Journal
ULTRASOUND IN MEDICINE AND BIOLOGY
Volume 44, Issue 6, Pages 1266-1280Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ultrasmedbio.2018.02.006
Keywords
Microbubbles; Contrast-enhanced ultrasound; Accelerated blood clearance; Polyethylene glycol; Anti-PEG antibodies
Funding
- National Science Foundation Graduate Research Fellowship
- National Institutes of Health National Research Service Award Individual Predoctoral Fellowships [F31]
- David and Lucile Packard Foundation [2013-39274]
- National Institutes of Health [R21 EB017938, U01 CA189281, R01 CA195051]
- University of North Carolina Research Opportunities Initiative Grant in Pharmacoengineering
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Emerging evidence suggests that the immune system can recognize polyethylene glycol (PEG), leading to the accelerated blood clearance (ABC) of PEGylated particles. Our aim here was to study the generation of anti-PEG immunity and changes in PEGylated microbubble pharmacokinetics during repeated contrast-enhanced ultrasound imaging in rats. We administered homemade PEGylated microbubbles multiple times over a 28-d period and observed dramatically accelerated clearance (4.2 x reduction in half-life), which was associated with robust anti-PEG IgM and anti-PEG IgG antibody production. Dosing animals with free PEG as a competition agent before homemade PEGylated microbubble administration significantly prolonged microbubble circulation, suggesting that ABC was largely driven by circulating anti-PEG antibodies. Experiments with U.S. Food and Drug Administration-approved Definity microbubbles similarly resulted in ABC and the generation of anti-PEG antibodies. Experiments repeated with non-PEGylated Optison microbubbles revealed a slight shift in clearance, indicating that immunologic factors beyond anti-PEG immunity may play a role in ABC, especially of non-PEGylated agents. (C) 2018 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology.
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