Allen T M, Hansen C, Rutledge J
Pharmacology Department, University of Alberta, Edmonton, Canada.
Biochim Biophys Acta. 1989 May 19;981(1):27-35. doi: 10.1016/0005-2736(89)90078-3.
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.
由于脂质体药物递送系统会迅速被网状内皮（单核吞噬细胞）系统摄取，其许多应用受到了短循环半衰期的限制。我们最近描述了在小鼠体内具有长循环半衰期的脂质体制剂（艾伦，T.M.和乔恩，A.（1987年）《欧洲生物化学学会联合会快报》223，42 - 46）。本手稿介绍了对实现具有延长循环半衰期的脂质体至关重要的主要因素的研究。在小鼠体内具有最长循环半衰期的脂质体，其组成模仿红细胞膜的外层小叶（卵磷脂/鞘磷脂/胆固醇/神经节苷脂GM1，摩尔比1:1:1:0.14）。还研究了其他几种神经节苷脂和糖脂，但在延长循环半衰期的能力方面，没有一种能替代GM1。然而，其他带有大基团头的带负电荷脂质，即硫脂和磷脂酰肌醇，在延长循环半衰期方面有一定作用，但在这方面GM1明显更优。由鞘磷脂或其他高相变脂质赋予的双层刚性，与带负电荷的成分，尤其是GM1协同作用，延长了循环时间。脂质体的循环半衰期随着尺寸减小而增加，但即使是最佳配方中更大（0.2 - 0.4微米）的脂质体，其循环半衰期也显著延长。静脉注射和腹腔注射时，脂质体进入肝脏和脾脏以外组织的摄取量随着脂质体循环时间的增加而增加。脂质体似乎在注射后6至24小时之间从循环进入躯体。我们实现脂质体循环时间显著延长的能力使脂质体的一些治疗应用成为可能，而这些应用在此之前是无法实现的。
