Efficient ultrasound-mediated drug delivery to orthotopic liver tumors – Direct comparison of doxorubicin-loaded nanobubbles and microbubbles

Abstract

Liver metastasis is a major obstacle in treating aggressive cancers, and current therapeutic options often prove insufficient. To overcome these challenges, there has been growing interest in ultrasound-mediated drug delivery using lipid-shelled microbubbles (MBs) and nanobubbles (NBs) as promising strategies for enhancing drug delivery to tumors. Our previous work demonstrated the potential of Doxorubicin-loaded C3F8 NBs (hDox-NB, 280 +/- 123 nm) in improving cancer treatment in vitro using low-frequency ultrasound. In this study, we investigated the pharmacokinetics and biodistribution of sonicated hDox-NB in orthotopic rat liver tumors. We compared the delivery and therapeutic efficiency of hDox-NBs with size-isolated MBs (hDox-MB, 1104 +/- 373 nm). Results showed a similar accumulation of hDox in tumors treated with hDox-MBs and unfocused therapeutic ultrasound (hDox-MB+TUS) and hDox-NB+TUS. However, significantly increased apoptotic cell death in the tumor and fewer off-target apoptotic cells in the normal liver were found in the treatment with hDox-NB+TUS. The tumor-to-liver apoptotic ratio was elevated 9.4-fold following treatment with hDox-NB+TUS compared to hDox-MB+TUS, suggesting that the therapeutic efficacy and specificity are significantly increased when using hDox-NB+TUS. These findings highlight the potential of this approach as a viable treatment modality for tumors in the liver. By elucidating the behavior of drug-loaded bubbles in vivo, we aim to contribute to developing more effective liver cancer treatments that could ultimately improve patient outcomes.