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

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere64
JournalBlood Cancer Journal
Volume2
Issue number4
DOIs
StatePublished - May 2012
Externally publishedYes

Keywords

  • Cell-adhesion-mediated drug resistance
  • Drug delivery
  • Multiple myeloma
  • Nanoparticle
  • Selective targeting
  • VLA-4

ASJC Scopus subject areas

  • Hematology
  • Oncology

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    Kiziltepe, T., Ashley, J. D., Stefanick, J. F., Qi, Y. M., Alves, N. J., Handlogten, M. W., Suckow, M. A., Navari, R. M., & Bilgicer, B. (2012). Rationally engineered nanoparticles target multiple myeloma cells, overcome cell-adhesion-mediated drug resistance, and show enhanced efficacy in vivo. Blood Cancer Journal, 2(4), [e64]. https://doi.org/10.1038/bcj.2012.10