MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
Biomaterials. 2015 Jul;56:140-53. doi: 10.1016/j.biomaterials.2015.04.002. Epub 2015 Apr 17.
Clinical acceptance of photodynamic therapy is currently hindered by poor depth efficacy and inefficient activation of the cell death machinery in cancer cells during treatment. To address these issues, photoactivation using two-photon absorption (TPA) is currently being examined. Mitochondria-targeted therapy represents a promising approach to target tumors selectively and may overcome the resistance in current anticancer therapies. Herein, four ruthenium(II) polypyridyl complexes (RuL1-RuL4) have been designed and developed to act as mitochondria-targeted two-photon photodynamic anticancer agents. These complexes exhibit very high singlet oxygen quantum yields in methanol (0.74-0.81), significant TPA cross sections (124-198 GM), remarkable mitochondrial accumulation, and deep penetration depth. Thus, RuL1-RuL4 were utilized as one-photon and two-photon absorbing photosensitizers in both monolayer cells and 3D multicellular spheroids (MCSs). These Ru(II) complexes were almost nontoxic towards cells and 3D MCSs in the dark and generate sufficient singlet oxygen under one- and two-photon irradiation to trigger cell death. Remarkably, RuL4 exhibited an IC50 value as low as 9.6 μM in one-photon PDT (λirr = 450 nm, 12 J cm(-2)) and 1.9 μM in two-photon PDT (λirr = 830 nm, 800 J cm(-2)) of 3D MCSs; moreover, RuL4 is an order of magnitude more toxic than cisplatin in the latter test system. The combination of mitochondria-targeting and two-photon activation provides a valuable paradigm to develop ruthenium(II) complexes for PDT applications.
光动力疗法的临床应用目前受到治疗过程中癌症细胞内死亡机制的深度疗效和效率低下的限制。为了解决这些问题，目前正在研究使用双光子吸收（TPA）进行光激活。线粒体靶向治疗代表了一种有前途的靶向肿瘤的方法，可能克服当前抗癌疗法中的耐药性。在此，设计和开发了四个钌（II）多吡啶配合物（RuL1-RuL4）作为线粒体靶向双光子光动力抗癌剂。这些配合物在甲醇中表现出非常高的单线态氧量子产率（0.74-0.81）、显著的 TPA 截面（124-198 GM）、显著的线粒体积累和深穿透深度。因此，RuL1-RuL4 被用作单层细胞和 3D 多细胞球体（MCSs）中的单光子和双光子吸收光敏剂。这些 Ru(II)配合物在黑暗中对细胞和 3D MCSs 几乎没有毒性，并且在单光子和双光子辐照下产生足够的单线态氧来触发细胞死亡。值得注意的是，RuL4 在单光子 PDT（λirr = 450nm，12J cm(-2)) 中对 3D MCS 的 IC50 值低至 9.6 μM，在双光子 PDT（λirr = 830nm，800 J cm(-2)) 中低至 1.9 μM；此外，RuL4 在后者的测试系统中比顺铂毒性高一个数量级。线粒体靶向和双光子激活的结合为开发用于 PDT 应用的钌（II）配合物提供了有价值的范例。
