Irregular tumour vasculature and elevated interstitial fluid pressure act as barriers to extravasation of anti-cancer agents, making it difficult to deliver therapeutically relevant drug concentrations away from blood vessels.
In recent years, significant progress has been made in the development of drug delivery systems that combine therapeutic ultrasound with microbubble technologies, for applications such as thrombolysis, reversible opening of the blood brain barrier, and gene therapy for cardiovascular disorders. Several such systems exploit acoustic cavitation that is instigated by the time-varying acoustic pressure in the presence of intravenously administered stabilised micro-bubbles.
Research carried out in the Biomedical Ultrasonics & Biotherapy Laboratory (BUBL) aims to study whether ultrasound-induced cavitation can be used to overcome the physiological barriers presented by tumour vasculature in order to enhance the therapeutic effect of otherwise potent anticancer agents throughout the tumour. The use of focused ultrasound provides a unique opportunity to disturb the tumour micro-environment in a controlled manner in order to promote the delivery of anticancer agents whilst leaving surrounding healthy tissues unaffected.
The attached Figure illustrates the impact of cavitation on the extravasation of Evans Blue attached to molecules of similar size to commonly used anticancer drugs in an in vitro model. The circular region corresponds to a transverse cross-section of a model 2-mm vessel traversing the tissue mimicking material, through which the Evans-blue-bonded molecules were made to flow.
As part of an EPSRC Challenging Engineering grant, we seek to establish a direct link between the delivery of anticancer agents and the underlying cavitation mechanisms that are responsible for specific in vitro and in vivo bioeffects. In order to exploit the full therapeutic potential of the proposed drug delivery system, cavitation activity must be controlled, enhanced and optimized at the site of interest. This can be achieved by monitoring the broadband noise, harmonic and subharmonc emissions arising from various types of volumetric and shape oscillations that arise as a result of different cavitational behaviours. Non-invasive passive and active monitoring of these emissions is being envisaged as a means of correlating particular types of cavitational activity with particular enhancements in drug activity and uptake.
Whilst ultrasound-induced cavitation can provide a most useful tool for enhancing drug activity and uptake, ultrasound itself can be used as a trigger for localized drug release. This can be achieved by combining the ability of High Intensity Focussed Ultrasound (HIFU) to generate mild or severe localized heating with the use of thermosensitive vesicles that encapsulate a chemotherapy drug or other oncolytic agent. The use of heating as a release mechanism presents the added advantage that cancerous cells are rendered more vulnerable at mild hyperthermia temperatures (39-42C) than healthy cells. Using ultrasound-induced heating for release of the encapsulated agent therefore combines the advantages of localized release and improved differentiation between healthy and cancerous cells.
- C.-C. Coussios and R.A. Roy, ‘Applications of Acoustics and Cavitation to Non-Invasive Therapy and Drug Delivery’, Annual Review of Fluid Mechanics 40: 395-420 (2008).
- S. Datta, C.-C. Coussios, A.Y. Ammi, T.D. Mast, G.M. de Courten-Myers and C.K. Holland, ‘Ultrasound-Enhanced Thrombolysis using Definity® as a Cavitation Nucleation Agent’¸ Ultr. Med. Biol. 34(9):1421-33 (2007)
- S Datta, C.-C. Coussios, L.E. McAdory, J. Tan, T. Porter,G. De Courten-Myer, C.K. Holland, ‘Correlation of cavitation with ultrasound enhancement of thrombolysis’, Ultrasound Med. Biol 32: 1257-1267 (2006).