Esser Alison K, Schmieder Anne H, Ross Michael H, Xiang Jingyu, Su Xinming, Cui Grace, Zhang Huiying, Yang Xiaoxia, Allen John S, Williams Todd, Wickline Samuel A, Pan Dipanjan, Lanza Gregory M, Weilbaecher Katherine N
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Nanomedicine. 2016 Jan;12(1):201-11. doi: 10.1016/j.nano.2015.10.003. Epub 2015 Oct 27.
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.
烟曲霉素是一种不稳定的抗血管生成霉菌毒素，被合成成一种稳定的对脂肪酶敏感的前药，并被整合到整合素靶向的脂质包裹纳米颗粒（αvβ3-Fum-PD NP）中。评估了将αvβ3-Fum-PD NP与唑来膦酸（ZA）联合使用的双重抗血管生成疗法，唑来膦酸是一种具有抗血管生成作用的长效破骨细胞抑制剂。在体外，αvβ3-Fum-PD NP降低了（P<0.05）内皮细胞活力，而不影响巨噬细胞活力。ZA在高剂量时抑制（P<0.05）巨噬细胞活力，但不影响内皮细胞增殖。兔VX2肿瘤的三维磁共振新生血管成像显示ZA无效果，而单独使用αvβ3-Fum-PD NP以及与ZA联合使用均可减少血管生成（P<0.05）。免疫组织化学显示，αvβ3-Fum-PD NP和ZA联合使用可使微血管减少（P<0.05），双重疗法可进一步减少微血管（P<0.05）。在体内，ZA并未减少肿瘤巨噬细胞数量和癌细胞增殖，而αvβ3-Fum-PD-NPs可降低这两项指标。如果巨噬细胞对ZA的摄取增加，ZA与αvβ3-Fum-PD-NP的双重疗法可能会提供增强的新辅助效用。临床编辑评论：尽管抗血管生成是对抗癌症的治疗方式之一，但许多癌症对VEGF通路抑制剂产生耐药性。在本文中，作者在体外和体内实验中研究了使用烟曲霉素、整合素靶向脂质包裹纳米颗粒（αvβ3-Fum-PD NP）和唑来膦酸（ZA）的双重疗法。这种联合方法可能为未来抗癌药物的设计提供思路。
