Dual-therapy with αvβ3-targeted Sn2 lipase-labile Fumagillin-prodrug Nanoparticles and Zoledronic Acid in the Vx2 Rabbit Tumor Model

Publication date: Available online 27 October 2015 Source:Nanomedicine: Nanotechnology, Biology and Medicine Author(s): Alison K. Esser, Anne H. Schmieder, Michael H. Ross, Jingyu Xiang, Xinming Su, Grace Cui, Huiying Zhang, Xiaoxia Yang, John S. Allen, Todd Williams, Samuel A. Wickline, Dipanjan Pan, Gregory M. Lanza, Katherine N. Weilbaecher Fumagillin, an unstable anti-angiogenesis mycotoxin, was synthesized into a stable lipase-labile prodrug and incorporated into integrin-targeted lipid-encapsulated nanoparticles (αvβ3-Fum-PD NP). Dual anti-angiogenic therapy combining αvβ3-Fum-PD NP with zoledronic acid (ZA), a long-acting osteoclast inhibitor with proposed anti-angiogenic effects, was evaluated. In vitro, αvβ3-Fum-PD NP reduced (p<0.05) endothelial cell viability and tube formation without impacting macrophage viability. ZA suppressed (p<0.05) macrophage viability at high dosages in vitro but not endothelial cell proliferation. 3D MRI neovascular imaging of 17d rabbit Vx2 tumors showed no effect with ZA, whereas αvβ3-Fum-PD NP alone and with ZA decreased angiogenesis (p<0.05). Immunohistochemistry revealed decreased (p<0.05) microvascularity with αvβ3-Fum-PD NP and ZA and further microvascular reduction (p<0.05) with the dual-therapy. However, in vivo, ZA did not decrease tumor macrophage numbers nor cancer cell proliferation, whereas αvβ3-Fum-PD-NPs reduced both measures. Dual-therapy with ...

Source: Nanomedicine: Nanotechnology, Biology and Medicine - October 27, 2015 Category: Nanotechnology Source Type: research