Physical-chemistry characteristics and biodistribution of poly(ethylene glycol)-coated liposomes using poly(oxyethylene) cholesteryl ether.
Poly(ethylene glycol)-coated liposomes were prepared with poly(oxyethylene) cholesteryl ethers (mPEG-Chol). PEG unit numbers tested were 50, 100 and 200, of which the average molecular weights (m) of PEG were 2200, 4400 and 8800, respectively. Properties of both PEG-coated liposomes and PEG-Chol molecules were investigated. These liposomes exhibited a long circulation time in the blood after i.v. injection in rats, estimated by both the lipid membrane marker, L-alpha-dipalmitoylphosphatidylcholine [2-palmitoyl-9,10-3H](3H-DPPC), and an internal aqueous marker, 3H-inulin. Accumulation in the liver and spleen at 8h-post-injection was significantly reduced compared with conventional liposomes. The percentage of PEG-Chol incorporation in liposomal membranes was also investigated. Liposomes composed of egg yolk phosphatidylcholine (EPC)/PEG-Chol at various molar ratios were separated from free PEG-Chol molecules, which are not incorporated in liposomal membranes by chromatography over Sepharose CL-4B columns, PEG-Chol incorporation reached approx. 14 and 18 mol% of the total lipids with 25% PEG-Chol unit numbers of 200 and 50, respectively. The occupied area per molecule of PEG-Chol was larger than that of Chol, and the fluorescence anisotropy (r) of the initial 25 mol% (8800)PEG-Chol liposomes was smaller than that observed for 12.5 mol% Chol liposomes. PEG-coated liposomes containing calcein were incubated at 37 degrees C in heat-inactivated fetal bovine serum (FBS). In the presence of FBS, calcein leakage was increased with PEG-Chol percentage incorporation and an increase in FBS concentration. The amount released from PEG-coated liposomes represented 60% at maximum and was larger than that of the control liposomes. PEG-Chol molecules are interesting compounds since they can be easily synthesized in a large amount on an industrial scale. The basic physical-chemistry characteristics investigated in this article are critical to assess the pharmacological application of PEG-Chol liposomes as drug delivery systems.
Ishiwata
H
H
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Vertut-Doï
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A
Hirose
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Miyajima
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D000818:Animals; D016880:Anisotropy; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers; D016650:Fluorescein-5-isothiocyanate; D008081:Liposomes; D008297:Male; D008563:Membrane Lipids / Q000737:chemistry; D008823:Micelles; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution
D004337:Drug Carriers; D008081:Liposomes; D008563:Membrane Lipids; D008823:Micelles; C095164:poly(oxyethylene) cholesteryl ether; D011092:Polyethylene Glycols; D002784:Cholesterol; D016650:Fluorescein-5-isothiocyanate