肝癌具有恶性程度高、进展快、易侵袭转移、预后差等特点，将化疗与其他治疗方法联合是肝癌治疗领域的重要研究课题。课题组前期研究发现低毒性天然产物熊果酸（UA）联合分子靶向药物索拉非尼（Sora）能有效抑制肝癌细胞的增殖、粘附与迁移，并具有显著的协同增敏作用。因此，本项目提出“利用疏水性抗癌药物之间的分子识别，构筑高载药量、兼具肝癌靶向及良好细胞膜穿透性能的多功能纳米系统”的新策略。拟构建一种穿膜肽功能化修饰、核酸适配体介导的双药自组装靶向纳米递释系统，以期实现体内靶向及药物共递送。纳米系统由疏水性药物UA和Sora利用分子间识别自组装成疏水性内核，核酸适配体修饰的穿膜肽进一步包裹内核形成亲水外壳。共载体系可借助核酸适配体的靶向识别首先聚集于肿瘤部位，并通过穿膜肽促进药物有效摄取，最终通过两种抗癌药物的多机制、多靶点联合作用达到协同治疗效果。研究可为肝癌靶向治疗及肝癌转移防治提供新策略。

Hepatocellular carcinoma (HCC) is characterized by the high degree of malignancy, rapid progress, easy invasion and metastasis, as well as poor prognosis capacities. Chemotherapy combined with other therapeutic strategies has become an important research theme in HCC treatment. Our previous studies showed that the combination treatment of ursolic acid (UA), a low toxicity natural product, and molecular targeted agent sorafenib (Sora) could effectively inhibit the proliferation, adhesion and migration of liver cancer cells, and had significant chemosensitization effects. Inspired by these findings, we propose a new strategy of "Constructing a multifunctional nanodelivery system based on the molecular recognition of two hydrophobic anticancer drugs with high drug loading, HCC targeting and transmembrane penetration characteristics". In this project, we plan to design a dual drug self-assembly nanodelivery system modified by cell penetrating peptide via aptamer mediated to achieve in vivo targeting and co-delivery of UA and Sora for HCC therapy. The core-shell structured nanoparticles are prepared as following: a hydrophobic core of the nanoparticles is formed by UA and Sora through intermolecular interactions, then UA/Sora core is encapsulated by aptamer modified low molecular weight protamine (LMWP) to form a hydrophilic shell. The nanosystem can be accumulated in the tumor sites due to the targeting function of aptamers and promote the cell uptake of nanodrugs effectively owning to the transmembrane penetration property of LMWP. Finally, the multifunctional nanoparticles delivery system is expected to achieve synergistic therapeutic effects through the combination of multiple mechanisms and targets of two anticancer drugs. The study may provide novel strategies for targeted therapy of HCC as well as prevention of liver cancer metastasis.