title: Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles.
abstract: Leishmaniasis is a disease caused by parasites of Leishmania sp., which effects nearly 12 million people worldwide and is associated with treatment complications due to widespread parasite resistance toward pathogen-directed therapeutics. The current treatments for visceral leishmaniasis (VL), the systemic form of the disease, involve pathogen-mediated drugs and have long treatment regimens, increasing the risk of forming resistant strains. One way to limit emergence of resistant pathogens is through the use of host-mediated therapeutics. The host-mediated therapeutic AR-12, which is FDA IND-approved for cancer treatment, has shown activity against a broad spectrum of intracellular pathogens; however, due to hydrophobicity and toxicity, it is difficult to reach therapeutic doses. We have formulated AR-12 into microparticles (AR-12/MPs) using the novel biodegradable polymer acetalated dextran (Ace-DEX) and used this formulation for the systemic treatment of VL. Treatment with AR-12/MPs significantly reduced liver, spleen, and bone marrow parasite loads in infected mice, while combinatorial therapies with amphotericin B had an even more significant effect. Overall, AR-12/MPs offer a unique, host-mediated therapy that could significantly reduce the emergence of drug resistance in the treatment of VL.
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
authors.forename: M A
authors.initials: MA
authors.lastname: Collier
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
authors.forename: K J
authors.initials: KJ
authors.lastname: Peine
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: S
authors.initials: S
authors.lastname: Gautam
authors.affiliation: Department of Pathology, The Ohio State's Wexner Medical Center, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: S
authors.initials: S
authors.lastname: Oghumu
authors.affiliation: Department of Pathology, The Ohio State's Wexner Medical Center, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: S
authors.initials: S
authors.lastname: Varikuti
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: H
authors.initials: H
authors.lastname: Borteh
authors.affiliation: Department of Pathology, The Ohio State's Wexner Medical Center, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: T L
authors.initials: TL
authors.lastname: Papenfuss
authors.affiliation: College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, United States.
authors.forename: A R
authors.initials: AR
authors.lastname: Sataoskar
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
authors.forename: E M
authors.initials: EM
authors.lastname: Bachelder
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States. Electronic address: ainsliek@email.unc.edu.
authors.forename: K M
authors.initials: KM
authors.lastname: Ainslie
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001853:Bone Marrow / Q000469:parasitology; D003911:Dextrans / Q000737:chemistry; D005260:Female; D057927:Hydrophobic and Hydrophilic Interactions; D007893:Leishmania donovani / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008099:Liver / Q000469:parasitology; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D011108:Polymers / Q000737:chemistry; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D013154:Spleen / Q000469:parasitology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D003911:Dextrans; C500894:OSU 03012; D011108:Polymers; D011720:Pyrazoles; D013449:Sulfonamides; D000666:Amphotericin B
keywords: AR-12; Dose sparing; Drug delivery; Microparticles; Visceral leishmaniasis