特异溶蚀骨靶向的树形高分子复合材料光热治疗骨转移瘤的机制研究

The incidence of bone metastatic tumors is increasing year by year. Currently, bone metastasis still remains a formidable challenge in clinical therapy, although the treatment is diverse. Because of the diversity of tumor species and complex genetic background, it is difficult to design the universal target probe. In this research proposal, the carboxyl terminus is innovatively used as a universal targeted probe for bone metastatic tumors. Detailedly, a carboxylate-terminated poly-amidoamine dendrimer-encapsulated metal nanopaticles will be prepared and used as nanocarriers of cisplantin in the combined photothermal-chemo treatment of cancer bone metastases. The carboxylate groups of the novel multifunctional nanoparticles specifically chelated exposed calcium ion of the erosion bone damaged by tumor. By this strategy, a multifunctional nanocarrier with erosion bone targeting ability and the photothermal therapy at facile temperature will be realized. In vitro antitumor activity, the in vivo biodistribution and therapeutic efficacy, and the anticancer mechanism of the new nanoparticles will be tested. This study will provide a new insight into the treatment of bone metastatic tumors using nanomedicines.

骨转移瘤发病率逐年攀升，虽然治疗手段多样但其疗效差强人意。因瘤种多样，遗传背景复杂，其通用型靶向探针设计困难。本项目利用骨转移瘤病灶表面裸露大量钙离子的共性特点，创新性以类钙离子螯合剂的双羧基末端作为骨转移瘤通用型靶向探针，并设计多功能纳米复合物用于骨转移瘤的治疗研究。具体方案为：以带羧基末端的聚酰胺胺树形高分子为载体，表面负载顺铂同时内部包裹金属纳米光热颗粒。此多功能复合物中，双羧基末端与溶蚀骨表面高效螯合实现骨转移瘤的特异靶向；顺铂负责化疗；金属颗粒负责光热消融。光热作用对肿瘤细胞造成瞬间杀伤作用与顺铂的长程杀灭肿瘤作用相互协同，可将光热治疗温度降至更安全的范围，实现低温光热-化疗一体化、协同治疗骨转移瘤。本研究将从细胞学及动物实验等方面全面评估该类复合物的疗效和生物安全性，探索其作用机制，并评价其作为骨肿瘤普适性治疗手段的可能性，为其进一步应用于临床奠定基础。

骨恶性肿瘤瘤种多样，遗传背景复杂，其通用型靶向探针设计困难。本项目以骨肿瘤靶向探针设计和纳米光热治疗为核心，主要完成以下四方面工作：（1）以植酸为骨肿瘤靶向探针，设计了无载体的骨肿瘤靶向植酸-顺铂复合物；（2）以植酸为骨肿瘤靶向探针，设计了具有骨肿瘤靶向的光热植酸-铂纳米颗粒复合物；（3）以阿仑膦酸为靶向探针，设计了聚乙二醇-阿仑膦酸钠修饰的聚多巴胺纳米粒子,并在其表面负载自噬抑制剂氯喹，构建新型骨靶向的光热纳米多功能复合物。（4）以8个天冬氨酸的短肽和RGD2为靶向探针，修饰含钆的聚多巴胺纳米颗粒PDA@Gd，构建了新型的具有溶蚀骨靶向、抑制骨破坏及核磁显像能力的多功能纳米光热材料PDA@Gd-D8/RGD2。这四方面的工作均在体外以及动物体内证明了其优异的骨肿瘤治疗效果。