同时以肿瘤相关成纤维细胞和骨髓瘤细胞为治疗靶点的多发性骨髓瘤纳米递药研究

It was now well recognized that drug resistance and relapse posed great challenge in the treatment of multiple myeloma (MM). In previous study, we developed drug delivery system aiming at special cell component or extracellular matrix in tumor microenvironment and obtained favorable therapeutic effects. As cancer-associated fibroblasts (CAF) was highly associated with the drug resistance, relapse and prognosis of MM. In the present study, an active targeting drug delivery system targeting both CAF and MM cells for MM treatment was developed, with platelet derived growth factor receptor-β (PDGFR-β) overexpressed in both CAF and MM cells as the therapeutic target, cyclopeptide with special affinity for PDGFR-β as the targeting moiety, nanoparticles based on FDA approved polyester material as the carrier and classical chemotherapeutics paclitaxel as the model drug. As compared with current research mainly targeting MM cells, the superiority of the active targeting drug delivery system was that it could simultaneously destroy the seed MM cells and its soil CAF within MM which could open a new avenue for the development of MM treatment regimen.

众所周知，多发性骨髓瘤（MM）的原发耐药及复发是临床上的难点问题。前期研究中我们建立了针对微环境中特定细胞成分和细胞外基质的递药系统并收获良好的疗效。由于肿瘤相关成纤维细胞（CAF）与MM耐药、复发及预后密切相关，本研究以CAF和骨髓瘤细胞表面均高表达的血小板来源生长因子受体-β (PDGFR-β)为治疗靶点，以与其具有特异性高亲和力的环肽为靶向功能分子，以美国FDA批准的聚酯类材料构建的纳米粒为递药载体，以经典化疗药物紫杉醇为模型药物，建立可以同时破坏CAF和骨髓瘤细胞的主动靶向纳米递药系统。与当前研究侧重于以骨髓瘤细胞为治疗位点相比，该策略的优势在于可以同时破坏MM的种子骨髓瘤细胞及其生存的土壤CAF，为MM的治疗提供新的研究思路。

本项目以对血小板来源的生长因子受体β具有高度亲和力的环肽分子为靶向功能分子，聚乙二醇-聚乳酸嵌段共聚物为载体，紫杉醇为模型药物，血小板来源的生长因子受体β为治疗靶点，构建一种新型的多发性骨髓瘤靶向递药治疗系统。该系统设计简单，可以靶向系统药物至骨髓瘤细胞和肿瘤相关成纤维细胞，同时破坏骨髓瘤的“种子（骨髓瘤细胞）”和“土壤（肿瘤相关成纤维细胞）”，有效地抑制骨髓瘤的生长，提高了对骨髓瘤的治疗效果。相关研究成果发表SCI论文6篇。