Irinotecan,one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer,suffers from extremely low activatability and non-selective tumor activation.7-Ethyl-10-hydroxy-camptothecin...Irinotecan,one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer,suffers from extremely low activatability and non-selective tumor activation.7-Ethyl-10-hydroxy-camptothecin(SN38),the active metabolite of irinotecan,has been limited in clinical development due to poor water solubility and stability.Here,the thioether bond and disulfide bond were employed as response modules to construct tumor-selective SN38 prodrug nanoassemblies(SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs).11-Henicosanol was chosen as a self-assembly module to enhance stability.Both SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs presented ultra-high in vivo stability with a 12146-fold and 23151-fold elevation in the area under the curve(AUC)compared to SN38.Moreover,SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs showed a significant reduction of SN38exposure in blood compared to irinotecan.Importantly,the prodrug nanoassemblies enabled selective activation within tumor cells,and the conversion rates of SN38-SS-C_(21) NPs and SN38-S-C_(21) NPs to SN38 were 10-and 7-fold higher than irinotecan.Compared with SN38-S-C_(21) NPs,the superior in vivo stability,SN38 conversion efficiency and tumor selectivity of SN38-SSC_(21) NPs resulted in potent antitumor effects and safety.Our findings proved that the disulfide bond was more suitable for constructing high-performance SN38 prodrug nanoassemblies,which showed significant promise for the rational design of SN38 nanomedicines.展开更多
Carbon monoxide(CO)is a crucial gaseous signaling molecule that regulates various physiological and pathological processes,and may exert an anti-inflammatory and protective role in drug-induced liver injury(DILI).Desp...Carbon monoxide(CO)is a crucial gaseous signaling molecule that regulates various physiological and pathological processes,and may exert an anti-inflammatory and protective role in drug-induced liver injury(DILI).Despite this,understanding the exact relationship between CO and the occurrence and development of DILI remains challenging.Hence,there is an urgent need to develop a reliable and robust tool for the rapid visual detection and assessment of CO in this context.Herein,we presented a novel near-infrared(NIR)fluorescent nanoprobe with aggregation-induced emission(AIE)properties and excited-state intramolecular proton transfer(ESIPT)characteristics for the detection and imaging of CO both in vitro and in vivo.Simultaneously,the nanoprobe enables self-assembly form nanoaggregates in aqueous media with high biocompatible,which can sense CO in situ through the conversion of yellowto-red fluorescence facilitated aggregation-induced dual-color fluorescence.What is more,this nanoprobe shows ratiometric respond to CO,which demonstrates excellent stability,high sensitivity(with a detection limit of 12.5 nmol/L),and superior selectivity.Crucially,this nanoprobe enables the visual detection of exogenous and endogenous CO in living cells and tissues affected by DILI,offering a user-friendly tool for real-time visualization of CO in living system.Hence,it holds great promise in advancing our understanding of CO’s role.展开更多
To clarify the role of TAFI in hypertensive disorders in pregnancy, 22 subjects, including 10 with pre-eclampsia （PE） and 12 with gestational hypertension were examined for the levels of TAFI and thrombin-antithromb...To clarify the role of TAFI in hypertensive disorders in pregnancy, 22 subjects, including 10 with pre-eclampsia （PE） and 12 with gestational hypertension were examined for the levels of TAFI and thrombin-antithrombin （TAT） complex. Thirty normal pregnant women served as controls. ELISA was employed for the detection. The results showed that the TAFI antigen levels in normal pregnancy group, gestational hypertension group and PE group were （85.35±24.69）%, （99.65±18.27）%, （110.12±23.36）%; （97.06±21.40）%, （114.08±27.76）%, （125.49±24.70）%; （106.6±19.21）%, （129.2±25.07）%, （139.1±30.12）%, in the 1st, 2nd and 3rd trimester respectively. No significant differences were found between the normal pregnancy group and gestational hypertension group but significant difference existed between normal pregnancy group and PE group in each trimester （P〈0.05）. TAT complexes were significantly higher in patients with PE than that in controls （P〈0.05）, but no correlation was found between TAT and TAFI. It is concluded that TAFI may contributed to the impairment of fibrinolysis in the patients with PE and may serves as a sensitive indicator for PE, but it may not help in the diagnosis of the gestational hypertension.展开更多
In this study, a fucoidan-based theranostic nanogel(CFN-gel) consisting of a fucoidan backbone, redox-responsive cleavable linker and photosensitizer is developed to achieve acti-vatable near-infrared fluorescence ima...In this study, a fucoidan-based theranostic nanogel(CFN-gel) consisting of a fucoidan backbone, redox-responsive cleavable linker and photosensitizer is developed to achieve acti-vatable near-infrared fluorescence imaging of tumor sites and an enhanced photodynamic therapy(PDT) to induce the com-plete death of cancer cells. A CFN-gel has nanomolar a nity for P-selectin, which is overexpressed on the surface of tumor neovascular endothelial cells as well as many other cancer cells. Therefore, a CFN-gel can enhance tumor accumulation through P-selectin targeting and the enhanced permeation and retention e ect. Moreover, a CFN-gel is non-fluorescent and non-phototoxic upon its systemic administration due to the aggregation-induced self-quenching in its fluorescence and singlet oxygen generation. After internalization into cancer cells and tumor neovascular endothelial cells, its photoactivity is recovered in response to the intracellular redox potential, thereby enabling selective near-infrared fluorescence imaging and an enhanced PDT of tumors. Since a CFN-gel also shows nanomolar a nity for the vascular endothelial growth factor, it also provides a significant anti-tumor e ect in the absence of light treatment in vivo. Our study indicates that a fucoidan-based theranostic nanogel is a new theranostic material for imaging and treating cancer with high e cacy and specificity.展开更多
AIM: To evaluate the effects of butein on inflammatory cytokines, matrix metalloproteinase-9(MMP-9), andcolitis in interleukin(IL)-10-/- mice.METHODS: To synchronize colitis, 8- to 10-wk-old IL-10-/- mice were fed pel...AIM: To evaluate the effects of butein on inflammatory cytokines, matrix metalloproteinase-9(MMP-9), andcolitis in interleukin(IL)-10-/- mice.METHODS: To synchronize colitis, 8- to 10-wk-old IL-10-/- mice were fed pellet-chow containing piroxicam for 2 wk. Subsequently, phosphate-buffered saline or butein(1 mg/kg per day, ip) was injected for 4 wk. Histologic scores, inflammatory cytokines, MMP-9 and phosphorylated signal transducer and activator of transcription 3(p STAT3) expressions were analyzed in IL-10-/- mice and in Colo 205 cells.RESULTS: Butein reduced the colonic inflammatory score by > 50%. Expression levels of IL-6, IL-1β, interferon(IFN)-γ and MMP-9 were decreased in the colons of mice exposed to butein, whereas other inflammatory cytokines(IL-17 A, IL-21 and IL-22) were unchanged. Immunohistochemical staining for p STAT3 and MMP-9 was significantly decreased in the buteintreated groups compared with the controls. Butein inhibited IL-6-induced activation of STAT3 in Colo 205 cells.CONCLUSION: Butein ameliorated colitis in IL-10-/-mice by regulating IL-6/STAT3 and MMP-9 activation.展开更多
Caspases are a family of proteases that play critical roles in controlling inflammation and cell death.Apoptosis is a caspase-3 mainly controlled behavior to avoid inflammation and damage to surrounding cells,whereas ...Caspases are a family of proteases that play critical roles in controlling inflammation and cell death.Apoptosis is a caspase-3 mainly controlled behavior to avoid inflammation and damage to surrounding cells,whereas anomalistic cell apoptosis may be associated with many diseases.The detection and imaging of caspase-3 will be of great significance in evaluating the early therapeutic effect of tumors.Developing smart fluorescent probes may be helpful for the visualization of the rapeutic effect compared with "always on" probes.Thus,more and more works toward activatable fluorescent probes for caspase-3 imaging have been reported.In addition,multifunctional probes have also been designed to further improve the imaging of caspase-3.Herein,this review systematically summarized the representative wo rk of caspase-3 from the perspective of molecular design that it will play a guiding role in the design of probes that respond to caspase-3.Also,challenges and perspectives toward the field for imaging of cell apoptosis(caspase-3) are also discussed.展开更多
CO2sequestration by mineral carbonation can permanently store CO2and mitigate climate change. However, the cost and reaction rate of mineral carbonation must be balanced to be viable for industrial applications. In th...CO2sequestration by mineral carbonation can permanently store CO2and mitigate climate change. However, the cost and reaction rate of mineral carbonation must be balanced to be viable for industrial applications. In this study, it was attempted to reduce the carbonation costs by using mine waste rock as a feed stock and to enhance the reaction rate using wet mechanical activation as a pre-treatment method. Slurry rheological properties, particle size distribution, specific surface area, crystallinity, and CO2 sequestration reaction efficiency of the initial and mechanically activated mine waste rock and olivine were characterized. The results show that serpentine acts as a catalyst, increasing the slurry yield stress, assisting new surface formation, and hindering the size reduction and structure amorphization. Mechanically activated mine waste rock exhibits a higher carbonation conversion than olivine with equal specific milling energy input. The use of a high-speed stirred mill may render the mineral carbonation suitable for mining industrial practice.展开更多
Recent years have seen the design and implementation of many optical activatable smart probes.These probes are activatable because they change their optical properties and are smart because they can identify specific ...Recent years have seen the design and implementation of many optical activatable smart probes.These probes are activatable because they change their optical properties and are smart because they can identify specific targets.This broad class of detection agents has allowed previously unperformed visualizations,facilitating the study of diverse biomolecules including enzymes,nucleic acids,ions and reactive oxygen species.Designed to be robust in an in vivo environment,these probes have been used in tissue culture cells and in live small animals.An emerging class of smart probes has been designed to harness the potency of singlet oxygen generating photosensitizers.Combining the discrimination of activatable agents with the toxicity of photosensitizers represents a new and powerful approach to disease treatment.This review highlights some applications of activatable smart probes with a focus on developments of the past decade.展开更多
Antibacterial agent of activatable photosensitizer not only has the advantages of traditional photosensitizers,such as good curative effect and low resistance,but also has better selectivity for bacteria and lower tox...Antibacterial agent of activatable photosensitizer not only has the advantages of traditional photosensitizers,such as good curative effect and low resistance,but also has better selectivity for bacteria and lower toxicity to normal tissues.Limited reports of activatable photosensitizer can be used to treat drugresistant bacteria.In order to meet this challenge,we designed and synthesized an activatable photosensitizer(Ce-OHOA),which can not only selectively identify methicillin-resistant Staphylococcus aureus(MRSA)with high expression ofβ-lactamase by fluorescence imaging,but also kill MRSA with less than10 times the concentration and 10 times the irradiation dose of CySG-2 reported.Ce-OHOA not only combines the dual functions of fluorescence diagnosis and photodynamic therapy,but also selectively acts on bacteria with high expression ofβ-lactamase and has little toxicity to normal cells.We expect that the study of this activating photosensitizer will provide a new solution for antibacterial photodynamic therapy(aPDT)of drug-resistant bacteria.展开更多
Precision medicine calls for advanced theranostics that integrate controllable diagnostic and therapeutic capabilities into one platform for disease treatment in the early stage.Phototheranostics such as fluorescence ...Precision medicine calls for advanced theranostics that integrate controllable diagnostic and therapeutic capabilities into one platform for disease treatment in the early stage.Phototheranostics such as fluorescence imaging(FLI),photoacoustic imaging(PAI),photodynamic therapy(PDT),and photothermal therapy(PTT)have attracted considerable attention in recent years,which mainly employ different excited-state energy dissipation pathways of a chromophore.According to the Jablonski diagram,FLI is related to the radiative process,PAI and PTT are derived from the nonradiative thermal deactivation,and PDT originates from the triplet state energy,in which these processes are usually competitive.Therefore,it is critically important to precisely tune the photophysical energy transformation processes to realize certain diagnosis and treatment properties in optimal state for boosting biomedical applications.Currently,there are mainly two strategies including chemical structure and aggregate behavior changes that relate to the regulation of excited state energy dissipation.In this review,we will discuss the recent advances of smart molecular probes that the photophysical properties can be regulated by external triggers and their applications in biomedical fields.We will summarize the development of activatable phototheranostic molecular probes in response to stimuli such as reactive oxygen species,pH,light,hypoxia,enzyme and gas.The assembly and disassembly of molecular aggregates that greatly affect the photophysical energy transformation processes will also be highlighted.This review aims to provide valuable insights into the development of more accurate diagnostic and therapeutic systems,thereby advancing the emerging field of smart medicine.展开更多
The single-locked photosensitizers(PSs)still suffer from off-target activation and skin phototoxicity in photodynamic therapy(PDT).Moreover,the efficacy of PDT is significantly limited by the antioxidant defense syste...The single-locked photosensitizers(PSs)still suffer from off-target activation and skin phototoxicity in photodynamic therapy(PDT).Moreover,the efficacy of PDT is significantly limited by the antioxidant defense system of tumor cells,particularly reduced glutathione(GSH).To address these limitations,we have developed a programmed activatable PS,designated as LET-19,specifically designed for acidity/GSH dual-locked PDT of tumors.LET-19 is constructed upon an iodinated cyanine structure,incorporating an oxazinane moiety and a 3,5-bis(trifluoromethyl)benzenethiol group.One lock is the oxazinane moiety that is capable of responding to acidic tumor microenvironment(TME),another lock is the 3,5-bis(trifluoromethyl)benzenethiol group that reacts to GSH.Notably,the fluorescence(FL),photoacoustic(PA),and photodynamic properties of LET-19 are initially suppressed.The programmed activation of acidity/GSH dual-locked PS is achieved by following steps:i)Once LET-19 enters tumor tissues,it is activated by the acidic TME;ii)Subsequently,LET-19 is taken up by tumor cells and further activated by GSH.Only in the occurrence of H+and GSH,whether in vitro or in vivo,both of the responsive units were sequentially recognized,thereby restoring FL/PA signals and the photodynamic capability of LET-19.This mechanism allows LET-19 to perform precise tumor identification by FL/PA dual-modality imaging,as well as improve the efficacy and safety of PDT.Meanwhile,in vitro and in vivo results demonstrate that LET-19 depletes GSH to inhibit the activity of glutathione peroxidase 4,disrupting redox homeostasis and thus amplifying the efficacy of PDT.This study provides a strategy to construct programmed activatable PSs for precision photodynamic theranostics of tumors.展开更多
Colon cancer is one of the malignant tumors with high morbidity and mortality worldwide,and its etiology is closely related to high levels of hydrogen sulfide(H_(2)S).To date,H_(2)S-activated near-infrared(NIR)fluores...Colon cancer is one of the malignant tumors with high morbidity and mortality worldwide,and its etiology is closely related to high levels of hydrogen sulfide(H_(2)S).To date,H_(2)S-activated near-infrared(NIR)fluorescent(FL)probes with high tumor tropism are still scarce.In this work,we created a new NIR FL probes(Cy-DG)that enables colon cancer targeted imaging and rapid fecal optical analysis by introducing an H_(2)S-recognition moiety and two D-glucosamine fragments on the scaffold of QCy7.Cy-DG exhibits excellent properties,including specific"off-on"response toward H_(2)S,intense NIR emission at 703 nm,large Stokes shift(118 nm),and high sensitivity(limit of detection(LOD),0.48μmol/L).Notably,the presence of D-glucosamine allows Cy-DG to be preferentially taken up by cancer cells.After intravenous administration,Cy-DG was able to efficiently accumulate in a MC38 intestinal cancer model and sensitively detect endogenous H_(2)S in vivo,showing 5.94-fold higher fluorescence intensity in small tumors<5 mm.Furthermore,Cy-DG was successfully used to detect H_(2)S in feces samples from colon cancer-bearing mice.We believe that Cy-DG has great potential as a powerful diagnostic tool for H_(2)S-related disorder and stool examinations in the future.展开更多
Melanoma is one of the most aggressive and deadliest forms of skin cancer.Besides traditional medicinal techniques,the use of photodynamic therapy is receiving increasing attention as a complementary method.Despite re...Melanoma is one of the most aggressive and deadliest forms of skin cancer.Besides traditional medicinal techniques,the use of photodynamic therapy is receiving increasing attention as a complementary method.Despite recent advances in the field,the majority of compounds unselectively localize inside the organism and are excited with blue or ultraviolet light,limiting the application of this method to superficial tumors.To overcome these drawbacks.展开更多
Quantitative visualization of pivotal biomarkers and accurate delineation of tumor lesion boundary are highly significant to assist surgeon precisely resect the tumors and reduce the risk of recurrence.Activatable flu...Quantitative visualization of pivotal biomarkers and accurate delineation of tumor lesion boundary are highly significant to assist surgeon precisely resect the tumors and reduce the risk of recurrence.Activatable fluorescent probes hold great promise for intraoperative guidance of tumor surgery with high signal-to-background ratio(SBR).Here,we report a γ-glutamyl transpeptidase(GGT)-activated fluorogenic probe Indol-Glu for quantitative visualization of GGT and fluorescence-guided tumor resection.The fluorescence of Indol-Glu was initially“off”state but was specifically activated by GGT to produce enhanced near-infrared(NIR)fluorescence(~37-fold at 741 nm).It is also accompanied by the formation of self-assemblies in the tumor microenvironment resulting in prolonged retention in tumor tissues,which was demonstrated to be able to apply for NIR imaging-guided surgical resection of GGT-overexpressed luciferase-transfected hepatocellular carcinoma(HCC/Luc)tumor.More notably,taking advantage of the ratiometric photoacoustic signal(PA_(690)/PA_(800))characteristic of Indol-Glu under the digestion of GGT,quantitative visual assessment of GGT activities in various tumor models was achieved in living mice.We believe that this research work may offer a powerful tool for precise diagnosis and surgical resection of malignant tumors.展开更多
Hypoxia is frequently found in the center of solid tumors.It contributes to drug resistance and is a major obstacle in the development of effective cancer therapy.Designing activatable theranostic agents for hypoxic c...Hypoxia is frequently found in the center of solid tumors.It contributes to drug resistance and is a major obstacle in the development of effective cancer therapy.Designing activatable theranostic agents for hypoxic cancer cells remains a big challenge.We herein report five novel cyclometalated iridium(Ⅲ)complexes with an attached anthraquinone moiety(Ir1–5)for hypoxic cancer cell therapy.The complexes efficiently respond to hypoxia with a turn-on yellow phosphorescence and were successfully used to detect hypoxia within 3D multicellular tumor spheroids.Moreover,the complexes are cytotoxic towards HeLa(human cervical carcinoma),HepG2(Human hepatocellular carcinoma),A549(human lung carcinoma),and A549R(cisplatin-resistant human lung carcinoma)cell lines,with Ir2 more than 50 times as active as cisplatin against the A549R cell line.Investigation of the localization of Ir1–5 indicates that mitochondria are the main cellular targets.Mitochondrial dysfunction and caspase-3 activation were found to be involved in the apoptotic cell death pathway induced by the complexes.These results demonstrate that the complexes have great potential for tumor diagnosis and therapy in the future.展开更多
A stimuli-activatable theranostic system enabling selective imaging and controlled phototherapies is highly essential for precise cancer diagnosis and treatment.Herein,we designed a smart theranostic nanoprobe that co...A stimuli-activatable theranostic system enabling selective imaging and controlled phototherapies is highly essential for precise cancer diagnosis and treatment.Herein,we designed a smart theranostic nanoprobe that comprised a photosensitizer(PS),gold nanorods(AuNRs)and a matrix metalloproteinase 2(MMP2)-responsive peptide linker.Apart from being applied for photodynamic therapy(PDT),PS has also been widely used for fluorescence imaging.Spatiotemporal control of the photoactivity of PS is of great importance for cancer theranostics.In the present work,due to the presence of Förster resonance energy transfer(FRET)between PS and AuNRs,the fluorescence and 1O_(2)production of PS were suppressed during the circulation,avoiding adverse damage to normal tissues;however,the nanoprobe could be activated for targeted imaging and selective PDT when the peptide linker was cleaved by overexpressed MMP2 in cancer cells.More importantly,the restored fluorescence could be successfully used to quantitatively detect MMP2 with a detection limit of 29 pM and to light up cancer cells,further guiding synergistically activated PDT/PTT(photothermal therapy)for highly efficient and special killing of cancer cells.This study can help design smart cancer-related biomarker-activatable theranostic probes for molecular sensing and site-specific cancer treatment.展开更多
The biggest challenge in using CRISPR technologies,which limits their widespread application in medicine,is off-target effects.These effects could,in principle,be minimized by ensuring that CRISPR is activated primari...The biggest challenge in using CRISPR technologies,which limits their widespread application in medicine,is off-target effects.These effects could,in principle,be minimized by ensuring that CRISPR is activated primarily in the targeted cells,thereby reducing the likelihood of unintended genetic modifications in non-target tissues.Therefore,the development of a light activatable CRISPR approach to dynamically control gene activation in both space and time would be highly beneficial.A drawback is that the overwhelming majority of recently introduced light activatable CRISPR systems require UV or blue light exposure,severely limiting the penetration depth of light in tissue at which CRISPR can be activated,and,in the case of UV light,raising safety concerns.A small number of systems that activate CRISPR using longer wavelengths are hindered by either slow light activation or issues related to toxicity and biocompatibility of the proposed techniques in humans.To address this,we developed a split-Cas9/dCas9 system in which activation is achieved through a near-infrared photocleavable dimerization complex.This photoactivation method can be safely used in humans in vivo,easily adapted to different split-Cas9/dCas9 systems,and enables rapid,spatially precise light activation across various cell types.展开更多
An activatable photosensitizer that could induce phototoxicity only in target sites is highly demanded to overcome the potential off-target toxicity in photodynamic therapy.It is of great significance to design tailor...An activatable photosensitizer that could induce phototoxicity only in target sites is highly demanded to overcome the potential off-target toxicity in photodynamic therapy.It is of great significance to design tailored photosensitizers with a new caging mechanism that can be activated by molecular signatures of pathogenic tissues.Herein,we report a novel supramolecularly activatable photosensitizer that employs cucurbit[7]uril(CB[7])to regulate the J-aggregate and monomer state of a thio-pentamethine cyanine dye withα-naphthyl group on side arms(Naph-α-TCy5),switching its photosensitizing property between off-on states.The host–vip complex Naph-α-TCy5-CB[7]is a caged photosensitizer with a superior luminescence property in an aqueous solution.It could be effectively activated by polyamines in cancer cells through competitive host–vip complexation;then the restored J-aggregates of Naph-α-TCy5 could efficiently generate singlet oxygen.Eventually,the supramolecularly activatable Naph-α-TCy5-CB[7]demonstrated appreciable antitumor bioactivity in vivo with excellent biosafety.It is anticipated that this design strategy of supramolecularly activatable photosensitizers opens new horizons for efficient photodynamic therapy with specificity and safety.展开更多
Real-time intraoperative guidance is indispensable for ensuring complete and safe tumor resection during oncological surgery.Activatable fluorescence probes have demonstrated promise in guiding surgery during intricat...Real-time intraoperative guidance is indispensable for ensuring complete and safe tumor resection during oncological surgery.Activatable fluorescence probes have demonstrated promise in guiding surgery during intricate procedures,offering high-contrast images with the“turn-on”fluorescence signal upon reaction with tumor markers.However,single-factor activatable probes still encounter the limitation of potentially generating“false positive”results in the complex in vivo environment.Herein,we have developed a dualfactor recognition activatable probe,NBD-BDP-E,to further enhance specificity to tumors via a cascade process.The incorporation of an epidermal growth factor receptor(EGFR)inhibitor,erlotinib,in the probe ensures tumor recognition and accelerated cellular uptake firstly.Following the probe response to the high concentration of Glutathione in cells,molecular fluorescence emission is restored for fluorescence image guidance.Ultimately,the d-PeT-based activatable probe,NBD-BDP-E,exhibited the ability to light up an EGFR-overexpressed tumor tissue accurately with a superior tumor-to-normal tissue ratio for image-guided surgery via in situ spraying.Moreover,it shows the ability to image tumor tissue about 1 mm in diameter,highlighting the potential for this probe to be used as a tool in surgical resection.展开更多
Dysregulated energy metabolism has recently been recognized as an emerging hallmark of cancer.Tumor cells,which are characterized by abnormal glycolysis,exhibit a lower extracellular pH(6.5–7.0)than nor-mal tissues(...Dysregulated energy metabolism has recently been recognized as an emerging hallmark of cancer.Tumor cells,which are characterized by abnormal glycolysis,exhibit a lower extracellular pH(6.5–7.0)than nor-mal tissues(7.2–7.4),providing a promising target for tumor-specific imaging and therapy.However,most pH-sensitive materials are unable to distinguish such a subtle pH difference owing to their wide and continuous pH-responsive range.In this study,we developed an efficient strategy for the fabrication of a tumor metabolic acidity-activatable calcium phosphate(CaP)fluorescent probe(termed MACaP9).Unlike traditional CaP-based biomedical nanomaterials,which only work within more acidic organelles,such as endosomes and lysosomes(pH 4.0–6.0),MACaP9 could not only specifically respond to the tumor extra-cellular pH but also rapidly convert pH variations into a distinct fluorescence signal to visually dis-tinguish tumor from normal tissues.The superior sensitivity and specificity of MACaP9 enabled high-contrast visualization of a broad range of tumors,as well as small tumor lesions.展开更多
基金supported by the National Key R&D Program of China(2022YFE0111600)the Key Research and Development Program of Liaoning Province(2024JH2/102500061)+7 种基金the Youth Innovation Team of Liaoning Provincial Department of Education(LJ222410163049)the Liaoning Revitalization Talents Program(XLYC2203083)the Open Fund of High-level Key Discipline of Chemistry of Chinese Medicine of the State Administration of Traditional Chinese Medicinethe Anhui University of Chinese Medicine(HKDCCM2024007)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(CPSF)(GZC20231-732)the China Postdoctoral Science Foundation(2023TQ0222,2023MD744229)the General Program of Department of Education of Liaoning Province(JYTMS20231372)the Doctoral Scientific Research Staring Foundation of Liaoning Province(2024-BS-073)。
文摘Irinotecan,one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer,suffers from extremely low activatability and non-selective tumor activation.7-Ethyl-10-hydroxy-camptothecin(SN38),the active metabolite of irinotecan,has been limited in clinical development due to poor water solubility and stability.Here,the thioether bond and disulfide bond were employed as response modules to construct tumor-selective SN38 prodrug nanoassemblies(SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs).11-Henicosanol was chosen as a self-assembly module to enhance stability.Both SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs presented ultra-high in vivo stability with a 12146-fold and 23151-fold elevation in the area under the curve(AUC)compared to SN38.Moreover,SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs showed a significant reduction of SN38exposure in blood compared to irinotecan.Importantly,the prodrug nanoassemblies enabled selective activation within tumor cells,and the conversion rates of SN38-SS-C_(21) NPs and SN38-S-C_(21) NPs to SN38 were 10-and 7-fold higher than irinotecan.Compared with SN38-S-C_(21) NPs,the superior in vivo stability,SN38 conversion efficiency and tumor selectivity of SN38-SSC_(21) NPs resulted in potent antitumor effects and safety.Our findings proved that the disulfide bond was more suitable for constructing high-performance SN38 prodrug nanoassemblies,which showed significant promise for the rational design of SN38 nanomedicines.
基金the National Natural Science Foundation of China(Nos.82272067,81974386,22107123 and M-0696)the Natural Science Foundation of Hunan Province(Nos.2021JJ41008,2022JJ80052,2022JJ40656,2023JJ20077)+2 种基金the Key Project of Changsha Science and Technology Plan(No.kh2201059)the Scientific Research Project of Health Commission of Hunan Province(No.B202313057213)the Youth Science Foundation of Xiangya Hospital(No.2022Q16).
文摘Carbon monoxide(CO)is a crucial gaseous signaling molecule that regulates various physiological and pathological processes,and may exert an anti-inflammatory and protective role in drug-induced liver injury(DILI).Despite this,understanding the exact relationship between CO and the occurrence and development of DILI remains challenging.Hence,there is an urgent need to develop a reliable and robust tool for the rapid visual detection and assessment of CO in this context.Herein,we presented a novel near-infrared(NIR)fluorescent nanoprobe with aggregation-induced emission(AIE)properties and excited-state intramolecular proton transfer(ESIPT)characteristics for the detection and imaging of CO both in vitro and in vivo.Simultaneously,the nanoprobe enables self-assembly form nanoaggregates in aqueous media with high biocompatible,which can sense CO in situ through the conversion of yellowto-red fluorescence facilitated aggregation-induced dual-color fluorescence.What is more,this nanoprobe shows ratiometric respond to CO,which demonstrates excellent stability,high sensitivity(with a detection limit of 12.5 nmol/L),and superior selectivity.Crucially,this nanoprobe enables the visual detection of exogenous and endogenous CO in living cells and tissues affected by DILI,offering a user-friendly tool for real-time visualization of CO in living system.Hence,it holds great promise in advancing our understanding of CO’s role.
基金a grant from the Key Program of Clinical Sciences of Ministry of Health of China (No. WGCF468)
文摘To clarify the role of TAFI in hypertensive disorders in pregnancy, 22 subjects, including 10 with pre-eclampsia （PE） and 12 with gestational hypertension were examined for the levels of TAFI and thrombin-antithrombin （TAT） complex. Thirty normal pregnant women served as controls. ELISA was employed for the detection. The results showed that the TAFI antigen levels in normal pregnancy group, gestational hypertension group and PE group were （85.35±24.69）%, （99.65±18.27）%, （110.12±23.36）%; （97.06±21.40）%, （114.08±27.76）%, （125.49±24.70）%; （106.6±19.21）%, （129.2±25.07）%, （139.1±30.12）%, in the 1st, 2nd and 3rd trimester respectively. No significant differences were found between the normal pregnancy group and gestational hypertension group but significant difference existed between normal pregnancy group and PE group in each trimester （P〈0.05）. TAT complexes were significantly higher in patients with PE than that in controls （P〈0.05）, but no correlation was found between TAT and TAFI. It is concluded that TAFI may contributed to the impairment of fibrinolysis in the patients with PE and may serves as a sensitive indicator for PE, but it may not help in the diagnosis of the gestational hypertension.
基金supported by the Ministry of Oceans and Fisheries,Korea(the project title:Development of marine material based near infrared fluorophore complex and diagnostic imaging instruments)by a Grant(1910070)from the National Cancer Center
文摘In this study, a fucoidan-based theranostic nanogel(CFN-gel) consisting of a fucoidan backbone, redox-responsive cleavable linker and photosensitizer is developed to achieve acti-vatable near-infrared fluorescence imaging of tumor sites and an enhanced photodynamic therapy(PDT) to induce the com-plete death of cancer cells. A CFN-gel has nanomolar a nity for P-selectin, which is overexpressed on the surface of tumor neovascular endothelial cells as well as many other cancer cells. Therefore, a CFN-gel can enhance tumor accumulation through P-selectin targeting and the enhanced permeation and retention e ect. Moreover, a CFN-gel is non-fluorescent and non-phototoxic upon its systemic administration due to the aggregation-induced self-quenching in its fluorescence and singlet oxygen generation. After internalization into cancer cells and tumor neovascular endothelial cells, its photoactivity is recovered in response to the intracellular redox potential, thereby enabling selective near-infrared fluorescence imaging and an enhanced PDT of tumors. Since a CFN-gel also shows nanomolar a nity for the vascular endothelial growth factor, it also provides a significant anti-tumor e ect in the absence of light treatment in vivo. Our study indicates that a fucoidan-based theranostic nanogel is a new theranostic material for imaging and treating cancer with high e cacy and specificity.
基金Supported by Grants from the National Research Foundation of Korea,No.R1102452Korea University,No.K1220161by experimental techniques from the Core Laboratory for Convergent Translational Research of College of Medicine
文摘AIM: To evaluate the effects of butein on inflammatory cytokines, matrix metalloproteinase-9(MMP-9), andcolitis in interleukin(IL)-10-/- mice.METHODS: To synchronize colitis, 8- to 10-wk-old IL-10-/- mice were fed pellet-chow containing piroxicam for 2 wk. Subsequently, phosphate-buffered saline or butein(1 mg/kg per day, ip) was injected for 4 wk. Histologic scores, inflammatory cytokines, MMP-9 and phosphorylated signal transducer and activator of transcription 3(p STAT3) expressions were analyzed in IL-10-/- mice and in Colo 205 cells.RESULTS: Butein reduced the colonic inflammatory score by > 50%. Expression levels of IL-6, IL-1β, interferon(IFN)-γ and MMP-9 were decreased in the colons of mice exposed to butein, whereas other inflammatory cytokines(IL-17 A, IL-21 and IL-22) were unchanged. Immunohistochemical staining for p STAT3 and MMP-9 was significantly decreased in the buteintreated groups compared with the controls. Butein inhibited IL-6-induced activation of STAT3 in Colo 205 cells.CONCLUSION: Butein ameliorated colitis in IL-10-/-mice by regulating IL-6/STAT3 and MMP-9 activation.
基金financially supported by the National Natural Science Foundation of China(Nos.22074050,22022404,21804033)Wuhan Scientific and Technological Projects(No.2019020701011441)+2 种基金Open Research Fund supported by the Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Fund(No.SKL-HIDCA-2019-11)State Key Laboratory of Elemento-Organic Chemistry,Nankai University(No.201901)the ministry of education Key laboratory for the Synthesis and Application of Organic Functional Molecules,Hubei University(No.KLSAOFM2011).
文摘Caspases are a family of proteases that play critical roles in controlling inflammation and cell death.Apoptosis is a caspase-3 mainly controlled behavior to avoid inflammation and damage to surrounding cells,whereas anomalistic cell apoptosis may be associated with many diseases.The detection and imaging of caspase-3 will be of great significance in evaluating the early therapeutic effect of tumors.Developing smart fluorescent probes may be helpful for the visualization of the rapeutic effect compared with "always on" probes.Thus,more and more works toward activatable fluorescent probes for caspase-3 imaging have been reported.In addition,multifunctional probes have also been designed to further improve the imaging of caspase-3.Herein,this review systematically summarized the representative wo rk of caspase-3 from the perspective of molecular design that it will play a guiding role in the design of probes that respond to caspase-3.Also,challenges and perspectives toward the field for imaging of cell apoptosis(caspase-3) are also discussed.
基金financially supported by the State Scholarship Fund from the China Scholarship Council(No.2008110820) and Carbon Management Canada
文摘CO2sequestration by mineral carbonation can permanently store CO2and mitigate climate change. However, the cost and reaction rate of mineral carbonation must be balanced to be viable for industrial applications. In this study, it was attempted to reduce the carbonation costs by using mine waste rock as a feed stock and to enhance the reaction rate using wet mechanical activation as a pre-treatment method. Slurry rheological properties, particle size distribution, specific surface area, crystallinity, and CO2 sequestration reaction efficiency of the initial and mechanically activated mine waste rock and olivine were characterized. The results show that serpentine acts as a catalyst, increasing the slurry yield stress, assisting new surface formation, and hindering the size reduction and structure amorphization. Mechanically activated mine waste rock exhibits a higher carbonation conversion than olivine with equal specific milling energy input. The use of a high-speed stirred mill may render the mineral carbonation suitable for mining industrial practice.
基金supported by Canadian Cancer Society Grant#018510 through the National Cancer Institute of Canada.
文摘Recent years have seen the design and implementation of many optical activatable smart probes.These probes are activatable because they change their optical properties and are smart because they can identify specific targets.This broad class of detection agents has allowed previously unperformed visualizations,facilitating the study of diverse biomolecules including enzymes,nucleic acids,ions and reactive oxygen species.Designed to be robust in an in vivo environment,these probes have been used in tissue culture cells and in live small animals.An emerging class of smart probes has been designed to harness the potency of singlet oxygen generating photosensitizers.Combining the discrimination of activatable agents with the toxicity of photosensitizers represents a new and powerful approach to disease treatment.This review highlights some applications of activatable smart probes with a focus on developments of the past decade.
基金financially supported by the National Natural Science Foundation of China (No.21977081)Zhejiang Provincial Natural Science of Foundation of China (No.LQ21H190006)。
文摘Antibacterial agent of activatable photosensitizer not only has the advantages of traditional photosensitizers,such as good curative effect and low resistance,but also has better selectivity for bacteria and lower toxicity to normal tissues.Limited reports of activatable photosensitizer can be used to treat drugresistant bacteria.In order to meet this challenge,we designed and synthesized an activatable photosensitizer(Ce-OHOA),which can not only selectively identify methicillin-resistant Staphylococcus aureus(MRSA)with high expression ofβ-lactamase by fluorescence imaging,but also kill MRSA with less than10 times the concentration and 10 times the irradiation dose of CySG-2 reported.Ce-OHOA not only combines the dual functions of fluorescence diagnosis and photodynamic therapy,but also selectively acts on bacteria with high expression ofβ-lactamase and has little toxicity to normal cells.We expect that the study of this activating photosensitizer will provide a new solution for antibacterial photodynamic therapy(aPDT)of drug-resistant bacteria.
基金supported by the NSFC(82172081 and 52103168)the Science and Technology Program of Tianjin,China(21JCZDJC00970 and 22JCQNJC01640)Tianjin Key Medical Discipline(Specialty)Construction Project,and the Fundamental Research Funds for the Central Universities(63243137).
文摘Precision medicine calls for advanced theranostics that integrate controllable diagnostic and therapeutic capabilities into one platform for disease treatment in the early stage.Phototheranostics such as fluorescence imaging(FLI),photoacoustic imaging(PAI),photodynamic therapy(PDT),and photothermal therapy(PTT)have attracted considerable attention in recent years,which mainly employ different excited-state energy dissipation pathways of a chromophore.According to the Jablonski diagram,FLI is related to the radiative process,PAI and PTT are derived from the nonradiative thermal deactivation,and PDT originates from the triplet state energy,in which these processes are usually competitive.Therefore,it is critically important to precisely tune the photophysical energy transformation processes to realize certain diagnosis and treatment properties in optimal state for boosting biomedical applications.Currently,there are mainly two strategies including chemical structure and aggregate behavior changes that relate to the regulation of excited state energy dissipation.In this review,we will discuss the recent advances of smart molecular probes that the photophysical properties can be regulated by external triggers and their applications in biomedical fields.We will summarize the development of activatable phototheranostic molecular probes in response to stimuli such as reactive oxygen species,pH,light,hypoxia,enzyme and gas.The assembly and disassembly of molecular aggregates that greatly affect the photophysical energy transformation processes will also be highlighted.This review aims to provide valuable insights into the development of more accurate diagnostic and therapeutic systems,thereby advancing the emerging field of smart medicine.
基金supported by National Natural Science Foundation of China(U23A2097,82302362,and T2421003)Shenzhen Science and Technology Program(JCYJ20220818095806014,KQTD20190929172538530,and JCYJ20240813143026034)+3 种基金the Key Project of Department of Education of Guangdong Province(2025ZDZX2060)Research Team Cultivation Program of Shenzhen University(2023QNT019)the Shenzhen University 2035 Program for Excellent Research(2023B006)the Program for Youzuzhikeyan of Shenzhen University(SZU2024YZZKY002).
文摘The single-locked photosensitizers(PSs)still suffer from off-target activation and skin phototoxicity in photodynamic therapy(PDT).Moreover,the efficacy of PDT is significantly limited by the antioxidant defense system of tumor cells,particularly reduced glutathione(GSH).To address these limitations,we have developed a programmed activatable PS,designated as LET-19,specifically designed for acidity/GSH dual-locked PDT of tumors.LET-19 is constructed upon an iodinated cyanine structure,incorporating an oxazinane moiety and a 3,5-bis(trifluoromethyl)benzenethiol group.One lock is the oxazinane moiety that is capable of responding to acidic tumor microenvironment(TME),another lock is the 3,5-bis(trifluoromethyl)benzenethiol group that reacts to GSH.Notably,the fluorescence(FL),photoacoustic(PA),and photodynamic properties of LET-19 are initially suppressed.The programmed activation of acidity/GSH dual-locked PS is achieved by following steps:i)Once LET-19 enters tumor tissues,it is activated by the acidic TME;ii)Subsequently,LET-19 is taken up by tumor cells and further activated by GSH.Only in the occurrence of H+and GSH,whether in vitro or in vivo,both of the responsive units were sequentially recognized,thereby restoring FL/PA signals and the photodynamic capability of LET-19.This mechanism allows LET-19 to perform precise tumor identification by FL/PA dual-modality imaging,as well as improve the efficacy and safety of PDT.Meanwhile,in vitro and in vivo results demonstrate that LET-19 depletes GSH to inhibit the activity of glutathione peroxidase 4,disrupting redox homeostasis and thus amplifying the efficacy of PDT.This study provides a strategy to construct programmed activatable PSs for precision photodynamic theranostics of tumors.
基金financial support from the National Natural Science Foundation of China(Nos.22422407,22174078)the Fundamental Research Funds for the Central Universities,Nankai University(No.020-63253156)support from the Doctoral Foundation Program of Henan University of Technology(No.2021BS035)。
文摘Colon cancer is one of the malignant tumors with high morbidity and mortality worldwide,and its etiology is closely related to high levels of hydrogen sulfide(H_(2)S).To date,H_(2)S-activated near-infrared(NIR)fluorescent(FL)probes with high tumor tropism are still scarce.In this work,we created a new NIR FL probes(Cy-DG)that enables colon cancer targeted imaging and rapid fecal optical analysis by introducing an H_(2)S-recognition moiety and two D-glucosamine fragments on the scaffold of QCy7.Cy-DG exhibits excellent properties,including specific"off-on"response toward H_(2)S,intense NIR emission at 703 nm,large Stokes shift(118 nm),and high sensitivity(limit of detection(LOD),0.48μmol/L).Notably,the presence of D-glucosamine allows Cy-DG to be preferentially taken up by cancer cells.After intravenous administration,Cy-DG was able to efficiently accumulate in a MC38 intestinal cancer model and sensitively detect endogenous H_(2)S in vivo,showing 5.94-fold higher fluorescence intensity in small tumors<5 mm.Furthermore,Cy-DG was successfully used to detect H_(2)S in feces samples from colon cancer-bearing mice.We believe that Cy-DG has great potential as a powerful diagnostic tool for H_(2)S-related disorder and stool examinations in the future.
基金supported by the National Natural Science Foundation of China(No.22120102002)the Science and Technology Innovation Program of Hunan Province of China(No.2021RC5028).
文摘Melanoma is one of the most aggressive and deadliest forms of skin cancer.Besides traditional medicinal techniques,the use of photodynamic therapy is receiving increasing attention as a complementary method.Despite recent advances in the field,the majority of compounds unselectively localize inside the organism and are excited with blue or ultraviolet light,limiting the application of this method to superficial tumors.To overcome these drawbacks.
基金the financial support from the National Natural Science Foundation of China(Nos.T2325019 and 22077092)Basic Research Program of Jiangsu(No.BK20243030)+3 种基金the special project of“Technological innovation”project of CNNC Medical Industry Co.Ltd(No.ZHYLYB2021001)Four“Batches”Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province(No.2022XM19)the Open Project Program of the State Key Laboratory of Radiation Medicine and Protection(Nos.GZK1202309,GZK12023050,GZK12024016,and GZK12024013)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions。
文摘Quantitative visualization of pivotal biomarkers and accurate delineation of tumor lesion boundary are highly significant to assist surgeon precisely resect the tumors and reduce the risk of recurrence.Activatable fluorescent probes hold great promise for intraoperative guidance of tumor surgery with high signal-to-background ratio(SBR).Here,we report a γ-glutamyl transpeptidase(GGT)-activated fluorogenic probe Indol-Glu for quantitative visualization of GGT and fluorescence-guided tumor resection.The fluorescence of Indol-Glu was initially“off”state but was specifically activated by GGT to produce enhanced near-infrared(NIR)fluorescence(~37-fold at 741 nm).It is also accompanied by the formation of self-assemblies in the tumor microenvironment resulting in prolonged retention in tumor tissues,which was demonstrated to be able to apply for NIR imaging-guided surgical resection of GGT-overexpressed luciferase-transfected hepatocellular carcinoma(HCC/Luc)tumor.More notably,taking advantage of the ratiometric photoacoustic signal(PA_(690)/PA_(800))characteristic of Indol-Glu under the digestion of GGT,quantitative visual assessment of GGT activities in various tumor models was achieved in living mice.We believe that this research work may offer a powerful tool for precise diagnosis and surgical resection of malignant tumors.
基金supported by the National Science Foundation of China(No.21525105,21778079)the 973 Program(No.2015CB856301)+2 种基金the Ministry of Education of China(No.IRT-17R111)the Pearl River S&T Nova Program of Guangzhou(No.201806010136)the Fundamental Research Funds for the Central Universities(No.17lgjc11).
文摘Hypoxia is frequently found in the center of solid tumors.It contributes to drug resistance and is a major obstacle in the development of effective cancer therapy.Designing activatable theranostic agents for hypoxic cancer cells remains a big challenge.We herein report five novel cyclometalated iridium(Ⅲ)complexes with an attached anthraquinone moiety(Ir1–5)for hypoxic cancer cell therapy.The complexes efficiently respond to hypoxia with a turn-on yellow phosphorescence and were successfully used to detect hypoxia within 3D multicellular tumor spheroids.Moreover,the complexes are cytotoxic towards HeLa(human cervical carcinoma),HepG2(Human hepatocellular carcinoma),A549(human lung carcinoma),and A549R(cisplatin-resistant human lung carcinoma)cell lines,with Ir2 more than 50 times as active as cisplatin against the A549R cell line.Investigation of the localization of Ir1–5 indicates that mitochondria are the main cellular targets.Mitochondrial dysfunction and caspase-3 activation were found to be involved in the apoptotic cell death pathway induced by the complexes.These results demonstrate that the complexes have great potential for tumor diagnosis and therapy in the future.
基金National Natural Science Foundation of China(Projects 21601074,21431002,31471233 and 31771447)Fundamental Research Funds for the Central Universities(Project lzujbky-2017-Ot05,lzujbky-2018-Ot01 and lzujbky-2018-k05)Foundation of the Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations grant lzujbky-2017-kb05。
文摘A stimuli-activatable theranostic system enabling selective imaging and controlled phototherapies is highly essential for precise cancer diagnosis and treatment.Herein,we designed a smart theranostic nanoprobe that comprised a photosensitizer(PS),gold nanorods(AuNRs)and a matrix metalloproteinase 2(MMP2)-responsive peptide linker.Apart from being applied for photodynamic therapy(PDT),PS has also been widely used for fluorescence imaging.Spatiotemporal control of the photoactivity of PS is of great importance for cancer theranostics.In the present work,due to the presence of Förster resonance energy transfer(FRET)between PS and AuNRs,the fluorescence and 1O_(2)production of PS were suppressed during the circulation,avoiding adverse damage to normal tissues;however,the nanoprobe could be activated for targeted imaging and selective PDT when the peptide linker was cleaved by overexpressed MMP2 in cancer cells.More importantly,the restored fluorescence could be successfully used to quantitatively detect MMP2 with a detection limit of 29 pM and to light up cancer cells,further guiding synergistically activated PDT/PTT(photothermal therapy)for highly efficient and special killing of cancer cells.This study can help design smart cancer-related biomarker-activatable theranostic probes for molecular sensing and site-specific cancer treatment.
基金supported by US National Science Foundation grants EFRI 1830878,CBET 1948722,CBET 2220273,and CBET 2325317US National Institutes of Health grants R01 EB025173,R01 CA228029,R01 CA293050,R01 GM143749,and R21 AG085089.
文摘The biggest challenge in using CRISPR technologies,which limits their widespread application in medicine,is off-target effects.These effects could,in principle,be minimized by ensuring that CRISPR is activated primarily in the targeted cells,thereby reducing the likelihood of unintended genetic modifications in non-target tissues.Therefore,the development of a light activatable CRISPR approach to dynamically control gene activation in both space and time would be highly beneficial.A drawback is that the overwhelming majority of recently introduced light activatable CRISPR systems require UV or blue light exposure,severely limiting the penetration depth of light in tissue at which CRISPR can be activated,and,in the case of UV light,raising safety concerns.A small number of systems that activate CRISPR using longer wavelengths are hindered by either slow light activation or issues related to toxicity and biocompatibility of the proposed techniques in humans.To address this,we developed a split-Cas9/dCas9 system in which activation is achieved through a near-infrared photocleavable dimerization complex.This photoactivation method can be safely used in humans in vivo,easily adapted to different split-Cas9/dCas9 systems,and enables rapid,spatially precise light activation across various cell types.
基金supported by the National Natural Science Foundation of China(grant nos.22193020,22193021,and 21821001)the Strategic Priority Research Program of the Chinese Academy of Sciences(grant no.XDB36000000).
文摘An activatable photosensitizer that could induce phototoxicity only in target sites is highly demanded to overcome the potential off-target toxicity in photodynamic therapy.It is of great significance to design tailored photosensitizers with a new caging mechanism that can be activated by molecular signatures of pathogenic tissues.Herein,we report a novel supramolecularly activatable photosensitizer that employs cucurbit[7]uril(CB[7])to regulate the J-aggregate and monomer state of a thio-pentamethine cyanine dye withα-naphthyl group on side arms(Naph-α-TCy5),switching its photosensitizing property between off-on states.The host–vip complex Naph-α-TCy5-CB[7]is a caged photosensitizer with a superior luminescence property in an aqueous solution.It could be effectively activated by polyamines in cancer cells through competitive host–vip complexation;then the restored J-aggregates of Naph-α-TCy5 could efficiently generate singlet oxygen.Eventually,the supramolecularly activatable Naph-α-TCy5-CB[7]demonstrated appreciable antitumor bioactivity in vivo with excellent biosafety.It is anticipated that this design strategy of supramolecularly activatable photosensitizers opens new horizons for efficient photodynamic therapy with specificity and safety.
基金supported by National Natural Science Foundation of China(grant nos.21925802 and 22338005)Liaoning Binhai Laboratory(grant no.LBLB-2023-03)the Fundamental Research Funds for the Central Universities(grant no.DUT22LAB601).
文摘Real-time intraoperative guidance is indispensable for ensuring complete and safe tumor resection during oncological surgery.Activatable fluorescence probes have demonstrated promise in guiding surgery during intricate procedures,offering high-contrast images with the“turn-on”fluorescence signal upon reaction with tumor markers.However,single-factor activatable probes still encounter the limitation of potentially generating“false positive”results in the complex in vivo environment.Herein,we have developed a dualfactor recognition activatable probe,NBD-BDP-E,to further enhance specificity to tumors via a cascade process.The incorporation of an epidermal growth factor receptor(EGFR)inhibitor,erlotinib,in the probe ensures tumor recognition and accelerated cellular uptake firstly.Following the probe response to the high concentration of Glutathione in cells,molecular fluorescence emission is restored for fluorescence image guidance.Ultimately,the d-PeT-based activatable probe,NBD-BDP-E,exhibited the ability to light up an EGFR-overexpressed tumor tissue accurately with a superior tumor-to-normal tissue ratio for image-guided surgery via in situ spraying.Moreover,it shows the ability to image tumor tissue about 1 mm in diameter,highlighting the potential for this probe to be used as a tool in surgical resection.
基金the National Key Research and Development Program of China(2017YFC1309100,2017YFA0205200,and 2020YFA0211100)National Natural Science Foundation of China(81671753,91959124,21804104,32071406,51922077,and 51872205)+6 种基金China Postdoctoral Science Foundation(2019M650259)the Youth Innovation Team of Shaanxi UniversitiesNatural Science Foundation of Shaanxi Province of China(2020PT-020)the Fundamental Research Funds for the Central Universities(JB211202,and JC2112)the Open Project Program of the State Key Laboratory of Cancer Biology(Fourth Military Medical University)(CBSKL2019ZDKF06)the Foundation of National Facility for Translational Medicine(Shanghai)(TMSK2020-012)Young Talents Program,and Shanghai Municipal Commission of Health and Family Planning Foundation(2017YQ050)。
文摘Dysregulated energy metabolism has recently been recognized as an emerging hallmark of cancer.Tumor cells,which are characterized by abnormal glycolysis,exhibit a lower extracellular pH(6.5–7.0)than nor-mal tissues(7.2–7.4),providing a promising target for tumor-specific imaging and therapy.However,most pH-sensitive materials are unable to distinguish such a subtle pH difference owing to their wide and continuous pH-responsive range.In this study,we developed an efficient strategy for the fabrication of a tumor metabolic acidity-activatable calcium phosphate(CaP)fluorescent probe(termed MACaP9).Unlike traditional CaP-based biomedical nanomaterials,which only work within more acidic organelles,such as endosomes and lysosomes(pH 4.0–6.0),MACaP9 could not only specifically respond to the tumor extra-cellular pH but also rapidly convert pH variations into a distinct fluorescence signal to visually dis-tinguish tumor from normal tissues.The superior sensitivity and specificity of MACaP9 enabled high-contrast visualization of a broad range of tumors,as well as small tumor lesions.
