Back to Search Start Over

Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat.

Authors :
Lanza GM
Jenkins J
Schmieder AH
Moldobaeva A
Cui G
Zhang H
Yang X
Zhong Q
Keupp J
Sergin I
Paranandi KS
Eldridge L
Allen JS
Williams T
Scott MJ
Razani B
Wagner EM
Source :
Theranostics [Theranostics] 2017 Jan 01; Vol. 7 (2), pp. 377-389. Date of Electronic Publication: 2017 Jan 01 (Print Publication: 2017).
Publication Year :
2017

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 α <subscript>v</subscript> β <subscript>3</subscript> -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 α <subscript>v</subscript> β <subscript>3</subscript> -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 simultaneous <superscript>19</superscript> F/ <superscript>1</superscript> H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (α <subscript>v</subscript> β <subscript>3</subscript> -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 α <subscript>v</subscript> β <subscript>3</subscript> -No-Drug micelles while α <subscript>v</subscript> β <subscript>3</subscript> -Dxtl-PD or α <subscript>v</subscript> β <subscript>3</subscript> -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 α <subscript>v</subscript> β <subscript>3</subscript> <superscript>+</superscript> macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the α <subscript>v</subscript> β <subscript>3</subscript> -Dxtl-PD micelles. Additionally, α <subscript>v</subscript> β <subscript>3</subscript> -Dxtl-PD decreased BAL eosinophil and α <subscript>v</subscript> β <subscript>3</subscript> <superscript>+</superscript> CD45 <superscript>+</superscript> leukocytes relative to α <subscript>v</subscript> β <subscript>3</subscript> -No-Drug micelles, whereas α <subscript>v</subscript> β <subscript>3</subscript> -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.<br />Competing Interests: The authors have declared that no competing interest exists.

Details

Language :
English
ISSN :
1838-7640
Volume :
7
Issue :
2
Database :
MEDLINE
Journal :
Theranostics
Publication Type :
Academic Journal
Accession number :
28042341
Full Text :
https://doi.org/10.7150/thno.16627