title: Long-acting antituberculous therapeutic nanoparticles target macrophage endosomes.
abstract: Eradication of Mycobacterium tuberculosis (MTB) infection requires daily administration of combinations of rifampin (RIF), isoniazid [isonicotinylhydrazine (INH)], pyrazinamide, and ethambutol, among other drug therapies. To facilitate and optimize MTB therapeutic selections, a mononuclear phagocyte (MP; monocyte, macrophage, and dendritic cell)-targeted drug delivery strategy was developed. Long-acting nanoformulations of RIF and an INH derivative, pentenyl-INH (INHP), were prepared, and their physicochemical properties were evaluated. This included the evaluation of MP particle uptake and retention, cell viability, and antimicrobial efficacy. Drug levels reached 6 μg/10(6) cells in human monocyte-derived macrophages (MDMs) for nanoparticle treatments compared with 0.1 μg/10(6) cells for native drugs. High RIF and INHP levels were retained in MDM for >15 d following nanoparticle loading. Rapid loss of native drugs was observed in cells and culture fluids within 24 h. Antimicrobial activities were determined against Mycobacterium smegmatis (M. smegmatis). Coadministration of nanoformulated RIF and INHP provided a 6-fold increase in therapeutic efficacy compared with equivalent concentrations of native drugs. Notably, nanoformulated RIF and INHP were found to be localized in recycling and late MDM endosomal compartments. These were the same compartments that contained the pathogen. Our results demonstrate the potential of antimicrobial nanomedicines to simplify MTB drug regimens.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, and.
authors.forename: Benson J
authors.initials: BJ
authors.lastname: Edagwa
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA; and.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, and.
authors.forename: Pavan
authors.initials: P
authors.lastname: Puligujja
authors.affiliation: Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, and.
authors.forename: JoEllyn
authors.initials: J
authors.lastname: McMillan
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, and.
authors.forename: Xinming
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, and hegendel@unmc.edu.
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, and.
authors.forename: Prabagaran
authors.initials: P
authors.lastname: Narayanasamy
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D011992:Endosomes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D053758:Nanoparticles; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents
keywords: MDM; Mycobacterium smegmatis; Mycobacterium tuberculosis; immunoisolation; subcellular trafficking