Optical Surface Applicator Light Dosimetry for Ruthenium-based Photosensitizer Mediated Intraoperative Photodynamic Therapy

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SUMMARY Patients with non-small cell lung cancer (NSCLC) with pleural dissemination face a dire prognosis. Several clinical studies reported that adding intraoperative photodynamic therapy (IO-PDT) to the standard of care surgery prolonged the survival of patients with NSCLC with pleural dissemination. The IO-PDT is accomplished by using a hand-held laser light source to activate a photosensitizer that was administered via intravenous injection 24-48 h prior to treatment. The light delivery is associated with wide variation of light dose rate (irradiance) that can result in inconsistent response to IO-PDT. The intravenous administration of currently used photosensitizers are very sensitive to the variation in light irradiance and are associated with photosensitivity. This proposal aims to improve IO-PDT by: • Using our optical surface applicator (OSA) that precisely controls the irradiance. • Utilizing a safe and potent novel photosensitizer (TLD1433) that can be administered via instillation to reduce photosensitivity during and after surgery and be activated at high irradiance in low oxygen concentrations that will minimize treatment time and be effective in a range of light irradiances. Our overall hypothesis is that the OSA can effectively activate TLD1433 for IO-PDT at high irradiance and low oxygen concentration. To test our hypothesis, we propose to conduct the following aims: Aim 1. To demonstrate that TLD1433-mediated PDT is highly efficient at low oxygen concentration, in vitro, in comparison to the FDA approved photosensitizer (Photofrin®). We will study the in vitro response of lung cancer cells to TLD1433-PDT and Photofrin-PDT at different oxygen concentrations and a range of light irradiance and fluence (dose). The primary endpoint will be cell survival. The secondary endpoint will be the PDT induced photoreaction that will be measured by the degree of the signal transducer and activator of transcription 3 (STAT3) crosslinking, a metric for the photodynamically induced photoreaction via singlet oxygen production. Aim 2. To evaluate the response to TLD1433 mediated IO-PDT with OSA at high irradiance, in vivo, in rats with pleural malignancy. We will use TLD1433-PDT by instillation or Photofrin®-PDT via tail vein injection to treat A549-Luc tumors implanted in lung of experimental rats. The primary endpoint will be PDT induced changes in tumor vascularity that will be evaluated with magnetic resonance imaging (MRI), that could be used as predictive measure for PDT induce ablation and hypoxia. The secondary endpoint will be depth of ablation and hypoxia levels in tumor and normal tissue, ex vivo. These results from this study will be used to guide future studies, where we will test the safety and efficacy of TLD1433 mediated IO-PDT in the treatment of NSCLC, and the use of MRI to predict treatment response via changes in tumor vasculature.