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

用于钌基光敏剂介导的术中光动力治疗的光学表面照射器光剂量测定

• 批准号: 10454364
• 负责人: GAL SHAFIRSTEIN
• 金额: $ 18.19万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-20 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454364
• 关键词: A549; Ablation; Biodistribution; Biological Assay; Biomedical Engineering; Blood Vessels; Cancerous; Cell Survival; Chest; Clinical Research; Data; Devices; Diffuse; Disease; Dose; Dose-Rate; Drug usage; Effectiveness; FDA approved; Face; Fiber; Future; Hand; Hypoxia; Implant; In Vitro; Injections; Lasers; Light; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Manuals; Measures; Mediating; Movement; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Operative Surgical Procedures; Optics; Oxygen; Oxygen Consumption; PUVA Photochemotherapy; Patients; Phase; Photosensitivity; Photosensitizing Agents; Pleural; Prediction of Response to Therapy; Production; Prognosis; Rattus; Reaction; Reactive Oxygen Species; Reporting; Ruthenium; Singlet Oxygen; Source; Stat3 protein; Surface; Systemic Therapy; Tail; Testing; Thoracic cavity structure; Time; Tissues; Treatment Efficacy; Tumor Tissue; Variant; Veins; base; cancer cell; crosslink; improved; in vivo; intravenous administration; intravenous injection; light dosimetry; lung cancer cell; non-muscle invasive bladder cancer; novel; novel therapeutics; primary endpoint; response; safety testing; secondary endpoint; standard of care; surgery outcome; tumor

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.

概括 胸膜传播的非小细胞肺癌（NSCLC）患者面临可怕的预后。一些 临床研究报告说，在护理标准中添加术中光动力疗法（IO-PDT） 手术延长了NSCLC患者进行胸膜传播的生存。 IO-PDT已完成 通过使用手持激光源来激活通过静脉注射的光敏剂 治疗前24-48小时注射。光输送与光剂量率的广泛变化有关 （辐照）可能导致对IO-PDT的反应不一致。当前使用的静脉管理 光敏剂对光辐照度的变化非常敏感，并且与光敏度有关。 该建议旨在改善IO-PDT： •使用精确控制辐照度的光学表面涂抹器（OSA）。 •利用可以通过滴注来减少的安全有潜在的新型光敏剂（TLD1433） 手术期间和之后的光敏性，并在低氧气中以高辐照度激活 这将使治疗时间最小化并在一系列光辐照度中有效。 我们的总体假设是，在高辐照度下，OSA可以有效地激活IO-PDT的TLD1433 和低氧浓度。为了检验我们的假设，我们建议执行以下目的： 目的1。证明TLD1433介导的PDT在低氧浓度下高效，在 与FDA批准的光敏剂（PhotoFrin®）相比，体外。我们将研究体外反应 在不同的氧气浓度和一系列光线下，肺癌细胞和TLD1433-PDT和光蛋白-PDT 辐照度和通知（剂量）。主要终点将是细胞存活。次要终点将是PDT 诱导的光反应将通过信号换能器的程度和转录激活剂进行测量 3（STAT3）交联，一种通过单线氧的光动力学诱导的光电诱导的度量。 目的2。评估对TLD1433的响应，并在高辐照度上使用OSA，在体内，在 大鼠患有胸膜恶性肿瘤。我们将通过尾静脉注入来使用滴注或Photofrin®-PDT使用TLD1433-PDT 治疗植入实验大鼠肺中的A549-LUC肿瘤。主要终点将是PDT诱导的 可以使用磁共振成像（MRI）评估的肿瘤血管变化，可以使用 作为PDT的预测测量诱导消融和缺氧。次要终点将是消融的深度 肿瘤和正常组织中的缺氧水平，离体。 这项研究的这些结果将用于指导未来的研究，我们将测试 TLD1433在NSCLC治疗中介导的IO-PDT，并使用MRI预测通过 肿瘤脉管系统的变化。