title: Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.
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.
authors.affiliation: Unidad de Enfermedades Infecciosas y Microbiología, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain; Instituto de Parasitología y Biomedicina "López-Neyra" (IPBLN-CSIC), PTS Granada, Armilla, Spain; Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica (GENYO), PTS Granada, Granada, Spain.
authors.forename: Juan D
authors.initials: JD
authors.lastname: Unciti-Broceta
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Granada, Granada, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Arias
authors.affiliation: Unidad de Enfermedades Infecciosas y Microbiología, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain; Instituto de Parasitología y Biomedicina "López-Neyra" (IPBLN-CSIC), PTS Granada, Armilla, Spain; Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica (GENYO), PTS Granada, Granada, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Maceira
authors.affiliation: Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica (GENYO), PTS Granada, Granada, Spain; Departamento de Agronomía, Universidad de Almería, Almería, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Soriano
authors.affiliation: Unidad de Enfermedades Infecciosas y Microbiología, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain; Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica (GENYO), PTS Granada, Granada, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Ortiz-González
authors.affiliation: Unidad de Enfermedades Infecciosas y Microbiología, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Hernández-Quero
authors.affiliation: Unidad de Metabolismo Óseo, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Muñóz-Torres
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Harry P
authors.initials: HP
authors.lastname: de Koning
authors.affiliation: Unit of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; Department of Structural Biology, VIB, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Magez
authors.affiliation: Unidad de Enfermedades Infecciosas y Microbiología, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain; Instituto de Parasitología y Biomedicina "López-Neyra" (IPBLN-CSIC), PTS Granada, Armilla, Spain; Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica (GENYO), PTS Granada, Granada, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Garcia-Salcedo
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000008:administration & dosage; D048271:Chitosan / Q000008:administration & dosage / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics; D004351:Drug Resistance / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D020128:Inhibitory Concentration 50; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods*; D053758:Nanoparticles / Q000627:therapeutic use; D010419:Pentamidine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D060888:Real-Time Polymerase Chain Reaction; D014344:Trypanocidal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D000913:Antibodies, Protozoan; D004337:Drug Carriers; D014344:Trypanocidal Agents; D010419:Pentamidine; D048271:Chitosan