Passive acoustic mapping for cavitation-mediated drug delivery monitoring

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. 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. 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. 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. 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.