MRP1（耐药相关蛋白1）介导的RB（视网膜母细胞瘤）多耐药性是RB药物治疗失败的主要原因之一。本研究利用RB高表达Legumain的生物学特点，选用生物相容性好的大分子聚合物（透明质酸、壳聚糖等）作为基本骨架，合成Legumain响应释放的药物载体。用Legumain的底物肽段将阿霉素桥接（化学键合）至骨架结构上，并进一步将MRP1抑制剂通过物理作用包载，形成抑制剂与抗癌药物先后释放的共包载体系。研究底物肽段氨基酸组成对共载体系体外释药性能的影响，阐明载体中肽段的氨基酸组成与Legumain释药调控的关系。研究共包载体系抑制耐药型RB细胞的效果，及逆转RB细胞多耐药性的分子机制。构建RB的裸鼠模型，通过玻璃体注射给药，研究共包载体系逆转RB实体瘤多耐药性，诱导肿瘤凋亡的机制，为探索RB药物治疗新方法奠定基础。

MRP1 (multidrug resistance-associated proteins 1) mediated drug resistance is a major impediment to chemotherapy of RB (retinoblastoma). As legumain was highly up-regulated in RB, we designed a series of legumain-responsive nano-carrier using hyaluronic acid, chitosan etc. as the skeleton structure. Doxorubicin was conjugated to the skeleton materials bridged with a legumain degradable peptide (PEP) and the resultant materials were further crosslinked to form nanoparticle. This nanoparticle was further subjected to load MRP1 inhibitor with physic force forming a step-released co-delivery system. The effect of PEP composition on the profile of legumain-mediated drug release was characterized. The in vitro and in vivo bio-effect of this co-delivery system was evaluated using drug resistance cancer cell line and nude mice cancer model. Furthermore, the mechanism of this co-delivery system reversed multidrug resistance and induced cell apoptosis will be studied. This work can be contributed to development a new strategy to RB treatment.