The development of straightforward accesses to organic functional materials through C-H activation is a revolutionary trend in organic synthesis. In this article, we propose a concise strategy to construct a large library of donor-acceptor-type biheteroaryl fluorophores via the palladium-catalyzed oxidative C-H/C-H cross-coupling of electron-deficient 2H-indazoles with electron-rich heteroarenes. The directly coupled biheteroaryl fluorophores, named Indazo-Fluors, exhibit continuously tunable full-color emissions with quantum yields up to 93% and large Stokes shifts up to 8705 cm(-1) in CH2Cl2. By further fine-tuning of the substituent on the core skeleton, Indazo-Fluor 3l (FW = 274; λem = 725 nm) is obtained as the lowest molecular weight near-infrared (NIR) fluorophore with emission wavelength over 720 nm in the solid state. The NIR dye 5h specifically lights up mitochondria in living cells with bright red luminescence. Typically, commercially available mitochondria trackers suffer from poor photostability. Indazo-Fluor 5h exhibits superior photostability and very low cytotoxicity, which would be a prominent reagent for in vivo mitochondria imaging.

Inflammation is a protective response to stimuli trauma, which can also lead to severe tissue injury. The existing anti-inflammatory drugs, such as corticosteroids and glucocorticoids, generally exhibit side effects and poor accumulation in inflammatory tissue. Hence, a theranostic nanoplatform with serial reactive oxygen species (ROS) responsiveness and two-photon AIE bioimaging has been constructed for dimensional diagnosis and accurate therapy of inflammation. Prednisolone (Pred) is bridged to a two-photon fluorophore (TP) developed by us via a ROS sensitive bond to form a diagnosis-therapy compound TPP, which is then loaded by the amphipathic polymer PMPC–PMEMA (PMM) through self-assembling into the core–shell structured micelles (TPP@PMM). With a particle size of 57.5 nm, TPP@PMM can realize the accumulation in the inflammatory site via the oedematous tissue and the accurate release of anti-inflammatory drug Pred through the serial response to the local overexpressed ROS. The micellar structure is first interrupted by the ROS triggered hydrophobic-to-hydrophilic conversion of PMEMA, which allows the release of TPP. Then the ROS responsive bond in TPP is subsequently broken, resulting in the accurate delivery of Pred and the inflammation therapy. Furthermore, TPP@PMM can be traced in vivo with a distinct two-photon imaging due to the AIE active fluorophore TP. The theranostic TPP@PMM reveals high-resolution inflammation diagnosis and efficient anti-inflammatory activity owing to the two-photon fluorophore and the serial ROS responsiveness and has been proven to achieve the efficient treatment of acute lung injury, arthritis, and atherosclerosis. Therefore, TPP@PMM holds considerable promise as a potential strategy for acute and chronic inflammation theranostics.

Intelligent polymeric micelles for antitumor drug delivery and tumor bioimaging have drawn a broad attention because of their reduced systemic toxicity, enhanced efficacy of drugs, and potential application of tumor diagnosis. Herein, we developed a multifunctional polymeric micelle system based on a pH and redox dual-responsive mPEG-P(TPE- co-AEMA) copolymer for stimuli-triggered drug release and aggregation-induced emission (AIE) active imaging. These mPEG-P(TPE- co-AEMA)-based micelles showed excellent biocompatibility and emission property, exhibiting great potential application for cellular imaging. Furthermore, the antitumor drug doxorubicin (DOX) could be encapsulated during self-assembly process with high loading efficiency, and a DOX-loaded micelle system with a size of 68.2 nm and narrow size distribution could be obtained. DOX-loaded micelles demonstrated great tumor suppression ability in vitro, and the dual-responsive triggered intracellular drug release could be further traced. Moreover, DOX-loaded micelles could efficiently accumulate at the tumor site because of enhanced permeability and retention effect and long circulation of micelles. Compared with free DOX, DOX-loaded micelles exhibited better antitumor effect and significantly reduced adverse effects. Given the efficient accumulation targeting to tumor tissue, dual-responsive drug release, and excellent AIE property, this polymeric micelle would be a potential candidate for cancer therapy and diagnosis.

Relatively mild and highly efficient CuI-catalyzed N-arylation procedures for nitrogen-containing heterocycles (e.g., imidazoles, benzimidazoles, pyrroles, pyrazoles, indoles, triazoles, etc.) with aryl and heteroaryl halides have been developed. The protocols can be performed easily and tolerate a number of functional groups, such as ester, nitrile, nitro, ketone, free hydroxyl, and free primary amine on the aryl halide.

In recent years, photodynamic therapy (PDT) has drawn much attention as a noninvasive and safe cancer therapy method due to its fine controllability, good selectivity, low systemic toxicity, and minimal drug resistance in contrast to the conventional methods (for example, chemotherapy, radiotherapy, and surgery). However, some drawbacks still remain for the current organic photosensitizers such as low singlet oxygen (1O2) quantum yield, poor photostability, inability of absorption in the near-infrared (NIR) region, short excitation wavelength, and limited action radius of singlet oxygen, which will strongly limit the PDT treatment efficiency. As a consequence, the development of efficient photosensitizers with high singlet oxygen quantum yield, strong fluorescent emission in the aggregated state, excellent photostability, NIR excitation wavelength ranging in the biological transparency window, and highly specific targeting to mitochondria is still in great demand for the enhancement of PDT treatment efficiency. In this study, two new two-photon AIEgens TPPM and TTPM based on a rigid D−π–A skeleton have been designed and synthesized. Both AIEgens TPPM and TTPM show strong aggregation-induced emission (AIE) with the emission enhancement up to 290-folds, large two-photon absorption with the two-photon absorption cross section up to 477 MG, and highly specific targeting to mitochondria in living cells with good biocompatibility. They can serve as two-photon bioprobes for the cell and deep tissue bioimaging with a penetration depth up to 150 μm. Furthermore, high 1O2 generation efficiency with high 1O2 quantum yield under white light irradiation has been found for both TPPM and TTPM and high PDT efficiency to HeLa cells under white light irradiation has also been proven. To the best of our knowledge, AIEgens in this work constitute one of the strongest emission enhancements and one of the highest 1O2 generation efficiencies in the reported organic AIEgens so far. The great AIE feature, large two-photon absorption, high specificity to mitochondria in living cells, and high PDT efficiency to living cells as well as excellent photostability and biocompatibility of these novel AIEgens TPPM and TTPM reveal great potential in clinical applications of two-photon cell and tissue bioimaging and image-guided and mitochondria-targeted photodynamic cancer therapy.