Fumagillin suppresses angiogenesis in cancer models and clinical trials, but it is associated with neurotoxicity at systemic doses. In this study, αvβ3-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 αvβ3-targeted fumagillin nanoparticles (30 μg/kg), αvβ3-targeted nanoparticles without drug, nontargeted fumagillin nanoparticles (30 μg/kg) or saline. On day 16, MRI was performed with αvβ 3-targeted paramagnetic nanoparticles to quantify tumor size and assess neovascularity. Tumor volume was reduced among rabbits receiving αvβ3-targeted fumagillin nanoparticles (470±120 mm3) compared with the three control groups: nontargeted fumagillin nanoparticles (1370±300 mm3, P<0.05), αvβ3-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 αvβ3-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 αvβ 3-targeted fumagillin nanoparticles could provide a safe and effective means to deliver MetAP2 inhibitors alone or in combination with cytotoxic or immunotherapy.
- Drug delivery
- Molecular imaging