TY - JOUR
T1 - Minute dosages of αvβ3-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits
AU - Winter, Patrick M.
AU - Schmieder, Anne H.
AU - Caruthers, Shelton D.
AU - Keene, Jeffery L.
AU - Zhang, Huiying
AU - Wickline, Samuel A.
AU - Lanza, Gregory M.
PY - 2008/8
Y1 - 2008/8
N2 - 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.
AB - 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.
KW - Cancer
KW - Drug delivery
KW - MRI
KW - Molecular imaging
UR - http://www.scopus.com/inward/record.url?scp=48749099374&partnerID=8YFLogxK
U2 - 10.1096/fj.07-103929
DO - 10.1096/fj.07-103929
M3 - Article
C2 - 18362202
AN - SCOPUS:48749099374
SN - 0892-6638
VL - 22
SP - 2758
EP - 2767
JO - FASEB Journal
JF - FASEB Journal
IS - 8
ER -