| Summary: | <p>Advances in biomedical science have led to the development and clinical translation
of novel potent anti-cancer agents, particularly antibodies and oncolytic viruses.
However, many fail to translate to mainstream clinical use - not because they are
incapable of triggering the desired biological response, but because they are unable
to reach their target locations in the required concentrations to be effective. Bubbles
excited by an acoustic field, also known as acoustic cavitation, have been used to
aid the delivery of these biologically active materials.</p>
<p>Passive Acoustic Mapping (PAM) has recently been developed as a method of
monitoring ultrasound-mediated drug delivery. However, while PAM has been used
extensively in determining the location of cavitation activity, far less work has been
done utilising PAM to quantify the spatially and temporally varying intensity of
cavitation activity and relate that to a biological effect, with much of the previous
work being conducted in the context of histotripsy.</p>
<p>This thesis has three main aims: demonstrating that PAM can be used quantitatively to allow for accurate monitoring of biological effects relating to the safety and
efficacy of drug delivery in solid tumours; showing the utility of direct measurements
of the cavitation activity by exploring how the relationship between cavitation
and bioeffect is independent of how the cavitation is generated; and developing
a novel form of the PAM algorithm that is capable of generating a universally
reproducible measurement of cavitation energy.</p>
<p>In pursuit of the first aim a large in vivo dataset is utilised, and it is demonstrated
that PAM is capable of quantitatively relating a metric of cavitation energy density
called cavitation dose with the enhancement of drug delivery, up-regulation of genes
associated with immune response, and improved survival outcomes in the context
of cavitation enhanced drug delivery. In pursuit of the second aim it is shown that
the cavitation dose metric can also be used to monitor cellular safety in the context
of haemolysis, with the relationship between cavitation dose and haemolysis being
found to be independent of the pressure, pulse length, and cavitation agent type
and concentration used. Finally for the final aim a novel form of the PAM algorithm
is developed, which is capable of generating universally reproducible measurements
of cavitation energy with adequate spatial resolution, at a low computational cost.</p>
<p>Overall the work conducted as part of this thesis provides evidence that a set-up
independent, energy-preserving metric of cavitation dose is possible, and that this
metric can be shown to be potentially predictive of both treatment safety and efficacy
in the context of ultrasound-enhanced drug delivery and immunomodulation. It is
hoped that this approach will inspire future researchers to investigate its applicability
across the ever-growing range of therapeutic ultrasound applications ranging from
transdermal drug delivery to opening the blood brain barrier.</p>
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