Zhu Timothy C, Kim Michele M, Liang Xing, Finlay Jarod C, Busch Theresa M
Department of Radiation Oncology, University of Pennsylvania, TRC 4W, 3400 Civic Center Blvd, Philadelphia, Pennsylvania 19104, United States.
Photonics Lasers Med. 2015 Feb;4(1):59-71. doi: 10.1515/plm-2014-0037.
Dosimetry of singlet oxygen (O) is of particular interest because it is the major cytotoxic agent causing biological effects for type-II photosensitizers during photodynamic therapy (PDT). An model to determine the singlet oxygen threshold dose, [O], for PDT was developed.
An radiation-induced fibrosarcoma (RIF) tumor mouse model was used to correlate the radius of necrosis to the calculation based on explicit PDT dosimetry of light fluence distribution, tissue optical properties, and photosensitizer concentrations. Inputs to the model include five photosensitizer-specific photochemical parameters along with [O]. Photosensitizer-specific model parameters were determined for benzoporphyrin derivative monoacid ring A (BPD) and compared with two other type-II photosensitizers, Photofrin and m-tetrahydroxyphenylchlorin (mTHPC) from the literature.
The mean values (standard deviation) of the [O] are approximately 0.56 (0.26) and 0.72 (0.21) mM (or 3.6×10 and 4.6×10 singlet oxygen per cell to reduce the cell survival to 1/e) for Photofrin and BPD, respectively, assuming that the fraction of generated singlet oxygen that interacts with the cell is 1. While the values for the photochemical parameters (ξ, σ, , β) used for BPD were preliminary and may need further refinement, there is reasonable confidence for the values of the singlet oxygen threshold doses.
In comparison, the [O] value derived from mouse study was reported to be 0.4 mM for mTHPC-PDT. However, the singlet oxygen required per cell is reported to be 9×10 per cell per 1/ fractional kill in an mTHPC-PDT study on a rat prostate cancer cell line (MLL cells) and is reported to be 7.9 mM for a multicell EMT6/Ro spheroid model for mTHPC-PDT. A theoretical analysis is provided to relate the number of singlet oxygen required per cell to reach cell killing of 1/ to singlet oxygen threshold dose (in mM). The sensitivity of threshold singlet oxygen dose for our experiment is examined. The possible influence of vascular vs. apoptotic cell killing mechanisms on the singlet oxygen threshold dose is discussed by comparing [O] for BPD with 3 hr and 15 min drug-light-intervals, with the later being known to have a dominantly vascular effect.
The experimental results of threshold singlet oxygen concentration in an RIF tumor model for Photofrin, BPD, and mTHPC are about 20 times smaller than those observed . These results are consistent with knowledge that factors other than singlet oxygen-mediated tumor cell killing can contribute to PDT damage .
单线态氧（O）的剂量测定尤为重要，因为它是光动力疗法（PDT）期间导致II型光敏剂产生生物学效应的主要细胞毒性剂。开发了一种用于确定PDT单线态氧阈值剂量[O]的模型。
使用辐射诱导的纤维肉瘤（RIF）肿瘤小鼠模型，将坏死半径与基于光通量分布、组织光学性质和光敏剂浓度的显式PDT剂量测定计算相关联。该模型的输入包括五个光敏剂特异性光化学参数以及[O]。确定了苯并卟啉衍生物单酸环A（BPD）的光敏剂特异性模型参数，并与文献中的其他两种II型光敏剂卟吩姆钠和间四羟基苯基氯卟啉（mTHPC）进行了比较。
假设与细胞相互作用的单线态氧生成分数为1，则卟吩姆钠和BPD的[O]平均值（标准差）分别约为0.56（0.26）和0.72（0.21）mM（或每细胞3.6×10和4.6×10个单线态氧以将细胞存活率降低至1/e）。虽然用于BPD的光化学参数（ξ、σ、、β）值是初步的，可能需要进一步完善，但单线态氧阈值剂量的值有合理的可信度。
相比之下，在小鼠研究中得出的mTHPC-PDT的[O]值据报道为0.4 mM。然而，在大鼠前列腺癌细胞系（MLL细胞）的mTHPC-PDT研究中，据报道每细胞每1/分数杀伤所需的单线态氧为9×10个/细胞，并且在mTHPC-PDT的多细胞EMT6/Ro球体模型中据报道为7.9 mM。提供了一种理论分析，以将每细胞达到1/细胞杀伤所需的单线态氧数量与单线态氧阈值剂量（以mM为单位）相关联。检查了我们实验中阈值单线态氧剂量的敏感性。通过比较BPD在3小时和15分钟药物-光间隔下的[O]，讨论了血管与凋亡细胞杀伤机制对单线态氧阈值剂量的可能影响，已知后者具有主要的血管效应。
在RIF肿瘤模型中，卟吩姆钠、BPD和mTHPC的阈值单线态氧浓度的实验结果比观察到的结果小约20倍。这些结果与以下认识一致，即除单线态氧介导的肿瘤细胞杀伤之外的因素也可导致PDT损伤。
