Highly Charged Ruthenium(II) Polypyridyl Complexes as Lysosome-Localized Photosensitizers for Two-Photon Photodynamic Therapy.

Photodynamic therapy (PDT) is a noninvasive medical technique that has received increasing attention over the last years and been applied for the treatment of certain types of cancer. However, the currently clinically used PDT agents have several limitations, such as low water solubility, poor photostability, and limited selectivity towards cancer cells, aside from having very low two-photon cross-sections around 800 nm, which limits their potential use in TP-PDT. To tackle these drawbacks, three highly positively charged ruthenium(II) polypyridyl complexes were synthesized. These complexes selectively localize in the lysosomes, an ideal localization for PDT purposes. One of these complexes showed an impressive phototoxicity index upon irradiation at 800 nm in 3D HeLa multicellular tumor spheroids and thus holds great promise for applications in two-photon photodynamic therapy.

Huang H ，Yu B ，Zhang P ，Huang J ，Chen Y ，Gasser G ，Ji L ，Chao H ... -  《-》

Critical Overview of the Use of Ru(II) Polypyridyl Complexes as Photosensitizers in One-Photon and Two-Photon Photodynamic Therapy.

Heinemann F ，Karges J ，Gasser G 《-》

Ruthenium(II) polypyridyl complexes as mitochondria-targeted two-photon photodynamic anticancer agents.

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.

Liu J ，Chen Y ，Li G ，Zhang P ，Jin C ，Zeng L ，Ji L ，Chao H ... -  《-》

Evaluation of the Medicinal Potential of Two Ruthenium(II) Polypyridine Complexes as One- and Two-Photon Photodynamic Therapy Photosensitizers.

Two [Ru(phen)2 dppz]2+ derivatives (phen=1,10-phenantroline, dppz=dipyrido[3,2-a:2',3'-c]phenazine) with different functional groups on the dppz ligand [dppz-7,8-(OMe)2 (1), dppz-7,8-(OH)2 (2)] have been synthesized, characterized and investigated as photosensitizers (PSs) for photodynamic therapy (PDT) against cancer. Both complexes showed intense red phosphorescence and promising singlet oxygen (1 O2 ) quantum yields of 75 % (1) and 54 % (2) in acetonitrile. Complex 1 (logPo/w =-0.52, 2.4 nmol Ru per mg protein) was found to be more lipophilic, having also a higher cellular uptake efficiency compared to 2 (logPo/w =-0.20, 0.9 nmol Ru per mg protein). Complex 1 localized evenly in HeLa cells whereas 2, was mainly visualized in the cell membrane by confocal microscopy. In the dark, complex 1 (IC50 =36.5 μm) was found to be more toxic than complex 2 (IC50 >100 μm) on a HeLa cells monolayer. Importantly, in view of PDT applications, both complexes were found to be non-toxic in the dark towards multicellular HeLa spheroids (IC50 >100 μm). Upon one-photon irradiation (420 nm, 9.27 J cm-2 ), 1 exhibited higher phototoxicity (IC50 =3.1 μm) than 2 (IC50 =16.7 μm) on HeLa cell monolayers. When two-photon irradiation (800 nm, 9.90 J cm-2 ) was applied, only 1 (IC50 =9.5 μm) was found to be active toward HeLa spheroids. This study demonstrates that the functional group on the intercalative ligand has a strong influence on the cellular localization and anticancer activity of RuII polypyridyl complexes.

Hess J ，Huang H ，Kaiser A ，Pierroz V ，Blacque O ，Chao H ，Gasser G ... -  《-》

The stepwise photodamage of organelles by two-photon luminescent ruthenium(ii) photosensitizers.

Qiu K ，Wen Y ，Ouyang C ，Liao X ，Liu C ，Rees TW ，Zhang Q ，Ji L ，Chao H ... -  《-》