Novel nanoemulsion for enhanced efficacy and better safety of benznidazole in the treatment of Chagas Disease

• Grant number: 19/08796-5
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2019
• End date: September 30, 2021
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Agreement: Texas A&M University
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Giuseppe Palmisano
• Grantee: Giuseppe Palmisano
• Principal researcher abroad: Srinath Palakurthi
• Institution abroad: Texas A&M University, United States
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/15549-1 - Post-translational modifications in Chagas Disease biological processes and diagnostics: novel methodological approaches and biological applications, AP.JP2

Abstract

Chagas disease is a neglected disease caused by the unicellular protozoan Trypanosoma cruzi parasite, endemic in 21 Latin American countries where 70 million people are at risk of infection and 6-7 million people are infected. Benznidazole (BNZ) is the first-line drug for the treatment of Chagas disease (CD). Although it is highly effective in the acute phase, moderate efficacy and dose-limiting toxicity and development of drug resistance are its major limitations. To improve the BNZ therapeutic efficacy and to reduce its toxicity, here we propose a combination of BNZ and copaiba oil. Copaiba oil is an FDA-approved food additive with proven trypanocidal activity in vitro and in vivo. In this project, we will develop a novel nanoemulsion engineered on a combination of BNZ and copaiba oil to enhance therapeutic efficacy and decrease the effective dose of BNZ required for optimal efficacy, and thereby reduce the toxicity associated with long-term use of BNZ for chronic CD. Because of stability, ease of administration for lipophilic drugs/oils as emulsion dosage form, it is hypothesized that a stable nanoemulsion (o/w) containing BNZ and copaiba oil not only enhances therapeutic efficacy but minimizes the systemic toxicity by reducing the effective dose required for optimal efficacy. The proposal has two specific aims: 1) Optimize BNZ loading, stability and drug release from the nanoemulsion; 2) Determine the in vitro efficacy and toxicity using appropriate cell culture models. During the first phase of the project, we will optimize the nanoemulsion synthesis and characterization and evaluate it's in vitro activity. Moreover, we have planned to develop targeted nanoemulsion formulation, determine the pharmacokinetics, in vivo efficacy and toxicity studies with the primary aim to provide a safer treatment for Chagas disease. The data generated during this project will be the basis for publishing scientific articles and submitting proposals for long-term funding from national and international agencies (CNPq, NIH, WHO). We assembled a strong multi and interdisciplinary research team comprising of Srinath Palakurthi (with expertise in nanotechnology for drug delivery), Giuseppe Palmisano (with expertise in parasitology and proteomics), and through this TAMU-FAPESP collaborative program, we anticipate to develop sustainable long-term collaboration to develop novel therapeutics for Chagas disease. Towards this end, we will interact on weekly basis to discuss the research progress, integrate our efforts by visiting the respective institutions to access the resources and expertise, exchange methods and techniques, and coordinate mini-symposia and workshops. The long-term objective of this TAMU-FAPESP collaborative proposal is to develop a novel nanoemulsion formulation with improved efficacy and safety in the treatment of Chagas disease. If successful, we anticipate a rapid translation of the proposed nanoemulsion into a clinically effective drug product. (AU)