RT Journal Article
T1 Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.
A1 Unciti-Broceta, Juan D
A1 Arias, José L
A1 Maceira, José
A1 Soriano, Miguel
A1 Ortiz-González, Matilde
A1 Hernández-Quero, José
A1 Muñóz-Torres, Manuel
A1 de Koning, Harry P
A1 Magez, Stefan
A1 Garcia-Salcedo, José A
K1 Anticuerpos antiprotozoarios
K1 Modelos animales de enfermedad
K1 Portadores de fármacos
K1 Resistencia a medicamentos
K1 Ensayo de cambio de movilidad electroforética
K1 Concentración 50 inhibidora
K1 Ratones consanguíneos C57BL
K1 Terapia molecular dirigida
K1 Nanopartículas
K1 Pentamidina
K1 Reacción en cadena en tiempo real de la polimerasa
K1 Tripanocidas
AB 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.
PB Public Library of Science
YR 2015
FD 2015-06-25
LK http://hdl.handle.net/10668/2312
UL http://hdl.handle.net/10668/2312
LA en
NO Unciti-Broceta JD, Arias JL, Maceira J, Soriano M, Ortiz-González M, Hernández-Quero J, et al. Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. PLoS Pathog.. 2015                         ; 11(6):e1004942
NO Journal Article; Research Support, Non-U.S. Gov't;
DS RISalud
RD Apr 19, 2025