title: Development of an ultrasound sensitive oxygen carrier for oxygen delivery to hypoxic tissue.
abstract: Radiation therapy is frequently used in the treatment of malignancies, but tumors are often more resistant than the surrounding normal tissue to radiation effects, because the tumor microenvironment is hypoxic. This manuscript details the fabrication and characterization of an ultrasound-sensitive, injectable oxygen microbubble platform (SE61O2) for overcoming tumor hypoxia. SE61O2 was fabricated by first sonicating a mixture of Span 60 and water-soluble vitamin E purged with perfluorocarbon gas. SE61O2 microbubbles were separated from the foam by flotation, then freeze dried under vacuum to remove all perfluorocarbon, and reconstituted with oxygen. Visually, SE61O2 microbubbles were smooth, spherical, with an average diameter of 3.1 μm and were reconstituted to a concentration of 6.5 E7 microbubbles/ml. Oxygen-filled SE61O2 provides 16.9 ± 1.0 dB of enhancement at a dose of 880 μl/l (5.7 E7 microbubbles/l) with a half-life under insonation of approximately 15 min. In in vitro release experiments, 2 ml of SE61O2 (1.3 E8 microbubbles) triggered with ultrasound was found to elevate oxygen partial pressures of 100ml of degassed saline 13.8 mmHg more than untriggered bubbles and 20.6 mmHg more than ultrasound triggered nitrogen-filled bubbles. In preliminary in vivo delivery experiments, triggered SE61O2 resulted in a 30.4 mmHg and 27.4 mmHg increase in oxygen partial pressures in two breast tumor mouse xenografts.
authors.affiliation: Department of Radiology, Thomas Jefferson University, 132 South 10th Street, Philadelphia, PA 19107, USA. Electronic address: john.eisenbrey@jefferson.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Eisenbrey
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Albala
authors.affiliation: Department of Radiology, Thomas Jefferson University, 132 South 10th Street, Philadelphia, PA 19107, USA; Temple University School of Medicine, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kramer
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Daroshefski
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA.
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.affiliation: Department of Radiology, Thomas Jefferson University, 132 South 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Ji-Bin
authors.initials: JB
authors.lastname: Liu
authors.affiliation: Department of Radiology, Thomas Jefferson University, 132 South 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Stanczak
authors.affiliation: Department of Radiology, Thomas Jefferson University, 132 South 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Kane
authors.affiliation: Department of Radiology, Thomas Jefferson University, 132 South 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Flemming
authors.initials: F
authors.lastname: Forsberg
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Wheatley
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D008819:Mice, Nude; D045423:Microbubbles; D009369:Neoplasms / Q000378:metabolism*; D010100:Oxygen / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000069453:Ultrasonic Waves
chemical_list: D004337:Drug Carriers; D010100:Oxygen
keywords: Microbubble; Oxygen delivery; Surfactant; Tumor hypoxia; Ultrasound contrast agent