Spin–Orbit Charge‐Transfer Intersystem Crossing (ISC) in Compact Electron Donor–Acceptor Dyads: ISC Mechanism and Application as Novel and Potent Photodynamic Therapy Reagents

• Published in: Chemistry : a European journal 2020-01, Vol.26 (5), p.1091-1102
• Main Authors: Wang, Zhijia, Ivanov, Mikhail, Gao, Yuting, Bussotti, Laura, Foggi, Paolo, Zhang, Huimin, Russo, Nino, Dick, Bernhard, Zhao, Jianzhang, Di Donato, Mariangela, Mazzone, Gloria, Luo, Liang, Fedin, Matvey
• Format: Article
• Language: English
• Subjects: Absorption spectra; Absorption spectroscopy; Atomic energy levels; Biocompatible Materials - chemical synthesis; Biocompatible Materials - chemistry; Biocompatible Materials - pharmacology; Bodipy; Cell Survival - drug effects; Charge transfer; Chemistry; Drug Design; Electron paramagnetic resonance; electron spin polarization; Electron Spin Resonance Spectroscopy; Electrons; HeLa Cells; Humans; perylenes; Photodynamic therapy; Photosensitizing Agents - chemical synthesis; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; Phototoxicity; Polarity; Potential energy; Quantum Theory; Reagents; Singlet Oxygen - chemistry; Singlet Oxygen - metabolism; Solvents - chemistry; Spectrum analysis; Spin Labels; spin–orbital charge-transfer intersystem crossing (SOCT-ISC); Toxicity; Triplet state
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201904306

Spin–orbit charge‐transfer intersystem crossing (SOCT‐ISC) is useful for the preparation of heavy atom‐free triplet photosensitisers (PSs). Herein, a series of perylene‐Bodipy compact electron donor/acceptor dyads showing efficient SOCT‐ISC is prepared. The photophysical properties of the dyads were studied with steady‐state and time‐resolved spectroscopies. Efficient triplet state formation (quantum yield ΦT=60 %) was observed, with a triplet state lifetime (τT=436 μs) much longer than that accessed with the conventional heavy atom effect (τT=62 μs). The SOCT‐ISC mechanism was unambiguously confirmed by direct excitation of the charge transfer (CT) absorption band by using nanosecond transient absorption spectroscopy and time‐resolved electron paramagnetic resonance (TREPR) spectroscopy. The factors affecting the SOCT‐ISC efficiency include the geometry, the potential energy surface of the torsion, the spin density for the atoms of the linker, solvent polarity, and the energy matching of the 1CT/3LE states. Remarkably, these heavy atom‐free triplet PSs were demonstrated as a new type of efficient photodynamic therapy (PDT) reagents (phototoxicity, EC50=75 nm), with a negligible dark toxicity (EC50=78.1 μm) compared with the conventional heavy atom PSs (dark toxicity, EC50=6.0 μm, light toxicity, EC50=4.0 nm). This study provides in‐depth understanding of the SOCT‐ISC, unveils the design principles of triplet PSs based on SOCT‐ISC, and underlines their application as a new generation of potent PDT reagents. Heavy atom‐free triplet photosensitisers (BDP‐Perylene) with strong absorption of visible light, high intersystem crossing (ISC) efficiency (60 %) and super long triplet lifetime (437 μs) are reported. The ISC mechanism and design rationales of the spin–orbit charge‐transfer intersystem crossing (SOCT‐ISC) photosensitiser were studied. These novel photosensitisers are demonstrated as a potent, completely new type of PDT reagents, achieving significantly reduced undesired dark toxicity, in stark contrast to the conventional heavy atom‐containing triplet photosensitisers.