University of Ontario Institute of Technology, Faculty of Science, 2000 Simcoe Street North, Oshawa, ON L1G 0C5, Canada.
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210046, China.
Org Biomol Chem. 2022 Mar 30;20(13):2626-2635. doi: 10.1039/d1ob02468j.
Corrole molecules are a new generation of photosensitizers (PS) due to their ease of tunability for different medical applications. Their ability to initiate cellular death using a wide range of non-toxic wavelengths allows for the creation of non-invasive treatments. This work focuses on creating potent and non-invasive treatments by advancing siRNA therapeutics by directly conjugating siRNAs with the photosensitizer, corrole. Combining gene silencing with photodynamic therapy (PDT) creates a non-invasive dual therapy system. Basic synthetic designs were explored to create novel corrole-phosphoramidites and from these, a small library of corrole-functionalized short interfering RNAs (corrole-siRNAs) were synthesized. Corrole-siRNA conjugates showed promising results when evaluated for gene silencing and PDT therapy Gene silencing effects were evaluated in cells by measuring the knockdown activity of the luciferase reporter gene. Gene silencing studies from four siRNAs showed promising dose dependent knockdown with ICs of 387.8, 77.8, 60.0, and 49.4 pM in the absence of red light, and 101.0, 57.2, 55.3, and 23.8 pM in the presence of red light. Furthermore, PDT showed approximately a 50% decrease in cell viability for red-light irradiated cells treated with corrole-siRNAs, demonstrating the effective role of corrole to act as a photosensitizer while still maintaining robust siRNA activity. In conclusion, corrole-siRNAs show a promising path for developing novel siRNA combination therapy.
卟啉分子是新一代的光敏剂（PS），因为它们可以很容易地针对不同的医学应用进行调谐。它们能够在使用广泛的无毒波长范围内引发细胞死亡，从而可以创建非侵入性的治疗方法。这项工作通过直接将 siRNA 与光敏剂卟啉缀合，来推进 siRNA 治疗方法，从而专注于创建有效的非侵入性治疗方法。将基因沉默与光动力疗法（PDT）相结合，创建了一种非侵入性的双重治疗系统。探索了基本的合成设计，以创建新型的卟啉-磷酰胺和从这些中，合成了一小部分卟啉功能化的短干扰 RNA（卟啉-siRNA）。当评估基因沉默和 PDT 治疗时，卟啉-siRNA 缀合物显示出有希望的结果。通过测量荧光素酶报告基因的敲低活性来评估细胞中的基因沉默效果。四种 siRNA 的基因沉默研究表明，在没有红光的情况下，IC50 值分别为 387.8、77.8、60.0 和 49.4 pM，在有红光的情况下，IC50 值分别为 101.0、57.2、55.3 和 23.8 pM，具有有希望的剂量依赖性敲低。此外，PDT 显示，用卟啉-siRNA 处理的红光照射的细胞的细胞活力大约降低了 50%，证明了卟啉作为光敏剂的有效作用，同时仍然保持了强大的 siRNA 活性。总之，卟啉-siRNA 为开发新型 siRNA 联合治疗方法提供了有希望的途径。
