Yin Huimin, Stephenson Mat, Gibson Jordan, Sampson Eric, Shi Ge, Sainuddin Tariq, Monro Susan, McFarland Sherri A
Department of Chemistry, Acadia University , 6 University Avenue, Wolfville, Nova Scotia B4P 2R6, Canada.
Inorg Chem. 2014 May 5;53(9):4548-59. doi: 10.1021/ic5002368. Epub 2014 Apr 11.
The purpose of the present investigation was to ascertain whether (3)IL excited states with microsecond lifetimes are universally potent for photodynamic applications, and if these long-lived states are superior to their (3)MLCT counterparts as in vitro PDT agents. A family of blue-green absorbing, Ru(II)-based transition metal complexes derived from the π-expansive dppn ligand was prepared and characterized according to its photodynamic activity against HL-60 cells, and toward DNA in cell-free media. Complexes in this series that are characterized by low-energy and long-lived (3)IL excited states photocleaved DNA with blue, green, red, and near-IR light. This panchromatic photodynamic effect translated to in vitro multiwavelength photodynamic therapy (PDT) with red-light cytotoxicities as low as 1.5 μM (EC50) for the parent complex and 400 nM for its more lipophilic counterpart. This potency is similar to that achieved with Ru(II)-based dyads containing long-lived (3)IL excitons located on appended pyrenyl units, and appears to be a general property of sufficiently long-lived excited states. Moreover, the red PDT observed for certain members of this family was almost 5 times more potent than Photofrin with therapeutic indices 30 times greater. Related Ru(II) complexes having lowest-lying (3)MLCT states of much shorter duration (≤1 μs) did not yield DNA photodamage or in vitro PDT with red or near-IR light, nor did the corresponding Os(II) complex with a submicrosecond (3)IL excited state lifetime. Therefore, metal complexes that utilize highly photosensitizing (3)IL excited states, with suitably long lifetimes (≫ 1 μs), are well-poised to elicit PDT at wavelengths even where their molar extinction coefficients are very low (<100 M(-1) cm(-1)). Herein we demonstrate that such unexpected reactivity gives rise to very effective PDT in the typical therapeutic window (600-850 nm).
本研究的目的是确定具有微秒级寿命的（3）IL激发态是否在光动力应用中普遍具有强大作用，以及这些长寿命态作为体外光动力疗法（PDT）药物是否优于其（3）MLCT对应物。制备了一族基于π-扩展dppn配体的吸收蓝绿光的Ru（II）基过渡金属配合物，并根据其对HL-60细胞以及无细胞培养基中DNA的光动力活性进行了表征。该系列中以低能量和长寿命（3）IL激发态为特征的配合物，能用蓝光、绿光、红光和近红外光光裂解DNA。这种全色光动力效应转化为体外多波长光动力疗法（PDT），母体配合物的红光细胞毒性低至1.5 μM（EC50），其更具亲脂性的对应物为400 nM。这种效力与含有位于附加芘基单元上的长寿命（3）IL激子的Ru（II）基二元体系所达到的效力相似，并且似乎是足够长寿命激发态的一般特性。此外，该家族某些成员观察到的红光PDT效力几乎是血卟啉单甲醚的5倍，治疗指数大30倍。具有持续时间短得多（≤1 μs）的最低（3）MLCT态的相关Ru（II）配合物，在用红光或近红外光照射时不会产生DNA光损伤或体外PDT，具有亚微秒（3）IL激发态寿命的相应Os（II）配合物也不会。因此，利用具有适当长寿命（≫1 μs）的高度光敏（3）IL激发态的金属配合物，即使在其摩尔消光系数非常低（<100 M⁻¹ cm⁻¹）的波长下，也很适合引发PDT。在此我们证明，这种意想不到的反应性在典型治疗窗口（600 - 850 nm）中产生了非常有效的PDT。
