AEG-1 siRNA和阿霉素共传递抑制骨肉瘤生长和转移作用及机制研究

Osteosarcoma is characterized by rapid growth, high invasiveness, easy to recurrance and early pulmonary metastasis in children and adolescents. Adjuvant chemotherapy is an important factor to determine the prognosis of patients with osteosarcoma, however, the side effects during chemotherapy and drug resistance seriously affect the efficacy of chemotherapy. Therefore we assume that combining chemotherapy drugs with genes could reduce the side effects, improve the sensitivity of tumor cells to chemotherapeutic drugs of osteosarcoma. In the present, the high efficient co-delivery system is insuficient, and the mechanism of synergistic therapy is unclear. And another key point of synergistic therapy is to find the specific tageted genes and efficient drugs. Previously, we have demonstrated that AEG-1 was over-expression in osteosarcoma tissues, and could increase the proliferation and invasive ability of osteosarcoma cells. Doxorubicin is one of the most effective drug treating with osteosarcoma, however it is of high cardiotoxicity. Therefore, in the present research, we plan to construct novel multifunctional polymer carrier loaded with AEG-1 siRNA and Doxorubicin, and on this basis, build on the targeted co-delivery system to investigate the synergistic effect and mechanism of how it inhibits the growth, invasion and metastasis of osteosarcoma in vivo and in vitro. Moreover, it will provide a novel approach and effect stragegy for treatment of osteosarcoma.

骨肉瘤好发于儿童和青少年，其生长速度快、侵袭性强，易复发和早期发生肺转移。辅助化疗是决定骨肉瘤患者预后的重要因素，然而化疗药物的毒副作用和化疗耐药两个因素严重影响化疗疗效。采用化疗药物与基因药物联合治疗骨肉瘤，有望在降低有关毒副作用的同时，提高肿瘤细胞对化疗药物的敏感性，进而增强其疗效。但目前尚缺乏高效的共传递系统，且有关联合治疗的作用机理还不清楚。联合治疗另一关键点是寻找特异的靶基因和高效的药物。前期的研究证实癌基因AEG-1在人骨肉瘤组织中高表达，并促进骨肉瘤细胞的增殖和侵袭能；阿霉素是迄今为止骨肉瘤化疗最有效的药物之一，但心脏毒性大。为此，本项目拟设计制备多功能新型聚合物载体，用于共负载AEG-1 siRNA和阿霉素；在此基础上，构建有关靶向性共传递体系，并通过体内外实验研究其对骨肉瘤生长和转移的协同抑制功效与作用机理，以期获得有关骨肉瘤治疗的新模式和有效方法。