Preclinical and Clinical Evidence for Disappearance of Long-Circulating Characteristics of Polyethylene Glycol Liposomes at Low Lipid Dose1

Abstract

This study describes the effect of the lipid dose of^99mTc-polyethylene glycol (PEG) liposomes in the low-dose range (0.02–1.0 μmol/kg) on the pharmacokinetics and biodistribution in rats, rabbits, and humans. The biodistribution and pharmacokinetics of ^99mTc-PEG liposomes at various dose levels were studied in rats and rabbits with a focalEscherichia coli infection. Scintigraphic images were recorded on a gamma camera. In addition, the role of macrophages in the biodistribution of a low-dose PEG liposome injection was studied. Finally, the pharmacokinetics of ^99mTc-PEG liposomes at two lipid dose levels was studied in four patients. At a dose level of 0.03 μmol/kg, the blood level in rats at 4 h postinjection was significantly lower than at the highest dose level (1.1 μmol/kg). The same effect was observed in rabbits where enhanced clearance was observed at a dose level of 0.02 μmol/kg. The circulatory half-life decreased from 10.4 to 3.5 h (at 1.0 and 0.02 μmol/kg, respectively). At the lowest dose level, liposomes were mainly taken up by the liver and to a lesser extent by the spleen. Injection of a low dose of PEG liposomes in macrophage-depleted rabbits resulted in normal pharmacokinetics, suggesting involvement of macrophages in the effectuation of the rapid elimination of the liposomes from the circulation. Most importantly, the rapid clearance of low-dose PEG liposomes was also observed in humans when relatively low lipid doses were administered. This study showed that at very low lipid doses the biodistribution of PEG liposomes is dramatically altered.