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 (SE61 O2 ) for overcoming tumor hypoxia. SE61 O2 was fabricated by first sonicating a mixture of Span 60 and water-soluble vitamin E purged with perfluorocarbon gas. SE61 O2 microbubbles were separated from the foam by flotation, then freeze dried under vacuum to remove all perfluorocarbon, and reconstituted with oxygen. Visually, SE61 O2 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 SE61 O2 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 SE61 O2 (1.3 E8 microbubbles) triggered with ultrasound was found to elevate oxygen partial pressures of 100 ml 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 SE61 O2 resulted in a 30.4 mmHg and 27.4 mmHg increase in oxygen partial pressures in two breast tumor mouse xenografts.