Vismodegib polymeric nanoparticles for targeting the pancreatic tumour microenvironment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths globally with 5-year survival rates estimated to be around 5%. The extremely resistant nature of the tumour cells and the limited drug penetration in the stroma makes PDAC difficult to treat. In recent years, focus has shifted to targeting the tumour microenvironment (TME), which presents as a major barrier to successful treatment. One of the most prominent cells of the TME are the cancer-associated fibroblasts (CAFs) that are activated early in tumour progression and remodel the TME to maintain a tumour-permissive environment. CAFs also deposit large amounts of extracellular matrix (ECM) proteins to build a dense stromal microenvironment that encourages resistance and prevents drug delivery. As such, an area of interest is to improve therapeutic efficacy by modulating the TME via the CAFs. This would re-sensitise the tumour to existing therapies such as chemotherapy to improve patient outcome.

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.

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.

Thesis is embargoed until 31st December 2027.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Wafa Al-Jamal (Supervisor) & Colin McCoy (Supervisor)