实现了靶向释药。研究将重点探讨Ab-SFB/PHA-NP逆转病理性信号转导，抑制肿瘤细胞存活、增殖和侵袭的同时，通过下调PD-L1表达，促进细胞毒性T细胞增殖与细胞活性，抑制T调节细胞等免疫抑制细胞募集与功能等途径激活内源免疫应答，实现增强肿瘤免疫应答，抑制肝癌进展的效应；评估该载体安全性。课题有望证实Ab-SFB/PHA-NP通过靶向关键信号通路和免疫逃逸途径，提高抗肝癌疗效。

Sorafenib (SFB)，the first-line treatment for hepatocellular carcinoma (HCC)，often develops resistance and drives HCC progression by inducing overproduction of hepatocyte growth factor (HGF); overexpression and phosphorylation of mesenchymal-epithelial conversion factor (c-Met) kinase; further activation of Ras/Raf/MAPK and PI3K/Akt/mTOR pathways with adaptin to activate the PD-L1/PD-1 pathway to induce immunosuppressive microenvironment, tumor immune escape, and tumor anti-apoptosis and proliferation. Based on nanoparticle (NP) technology, we produced Anti-GPC3 antibody (Ab)-SFB-NP combined with a selective c-Met inhibitor (PHA-665752) to obtain a dual-drug nano-carrier (Ab-SFB/PHA-NP) of targeted delivery and controlled release. The study will focus on exploring the role of Ab-SFB / PHA-NP in reversing pathological signaling, while inhibiting the survival, proliferation and invasion of tumor cells, down-regulating PD-L1 expression, restoring killer T cell infiltration and cytotoxicity; inhibiting immune suppressive cell(T regulatory cells) recruitment and function mediated by intrinsic signals and enhancing the effect of tumor immune response; and evaluating the safety of Ab-SFB/PHA-NP. The project is expected to confirm that Ab-SFB/PHA-NP can improve the efficacy of SFB against HCC by targeting key signaling and immune escape pathways and provide a basis for new molecular treatment strategies for HCC.