Porphyrin and metalloporphyrin agents for the personalised treatment and imaging of cancers

Sandland, Jordan

Abstract

The improvement of cancer medicine by utilizing the approach of personalised medicine has been investigated, principally, through the combination of diagnostic imaging (PET imaging) with treatment modalities (radiotherapy). Radiotherapy is key to both curative and palliative care and can be administered as adjuvant or neoadjuvant therapy, with or without combination therapies. Over the last few decades, research has been carried out into “radiosensitizers” – molecules which enhance the effects of ionizing radiation. To date, the mechanism of action of porphyrin-based radiosensitizers is still disputed. In this thesis the mechanism of action has been probed by investigating the synthesis and biological evaluation of a small library of trans-A2-diphenylporphyrin-based radiosensitizers with the aims of improving the therapeutic effects of radiotherapy. A lead structure has been identified which contains the core motif of a porphine ring chelated to Cu(II) in the pyrrolic cavity, nitro groups in the 5- and 15-meso positions and hydrophilic aryl rings in the 10- and 20-meso positions of the porphine unit. This hydrophilic compound has been evaluated through clonogenic assays, FACS assays, comet assays, and immunofluorescence microscopy assays on HT-29 (p53 null) and HCT-116 (p53 WT) colorectal cancer cell lines. This porphyrin has been found to not only enhance the effects of ionizing radiation by a substantial margin, but also enhance the proportion of cells undergoing radiation-induced cell cycle arrest and increases the proportion of cells undergoing apoptosis as there mechanism of death. Using “click” chemistry, the radiosensitizer was conferred with a powerful imaging modality (PET imaging). The successful radiochemical synthesis of a conjugatable [18F] radiolabelled heterobifunctional prosthetic was optimised, and the “hot” conjugation procedure to yield the [18F] radiolabelled radiosensitizer was carried out.
Additionally, the field of dual-therapeutics has been investigated. The Ru(II) arene 1,3,5-triaza-7-phosphaadamantane (RAPTA) family of chemotherapeutics has recently emerged with several key advantages over the use of traditional Pt(II) therapeutics, including fewer off-target side effects and fewer mechanisms of resistance. To date, only a few examples of dual-therapeutic porphyrin-Ru(II) conjugates exist. A water-soluble cationic porphyrin-[Ru(η6-arene)(C2O4)PTA] conjugate which retains its exquisite photochemical properties has been successfully synthesised. This novel conjugate was found to be readily internalized by HT-29 (p53 null) cancer cells, and MTT assays found that this unique conjugate is 2.5 times more cytotoxic in the “dark” when compared to the RAPTA species alone, while still acting as a photodynamic sensitizer when irradiated with white light. We attribute the extra decrease in cell viability to the natural ability of the cationic porphyrin to be internalised by the cancer cells. Herein, this thesis focuses on the synthesis of porphyrins as theranostic radiosensitizers, and porphyrins as theranostic dual-therapeutics with in vitro biological evaluation carried out to determine their efficacy and mechanism of action.

Citation

Sandland, J. (2019). Porphyrin and metalloporphyrin agents for the personalised treatment and imaging of cancers. (Thesis). University of Hull. Retrieved from https://hull-repository.worktribe.com/output/4398472

• Thesis Type: Thesis
• Deposit Date: Sep 25, 2023
• Publicly Available Date: Sep 25, 2023
• Keywords: Chemistry
• Public URL: https://hull-repository.worktribe.com/output/4398472
• Additional Information: Department of Chemistry; The University of Hull
• Award Date: Sep 1, 2019