Article-Journal

The acquisition of resistance to chemotherapy is a major hurdle for successful cancer therapy. Herein, a new light-responsive drug delivery nanoparticle system is developed to overcome doxorubicin (DOX) resistance in breast cancer cells. The nanoparticles with high drug loading capacity are self-assembled from an amphiphilic polymer which is composed of a hydrophobic photosensitizer (PS) with aggregation-induced emission (AIE) characteristics and a biocompatible and hydrophilic poly(ethylene glycol) (PEG) conjugated via a reactive oxygen species (ROS) cleavable thioketal (TK) linker. The AIE PS makes the nanoparticles visible for high-quality imaging and capable of generating ROS upon light irradiation. When exposed to white light irradiation, the ROS generated from the PS could not only induce the endo-lysosomal membrane rupture, but also break the nanoparticles. This results in facilitated endo-lysosomal escape and triggered cytosol release of DOX, which can significantly improve intracellular DOX accumulation and retention in drug resistant MDA-MB-231 breast cancer cells. With light irradiation, the drug loaded nanoparticles can significantly inhibit the growth of DOX-resistant MDA-MB-231 cells. These results reveal that AIEgen based nanoparticles offer a potentially effective approach to overcome drug resistance in cancer cells.

Bioorthogonal turn-on probes have been widely utilized in visualizing various biological processes. Most of the currently available bioorthogonal turn-on probes are blue or green emissive fluorophores with azide or tetrazine as functional groups. Herein, we present an alternative strategy of designing bioorthogonal turn-on probes based on red-emissive fluorogens with aggregation-induced emission characteristics (AIEgens). The probe is water soluble and non-fluorescent due to the dissipation of energy through free molecular motion of the AIEgen, but the fluorescence is immediately turned on upon click reaction with azide-functionalized glycans on cancer cell surface. The fluorescence turn-on is ascribed to the restriction of molecular motion of AIEgen, which populates the radiative decay channel. Moreover, the AIEgen can generate reactive oxygen species (ROS) upon visible light (λ=400-700 nm) irradiation, demonstrating its dual role as an imaging and phototherapeutic agent.

The isomerization and optical properties of the cis and trans isomers of tetraphenylethene (TPE) derivatives with aggregation-induced emission (AIEgens) have been sparsely explored. We have now observed the tautomerization-induced isomerization of a hydroxy-substituted derivative, TPETH-OH, under acidic but not under basic conditions. Replacing the proton of the hydroxy group in TPETH-OH with an alkyl group leads to the formation of TPETH-MAL, for which the pure cis and trans isomers were obtained and characterized by HPLC analysis and NMR spectroscopy. Importantly, cis-TPETH-MAL emits yellow fluorescence in DMSO at −20 °C whereas trans-TPETH-MAL shows red fluorescence under the same conditions. Moreover, the geometry of cis- and trans-TPETH-MAL remains unchanged when they undergo thiol–ene reactions to form cis- and trans-TPETH-cRGD, respectively. Collectively, our findings improve our fundamental understanding of the cis/trans isomerization and photophysical properties of TPE derivatives, which will guide further AIEgen design for various applications.

The accurate detection of biological substances is highly desirable to study various biological processes and evaluate disease progression. Herein, we report a self-validated fluorescent probe which is composed of a coumarin fluorophore as the energy donor and a fluorogen with aggregation-induced emission characteristics (AIEgen) as the energy quencher linked through a caspase-3 specific peptide substrate. Unlike the traditionally widely studied fluorescence resonance energy transfer (FRET) probes, our new generation of FRET probe is non-fluorescent itself due to the energy transfer as well as the dissipation of the acceptor energy through the free molecular motion of AIEgen. Upon interaction with caspase-3, the probe displays strong green and red fluorescent signals synchronously due to the separation of the donor-quencher and aggregation of the released AIEgen. The fluorescence turn-on with dual signal amplification allows real-time and self-validated enzyme detection with a high signal-to-background ratio, providing a good opportunity to accurately monitor various biological processes in a real-time manner.

Robust luminescent dyes with efficient two-photon fluorescence are highly desirable for biological imaging applications, but those suitable for organic dots fabrication are still rare because of aggregation-caused quenching. In this work, a red fluorescent silole, 2,5-bis[5-(dimesitylboranyl)thiophen-2-yl]-1-methyl-1,3,4-triphenylsilole ((MesB)2DTTPS), is synthesized and characterized. (MesB)2DTTPS exhibits enhanced fluorescence efficiency in nanoaggregates, indicative of aggregation-enhanced emission (AEE). The organic dots fabricated by encapsulating (MesB)2DTTPS within lipid-PEG show red fluorescence peaking at 598 nm and a high fluorescence quantum yield of 32%. Upon excitation at 820 nm, the dots show a large two-photon absorption cross section of 3.43 × 105 GM, which yields a two-photon action cross section of 1.09 × 105 GM. These (MesB)2DTTPS dots show good biocompatibility and are successfully applied to one-photon and two-photon fluorescence imaging of MCF-7 cells and two-photon in vivo visualization of the blood vascular of mouse muscle in a high-contrast and noninvasive manner. Moreover, the 3D blood vasculature located at the mouse ear skin with a depth of over 100 μm can also be visualized clearly, providing the spatiotemporal information about the whole blood vascular network.

The real-time monitoring of reactive oxygen species (ROS, particularly singlet oxygen) generation during photodynamic therapy is a great challenge due to the extremely short half-life and small radius of action. To tackle this issue, we herein report a bioprobe composed of a red emissive photosensitizer (PS) with aggregation-induced emission (AIE) characteristics and a fluorogenic green emissive rhodol dye conjugated via a singlet oxygen cleavable aminoacrylate (AA) linker. The probe emits red fluorescence in water, and the red emissive PS can be used for probe self-tracking. Upon image-guided light irradiation, the generated singlet oxygen cleaves the AA linker to yield green fluorescence turn-on of rhodol, which offers real-time and in situ monitoring of singlet oxygen generation during photodynamic ablation of cancer cells, providing a strategy for the early evaluation of the therapeutic effect.

The currently available photosensitizers (PSs) for photodynamic therapy (PDT) can easily lead to undesirable normal cell death due to their intrinsic photo-toxicity and lack of selectivity for cancer cells. Activatable PSs with high therapeutic efficiency towards cancer cells but minimized side effects on normal cells are thus highly desirable. In this work, we developed a probe with dual-targeted activatable PSs that can recognize and ablate cancer cells with high selectivity. The probe is composed of a fluorophore with aggregation-induced emission (AIE) characteristics which can be used as an imaging agent as well as a PS, a quencher moiety that can be cleaved upon encountering biothiols, and a cyclic arginine–glycine–aspartic acid (cRGD) tripeptide for targeting cancer cells with overexpressed αvβ3 integrin. The probe itself is non-fluorescent and its ability to generate reactive oxygen species (ROS) is prohibited. However, it could be selectively activated to offer specific fluorescence turn-on with efficient ROS generation in the aggregated state, which was used to ablate cancer cells overexpressing both αvβ3 integrin receptors and glutathione. As compared to conventional activatable PSs which show quenched fluorescence and reduced ROS generation in the aggregated state, the dual-selection process with enhanced fluorescence and efficient ROS generation of the activated AIE probe in aggregated state offers a high signal-to-background ratio for MDA-MB-231 cancer cell imaging and ablation. This strategy thus opens up new opportunities for designing activatable PSs with high selectivity and low intrinsic photo-toxicity for photodynamic cancer cell ablation.

The efficiency of the intersystem crossing process can be improved by reducing the energy gap between the singlet and triplet excited states (ΔEST), which offers the opportunity to improve the yield of the triplet excited state. Herein, we demonstrate that modulation of the excited states is also an effective strategy to regulate the singlet oxygen generation of photosensitizers. Based on our previous studies that photosensitizers with aggregation-induced emission characteristics (AIE) showed enhanced fluorescence and efficient singlet oxygen production in the aggregated state, a series of AIE fluorogens such as TPDC, TPPDC and PPDC were synthesized, which showed ΔEST values of 0.48, 0.35 and 0.27 eV, respectively. A detailed study revealed that PPDC exhibited the highest singlet oxygen efficiency (0.89) as nanoaggregates, while TPDC exhibited the lowest efficiency (0.28), inversely correlated with their ΔEST values. Due to their similar optical properties, TPDC and PPDC were further encapsulated into nanoparticles (NPs). Subsequent surface modification with cell penetrating peptide (TAT) yielded TAT-TPDC NPs and TAT-PPDC NPs. As a result of the stronger singlet oxygen generation, TAT-PPDC NPs showed enhanced cancer cell ablation as compared to TAT-TPDC NPs. Fine-tuning of the singlet-triplet energy gap is thus proven to be an effective new strategy to generate efficient photosensitizers for photodynamic therapy.

Integrated systems that offer traceable cancer therapy are highly desirable for personalized medicine. Herein, a probe is reported that is composed of a red-emissive photosensitizer (PS) with aggregation-induced emission characteristics and a built-in apoptosis sensor with activatable green emission for targeted cancer cell ablation and real-time monitoring of PS activation and therapeutic response. The probe is nonemissive in aqueous media and can be selectively uptaken by alpha(v)beta(3) integrin overexpressed cancer cells. Cleavage of the probe by intracellular glutathione leads to release of the apoptosis sensor and red fluorescence turn-on to report the PS activation. Upon light irradiation, the PS can generate reactive oxygen species to induce cell apoptosis and activate caspase-3/-7, which will cleave the apoptosis sensor to yield intense green fluorescence. Both the red and green emission can be obtained through a single wavelength excitation, which makes the probe very convenient for therapeutic protocol development.

A novel white-light-emitting organic molecule, which consists of carbazolyl- and phenothiazinyl-substituted benzophenone (OPC) and exhibits aggregation-induced emission-delayed fluorescence (AIE-DF) and mechanofluorochromic properties was synthesized. The CIE color coordinates of OPC were directly measured with a non-doped powder, which presented white-emission coordinates (0.33, 0.33) at 244 K to 252 K and (0.35, 0.35) at 298 K. The asymmetric donor-acceptor-donor’ (D-A-D’) type of OPC exhibits an accurate inherited relationship from dicarbazolyl-substituted benzophenone (O2C, D-A-D) and diphenothiazinyl-substituted benzophenone (O2P, D’-A-D’). By purposefully selecting the two parent molecules, that is, O2C (blue) and O2P (yellow), the white-light emission of OPC can be achieved in a single molecule. This finding provides a feasible molecular strategy to design new AIE-DF white-light-emitting organic molecules.