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

总结 非小细胞肺癌（NSCLC）伴胸膜播散的患者面临着可怕的预后。几 临床研究报告，将术中光动力疗法（IO-PDT）添加到护理标准中， 手术可延长胸膜播散的NSCLC患者的生存期。IO-PDT已完成 通过使用手持式激光光源激活静脉注射的光敏剂 在治疗前24-48小时注射。光传输与光剂量率的广泛变化有关 这可能导致对IO-PDT的反应不一致。目前使用的静脉给药 光敏剂对光辐照度的变化非常敏感，并且与光敏性有关。 该提案旨在通过以下方式改进IO-PDT： ·使用我们的光学表面施加器（OSA），精确控制辐照度。 ·利用安全有效的新型光敏剂（TLD 1433），其可以通过滴注施用以减少 手术期间和手术后的光敏性，并在低氧浓度下的高辐照度下被激活 这将使治疗时间最小化并且在一定范围的光辐照度下有效。 我们的总体假设是，OSA可以有效地激活TLD 1433 IO-PDT在高辐照度 和低氧浓度。为了检验我们的假设，我们建议进行以下目标： 目标1。为了证明TLD 1433介导的PDT在低氧浓度下是高效的， 与FDA批准的光敏剂（Photofrin®）相比，我们将研究体外反应 肺癌细胞对TLD 1433-PDT和Photofrin-PDT在不同氧浓度和光照范围下的作用 辐照度和通量（剂量）。主要终点将是细胞存活。次要终点为PDT 诱导的光反应，将通过信号转导和转录激活因子的程度来测量 3（STAT 3）交联，通过单线态氧产生的光动力学诱导的光反应的度量。 目标二。为了评估在高辐照度下，在体内，在高辐照度下，在OSA中对TLD 1433介导的IO-PDT的响应， 胸膜恶性肿瘤大鼠。我们将通过滴注使用TLD 1433-PDT或通过尾静脉注射使用Photofrin®-PDT 治疗实验性大鼠肺内种植的A549-Luc肿瘤。主要终点为PDT诱导的 肿瘤血管分布的变化将通过磁共振成像（MRI）进行评估， 作为PDT诱导消融和缺氧的预测指标。次要终点为消融深度 以及离体肿瘤和正常组织中的缺氧水平。 本研究的这些结果将用于指导未来的研究，我们将在这些研究中测试 TLD 1433介导的IO-PDT治疗NSCLC，以及使用MRI预测治疗反应， 肿瘤血管的变化。

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.