Quasi-intrinsic cytosine analogues for two-photon photodynamic therapy with Type I/II mechanism

Abstract

Two-photon photodynamic therapy (TP-PDT) provides a broad prospect for cancer treatment due to its deep penetration, minimal invasiveness and fewer side effects. In this work, a series of quasi-intrinsic photosensitizers (PSs) are proposed for TP-PDT based on the cytosine. To ensure the efficient intersystem crossing rates and strong absorption within the therapeutic window (600–900 nm), the ring-expansion and substitution of F and Cl halogen atoms are considered. Our calculations revealed that these C-analogues could maintain the fundamental pyrimidine skeleton with inherently planarity and possess relatively low logP values contributing to their enhanced cancer cell-targeting capability. More importantly, the modifications could bring significant red-shifted one-photon absorption and enlarged two-photon absorption cross-section that responsible for selective excitation during PDT. Following the vertical photoexcitation, the population in the long-lived triplet state are characterized by examining the deactivation rates and the corresponding decay lifetime. Additionally, the generation of reactive oxygen species for PDT is confirmed through calculations of ionization potential as well as electron affinity (type I mechanism), and the T₁ energy (type II mechanism). Besides, the effects of base pairing on photosensitivity are investigated to evaluate the usefulness of proposed PSs in TP-PDT. These nucleobase derivatives are expected to contribute broader advancement of PDT and provide theoretical clues for enhancing cancer treatment efficacy with reduced cytotoxicity and improved biocompatibility.