Remote Loading: The Missing Piece for Achieving High Drug Payload and Rapid Release in Polymeric Microbubbles

The use of drug-loaded microbubbles for targeted drug delivery, particularly in cancer treatment, has been extensively studied in recent years. However, the loading capacity of microbubbles has been limited due to their surface area. Typically, drug molecules are loaded on or within the shell, or drug-loaded nanoparticles are coated on the surfaces of microbubbles. To address this significant limitation, we have introduced a novel approach. For the first time, we employed a transmembrane ammonium sulfate and pH gradient to load doxorubicin in a crystallized form in the core of polymeric microcapsules. Subsequently, we created remotely loaded microbubbles (RLMBs) through the sublimation of the liquid core of the microcapsules. Remotely loaded microcapsules exhibited an 18-fold increase in drug payload compared with physically loaded microcapsules. Furthermore, we investigated the drug release of RLMBs when exposed to an ultrasound field. After 120 s, an impressive 82.4 ± 5.5% of the loaded doxorubicin was released, demonstrating the remarkable capability of remotely loaded microbubbles for on-demand drug release. This study is the first to report such microbubbles that enable rapid drug release from the core. This innovative technique holds great promise in enhancing drug loading capacity and advancing targeted drug delivery.