title: Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge.
abstract: Francisella tularensiscauses tularemia and is a potential biothreat. Given the limited antibiotics for treating tularemia and the possible use of antibiotic-resistant strains as a biowarfare agent, new antibacterial agents are needed. AR-12 is an FDA-approved investigational new drug (IND) compound that induces autophagy and has shown host-directed, broad-spectrum activityin vitroagainstSalmonella entericaserovar Typhimurium andF. tularensis We have shown that AR-12 encapsulated within acetalated dextran (Ace-DEX) microparticles (AR-12/MPs) significantly reduces host cell cytotoxicity compared to that with free AR-12, while retaining the ability to controlS.Typhimurium within infected human macrophages. In the present study, the toxicity and efficacy of AR-12/MPs in controlling virulent type AF. tularensisSchuS4 infection were examinedin vitroandin vivo No significant toxicity of blank MPs or AR-12/MPs was observed in lung histology sections when the formulations were given intranasally to uninfected mice. In histology sections from the lungs of intranasally infected mice treated with the formulations, increased macrophage infiltration was observed for AR-12/MPs, with or without suboptimal gentamicin treatment, but not for blank MPs, soluble AR-12, or suboptimal gentamicin alone. AR-12/MPs dramatically reduced the burden ofF. tularensisin infected human macrophages, in a manner similar to that of free AR-12. However,in vivo, AR-12/MPs significantly enhanced the survival ofF. tularensisSchuS4-infected mice compared to that seen with free AR-12. In combination with suboptimal gentamicin treatment, AR-12/MPs further improved the survival ofF. tularensisSchuS4-infected mice. These studies provide support for Ace-DEX-encapsulated AR-12 as a promising new therapeutic agent for tularemia.
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Ky V
authors.initials: KV
authors.lastname: Hoang
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Curry
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Collier
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Borteh
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Bachelder
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Gunn
authors.affiliation: UNC Eshelman School of Pharmacy, Division of Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina, USA ainsliek@email.unc.edu.
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Ainslie
mesh_terms: D000080:Acetals / Q000737:chemistry*; D000281:Administration, Intranasal; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D058491:Bacterial Load / Q000187:drug effects; D003911:Dextrans / Q000737:chemistry*; D004337:Drug Carriers / Q000138:chemical synthesis*; D004339:Drug Compounding; D004357:Drug Synergism; D005260:Female; D005604:Francisella tularensis / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D005839:Gentamicins / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D011720:Pyrazoles / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D016019:Survival Analysis; D014406:Tularemia / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000473:pathology
chemical_list: D000080:Acetals; D000900:Anti-Bacterial Agents; D003911:Dextrans; D004337:Drug Carriers; D005839:Gentamicins; C500894:OSU 03012; D011720:Pyrazoles; D013449:Sulfonamides