Table of Contents
International Journal of Molecular Imaging
Volume 2016 (2016), Article ID 5768312, 11 pages
http://dx.doi.org/10.1155/2016/5768312
Research Article

Understanding Lung Deposition of Alpha-1 Antitrypsin in Acute Experimental Mouse Lung Injury Model Using Fluorescence Microscopy

1Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Andover, MA, USA
2Drug Safety R&D, Pfizer Inc., Andover, MA, USA
3Clinical R&D, Pfizer Inc., Cambridge, MA, USA
4Molecular Imaging Laboratory, Pfizer Inc., Andover, MA, USA
5Rare Disease RU, Pfizer Inc., Cambridge, MA, USA

Received 6 June 2016; Revised 26 September 2016; Accepted 26 October 2016

Academic Editor: Helmut Sinzinger

Copyright © 2016 Mengmeng Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Human plasma-derived α1-antitrypsin (AAT) delivered by intravenous infusion is used as augmentation therapy in patients with emphysema who have a genetic mutation resulting in deficiency of AAT. Inhalation is an alternative route of administration that can potentially increase the efficacy and convenience of treatment. This study was conducted to determine whether delivery to the lungs, initially via the intratracheal (IT) route of administration, would deliver efficacious levels of a recombinant AAT (rAAT) to the site of action in the lungs in mice. 125I-radiolabeled rAAT, fluorophore-conjugated rAAT (rAAT-Alexa488), and NE680 (neutrophil elastase 680, a silent fluorescent substrate of neutrophil elastase which fluoresces in the near-infrared range upon activation by neutrophil elastase) were used to characterize the pharmacokinetics and tissue distribution profile, distribution of rAAT within the lung, and efficacy of rAAT to inhibit neutrophil elastase at the site of action, respectively. The study has demonstrated that rAAT was able to gain access to locations where neutrophil elastase was localized. The histochemical quantification of rAAT activity relative to dose at the site of action provided here will improve confidence in predicting the human dose via the inhalation route.