Abstract
Purpose. The purpose of this study was to investigate polyethyleneglycol (PEG)-phosphatidylethanolamine (PE) conjugate interaction with cholesterol-phospholipid mixtures in an attempt to explain the effect of cholesterol on liposome circulation time.
Methods. Differential scanning calorimetry, NMR, electron microscopy, dynamic light scattering and fluorescence spectroscopy were the major methods used.
Results. Studies performed in the absence of cholesterol indicated the formation of three distinct physical states depending on the chain length of PEG in PEG-PE. Mixed micelle formation was observed at concentrations of PEG( 1,000)-DPPE above 7 mol% of lipid. Phase separated lamellae were observed at all concentrations of PEG( 12,000)-DPPE (Bedu-Addo et al. Pharm. Res. 13:710–717 (1996)). Upon incorporation of high concentrations of cholesterol >30 mol% into the lipid bilayer, the formation of phase separated lamellae was completely inhibited and the formation of mixed micelles significantly reduced. At high concentrations of PEG( 1,000)-PE, solubilization of the bilayer occurred with preferential solubilization of cholesterol over phosphati-dylcholine. Maximum steric stabilization (surface protection) was observed with low concentrations of short chain PEG-PE and high concentrations of cholesterol.
Conclusions. The study provides a physical mechanism for the following observations: the blood circulation time is significantly increased or decreased with liposomes highly enriched with cholesterol or PEG-PE respectively.
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REFERENCES
G. Gregoriadis. Liposomes as drug carriers, recent trends and progress, John Wiley and Sons, New York, 1988.
T. M. Allen, G. A. Austin, A. Chonn, L. Lin, and K. C. Lee. Uptake of liposomes by cultured mouse bone marrow macrophages: influence of liposome composition and size. Biochim. Biophys. Acta 1061:56–64 (1991).
T. P. W. McMullen, R. N. A. H. Lewis, and R. N. McElhaney. Differential scanning calorimetric study of the effect of cholesterol on the thermotropic phase behavior of a homologous series of linear saturated phosphatidylcholines. Biochemistry 32:516–522 (1993).
F. Bedu-Addo, P. Tang, Y. Xu, and L. Huang. Effects of polyethyleneglycol chain length and phospholipid acyl chain composition on the interaction of polyethyleneglycol-phospholipid conjugates with phospholipid: Implications in liposomal drug delivery. (Submitted together with the present paper for review).
M. A. Urbanja, J. L. Nieva, F. M. Goni, and A. Alonso. The influence of membrane composition on the solubilizing effects of Triton X-100. Biochim. Biophys. Acta 904:337–345 (1987).
G. Rendina. Experimental methods in biochemistry, Saunders, Philadelphia 1971.
R. H. Burdon, and P. H. von Knippenberg. Laboratory techniques in biochemistry and molecular biology, Elsevier, New York, 1986.
V. P. Torchilin, V. G. Omelyanenko, M. I. Papisov, A. A. Bogdanov, V. S. Tubetskoy, J. N. Heron, and C. A. Gentry. Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer coated liposome longevity. Biochim. Biophys. Acta 1195:11–20 (1994).
M. Bloom, E. Evans, and O. G. Mouritsen. Physical properties of the fluid lipid-bilayer component of cell membranes: a perspective. Q. Rev. Biophys. 24:293–397 (1991).
H. L. Scott. Lipid-cholesterol phase diagrams: Theoretical and numerical aspects. In L. Finegold (ed.) Cholesterol in membrane models, CRC Press, Boca Raton, Florida, 1993, pp. 198–220.
A. K. Groen, B. G. Goldhorn, P. H. M. Egbers, R. A. F. M. Chamuleau, G. N. J. Tytgat, and W. M. M. Bovee. Use of 1H-NMR to determine the distribution of lecithin between the micellar and vesicular phases in model bile. J. Lipid Res. 31:1315–1321 (1990).
A. M. W. Lancee-Hermkens, and B. De Kruijff. 13C NMR measurements of unsonicated phosphatidylcholine bilayers of different fatty acid and sterol composition. Biochim. Biophys. Acta 470:141–151 (1977).
J. N. Israelachvili. Intermolecular and surface forces. Academic Press, New York, 1994.
K. Maruyama, T. Yuda, A. Okamoto, C. Ishikura, S. Kojima, and M. Iwatsuru. Effect of molecular weight in amphiphatic polyethyleneglycol on prolonging the circulation time of large unilamellar liposomes. Chem. Pharm. Bull. 39:1620–1622 (1991).
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Bedu-Addo, R.K., Tang, P., Xu, Y. et al. Interaction of Polyethyleneglycol-Phospholipid Conjugates with Cholesterol-Phosphatidylcholine Mixtures: Sterically Stabilized Liposome Formulations. Pharm Res 13, 718–724 (1996). https://doi.org/10.1023/A:1016043431778
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DOI: https://doi.org/10.1023/A:1016043431778