Vol. 292, Issue 3, 1071-1079, March 2000

Accelerated Blood Clearance and Altered Biodistribution of Repeated Injections of Sterically Stabilized Liposomes¹

Els T. M. Dams , Peter Laverman, Wim J. G. Oyen, Gert Storm, Gerrit L. Scherphof, Jos W. M. van der Meer, Frans H. M. Corstens and Otto C. Boerman

Departments of Nuclear Medicine (E.T.M.D., P.L., W.J.G.O., F.H.M.C., O.C.B.) and Internal Medicine (E.T.M.D., J.W.M.M.), University Medical Centre St. Radboud, Nijmegen; Department of Pharmaceutics (G.S.), Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht; and Department of Physiological Chemistry (G.L.S.), University of Groningen, Groningen, the Netherlands

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 of ^99mTc-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.