Dual-therapy with α_vβ₃-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model

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• 作者：Alison K. Esser ; PhD^a ; Anne H. Schmieder ; MS^b ; Michael H. Ross ; BS^a ; Jingyu Xiang ; MD^a ; Xinming Su ; PhD^a ; Grace Cui ; MS^b ; Huiying Zhang ; MD^b ; Xiaoxia Yang ; BS^b ; John S. Allen ; BS^b ; Todd Williams ; BS^b ; Samuel A. Wickline ; MD^b ; Dipanjan Pan ; PhD^c ; Gregory M. Lanza ; MD ; PhD^b ; ¹ ; ^{greg.lanza@mac.com" class="auth_mail" title="E-mail the corresponding author} ; ^{greg.lanza@me.com" class="auth_mail" title="E-mail the corresponding author} ; Katherine N. Weilbaecher ; MD^a ; ¹ ; ^{kweilbae@wustl.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Fumagillin ; Zoledronic acid ; Cancer ; Nanoparticle ; MRI ; Molecular imaging
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：12
• 期：1
• 页码：201-211
• 全文大小：1798 K

文摘

Fumagillin, an unstable anti-angiogenesis mycotoxin, was synthesized into a stable lipase-labile prodrug and incorporated into integrin-targeted lipid-encapsulated nanoparticles (α_vβ₃-Fum-PD NP). Dual anti-angiogenic therapy combining α_vβ₃-Fum-PD NP with zoledronic acid (ZA), a long-acting osteoclast inhibitor with proposed anti-angiogenic effects, was evaluated. In vitro, α_vβ₃-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 α_vβ₃-Fum-PD NP alone and with ZA decreased angiogenesis (P < 0.05). Immunohistochemistry revealed decreased (P < 0.05) microvascularity with α_vβ₃-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 α_vβ₃-Fum-PD-NPs reduced both measures. Dual-therapy with ZA and α_vβ₃-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.