Blood Can J：纳米粒子治疗多发性骨髓瘤

近日，圣母大学的研究人员已经研制出一种纳米粒子，该粒子显示出巨大的用于治疗多发性骨髓瘤（MM）的潜力。

治疗MM的临床医生面对的困难之一就是：这种类型的癌细胞对先进的化疗治疗手段产生了耐药性。
 
化学和生物分子工程助理教Başar Bilgiçer说：我们设计的纳米粒子有多重功效。首先，它们减少了多发性骨髓瘤对阿霉素抗药性的产生。第二，这些纳米粒子实际上可以使得癌细胞尽可能对的接触到药物纳米粒。第三，该纳米粒还可以减少药物对健康器官的毒性作用。

该纳米粒子涂有一种特殊的肽，是针对多发性骨髓瘤细胞外的特定受体。多发性骨髓瘤细胞上的特定受体可以促使细胞粘附在骨髓组织上，诱导细胞产生药物的耐药。通过使用新开发的肽，纳米粒子能够绑定到该受体，防止癌细胞粘附在骨髓。

粒子还能携带化疗药物。当一个粒子附着到MM细胞上，细胞迅速接触到纳米粒子，然后粒子释放药物，从而导致癌细胞死亡。

同时有关老鼠动物实验研究表明，阿霉素纳米粒子配方对其他组织如肾脏和肝脏的毒性大大减少。
 
这项研究刊登在Blood Cancer Journal杂志上。该研究由印第安纳临床与转化科学研究所资金支持。

doi:10.1038/bcj.2012.10
PMC:
PMID:

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

T Kiziltepe, J D Ashley, J F Stefanick, Y M Qi, N J Alves, M W Handlogten, M A Suckow, R M Navari, B Bilgicer.

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.