Lipid-shelled microbubbles for ultrasound-triggered release of bioactive gases to treat stroke and cardiovascular disease

Ischemia-reperfusion-induced neurological injury is a primary cause of stroke disability. Xenon (Xe), a bioactive gas, has potential as an effective and nontoxic neuroprotectant for the treatment of ischemic stroke. Nitric oxide (NO) is a potent bioactive gas capable of inducing vasodilatory, anti-inflammatory, neuroprotectant and bactericidal effects. The goal of this work was to develop lipid-shelled microbubbles for site-specific release of Xe or NO upon pulsed ultrasound exposure. Gas-loaded microbubbles were synthesized by high-shear mixing of a lipid dispersion in a vial that contained, Xe or NO, and octafluoropropane (OFP) in combination. Attenuation spectroscopy measurements demonstrate the feasibility of 6-MHz pulsed Doppler ultrasound-triggered release of Xe or NO from microbubbles. The addition of OFP in the lipid-shelled microbubbles increased the number density, size, and stability of the microbubbles, particularly in undersaturated saline. Gas chromatography mass spectrometry was employed to measure Xe dose (127 ± 29 μl Xe/mg lipid). The payload of NO in the microbubbles (97 ± 12 μl NO/mg lipid) was assessed using an amperometric sensor. Intravenous administration of microbubbles carrying a neuroprotective or a vasodilatory gas in combination with ultrasound exposure has potential as a novel noninvasive strategy for local therapeutic delivery to modulate the effects or duration of cerebral ischemia.