Department of Pharmaceutical Science & Technology, College of Chemistry and Biology, Donghua University, Shanghai, 201620, China.
Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička c. 54, 10000, Croatia.
Eur J Med Chem. 2019 Sep 1;177:144-152. doi: 10.1016/j.ejmech.2019.05.050. Epub 2019 May 18.
Effective photosensitizers are particularly important factor in clinical photodynamic therapy (PDT). However, there is a scarcity of photosensitizers for simultaneous cancer photo-diagnosis and targeted PDT. Herein, two novel dimethyl 2-(guanidinyl)ethylamino chlorin e photosensitizers were synthesized and their efficacy in PDT in A549 tumor was investigated. It was shown that compounds 3 and 4 have a long absorption wavelength in the near infrared region and strong fluorescence emission with slow photo-bleaching rate and markedly strong ability of O generation. They exhibited lower cytotoxicity and higher photo-cytotoxicity in vitro compared to the known anticancer drug m-THPC in MTT assay in A549 lung cancer cell lines. Compound 4 exhibit better inhibition effect than compound 3 and the IC value of compound 4 was 0.197 μM/L under 2 J/cm laser irradiation, while compound 3 showed better anti-tumor effects compared to compound 4 in vivo. Intracellular ROS generation was found to be responsible for apoptotic cell death in DCFDA assay. Subcellular localization confirmed the damage site of compounds 3 and 4 in PDT. These findings suggest that the two novel photosensitizers might serve as potential photosensitizers for improved therapeutic efficiency of PDT.
有效的光敏剂是临床光动力疗法（PDT）的一个特别重要的因素。然而，同时用于癌症光诊断和靶向 PDT 的光敏剂却很匮乏。在此，我们合成了两种新型二甲基 2-(胍基)乙基氨基氯代叶啉类光敏剂，并研究了它们在 A549 肿瘤 PDT 中的疗效。结果表明，化合物 3 和 4 在近红外区域具有较长的吸收波长和较强的荧光发射，具有较慢的光漂白率和明显较强的 O 生成能力。与已知的抗癌药物 m-THPC 相比，它们在 A549 肺癌细胞系的 MTT 测定中具有更低的细胞毒性和更高的光细胞毒性。化合物 4 的抑制效果优于化合物 3，在 2 J/cm 激光照射下，化合物 4 的 IC 值为 0.197 μM/L，而化合物 3 在体内表现出比化合物 4 更好的抗肿瘤效果。在 DCFDA 测定中发现细胞内 ROS 生成是导致细胞凋亡的原因。亚细胞定位证实了化合物 3 和 4 在 PDT 中的损伤部位。这些发现表明，这两种新型光敏剂可能作为提高 PDT 治疗效果的潜在光敏剂。
