title: Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes.
abstract: 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 (99m)Tc-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.
authors.affiliation: Department of Nuclear Medicine, University Medical Center St. Radboud, Nijmegen, The Netherlands.
authors.forename: E T
authors.initials: ET
authors.lastname: Dams
authors.forename: P
authors.initials: P
authors.lastname: Laverman
authors.forename: W J
authors.initials: WJ
authors.lastname: Oyen
authors.forename: G
authors.initials: G
authors.lastname: Storm
authors.forename: G L
authors.initials: GL
authors.lastname: Scherphof
authors.forename: J W
authors.initials: JW
authors.lastname: van Der Meer
authors.forename: F H
authors.initials: FH
authors.lastname: Corstens
authors.forename: O C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D003165:Complement System Proteins / Q000502:physiology; D004337:Drug Carriers; D005260:Female; D007267:Injections; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D011092:Polyethylene Glycols; D003165:Complement System Proteins