Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes

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Abstract

Incorporation of dioleoyl N-(monomethoxy polyethyleneglycol succinyl)phosphatidylethanolamine (PEG-PE) into large unilamellar liposomes composed of egg phosphatidylcholine:cholesterol (1:1) does not significantly increase the content leakage when the liposomes are exposed to 90% human serum at 37 degrees C, yet the liposomes show a significant increase in the blood circulation half-life (t1/2 = 5 h) as compared to those without PEG-PE(t1/2 less than 30 min). The PEG-PE's activity to prolong the circulation time of liposomes is greater than that of the ganglioside GM1, a well-described glycolipid with this activity. Another amphipathic PEG derivative, PEG stearate, also prolongs the liposome circulation time, although its activity is less than that of GM1. Amphipathic PEGs may be useful for the sustained release and the targeted drug delivery by liposomes.

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Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.

A. Gabizon, D Papahadjopoulos (1988)

The rapid clearance of circulating liposomes from the bloodstream, coupled with their high uptake by liver and spleen, has thus far been an obstacle to any attempts at targeting to tumors. We have assessed the impact of liposome composition on their clearance from the circulation in normal and tumor-bearing mice and on their uptake by tumors and various normal tissues. By selective changes in lipid composition, while maintaining a mean particle diameter of approximately equal to 100 nm, we have achieved up to a 60-fold increase in the fraction of recovered dose present in blood 24 hr after i.v. injection. Concomitantly, there was a decrease by a factor of 4 of the recovered dose localizing in the liver and spleen, the major organs of the reticuloendothelial system. Parallel experiments in tumor-bearing mice demonstrated a 25-fold increase of the liposome concentration in the tumor when formulations with long and short blood residence time were compared. The most favorable results were obtained with liposomes containing a small molar fraction of a negatively charged glycolipid, such as monosialoganglioside or phosphatidylinositol, and a solid-phase neutral phospholipid as the bulk component. The bio-distribution of such formulations is of considerable therapeutic potential in cancer for increasing the concentration of cytotoxic agents in tumors while minimizing the likelihood of toxicity to the reticuloendothelial system.

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Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues.

Peter Rutledge, M. Hansen, T Allen (1989)

Many of the applications of liposomes drug-delivery systems have been limited by their short circulation half-lives as a result of rapid uptake into the reticuloendothelial (mononuclear phagocyte) system. We have recently described liposomes formulations with long circulation half-lives in mice (Allen, T.M. and Chonn, A. (1987) FEBS Lett. 223, 42-46). A study of the principal factors important to the attainment of liposomes with prolonged circulation half-lives is presented in this manuscript. Liposomes with the longest circulation half-lives, in mice, had compositions which mimicked the outer leaflet of red blood cell membranes (egg phosphatidylcholine/sphingomyelin/cholesterol/ganglioside GM1, molar ratio 1:1:1:0.14). Several other gangliosides and glycolipids were examined, but none could substitute for GM1 in their ability to prolong circulation half-lives. However, other negatively charged lipids with bulky headgroups, i.e., sulfatides and phosphatidylinositol, had some effect in prolonging circulation half-lives, but GM1 was clearly superior in this regard. Bilayer rigidity, imparted by sphingomyelin or other high-phase-transition lipids, acted synergistically with the negatively charged components, especially GM1, in extending circulation times. Circulation half-lives of liposomes increased with decreasing size, but even larger (0.2-0.4 microns) liposomes of the optimum formulations had significantly prolonged half-lives in circulation. Uptake of liposomes into tissues other than liver and spleen increased with increasing circulation times of the liposomes for i.v. and for i.p. injections. Liposomes appeared to move from the circulation into the carcass between 6 and 24 h post-injection. Our ability to achieve significant prolongation in circulation times of liposomes makes possible a number of therapeutic applications of liposomes which, until now, have not been achievable.