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 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.

Inhalable nanotherapeutics to improve treatment efficacy for common lung diseases

“…Furthermore, inflammatory cell numbers within bronchoalveolar sites were reduced by both Fum and Dxtl nanotherapies, as represented in Figure f. These results demonstrate the potential of an inhaled antiangiogenic nanotherapeutic to ameliorate symptoms of asthma; assessments of biodistribution and any systemic toxicity would further validate the use of this system (Lanza et al, ).…”

“…(f) Bronchoalveolar (BAL) cell profiles showing a lower percentage of eosinophils (EOS) in HDM rats receiving α V β 3 ‐Dxtl‐PD and α V β 3 ‐Fum‐PD micelles (left) and flow cytometry of BAL fluid (right) revealing that α V β 3 ‐Fum‐PD and α V β 3 ‐Dxtl‐PD micelles decreased α V β 3 + macrophage/monocyte numbers versus empty micelles(* p < 0.05, *** p < 0.001). (Reprinted with permission from Lanza et al (). Copyright 2017 Ivyspring International Publisher)…”

Local Intratracheal Delivery of Perfluorocarbon Nanoparticles to Lung Cancer Demonstrated with Magnetic Resonance Multimodal Imaging

“…In humans, the biological half-life estimate for PFOB is typically cited as 3-4 d, while PFCE intrapulmonary persistence is clinically too long (>60 d) 52 . Recently, 19 F neovascular molecular imaging studies at 3T (clinical) utilized α v β 3 -targeted PFOB nanoparticles to detect the sparse α v β 3 -intergrin expression of pulmonary neovasculature in rat models of acute lung ischemia and asthma 53 - 55 . These data considered in combination with the strong serial 1 H/ 19 F data presented in this report suggest that substitution of PFCE with PFOB would not compromise the theranostic potential of the nanoplatform approach.…”

Perfluorooctylbromide nanoparticles for ultrasound imaging and drug delivery

“…In contrast to liposomal drug delivery, which generally requires endocytosis, the mechanism by which targeted PFOB NPs with a lipid-coating transport drugs involves lipid exchange or lipid mixing between the lipid monolayer of the delivery system and the targeted cell membrane, termed "contactfacilitated drug delivery." [77][78][79][80] PFOB NPs have been loaded with different drugs for various applications, such as antiinflammatory arthritis therapy, 32,81,82 bone fracture healing, 83,84 dust mite-triggered asthma therapy, 85 cytotoxicity reduction in the loaded drug, 86 analyses of complement activation, 87 thrombolytic therapy, 88,89 prevention of restenosis, 77,90 atherosclerosis therapy and cancer therapy. The capacity to deliver a payload to the targeted site could be of great benefit, leading to the development of targeted anticancer and anti-atherosclerosis therapeutics based on this platform.…”