title: Development and In Vivo Evaluation of a Novel Histatin-5 Bioadhesive Hydrogel Formulation against Oral Candidiasis.
abstract: Oral candidiasis (OC), caused by the fungal pathogen Candida albicans, is the most common opportunistic infection in HIV(+) individuals and other immunocompromised populations. The dramatic increase in resistance to common antifungals has emphasized the importance of identifying unconventional therapeutic options. Antimicrobial peptides have emerged as promising candidates for therapeutic intervention due to their broad antimicrobial properties and lack of toxicity. Histatin-5 (Hst-5) specifically has exhibited potent anticandidal activity indicating its potential as an antifungal agent. To that end, the goal of this study was to design a biocompatible hydrogel delivery system for Hst-5 application. The bioadhesive hydroxypropyl methylcellulose (HPMC) hydrogel formulation was developed for topical oral application against OC. The new formulation was evaluated in vitro for gel viscosity, Hst-5 release rate from the gel, and killing potency and, more importantly, was tested in vivo in our mouse model of OC. The findings demonstrated a controlled sustained release of Hst-5 from the polymer and rapid killing ability. Based on viable C. albicans counts recovered from tongues of treated and untreated mice, three daily applications of the formulation beginning 1 day postinfection with C. albicans were effective in protection against development of OC. Interestingly, in some cases, Hst-5 was able to clear existing lesions as well as associated tissue inflammation. These findings were confirmed by histopathology analysis of tongue tissue. Coupled with the lack of toxicity as well as anti-inflammatory and wound-healing properties of Hst-5, the findings from this study support the progression and commercial feasibility of using this compound as a novel therapeutic agent.
authors.affiliation: Department of Molecular Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland, USA Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Kong
authors.affiliation: Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Tsui
authors.affiliation: School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Boyce
authors.affiliation: School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ibrahim
authors.affiliation: School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Hoag
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, Maryland, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Karlsson
authors.affiliation: Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Meiller
authors.affiliation: Department of Molecular Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland, USA Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland, USA mrizk@umaryland.edu.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Jabra-Rizk
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001672:Biocompatible Materials / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects*; D002180:Candidiasis, Oral / Q000188:drug therapy*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000627:therapeutic use; D025141:Drug Resistance, Fungal; D005260:Female; D054808:Histatins / Q000627:therapeutic use*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000627:therapeutic use*; D008747:Methylcellulose / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D014059:Tongue / Q000382:microbiology
chemical_list: D000935:Antifungal Agents; D001672:Biocompatible Materials; D004337:Drug Carriers; D054808:Histatins; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D008747:Methylcellulose