PT - JOURNAL ARTICLE AU - Els T. M. Dams AU - Peter Laverman AU - Wim J. G. Oyen AU - Gert Storm AU - Gerrit L. Scherphof AU - Jos W. M. van der Meer AU - Frans H. M. Corstens AU - Otto C. Boerman TI - Accelerated Blood Clearance and Altered Biodistribution of Repeated Injections of Sterically Stabilized Liposomes DP - 2000 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1071--1079 VI - 292 IP - 3 4099 - http://jpet.aspetjournals.org/content/292/3/1071.short 4100 - http://jpet.aspetjournals.org/content/292/3/1071.full SO - J Pharmacol Exp Ther2000 Mar 01; 292 AB - Sterically stabilized liposomes are considered promising carriers of therapeutic agents because they can facilitate controlled release of the drugs, thereby reducing drug-related toxicity and/or targeted delivery of drugs. Herein, we studied the pharmacokinetics and biodistribution of repeated injections of radiolabeled polyethyleneglycol (PEG) liposomes. Weekly injections of99mTc-PEG liposomes dramatically influenced the circulatory half-life in rats. Biodistribution 4 h after the second dose showed a significantly reduced blood content (from 52.6 ± 3.7 to 0.6 ± 0.1% injected dose (ID), P < .01) accompanied by a highly increased uptake in the liver (from 8.1 ± 0.8 to 46.2 ± 9.8%ID, P < .01) and in the spleen (from 2.2 ± 0.2 to 5.3 ± 0.7%ID,P < .01). At subsequent injections the effect was less pronounced: after the fourth dose, the pharmacokinetics of the radiolabel had almost returned to normal. The same phenomenon was observed in a rhesus monkey, but not in mice. The enhanced blood clearance of the PEG liposomes also was observed in rats after transfusion of serum from rats that had received PEG liposomes 1 week earlier, indicating that the enhanced blood clearance was caused by a soluble serum factor. This serum factor was a heat-labile molecule that coeluted on a size exclusion column with a 150-kDa protein. In summary, i.v. administration of sterically stabilized PEG liposomes significantly altered the pharmacokinetic behavior of subsequently injected PEG liposomes in a time- and frequency-dependent manner. The observed phenomenon may have important implications for the repeated administration of sterically stabilized liposomes for targeted drug delivery. The American Society for Pharmacology and Experimental Therapeutics