title: Imidazolium salts as small-molecule urinary bladder exfoliants in a murine model.
abstract: We present a novel family of small-molecule urinary bladder exfoliants that are expected to be of great value in preclinical studies of urologic conditions and have improved potential for translation compared with prior agents. There is broad urologic interest in the therapeutic potential of such exfoliating agents. The primary agent used in preclinical models, the cationic peptide protamine sulfate (PS), has limited translational potential due to concerns including systemic adverse reactions and bladder tissue injury. Intravesical application of a safe, systemically nontoxic exfoliant would have potential utility in the eradication of Escherichia coli and other uropathogens that reside in the bladder epithelium following cystitis, as well as in chronic bladder pain and bladder cancer. Here, we introduce a family of imidazolium salts with potent and focused exfoliating activity on the bladder epithelium. Synthesis and purification were straightforward and scalable, and the compounds exhibited prolonged stability in lyophilized form. Most members of the compound family were cytotoxic to cultured uroepithelial cells, with >10-fold differences in potency across the series. Upon topical (intravesical) administration of selected compounds to the murine bladder, complete epithelial exfoliation was achieved with physiologically relevant imidazolium concentrations and brief contact times. The exfoliative activity of these compounds was markedly improved in comparison to PS, as assessed by microscopy, immunofluorescence, and immunoblotting for uroplakins. Bladder uroepithelium regenerated within days to yield a histologically normal appearance, and no toxicity was observed. Finally, the chemical scaffold offers an opportunity for inclusion of antimicrobials or conjugation with chemotherapeutic or other moieties.
authors.affiliation: Department of Chemistry and Center for Silver Therapeutics Research, University of Akron, Akron, Ohio, USA.
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Wagers
authors.affiliation: Department of Pediatrics, Washington University, St. Louis, Missouri, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Tiemann
authors.affiliation: Department of Chemistry and Center for Silver Therapeutics Research, University of Akron, Akron, Ohio, USA.
authors.forename: Kerri L
authors.initials: KL
authors.lastname: Shelton
authors.affiliation: Department of Chemistry and Center for Silver Therapeutics Research, University of Akron, Akron, Ohio, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Kofron
authors.affiliation: Department of Chemistry and Center for Silver Therapeutics Research, University of Akron, Akron, Ohio, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Panzner
authors.affiliation: Department of Chemistry, Department of Chemical Engineering, and Department of Materials Science and Engineering, Texas A&M University, College Station, Texas, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Wooley
authors.affiliation: Department of Chemistry and Center for Silver Therapeutics Research, University of Akron, Akron, Ohio, USA.
authors.forename: Wiley J
authors.initials: WJ
authors.lastname: Youngs
authors.affiliation: Department of Pediatrics, Washington University, St. Louis, Missouri, USA Department of Molecular Microbiology, Washington University, St. Louis, Missouri, USA dhunstad@wustl.edu.
authors.forename: David A
authors.identifier: http://orcid.org/0000-0002-9848-0975
authors.initials: DA
authors.lastname: Hunstad
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D001743:Urinary Bladder / Q000187:drug effects*; D019459:Urothelium / Q000166:cytology
chemical_list: D000900:Anti-Bacterial Agents; D007093:Imidazoles