title: Fumagillin prodrug nanotherapy suppresses macrophage inflammatory response via endothelial nitric oxide.
abstract: 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 N(G)-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.
authors.affiliation: Division of Rheumatology and ‡Division of Cardiology, Department of Medicine, Washington University School of Medicine , Saint Louis, Missouri, United States.
authors.forename: Hui-fang
authors.initials: HF
authors.lastname: Zhou
authors.forename: Huimin
authors.initials: H
authors.lastname: Yan
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Luke E
authors.initials: LE
authors.lastname: Springer
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wickline
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Pan
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lanza
authors.forename: Christine T N
authors.initials: CT
authors.lastname: Pham
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001168:Arthritis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008049:Lipase / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D050997:Nanomedicine; D053758:Nanoparticles; D009569:Nitric Oxide / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D016207:Cytokines; D005231:Fatty Acids, Unsaturated; D011355:Prodrugs; D012717:Sesquiterpenes; D051996:Transcription Factor RelA; D009569:Nitric Oxide; C026211:fumagillin; D055372:AMP-Activated Protein Kinases; D008049:Lipase