Minute dosages of alpha(nu)beta3-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits.
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.
Winter
Patrick M
PM
Washington University Medical School, Campus Box 8215, 4320 Forest Park Ave., St. Louis, MO 63108, USA. patrick@cvu.wustl.edu
Schmieder
Anne H
AH
Caruthers
Shelton D
SD
Keene
Jeffery L
JL
Zhang
Huiying
H
Wickline
Samuel A
SA
Lanza
Gregory M
GM
D000230:Adenocarcinoma / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D003510:Cyclohexanes / Q000008:administration & dosage*; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008297:Male; D063208:Methionyl Aminopeptidases; D053758:Nanoparticles; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D011817:Rabbits; D012717:Sesquiterpenes / Q000008:administration & dosage
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D039302:Integrin alphaVbeta3; D012717:Sesquiterpenes; C026211:fumagillin; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases