Cancer researchers working on new ways to treat multiple myeloma (MM) have devised multifunctional nanoparticles that specifically deliver the chemotherapeutic agent doxorubicin to MM cells while blocking the development of resistance to the drug.

Investigators at the University of Notre Dame (Notre Dame, IN, USA) employed complex bioengineering techniques to create the particles. They used micellar nanoparticles as dynamic self-assembling scaffolds to present simultaneously peptide antagonists of the MM surface marker VLA-4 and conjugates of the chemotherapeutic drug doxorubicin (Dox). These particles were designed to selectively target MM cells and to overcome cell-adhesion-mediated drug resistance (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.

Results published in the April 20, 2012, online edition of Blood Cancer Journal revealed that 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, the multifunctional nanoparticles overcame CAM-DR, and were more effective than Dox alone when MM cells were cultured on fibronectin-coated plates. In a MM xenograft model, nanoparticles preferentially homed to MM tumors with about a10-fold concentration of the drug accumulating in tumors. The drug-loaded nanoparticles dramatically inhibited tumor growth with a reduced overall systemic toxicity.

“The nanoparticles we have designed accomplish many things at once,” said senior author Dr. Başar Bilgiçer, assistant professor of chemical and biomolecular engineering at the University of Notre Dame. “First, they reduce the development of resistance to doxorubicin. Second, they actually get the cancer cells to actively consume the drug-loaded nanoparticles. Third, they reduce the toxic effect the drug has on healthy organs.”

Testing of the multifunctional nanoparticles in human clinical trials will begin after completion of further studies to improve the design of the nanoparticles and to define the optimum amount and combination of the chemotherapeutic drugs.

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