骨靶向光热-化疗联合治疗癌症骨转移的研究

Malignant cancers usually develop bone metastases. However, the clinical treatments commonly fail to suppress bone metastases and the occurrence of skeletal-related events. Nanomaterial-mediated new therapies hold great promise for the treatment of bone metastases, but the strategies for targeting delivery of nanomaterials to bone tissues should be developed. In this study, a bone-targeted nanocarrier will be developed, and the combined chemo-photothermal therapy will be applied to treat bone metastases. Bone-targeted molecules including alendronate, oligopeptides with eight repetitive sequences of aspartate (Asp8) or six repetitive sequences of aspartate, serine, serine ((AspSerSer)6) will be conjugated on the surface of polydopamine nanospheres (PDNs), and their capability to enhance the active targeting of PDNs to bone metastases will be further determined. Furthermore, the therapeutic effect of bone-targeted photothermal therapy over bone metastases will be evaluated. Finally, the bone-targeted chemo-photothermal therapy will be used to treat bone metastases. This study would establish important principles for the rational design of bone-targeted nanocarriers, and also provide new therapeutic strategies for the treatment of bone metastases and other bone-related diseases.

癌症骨转移目前缺乏有效的临床治疗手段。光热联合化疗可以发挥多重协同效应从而高效地杀死癌细胞。纳米材料介导的新型疗法有望成为癌症骨转移治疗的新突破点，而将纳米治疗载体靶向输运到骨组织病灶是该领域亟待解决的首要问题。本项目拟研究的内容包括：1.构建高效的骨靶向纳米输运载体；2.实施靶向光热疗治疗癌症骨转移；3.实施靶向光热联合化疗治疗癌症骨转移。项目以纳米聚多巴胺球为研究对象，首先研究不同骨靶向分子（阿仑膦酸盐、寡肽分子Asp8和(AspSerSer)6）介导聚多巴胺球主动靶向癌症骨转移病灶的能力，并评估光热治疗癌症骨转移的效果；随后研究载药聚多巴胺球介导的靶向光热联合化疗治疗癌症骨转移的效果。本项目的实施将为纳米治疗载体的骨靶向输运提供重要的参考依据，并为癌症骨转移及其他骨相关疾病的治疗提供新的方法和思路。

癌症骨转移发病率高,同时缺乏有效的临床治疗手段。纳米材料介导新型疗法有望成为治疗癌症骨转移的新策略，但是低下的靶向效率致使纳米材料介导的新型疗法不能广泛用骨肿瘤治疗。为此，我们开展了靶向光热治疗以及光热治疗联合其他治疗策略治疗骨肿瘤的研究。我们首先研究了四种不同骨靶向分子递送纳米材料的效率，包括阿仑膦酸钠、天冬氨酸寡肽分子、植酸以及表面为羧基的树形高分子，其中植酸以及表面为羧基的树形高分子是我们发现的新型骨靶向分子；实验证明四种骨靶向分子都表现出优异的骨结合能力以及骨靶向能力，其中天冬氨酸寡肽分子、植酸以及表面为羧基的树形高分子对肿瘤中溶骨组织表现出更高的选择性，并且四种骨靶向分子介导的光热治疗均能有效地抑制骨肿瘤的生长以及骨溶蚀的发生。随后，我们构建了两种基于光热治疗的骨靶向联合治疗载体，一个是阿伦磷酸钠修饰的聚多巴胺装载化疗药物羟基喜树碱;另一个是天然抗癌分子植酸修饰的铂纳米颗粒。实验证明两种联合治疗在低温43℃左右的条件下就可以有效地抑制骨肿瘤生长和骨溶蚀发生。该项目研究初步证明了靶向光热治疗以及光热治疗联合其他治疗策略治疗癌症骨转移的可行性，为临床治疗提供新的思路。