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This article reviews recent progress in the development of carbon dioxide (CO 2 ) bubble-generating drug carriers, including their designs and operating mechanisms; these carriers constitute an advanced class of stimuli-responsive delivery systems with considerable potential. The drug carriers contain stimuli-responsive agents, which are stable before they reach the target location, but enable rapid drug release that is triggered by the generation of CO 2 bubbles, which are chemically inert, under certain stimuli. These CO 2 bubble-generating carrier systems can be used to accumulate locally a delivered drug at the diseased tissue, while reducing side effects on the normal tissue, improving their therapeutic effectiveness. Since the generated CO 2 bubbles are hyperechogenic, they may also be used as an ultrasound contrast agent in elucidating the status of the carriers and providing real-time diagnostic images. Perspectives of the future of applications of gases with therapeutic effects, such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S), in such bubble-generating carrier systems, are also briefly discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Leroux et al. performed a set of experiments reported in our study and claim that they failed to reproduce the thermoresponsive liposomal system containing ammonium bicarbonate (ABC) that could trigger drug release under mild heating. We disagree with their assessments and speculate that the different method used by Leroux et al. to prepare the aqueous ABC is the culprit. [ABSTRACT FROM AUTHOR]