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

基本信息

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
项目类别：
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

项目摘要

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.

概括患有胸膜播散的非小细胞肺癌（NSCLC）患者面临着可怕的预后。临床研究报告称，将术中光动力疗法 (IO-PDT) 添加到护理标准中手术延长了伴有胸膜播散的 NSCLC 患者的生存期。使用手持式激光光源激活通过静脉注射的光敏剂治疗前 24-48 小时注射与光剂量率的较大变化相关。（辐照度）可能导致 IO-PDT 响应不一致。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。 • 使用安全有效的新型光敏剂 (TLD1433)，可通过滴注方式给药，以减少手术期间和手术后的光敏性，并在低氧浓度的高辐照度下被激活这将最大限度地减少治疗时间，并在一系列光辐照度下有效。我们的总体假设是 OSA 可以在高辐照度下有效激活 TLD1433 进行 IO-PDT 为了检验我们的假设，我们建议实现以下目标：目标 1. 证明 TLD1433 介导的 PDT 在低氧浓度下高效与 FDA 批准的光敏剂 (Photofrin®) 进行比较，我们将研究体外反应。肺癌细胞在不同氧浓度和一系列光下对 TLD1433-PDT 和 Photofrin-PDT 的影响主要终点是细胞存活率，次要终点是 PDT。诱导的光反应，通过信号转导器和转录激活剂的程度来测量 3 (STAT3) 交联，通过单线态氧产生的光动力诱导光反应的指标。目标 2. 在体内、高辐照度下评估 TLD1433 介导的 IO-PDT 与 OSA 的反应患有胸膜恶性肿瘤的大鼠我们将通过滴注使用 TLD1433-PDT 或通过尾静脉注射使用 Photofrin®-PDT。治疗植入实验大鼠肺部的 A549-Luc 肿瘤的主要终点是 PDT 诱导。肿瘤血管分布的变化将通过磁共振成像（MRI）进行评估，可用于作为 PDT 引起消融和缺氧的预测指标，次要终点是消融深度。以及离体肿瘤和正常组织中的缺氧水平。这项研究的这些结果将用于指导未来的研究，我们将测试其安全性和有效性 TLD1433介导的IO-PDT治疗NSCLC，以及使用MRI通过以下方式预测治疗反应肿瘤血管系统的变化。