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In Vivo Imaging of ⁶⁴Cu-Labeled Polymer Nanoparticles Targeted to the Lung Endothelium

Raffaella Rossin¹, Silvia Muro^2,3, Michael J. Welch¹, Vladimir R. Muzykantov^2,3 and Daniel P. Schuster^,1,4

¹ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri; ² Institute for Environmental Medicine, University of Pennsylvania Medical School, Philadelphia, Pennsylvania; ³ Department of Pharmacology, University of Pennsylvania Medical School, Philadelphia, Pennsylvania; and ⁴ Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri

Correspondence: For correspondence or reprints contact: Raffaella Rossin, PhD, Department of Biomolecular Engineering, Philips Research Laboratories, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands. E-mail: raffaella.rossin{at}philips.com

Nanoparticles (NPs) targeting the intercellular adhesion molecule 1 (ICAM-1) hold promise as a mean of delivering therapeutics to the pulmonary endothelium in patients with acute and chronic respiratory diseases. As these new materials become available, strategies are needed to understand their behavior in vivo. We have evaluated the use of ⁶⁴Cu and PET to noninvasively image the lung uptake and distribution of NPs coated with an anti-ICAM antibody. Methods: Model fluorescent NPs were coated with a mixture of an anti-ICAM antibody (or nonspecific IgG) and ⁶⁴Cu-DOTA-IgG (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Biodistribution and small-animal PET and CT studies were performed in healthy mice and in mice pretreated with lipopolysaccharides (LPSs). Metabolism studies were also performed to evaluate the stability of ⁶⁴Cu-labeled NPs in lungs in vivo. Results: The lungs of mice administered anti-ICAM NPs labeled with ⁶⁴Cu were clearly imaged by small-animal PET 1, 4, and 24 h after administration. Both biodistribution and small-animal imaging showed a 3- to 4-fold higher uptake in the lungs of mice injected with ICAM-targeted NPs relative to that of the control group. Lung uptake was further enhanced by pretreating the mice with LPS, presumably because of ICAM-1 upregulation. However, an approximately 2-fold decrease in lung signal was observed in each experimental group over 24 h. Metabolism studies in lung tissues harvested from mice injected with ⁶⁴Cu-labeled anti-ICAM NPs showed considerable release of a small ⁶⁴Cu-radiometabolite from the NPs beginning as early as 1 h after injection. A decrease in lung fluorescence was also observed, most likely reflecting partial release of NPs from the lungs in vivo. Conclusion: The use of small-animal PET to track ⁶⁴Cu-labeled nanostructures in vivo shows potential as a strategy for the preclinical screening of new NP drug delivery agents targeting the lung endothelium and other tissues. Future design optimization to prolong the stability of the radiolabel in vivo will further improve this promising approach.

Key Words: ⁶⁴Cu • nanoparticles • ICAM-1 • pulmonary endothelium • PET

Deceased.

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.

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