Development of an ultrasound sensitive oxygen carrier for oxygen delivery to hypoxic tissue

摘要

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 mu m 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 mu l/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. (C) 2014 Elsevier B.V. All rights reserved.