Barnett, Christopher Marc;
(2019)
Photochemical Internalisation to Improve the Therapeutic Indices of Chemotherapy Drugs and Nanoformulations.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Photochemical internalisation (PCI) is a novel, minimally-invasive, drug delivery technology that facilitates the delivery of therapeutic molecules into the cytosol of cells. Owing to PCI being initiated by light, treatment is confined to the specific area of illumination and adverse effects in distant tissues are therefore minimised. PCI can enhance the targeted intracellular delivery of therapeutics unable to penetrate cellular membranes and of those sequestered within endosomes and lysosomes whereby they are unable to exert their therapeutic potential. To date, PCI studies have predominantly used immunotoxins as the chemotherapeutic component with relatively few investigating the benefit of PCI in the delivery of clinically-approved small molecule chemotherapy drugs. Three-dimensional (3D) in vitro cell culture models of breast cancer (MDA-MB-231 and MCF-7 cells) and pancreatic cancer (MiaPaCa-2 cells) were used in this work. First, the performance of a range of chemotherapy drugs was tested in 3D breast cancer models with key parameters identified for subsequent use in light treatment experiments. PDT and PCI experiments were then performed and novel PCI-drug combinations compared to PCI of bleomycin (a model PCI chemotherapeutic drug). Excitingly, several promising new PCI-drug combinations were seen to outperform PCI-bleomycin. In particular, PCI-vincristine and PCI delivery of the vinca alkaloids, in general, was seen to perform impressively across all of the treatment outcomes of potency, efficacy, and synergy - as determined by means of a cell viability assay. Key PCI-drug combinations were then taken forward to investigations with alterations made in both PCI regimen and cell culture conditions. Both variations were seen to significantly impact upon PCI treatment outcomes. Finally, PCI-drug combinations were then tested in a 3D model of pancreatic cancer. In addition to this, novel gemcitabine nanoformulations (gemcitabine-squalene and gemcitabine-polymer) were combined in PCI regimens and the former bioconjugate was seen to vastly improve treatment outcomes in both pancreatic and breast cancer models.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Photochemical Internalisation to Improve the Therapeutic Indices of Chemotherapy Drugs and Nanoformulations |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices 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 Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10072636 |
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