title: Nanobody conjugated PLGA nanoparticles for active targeting of African Trypanosomiasis.
abstract: Targeted delivery of therapeutics is an alternative approach for the selective treatment of infectious diseases. The surface of African trypanosomes, the causative agents of African trypanosomiasis, is covered by a surface coat consisting of a single variant surface glycoprotein, termed VSG. This coat is recycled by endocytosis at a very high speed, making the trypanosome surface an excellent target for the delivery of trypanocidal drugs. Here, we report the design of a drug nanocarrier based on poly ethylen glycol (PEG) covalently attached (PEGylated) to poly(D,L-lactide-co-glycolide acid) (PLGA) to generate PEGylated PLGA nanoparticles. This nanocarrier was coupled to a single domain heavy chain antibody fragment (nanobody) that specifically recognizes the surface of the protozoan pathogen Trypanosoma brucei. Nanoparticles were loaded with pentamidine, the first-line drug for T. b. gambiense acute infection. An in vitro effectiveness assay showed a 7-fold decrease in the half-inhibitory concentration (IC50) of the formulation relative to free drug. Furthermore, in vivo therapy using a murine model of African trypanosomiasis demonstrated that the formulation cured all infected mice at a 10-fold lower dose than the minimal full curative dose of free pentamidine and 60% of mice at a 100-fold lower dose. This nanocarrier has been designed with components approved for use in humans and loaded with a drug that is currently in use to treat the disease. Moreover, this flexible nanobody-based system can be adapted to load any compound, opening a range of new potential therapies with application to other diseases.
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; GENYO, Centro de Genómica e Investigación Oncológica: Pfizer/Universidad de Granada/Junta de Andalucía, PTS Granada, Granada, Spain.
authors.forename: Juan D
authors.initials: JD
authors.lastname: Unciti-Broceta
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; GENYO, Centro de Genómica e Investigación Oncológica: Pfizer/Universidad de Granada/Junta de Andalucía, PTS Granada, Granada, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Maceira
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; GENYO, Centro de Genómica e Investigación Oncológica: Pfizer/Universidad de Granada/Junta de Andalucía, PTS Granada, Granada, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Del Castillo
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: 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: GENYO, Centro de Genómica e Investigación Oncológica: Pfizer/Universidad de Granada/Junta de Andalucía, 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; Instituto de Parasitología y Biomedicina "López-Neyra" (IPBLN-CSIC), PTS Granada, Armilla, Spain; GENYO, Centro de Genómica e Investigación Oncológica: Pfizer/Universidad de Granada/Junta de Andalucía, PTS Granada, Granada, Spain. Electronic address: jags@genyo.es.
authors.forename: José A
authors.initials: JA
authors.lastname: García-Salcedo
mesh_terms: D000818:Animals; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D004705:Endocytosis; D000939:Epitopes / Q000276:immunology; D005260:Female; D019344:Lactic Acid / Q000737:chemistry; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010419:Pentamidine / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D061905:Single-Domain Antibodies / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D014344:Trypanocidal Agents / Q000008:administration & dosage* / Q000737:chemistry; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D004337:Drug Carriers; D000939:Epitopes; D061905:Single-Domain Antibodies; D014344:Trypanocidal Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010419:Pentamidine
keywords: Human African trypanosomiasis; Nanobody nanoparticles conjugation; PEGylation; PLGA; Polymeric nanoparticles; Specific cell targeting