Optimizing singlet oxygen dosimetry for photodynamic therapy (PDT)

光动力学疗法（PDT）中单线态氧剂量测定的优化 摘要 本项目的总体目标是通过三种方法优化临床单线态氧（1 O2）剂量学（SOD） 互补和竞争技术：时间分辨单线态氧发光剂量测定法（TSOLD）， 多光谱单线态氧发光剂量测定法（MSOLD）和单线态氧显式剂量测定法（SOED）。 TSOLD仪器基于光纤，通过红外时间相关技术实现超低噪声检测。 单光子计数可用于PDT前后测定细胞毒性1 O2浓度（[1 O2]） 基于其1270 nm的发光发射在肿瘤中产生，因为它利用短（ns）脉冲激光用于 1 O2激发，其独立于PDT治疗激光。最新研制的MSOLD仪器 测量由处理光激发的单线态氧的发光光谱，因此能够 在PDT期间监测[1 O2]而不干扰治疗。然而，与TSOLD不同，MSOLD可以 由于磷光背景数量级大于[1 O2]， 单线态氧信号。SOED仪器可以在PDT期间实时地在体内使用以测量反应的 基于光通量率、组织氧的显式测量， 浓度和光敏剂浓度。TSOLD或MSOLD信号将用作 SOED系统，使其更强大的占当地氧气微环境。在这里， 临床翻译是比较和确定三种技术的最合适组合， 通过在接受胸膜内PDT治疗恶性胸膜间皮瘤的患者的多个部位进行测量， 这在宾夕法尼亚大学的Photofrin介导的临床试验中显示出了巨大的潜力。此外，比较将 可在光敏剂溶液、组织模拟模型和体内肿瘤中制备， 在广泛的治疗条件下的条件。肿瘤缓解与1 O2的相关性 将在临床前评估三种临床光敏剂（Photofrin、BPD和ALA）的测量结果。 模型SOED仪器将在同一时间和地点使用，以计算“明确的”轻药物- 氧剂量参数以及组织光学特性。后者将用于校正测量的 光衰减的1 O2信号，以计算细胞毒性剂的绝对浓度。显式 剂量参数将在已建立的宏观生物物理模型中用作SOED的输入，以预测 瞬时和累积单线态氧浓度（[1 O2]）与TSOLD和MSOLD比较 结果分别。该项目的结果将是确定最佳组合 （TSOLD/MSOLD/SOED）在临床相关条件下进行的PDT间皮瘤临床试验中用于SOD 条件我们假设，定量SOD比定量SOD更能预测PDT的疗效。 目前使用的显式或隐式（基于光漂白的）技术。此外，我们假设， 优化的SOD系统将提供实时反馈，以便治疗可以个性化。

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.