Effect of nanoparticles containing a drug combination targeting different steps of the T. cruzi cell invasion/replication on T. cruzi infection

Resumo

Chronic Chagas disease affects 10 million people, one-third of which will develop life-threatening cardiac disease years after infection. One of the most challenging tasks for the control and treatment of chronic Chagas disease is the development of anti-Trypanosoma cruzi therapy effective at this phase, the one where most cases are diagnosed. Benznidazole, which together with Nifurtimox are the only available Trypanocidal Drugs are effective only at the acute phase of infection; Benznidazole treatment of chronically infected patients only shows limited effectiveness, if any. The biology of the host cell-parasite interaction indicates therapeutic targets that have been little explored in the therapy against T. cruzi infection. Combined antimicrobial therapy employing drugs effective at multiple life cycle steps has been applied successfully in the treatment of HIV-infected patients. We hypothesize that treatment with a combination of drugs capable of interfering with distinct steps of the T. cruzi invasion and replication could be more effective than benznidazole treatment alone. Colchicine, an inhibitor of microtubule polymerization, and chloroquine, which inhibits Lysosomes/endosome acidification, have been shown to inhibit T. cruzi internalization and escape from the parasitophorous vesicle to the cytosol in vitro, respectively; both drugs have been licensed for human use decades ago and their toxicity profile is well known. In order to reduce toxicity, we will test the effectiveness of encapsulated Benznidazole-Colchicine-Chloroquine gelatin nanoparticles. We will test the anti-T.cruzi activity of this nanoparticle drug combination in in vitro models of host cell infection and in the Syrian hamster model. (AU)