Charge Transfer-Promoted Excited State of a Heavy-Atom-Free Photosensitizer for Efficient Application of Mitochondria-Targeted Fluorescence Imaging and Hypoxia Photodynamic Therapy.

Conventional photosensitizers (PSs) used in photodynamic therapy (PDT) have shown preliminary success; however, they are often associated with several limitations including potential dark toxicity in healthy tissues, limited efficacy under acidic and hypoxic conditions, suboptimal fluorescence imaging capabilities, and nonspecific targeting during treatment. In response to these challenges, we developed a heavy-atom-free PS, denoted as Cz-SB, by incorporating ethyl carbazole into a thiophene-fused BODIPY core. A comprehensive investigation into the photophysical properties of Cz-SB was conducted through a synergistic approach involving experimental and computational investigations. The enhancement of intersystem crossing (kISC) and fluorescence emission (kfl) rate constants was achieved through a donor-acceptor pair-mediated charge transfer mechanism. Consequently, Cz-SB demonstrated remarkable efficiency in generating reactive oxygen species (ROS) under acidic and low-oxygen conditions, making it particularly effective for hypoxic cancer PDT. Furthermore, Cz-SB exhibited good biocompatibility, fluorescence imaging capabilities, and a high degree of localization within the mitochondria of living cells. We posit that Cz-SB holds substantial prospects as a versatile PS with innovative molecular design, representing a potential "one-for-all" solution in the realm of cancer phototheranostics.

Rational Molecular Design of Efficient Heavy-Atom-Free Photosensitizers for Cancer Photodynamic Therapy.

Photodynamic therapy has emerged as a promising modality for treatment of cancer due to its minimal invasiveness and high selectivity. However, development of advanced photosensitizers (PSs) for clinical translation of photodynamic therapy remains challenging. To overcome the limitations of common photosensitizers containing heavy atoms, we herein developed highly effective heavy-atom-free photosensitizers based on strong donor-π-acceptor-type structures (PTZ-CN and PXZ-CN) for bioimaging and photodynamic ablation of cancer. These PSs exhibited bright fluorescence emission with a large Stokes shift as well as considerable reactive oxygen generation capability under specific conditions. Notably, PTZ-CN could produce reactive oxygen species more efficiently than Ru(bpy)3 2+ (commercial PS) with an approximately 2.2-fold via type I and type II photochemical mechanisms. In addition, their stable nanoparticles were easily formed by self-assembly in an aqueous solution without employing a polymer. More importantly, PTZ-CN/PXZ-CN exhibited bright fluorescence and excellent photodynamic performance with negligible dark cytotoxicity toward HeLa cells. This study demonstrates the promising potential of donor-π-acceptor-type molecule-based PSs in fluorescence image-guided photodynamic therapy.

A coumarin-based reversible two-photon fluorescence probe for imaging glutathione near N-methyl-D-aspartate (NMDA) receptors.

Glutathione (GSH) is known to play a key role in the modulation of the redox environment in N-methyl-d-aspartate (NMDA) receptors. Coumarin derivative 1 bearing cyanoacrylamide and ifenprodil moieties was synthesized and reported to monitor GSH near NMDA receptors. The cyanoacrylamide moiety allows probe 1 to monitor GSH reversibly at pH 7.4 and the ifenprodil group acts as a directing group for NMDA receptors. Two-photon fluorescence microscopy allows probe 1 to successfully sense endogenous GSH in neuronal cells and hippocampal tissues with excitation at 750 nm. Furthermore, the addition of H2O2 and GSH induced a decrease and an increase in fluorescence emission. Probe 1 can serve as a potential practical imaging tool to get important information on GSH in the brain.

Simultaneous Detection of Hypochlorite and Singlet Oxygen by a Thiocoumarin-Based Ratiometric Fluorescent Probe.

The development of fluorescent probes derived from thiocarbonyl compounds for reactive oxygen species has been actively pursued in recent years. However, a better understanding of the optical response behaviors of thiocarbonyl compounds toward reactive oxygen species remains a challenge. Along with this, further studies to overcome the limitation of a single emission channel and aggregation-caused quenching features of thiocarbonyl-based fluorescent probes are highly desirable. Due to the important role of hypochlorite and singlet oxygen in biological processes and their common coexistence in living systems with frequent intertransformations, the design of a fluorescent probe that can recognize both hypochlorite and singlet oxygen is of great interest. Herein, a thiocarbonyl-based ratiometric fluorescent probe (Fcoum-S) for simultaneous detection of hypochlorite and singlet oxygen in aqueous solution and living cells was designed and synthesized. Upon the addition of hypochlorite in Fcoum-S solution (phosphate-buffered saline, 10 mM, pH 7.4, 10% acetonitrile), a ratiometric fluorescence response was observed via a specific hypochlorite-promoted desulfurization reaction with a good linear relationship between the ratio of fluorescence intensities at 526 and 602 nm (I 526nm/I 602nm) and the hypochlorite concentrations (a low detection limit of 0.15 µM). Furthermore, upon green light irradiation, Fcoum-S was efficiently desulfurized to its oxo analogue (Fcoum-O) by in situ generated singlet oxygen, leading to a significant change in fluorescence. Fcoum-S could work well in an aqueous medium owing to the high reactivity of the thiocarbonyl group and the aggregation-induced emission characteristics. More importantly, Fcoum-S could target mitochondria and was successfully utilized for fluorescence imaging of mitochondrial hypochlorite/singlet oxygen in live cells. This work provides a molecular design guideline for further exploring thioketone derivatives as fluorescent probes.