基于化学-免疫联合治疗理念构建GPC3靶向载体用于异靶点药物共递送的研究

Chemoimmunotherapy is one of the hotspots in current tumor therapy, especially for the combination therapy of chemodrugs and immune checkpoint antibodies which showed good prospects in clinical applications. However, the target cells of chemo-drugs and immune checkpoint antibodies is different. The design of traditional drug coloaded carriers usually focus on one target, which could not satisfy the requirement of the combination of drugs with different targets. Therefore, the glypican-3 (GPC3) antibody target sorafenib and T-cell immunoglobulin and mucin domain 3 (Tim-3) antibody co-loaded carriers was designed for the co-delivery of drugs with different targets. GPC3 was selected as novel the drug delivery target for hepatocellular carcinoma (HCC) for the first time. The change of pH in tumor microenvironment was employed to achieve the triggered separation of drugs. Chemodrugs were uptaked by tumor cells for chemotherapy, Tim-3 antibodies were release in tumor microenvironment to block the Tim-3 which were distributed on the surface of T-cell for immunotherapy. Thus, the co-delivery of drugs with different targets were achieved, which had important significance in chemoimmunotherapy. This study will provide novel drug carriers for chemoimmunotherapy and lay experimental bases for the clinical application of chemoimmunotherapy.

化学-免疫联合给药是目前肿瘤治疗的研究热点之一，特别是免疫检验点单抗与化疗药物联用策略展示了良好的临床应用前景。化疗药物和免疫检验点单抗的治疗靶细胞不同，传统共载载体往往针对单靶点设计，难以满足异靶点药物联合给药需求。基于此，课题拟设计共载索拉菲尼与Tim-3单抗的GPC3靶向载体用于异靶点药物共递送。首次选取磷脂酰肌醇蛋白聚糖3（glypican-3，GPC3）作为为肝癌化疗药物递送新靶点，利用肿瘤微环境pH改变实现T细胞免疫球蛋白和粘蛋白结构域3（T-cell immunoglobulin and mucin domain 3，Tim-3）单抗与载体的触发式分离。Tim-3单抗释放于肿瘤微环境，封闭T细胞表面Tim-3进行免疫治疗，载体介导索拉菲尼入胞进行化学治疗，实现异靶点药物共递送，在化学-免疫联合给药领域具有重要意义。课题为化学-免疫联合治疗提供新载体，为其临床应用奠定实验基础。

癌症是严重威胁人类健康的重大疾病之一，化学-免疫联合给药是目前癌症治疗的研究热点，该方法具备协同两种治疗机理、起效时间互补、治疗效果可相互促进的优势，展现了良好的应用前景。课题针对化学-免疫联合给药中如何实现不同药物在体内协同药动学和分布性质、高特异性靶向递送、及化疗药物和免疫检验点单抗的治疗靶细胞不同的科学问题，设计了一种具备肿瘤组织定位分离的异靶点工艺送系统。主要研究结果包括：①筛选和验证了肝癌细胞表面高特异性表达的磷脂酰肌醇蛋白聚糖3（glypican-3，GPC3）作为为肝癌化疗药物递送新靶点，验证了其高特异性和体内递送的高选择性，为肝癌药物体内高特异性靶向递送中载体靶向因子的设计提供指导和奠定基础；②设计制备具有“开-关”性质的肿瘤定位释药载索拉非尼纳米载体，该载体具备pH敏感的“开-关”，可实现不同pH下药物释放速度的反复调节，体内实验表明该载体可提高肿瘤部位药物的蓄积，显著提要化疗药物的治疗效果，从而为药物的定位释放提供思路；③根据课题设计设计和制备异靶点递送载体实现索拉非尼与Tim3单抗的异靶点共递送，该载体具备体内外肿瘤异靶点递送的性质，动物实验结果表明该载体实现了索拉非尼与Tim3单抗的联合抗肿瘤效果，同时中和或逆转化疗带来的肿瘤免疫因子的转变，提高肝癌治疗效果，为化学免疫联合治疗提供有效的药物递送系统。综合上述，本研究在高特异性靶向递送靶点、响应性药物释放和异靶点共递送化学/免疫治疗药物上取得了良好的研究进展，为未来癌症化学免疫联合治疗奠定了坚实的基础；相关研究内容目前发表SCI文章3篇，其中影响因子大于5分1篇，顺利完成预期发表2篇高SCI文章的技术指标。培养博士生1名，培养硕士生3名，圆满完成了课题的设计和目标。