Nanoparticle formulations for enhanced sonodynamic therapy

Abstract

The primary objective of this thesis was to investigate the potential of sonodynamic therapy (SDT), using poly(lactic-co-glycolic acid) (PLGA)-based nanoparticle formulations, as a novel approach to treating pancreatic cancer, a malignancy with notably poor prognosis and significant resistance to current therapies. The thesis is structured to address the key limitations of existing treatments and explore how SDT could offer a targeted, stimulus-responsive alternative for enhanced therapeutic efficacy.

Chapter 1 introduces the challenges associated with treating pancreatic cancer, limitations of conventional therapies, and the conceptual basis for SDT. Chapter 2 outlines the experimental methodologies employed across the thesis. Chapter 3 describes the preparation and characterisation of PLGA nanoparticles containing the sonosensitiser Rose Bengal (RB) and imaging agent indocyanine green (ICG). In Chapter 4, the in vitro and in vivo efficacy of PLGA-RB-ICG nanoparticles was evaluated in human and murine models of pancreatic cancer. Results demonstrated that these nanoparticles could effectively accumulate in tumour tissue and provide a theranostic platform for real-time monitoring and targeted cytotoxicity. Efficacy studies demonstrated significant tumour cytotoxicity with the PLGA-PEI-RB-ICG mediated-SDT approach. In syngeneic murine models it was found that this approach suggested remodelling of the tumour microenvironment (TME) by reducing collagen deposition and altering cancer-associated fibroblasts (CAF) to favour a more tumour restrictive phenotype in SDT-treated tumours. Chapter 5 explored the immune-modulatory potential of an enhanced formulation incorporating the immune stimulant imiquimod (IMQ), revealing that SDT could induce systemic anti-tumour responses, eliciting clear abscopal effects in murine models. Flow cytometry confirmed increased CD8+ T-cell infiltration and decreased regulatory T cells (CD4+FoxP3+, CTLA4+) in target and off-target tumour sites, indicating potential for long-term tumour control. The results provide a foundation for nanoparticle-mediated SDT as a promising modality for pancreatic cancer therapy, with potential applications in combination regimens to overcome traditional barriers to effective treatment. Final conclusions and prospective directions are discussed in Chapter 6.

Date of Award	Jun 2025
Original language	English
Sponsors	Department for the Economy
Supervisor	Anthony McHale (Supervisor), Bridgeen Callan (Supervisor) & John Callan (Supervisor)