Vismodegib polymeric nanoparticles for targeting the pancreatic tumour microenvironment

This would re-sensitise the tumour to existing therapies such as chemotherapy to improve patient outcome.<br><br>The clinically approved drug vismodegib, targets the Hedgehog signalling pathway via its receptor, Smoothened and has been tested in clinical trials for pancreatic cancer. This pathway is involved in the activation of CAFs via paracrine signalling from the tumour cells. Despite promising pre-clinical results, vismodegib failed in clinical trials when in combination with the chemotherapeutic drug gemcitabine, providing no additional benefit for patients.

Vismodegib is poorly water soluble, which is a limiting factor for its systemic bioavailability. To address this issue, the use of nanoparticles (NPs) as a delivery system has been explored to improve clinical translation. Therefore, we aim to encapsulate vismodegib into PLGA nanoparticles to improve therapeutic efficacy and sensitise tumour cells to gemcitabine treatment.<br><br>We successfully developed a 3D spheroid co-culture model demonstrating their cell distribution, drug response and nanoparticle uptake with fluorescently labelled NPs.

Then, we formulated Vis-PLGA NPs achieving high encapsulation and a sustained drug release profile for in vitro testing. Lastly, we assessed the efficacy of our Vis-PLGA NPs in both 2D and 3D models. This work provides justification for future studies to assess Vis-PLGA NPs accumulation and blood circulation for PDAC treatment in in vivo models.<br><br><i>Thesis is embargoed until 31st December 2027</i>.<br><br>