Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 443, Issue 1-2, Pages 17-25Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2013.01.012
Keywords
Pegylated liposomes; Repeated injection; Accelerated blood clearance; Time interval; Topotecan
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Funding
- National Basic Research Program of China [2010CB735603]
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Repeated injection of pegylated liposomes could elicit the disappearance of long-circulating characteristic, referred to as accelerated blood clearance phenomenon. ABC phenomenon typically occurs when entrapped drugs are not cytotoxic, but recently it was reported that multiple doses of pegylated liposomal topotecan, a cytotoxic drug, could also induce the phenomenon in rats. To reveal whether the phenomenon could be induced in dogs and the effect of time interval between doses on the magnitude of ABC, pLT was repeatedly injected into beagle dogs with a time interval of 7, 21 and 28 days. The anti-PEG Ig M levels were detected using ELISA. It was found that ABC phenomenon could be induced in dogs by pLT. Inter-individual difference in anti-PEG antibody production could be observed, and antibody levels were directly correlated with the magnitude of ABC. Furthermore, time interval between doses had marked effect on the magnitude of ABC phenomenon. When the time interval was prolonged from 1 week to 4 weeks, ABC phenomenon could be eliminated. By comparing the pharmacokinetic profiles of lipid vesicles and entrapped topotecan, it was found that empty pegylated vesicles be formed in circulation, which might be responsible for the occurrence of ABC phenomenon. (C) 2013 Published by Elsevier B.V.
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