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

• Grant number: 14/50708-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2015
• End date: January 31, 2019
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Edecio Cunha Neto
• Grantee: Ramendra Pati Pandey
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PANDEY, RAMENDRA P.; NASCIMENTO, MARILDA SAVOIA; FRANCO, CAIO HADDAD; BORTOLUCI, KARINA; SILVA, MARCELO NUNES; ZINGALES, BIANCA; GIBALDI, DANIEL; BARRIOS, LEDA CASTANO; LANNES-VIEIRA, JOSELI; CARISTE, LEONARDO MORO; et al. Drug Repurposing in Chagas Disease: Chloroquine Potentiates Benznidazole Activity against Trypanosoma cruzi In Vitro and In Vivo. Antimicrobial Agents and Chemotherapy, v. 66, n. 11, p. 17-pg., 2022-10-31. (16/15209-0, 14/50708-2)