Martinez De Pinillos Bayona, A; (2016) Light-based therapies in prostate cancer treatment. Doctoral thesis , UCL (University College London).

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Abstract

Photodynamic Therapy (PDT) and Photochemical Internalisation (PCI) are both light-based therapies which can be used for the focal treatment of cancer. Both PDT and PCI require the combination of photosensitisers, light and molecular oxygen to induce photooxidative reactions that damage biomolecules. However, while PDT employs a photosensitiser as the sole therapeutic agent, PCI combines low-dose PDT with another therapeutic agent to enable the improved delivery of this agent to its intended subcellular targets. The overall aim of this study was to investigate PDT and PCI for prostate cancer in both in vitro and in vivo tumour models. In the PCI procedures, the ribosome inactivating protein type 1 saporin was used as a model chemotherapy agent. We have concluded an enhancement in cell killing in prostate carcinoma cells after PCI compared to PDT in 2-dimensional models, i.e. 80% cell death, compared to 32% killing after PDT. Similar observations resulted from qualitative observations in the 3-dimensional model. Moreover, conjugation of a photosensitiser to cell penetrating peptides (TAT or Antp), resulted in a similar difference in cytotoxicity after PCI and PDT using lower concentrations of the conjugates - 76% and 14% respectively. These data confirm the synergistic effect of drug and photosensitiser in PCI. Three different clinically relevant photosensitisers were used in vivo in a subcutaneous rat model. Vascular-targeted PDT resulted in the most efficient treatment, and photosensitisers targeting a cellular effect, showed a better outcome with shorter drug-light intervals. The analysis of tumour samples through immunohistochemistry and molecular analysis revealed an innate inflammatory response that led to an adaptive immune response. A highly suppressive tumour microenvironment was suggested by the infiltration of regulatory T cells (FoxP3+), up-regulation of PD-L1 and down-regulation of cytolytic proteins (i.e. Perforin). Moreover, the beneficial effect of using immunoadjuvants (cyclophosphamide) was investigated. Light based therapies could play an important role in prostate cancer treatment both eradicating tumours and generating long-term immune protection against secondary tumour deposits.

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