Differences in colloidal structure of PEGylated nanomaterials dictate the likelihood of accelerated blood clearance

• Published in: Journal of pharmaceutical sciences Vol. 100; no. 11; pp. 5069 - 5077
• Main Authors: Kaminskas, Lisa M., Mcleod, Victoria M., Porter, Christopher J.H., Boyd, Ben J.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.11.2011; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association; Elsevier Limited
• Subjects: accelerated blood clearance; Biological and medical sciences; clearance; Colloids; formulation; General pharmacology; Immunoglobulin M - immunology; Likelihood Functions; lipids/lipoproteins; liposome; Liposomes; Medical sciences; micelle; Micelles; Nanostructures; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics; Pharmacology. Drug treatments; polyethylene glycol; Polyethylene Glycols - chemistry; polyethylene glycol; micelle; lipids/lipoproteins; accelerated blood clearance; pharmacokinetics; formulation; clearance; liposome; Biological fluid; Pharmaceutical technology; Liposome; Micelle; Lipids; Clearance; Lipoprotein; Blood; Ethylene oxide polymer; Cyclic ether polymer; Formulation; Pegylated form; Pharmacokinetics
• DOI: 10.1002/jps.22682
• ISSN: 0022-3549

PEGylated liposomes are known to exhibit accelerated clearance from systemic circulation on repeat administration (the so‐called “accelerated blood clearance” or ABC effect); however, little is known about this effect for other PEGylated colloidal drug delivery systems. Furthermore, our understanding of the mechanisms by which the ABC effect is induced is limited. This article further addresses these issues by examining the impact of colloid types [polyethylene glycol (PEG)–liposomes, PEG–micelles] of varying sizes on the appearance of the ABC effect when readministered 7 days after a “priming” dose. Intravenous injection of PEG–liposomes and putative PEG–micelles induced the production of anti‐PEG immunoglobulin (Ig) M, although decreasing the average particle size led to reduced IgM titres. The ABC effect was observed for PEGylated phospholipid/cholesterol‐based liposomes 7 days after an initial “priming” dose of liposome; however, addition of increasing levels of PEGylated lipid to form micelles reduced the propensity of observation of the ABC effect, correlating with the reduced IgM production. The results suggest that although PEG–micelles may stimulate limited production of anti‐PEG IgM, which leads to accelerated clearance of subsequently administered PEG–liposomes, PEGylated micelles themselves are not substrates for IgM binding and do not exhibit a similar ABC. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:5069–5077, 2011