Model-dependent modulation of radiotherapeutic efficacy with oxygen microbubbles and ultrasound

Oxygenation of hypoxic tumors during radiation therapy can increase tumor damage and improve radiotherapeutic efficacy. Lipid-shelled microbubbles can be used with ultrasound for a variety of enhanced therapeutic applications, including drug delivery. Further, the bubbles themselves can be used as carriers for therapeutic gas, such as oxygen. Upon ultrasound activation, oxygen microbubbles (OMBs) release oxygen, improving the oxygenation status of the tumor microenvironment. This process enhances the generation of reactive oxygen species (ROS) during radiotherapy, leading to increased DNA damage and tumor cell death. In developing and evaluating OMBs for the modulation of radiotherapeutic efficacy, we observed model-dependent differences in response to radiation after treatment with oxygen microbubbles. Curiously, in an immune-competent rat fibrosarcoma allograft model, treatment with OMBs and ultrasound was radioprotective, whereas a study in immunocompromised mice bearing CAL27 xenograft tumors oppositely demonstrated radiosensitization and improved anti-tumor efficacy. Some evidence implicates vasodynamic effects on tumor perfusion in the acute radiotherapy window, though additional studies comparing immune competent and deficient mice of the same tumor model also demonstrate differences in outcome following ultrasound and OMB-enhanced radiation therapy.