Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes

Sterically stabilized liposomes are considered promising carriers of therap eutic agents because they can facilitate controlled release of the drugs, t hereby reducing drug-related toxicity and/or targeted delivery of drugs. He rein, we studied the pharmacokinetics and biodistribution of repeated injec tions of radiolabeled polyethyleneglycol (PEG) liposomes. Weekly injections of Tc-99m-PEG liposomes dramatically influenced the circulatory half-life in rats. Biodistribution 4 h after the second dose showed a significantly r educed 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 pro nounced: after the fourth dose, the pharmacokinetics of the radiolabel had almost returned to normal. The same phenomenon was observed in a rhesus mon key, but not in mice. The enhanced blood clearance of the PEG liposomes als o was observed in rats after transfusion of serum from rats that had receiv ed PEG liposomes 1 week earlier, indicating that the enhanced blood clearan ce was caused by a soluble serum factor. This serum factor was a heat-labil e molecule that coeluted on a size exclusion column with a 150-kDa protein. In summary, i.v. administration of sterically stabilized PEG liposomes sig nificantly altered the pharmacokinetic behavior of subsequently injected PE G liposomes in a time- and frequency-dependent manner. The observed phenome non may have important implications for the repeated administration of ster ically stabilized liposomes for targeted drug delivery.