Designing treatment individualization in photodynamic therapy to compensate for pharmacokinetic variability

The main theme of this thesis is to investigate the origins of photosensitizer pharmacokinetic variability, how this pharmacokinetic variation affects photodynamic therapy (PDT), and to search for innovative strategies to reduce the inter-individual pharmacokinetic variability and variability in treatment response. PDT involves photosensitizer administration and light irradiation to the tissue to be destroyed. With this inherent dual selectivity, PDT can have high inter-individual variability in response to treatment, due to the variation in photosensitizer uptake, delivered light dose, and tumor oxygenation. Although light irradiation dosimetry can be achieved to improve the treatment in clinical practice, inter-individual photosensitizer pharmacokinetic variability has not been optimized as extensively. The ability to individualize PDT treatment according individual photosensitizer pharmacokinetics has not yet been investigated. To address this issue in a mechanistic way this study focuses on the microscopic transport pathways of the drug. Both transvascular and interstitial transport processes have been characterized in the Dunning prostate MAT-LyLu tumor model using the drug verteporfin. The dominant factors determining macroscopic tumor uptake at two time points after drug administration have been identified. Correlation between verteporfin pharmacokinetics and PDT treatment efficacy has also been studied in this thesis such that a cause-effect relationship can be established connecting the photosensitizer microscopic transport process with its pharmacokinetics and treatment efficacy. Two strategies to reduce the inter-individual variability in response to PDT are then proposed. The first approach addresses the photosensitizer microscopic transport processes by modulating photosensitizer transport parameters such that an enhanced photosensitizer delivery can be achieved. The second approach utilizes photosensitizer dosimetry techniques to control the PDT light treatment. In both approaches, the interindividual variability in response to PDT was reduced. Thus, the study illustrates that a focused quantification of mechanisms of drug delivery combined with subject-specific changes can have a significant impact upon how to optimize therapy.