Enhanced anticryptococcal activity of chloroquine in phosphatidylserine-containing liposomes in a murine model

Objectives: The anticryptococcal activity of chloroquine was assessed after incorporation in phosphatidylserine (PS)-containing negatively charged liposomes in a murine model. Methods: In the present study, we investigated the antifungal activity of chloroquine entrapped in PS liposomes against Cryptococcus neoformans in the macrophage cell line J 774 and in a murine model. Mice were treated with free as well as liposomal formulations of chloroquine before and after challenging with C. neoformans infection. The anticryptococcal activity of chloroquine was also evaluated in combination with fluconazole in the treatment of systemic murine cryptococcosis. The efficacy of chloroquine treatment was assessed by continued survival as well as by colony forming units (cfu) in liver and brain of treated mice. Results: Chloroquine entrapped in PS liposomes shows increased activity against C. neoformans infection both in in vitro and in vivo studies. Moreover, the antifungal activity of fluconazole increases when used in combination with liposomal chloroquine. Chloroquine in PS liposomes was found to be more effective in comparison with the same dose of free chloroquine or chloroquine entrapped in neutral liposomes. Conclusions: The enhanced anticryptococcal activity of chloroquine in PS liposomes seems to be due to uptake of drug-containing PS liposomes by macrophages. It can be assumed that liposome-mediated delivery of chloroquine to macrophages results in an unfavourable (alkaline) environment for the growth of C. neoformans inside macrophages.