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

Abstract

Abstract 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 O 2 ) quantum yields of 75 % ( 1 ) and 54 % ( 2 ) in acetonitrile. Complex 1 (log P o/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 (log P o/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 (IC 50 =36.5 μ m ) was found to be more toxic than complex 2 (IC 50 >100 μ m ) 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 (IC 50 >100 μ m ). Upon one‐photon irradiation (420 nm, 9.27 J cm −2 ), 1 exhibited higher phototoxicity (IC 50 =3.1 μ m ) than 2 (IC 50 =16.7 μ m ) on HeLa cell monolayers. When two‐photon irradiation (800 nm, 9.90 J cm −2 ) was applied, only 1 (IC 50 =9.5 μ m ) 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 Ru II polypyridyl complexes.