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Keywords:

  • monitoring drug delivery;
  • ultrasound;
  • ultrasound-mediated drug delivery;
  • fluorescence imaging;
  • intercalating dyes;
  • TOTO-3

Abstract

Many potent anti-cancer drugs have an intracellular mode of action, but are limited in crossing the cell membrane, resulting in a reduced clinical efficacy. Ultrasound (US) is known to facilitate the penetration of drugs into tumors cells. However (molecular) imaging techniques that monitor in vivo the underlying processes of US-triggered drug delivery are lacking. The objective of this study was to demonstrate the feasibility of using a fluorescent nuclear acid stain (TOTO-3) as a model drug to monitor in real-time US-mediated delivery by in vivo fluorescence imaging. Following co-injection of TOTO-3 and microbubbles US was applied to the tumor. The time course of the drug delivery process was monitored by fluorescence imaging. Immunohistological analysis and in vitro experiments were performed to investigate the results in more detail. A significant signal intensity enhancement of the US-treated tumor was observed that indicates intracellular delivery of the dye. In the control tumor TOTO-3 signal was strongly associated with macrophages, which was not the case for the sonicated tumor. The capability of macrophages to uptake TOTO-3 was confirmed in vitro. This study demonstrates that an optical contrast agent with similar characteristics to an anti-cancer drug may be used for continuous in vivo monitoring of the drug delivery process. Copyright © 2010 John Wiley & Sons, Ltd.