Labib, Peter Lawrence Zaki;
(2023)
5-Aminolevulinic acid and silver sulphide quantum dots for biophotonic diagnostics in pancreatic cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Introduction: Up to 28% of patients with pancreatic ductal adenocarcinoma (PDAC) undergoing curative-intent surgery develop local recurrence at the operation site. New surgical methods to improve the likelihood of complete local resection are needed, and fluorescence-guided surgery (FGS) is one possible approach. This thesis investigated aminolevulinic acid (ALA), near-infrared (NIR) silver sulphide quantum dots (Ag2S QDs), QD-cetuximab and QD-ALA nanoconjugates as potential fluorescent contrast agents for FGS. / Methods: PDAC cell lines CFPAC-1 and PANC-1 and pancreatic ductal cell line H6c7 were incubated with increasing concentrations of ALA, QDs, QD-cetuximab and QD-ALA in vitro and underwent fluorescence microscopy and toxicity assays. ALA-induced red fluorescence was quantified with a plate reader and flow cytometry. Following incubation with dose equivalent QDs, QD-cetuximab, QD-ALA and ALA, red and NIR fluorescence was measured by flow cytometry. Signal-to-noise ratios (SNRs) were calculated using median fluorescence values of CFPAC-1/PANC-1 and H6c7. Expression of enzymes and transporters in the haem biosynthesis pathway pre- and post-ALA exposure was determined by quantitative polymerase chain reaction. / Results: ALA led to significant red fluorescence in CFPAC-1 but not PANC-1. CFPAC-1:Hc67 SNRs were >5, suggesting contrast enhancement of cancer cells adequate for effective FGS. Assessment of membrane transporters for the contrast agents demonstrated that CFPAC-1 expressed ALA influx transporter PEPT1. PANC-1 did not express PEPT1 and upregulated the porphyrin efflux transporter ABCG2 in response to ALA exposure. QDs were well tolerated at high concentrations and led to SNRs >5 in PANC-1 but not CFPAC-1. QD-cetuximab demonstrated significant cytotoxicity, negatively impacting cellular uptake. QD-ALA enhanced QD uptake in CFPAC-1 but had highest uptake in H6c7, resulting in low SNRs. / Conclusion: ALA and Ag2S QDs can generate high SNRs in susceptible PDAC and should be further investigated for use in FGS. Functionalised QD nanoconjugates require further modification in vitro prior to clinical translation.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | 5-Aminolevulinic acid and silver sulphide quantum dots for biophotonic diagnostics in pancreatic cancer |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Pancreatic cancer, Fluorescence guided surgery, Biophotonics, Aminolevulinic acid, Quantum dots |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10171305 |
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