title: Ionic liquids as a class of materials for transdermal delivery and pathogen neutralization.
abstract: Biofilm-protected microbial infections in skin are a serious health risk that remains to be adequately addressed. The lack of progress in developing effective treatment strategies is largely due to the transport barriers posed by the stratum corneum of the skin and the biofilm. In this work, we report on the use of Ionic Liquids (ILs) for biofilm disruption and enhanced antibiotic delivery across skin layers. We outline the syntheses of ILs, analysis of relevant physicochemical properties, and subsequent neutralization effects on two biofilm-forming pathogens: Pseudomonas aeruginosa and Salmonella enterica. Further, the ILs were also examined for cytotoxicity, skin irritation, delivery of antibiotics through the skin, and treatment of biofilms in a wound model. Of the materials examined, choline-geranate emerged as a multipurpose IL with excellent antimicrobial activity, minimal toxicity to epithelial cells as well as skin, and effective permeation enhancement for drug delivery. Specifically, choline-geranate was comparable with, or more effective than, bleach treatment against established biofilms of S. enterica and P. aeruginosa, respectively. In addition, choline-geranate increased delivery of cefadroxil, an antibiotic, by >16-fold into the deep tissue layers of the skin without inducing skin irritation. The in vivo efficacy of choline-geranate was validated using a biofilm-infected wound model (>95% bacterial death after 2-h treatment). This work establishes the use of ILs for simultaneous enhancement of topical drug delivery and antibiotic activity.
authors.affiliation: Center for Bioengineering and Department of Chemical Engineering, University of California, Santa Barbara, CA 93106;
authors.forename: Michael
authors.initials: M
authors.lastname: Zakrewsky
authors.affiliation: Materials Chemistry, Materials Physics and Applications Division and.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Lovejoy
authors.affiliation: Bioenergy and Biome Science Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545;
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Kern
authors.affiliation: Materials Chemistry, Materials Physics and Applications Division and.
authors.forename: Tarryn E
authors.initials: TE
authors.lastname: Miller
authors.affiliation: Department of Chemical Engineering, University of California, Santa Barbara, CA 93106;
authors.forename: Vivian
authors.initials: V
authors.lastname: Le
authors.affiliation: Bioenergy and Biome Science Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545;
authors.forename: Amber
authors.initials: A
authors.lastname: Nagy
authors.affiliation: Bioenergy and Biome Science Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545;
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Goumas
authors.affiliation: Bioenergy and Biome Science Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545;
authors.forename: Rashi S
authors.initials: RS
authors.lastname: Iyer
authors.affiliation: Department of Physical Sciences - Chemistry, Dixie State University, St. George, UT 84770; and.
authors.forename: Rico E
authors.initials: RE
authors.lastname: Del Sesto
authors.affiliation: Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, AZ 86011.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Koppisch
authors.affiliation: Bioenergy and Biome Science Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545; samir@engineering.ucsb.edu dfox@lanl.gov.
authors.forename: David T
authors.initials: DT
authors.lastname: Fox
authors.affiliation: Center for Bioengineering and Department of Chemical Engineering, University of California, Santa Barbara, CA 93106; samir@engineering.ucsb.edu dfox@lanl.gov.
authors.forename: Samir
authors.initials: S
authors.lastname: Mitragotri
mesh_terms: D000279:Administration, Cutaneous; D018441:Biofilms / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D016503:Drug Delivery Systems; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D052578:Ionic Liquids / Q000494:pharmacology*; D007509:Irritants / Q000633:toxicity; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology*; D015203:Reproducibility of Results; D019779:Salmonella enterica / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000187:drug effects; D017768:Skin, Artificial / Q000382:microbiology; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D052578:Ionic Liquids; D007509:Irritants
keywords: antibacterial; antibiotic resistance; antimicrobial agents; formulation; ion-pairing