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

体内分布 脂质体 药代动力学 药理学 化学 PEG比率 毒品携带者 分布(数学) 毒性 脾脏 药物输送 药品 医学 生物化学 免疫学 体外 数学分析 数学 有机化学 财务 经济
作者
E.T.M. Dams,Peter Laverman,Wim J.G. Oyen,Gert Storm,Gl Scherphof,J.W.M. van der Meer,Frans H.M. Corstens,Otto C. Boerman
出处
期刊:PubMed 卷期号:292 (3): 1071-9 被引量:506
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摘要

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.

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