title: A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.
abstract: BACKGROUND
  Amphotericin B (AmB), the most effective drug against leishmaniasis, has serious toxicity. As Leishmania species are obligate intracellular parasites of antigen presenting cells (APC), an immunopotentiating APC-specific AmB nanocarrier would be ideally suited to reduce the drug dosage and regimen requirements in leishmaniasis treatment. Here, we report a nanocarrier that results in effective treatment shortening of cutaneous leishmaniasis in a mouse model, while also enhancing L. major specific T-cell immune responses in the infected host.
  
  
  METHODS
  We used a Pan-DR-binding epitope (PADRE)-derivatized-dendrimer (PDD), complexed with liposomal amphotericin B (LAmB) in an L. major mouse model and analyzed the therapeutic efficacy of low-dose PDD/LAmB vs full dose LAmB.
  
  
  RESULTS
  PDD was shown to escort LAmB to APCs in vivo, enhanced the drug efficacy by 83% and drug APC targeting by 10-fold and significantly reduced parasite burden and toxicity. Fortuitously, the PDD immunopotentiating effect significantly enhanced parasite-specific T-cell responses in immunocompetent infected mice.
  
  
  CONCLUSIONS
  PDD reduced the effective dose and toxicity of LAmB and resulted in elicitation of strong parasite specific T-cell responses. A reduced effective therapeutic dose was achieved by selective LAmB delivery to APC, bypassing bystander cells, reducing toxicity and inducing antiparasite immunity.
authors.affiliation: Department Ophthalmology, Bascom Palmer Eye Institute.
authors.forename: Pirouz M
authors.initials: PM
authors.lastname: Daftarian
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Stone
authors.forename: Leticia
authors.initials: L
authors.lastname: Kovalski
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Aram
authors.initials: A
authors.lastname: Vosoughi
authors.forename: Maitee
authors.initials: M
authors.lastname: Urbieta
authors.forename: Pat
authors.initials: P
authors.lastname: Blackwelder
authors.forename: Emre
authors.initials: E
authors.lastname: Dikici
authors.forename: Paolo
authors.initials: P
authors.lastname: Serafini
authors.forename: Stephanie
authors.initials: S
authors.lastname: Duffort
authors.forename: Richard
authors.initials: R
authors.lastname: Boodoo
authors.forename: Alhelí
authors.initials: A
authors.lastname: Rodríguez-Cortés
authors.forename: Vance
authors.initials: V
authors.lastname: Lemmon
authors.forename: Sapna
authors.initials: S
authors.lastname: Deo
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberola
authors.forename: Victor L
authors.initials: VL
authors.lastname: Perez
authors.forename: Sylvia
authors.initials: S
authors.lastname: Daunert
authors.forename: Arba L
authors.initials: AL
authors.lastname: Ager
mesh_terms: D056704:Adaptive Immunity; D000666:Amphotericin B / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000633:toxicity; D050091:Dendrimers / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004337:Drug Carriers; D000939:Epitopes; D005260:Female; D007274:Injections, Intraperitoneal; D018320:Leishmania major / Q000187:drug effects* / Q000276:immunology; D054332:Leishmaniasis Vaccines; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D017780:Malaria Vaccines / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles
chemical_list: D000981:Antiprotozoal Agents; D050091:Dendrimers; D004337:Drug Carriers; D000939:Epitopes; D054332:Leishmaniasis Vaccines; D017780:Malaria Vaccines; C401223:PADRE 45; C104700:PAMAM Starburst; C068538:liposomal amphotericin B; D000666:Amphotericin B
keywords: adoptive immunity; immunochemotherapy; intracellular; leishmaniasis; nanocarrier; obligate intracellular parasites; vaccine
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