Increased efficacy of phosphonoformate and phosphonoacetate inhibition of herpes simplex virus type 2 replication by encapsulation in liposomes

Abstract

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.

Liposomes as carriers of antimicrobial agents or immunomodulatory agents in the treatment of infections

“…This was demonstrated for herpes simplex virusinfected monkey kidney cells or rabbit corneal cells treated with foscarnet or acyclovir (38). Some in vitro studies indicate that intracellular viral infections in nonphagocytic cells can be more effectively treated when the antiviral agent is administered in the liposome-encapsulated form.…”

Liposomal encapsulation of foscarnet protects against hypocalcemia induced by free foscarnet

“…Furthermore, LE-PFA was shown to be more effective against herpes simplex virus (type 2) replication than free PFA, without any increase in cytotoxicity (34). It was also demonstrated that the 50% lethal dose (LD 50 ) of amBisome (LE-amphotericin B) in mice was greater than 175 mg/kg (76-fold), compared with 2.3 mg/kg for conventional (free) amphotericin B (30).…”

“…It was also shown that LE-ganciclovir and LE-PFA had greater anti-CMV activities in human embryonic lung fibroblast cells (3). Furthermore, LE-PFA was shown to be more effective (in Vero cell tissue culture) against herpes simplex virus (type 2) replication than was the free drug, without any increase in cytotoxicity (34).…”

Liposomes as delivery systems in the prevention and treatment of infectious diseases

“…The data obtained from other animal studies on the efficacy of liposome-encapsulated antiviral agents in various models of viral infection, caused by herpes simplex virus, influenza virus, Rauscher murine leukaemia virus, or murine AIDS, are contradictory with respect to the efficacy of antiviral agent when administered in the liposome-encapsulated form [17][18][19]. Also data from in vitro studies in which various cell types infected with various viral strains were exposed to antiviral agent in the free form or liposome-encapsulated form are contradictory [19][20][21]. In some studies antiviral antibody was incorporated into liposomes.…”