Theoretical Study of Iridium-based PDT Photosensitizers for Improving Two-Photon Absorption, Triplet Lifetime and Lipophilicity through Ligand Tuning

TL;DR

This theoretical study explores how ligand modifications in iridium-based photosensitizers can enhance their two-photon absorption, triplet lifetime, and lipophilicity for improved photodynamic therapy applications.

Contribution

It introduces a ligand tuning strategy to optimize iridium complexes for better PDT efficacy, focusing on photophysical properties and biocompatibility.

Findings

Complexes a2, b2, and b1-r show high TPA cross-sections and long triplet lifetimes.

Asymmetric ligand modifications improve photosensitization performance.

b1-r complex can utilize both Type I and Type II PDT mechanisms.

Abstract

Iridium-based photosensitizers have attracted significant attention in photodynamic therapy (PDT) due to their exceptional photophysical properties and chemical stability, as well as tunable phosphorescence emission spectrum and high triplet state production yields. Photosensitizers with large two-photon absorption (TPA) and mitochondrial targeting capabilities are particularly promising for clinical PDT, as they enable deeper tissue penetration and reduced damage to normal cells. In this study, we theoretically studied photophysical, photodynamic properties and photosensitization reaction mechanism of a series of iridium-based photosensitizers with modified C^N and N^N ligands (a2-a6, b1/b1-r and b2/b2-r) by TDDFT/DFT methods. The photophysical properties, including one- and two-photon absorption spectra, frontier molecular orbitals, and singlet and triplet excitation energies, were calculated. Additionally, rate constants for intersystem crossing, fluorescence, and phosphorescence, along with water solubility and lipophilicity metrics (logP), were determined to assess both efficacy and biocompatibility. The results elucidate the modulation roles of the chelated ligands and ancillary ligands in TP-PDT efficiency, indicating that the asymmetric iso-fused-benzene ring modification to the N^N ligand is a robust design strategy for comprehensively enhancing photosensitization performance. Complexes a2, b2 and b1-r show greater promise as candidates for two-photon PDT photosensitizers, owing to their large TPA cross-sections, extended triplet state lifetimes, and balanced water solubility and lipophilicity. Notably, the b1-r complex can undergo both Type I and Type II PDT photosensitization mechanisms, which will help address the issue of drug resistance arising from the hypoxic environment in deep-seated tumors.