Ultrasound
contrast agents consist of gas microbubbles (1 – 10 m) 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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