Szoka F C, Chu C J
Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143-0446.
Antimicrob Agents Chemother. 1988 Jun;32(6):858-64. doi: 10.1128/AAC.32.6.858.
Phosphonoformate and phosphonoacetate encapsulated in liposomes have substantially greater activity against herpes simplex virus type 2 in Vero cell tissue culture than the nonencapsulated compounds at the same dose. Encapsulation of phosphonoformate in liposomes resulted in a 30-fold increase of the antiviral effect with no increase in cytotoxicity measured by inhibition of thymidine incorporation into normal Vero cells. Thus, the selectivity of the liposomal drug increased 27-fold compared with the nonencapsulated compound. Liposome encapsulation of phosphonoacetate at a ratio of 0.3 mumol/mumol of lipid resulted in a 150-fold increase of antiviral activity with a concomitant 250-fold increase in cytotoxicity. However, the selectivity of phosphonoacetate could be increased by reducing the drug-to-lipid ratio. Liposome uptake by Vero cells, measured by the cell association of a nonexchangeable radiolabeled lipid, plateaued after 24 h of incubation and saturated at 60 nmol of lipid per mg of cellular protein at a lipid concentration of 300 microM. The saturation of liposome uptake on the Vero cells may account for the 27-fold increase in selectivity observed with the liposomal phosphonoformate. The greater activity of the encapsulated phosphono compounds is most likely due to their increased transport into the cytoplasm; this occurs subsequent to the uptake and processing of the liposome in the lysosomes of the cell. Liposome encapsulation of these agents may result in superior efficacy against viral infections residing in endocytotically and phagocytically active cells such as macrophages.
脂质体包裹的膦甲酸和膦乙酸在相同剂量下，于Vero细胞组织培养中对单纯疱疹病毒2型的活性显著高于未包裹的化合物。脂质体包裹膦甲酸使抗病毒效果提高了30倍，同时通过抑制胸苷掺入正常Vero细胞来测定的细胞毒性并未增加。因此，与未包裹的化合物相比，脂质体药物的选择性提高了27倍。以0.3 μmol/μmol脂质的比例将膦乙酸包裹在脂质体中，抗病毒活性提高了150倍，同时细胞毒性增加了250倍。然而，降低药物与脂质的比例可提高膦乙酸的选择性。通过不可交换的放射性标记脂质的细胞结合来测量Vero细胞对脂质体的摄取，孵育24小时后达到平稳状态，在脂质浓度为300 μM时，每毫克细胞蛋白摄取60 nmol脂质时达到饱和。Vero细胞上脂质体摄取的饱和可能解释了脂质体包裹的膦甲酸观察到的选择性提高27倍的现象。包裹的膦化合物活性更高很可能是由于它们向细胞质的转运增加；这发生在细胞溶酶体中脂质体的摄取和处理之后。这些药物的脂质体包裹可能会对存在于内吞和吞噬活性细胞（如巨噬细胞）中的病毒感染产生更好的疗效。
