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Photochemotherapeutic Properties of a Linear Tetrapyrrole Palladium(II) Complex displaying an Exceptionally High Phototoxicity Index
Inorganic Chemistry ( IF 4.3 ) Pub Date : 2018-08-22 00:00:00 , DOI: 10.1021/acs.inorgchem.8b01225 Andrea M. Potocny , Rachel S. Riley , Rachel K. O’Sullivan , Emily S. Day 1 , Joel Rosenthal
Inorganic Chemistry ( IF 4.3 ) Pub Date : 2018-08-22 00:00:00 , DOI: 10.1021/acs.inorgchem.8b01225 Andrea M. Potocny , Rachel S. Riley , Rachel K. O’Sullivan , Emily S. Day 1 , Joel Rosenthal
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Photodynamic therapy (PDT) represents a minimally invasive and highly localized treatment strategy to ablate tumors with few side effects. In PDT, photosensitizers embedded within tumors are activated by light and undergo intersystem crossing, followed by energy transfer to molecular oxygen, resulting in the production of toxic singlet oxygen (1O2). Previously, we reported a robust, linear tetrapyrrole palladium(II) complex, Pd[DMBil1], characterized by its facile and modular synthesis, broad absorption profile, and efficient 1O2 quantum yield of ΦΔ = 0.8 in organic media. However, the insolubility of this porphyrinoid derivative in aqueous solution prevents its use under biologically relevant conditions. In this work, we report the synthesis of Pd[DMBil1]-PEG750, a water-soluble dimethylbiladiene derivative that is appended with a poly(ethylene) glycol (PEG) functionality. Characterization of this complex shows that this PEGylated biladiene architecture maintains the attractive photophysical properties of the parent complex under biologically relevant conditions. More specifically, the absorption profile of Pd[DMBil1]-PEG750 closely matches that of Pd[DMBil1] and obeys the Beer–Lambert Law, suggesting that the complex does not aggregate under biologically relevant conditions. Additionally, the emission spectrum of Pd[DMBil1]-PEG750 retains the fluorescence and phosphorescence features characteristic of Pd[DMBil1]. Importantly, the PEGylated photosensitizer generates 1O2 with ΦΔ = 0.57, which is well within the range to warrant interrogation as a potential PDT agent for treatment of cancer cells. The Pd[DMBil1]-PEG750 is biologically compatible, as it is taken up by MDA-MB-231 triple negative breast cancer (TNBC) cells and has an effective dose (ED50) of only 0.354 μM when exposed to λex > 500 nm light for 30 min. Impressively, the lethal dose (LD50) of Pd[DMBil1]-PEG750 without light exposure was measured to be 1.87 mM, leading to a remarkably high phototoxicity index of ∼5300, which is vastly superior to existing photosensitizers that form the basis for clinical PDT treatments. Finally, through flow cytometry experiments, we show that PDT with Pd[DMBil1]-PEG750 induces primarily apoptotic cell death in MDA-MB-231 cells. Overall these results demonstrate that Pd[DMBil1]-PEG750 is an easily prepared, biologically compatible, and well-tolerated photochemotherapeutic agent that can efficiently drive the photoinduced apoptotic death of TNBC cells.
中文翻译：
线性四吡咯钯（II）配合物表现出极高的光毒性指数的光化学治疗性质。
光动力疗法（PDT）代表了一种微创且高度局部化的治疗策略，可消融几乎没有副作用的肿瘤。在PDT中，嵌入在肿瘤中的光敏剂会被光激活并进行系统间交换，然后将能量转移到分子氧中，从而产生有毒的单线态氧（1 O 2）。先前，我们报道了一个强大，线性四吡咯钯（II）络合物，PD [DMBil1] ，其特征在于它的轻便和模块化合成，宽的吸收曲线，高效1 Ò 2 Φ的量子产率Δ= 0.8（在有机媒体中）。然而，该卟啉类衍生物在水溶液中的不溶性阻止了其在生物学相关条件下的使用。在这项工作中，我们报告了Pd [DMBil1] -PEG 750的合成，Pd [DMBil1] -PEG 750是一种水溶性的二甲基双二烯衍生物，具有聚乙二醇（PEG）官能团。该复合物的表征表明，在生物学相关条件下，这种聚乙二醇化的二甲苯结构保持了母体复合物的诱人光物理性质。更具体地，该吸收曲线的Pd [DMBil1] -PEG 750紧密匹配的PD [DMBil1]并遵守比尔-朗伯定律，表明该复合物在生物学相关条件下不会聚集。此外，发射光谱的Pd [DMBil1] -PEG 750保留了荧光和磷光的功能特性的Pd [DMBil1] 。重要的是，聚乙二醇化的光敏剂产生1 ö 2与Φ Δ = 0.57，这是还有一个潜在的PDT试剂用于治疗癌细胞的范围，以令询问内。在PD [DMBil1] -PEG 750是生物相容的，因为它是采取了由MDA-MB-231三阴性乳腺癌（TNBC）细胞，并且具有的有效剂量（ED 50仅0.354μM的）当暴露于λ例如> 500 nm光线持续30分钟。令人印象深刻的是，未曝光的Pd [DMBil1] -PEG 750的致死剂量（LD 50）为1.87 mM，导致高达5300的极高的光毒性指数，大大优于现有的光敏剂，该光敏剂是临床PDT治疗。最后，通过流式细胞仪实验，我们显示Pd [DMBil1] -PEG 750的PDT主要诱导MDA-MB-231细胞凋亡。总体而言，这些结果表明，Pd [DMBil1] -PEG 750是一种易于制备，生物相容且耐受良好的光化学治疗剂，可以有效地驱动TNBC细胞的光诱导凋亡。
更新日期：2018-08-22
中文翻译：
线性四吡咯钯（II）配合物表现出极高的光毒性指数的光化学治疗性质。
光动力疗法（PDT）代表了一种微创且高度局部化的治疗策略，可消融几乎没有副作用的肿瘤。在PDT中，嵌入在肿瘤中的光敏剂会被光激活并进行系统间交换，然后将能量转移到分子氧中，从而产生有毒的单线态氧（1 O 2）。先前，我们报道了一个强大，线性四吡咯钯（II）络合物，PD [DMBil1] ，其特征在于它的轻便和模块化合成，宽的吸收曲线，高效1 Ò 2 Φ的量子产率Δ= 0.8（在有机媒体中）。然而，该卟啉类衍生物在水溶液中的不溶性阻止了其在生物学相关条件下的使用。在这项工作中，我们报告了Pd [DMBil1] -PEG 750的合成，Pd [DMBil1] -PEG 750是一种水溶性的二甲基双二烯衍生物，具有聚乙二醇（PEG）官能团。该复合物的表征表明，在生物学相关条件下，这种聚乙二醇化的二甲苯结构保持了母体复合物的诱人光物理性质。更具体地，该吸收曲线的Pd [DMBil1] -PEG 750紧密匹配的PD [DMBil1]并遵守比尔-朗伯定律，表明该复合物在生物学相关条件下不会聚集。此外，发射光谱的Pd [DMBil1] -PEG 750保留了荧光和磷光的功能特性的Pd [DMBil1] 。重要的是，聚乙二醇化的光敏剂产生1 ö 2与Φ Δ = 0.57，这是还有一个潜在的PDT试剂用于治疗癌细胞的范围，以令询问内。在PD [DMBil1] -PEG 750是生物相容的，因为它是采取了由MDA-MB-231三阴性乳腺癌（TNBC）细胞，并且具有的有效剂量（ED 50仅0.354μM的）当暴露于λ例如> 500 nm光线持续30分钟。令人印象深刻的是，未曝光的Pd [DMBil1] -PEG 750的致死剂量（LD 50）为1.87 mM，导致高达5300的极高的光毒性指数，大大优于现有的光敏剂，该光敏剂是临床PDT治疗。最后，通过流式细胞仪实验，我们显示Pd [DMBil1] -PEG 750的PDT主要诱导MDA-MB-231细胞凋亡。总体而言，这些结果表明，Pd [DMBil1] -PEG 750是一种易于制备，生物相容且耐受良好的光化学治疗剂，可以有效地驱动TNBC细胞的光诱导凋亡。
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