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Novel Synergistic Therapy for Metastatic Breast Cancer: Magnetic Nanoparticle Hyperthermia of the Neovasculature Enhanced by a Vascular Disruption Agent
Annual rept. 1 Jun 2011-31 May 2012
NEW MEXICO UNIV HEALTH SCIENCES CENTER ALBUQUERQUE HEALTH SCIENCES CENTER
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Vascular disruption agents VDAs have been shown to selectively destroy established tumor vasculature, which results in the ischemic death of up to 99 of tumor cells. The weakness of VDA monotherapy is that it often leaves a rim of surviving tumor cells which can then regrow and spread. The overall goal of this study addressed in Task 2 is to enhance VDA therapy by inducing hyperthermia, targeted to the neovascular endothelium, through the use of superparamagnetic iron oxide nanoparticles SPIONs, in order to halt, or significantly slow down tumor growth. Therefore, the first aim of this study Task 1 is to maximize the delivery of SPIONs to the tumor rim, through a combination of neovascular targeting and increased vascular permeability induced by the VDA. Covalent coupling of a primary amine on the antibody to a carboxyl on the SPIONs activated by EDCSulfo-NHS resulted in colloidally-stable particles that showed specific binding to VEGFR-2 expressing cells in vitro. Current in vivo results suggest a synergistic enhancement of SPION delivery to the tumor rim when VEGFR-2 targeting of PEG-coated particles and 15 min pre-administration of DMXAA a VDA are employed. The results suggest that the combination of targeting the neovasculature and increasing vascular permeability through the action of the VDA is an effective SPION delivery strategy. Quantitative chemical analysis of tumor samples are ongoing to obtain statistically-significant iron quantitation. In vitro testing of SPION heating in the presence of an alternating magnetic field has been successful and demonstrates that heating is optimized using 20 nm SPIONs. However, in vivo testing of hyperthermia therapy in mice receiving targeted SPIONs after DMXAA pre-treatment is currently on hold, pending a solution to the problem of poor long-term survival of the mice after DMXAA administration.
APPROVED FOR PUBLIC RELEASE