Oxygen Sensitive Drug Release Using Hemoglobin Microbubbles: A New Approach to Targeting Hypoxia in Ultrasound-Mediated Drug Delivery

Abstract

Targeted drug delivery strategies using focused ultrasound (FUS) are gaining prominence in clinical application. FUS offers deep tissue penetration and precise targeting capabilities. The capabilities of FUS in targeted drug delivery are greatly enhanced by the introduction of ultrasound contrast agents (UCAs – also known as microbubbles). This study introduces a novel hypoxia-targeting drug delivery system using hemoglobin microbubbles (HbMBs) conjugated with doxorubicin-loaded liposomes (LDOX). Previously, we reported that HbMBs exhibit significant acoustic response differences between oxygenated and deoxygenated environments due to hemoglobin’s conformational changes, which alters the MBs’ shell elasticity as well as resonance frequency. In this study, we coated the surface of HBMBs with LDOX to create Lip-HBMB complex and subsequently investigated its drug release at different oxygen partial pressures (pO₂) when exposed to an ultrasound field. Results showed significantly higher drug release at lower oxygen levels, with about 10-times higher release at 5 mmHg pO₂ than 160 mmHg pO₂ at 0.5 W/cm² US intensity and 3 MHz frequency. This highlights Lip-HbMBs’ potential for targeted drug delivery to hypoxic tumor regions, marking a significant advancement in focused ultrasound-mediated drug delivery. This study marks the first-ever report of ultrasound-mediated oxygen-sensitive drug uncaging, which holds promise in enhancing FUS specificity and addressing the challenges posed by metastatic cancer.