Antiviral Activity and Pharmacokinetics of Liposome-Encapsulated Phosphonoformate in Rauscher Murine Leukemia Virus-Infected Mice

Abstract

Liposomal delivery of phosphonoformate (PF), an antiviral agent with poor membrane permeability, was evaluated using a passive targeting strategy to treat Rauscher murine leukemia virus (RMLV) infection. Pharmacokinetic studies in RMLV infected mice using the nonmetabolized [¹⁴C]PF reveal that nonencapsulated PF is rapidly excreted with an approximate clearance of 18.8 g blood/hour, while liposome (egg phos-phatidylcholine/egg phosphatidylglycerol/cholesterol: 9:1:8)-encapsulated PF has an approximate clearance of 0.61–0.96 g blood/hr. When administered in the liposome encapsulated form, 50–80% of the dose is found in the liver, spleen, and blood at 3 hr postinjection. The area under the drug level-time curve (AUC) in the liver and spleen following a single dose of encapsulated PF is 1.3–1.7 times higher than the AUC of a 25-fold larger dose of nonencapsulated PF. Biodistribution studies of ¹²⁵I-labeled liposomes or encapsulated [¹⁴C]PF in vivo show that the specific uptake of liposomes and entrapped contents (amount/g tissue) by RMLV-infected spleen declines as the disease progresses. Uptake studies in vitro show a low level of liposomal uptake by the virally infected nonadherent spleen cells when compared to endocytically active cells. Treatment with non-encapsulated PF (500 mg/kg) or liposome-encapsulated PF (20 mg/kg) was started 1 day after virus infection. PF encapsulated in liposomes has an increased potency evaluated as the reduction of the RMLV-infected liver weight on day 20 when compared with nonencapsulated drug. A similar enhancement by liposomal drug in decreasing the infected spleen weight is not observed. Moreover, the viral infection is enhanced when the reticuloendothelial system (RES) is saturated with high doses of liposomal PF. Thus although the pharmacokinetic data show an elevated spleen level of PF, the chemotherapy results reflect the inability of viral target cells to take up liposomes in the spleen.