Nanomedicine: is there a hope for Chagas?s disease patients?

MORILLA, ROMERO

Conferencia; CLINAM 2012; 2012

With 15-20 millions infected (2-3 % the population of South and Central America plussouth California), an incidence of 200.000 new cases per year, an estimated annual mortality of50.000 and more than 6,5 billons USD annual lost due to mortality and morbidity (WHO), theChagas disease remains as the main parasitic disease of the Americas. Nowadays, there is nocure for this orphan disease. Because of the lack of interest of pharmaceutical companies andthe absent intervention of the governments, there are only two drugs approved for treatment:the hydrophobic nitroimidazole benznidazole and in certain cases the nitrofurane nifurtimox,both administered by the oral route. These have been the only available drugs during the lasthalf century, in spite of being effective only in the acute phase of paediatric patients, after two orthree months of heavy daily doses. These drugs are poorly tolerated by the adults, whomfrequently discontinue the treatments. In spite of their high bioavailability, the trypanocidalactivity of these drugs is against trypomastigotes, the extracellular forms, present in bloodduring the short periods of parasitemia of the frequently asymptomatic acute phase. They arehowever, inefficient to target intracellular amastigotes nests. Because of these reasons, there isa strong need of developing new treatments capable of eliminating the intracellular forms, withinshort periods of time while remaining economically affordable for low income population. In thiscontext nanotechnology could build strategic therapeutics, alternative to the search for newtherapeutic targets that proposes the medicinal chemistry. In the acute phase, when thereticule endothelial system cells are colonized, a nano-objects based treatment must rely on theintracellular delivery of trypanocidal drugs. Our laboratory has successfully faced this approachon preclinical models. Balb-c mice infected with lethal doses of RA strain trypomastigotes,received nine intravenous doses of 100 nm diameter pH-sensitive liposomes loaded with thehydrosoluble nitroimidazole etanidazole, a drug with a very low trypanocidal activity in its freeform. After 3 weeks (at a 200 fold lower dose of etanidazole than in the free form that resultedinnocuous) the parasitemia was eliminated. The effect was achieved by pH sensitive liposomesthat were taken up by infected cells by a degradative pynocitic pathway; this led to a massivedelivery of etanidazole to the cell cytoplasm where the amastigotes reside. Remarkably, thepH-sensitive liposomes are not active against trypomastigotes. In other words, the parasitemiawas reduced after modifying the intracellular traffic of the etanidazole to favour cytoplasmtargeting. The ultimate challenge of an antichagasic treatment is however, impairing or reducingthe cardiac damage caused by the perpetuation of the amastigotes within cardiomiocytes. Hereanatomic pathological changes in the envelope of cardiac cells could be used to achieve apassive targeting of nano-objets against targets other than phagocytic cells. This should beachieved during the initial stadium of the chronic chagasic cardiomiopathy or even better duringthe indeterminate form. The thickening and loss of permeability barrier of the basementmembrane enveloping cardiac cells is also found in diabetes and metabolic syndrome.Therefore, different to the occurred with amphotericin B and its nanotechnological formulation,the targeted to cardiomiocytes based-antichagasic treatments, could led to a technical platformuseful against diseases affecting developed countries.