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

被引:0
作者
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
机构
[1] University of Notre Dame,Department of Chemical and Biomolecular Engineering
[2] Advanced Diagnostics and Therapeutics,Department of Biological Sciences University of Notre Dame
[3] University of Notre Dame,Department of Chemistry and Biochemistry
[4] University of Notre Dame,undefined
[5] Indiana University School of Medicine South Bend,undefined
[6] University of Notre Dame,undefined
来源
Blood Cancer Journal | 2012年 / 2卷
关键词
drug delivery; nanoparticle; multiple myeloma; selective targeting; VLA-4; cell-adhesion-mediated drug resistance;
D O I
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中图分类号
学科分类号
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.
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页码:e64 / e64
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