Fidler I J, Raz A, Fogler W E, Kirsh R, Bugelski P, Poste G
Cancer Res. 1980 Dec;40(12):4460-6.
Factors affecting the localization of liposomes injected i.v. in the lung have been studied to identify the optimal type of liposome for delivery of macrophage-activating agents to the lung to augment the tumoricidal activity of alveolar macrophages (AM). Comparison of pulmonary retention of liposomes of differing size, surface charge, and composition following i.v. injection into inbred mice revealed that large multilamellar (MLV) and reversed-phase-evaporation (REV) liposomes are arrested in the lung more efficiently than are small unilamellar liposomes of identical lipid composition. MLV and REV containing negatively charged amphiphiles arrest in the lung more efficiently than do neutral MLV's or REV's or MULV's and REV's containing positively charged amphiphiles. Comparison of the ability of liposomes containing a variety of negatively charged amphiphiles to localize in the lung established that optimal localization was achieved using MLV and REV prepared from phosphatidylserine (PS) and phosphatidylcholine (PC) (3:7 mol ratio) or PS:PC:lysolecithin (4.95:4.95:0.1 mol ratio). The proportion of these liposomes retained in the lung after i.v. injection was constant over a wide dose range (0.02 to 20 mumol phospholipid per mouse), but hemodilution due to i.v. inoculation of liposomes in volumes exceeding 0.2 ml reduced retention in the lung. Uptake of liposomes by AM was demonstrated by showing that i.v. injection of PS:PC MLV liposomes containing fluorescein-labeled bovine serum albumin resulted in localization of fluorescence within AM recovered by pulmonary lavage. Similarly, AM recovered after i.v. injection of PS:PC MLV liposomes containing lymphokine preparations rich in macrophage-activating factor (MAF) activity exhibited tumoricidal activity. In contrast, macrophages recovered from control animals given injections of unencapsulated MAF or liposomes containing lymphocyte supernatants without MAF activity were devoid of cytotoxic activity. Neutral (PC) MLV liposomes containing MAF, which show only very limited retention in the lung, were ineffective in activating AM in situ. We conclude that negatively charged MLV liposomes (PS:PC, 3:7 mol ratio) localize efficiently in the lung and that macrophage-activating agents encapsulated within such liposomes can successfully activate lung macrophages in situ.
研究了影响静脉注射脂质体在肺部定位的因素，以确定将巨噬细胞激活剂递送至肺部以增强肺泡巨噬细胞（AM）杀肿瘤活性的最佳脂质体类型。对近交系小鼠静脉注射不同大小、表面电荷和组成的脂质体后肺部滞留情况进行比较，结果显示，与相同脂质组成的小单层脂质体相比，大多层脂质体（MLV）和反相蒸发（REV）脂质体在肺部的滞留效率更高。含有带负电荷两亲物的MLV和REV在肺部的滞留效率高于中性MLV或REV，以及含有带正电荷两亲物的MULV和REV。比较含有多种带负电荷两亲物的脂质体在肺部的定位能力，结果表明，使用由磷脂酰丝氨酸（PS）和磷脂酰胆碱（PC）（摩尔比3:7）或PS:PC:溶血卵磷脂（摩尔比4.95:4.95:0.1）制备的MLV和REV可实现最佳定位。静脉注射后，这些脂质体在肺部的滞留比例在较宽的剂量范围内（每只小鼠0.02至20 μmol磷脂）保持恒定，但由于静脉注射脂质体的体积超过0.2 ml导致血液稀释，会降低其在肺部的滞留。通过静脉注射含有荧光素标记牛血清白蛋白的PS:PC MLV脂质体，结果显示肺部灌洗回收的AM内有荧光定位，从而证明了AM对脂质体的摄取。同样，静脉注射含有富含巨噬细胞激活因子（MAF）活性的淋巴因子制剂的PS:PC MLV脂质体后回收的AM表现出杀肿瘤活性。相比之下，注射未包封的MAF或不含MAF活性的淋巴细胞上清液的脂质体的对照动物回收的巨噬细胞没有细胞毒性活性。含有MAF的中性（PC）MLV脂质体在肺部的滞留非常有限，在原位激活AM方面无效。我们得出结论，带负电荷的MLV脂质体（PS:PC，摩尔比3:7）在肺部有效定位，封装在这种脂质体内的巨噬细胞激活剂可成功地在原位激活肺部巨噬细胞。
