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

摘要 伴有胸膜播散的非小细胞肺癌(NSCLC)患者面临着可怕的预后。几个 临床研究报告加入术中光动力疗法(IO-PDT)的护理标准 手术延长了伴有胸膜播散的非小细胞肺癌患者的生存。IO-PDT完成 通过使用手持激光光源激活通过静脉给药的光敏剂 治疗前24-48小时注射。光传输与光剂量率的大范围变化有关 (辐照度)，这可能导致对IO-PDT的反应不一致。目前常用的静脉给药方法 光敏剂对光照度的变化非常敏感，并与光敏性有关。 该提案旨在通过以下方式改进IO-PDT： ·使用我们的光学表面涂布器(OSA)精确控制辐照度。 ·使用一种安全有效的新型光敏剂(TLD1433)，可以通过滴注给药来减少 手术中和术后的光敏性以及在高辐射和低氧浓度下被激活 这将最大限度地减少治疗时间，并在一定范围的光线照射下有效。 我们的总体假设是，在高辐射条件下，OSA可以有效地激活IO-PDT的TLD1433 和低氧浓度。为了验证我们的假设，我们建议实现以下目标： 目的：1.证明TLD1433介导的光动力疗法在低氧浓度下是高效的。 在体外，与FDA批准的光敏剂(Photofrin®)进行比较。我们将研究体外反应 不同氧浓度和一定光照条件下肺癌细胞对TLD1433-PDT和Photofrin-PDT的影响 辐照度和通量(剂量)。主要终点将是细胞存活。次要端点将是PDT 诱导的光反应将通过信号转导和转录激活子的程度来衡量 3(STAT3)交联，一种通过产生单线态氧来光动力学诱导光反应的指标。 目的：评价TLD1433介导的IO-PDT与OSA在体内、体内、外照射下的反应。 大鼠胸膜恶性病变。我们将使用TLD1433-PDT通过滴注或Photofrin®-PDT经尾静脉注射 目的：治疗实验性大鼠肺内移植瘤A549-Luc。主要终点将是PDT诱导的 肿瘤血管的变化将通过磁共振成像(MRI)进行评估，这可能会被使用 作为PDT诱导消融和缺氧的预测指标。次要终点将是消融深度 以及体外肿瘤和正常组织中的低氧水平。 这项研究的这些结果将用于指导未来的研究，在那里我们将测试 TLD1433介导的IO-PDT治疗非小细胞肺癌及其MRI预测疗效 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.