Winter Patrick M, Schmieder Anne H, Caruthers Shelton D, Keene Jeffery L, Zhang Huiying, Wickline Samuel A, Lanza Gregory M
Washington University Medical School, Campus Box 8215, 4320 Forest Park Ave., St. Louis, MO 63108, USA.
FASEB J. 2008 Aug;22(8):2758-67. doi: 10.1096/fj.07-103929. Epub 2008 Mar 24.
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.
烟曲霉素在癌症模型和临床试验中可抑制血管生成，但全身给药时会伴有神经毒性。在本研究中，使用靶向α(nu)β(3)的烟曲霉素纳米颗粒，以微小剂量药物抑制新生血管生成并抑制VX-2腺癌的发展。荷瘤兔在植入后第6、9和12天接受靶向α(nu)β(3)的烟曲霉素纳米颗粒（30微克/千克）、不含药物的靶向α(nu)β(3)纳米颗粒、非靶向烟曲霉素纳米颗粒（30微克/千克）或生理盐水治疗。在第16天，使用靶向α(nu)β(3)的顺磁性纳米颗粒进行磁共振成像（MRI），以量化肿瘤大小并评估新生血管情况。与三个对照组相比，接受靶向α(nu)β(3)的烟曲霉素纳米颗粒治疗的兔的肿瘤体积减小（470±120立方毫米）：非靶向烟曲霉素纳米颗粒组（1370±300立方毫米，P<0.05）、不含药物的靶向α(nu)β(3)纳米颗粒组（1080±180立方毫米，P<0.05）和生理盐水组（980±80立方毫米，P<0.05）。对照兔（未用烟曲霉素）的磁共振分子成像显示新生血管主要分布在周边，占肿瘤边缘体积的7.2%，经靶向α(nu)β(3)的烟曲霉素纳米颗粒治疗后降至2.8%（P<0.05）。显微镜下，靶向烟曲霉素治疗后肿瘤实质倾向于出现T细胞浸润，而在对照动物中未观察到。这些结果表明，靶向α(nu)β(3)的烟曲霉素纳米颗粒可为单独递送甲硫氨酸氨肽酶2（MetAP2）抑制剂或与细胞毒性或免疫疗法联合使用提供一种安全有效的方法。
