ABSTRACT
RATIONALE AND OBJECTIVES: Contrast-carrying liposomes are potentially useful as computed tomography (CT) blood-pool agents. In the present study, preliminary safety, pharmacokinetics, and the CT imaging behavior of continuously extruded iopromide-carrying liposomes were studied. METHODS: Iopromide liposomes were prepared by continuous high-pressure extrusion. Cell membrane-damaging characteristics were assessed in vitro in dog erythrocytes. Acute and subchronic toxicity and pharmacokinetics parameters were determined in rats. Computed tomography imaging efficiency was studied in rabbits. RESULTS: The iopromide-carrying liposomes caused only minor morphological changes in dog erythrocytes. The median lethal dose in rats was approximately 4.5 g of total iodine per kilogram of body weight. In a subchronic tolerance study in rats that were administered six doses of 1 g iodine per kilogram twice a week, no adverse effects were observed. The pharmacokinetics in rats was dose dependent, and elimination of iopromide was almost complete within 7 days after intravenous administration. In rabbits, at a dose of 300 mg total iodine per kilogram, the iopromide-carrying liposomes displayed prolonged blood circulation, with mean CT density differences > 60 Hounsfield units (aorta) for up to 10 minutes. CONCLUSIONS: The iopromide liposomes were well tolerated, almost completely excreted, and have potential as a CT blood-pool imaging agent.
Subject(s)
Contrast Media/administration & dosage , Iohexol/administration & dosage , Tomography, X-Ray Computed , Animals , Aortography , Blood , Contrast Media/pharmacokinetics , Contrast Media/toxicity , Dogs , Dose-Response Relationship, Drug , Erythrocyte Membrane/drug effects , Female , In Vitro Techniques , Injections, Intravenous , Iohexol/analogs & derivatives , Iohexol/pharmacokinetics , Iohexol/toxicity , Liposomes , Male , Rabbits , Rats , Rats, Wistar , Vena Cava, Inferior/diagnostic imagingABSTRACT
RATIONALE AND OBJECTIVES: Surface-modified contrast-carrying liposomes potentially are useful as computed tomography (CT) blood-pool agents. The biodistribution and CT-imaging behavior of conventional as well as polyethylene glycol (PEG)-coated iopromide-carrying liposomes were tested. Two different types of PEG-ylated lipids were used to demonstrate possible differences. METHODS: Iopromide-containing liposomes were prepared by a continuous high-pressure extrusion method and subsequently PEG-ylated by simple mixing with either DSPE-PEG2000 or CHHS-PEG2000. The resulting liposomes were investigated in rats (biodistribution) and rabbits (imaging). RESULTS: Surface modification with CHHS-PEG consistently resulted in less effective stabilization of liposomes in the blood than with DSPE-PEG. In the biodistribution study, no significant differences in blood concentration could be found 1 hour after injection between the different formulations at a dose of 250 mg total iodine/kg body weight (approximately 500 mg lipid/kg). At this dose, the unmodified as well as the DSPE-PEG liposomes displayed prolonged blood circulation with CT density differences above 70 Hounsfield units (aorta) for up to 20 minutes (n = 1). CONCLUSIONS: DSPE-PEG-coated and unmodified liposomes proved to be useful for CT blood-pool imaging displaying favorable imaging properties. Future studies will have to demonstrate whether PEG-ylation offers diagnostic or toxicologic advantages over conventional vesicles in this indication.
Subject(s)
Blood Volume , Contrast Media/pharmacokinetics , Iohexol/analogs & derivatives , Liver/metabolism , Polyethylene Glycols/pharmacokinetics , Spleen/metabolism , Tomography, X-Ray Computed/methods , Animals , Delayed-Action Preparations , Drug Carriers , Iohexol/pharmacokinetics , Liposomes , Liver/diagnostic imaging , Male , Rabbits , Rats , Rats, Wistar , Spleen/diagnostic imaging , Tissue DistributionABSTRACT
RATIONALE AND OBJECTIVES: The objective of the present investigation was to demonstrate a new method for the production of iopromide-carrying liposomes. We studied biodistribution and elimination behavior, as well as the computed tomography (CT) liver imaging properties. METHODS: Iopromide-containing liposomes were prepared by the ethanol evaporation method and subsequently lyophilized. The resuspended liposomes were tested in rats and rabbits. RESULTS: After resuspension, liposomes with a mean diameter of 467 +/- 66 nm and an encapsulation rate of 41.5 +/- 5.5% were obtained. In rats, a marked accumulation of liposomal iopromide was found in the liver and spleen. In rabbits, complete renal elimination of iopromide within 7 days was demonstrated. At a dose of 150 mg total iodine/kg, a small tumor (< 0.5 cm) could be detected in a VX-2-bearing rabbit. CONCLUSIONS: The ethanol evaporation method proved to be suitable for the reproducible large-scale manufacture of iopromide liposomes with high encapsulation. The resuspended liposomes displayed favorable biodistribution, elimination and imaging characteristics.