Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues (original) (raw)

1989, Biochimica et Biophysica Acta (BBA) - Biomembranes

Many of the applications of liposomes drag-delivery systems have been limited by their short circulation half-lives as a result of rapid uptake into the retieuloendothelial (mononudear phagocyte) system. We have recently described li~ 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 Wesented in this manuscript. Liposomes with the longest circulation half-lives, in mice, had compositions which mimkked the outer leaflet of red blood cell membranes (egg phosphatidyleholine/sphingomyelin/cholesterol/ gangUoside GMa , molar ratio 1 : I : 1:0.1,1). Several other gangliosides and 81ycolipids were examined, but none could substitute for GMt in their ability to prolong circulation half-lives. However, other negatively charged lipids with bulky headllmUl~ i.e., sulfatides and i~lmsphatldyli~itol, had some effect in prolonging circulation half-lives, but GM! was clearly superior in this regard. Bilayer ril0dity, imparted by sphingomyelin or other high-phase-transition lipids, acted synergistically with the negatively charged components, especially GMt , in extending circulation times. Circulation half-Uves of Iiimsemes increased with decreasing size, but even larger (0.2-0.4 pro) 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. Liposornes appeared to move from the ¢irodation into the carcass between 6 and 24 h post-injection. Our ability to achieve significant prolongation in eireulation times of liposomes makes possible a number of therapeutic applications of liposomes which, until now, have not been achievable.