Ultrasound contrast agents consist of gas microbubbles (1 – 10 μm) that are coated by a protein, lipid or polymer. In addition to their diagnostic value, microbubbles have great potential as local drug delivery systems. Generally, two methods can be distinguished. The first is co-administration, i.e. the simultaneously administration of drugs and microbubbles where the vibrating microbubbles induce a transient increase in permeability of cell membranes and/or tissues. Elucidating this mechanism was one of the aims of this thesis. We found a direct correlation between vibrating microbubble-induced cell deformation and cell membrane permeability. Microbubbles induced transient pore formation, but also increased endocytosis. Endocytosis contribution was found to be dependent on the molecular size of the drug. Both intracellular calcium and reactive oxygen species were found to play a role in the mechanism of microbubble-induced increase in endothelial layer permeability. Targeted microbubbles could also increase cell membrane permeability, indicating that molecular imaging and drug delivery can be combined. The second class of therapeutic bubbles is the incorporation of a drug in the microbubble. Polymer microbubbles were constructed containing gas and therapeutics. Using ultrasound, the therapeutics were released from the microbubbles and taken up by cells. In addition, these microbubbles were found to induce an increase in endothelial cell membrane permeability as also observed with our co-administration studies. The research described in this thesis aids in understanding how to utilise bubbles for therapy in the most optimal way. However, many technical and pharmaceutical issues still need to be resolved before microbubble-mediated treatments in humans become available. For now, therapeutic bubbles are excitingly vibrant and bursting of great potential.

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N. de Jong (Nico) , A.F.W. van der Steen (Ton)
Erasmus University Rotterdam
This work was financially supported by innovation subsidies collaborative projects by the Dutch ministry of economic affairs under nr IS042035 and by NMP-LA-2008-213706 Sonodrugs. Financial support for the publication of this thesis was kindly provided by: - Bracco Suisse SA - Erasmus MC - Oldelft Ultrasound - Traskbritt
Erasmus MC: University Medical Center Rotterdam