Lipid Microbubbles as Ultrasound-Stimulated Oxygen Carriers for Controllable Oxygen Release for Tumor Reoxygenation

Microbubbles are proposed as a potentially novel method for oxygen delivery in vivo in initial studies. The lack of commercial microbubbles for oxygen delivery in preclinical research prompted us to fabricate an oxygen-loaded lipid microbubble. We aimed to extend the innovative strategy to modulate the tumor hypoxic microenvironment, using microbubbles intravenously as an oxygen carrier for the controllable tumor-specific delivery of oxygen by ultrasound (US). In our experiment, an oxygen-loaded lipid-coated microbubble (OLM) with mixed gas (O₂/C₃ F₈, 5:1 v/v) was fabricated and exhibited a higher rate of oxygen release to a desaturated solution through burst by US than that in the absence of US. Although in in vivo studies, OLMs could be imaged and triggered by US to elevate the pO₂ level in the breast VX2 tumor dramatically within a matter of minutes. The added presence of US-activated OLMs elicited a nearly six-fold increase in pO₂ levels within 1 min compared with that of the pre-injection. Owing to the high oxygen payload, great acoustic stability and acoustic properties, OLMs may be proposed as an ideal radio-sensitizer. We conclude that oxygen release mediated by ultrasound-targeted microbubble destruction is feasible and shows potential in image-guided, site-specific cancer radiotherapy.