The therapeutic effectiveness of chemotherapy is optimal only when tumor cells are subjected to a maximum drug exposure. To increase the intratumoral drug concentration and thus the efficacy of chemotherapy, a thermoresponsive bubble-generating liposomal system is proposed for triggering localized extracellular drug delivery. The key component of this liposomal formulation is the encapsulated ammonium bicarbonate (ABC), which is used to create the transmembrane gradient needed for a highly efficient encapsulation of doxorubicin (DOX). At an elevated temperature (42 °C), decomposition of ABC generates CO(2) bubbles, creating permeable defects in the lipid bilayer that rapidly release DOX and instantly increase the drug concentration locally. Because the generated CO(2) bubbles are hyperechogenic, they also enhance ultrasound imaging. Consequently, this new liposomal system encapsulated with ABC may also provide an ability to monitor a temperature-controlled drug delivery process.

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Bubbling over: After endocytosis and intracellular trafficking to lysosomes, liposomes containing ammonium bicarbonate can be thermally triggered to generate CO2 bubbles (see scheme). These bubbles grow rapidly and collapse violently to induce transient cavitation, a process that can disrupt the lysosomal membrane and release lysosomal proteases, thus leading to cell necrosis.

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