Patrick M. Winter, Anne H. Schmieder, Shelton D. Caruthers, Jeffery L. Keene, Huiying Zhang, Samuel A. Wickline, and Gregory M. Lanza
Fumagillin suppresses angiogenesis in cancer models and clinical trials, but it is associated with neurotoxicity at systemic doses. In this study, 3-targeted fumagillin nanoparticles were used to suppress the neovasculature and inhibit Vx-2 adenocarcinoma development using minute drug doses. Tumor-bearing rabbits were treated on days 6, 9, and 12 postimplantation with 3-targeted fumagillin nanoparticles (30 µg/kg), 3-targeted nanoparticles without drug, nontargeted fumagillin nanoparticles (30 µg/kg) or saline. On day 16, MRI was performed with 3-targeted paramagnetic nanoparticles to quantify tumor size and assess neovascularity. Tumor volume was reduced among rabbits receiving 3-targeted fumagillin nanoparticles (470±120 mm3) compared with the three control groups: nontargeted fumagillin nanoparticles (1370±300 mm3, P<0.05), 3-targeted nanoparticles without drug (1080±180 mm3, P<0.05) and saline (980±80 mm3, P<0.05). MR molecular imaging of control rabbits (no fumagillin) revealed a predominant peripheral distribution of neovascularity representing 7.2% of the tumor rim volume, which decreased to 2.8% (P<0.05) with 3-targeted fumagillin nanoparticle treatment. Microscopically, the tumor parenchyma tended to show T-cell infiltration after targeted fumagillin treatment, which was not appreciated in control animals. These results suggest that 3-targeted fumagillin nanoparticles could provide a safe and effective means to deliver MetAP2 inhibitors alone or in combination with cytotoxic or immunotherapy.—Winter, P. M., Schmieder, A. H., Caruthers, S. D., Keene, J. L., Zhang, H., Wickline, S. A., Lanza, G. M. Minute dosages of 3-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits.
Federation of American Societies for Experimental Biology Journal (03/24/08)