Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.

TitleSpecific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.
Publication TypeJournal Article
Year of Publication2015
AuthorsUnciti-Broceta, J. D., J. L. Arias, J. Maceira, M. Soriano, M. Ortiz-González, J. Hernández-Quero, M. Muñóz-Torres, H. P. de Koning, S. Magez, and J. A. Garcia-Salcedo
JournalPLoS Pathog
Volume11
Issue6
Paginatione1004942
Date Published2015 Jun
ISSN1553-7374
KeywordsAnimals, Antibodies, Protozoan, Chitosan, Disease Models, Animal, Drug Carriers, Drug Resistance, Electrophoretic Mobility Shift Assay, Female, Inhibitory Concentration 50, Mice, Mice, Inbred C57BL, Molecular Targeted Therapy, Nanoparticles, Pentamidine, Real-Time Polymerase Chain Reaction, Trypanocidal Agents, Trypanosomiasis, African
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.

DOI10.1371/journal.ppat.1004942
Alternate JournalPLoS Pathog.
PubMed ID26110623
PubMed Central IDPMC4482409
Grant ListG0701258 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom
Research group: