Optimizing singlet oxygen dosimetry for photodynamic therapy (PDT)

优化光动力治疗 (PDT) 的单线态氧剂量测定

• 批准号: 10651654
• 负责人: Robert Hugh Hadfield
• 金额: $ 55.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651654
• 关键词: Aminolevulinic Acid; Calibration; Clinical; Clinical Research; Clinical Trials; Consumption; Coupled; Cytotoxic agent; Detection; Development; Dose; Feedback; Fiber Optics; Generations; Goals; Growth; Hematoxylin and Eosin Staining Method; In Situ; Indium; Lasers; Light; Location; Malignant Pleural Mesothelioma; Malignant mesothelioma; Measurement; Measures; Mediating; Mesothelioma; Modality; Modeling; Monitor; Mus; Noise; Operative Surgical Procedures; Optics; Outcome; Oxygen; PUVA Photochemotherapy; Patients; Performance; Pharmaceutical Preparations; Photobleaching; Photons; Photosensitizing Agents; Phototherapy; Physiologic pulse; Pleural photodynamic therapy; Porfimer Sodium; Pre-Clinical Model; Property; Radiation; Reaction; Signal Transduction; Singlet Oxygen; Site; Stains; System; Techniques; Technology; Temperature; Testing; Time; Tissues; Treatment Efficacy; Uncertainty; attenuation; biophysical model; clinical application; clinical translation; clinically relevant; curative treatments; cytotoxic; design; design and construction; detector; diffuse reflectance spectroscopy; dosimetry; fibrosarcoma; first-in-human; gallium arsenide; head-to-head comparison; improved; in vivo; indexing; individual patient; instrument; interstitial; luminescence; minimally invasive; nanowire; novel; optical fiber; performance tests; phosphorescence; photon-counting detector; pre-clinical; preclinical evaluation; preclinical study; prototype; public health relevance; quantum; response; singlet state; temporal measurement; tumor

Optimizing Singlet Oxygen Dosimetry for Photodynamic Therapy (PDT) Abstract The overall objective of this project is to optimize clinical singlet oxygen (1O2) dosimetry (SOD) via three complementary and competing technologies: time-resolved singlet oxygen luminescence dosimetry (TSOLD), multispectral singlet oxygen luminescence dosimetry (MSOLD), and singlet oxygen explicit dosimetry (SOED). The TSOLD instrument is optical fiber-based and achieves ultralow noise detection via infrared time-correlated single-photon counting. It can be used before and after PDT to measure cytotoxic 1O2 concentration ([1O2]) generation in tumor based on its 1270 nm luminescence emission, since it utilizes a short (ns) pulsed laser for 1O2 excitation that is independent of the PDT treatment laser. The recently developed MSOLD instrument measures the luminescence spectrum of singlet oxygen excited by the treatment light, it is thus capable of monitoring [1O2] during PDT without interfering with the treatment. However, unlike TSOLD, MSOLD may introduce additional uncertainty in [1O2] due to a phosphorescence background orders of magnitude larger than the singlet oxygen signal. The SOED instrument can be used in-vivo during PDT in real-time to measure reacted 1O2 generated by the treatment light based on explicit measurement of the light fluence rate, tissue oxygen concentration, and photosensitizer concentration. The TSOLD or MSOLD signals will be used as an input to the SOED system to make it more robust to account for the local oxygen microenvironment. Here, the immediate clinical translation is to compare and determine the most suitable combination of the three technologies for SOD by measurements at multiple sites in patients undergoing intrapleural PDT for malignant pleural mesothelioma, which has shown significant potential in Photofrin-mediated clinical trials at UPenn. In addition, comparison will be made in photosensitizer solutions, tissue-simulating phantoms, and tumors in vivo under well-controlled conditions across a wide range of treatment conditions. Correlation of the tumor response with the1O2 measurements will be evaluated for three clinical photosensitizers (Photofrin, BPD, and ALA) in preclinical models. The SOED instrument will be used at the same time and locations to calculate the “explicit” light-drug- oxygen dose parameters as well as the tissue optical properties. The latter will be used to correct the measured 1O2 signal for light attenuation in order to calculate, the absolute concentration of the cytotoxic agent. The explicit dose parameters will be used as inputs for SOED in an established macroscopic biophysical model to predict the instantaneous and cumulative singlet oxygen concentration ([1O2]) for comparison with TSOLD and MSOLD results, respectively. The outcome of this project will be the determination of the optimal combination (TSOLD/MSOLD/SOED) for SOD in an ongoing PDT mesothelioma clinical trial under clinically-relevant conditions. We hypothesize that quantitative SOD will be significantly more predictive of PDT efficacy than the explicit or implicit (photobleaching-based) techniques used at present. Moreover, we hypothesize that the optimized SOD system will give real-time feedback so that treatment can be personalized.

优化用于光动力疗法（PDT）的单线氧气测定法 抽象的 该项目的总体目的是通过三个优化临床单重氧（1O2）剂量法（SOD） 互补和竞争技术：时间分辨的单氧发光剂量法（tsold）， 多光谱单氧发光剂量法（MSOLD）和单氧显式剂量法（SOED）。 TSOLD仪器是基于光纤的，并通过红外时与时间相关实现超低噪声检测 单光子计数。可以在PDT之前和之后使用它来测量细胞毒性1O2浓度（[[1O2]） 基于其1270 nm发光发射的肿瘤生成，因为它利用了短（NS）脉冲激光器 与PDT治疗激光器无关的1O2兴奋。最近开发的MSOLD仪器 测量通过处理光激发的单氧的发光光谱，因此能够 在PDT期间监测[1O2]，而无需干扰治疗。但是，与Tsold不同，MSOLD可能 由于磷光背景的数量级大于比[1O2]引入其他不确定性 单线氧信号。 SOED仪器可在PDT期间实时使用Vivo，以测量反应 1O2是由治疗灯基于明确测量光通量速率，组织氧气产生的 浓度和光敏剂浓度。 TSOLD或MSOLD信号将用作输入 SOED系统可以使局部氧气微环境更加强大。在这里，即时 临床翻译是要比较和确定SOD的三种技术的最合适组合 通过在接受胸膜内PDT的患者的多个部位进行测量，用于恶性胸膜间皮瘤， 这在UPENN的光蛋白介导的临床试验中表现出了巨大的潜力。另外，比较将 在光敏剂溶液，拟曲的幻象和体内肿瘤中制成 各种治疗条件的条件。肿瘤反应与1O2的相关性 将对临床前的三个临床光敏剂（Photofrin，bpd和ala）评估测量值 型号。 SOED仪器将在同一时间和位置使用来计算“明确”的光毒。 氧剂量参数以及组织光学特性。后者将用于纠正测量 1O2信号用于光衰减以计算，是细胞毒性剂的绝对浓度。显式 剂量参数将用作已建立的宏观生物物理模型中SO的输入，以预测 瞬时和累积的单线氧浓度（[1O2]），用于与Tsold和Msold进行比较 结果分别。该项目的结果将是确定最佳组合 在正在进行的PDT间皮瘤临床试验中，（tsold/msold/soed）在临床上与临床相关的临床试验中进行SOD 状况。我们假设定量SOD比PDT效率更明显地预测 目前使用的显式或隐式（基于光漂白的）技术。而且，我们假设 优化的SOD系统将提供实时反馈，以便可以个性化处理。