Development of protein-based cavitation nuclei for ultrasound-enhanced solid tumour immunotherapy

Thesis

Ultrasound (US)-mediated cavitation combined with checkpoint inhibitors has been shown to inhibit tumour growth and activate anti-tumour immunity. It has further been demonstrated that cavitation itself, without heating and mechanical ablation effects, can activate immune responses. However, to fully exploit the potential of US-mediated cavitation it is important to explore whether the composition of the Cavitation Agent (CA) can be designed to also raise anti-tumour immune responses.

This thesis investigates if immune activation can be enhanced by using different CAs. Four CAs comprised of either Mouse Serum Albumin (MSA) or Ovalbumin (OVA) were successfully synthesised: Microbubbles (MBs) of each protein and sub-micron Protein Cavitation Nuclei (PCaNs) of each protein. Each pair of CA (MSA MBs and OVA MBs, and MSA PCaNs and OVA PCaNs) had similar size distribution, concentration, and cavitation activity in vitro.

Two main in vivo studies were completed: one with MBs and one with PCaNs. In the former, it was observed that the MBs and the chosen US parameters did not produce sufficient cavitation doses for immune system activation. However, the PCaNs achieved two orders of magnitude greater cavitation dose and it was demonstrated that cavitation had a slight effect on the assessed immune cell populations. Furthermore, this effect was dependent on the CA used. Specifically, an increase of intratumoural macrophage level was observed for mice treated with OVA PCaNs and US, and evidence suggested that MSA PCaNs plus US caused tumour migration of neutrophils.

Authors: Maardalen, M

• DOI: 10.5287/ora-5rpzrrajq
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English