Novel Synergistic Therapy for Metastatic Breast Cancer: Magnetic Nanoparticle Hyperthermia of the Neovasculature Enhanced by a Vascular Disruption Agent.

摘要

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) was 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) was 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 primary amines on VEGFR-2 antibodies to carboxyl groups on the SPIONs activated by EDC/Sulfo-NHS resulted in stable particles that showed specific binding to endothelial cells in vitro. Current in vivo results suggest a modest 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; however, statistically-significant nanoparticle quantitation (by mass spectrometry) was not realized, due to high endogenous iron levels in tumor tissue. In vitro testing of SPION heating in the presence of an alternating magnetic field demonstrated that heating is optimized using 20 nm SPIONs. Reformulation of the poorly soluble DMXAA (using bicarbonate buffer to replace DMSO) was shown to improve long-term survival of the mice after DMXAA administration, which will enable in vivo longitudinal measurements of therapeutic efficacy to be carried out in a future study.