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Minute dosages of β₃-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits

Patrick M. Winter^*,1, Anne H. Schmieder^*, Shelton D. Caruthers^*,, Jeffery L. Keene, Huiying Zhang^*, Samuel A. Wickline^* and Gregory M. Lanza^*,1

^* Washington University Medical School, St. Louis, Missouri, USA;

Philips Medical Systems, Andover, Massachusetts, USA; and

Kereos, Inc., St. Louis, Missouri, USA

¹ Correspondence: Washington University Medical School, Campus Box 8215, 4320 Forest Park Ave., St. Louis, MO 63108, USA. E-mail: P.M.W, patrick{at}cvu.wustl.edu; or G.M.L., greg{at}cvu.wustl.edu

Fumagillin suppresses angiogenesis in cancer models and clinical trials, but it is associated with neurotoxicity at systemic doses. In this study, β₃-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 β₃-targeted fumagillin nanoparticles (30 µg/kg), β₃-targeted nanoparticles without drug, nontargeted fumagillin nanoparticles (30 µg/kg) or saline. On day 16, MRI was performed with β₃-targeted paramagnetic nanoparticles to quantify tumor size and assess neovascularity. Tumor volume was reduced among rabbits receiving β₃-targeted fumagillin nanoparticles (470±120 mm³) compared with the three control groups: nontargeted fumagillin nanoparticles (1370±300 mm³, P<0.05), β₃-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 β₃-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 β₃-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 β₃-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits.

Key Words: MRI • cancer • drug delivery • molecular imaging

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