title: Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat.
abstract: Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention.Objective:Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via αvβ3-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges.Results:Anti-neovascular effectiveness of αvβ3-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous19F/1H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (αvβ3-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving αvβ3-No-Drug micelles while αvβ3-Dxtl-PD or αvβ3-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but αvβ3+macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the αvβ3-Dxtl-PD micelles. Additionally, αvβ3-Dxtl-PD decreased BAL eosinophil and αvβ3+CD45+leukocytes relative to αvβ3-No-Drug micelles, whereas αvβ3-Fum-PD micelles did not.Conclusion:These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in a clinically relevant rodent model.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lanza
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Jenkins
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Anne H
authors.initials: AH
authors.lastname: Schmieder
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Aigul
authors.initials: A
authors.lastname: Moldobaeva
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Cui
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Huiying
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Philips Research Laboratories, Hamburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Keupp
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Ismail
authors.initials: I
authors.lastname: Sergin
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Krishna S
authors.initials: KS
authors.lastname: Paranandi
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Eldridge
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Allen
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Williams
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Scott
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Razani
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wagner
mesh_terms: D056151:Airway Remodeling; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001249:Asthma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology*; D003510:Cyclohexanes / Q000008:administration & dosage; D004195:Disease Models, Animal; D000077143:Docetaxel; D004337:Drug Carriers / Q000008:administration & dosage; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage; D008279:Magnetic Resonance Imaging; D008856:Microscopy, Fluorescence; D049329:Nanostructures / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage; D039981:Pyroglyphidae / Q000472:pathogenicity; D051381:Rats; D012717:Sesquiterpenes / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D004337:Drug Carriers; D005231:Fatty Acids, Unsaturated; D011355:Prodrugs; D012717:Sesquiterpenes; D043823:Taxoids; D000077143:Docetaxel; C026211:fumagillin
keywords: Angiogenesis; Asthma; Fluorine MRI; Nanomedicine; Prodrug; Respiratory function