Spectroscopic techniques for photodynamic therapy dosimetry

Abstract: Photodynamic therapy (PDT) as a cancer treatment modality relies on the simultaneous presence of three components; light, photosensitiser and oxygen. Once excited by the light, the photosensitiser can interact with oxygen, leading to the formation of toxic oxygen species. These reactive substances induce cellular damage within the irradiated tissue volume. PDT has been investigated for treating malignancies in numerous organs and is nowadays an approved treatment modality for certain types of malignancies of, for example, the skin, lungs, bladder and oesophagus. However, PDT still suffers from several drawbacks. For example, many photosensitisers accumulate also in non-malignant tissue, introducing the risk of damaging surrounding, sensitive tissue. Another drawback is the large intra- and inter-patient variation in treatment response despite utilising standardised light and photosensitiser doses. In this thesis, two approaches have been investigated with the aim to overcome on the one hand, the sub-optimal tumour-selective uptake of the photosensitiser, and on the other, the variable treatment effects. For both tasks, spectroscopic techniques were employed to monitor parameters relevant to the PDT effect. The first project involved pharmacokinetic studies of a novel, liposomal photosensitiser formulation for both topical and intravenous administration. The topical application route led to good tumour-selective uptake both in an animal skin tumour model and in human skin malignancies. However, the clinical treatment conditions, such as photosensitiser application time, light and photosensitiser doses, need to be further optimised. Furthermore, following systemic administration in a murine tumour model, the pharmacokinetics of this novel formulation led to a rapid biodistribution and clearance from the blood stream. The tumour-to-skin and tumour-to-muscle selectivity at two to eight hours after photosensitiser administration were higher than reported for the free mTHPC formulation. The second approach aimed at implementing realtime treatment feedback for interstitial PDT. The first in a series of instruments incorporated six optical fibres for light delivery and monitoring of light transmission and photosensitiser fluorescence in the target tissue. Post-treatment data analysis indicated significant differences between the intended and actual light dose distributions. Hence, we concluded there is a need for treatment monitoring and feedback in order to ascertain delivery of a prescribed light dose to the entire target tissue. More recently, the hardware has been adapted to interstitial PDT on the human prostate. The number of source fibres has been increased to 18 and realtime feedback based on a light dose threshold model has been implemented. We can now present a clinical instrument for interstitial PDT on prostate tissue incorporating modules for pre-treatment planning, monitoring of the optical properties of the target tissue and updating irradiation times in realtime. This realtime feedback scheme has been evaluated for simulated treatment scenarios for which it was concluded that the realtime dosimetry module makes it possible to deliver a certain light dose to the target tissue despite spatial and temporal variations of the optical properties of the target tissue.