Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model

Oct 31, 2015Nanomedicine : nanotechnology, biology, and medicine

Combined treatment with targeted fumagillin nanoparticles and zoledronic acid in a rabbit tumor model

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Abstract

αvβ3-Fum-PD NP reduced endothelial cell viability by P<0.05 without affecting macrophage viability.

Dual therapy with αvβ3-Fum-PD NP and zoledronic acid decreased angiogenesis (P<0.05) in rabbit tumors.
In vitro, zoledronic acid at high dosages suppressed macrophage viability but did not impact endothelial cell proliferation.
Immunohistochemistry indicated reduced microvascularity with both αvβ3-Fum-PD NP and zoledronic acid, with greater reduction observed with the dual therapy (P<0.05).
In vivo studies showed that αvβ3-Fum-PD NPs reduced tumor macrophage numbers and cancer cell proliferation, while zoledronic acid did not affect these measures.

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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 without impacting macrophage viability. ZA suppressed (P<0.05) macrophage viability at high dosages but not endothelial cell proliferation. 3D MR neovascular imaging of 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 dual-therapy. In vivo, ZA did not decrease tumor macrophage numbers nor cancer cell proliferation, whereas αvβ3-Fum-PD-NPs reduced both measures. Dual-therapy with ZA and αvβ3-Fum-PD-NP may provide enhanced neo-adjuvant utility if macrophage ZA uptake is increased. From the Clinical Editor: Although anti-angiogenesis is one of the treatment modalities in the fight against cancer, many cancers become resistant to VEGF pathway inhibitors. In this article, the authors investigated the use of dual therapy using fumagillin, integrin-targeted lipid-encapsulated nanoparticles (αvβ3- Fum-PD NP) and zoledronic acid (ZA), in both in-vitro and in-vivo experiments. This combination approach may provide an insight to the design of future drugs against cancers.

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Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model

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