Feasibility study of cavitation-induced liposomal doxorubicin release in an AT2 Dunning rat tumor model

Abstract

Background: Targeted and triggered release of liposomal drug using heat or ultrasound represents a promising treatment modality able to increase the therapeutic-totoxicity ratio of encapsulated drugs.

Purpose: To study the ability for high-intensity focused ultrasound to induce liposomal drug release mainly by focused inertial cavitation in vitro and in an animal model.

Methods: A 1 MHz ultrasound setup has been developed for in vitro and in vivo drug release from a specific liposomal doxorubicin formulation at a target cavitation dose.

Results: Controlled cavitation at 1 MHz was applied within the tumors 48 hours after liposome injection according to preliminary pharmacokinetic study. A small non-significant therapeutic effect of US-liposomal treatment was observed compared to liposomes alone suggesting no beneficial effect of ultrasound in the current setup.

Conclusion: The in vitro study provided a suitable ultrasound setup for delivering a cavitation dose appropriate for safe liposomal drug release. However, when converting to an in vivo model, no therapeutic benefit was observed. This may be due to a number of reasons, one of which may be the difficulty in converting in vitro findings to an in vivo model. In light of these findings, we discuss important design features for future studies.

Keywords::

• Ultrasound
• drug delivery
• liposome
• sonosensitivity

Acknowledgments

The authors wish to thank Sibylla Rögnvaldsson (Epitarget AS) for manufacturing and characterizing the liposomes used in the current study, Derek Tobin (Epitarget AS) for reviewing and proofreading the manuscript, and Elodie Constanciel, Michael Canney, and Rémi Souchon for their contribution on the estimation of temperature in non-linear regime.

Declaration of interest

This project is supported by the Norwegian Research Council. SF and EAN have ownership interests in Epitarget AS. The remaining authors have no such interest and report no conflict of interest. The authors alone are responsible for the content and writing of the current article, as well as the decision to publish.