The effect of some anticancer drugs can be severely reduced by entrapment of the drug molecules in intracellular acidic vesicles such as endosomes and lysosomes. Photochemical internalisation (PCI) is a novel technology for photochemical drug delivery where low doses of a photochemical treatment are employed to release entrapped drugs from such vesicles into the cytosol, from where they can reach their therapeutic target. This thesis discussed both the in vivo preclinical animal study and the first in human clinical trial of TPCS2a (Amphinex®) based PCI of bleomycin for treatment of patients with local recurrence or advanced/metastatic, cutaneous or subcutaneous malignancies. The preclinical in vivo experiments on Golden Syrian Hamsters investigated the bio-distribution of TPCS2a in normal and malignant oral tissues. The study was tested the selectivity of TPCS2a based PCI of bleomycin in the hamster cheek mucosa squamous cell carcinoma (SCC) model. The ratio of TPCS2a uptake in cancerous to normal tissue was 2:1 using fluorescence microscopy. Also, TPCS2a with PCI based bleomycin showed a selective necrotic effect on the cancerous tissues with a minor effect on the adjacent normal site, however this selectivity disappeared and tissue damage was observed on both cancerous and adjacent normal tissue when higher doses of TPCS2a or light were applied. The experiments concluded that PCI might be able to produce a selective therapeutic effect on cancer if appropriate drug and light doses used. Meanwhile, the first PCI clinical trial was undertaken to investigate the safety, pharmacokinetics (PK) of TPCS2a and the efficacy of treatment. No unexpected safety concerns were observed. The maximum tolerated dose (MTD) of TPCS2a was at 1 mg/kg. The maximum concentration of TPCS2a in blood was detected 30 minutes after administration. 0.25, 0.5, 1 and 1.5 mg/kg TPCS2a showed similar efficacy but the efficacy results of 0.125 mg/kg Amphinex® was not sufficient. This study was concluded that the treatment is safe with no reported major adverse events. The skin photosensitivity of the selected dose of TPCS2a (0.25 mg/kg) for phase II study was tolerable when the photosensitised skin was illuminated with 100.000 lux for 5 minutes. Although the study was too small to draw conclusions about the efficacy, these early results are promising and justify further studies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626846 |
| Date | January 2014 |
| Creators | Sultan, A. A. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1424414/ |
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