title: Crucial CD8(+) T-lymphocyte cytotoxic role in amphotericin B nanospheres efficacy against experimental visceral leishmaniasis.
abstract: This work aims to develop poly(d,l-lactide-co-glycolide) (PLGA)-nanospheres containing amphotericin B (AmB) with suitable physicochemical properties and anti-parasitic activity for visceral leishmaniasis (VL) therapy. When compared with unloaded-PLGA-nanospheres, the AmB-loaded PLGA-nanospheres displayed an increased particle size without affecting the polydispersity and its negative surface charge. AmB stability in the PLGA-nanospheres was >90% over 60-days at 30°C. The AmB-PLGA-nanospheres demonstrated significant in vitro and in vivo efficacy and preferential accumulation in the visceral organs. In addition, an immune-modulatory effect was observed in mice treated with AmB-PLGA-nanospheres, correlating with improved treatment efficacy. The in vitro cytotoxic response of the T-lymphocytes revealed that AmB-PLGA-nanospheres efficacy against VL infection was strictly due to the action of CD8(+)- but not CD4(+)-T lymphocytes. Overall, we demonstrate a crucial role for CD8(+) cytotoxic T lymphocytes in the efficacy of AmB-PLGA nanospheres, which could represent a potent and affordable alternative for VL therapy.
  
  
  BACKGROUND
  This study demonstrates a crucial role for CD8+ T lymphocytes in eliminating visceral leishmaniasis in a murine model by enhancing the cytotoxic efficacy of CD8+ T-cells via amphotericin-B-PLGA nanospheres, paving a way to a unique, potentially more potent and cost-effective therapeutic strategy.
authors.affiliation: IBMC-INEB, Infection and Immunology Unit, Parasite Disease Group, University of Porto, Portugal. Electronic address: slima@ff.up.pt.
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Costa Lima
authors.affiliation: IBMC-INEB, Infection and Immunology Unit, Parasite Disease Group, University of Porto, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Silvestre
authors.affiliation: IBMC-INEB, Infection and Immunology Unit, Parasite Disease Group, University of Porto, Portugal.
authors.forename: Daniela
authors.initials: D
authors.lastname: Barros
authors.affiliation: IBMC-INEB, Infection and Immunology Unit, Parasite Disease Group, University of Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar e Faculdade de Medicina, Universidade do Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Cunha
authors.affiliation: IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, Advanced Institute of Health Sciences-North (ISCS-N), CESPU, CRL, Gandra, Portugal; Department of Legal Medicine and Forensic Sciences, Faculty of Medicine, University of Porto, Porto, Portugal; REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Baltazar
authors.affiliation: IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, Advanced Institute of Health Sciences-North (ISCS-N), CESPU, CRL, Gandra, Portugal; Department of Legal Medicine and Forensic Sciences, Faculty of Medicine, University of Porto, Porto, Portugal; REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; Forensic Sciences Center (CENCIFOR), Portugal.
authors.forename: Ricardo Jorge
authors.initials: RJ
authors.lastname: Dinis-Oliveira
authors.affiliation: IBMC-INEB, Infection and Immunology Unit, Parasite Disease Group, University of Porto, Portugal; Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Portugal.
authors.forename: Anabela
authors.initials: A
authors.lastname: Cordeiro-da-Silva
mesh_terms: D000666:Amphotericin B / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D054118:Nanospheres / Q000737:chemistry*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D000666:Amphotericin B
keywords: Amphotericin B; CD8(+)-T lymphocytes; Immune-modulation; Poly(d,l-lactide-co-glycolide) nanospheres; Visceral leishmaniasis