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

作者：Lanza Gregory M^*; Jenkins John; Schmieder Anne H; Moldobaeva Aigul; Cui Grace; Zhang Huiying; Yang Xiaoxia; Zhong Qiong; Keupp Jochen; Sergin Ismail; Paranandi Krishna S; Eldridge Lindsey; Allen John S; Williams Todd; Scott Michael J; Razani Babak; Wagner Elizabeth M

来源：Theranostics, 2017, 7(2): 377-389.

DOI：10.7150/thno.16627

• Asthma
• Nanomedicine
• Prodrug
• Angiogenesis
• Fluorine MRI
• Respiratory function

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

• 出版日期2017