Schneider Lukas, Kalt Martina, Koch Samuel, Sithamparanathan Shanmugi, Villiger Veronika, Mattiat Johann, Kradolfer Flavia, Slyshkina Ekaterina, Luber Sandra, Bonmarin Mathias, Maake Caroline, Spingler Bernhard
Department of Chemistry, University of Zurich, CH-8057 Zurich, Switzerland.
Institute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland.
J Am Chem Soc. 2023 Mar 1;145(8):4534-4544. doi: 10.1021/jacs.2c11650. Epub 2023 Feb 13.
Here, we report six novel, easily accessible BODIPY-based agents for cancer treatment. In contrast to established photodynamic therapy (PDT) agents, these BODIPY-based compounds show additional photothermal activity and their cytotoxicity is not dependent on the generation of reactive oxygen species (ROS). The agents show high photocytotoxicity upon irradiation with light and low dark toxicity in different cancer cell lines in 2D culture as well as in 3D multicellular tumor spheroids (MCTSs). The ratio of dark to light toxicity (phototoxic index, PI) of these agents reaches striking values exceeding 830,000 after irradiation with energetically low doses of light at 630 nm. The oxygen-dependent mechanism of action (MOA) of established photosensitizers (PSs) hampers effective clinical deployment of these agents. Under hypoxic conditions (0.2% O), which are known to limit the efficiency of conventional PSs in solid tumors, photocytotoxicity was induced at the same concentration levels, indicating an oxygen-independent photothermal MOA. With a PI exceeding 360,000 under hypoxic conditions, both PI values are the highest reported to date. We anticipate that small molecule agents with a photothermal MOA, such as the BODIPY-based compounds reported in this work, may overcome this barrier and provide a new avenue to cancer therapy.
在此，我们报告了六种新型的、易于获取的用于癌症治疗的基于硼二吡咯（BODIPY）的试剂。与已有的光动力疗法（PDT）试剂不同，这些基于BODIPY的化合物具有额外的光热活性，并且它们的细胞毒性不依赖于活性氧（ROS）的产生。这些试剂在二维培养的不同癌细胞系以及三维多细胞肿瘤球状体（MCTS）中，光照后显示出高光细胞毒性，黑暗中显示出低毒性。在用630 nm低能量剂量光照后，这些试剂的黑暗毒性与光照毒性之比（光毒性指数，PI）达到惊人的值，超过830,000。已有的光敏剂（PS）的氧依赖性作用机制（MOA）阻碍了这些试剂的有效临床应用。在已知会限制传统PS在实体瘤中效率的低氧条件（0.2% O）下，相同浓度水平时诱导了光细胞毒性，表明是一种不依赖氧的光热MOA。在低氧条件下PI超过360,000，这两个PI值都是迄今为止报道的最高值。我们预计，具有光热MOA的小分子试剂，如本文报道的基于BODIPY的化合物，可能会克服这一障碍，并为癌症治疗提供一条新途径。
