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 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.
Footnotes
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Send reprint requests to: Otto C. Boerman, Ph.D., Department of Nuclear Medicine, University Medical Centre St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands. E-mail:O.Boerman{at}nugen.azn.nl
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↵1 This study was supported by Grant no. NGN 55.3665 from the Technology Foundation (Technologiestichting STW), the Netherlands.
- Abbreviations:
- DOX
- doxorubicin
- MPS
- mononuclear phagocyte system
- PEG
- polyethyleneglycol
- PHEPC
- partially hydrogenated egg-phosphatidylcholine
- DSPE
- distearoylphosphatidyl-ethanolamine
- HYNIC
- N-hydroxysuccinimidyl hydrazino nicotinate hydrochloride
- ID
- injected dose
- ROI
- region of interest
- Received August 13, 1999.
- Accepted November 19, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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