title: Targeted antibiotic delivery using low temperature-sensitive liposomes and magnetic resonance-guided high-intensity focused ultrasound hyperthermia.
abstract: Chronic non-healing wound infections require long duration antibiotic therapy, and are associated with significant morbidity and health-care costs. Novel approaches for efficient, readily-translatable targeted and localised antimicrobial delivery are needed. The objectives of this study were to 1) develop low temperature-sensitive liposomes (LTSLs) containing an antimicrobial agent (ciprofloxacin) for induced release at mild hyperthermia (∼42 °C), 2) characterise in vitro ciprofloxacin release, and efficacy against Staphylococcus aureus plankton and biofilms, and 3) determine the feasibility of localised ciprofloxacin delivery in combination with MR-HIFU hyperthermia in a rat model. LTSLs were loaded actively with ciprofloxacin and their efficacy was determined using a disc diffusion method, MBEC biofilm device, and scanning electron microscopy (SEM). Ciprofloxacin release from LTSLs was assessed in a physiological buffer by fluorescence spectroscopy, and in vivo in a rat model using MR-HIFU. Results indicated that < 5% ciprofloxacin was released from the LTSL at body temperature (37 °C), while >95% was released at 42 °C. Precise hyperthermia exposures in the thigh of rats using MR-HIFU during intravenous (i.v.) administration of the LTSLs resulted in a four fold greater local concentration of ciprofloxacin compared to controls (free ciprofloxacin + MR-HIFU or LTSL alone). The biodistribution of ciprofloxacin in unheated tissues was fairly similar between treatment groups. Triggered release at 42 °C from LTSL achieved significantly greater S. aureus killing and induced membrane deformation and changes in biofilm matrix compared to free ciprofloxacin or LTSL at 37 °C. This technique has potential as a method to deliver high concentration antimicrobials to chronic wounds.
authors.affiliation: a Center for Veterinary Health Sciences, Oklahoma State University , Stillwater , OK , USA .
authors.forename: Rachel
authors.initials: R
authors.lastname: Wardlow
authors.affiliation: b Department of Radiology , University of Texas Southwestern Medical Center , Dallas , TX .
authors.forename: Chenchen
authors.initials: C
authors.lastname: Bing
authors.affiliation: a Center for Veterinary Health Sciences, Oklahoma State University , Stillwater , OK , USA .
authors.forename: Joshua
authors.initials: J
authors.lastname: VanOsdol
authors.affiliation: a Center for Veterinary Health Sciences, Oklahoma State University , Stillwater , OK , USA .
authors.forename: Danny
authors.initials: D
authors.lastname: Maples
authors.affiliation: b Department of Radiology , University of Texas Southwestern Medical Center , Dallas , TX .
authors.forename: Michelle
authors.initials: M
authors.lastname: Ladouceur-Wodzak
authors.affiliation: a Center for Veterinary Health Sciences, Oklahoma State University , Stillwater , OK , USA .
authors.forename: Michele
authors.initials: M
authors.lastname: Harbeson
authors.affiliation: b Department of Radiology , University of Texas Southwestern Medical Center , Dallas , TX .
authors.forename: Joris
authors.initials: J
authors.lastname: Nofiele
authors.affiliation: b Department of Radiology , University of Texas Southwestern Medical Center , Dallas , TX .|d Clinical Sites Research Program, Philips Research , Briarcliff Manor , NY , and.
authors.forename: Robert
authors.initials: R
authors.lastname: Staruch
authors.affiliation: e Oklahoma Animal Disease Diagnostic Laboratory (OADDL), OSU , Stillwater , OK , USA.
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Ramachandran
authors.affiliation: a Center for Veterinary Health Sciences, Oklahoma State University , Stillwater , OK , USA .
authors.forename: Jerry
authors.initials: J
authors.lastname: Malayer
authors.affiliation: b Department of Radiology , University of Texas Southwestern Medical Center , Dallas , TX .|c Advanced Imaging Research Center, University of Texas Southwestern Medical Center , Dallas , TX .
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.affiliation: a Center for Veterinary Health Sciences, Oklahoma State University , Stillwater , OK , USA .
authors.forename: Ashish
authors.initials: A
authors.lastname: Ranjan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D002939:Ciprofloxacin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D065546:Drug Liberation; D057086:High-Intensity Focused Ultrasound Ablation / Q000379:methods*; D008081:Liposomes; D008279:Magnetic Resonance Imaging; D008297:Male; D008855:Microscopy, Electron, Scanning; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D013696:Temperature
chemical_list: D000900:Anti-Bacterial Agents; D008081:Liposomes; D002939:Ciprofloxacin
keywords: Chronic wound; MR-HIFU; image guided therapy; low temperature-sensitive liposomes (LTSL); triggered antibiotic release