Unciti-Broceta, Juan DArias, José LMaceira, JoséSoriano, MiguelOrtiz-González, MatildeHernández-Quero, JoséMuñóz-Torres, Manuelde Koning, Harry PMagez, StefanGarcia-Salcedo, José A2016-08-082016-08-082015-06-25Unciti-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):e1004942http://hdl.handle.net/10668/2312Journal Article; Research Support, Non-U.S. Gov't;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.enAnticuerpos antiprotozoariosModelos animales de enfermedadPortadores de fármacosResistencia a medicamentosEnsayo de cambio de movilidad electroforéticaConcentración 50 inhibidoraRatones consanguíneos C57BLTerapia molecular dirigidaNanopartículasPentamidinaReacción en cadena en tiempo real de la polimerasaTripanocidasMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies, ProtozoanMedical Subject Headings::Chemicals and Drugs::Macromolecular Substances::Polymers::Biopolymers::Chitin::ChitosanMedical Subject Headings::Diseases::Animal Diseases::Disease Models, AnimalMedical Subject Headings::Chemicals and Drugs::Pharmaceutical Preparations::Dosage Forms::Drug CarriersMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug ResistanceMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Chemistry Techniques, Analytical::Electrophoresis::Electrophoretic Mobility Shift AssayMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BLMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Molecular Targeted TherapyMedical Subject Headings::Technology, Industry, Agriculture::Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::NanoparticlesMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amidines::Benzamidines::PentamidineMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction::Real-Time Polymerase Chain ReactionMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiparasitic Agents::Antiprotozoal Agents::Trypanocidal AgentsMedical Subject Headings::Organisms::Eukaryota::Animalsresearch article26110623open access10.1371/journal.ppat.10049421553-7374PMC4482409