Fumagillin prodrug nanotherapy suppresses macrophage inflammatory response via endothelial nitric oxide.
Fumagillin prodrug nanotherapy suppresses macrophage inflammatory response via endothelial nitric oxide.
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DOI：
10.1021/nn502372n
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发表时间：
2014-07-22
期刊：
影响因子：
17.1
通讯作者：
Pham, Christine T. N.
中科院分区：
文献类型：
--
作者：
Zhou, Hui-fang;Yan, Huimin;Hu, Ying;Springer, Luke E.;Yang, Xiaoxia;Wickline, Samuel A.;Pan, Dipanjan;Lanza, Gregory M.;Pham, Christine T. N.
抗血管生成已被广泛探索用于治疗各种癌症和某些炎症过程。烟曲霉素是一种由烟曲霉产生的真菌毒素，可与甲硫氨酸氨基肽酶2（MetAP-2）结合，是一种有效的抗血管生成剂。然而，天然烟曲霉素溶解性差且极不稳定。我们已经开发了一种脂肪酶不稳定的烟曲霉素前药（Fum-PD），消除了光不稳定性的化合物。使用αvβ3-整合素靶向全氟化碳纳米载体将Fum-PD特异性递送至血管生成血管，我们在类风湿性关节炎（RA）实验模型中有效抑制了临床疾病。然而，Fum-PD靶向纳米颗粒抑制实验性RA炎症的确切机制仍然无法解释。我们在此提出的证据表明，Fum-PD纳米治疗间接抑制炎症实验性RA通过局部生产的内皮一氧化氮（NO）。Fum-PD诱导的NO激活AMP激活的蛋白激酶（AMPK），其随后调节巨噬细胞炎症反应。在体内，NO诱导的AMPK活化抑制哺乳动物雷帕霉素靶蛋白（mTOR）活性，并增强自噬通量，如p62耗竭和增加的自溶体形成所证明的。自噬反过来介导Ikappa B激酶（IKK）的降解，抑制NF-κB p65信号通路和炎性细胞因子释放。通过一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯（l-NAME）抑制NO产生，逆转Fum-PD纳米治疗诱导的NF-κ B介导的炎症反应抑制。这些意想不到的结果揭示了Fum-PD纳米疗法的活性，可以在血管生成依赖性疾病的治疗中进一步探索。
Antiangiogenesis has been extensively explored for the treatment of a variety of cancers and certain inflammatory processes. Fumagillin, a mycotoxin produced by Aspergillus fumigatus that binds methionine aminopeptidase 2 (MetAP-2), is a potent antiangiogenic agent. Native fumagillin, however, is poorly soluble and extremely unstable. We have developed a lipase-labile fumagillin prodrug (Fum-PD) that eliminated the photoinstability of the compound. Using αvβ3-integrin-targeted perfluorocarbon nanocarriers to deliver Fum-PD specifically to angiogenic vessels, we effectively suppressed clinical disease in an experimental model of rheumatoid arthritis (RA). The exact mechanism by which Fum-PD-loaded targeted nanoparticles suppressed inflammation in experimental RA, however, remained unexplained. We herein present evidence that Fum-PD nanotherapy indirectly suppresses inflammation in experimental RA through the local production of endothelial nitric oxide (NO). Fum-PD-induced NO activates AMP-activated protein kinase (AMPK), which subsequently modulates macrophage inflammatory response. In vivo, NO-induced AMPK activation inhibits mammalian target of rapamycin (mTOR) activity and enhances autophagic flux, as evidenced by p62 depletion and increased autolysosome formation. Autophagy in turn mediates the degradation of IkappaB kinase (IKK), suppressing the NF-κB p65 signaling pathway and inflammatory cytokine release. Inhibition of NO production by NG-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor, reverses the suppression of NF-κB-mediated inflammatory response induced by Fum-PD nanotherapy. These unexpected results uncover an activity of Fum-PD nanotherapy that may be further explored in the treatment of angiogenesis-dependent diseases.
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作者：
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