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 α _vβ ₃-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 _vβ ₃-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 ¹⁹F/ ¹H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (α _vβ ₃-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 _vβ ₃-No-Drug micelles while α _vβ ₃-Dxtl-PD or α _vβ ₃-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 _vβ ₃ ⁺ macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the α _vβ ₃-Dxtl-PD micelles. Additionally, α _vβ ₃-Dxtl-PD decreased BAL eosinophil and α _vβ ₃ ⁺ CD45 ⁺ leukocytes relative to α _vβ ₃-No-Drug micelles, whereas α _vβ ₃-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.