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Title: A mechanistic study of photochemical internalisation and enhanced drug delivery cancer cells
Author: Adigbli, D. K.
ISNI:       0000 0004 5364 8062
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Inefficient intracellular drug delivery is a significant limiting factor to success in cancer therapeutics. Photochemical internalisation (PCI) utilises the fundamental principles of photodynamic therapy (PDT): photosensitiser plus light and oxygen, at sub-lethal level to facilitate targeted intracellular drug delivery. This effect is mediated by reactive oxygen species (ROS). This thesis investigates the mechanisms underpinning sulfonated meso-tetraphenylporphine (TPPS2a) mediated PCI to enhance the delivery of two cytotoxins, saporin or mitoxantrone, and a novel Small Molecule Carrier (SMoC) in vitro. PCI of saporin was also assessed in a 3D-tumour model. In vitro experiments using 4T1 murine breast adenocarcinoma cells were performed to investigate which factors determined the likelihood of PDT versus PCI predominant cytotoxicity. The role of the intracellular REDOX environment in PDT/PCI was assessed using a free radical potentiator and quenchers. The results suggested that the localisation and total amount of ROS produced exerts the greatest influence in determining the likelihood of PDT versus PCI induced cell kill. In addition, PCI further enhanced SMoC-aided delivery of siRNA in MCF7 human breast cancer cells. A compressed collagen scaffold, embedded with 4T1 cells, was used to investigate TPPS2a-mediated PCI of saporin in a 3D tumour model. The results indicated that a 3D-model is potentially a useful tool for pre-clinical assessment of PCI. Bioluminescent PDT studies were also carried out on MCF7 cells transduced with luciferase and the 4T1-luc2 cell line, which is stably transfected with luciferase. These studies demonstrated that bioluminescence can be used to activate a photosensitiser for a cytotoxic effect (PDT). Overall, this thesis demonstrated that by further understanding the mechanisms that underpin PCI it is possible to further enhance its facilitative effects for drug delivery. The ongoing phase II clinical trials into PCI show its translational potential as a means to improve the therapeutic effectiveness of anti-cancer drugs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available