Innovative nanoparticles for the photodynamic therapy of lung cancer

Goddard, Zoe (2020) Innovative nanoparticles for the photodynamic therapy of lung cancer. Doctoral thesis, University of East Anglia.

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Abstract

Photodynamic therapy (PDT) involves the use of a photosensitiser drug which, when activated by visible light, causes the formation of cytotoxic singlet oxygen and subsequent cell death. Photosensitisers are hydrophobic and notoriously hard to deliver intravenously, but their attachment to gold nanoparticles has been found to overcome this issue. These nanoparticles can also be functionalised with directing ligands which can actively target the photosensitisers to lung cancers.

Herein, we investigate three classes of targeting moieties for the delivery of gold nanoparticles (AuNPs) functionalised with a zinc phthalocyanine photosensitiser (C11Pc) and polyethylene glycol (PEG) to lung cancers: peptides, antibodies and small molecules.

Two epidermal growth factor receptor (EGFR) targeting peptides were investigated as targeting moieties, with the composition of the peptide, coupling agents and solvent systems found to effect the singlet oxygen production and phototoxicity of the resulting nanoparticles. Excitingly, targeted phototoxicity was observed in EGFR overexpressing cell lines for one of these constructs, with 7% cell viability observed at 200 nM.

An investigation into the most efficient conjugation strategies for the addition of either an anti-EGFR or anti-HER2 antibody to C11Pc-PEG-AuNPs led to the exploration of both random chemical and protein based site-specific antibody conjugation. While no phototoxicity was observed, this led to the exploration of Fc binding peptides for site-specific antibody conjugation to gold nanoparticles.

Folic acid was investigated for the delivery of C11Pc-PEG-AuNPs to folate receptor alpha expressing lung cancers. Folic acid is a known quencher of singlet oxygen so steps towards a protease cleavable sequence were undertaken to allow for the cleavage of this directing ligand intracellularly, allowing for the switch on of the photodynamic activity in lung cancer cells.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Chris White
Date Deposited: 14 Apr 2021 08:54
Last Modified: 14 Apr 2021 08:54
URI: https://ueaeprints.uea.ac.uk/id/eprint/79735
DOI:

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