Enhanced anti-malarial efficacy of mefloquine delivered via cationic liposome in a murine model of experimental cerebral malaria.

Malaria is a longstanding global health challenge that continues to afflict over 90 countries located in tropical and subtropical regions of the globe. The rise of drug-resistant malarial parasites has curtailed the therapeutic efficacy of a number of once-effective anti-malarials, including mefloquine. In the present study, we have taken advantage of drug encapsulation approach to elevate the anti-malarial potential of mefloquine. Encouragingly, our findings unveil that liposomal formulations of mefloquine outperform equivalent doses of free mefloquine, both in laboratory cultures and in a murine model of malaria. Intriguingly, a cationic liposomal mefloquine formulation, administered at four successive doses of 3 mg/kg body weight, achieves complete resolution of cerebral malaria in the murine model while avoiding noticeable toxic repercussions. Altogether, our study furnishes pre-clinical validation for a therapeutic strategy that can remarkably enhance the drug efficacy, offering a revitalizing solution for failing anti-malarials.

Long circulatory liposomal maduramicin inhibits the growth of Plasmodium falciparum blood stages in culture and cures murine models of experimental malaria.

Malaria continues to be one of the deadliest infectious diseases and a global health menace. The emergence and spread of drug-resistant strains of malaria parasites have further made the process of disease management grimmer. Thus, there is an urgent need to identify promising antimalarial strategies that can target the blood stages as well as block parasite transmission. Maduramicin is one such ionophore selected out of a recent screen of gametocytocidal compounds that exhibit potent antiplasmodial activity. However, maduramicin's strong hydrophobic nature and associated toxicity restrict its application in chemotherapy. To alleviate this problem, we have developed a liposomal formulation loaded with the ionophore maduramicin for the treatment of chloroquine sensitive and resistant Plasmodium infections. Here, we show that maduramicin in PEGylated liposomal formulations displayed enhanced antiplasmodial activity in vitro compared to free maduramicin. Significantly, four consecutive doses of 1.5 mg kg-1 body weight of PEGylated maduramicin loaded lipid vesicles completely cured cerebral and chloroquine resistant murine models of malaria without any obvious toxic effects and suppressed the key inflammatory markers associated with the progression of the disease. PEGylated liposomal maduramicin also exhibited a prolonged plasma clearance rate, implying a greater chance of interaction and uptake by infected RBCs. Furthermore, we also provide evidence that the detrimental effect of liposomal maduramicin on parasite survival is mediated by increased ROS generation and subsequent perturbation of parasite mitochondrial membrane potential. This study presents the first report to demonstrate the potent antimalarial efficacy of maduramicin liposomes, a strategy that holds promise for the development of successful therapeutic intervention against malaria in humans.