Minute dosages of alpha(nu)beta3-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits.

Abstract

Fumagillin suppresses angiogenesis in cancer models and clinical trials, but it is associated with neurotoxicity at systemic doses. In this study, alpha(nu)beta(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 alpha(nu)beta(3)-targeted fumagillin nanoparticles (30 microg/kg), alpha(nu)beta(3)-targeted nanoparticles without drug, nontargeted fumagillin nanoparticles (30 microg/kg) or saline. On day 16, MRI was performed with alpha(nu)beta(3)-targeted paramagnetic nanoparticles to quantify tumor size and assess neovascularity. Tumor volume was reduced among rabbits receiving alpha(nu)beta(3)-targeted fumagillin nanoparticles (470+/-120 mm(3)) compared with the three control groups: nontargeted fumagillin nanoparticles (1370+/-300 mm(3), P<0.05), alpha(nu)beta(3)-targeted nanoparticles without drug (1080+/-180 mm(3), P<0.05) and saline (980+/-80 mm(3), 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 alpha(nu)beta(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 alpha(nu)beta(3)-targeted fumagillin nanoparticles could provide a safe and effective means to deliver MetAP2 inhibitors alone or in combination with cytotoxic or immunotherapy.

• Authors: Patrick M Winter, Anne H Schmieder, Shelton D Caruthers, Jeffery L Keene, Huiying Zhang, Samuel A Wickline, Gregory M Lanza
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 22 Issue 8 Pg. 2758-67 (Aug 2008) ISSN: 1530-6860 [Electronic] United States
• PMID: 18362202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Cyclohexanes
• Fatty Acids, Unsaturated
• Integrin alphaVbeta3
• Sesquiterpenes
• fumagillin
• Aminopeptidases
• Methionyl Aminopeptidases

Topics

• Adenocarcinoma (blood supply, drug therapy, metabolism, pathology)
• Aminopeptidases (antagonists & inhibitors)
• Angiogenesis Inhibitors (administration & dosage)
• Animals
• Cyclohexanes (administration & dosage)
• Fatty Acids, Unsaturated (administration & dosage)
• Integrin alphaVbeta3 (antagonists & inhibitors)
• Male
• Methionyl Aminopeptidases
• Nanoparticles
• Neovascularization, Pathologic (pathology, prevention & control)
• Rabbits
• Sesquiterpenes (administration & dosage)