State Key Laboratory of Photocatalysis on Energy and Environment, Faculty of Chemistry, Fuzhou University, Fuzhou 350116, P.R. China.
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
Nanoscale. 2023 Feb 16;15(7):3230-3242. doi: 10.1039/d2nr05403e.
Chemoradiation therapy (CRT), which combines a chemotherapeutic drug with ionizing radiation (IR), is the most common cancer treatment. At the molecular level, the binding of Pt-drugs to DNA sensitizes cancer cells to IR, mostly by increasing the damage induced by secondary low-energy (0-20 eV) electrons (LEEs). We investigate such enhancements by binding terpyridine-platinum (Tpy-Pt) to supercoiled plasmid DNA. Fifteen nanometer thick films of Tpy-Pt-DNA complexes in a molar ratio of 5 : 1 were irradiated with monoenergetic electrons of 5 and 10 eV, which principally attach to the DNA bases to form transient anions (TAs) decaying into a multitude of bond-breaking channels. At both energies, the effective yields of crosslinks (CLs), base damage (BD) related CLs, single and double strand breaks (SSBs and DSBs), non-DSB-cluster lesions, loss of supercoiled configuration and base lesions are 6.5 ± 1.5, 8.8± 3.0, 88 ± 11, 5.3 ± 1.3, 9.6 ± 2.2, 106 ± 17, 189 ± 31 × 10 per electron per molecule, and 11.9 ± 2.6, 19.9 ± 4.4, 128 ± 18, 7.7 ± 3.0, 13.4 ± 3.9, 144 ± 19, 229 ± 42 × 10 per electron per molecule, respectively. DNA damage increased 1.2-4.2-fold due to Tpy-Pt, the highest being for BD-related CLs. These enhancements are slightly higher than those obtained by the conventional Pt-drugs cisplatin, carboplatin and oxaliplatin, apart from BD-related CLs, which are about 3 times higher. Enhancements are related to the strong perturbation of the DNA helix by Tpy-Pt, its high dipole moment and its favorable binding to guanine (G), all of which increase bond-breaking TA formation. In CRT, Tpy-Pt could considerably enhance crosslinking within genomic DNA and between DNA and other components of the nucleus, causing roadblocks to replication and transcription, particularly within telomeres, where it binds preferentially within G-quadruplexes.
化学辐射疗法（CRT），将化疗药物与电离辐射（IR）相结合，是最常见的癌症治疗方法。在分子水平上，铂类药物与 DNA 的结合使癌细胞对 IR 敏感，主要是通过增加由低能（0-20 eV）二次电子（LEEs）引起的损伤。我们通过将三吡啶-铂（Tpy-Pt）结合到超螺旋质粒 DNA 上来研究这种增强作用。摩尔比为 5：1 的 Tpy-Pt-DNA 复合物的 15 纳米厚膜用 5 和 10 eV 的单能电子照射，这些电子主要附着在 DNA 碱基上形成瞬态阴离子（TA），衰减成多种键断裂通道。在这两种能量下，交联（CL）、碱基损伤（BD）相关 CL、单链和双链断裂（SSB 和 DSB）、非 DSB-簇损伤、超螺旋构型丧失和碱基损伤的有效产率分别为 6.5±1.5、8.8±3.0、88±11、5.3±1.3、9.6±2.2、106±17、189±31×10/每电子/分子，以及 11.9±2.6、19.9±4.4、128±18、7.7±3.0、13.4±3.9、144±19、229±42×10/每电子/分子，分别。由于 Tpy-Pt，DNA 损伤增加了 1.2-4.2 倍，最高的是 BD 相关 CL。这些增强作用略高于传统铂类药物顺铂、卡铂和奥沙利铂，除了 BD 相关 CL 约高 3 倍。增强作用与 Tpy-Pt 对 DNA 螺旋的强烈扰动、其高偶极矩及其与鸟嘌呤（G）的良好结合有关，所有这些都增加了键断裂 TA 的形成。在 CRT 中，Tpy-Pt 可以在基因组 DNA 内以及 DNA 与核内其他成分之间显著增强交联，从而阻碍复制和转录，特别是在端粒内，它优先结合于 G-四链体。
