Mr. Peter L. Labib Profile

Peter L. Labib

at UCL Institute for Liver and Digestive Health

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Proceedings Article | 7 August 2019 Paper

Effect of 5-aminolevulinic acid on the haem biosynthesis pathway in pancreatic cancer and pancreatic ductal epithelial cell lines

Peter Labib, Walid Al-Akkad, Brian Davidson, Alexander MacRobert, Stephen Pereira

Proceedings Volume 11070, 110706K (2019) https://doi.org/10.1117/12.2525085

KEYWORDS: Pancreatic cancer, Luminescence, Cancer, Tissues, Surgery, Tumors, Optical diagnostics

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Introduction: 5-aminolevulinic acid (ALA) generates protoporphyrin IX (PpIX)-induced fluorescence by acting as a substrate for the haem biosynthesis pathway. Despite suggestions that ALA could be used for pancreatic cancer photodiagnostics, the pancreatic cancer cell line PANC-1 only shows weak fluorescence following ALA administration. A possible explanation was that the haem biosynthesis pathway varies between cancers. Methods: We compared the mRNA expression of the haem biosynthesis pathway of PANC-1 (weak fluorescence) with the pancreatic cancer cell line CFPAC-1 (strong fluorescence) and the pancreatic ductal cell line H6c7 (control) with or without 24 hours ALA incubation. Cells were seeded on day one, fresh media with or without ALA (0.5mM) added on day two, and RNA extracted on day three. Quantitative real-time polymerase chain reaction was performed to assess the relative mRNA expression of four membrane transporters and eight enzymes responsible for haem biosynthesis. Results: Post-ALA incubation, CFPAC-1 demonstrated significant downregulation of cell membrane ALA influx transporter PEPT1, downregulation of ALA synthase and upregulation of the mitochondrial membrane transporter ABCB6. PANC-1, whilst showing similar changes to ALA synthase and ABCB6, showed significant upregulation of the PpIX efflux transporter ABCG2. PANC-1 also had minimal PEPT1 expression pre- and post-ALA. H6c7 demonstrated significant up- or downregulation of three transporters and five enzymes. Conclusion: Poor PpIX-induced fluorescence in PANC-1 is likely to be secondary to decreased ALA influx from low PEPT1 expression and increased ABCG2 expression. The use of nanocarriers to deliver ALA and/or ABCG2 inhibitors may improve ALA-induced fluorescence in PANC-1 and other ALA-resistant cancers.

Proceedings Article | 7 August 2019 Presentation + Paper

Targeting of epidermal growth factor receptor (EGFR)-positive pancreatic cancer cell lines with cetuximab-conjugated near-infrared silver sulphide quantum dots

Peter Labib, Elnaz Yaghini, Mahshid Hashemkhani, Brian Davidson, Alexander MacRobert, Marilena Loizidou, Havva Acar, Stephen Pereira

Proceedings Volume 11070, 1107013 (2019) https://doi.org/10.1117/12.2525086

KEYWORDS: Pancreatic cancer, Silver, Luminescence, Quantum dots, Surgery, Tumors, Near infrared, Receptors, Toxicity

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Introduction: Fluorescence-guided surgery could potentially reduce local recurrence after pancreatic cancer resection. However, the ideal contrast agent for this purpose is not yet determined. The monoclonal antibody cetuximab targets the EGFR receptor, which is overexpressed in 64% of pancreatic cancers. We investigated the efficacy of near-infrared emitting silver sulphide Quantum Dot (QD)-cetuximab nanoconjugates for targeting EGFR-positive pancreatic cancer. Methods: 2-Mercaptopropionic acid-coated QDs were prepared from AgNO₃ and Na₂S. Pancreatic cancer cell lines PANC-1 and CFPAC-1 were confirmed EGFR-positive using a commercial AlexaFluor488-cetuximab probe. Nonconjugated QD and cetuximab-conjugated QD (QD-cetuximab) toxicity was assessed after 24 and 48 hours using MTT assay. Fluorescence microscopy was performed following a) formaldehyde-fixed immunofluorescence and b) live staining with QD-cetuximab for four hours at concentrations corresponding to 0, 10, 50, 100, 200, 400 and 600μg ml-1 of silver. Results: Untargeted QDs were non-toxic in both cell lines after 48 hours at all investigated concentrations, whereas QDcetuximab was toxic at 100µg ml-1 after 24 hours in PANC-1 and at 10µg ml-1 in CFPAC^-1. Fixed immunofluorescence demonstrated EGFR targeting by QD-cetuximab at concentrations of 50μg ml^-1 upwards in both cell lines. Live staining demonstrated similar efficacy of EGFR targeting up to 50μg ml^-1, although a reduction of fluorescence at higher concentrations was observed when compared to fixed immunofluorescence. Conclusion: Silver sulphide QD-cetuximab nanoconjugates have the potential to target live EGFR-positive pancreatic cancer cells at doses of up to 50 μg ml^-1 . The reduction in QD fluorescence observed at higher concentrations is likely to be secondary to cetuximab toxicity.

Proceedings Article | 7 August 2019 Presentation + Paper

5-aminolevulinic acid as a potential contrast agent for image-guided surgery in pancreatic cancer

Peter Labib, Elnaz Yaghini, Brian Davidson, Alexander MacRobert, Stephen Pereira

Proceedings Volume 11070, 110704R (2019) https://doi.org/10.1117/12.2525084

KEYWORDS: Fluorescent markers, Luminescence, Pancreatic cancer, Surgery, Image-guided intervention, Tissues, Cancer

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Introduction: Pancreatic cancer often recurs following surgery suggesting new operative approaches are required. Fluorescence-guided surgery aims to assist surgeons in identifying tumour intraoperatively to facilitate complete resection. However, the ideal contrast agent for this purpose is not yet determined. The Rose criterion states that accurate imageguided surgery requires a Tumour-to-Background Ratio of contrast agent greater than 5. We investigated the potential of 5-aminolevulinic acid (ALA) for this purpose. Methods: Pancreatic cancer cell lines CFPAC-1 and PANC-1 were compared with the control pancreatic ductal cell line H6c7. Cells were seeded on day 1 and fluorescence measured on day 4 following 4, 8, 24 or 48 hours incubation with 0.25, 0.50, 0.75 or 1.00mM ALA. Fluorescence was measured using a plate reader and microscopy. Results: The maximum ALA-induced fluorescence for CFPAC-1 and PANC-1 was achieved after 48 hours incubation with 0.50mM ALA. Compared to cells incubated without ALA, a relative fluorescence increase of 39.4-fold in CFPAC-1 and 2.7-fold in PANC-1 was seen. ALA concentrations above 0.50mM did not result in higher fluorescence. In contrast, the control cell line H6c7 showed progressively increasing fluorescence with increasing ALA concentrations. The highest cancer/control cell fluorescence ratios for ALA were after 48 hours incubation with 0.25mM ALA; 122.9 in CFPAC-1 and 9.7 in PANC-1. Conclusion: ALA-induced fluorescence in CFPAC-1 is significantly higher than the control cell line H6c7. PANC-1 achieved only mildly increased fluorescence compared to H6c7. ALA has the potential to provide an adequate level of fluorescence for image-guided pancreatic surgery in ALA-susceptible cancers.

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