Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis
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AuthorUnciti-Broceta, Juan Diego; Arias Mediano, José Luis; Maceira, José; Soriano Rodríguez, Miguel; Ortiz-González, Matilde; Hernández-Quero, José; Muñoz-Torres, Manuel; Koning, Harry P. de; Magez, Stefan; García-Salcedo, José Antonio
Public Library of Science (PLOS)
NanoparticlesMouse modelsBloodParasitic diseasesTrypanosoma brucei gambienseDrug therapyPolymerase chain reactionDrug delivery
Unciti-Broceta, J.D.; et al. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. Plos Pathogens, 11(6): e1004942 (2015). [http://hdl.handle.net/10481/37222]
SponsorshipJAGS was funded by the European Union, grant FP7-HEALTH-2007-B-2.3.4-1.223048, NANOTRYP and Ministerio de Economía y Competitividad, Spain Plan Nacional de Investigación grant SAF2011- 30528. JLA was funded by Instituto de Salud Carlos III, Spain, grant FIS. 11/02571. HPdK was supported by a grant from the Medical Research Council (84733).
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.