Singlet Oxygen Dosimetry For Pleural Photodynamic Therapy

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Doctor of Philosophy (PhD)
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Physics & Astronomy
photodynamic therapy
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Photodynamic therapy (PDT) is a promising treatment modality that involves visible light and a photosensitizer to form reactive cytotoxic species, such as singlet oxygen in the case of type II PDT. Dosimetry of PDT has shown to be challenging due to the complex interactions between the key components of PDT: light, photosensitizer, and oxygen. Existing methods of quantifying dose involve monitoring one or two of these quantities. In conventional clinical settings, PDT is prescribed by the light fluence rate (mW/cm^2) and total light fluence (J/cm^2). However, many additional factors influence the effective ``dose'' that is being delivered. Variations in photosensitizer uptake in tumors, tissue oxygenation, and light penetration in tissues of varying tissue optical properties affect the photodynamic efficiency. Using explicit dosimetry, reacted singlet oxygen is calculated based on the measured light fluence, photosensitizer concentration, and oxygen concentration. A macroscopic singlet oxygen model is used for explicit dosimetry, which involves various photochemical parameters. Relevant photochemical parameters for in vivo explicit dosimetry for a type II photosensitizer benzoporphyrin monoacid ring-A (BPD) were determined using a mouse model, and further validated using a study evaluating long term treatment outcome. Phantom studies were also performed to model the generation of singlet oxygen and compare it with direct measurements using singlet oxygen luminescence dosimetry (SOLD). Fluorescence spectroscopy methods were used to measure the drug concentration. Tissue optical properties were determined by measuring the light fluence and using the diffusion approximation for a point source at a fixed distance. Oxygenation was measured by using a phosphorescence-based probe to measure oxygen partial pressure. These in vivo and in-phantom models provide controlled environments where extensive explicit measurements can be performed to validate the model and recognize which aspects of explicit dosimetry are more critical to correctly correlate treatment outcome and the calculated dosimetric quantity. The light component of PDT dosimetry was investigated further in a clinical setting. Patients undergoing surgery for malignant pleural mesothelioma are treated with intraoperative PDT. The current treatment protocol for a clinical trial at the University of Pennsylvania involves monitoring light fluence at 8 discrete locations within the pleural cavity. Quantifying and planning treatment can be greatly improved by monitoring the light fluence throughout the entire treatment area in real-time. This work aims to provide details for singlet oxygen explicit dosimetry (SOED) to quantify the reacted singlet oxygen species during PDT in in vivo and in-phantom models. Furthermore, the light fluence modeling and calculation aspect of PDT dosimetry was developed and improved for an ongoing pleural PDT study at the University of Pennsylvania.

Timothy C. Zhu
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