Currently over twenty clinical trials are under way to test the efficacy of anti-angiogenic agents. The rationale for testing these emerging agents is several fold including 1) the possibility to eliminate a plurality tumor cells by targeting a single vessel, 2) circumventing tumor drug delivery barriers and 3) lack of apparent drug resistance to anti-angiogenic agents. One of the major obstacles in assessing anti-angiogenesis has been the lack of in vivo monitoring tools. The overall goal of this project is to image both the """"""""lumen"""""""" of tumor neovessels (e.g. """"""""functional"""""""" vascular volume) to high resolution, and neovascular endothelium, biochemically and morphologically different from quiescent normal endothelium. The main hypothesis underlying the research is that phenotypic changes occurring during angiogenesis can be visualized by in vivo imaging and correlate closely with traditional histology or other microvascular parameters. We have previously developed a sterically protected graft co- polymer, PGC which 1) allows steady state MR imaging of tumor vascular volume fractions at high resolutions, 2) can potentially serve as an amplification strategy to image cell-surface endothelial markers and 3) has been used as a carrier for targeted drug delivery to the neovasculature. In preliminary studies we have validated the use of this molecule for imaging angiogenesis and have taken it through a phase I clinical trial at MGF. In collaboration with Drs. Jan and C. Lin (MGH) we will now investigate and compare the microvascular behavior of this agent to other available probes using intravital microscopy and for longitudinal in vivo MR imaging during anti-angiogenic during anti-angiogenic treatment in mouse models. In collaboration with Drs. M. Gimbrone, Jr. (BWH), D. Roberts (NCI) and A. Rosenzweig (MGH) we will investigate neovascular targeting strategies to image the expression of surface molecules on stimulated endothelial cells. Finally, we will use imaging to evaluate and optimize therapeutic gene delivery to tumor neovasculature. The project is a highly interactive as it relies on multi-disciplinary expertise. We expect that these studies will yield clinically important information relevant to monitoring angiogenesis and anti-angiogenesis.
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