文章：

合理设计的纳米颗粒靶向多发性骨髓瘤细胞，克服细胞粘附介导的耐药，并在体内显示出增强的疗效

Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo

原文发布日期：2012-04-20

DOI: 10.1038/bcj.2012.10

类型: Original Article

开放获取: 是

英文摘要：

In the continuing search for effective cancer treatments, we report the rational engineering of a multifunctional nanoparticle that combines traditional chemotherapy with cell targeting and anti-adhesion functionalities. Very late antigen-4 (VLA-4) mediated adhesion of multiple myeloma (MM) cells to bone marrow stroma confers MM cells with cell-adhesion-mediated drug resistance (CAM-DR). In our design, we used micellar nanoparticles as dynamic self-assembling scaffolds to present VLA-4-antagonist peptides and doxorubicin (Dox) conjugates, simultaneously, to selectively target MM cells and to overcome CAM-DR. Dox was conjugated to the nanoparticles through an acid-sensitive hydrazone bond. VLA-4-antagonist peptides were conjugated via a multifaceted synthetic procedure for generating precisely controlled number of targeting functionalities. The nanoparticles were efficiently internalized by MM cells and induced cytotoxicity. Mechanistic studies revealed that nanoparticles induced DNA double-strand breaks and apoptosis in MM cells. Importantly, multifunctional nanoparticles overcame CAM-DR, and were more efficacious than Dox when MM cells were cultured on fibronectin-coated plates. Finally, in a MM xenograft model, nanoparticles preferentially homed to MM tumors with ∼10 fold more drug accumulation and demonstrated dramatic tumor growth inhibition with a reduced overall systemic toxicity. Altogether, we demonstrate the disease driven engineering of a nanoparticle-based drug delivery system, enabling the model of an integrative approach in the treatment of MM.

摘要翻译： 

在持续探索有效癌症疗法的过程中，我们报道了一种多功能纳米颗粒的理性工程设计，该设计将传统化疗与细胞靶向及抗粘附功能相结合。多发性骨髓瘤细胞通过极晚期抗原-4介导与骨髓基质的粘附，使其获得细胞粘附介导的耐药性。在本设计中，我们采用胶束纳米颗粒作为动态自组装支架，同步呈现VLA-4拮抗肽与阿霉素偶联物，从而实现多发性骨髓瘤细胞的选择性靶向并克服细胞粘附介导的耐药性。阿霉素通过酸敏感性腙键与纳米颗粒偶联，VLA-4拮抗肽则通过可精确控制靶向功能数量的多步骤合成程序进行修饰。该纳米颗粒能被多发性骨髓瘤细胞高效内化并诱导细胞毒性。机制研究表明，纳米颗粒可引发多发性骨髓瘤细胞的DNA双链断裂和细胞凋亡。重要的是，当多发性骨髓瘤细胞在纤连蛋白包被的培养板上生长时，多功能纳米颗粒能克服细胞粘附介导的耐药性，且疗效优于游离阿霉素。最后在多发性骨髓瘤异种移植模型中，纳米颗粒优先富集于肿瘤部位，药物积累量提高约10倍，在显著抑制肿瘤生长的同时降低了全身毒性。本研究通过疾病导向的工程化设计，构建了基于纳米颗粒的药物递送系统，为多发性骨髓瘤治疗提供了一种整合性方法范式。

原文链接：

Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo