Specific cell targeting therapy bypasses drug resistance mechanisms in African trypanosomiasis

Unciti-Broceta, J. D., Arias, J. L., Maceira, J., Soriano, M., Ortiz-González, M., Hernández-Quero, J., Muñóz-Torres, M., De Koning, H. P. , Magez, S. and Garcia-Salcedo, J. A. (2015) Specific cell targeting therapy bypasses drug resistance mechanisms in African trypanosomiasis. PLoS Pathogens, 11(6), e1004942. (doi:10.1371/journal.ppat.1004942) (PMID:26110623) (PMCID:PMC4482409)

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Abstract

African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry
Authors: Unciti-Broceta, J. D., Arias, J. L., Maceira, J., Soriano, M., Ortiz-González, M., Hernández-Quero, J., Muñóz-Torres, M., De Koning, H. P., Magez, S., and Garcia-Salcedo, J. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in PLoS Pathogens 11(6):e1004942
Publisher Policy:Reproduced under a Creative Commons License

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