title: Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection.
abstract: AR-12 has been evaluated in clinical trials as an anti-cancer agent but also has demonstrated host-directed, broad-spectrum clearance of bacteria. We have previously shown that AR-12 has activity in vitro against Salmonella enterica serovar Typhimurium and Francisella species by inducing autophagy and other host immune pathways. AR-12 treatment of S. Typhimurium-infected mice resulted in a 10-fold reduction in bacterial load in the liver and spleen and an increased survival time. However, AR-12 treatment did not protect mice from death, likely due poor formulation. In the current study, AR-12 was encapsulated in a microparticulate carrier formulated from the novel degradable biopolymer acetalated dextran (Ace-DEX) and subsequently evaluated for its activity in human monocyte-derived macrophages (hMDMs). Our results show that hMDMs efficiently internalized Ace-DEX microparticles (MPs), and that encapsulation significantly reduced host cell cytotoxicity compared to unencapsulated AR-12. Efficient macrophage internalization of AR-12 loaded MPs (AR-12/MPs) was further demonstrated by autophagosome formation that was comparable to free AR-12 and resulted in enhanced clearance of intracellular Salmonella. Taken together, these studies provide support that Ace-DEX encapsulated AR-12 may be a promising new therapeutic agent to control intracellular bacterial pathogens of macrophages by targeting delivery and reducing drug toxicity.
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: Ky V
authors.initials: KV
authors.lastname: Hoang
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: Hassan M
authors.initials: HM
authors.lastname: Borteh
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: Murugesan V S
authors.initials: MV
authors.lastname: Rajaram
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, 4211 Marsico Hall, 125 Mason Farm Road, Chapel Hill, NC 27599, United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Peine
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Curry
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, 4211 Marsico Hall, 125 Mason Farm Road, Chapel Hill, NC 27599, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Collier
authors.affiliation: Department of Chemical and Bimolecular Engineering, College of Engineering, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Homsy
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, 4211 Marsico Hall, 125 Mason Farm Road, Chapel Hill, NC 27599, United States.
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, OH 43210, United States.
authors.forename: John S
authors.initials: JS
authors.lastname: Gunn
authors.affiliation: Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, 4211 Marsico Hall, 125 Mason Farm Road, Chapel Hill, NC 27599, United States. Electronic address: ainsliek@email.unc.edu.
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Ainslie
mesh_terms: D000080:Acetals / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003911:Dextrans / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D012480:Salmonella Infections / Q000188:drug therapy / Q000382:microbiology; D012486:Salmonella typhimurium / Q000187:drug effects*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D013499:Surface Properties
chemical_list: D000080:Acetals; D000900:Anti-Bacterial Agents; D003911:Dextrans; D004337:Drug Carriers; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C500894:OSU 03012; D011720:Pyrazoles; D013449:Sulfonamides
keywords: Autophagy; Drug resistance; Macrophage; Microparticles; Pathogens; Salmonella