Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in Europe and the only cancer, which has not seen an improvement in mortality figures in over 40 years. In fact, survival from PDAC is only anecdotal, with a 5- year survival rate of only 3% and a median survival of less than 6 months.Current therapy approaches often combining chemotherapy and surgery carry the only possibility of cure. However, only 15 - 20% of patients are considered resectable at the time of diagnosis, and of these patients who present with surgically amenable disease their median overall survival is still only 15 months. Consequently, this constitutes an extraordinary challenge and the urgent need to provide society with a novel, meaningful therapeutic strategy for this disease. This proposal aims to usher in the radically new concept of sonoporation-enhanced targeted therapy for combating this deadly disease. SONOPORATION is the transient formation of nanometre- to micrometre-sized pores in cell membranes by the use of ultrasound or ultrasound and microbubbles, allowing for intracellular uptake of drugs or genes. The application of sonoporation in enhancing cancer-therapies is only in its preliminary stages but our pilot preclinical and clinical data demonstrate great promise in treatment of PDAC. However, the effective clinical translation is limited by lack of preclinical modelling platforms. We propose through the innovation of multidisciplinary technology platforms and next generation preclinical modelling systems to bridge the translational divide. We will fabricate innovative microbubble drug delivery formats designed specifically to the needs of sonoporation-enhanced therapy in addition to developing radically new tissue organoid models and animal models of PDAC. Importantly, the results of this project will not only impact the future of PDAC therapy, but the novel technologies will effect all aspects of preclinical oncology drug development.