氧化还原敏感型前药/siRNA纳米共载体系的构建及其靶向抗肝癌作用研究

Heptocelluar carcinoma (HCC) is one of the most common cancer with insidious onset, insensitive to chemotherapy, poor prognosis, which makes its clinical treatment face an enormous challenge. It has been reported that the combination of gene therapy and chemotherapy could produce synergistic effects on HCC through different effect mechanisms. In this project, a novel nanosystem is designed to carry both the redox-responsive prodrug of doxorubicin and the small interfering RNA targeting c-myc (c-myc siRNA). The β-cyclodextrin cationic polymer is synthesized to be used as the carrier material. Doxorubicin is conjugated with amantadine by the disulfide bond to form the prodrug of doxorubincin and then grafted to the cationic polymer by the “host-huest” interaction between β-cyclodextrin and adamantane. c-myc siRNA is then comolexed with the polymer by the electrostatic interaction, thus realize the co-loading of doxorubincin and c-myc siRNA. Hyaluronic acid is a natural ligand for CD44 on the surfaces of liver cancer cells and liver cancer stem cells. Therefore, it is used as a modified material to be coated on the surface of above complexe to construct the hepatoma-targeted delivery nanosystem of doxorubincin and c-myc siRNA. Moreover, the in vitro and in vivo pharmacological activities of this nanosystem are evaluated and the mechanism of its synergistic effects is also investigated in this project. Altogether, this project will provide a new strategy and the reference data for the clinical treatment of HCC.

肝细胞癌是最常见的恶性肿瘤之一，具有发病隐匿，化疗不敏感，预后差等特点，给临床治疗带来了严峻的挑战。基因治疗联合化疗的策略可针对不同作用靶点发挥疗效，产生协同增敏的抗肝癌作用。本课题拟构建一种氧化还原敏感型阿霉素前药与原癌基因c-myc小干扰RNA（c-myc siRNA）的纳米共载体系，以期实现对肝癌的靶向联合治疗。首先合成β-环糊精阳离子聚合物，然后将阿霉素与金刚烷胺以二硫键偶联合成氧化还原敏感型前药，并通过β-环糊精与金刚烷分子间的“主-客体”相互作用接枝于阳离子聚合物；利用聚合物的电正性高效复合c-myc siRNA，实现两种治疗剂的共载；以肝癌及肝癌干细胞表面标志物CD44分子的天然配体-透明质酸为材料对纳米复合物进行表面修饰，构建肝癌靶向纳米共载体系。本课题还将对该纳米共载体系进行体内外药效学评价，并系统研究其协同作用机制，为临床肝癌的治疗提供方法依据与数据支持。

肝细胞癌是最常见的恶性肿瘤之一，具有发病隐匿，化疗不敏感，预后差等特点，给临床治疗带来了严峻的挑战。联合治疗的策略可针对不同作用靶点发挥疗效，产生协同增敏的抗肝癌作用。针对肝癌的分子生物学特点，本项目设计并构建了三种基于β-环糊精的纳米载药系统，并分别探索了他们在肝癌治疗中的应用前景。1) 联合阿霉素及索拉菲尼的氧化还原敏感性的纳米药物共载体系；2）靶向肝癌的透明质酸包裹的药物和基因纳米共载体系； 3）联合阿霉素和miR-122的纳米体系。这三种纳米载药系统均能够利用主-客体相互作用负载化疗药物阿霉素；然后通过合理的设计，利用静电相互作用或疏水作用分别负载基因（oligoRNA或miR-122）或另一种小分子药物索拉菲尼。本项目对纳米载体的性质进行了详细的表征，并且探讨了其对肝癌的作用机制，为肝癌的治疗提供了新思路。