Title: Developing a novel theranostic nanoparticle for precision surgery in pancreatic cancer
Funder: The Academy of Medical Sciences

Abstract: Background: Survival from pancreatic ductal adenocarcinoma (PDAC) has remained consistently poor, with 5-year survival rates of ~ 9%. A step-change is required if we are to improve on the current situation, with new strategies to improve the detection and eradication of disease. Photodynamic therapy (PDT) is a photochemistry-based approach that enables selective cancer cell killing using a tumour-localising photosensitiser activated by visible or near-infrared light. Clinical studies have proven the technical feasibility and safety of PDT for locally advanced PDAC, but the efficacy of PDT is limited by poor systemic delivery of the photosensitiser to the tumour site and difficulty in light delivery to the abdominal cavity. Nanoparticle technology offers a potential solution. Nanoparticles can be loaded with photosensitiser and functionalised with targeting ligands enabling cancer-specific accumulation for optimal PDT. This proposal builds on my experience in developing a multifunctional nanoparticle for PDT in colorectal cancer, modifying the approach to PDAC. Aim: To develop a multifunctional nanoparticle, containing a photosensitiser and conjugated with a cancer-specific recognition molecule, to enable intraoperative fluorescence localisation and PDT for PDAC. Objectives: To synthesise a multifunctional nanoparticle containing a photosensitiser and functionalise with a targeting ligand to PDAC. The nanoparticle will be evaluated in vitro to determine its fluorescence and PDT efficacy using 3D models of PDAC. Impact: The fabrication of this novel multifunctional nanoparticle that specifically targets PDAC will enhance the intraoperative diagnosis of tumour margins and lymph nodes involvement and eradicate residual micrometastases, thus, tailoring the surgery to the biology of the disease.

Lay abstract: Pancreatic cancer has one of the worst survival statistics of any cancer, with only 1 in 10 patients surviving for over 5-years. Surgery is the mainstay of treatment, but is only successful if all the cancer is removed. In over 25% of patients with pancreatic cancer, the tumour spreads outside the pancreas to form small deposits, known as metastases. These deposits are difficult to see at operation and if not removed will inevitably lead to disease recurrence. There is a clinical need to improve our ability to detect the extent of pancreatic cancer spread at operation and to ensure complete cancer removal. Previously, I have developed a silica nanoparticle (1000x smaller than the tip of a human hair) and loaded it with a photoactive drug called Foslip. A targeting molecule against colorectal cancer was attached to the surface of the nanoparticle. When activated by light, Foslip fluoresces, enabling the cancer to be visualised. Foslip also produces toxic oxygen molecules that are lethal to cancer cells; a process called photodynamic therapy. When my nanoparticle was injected into an animal model of colorectal cancer it was effective in producing cancer cell death. This proposal builds on my above experience, but modifies the approach to develop a nanoparticle that can target and kill pancreatic cancer. It will allow surgeons to accurately identify pancreatic cancers and metastatic disease with fluorescent imaging and kill any cancer cells left behind. This will ensure that the cancer is completely removed and reduce the risk of recurrent disease.

Research activity codes: 5.1 PHARMACEUTICALS;5.4 SURGERY
Health categories: CANCER AND NEOPLASMS