Dataset Information

Accelerated Clearance of Ultrasound Contrast Agents Containing Polyethylene Glycol is Associated with the Generation of Anti-Polyethylene Glycol Antibodies.

ABSTRACT: 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?×?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.

SUBMITTER: Fix SM

PROVIDER: S-EPMC6171506 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Accelerated Clearance of Ultrasound Contrast Agents Containing Polyethylene Glycol is Associated with the Generation of Anti-Polyethylene Glycol Antibodies.

Fix Samantha M SM Nyankima A Gloria AG McSweeney Morgan D MD Tsuruta James K JK Lai Samuel K SK Dayton Paul A PA

Ultrasound in medicine & biology 20180327 6

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 × reduction in half-lif ...[more]

PMID: 29602540

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Project description:Long blood half-life is one of the advantages of antibodies over small molecule drugs. At the same time, prolonged half-life is a problem for imaging applications or in the case of antibody-induced toxicities. There is a substantial need for antidotes that can quickly clear antibodies from systemic circulation and peripheral tissues. Engineered nanoparticles exhibit intrinsic affinity for clearance organs (mainly liver and spleen). trans-Cyclooctene (TCO) and methyltetrazine (MTZ) are versatile copper-free click chemistry components that are extensively being used for in vivo bioorthogonal couplings. To test the ability of nanoparticles to eliminate antibodies, we prepared a set of click-modified, clinically relevant antidotes based on several classes of drug carriers: phospholipid-PEG micelles, bovine serum albumin (BSA), and cross-linked dextran iron oxide (CLIO) nanoparticles. Mice were injected with IRDye 800CW-labeled, click-modified IgG followed by a click-modified antidote or PBS (control), and the levels of the IgG were monitored up to 72 h postinjection. Long-circulating lipid micelles produced a spike in IgG levels at 1 h, decreased IgG levels at 24 h, and did not decrease the area under the curve (AUC) and IgG accumulation in main organs. Long-circulating BSA decreased IgG levels at 1 and 24 h, decreased the AUC, but did not significantly decrease organ accumulation. Long-circulating CLIO nanoworms increased IgG levels at 1 h, decreased IgG levels at 24 h, did not decrease the AUC, and did not decrease the organ accumulation. On the other hand, short-circulating CLIO nanoparticles decreased IgG levels at 1 and 24 h, significantly decreasing the AUC and accumulation in the main organs. Multiple doses of CLIO and BSA were not able to completely eliminate the antibody from blood, despite the click reactivity of the residual IgG, likely due to exchange of IgG between blood and tissue compartments. Pharmacokinetic modeling suggests that short antidote half-life and fast click reaction rate should result in higher IgG depletion efficiency. Short-circulating click-modified nanocarriers are the most effective antidotes for elimination of antibodies from blood. This study sets a stage for future development of antidotes based on nanomedicine.

Dataset Information

Accelerated Clearance of Ultrasound Contrast Agents Containing Polyethylene Glycol is Associated with the Generation of Anti-Polyethylene Glycol Antibodies.

Publications

Accelerated Clearance of Ultrasound Contrast Agents Containing Polyethylene Glycol is Associated with the Generation of Anti-Polyethylene Glycol Antibodies.

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