Structure-oriented design strategy to construct NIR AIEgens to selectively combat gram (+) multidrug-resistant bacteria in vivo.

Multidrug-resistant (MDR) gram-positive bacteria are an inevitable source of infection for hospitalized patients and one of the reasons for the increased proportion of severe diseases. Therefore, constructing smart agents for specific and effective combating infections in vivo caused by MDR gram-positive strains is very urgent. Herein, we reported a structure-oriented design strategy (SODS) to reasonably construct an organic photo-antimicrobial near-infrared (NIR) AIEgen BDPTV equipped with a phenylboronic acid moiety, which could be bound to the thick peptidoglycan layer of MDR gram-positive bacteria, resulting in a tight distribution with the cell wall in a confined space. Compared to the contrast compounds DQVTA and DPTVN, upon photoirradiation of AIEgen BDPTV, the generation of abundant and highly toxic reactive oxygen species (ROS) irreversibly destroys MDR gram-positive bacteria through photodynamic therapy, which is better than commercial photosensitizers (including methylene blue, chlorin e6, and protoporphyrin IX) and antibiotic (cefoxitin). As a proof of concept, in vitro experimental results showed that methicillin-resistant Staphylococcus aureus (MRSA) were completely killed using AIEgen BDPTV. More importantly, AIEgen BDPTV was capable of successfully combating MRSA-infected wounds of mice, but not Escherichia coli (E. coli)-infected wounds. We hope that this strategy could provide a new method to design powerful AIEgens to avoid the overuse and misuse of antibiotics.

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.

Reactivity Differences Enable ROS for Selective Ablation of Bacteria.

An effective strategy to engineer selective photodynamic agents to surmount bacterial-infected diseases, especially Gram-positive bacteria remains a great challenge. Herein, we developed two examples of compounds for a proof-of-concept study where reactive differences in reactive oxygen species (ROS) can induce selective ablation of Gram-positive bacteria. Sulfur-replaced phenoxazinium (NBS-N) mainly generates a superoxide anion radical capable of selectively killing Gram-positive bacteria, while selenium-substituted phenoxazinium (NBSe-N) has a higher generation of singlet oxygen that can kill both Gram-positive and Gram-negative bacteria. This difference was further evidenced by bacterial fluorescence imaging and morphological changes. Moreover, NBS-N can also successfully heal the Gram-positive bacteria-infected wounds in mice. We believe that such reactive differences may pave a general way to design selective photodynamic agents for ablating Gram-positive bacteria-infected diseases.

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.

Fluorescence Probe for Imaging N-Methyl-d-aspartate Receptors and Monitoring GSH Selectively Using Two-Photon Microscopy.

N-Methyl-d-aspartate (NMDA) is an excitotoxic amino acid used to identify a specific subset of glutamate receptors. The activity of NMDA receptors is closely related to the redox level of the biological system. Glutathione (GSH) as an antioxidant plays a key role with regard to modulation of the redox environment. In this work we designed and developed a GSH-specific fluorescent probe with the capability of targeting NMDA receptors, which was composed of a two-photon naphthalimide fluorophore, a GSH-reactive group sulfonamide, and an ifenprodil targeting group for the NMDA receptor. This probe exhibited high selectivity toward GSH in comparison to other similar amino acids. Two-photon fluorescence microscopy allowed this probe to successfully monitor GSH in neuronal cells and hippocampal tissues with an excitation at 750 nm. It could serve as a potential practical imaging tool to explore the function of GSH and related biological processes in the brain.

A Simple Route toward Next-Generation Thiobase-Based Photosensitizers for Cancer Theranostics.

Sulfur-substituted biocompatible carbonyl fluorophores have been recognized as effective heavy-atom-free photosensitizers (PSs) for cancer therapy due to their remarkable phototherapeutic properties. However, guidelines on their molecular design are still a substantial challenge. Most of the existing thiocarbonyl-based PSs are nonemissive in both the solution and restricted states, which hinders their further biomedical applications. Herein, we report the interesting finding that sulfur-substituted coumarins exhibit an uncommon phenomenon, aggregation-induced emission. More intriguingly, we also found that the introduction of a strong electron-accepting trifluoromethyl group is crucial to facilitate the mitochondrial-targeting ability of neutral coumarin fluorophores. The resulting CMS-2 PS displayed selective imaging of mitochondria and exhibited much higher photodynamic therapy efficiency toward cancer cells than that of the commercial PS erythrosine B. This work provides deep insight into the molecular design of heavy-atom-free thiobase-based PSs and simultaneously offers a great opportunity to develop novel mitochondrial-targeting fluorescent indicators with neutral bioinspired platforms.

Design and synthesis of efficient heavy-atom-free photosensitizers for photodynamic therapy of cancer.

Novel thiocarbonyl derivatives (NIS and CRNS) with excellent ROS generation abilities are synthesized and studied as potential photosensitizers for one- and two-photon excited photodynamic therapy. In particular, NIS-Me and CRNS display outstanding phototoxicity toward HeLa cells under two-photon excitation (800 nm) with negligible dark toxicity.