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Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo.
MedLine Citation:
PMID:  22829966     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
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Publication Detail:
Type:  Journal Article     Date:  2012-04-20
Journal Detail:
Title:  Blood cancer journal     Volume:  2     ISSN:  2044-5385     ISO Abbreviation:  Blood Cancer J     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-07-25     Completed Date:  2012-10-02     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101568469     Medline TA:  Blood Cancer J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e64     Citation Subset:  -    
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