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

Theranostics. 2017 Jan 1;7(2):377-389. doi: 10.7150/thno.16627. eCollection 2017.


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 simultaneous 19F/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.

Keywords: Angiogenesis; Asthma; Fluorine MRI; Nanomedicine; Prodrug; Respiratory function.

MeSH terms

  • Airway Remodeling*
  • Angiogenesis Inhibitors / administration & dosage*
  • Animals
  • Asthma / diagnostic imaging
  • Asthma / drug therapy*
  • Asthma / pathology*
  • Cyclohexanes / administration & dosage
  • Disease Models, Animal
  • Docetaxel
  • Drug Carriers / administration & dosage
  • Fatty Acids, Unsaturated / administration & dosage
  • Magnetic Resonance Imaging
  • Microscopy, Fluorescence
  • Nanostructures / administration & dosage*
  • Prodrugs / administration & dosage
  • Pyroglyphidae / pathogenicity
  • Rats
  • Sesquiterpenes / administration & dosage
  • Taxoids / administration & dosage
  • Treatment Outcome


  • Angiogenesis Inhibitors
  • Cyclohexanes
  • Drug Carriers
  • Fatty Acids, Unsaturated
  • Prodrugs
  • Sesquiterpenes
  • Taxoids
  • Docetaxel
  • fumagillin