PaNanoMRI - Early detection of pre-malignant pancreatic cancer using multifunctional targeted nanoparticles for MR imaging with super-resolution reconstruction and MR fingerprinting

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of UK cancer death and incidence is rising. Most pancreatic malignancies are diagnosed at a late stage with dismal five-year survival.

Even with increased PDAC pre-test probability, low sensitivity/specificity for pre-malignant disease results in missed diagnoses.

Improved early detection, targeting pre-malignant rather than malignant PDAC is therefore essential to improving clinical outcomes.

Aims: To increase the diagnostic yield of magnetic resonance imaging (MRI) in patients with early/pre-malignant disease through the use of (a) novel multifunctional targeted nanoparticles and (b) application of super-resolution reconstruction (SRR) and MR fingerprinting (MRF). Methods: Hybrid iron oxide-gold magnetic nanoparticles (HNPs) will be synthesized using established methods.

The HNPs will be functionalised with a panel of targeting moieties, conjugated with antibodies and assessed for biochemical stability. Biocompatibility will be evaluated using haemolysis assays and cellular toxicity screening in several cell lines.

Best performing HNPs will proceed to in vitro 2D/3D studies utilizing cell viability (enzymatic and image cytometry), cell membrane integrity, and reactive oxygen species assays.

Fluorescence microscopy will be used to establish effective doses and incubation times, in several 2D cell lines and murine PanIN-3 organoids. The two best-performing HNPs at this stage will be selected for in vivo feasibility and MRI proof-of-concept.

Orthotopic immunocompromised murine models will be injected intravenously with candidate HNPs, with in vivo T1/T2 weighted 9.4T MRI for assessment of altered tissue-contrast.

Scanned subjects will be sacrificed for multi-organ histopathological analysis and immunohistochemistry and blood-sampling to assess for tissue damage, inflammation or other adverse effects.

In parallel to this, imaging protocols will be setup on a clinical MRI scanner, including the development of post-processing pipelines for SRR MRI, quantitative T1 and T2 mapping and MRF. Feasibility will be tested in a small sample of healthy volunteers and patients with known pancreatic adenocarcinoma.

How the results of this research will be used: The combination of enhanced MRI with novel nanotechnology will lay the foundation for transformative gains in patient survival, represent a major scientific/clinical achievement and herald a novel strategy for the early detection of rare and difficult to treat cancers.

The results of this project will be used to procure subsequent funding such as a CRUK Early Detection and Diagnosis Project Award, to support completion of biomarker validation studies, further technical validation of clinical SRR and MRF, submission of patents for developed HNPs and ultimately clinical translation into patients.