RT Journal Article
SR Electronic
T1 Accelerated Blood Clearance and Altered Biodistribution of Repeated Injections of Sterically Stabilized Liposomes
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1071
OP 1079
VO 292
IS 3
A1 Els T. M. Dams
A1 Peter Laverman
A1 Wim J. G. Oyen
A1 Gert Storm
A1 Gerrit L. Scherphof
A1 Jos W. M. van der Meer
A1 Frans H. M. Corstens
A1 Otto C. Boerman
YR 2000
UL http://jpet.aspetjournals.org/content/292/3/1071.abstract
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