Self-Chemiluminescence-Triggered Ir(III) Complex Photosensitizer for Photodynamic Therapy against Hypoxic Tumor.

The limited optical penetration depth and hypoxic tumor microenvironment (TME) are key factors that hinder the practical applications of conventional photodynamic therapy (PDT). To fundamentally address these issues, self-luminescent photosensitizers (PSs) can achieve efficient PDT. Herein, a self-chemiluminescence (CL)-triggered Ir complex PS, namely, IrL2, with low-O2-dependence type I photochemical processes is reported for efficient PDT. The rational design achieves efficient chemiluminescence resonance energy transfer (CRET) from covalently bonded luminol units to the Ir complex in IrL2 under the catalysis of H2O2 and hemoglobin (Hb) to generate O2•- and 1O2. Liposome IrL2H nanoparticles (NPs) are constructed by loading IrL2 and Hb. The intracellular H2O2 and loaded Hb catalyze the luminol part of IrL2H, and the Ir2 part is then excited to produce types I and II reactive oxygen species (ROS) through CRET, inducing cell death, even under hypoxic conditions, and promoting cell apoptosis. IrL2H is used for tumor imaging and inhibits tumor growth in 4T1-bearing mouse models through intratumoral injection without external light sources. This work provides new designs for transition metal complex PSs that conquer the limitations of external light sources and the hypoxic TME in PDT.

Superenhancement Photon Upconversion Nanoparticles for Photoactivated Nanocryometer.

Highly doped lanthanide luminescent nanoparticles exhibit unique optical properties, providing exciting opportunities for many ground-breaking applications, such as super-resolution microscopy, deep-tissue bioimaging, confidentiality, and anticounterfeiting. However, the concentration-quenching effect compromises their luminescence efficiency/brightness, hindering their wide range of applications. Herein, we developed a low-temperature suppression cross-relaxation strategy, which drastically enhanced upconversion luminescence (up to 2150-fold of green emission) in Er3+-rich nanosystems. The cryogenic field opens the energy transport channel of Er3+ multiphoton upconversion by further suppressing phonon-assisted cross-relaxation. Our results provide direct evidence for understanding the energy loss mechanism of photon upconversion, deepening a fundamental understanding of the upconversion process in highly doped nanosystems. Furthermore, it also suggests the potential applications of upconversion nanoparticles for extreme ambient-temperature detection and anticounterfeiting.

Manipulating the Injected Energy Flux via Host-Sensitized Nanostructure for Improving Multiphoton Upconversion Luminescence of Tm3.

Combating the concentration quenching effect by increasing the concentration of sensitized rare-earth ions in rational design upconversion nanostructure will make it easier to utilize injection energy flux and transfer it to emitters, resulting in improved upconversion luminescence (UCL). We proposed a host-sensitized nanostructure (active core@luminescent shell@inert shell) to improve multiphoton UCL of Tm3+ based on the LiLnF4 host. Yb3+ ions were isolated in the core as energy absorbents, and Tm3+ was doped in the interior LiYbF4 host shell. Compared with sandwich structured nanocrystals (Y@Y:Yb/Tm@Y), reverse structure (YbTm@Yb@Y), and fully doped structure (YbTm@YbTm@Y), the proposed structure achieved the highest efficiency of multiphoton UCL and favored a better FRET-based application performance as the Tm3+ located at an optimized spatial distribution. Furthermore, steady-state and dynamic analysis results demonstrate that by manipulating the spatial distribution of the active ions, excited energy can be tuned to enable multiphoton upconversion enhancement, overcoming the conventional limitations.

Mitochondria-Immobilized Unimolecular Fluorescent Probe for Multiplexing Imaging of Living Cancer Cells.

Cancer incidence and mortality are fast growing worldwide. Recently, multiplexing imaging methods have been reported to be vital for cancer diagnosis and therapy. Fluorescence imaging, which has intrinsic capabilities for multiplexing imaging, is suitable and ripe for cancer imaging. In biomedical research, using a single probe for multiplexing imaging can avoid larger invasive effects and ensure the same spatiotemporal distributions and metabolisms of the probes, which has advantages over using multiple probes. Therefore, developing unimolecular fluorescent probes for multiplexing imaging of living cancer cells is meaningful. We herein report a unimolecular fluorescent probe (ZED) that simultaneously detects cysteine/homocysteine, hypochlorous acid, mitochondrial membrane potential (Δψm), and opening of the mitochondrial permeability transition (MPT) pore in cells. These four analytes are key indicators predominantly associated with multiple aspects of carcinogenesis and cancer therapy in living cells. Besides, ZED also differentiates MCF-7 cells from HBL-100 cells. The sensing process is fast, selective, and sensitive in living cancer cells. As far as we know, ZED is the first probe that simultaneously detects four analytes in cells and the first probe that simultaneously detects Δψm and opening of the MPT pore in mitochondria.

Precisely Tailoring Upconversion Dynamics via Energy Migration in Core-Shell Nanostructures.

Upconversion emission dynamics have long been believed to be determined by the activator and its interaction with neighboring sensitizers. Herein this assumption is, however, shown to be invalid for nanostructures. We demonstrate that excitation energy migration greatly affects upconversion emission dynamics. "Dopant ions' spatial separation" nanostructures are designed as model systems and the intimate link between the random nature of energy migration and upconversion emission time behavior is unraveled by theoretical modelling and confirmed spectroscopically. Based on this new fundamental insight, we have successfully realized fine control of upconversion emission time behavior (either rise or decay process) by tuning the energy migration paths in various specifically designed nanostructures. This result is significant for applications of this type of materials in super resolution spectroscopy, high-density data storage, anti-counterfeiting, and biological imaging.

ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics.

Cholangiocarcinoma responses weakly to cisplatin. Mitochondrial dynamics participate in the response to various stresses, and mainly involve mitophagy and mitochondrial fusion and fission. Bcl-2 family proteins play critical roles in orchestrating mitochondrial dynamics, and are involved in the resistance to cisplatin. Here we reported that ABT737, combined with cisplatin, can promote cholangiocarcinoma cells to undergo apoptosis. We found that the combined treatment decreased the Mcl-1 pro-survival form and increased Bak. Cells undergoing cisplatin treatment showed hyperfused mitochondria, whereas fragmentation was dominant in the mitochondria of cells exposed to the combined treatment, with higher Fis1 levels, decreased Mfn2 and OPA1 levels, increased ratio of Drp1 60kD to 80kD form, and more Drp1 located on mitochondria. More p62 aggregates were observed in cells with fragmented mitochondria, and they gradually translocated to mitochondria. Mitophagy was induced by the combined treatment. Knockdown p62 decreased the Drp1 ratio, increased Tom20, and increased cell viability. Our data indicated that mitochondrial dynamics play an important role in the response of cholangiocarcinoma to cisplatin. ABT737 might enhance cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics and the balance within Bcl-2 family proteins. Furthermore, p62 seems to be critical in the regulation of mitochondrial dynamics.

Disrupting redox homeostasis for tumor therapy based on PDT/chemo/ferroptosis therapeutic hybrid liposomes.

Synergistic photodynamic therapy (PDT) with other therapeutic modalities can enhance the therapeutic efficacy of tumor treatment and reduce the adverse effects associated with drug leakage and off-target accumulation. However, shaping combined strategies for synergistic therapy remains challenging. Herein, we developed versatile hybrid liposomes self-assembled from Ce6-lipid conjugates and loaded with the chemo drug doxorubicin (DOX) and ferroptosis inducer Fe3O4 nanoparticles for synergistic PDT/chemo/ferroptosis therapy. Abundant ROS are generated by PDT upon 650 nm light irradiation, Fe3O4-mediated Fenton reaction, and DOX-induced apoptosis. Furthermore, amplifying oxidative stress in cancer cells to disrupt cellular redox homeostasis could accelerate tumor cell death through oxidative damage to lipids, proteins, and DNA. Overall, this work highlights liposome-based therapeutic nanoformulations, thus offering a breakthrough redox homeostasis-based synergistic PDT/chemo/ferroptosis therapy for lung cancer.

Long-wavelength triggered iridium(III) complex nanoparticles for photodynamic therapy against hypoxic cancer.

A long-wavelength triggered cationic iridium(III) complex, Ir5, and its corresponding nanoparticles with the ability to generate type I and type II reactive oxygen species have been synthesised. The complex targets mitochondria and achieves an excellent photodynamic therapy effect in hypoxic cancer cells.

Amplification of oxidative damage using near-infrared II-mediated photothermal/thermocatalytic effects for periodontitis treatment.

Periodontitis is a biofilm-related disease characterized by damage to the periodontal tissue and the development of systemic diseases. However, treatment of periodontitis remains unsatisfactory, especially with deep-tissue infections. This study describes rationally designed multifunctional photothermocatalytic agents for near-infrared-II light-mediated synergistic antibiofilm treatment, through modification of Lu-Bi2Te3 with Fe3O4 and poly(ethylene glycol)-b-poly(l-arginine) (PEG-b-PArg). Notably, 1064-nm laser irradiation led to photothermal/thermocatalytic effects, resulting in the synergistic generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and consequent damage to the biofilm. This treatment was based on the thermoelectric and photothermal conversion properties of Lu-Bi2Te3, the peroxidase-like catalytic capacity of Fe3O4, and the guanidinium polymer, PEG-b-PArg. Oxidative damage to biofilm was further enhanced by H2O2, resulting in the effective elimination of biofilm both in vitro and in vivo. These findings suggest that this synergistic therapeutic strategy is effective for the clinical treatment of periodontitis. STATEMENT OF SIGNIFICANCE: The current treatment for periodontitis involves time-consuming and labor-intensive clinical scaling of the teeth. The present study is the first to assess the efficacy of a photothermal catalyst for periodontitis treatment. This used near-infrared-II light at 1064 nm to induce oxidative damage in the biofilm, resulting in its degradation. The synergistic photothermal/thermoelectric effect produced deep tissue penetration and was well tolerated, and can kill the biofilm formed by periodontitis pathogens up to 5 orders of magnitude, effectively treating the biofilm-induced periodontitis.

Triphenylene-Based Emitters with Hybridized Local and Charge-Transfer Characteristics for Efficient Nondoped Blue OLEDs with a Narrowband Emission and a Small Efficiency Roll-Off.

Developing high-efficiency nondoped blue organic light-emitting diodes (OLEDs) with high color purity and low-efficiency roll-off is vital for display and lighting applications. Herein, we developed two asymmetric D-π-A blue emitters, PIAnTP and PyIAnTP, in which triphenylene is first utilized as a functional acceptor. The relatively weak charge transfer (CT) properties, rigid molecular structures, and multiple supramolecular interactions in PIAnTP and PyIAnTP can significantly enhance the fluorescence efficiency and suppress the structural relaxations to obtain a narrowband blue emission. The photophysical experiments and theoretical simulations reveal that they both exhibit a typical hybridized local and charge-transfer (HLCT) excited state and achieve high external quantum efficiency (EQE) via a "hot exciton" channel. As a result, PIAnTP- and PyIAnTP-based nondoped devices realize blue emission at 456 and 464 nm, corresponding to CIE coordinates of (0.16, 0.14) and (0.16, 0.19), narrow full width at half-maximums of 52 and 60 nm, and the high EQEs of 8.36 and 8.69%, respectively. More importantly, the PIAnTP- and PyIAnTP-based nondoped devices show small EQE roll-offs of only 5.9 and 2.4% at 1000 cd m-2, respectively. These results signify an advance in designing a highly efficient blue emitter for nondoped OLEDs.

Core-satellite nanoreactors based on cationic photosensitizer modified hollow CuS nanocage for ROS diffusion enhanced phototherapy of hypoxic tumor.

Photodynamic therapy (PDT) efficiency is directly affected by the reactive oxygen species (ROS) generated by photosensitizers. However, ROSs' ultrashort life span and limited diffusion distance restrict the PDT efficiency. Therefore, it is important to control the delivery strategy of photosensitizers for PDT treatment. Herein, the core-satellite nanoreactors were fabricated with oxygen generation and ROS diffusion properties. The hollow CuS encapsulating horseradish peroxidase (HRP) was combined with the cationic photosensitizers (PEI-Ce6). The unique photosensitizers delivery strategy makes the nanoreactors achieve ROS diffusion-enhanced PDT effect. First, HRP in "core" (HRP@CuS) can decompose hydrogen peroxide (H2O2) to O2, increasing O2 levels on the surface of the nanoreactor. Second, the Ce6 molecules covalent-linked with PEI are uniformly dispersed on the surface of CuS as a "satellite", avoiding Ce6 aggregation and causing more Ce6 molecules be activated to produce more 1O2. Due to the Ce6 was on the surface of the CuS nanocages, the generated ROS may ensure a larger diffusion range. Meanwhile, the inherently CuS nanocages exhibit photothermal and photoacoustic (PA) effect. The photothermal effect further enhances the ROS diffusion. Under the guidance of PA imaging, nanoreactors exhibit highly efficient hypoxic tumor ablation via photodynamic and photothermal effect. Overall, the core-satellite nanoreactors provide an effective strategy for tumor therapy, further promoting the research of photosensitizers delivery.

Bright Tm3+-based downshifting luminescence nanoprobe operating around 1800 nm for NIR-IIb and c bioimaging.

Fluorescence bioimaging based on rare-earth-doped nanocrystals (RENCs) in the shortwave infrared (SWIR, 1000-3000 nm) region has aroused intense interest due to deeper penetration depth and clarity. However, their downshifting emission rarely shows sufficient brightness beyond 1600 nm, especially in NIR-IIc. Here, we present a class of thulium (Tm) self-sensitized RENC fluorescence probes that exhibit bright downshifting luminescence at 1600-2100 nm (NIR-IIb/c) for in vivo bioimaging. An inert shell coating minimizes surface quenching and combines strong cross-relaxation, allowing LiTmF4@LiYF4 NPs to emit these intense downshifting emissions by absorbing NIR photons at 800 nm (large Stokes shift ~1000 nm with a absolute quantum yield of ~14.16%) or 1208 nm (NIR-IIin and NIR-IIout). Furthermore, doping with Er3+ for energy trapping achieves four-wavelength NIR irradiation and bright NIR-IIb/c emission. Our results show that Tm-based NPs, as NIR-IIb/c nanoprobes with high signal-to-background ratio and clarity, open new opportunities for future applications and translation into diverse fields.

CaGdF5 based heterogeneous core@shell upconversion nanoparticles for sensitive temperature measurement.

Lanthanide-doped upconversion nanoparticles (UCNPs) have attracted great attention in temperature sensing because of their widespread thermal quenching effect (TQE), a phenomenon in which luminescence intensity decreases as the temperature increases. However, enhancing the TQE of activated ions without changing the dopants or the host is still challenging. Herein, Yb3+ and Er3+ codoped UCNPs in a cubic CaGdF5 host were synthesized by a coprecipitation method for optical temperature sensing. Compared with the homogeneous shell (CaGdF5), those heterogeneous (CaF2) shelled UCNPs exhibited stronger upconversion luminescence (UCL) due to the significantly reduced multiphonon nonradiative relaxation. Further, we investigated the effects of homogeneous and heterogeneous shells on TQE. The relationship between the intensity ratio of the green emission bands of Er3+ ions (2H11/2 → 4I15/2 and 4S3/2 → 4I15/2) and temperature are obtained for these two core@shell UCNPs. The results demonstrated that the UCNPs with CaF2 shells are more sensitive to temperature in the 200-300 K. The maximum thermal sensitivity of CaGdF5:Yb,Er@CaF2 could reach 2.2% K-1 at 200 K. These results indicate that the heterogeneous core@shell UCNPs are promising for use as optical temperature sensors.

Modulation of the Tumor Immune Microenvironment by Bi2 Te3 -Au/Pd-Based Theranostic Nanocatalysts Enables Efficient Cancer Therapy.

Nanozymes with multienzyme-mimicking activities have shown great potential in cancer therapy due to their ability to modulate the complex tumor microenvironment (TME). Herein, a second near-infrared (NIR-II) photothermal-nanocatalyst by decorating Bi2 Te3 nanosheets with ultrasmall Au/Pd bimetallic nanoparticles (Bi2 Te3 -Au/Pd) to reverse the immunosuppressive TME is developed. The peroxidase (POD)-like and catalase (CAT)-like activities, and glutathione (GSH) consumption capacity of Au/Pd modulates the TME by disrupting the intracellular redox homeostasis and relieving hypoxia in the TME. Notably, the amplified oxidative stress induces the accumulation of lipid hydroperoxides (LPO) for enhanced ferroptosis. Moreover, upon NIR-II photoirradiation at 1064 nm, the localized heat generated by Bi2 Te3 not only directly ablates the cancer cells but also enhances the Au/Pd-mediated catalysis-mediated cancer therapy. Furthermore, both in vitro and in vivo studies confirm that the Bi2 Te3 -Au/Pd nanocatalysts (BAP NCs) can effectively suppress tumor growth by inducing immunogenic cell death (ICD), and suppressing metastasis and recurrence by the synergistic treatment. Overall, this study provides a promising theranostic strategy for effective tumor inhibition.

AIE-active iridium(III) complex integrated with upconversion nanoparticles for NIR-irradiated photodynamic therapy.

The integration of an aggregation induced emission (AIE)-active Ir(III) complex and upconversion nanoparticles (UCNPs) has achieved a NIR-irradiated photosensitizer (PS), UCNPs@Ir-2-N. This PS has satisfactory biocompatibility, excellent phototoxicity, good accumulation in cells and high 1O2 generation ability, thereby effectively killing 4T1 mouse cancer cells in vitro. This work has potential for future photodynamic therapy (PDT) applications.

AIE-active Ir(III) complexes functionalised with a cationic Schiff base ligand: synthesis, photophysical properties and applications in photodynamic therapy.

Photodynamic therapy (PDT) is a promising cancer treatment method. Traditional small-molecule photosensitizers (PSs) suffer from low intersystem crossing (ISC) ability and aggregation-caused quenching (ACQ), which adversely affects the luminous efficiency and singlet oxygen (1O2) yield of PSs in the aggregated state. Ir(III) complexes are promising PSs with long excited-state lifetime, good photophysical and photochemical properties and large Stokes shifts. Aggregation-induced emission (AIE) characteristics could reduce the nonradiative recombination and improve the ISC ability of excited states through the restriction of the intramolecular motions in aggregated states. Accordingly, two AIE-active Ir(III) complexes Ir-1-N+ and Ir-2-N+ were successfully designed and obtained based on Schiff base ligands. Experimental results showed that Ir-1-N+ and Ir-2-N+ have good photophysical properties and the corresponding nanoparticles (NPs) have good water solubility and 1O2 generation ability. Notably, Ir-2-N+ NPs can be efficiently taken up by mouse breast cancer cells (4T1 cells) with good biocompatibility, low dark toxicity and excellent phototoxicity. This work demonstrates a versatile strategy for exploiting efficient transition metal PSs with a cationic ligand in PDT.

An active-passive strategy for enhanced synergistic photothermal-ferroptosis therapy in the NIR-I/II biowindows.

Ferroptosis therapy (FT) is an attractive strategy to selectively damage cancer cells through lipid peroxide (LPO) over-accumulation. However, this therapy suffers from poor therapeutic efficacy due to the limited Fenton reaction efficiency and the evolved intrinsic resistance mechanism in the tumor microenvironment (TME). The exploitation of novel ferroptosis inducers is of significance for improving the efficacy of FT. Here, we develop a plate-like Bi2Se3-Fe3O4/Au (BFA) theranostic nanoplatform, which can increase the Fenton reaction rate to enhance FT in an active-passive way. In detail, benefiting from the internal synergistic effect of Fe3O4 NPs and Au NPs and external NIR-mediated hyperthermia, the BFA NPs can boost hydroxyl radical (˙OH) generation to enhance intracellular oxidative stress and further induce ferroptosis by inactivating glutathione peroxidase 4 (GPX4). Furthermore, the BFA NPs show high photothermal conversion efficiency in both the NIR-I and NIR-II windows (66.2% at 808 nm and 58.2% at 1064 nm, respectively); therefore, as a photothermal agent (PTA), they can also ablate cancer cells directly by NIR-triggered photothermal therapy (PTT). Meanwhile, BFA NPs could be used as an efficient diagnostic agent for photoacoustic (PA)/magnetic resonance (MR)/X-ray imaging to guide the synergistic therapy of photothermal-ferroptosis. Therefore, BFA NP-mediated enhanced photothermal-ferroptosis therapy represents a promising strategy for the application of nanomaterials in tumor therapy.

Synthesis and photoluminescence study of di-dendron dendrimers derived from mono-Boc-protected ethylenediamine cores.

This work is focused on the synthesis and optical properties of cone-shaped structural feature di-dendron polyamidoamine dendrimers up to the third generation with mono-Boc-protected ethylenediamine (EDA) as a core. Strong UV absorbance spectra and fluorescence spectra from di-dendron dendrimers with different terminal groups (-NH(2), -COOCH(3)) were studied under different conditions by varying experimental parameters such as concentration and pH. The optical density and fluorescence intensities increased when di-dendron dendrimers generation number increased from 0.5 to 3.0. It was confirmed that the concentration of di-dendron dendrimers plays an important role in fluorescence intensity. The increase in fluorescence intensity was linear in low concentration regions, but the intensity increased slowly in high concentration regions. The results also showed a rapid increase in fluorescence intensity at low pH. The formation of a fluorescence-emitting moiety had a close relationship to protonated tertiary amine groups in di-dendron dendrimers derived from mono-Boc-protected EDA cores. Furthermore, the formation of fluorescent chemical species was irreversible.

[The study on the UV and fluorescence properties of PAMAM dendrimers].

From 0.5 to 5.0 generation PAMAM dendrimers were synthesized with ethylenediamine core by Michael addition reaction and aminolysis reaction two repeated steps. The structure of dendrimers were confirmed by FTIR 1H NMR 13C NMR MS and all of these measurements showed that they were successfully synthesized. Furthermore, The authors studied the UV and fluorescence properties of different generation dendrimers. Because of diffenent terminal groups, it was found that the whole generation and half generation show different ultraviolet absorption peaks and the intensity of ultraviolet absorption is closely related to the molecular skeleton. There is no traditional fluorescence emission groups, but PAMAM dendrimers show the peculiar phenomenon. In this paper we detailedly studied the factors which affect PAMAM dendrimers fluorescence properties.