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

Nittayacharn, P. A.; Abenojar, E.; Cooley, M. B.; Berg, F.; Counil, C.; Sojahrood, A.; Khan, M. S.; Yang, C.; Berndl, E.; Golczak, M.; Kolios, M.; Exner, A.

doi:10.1101/2023.09.01.555196

bioRxiv · 10.1101/2023.09.01.555196

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

Nittayacharn, P. A.·Abenojar, E.·Cooley, M. B.·Berg, F.·Counil, C.·Sojahrood, A.·Khan, M. S.·Yang, C.·Berndl, E.·Golczak, M.·Kolios, M.·Exner, A.

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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-NBs in orthotopic rat liver tumors. We compared their delivery and therapeutic efficiency 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 upon 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 liver tumors. 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 and decrease off-target side effects.

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Nittayacharn, P. A., Abenojar, E., Cooley, M. B., Berg, F., Counil, C., Sojahrood, A., Khan, M. S., Yang, C., Berndl, E., Golczak, M., Kolios, M., Exner, A.. 2023-09-05. Efficient ultrasound-mediated drug delivery to orthotopic liver tumors: Direct comparison of doxorubicin-loaded nanobubbles and microbubbles. https://doi.org/10.1101/2023.09.01.555196

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