Fast-Responsive HClO-Activated Near-Infrared Fluorescent Probe for In Vivo Diagnosis of Inflammatory Bowel Disease and Ex Vivo Optical Fecal Analysis.

Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease, whose etiology is intimately related to the overproduction of hypochlorous acid (HClO). Optical monitoring of HClO in the living body favors real-time diagnosis of inflammatory diseases. However, HClO-activated near-infrared (NIR) fluorescent probes with rapid response and high inflammatory cell uptake are still lacking. Herein, we report an activatable acceptor-π-acceptor (A-π-A)-type NIR fluorescent probe (Cy-DM) bearing two d-mannosamine groups for the sensitive detection of HClO in early IBD and stool testing. Once reacted with HClO, nonfluorescent Cy-DM could be turned on within 2 s by generating a donor-π-acceptor (D-π-A) structure due to the enhanced intramolecular charge transfer mechanism, showing intense NIR fluorescence emission at 700 nm and a large Stokes shift of 115 nm. Moreover, it was able to sensitively and selectively image exogenous and endogenous HClO in the lysosomes of living cells with a detection limit of 0.84 µM. More importantly, because of the d-mannosamine modification, Cy-DM was efficiently taken up by inflammatory cells in the intestine after intravenous administration, allowing noninvasive visualization of endogenous HClO in a lipopolysaccharide-induced IBD mouse model with a high fluorescence contrast of 6.8/1. In addition, water-soluble Cy-DM has also been successfully applied in ex vivo optical fecal analysis, exhibiting a 3.4-fold higher fluorescence intensity in the feces excreted by IBD mice. We believe that Cy-DM is promising as an invaluable tool for rapid diagnosis of HClO-related diseases as well as stool testing.

Electron-Withdrawing Substituents Enhance the Type I PDT and NIR-II Fluorescence of BODIPY J Aggregates for Bioimaging and Cancer Therapy.

Organic dyes with simultaneously boosted near-infrared-II (NIR-II) fluorescence, type I photodynamic therapy (PDT), and photothermal therapy (PTT) in the aggregate state are still elusive due to the unclear structure-function relationship. Herein, electron-withdrawing substituents are introduced at the 5-indolyl positions of BODIPY dyes to form tight J-aggregates for enhanced NIR-II fluorescence and type I PDT/PTT. The introduction of an electron-rich julolidine group at the meso position and an electron-withdrawing substituent (-F) at the indolyl moiety can enhance intermolecular charge transfer and the hydrogen bonding effect, contributing to the efficient generation of superoxide radicals in the aggregate state. The nanoparticles of BDP-F exhibit NIR-II fluorescence at 1000 nm, good superoxide radical generation ability, and a high photothermal conversion efficiency (50.9%), which enabled NIR-II fluorescence-guided vasculature/tumor imaging and additive PDT/PTT. This work provides a strategy for constructing phototheranostic agents with enhanced NIR-II fluorescence and type I PDT/PTT for broad biomedical applications.

Diagnosis of Nonalcoholic Fatty Liver Disease via a H2S-Responsive Bioluminescent Probe Combined with Firefly Luciferase mRNA Delivery.

The early detection of nonalcoholic fatty liver disease (NAFLD) through bioluminescent probes is of great significance. However, there remains a challenge to apply them in nontransgenic natural animals due to the lack of exogenous luciferase. To address this issue, we herein report a new strategy for in situ monitoring of endogenous hydrogen sulfide (H2S) in the liver of NAFLD mice by leveraging a H2S-responsive bioluminescent probe (H-Luc) combined with firefly luciferase (fLuc) mRNA delivery. The probe H-Luc was created by installing a H2S recognition moiety, 2,4-dinitrophenol, onto the luciferase substrate (d-luciferin), which is allowed to release cage-free d-luciferin in the presence of H2S via a nucleophilic aromatic substitution reaction. In the meantime, the intracellular luciferase was introduced by lipid nanoparticle (LNP)-mediated fLuc mRNA delivery, rendering it suitable for bioluminescence (BL) imaging in vitro and in vivo. Based on this luciferase-luciferin system, the endogenous H2S could be sensitively and selectively detected in living cells, showing a low limit of detection (LOD) value of 0.72 µM. More importantly, after systematic administration of fLuc mRNA-loaded LNPs in vivo, H-Luc was able to successfully monitor the endogenous H2S levels in the NAFLD mouse model for the first time, displaying a 28-fold higher bioluminescence intensity than that in the liver of normal mice. We believe that this strategy may shed new light on the diagnosis of inflammatory liver disease, further elucidating the roles of H2S.

Visualization of Endogenous Hypochlorite in Drug-Induced Liver Injury Mice via a Bioluminescent Probe Combined with Firefly Luciferase mRNA-Loaded Lipid Nanoparticles.

Drug-induced liver injury (DILI) is a common liver disease with a high rate of morbidity, and its pathogenesis is closely associated with the overproduction of highly reactive hypochlorite (ClO-) in the liver. However, bioluminescence imaging of endogenous hypochlorite in nontransgenic natural mice remains challenging. Herein, to address this issue, we report a strategy for imaging ClO- in living cells and DILI mice by harnessing a bioluminescent probe formylhydrazine luciferin (ClO-Luc) combined with firefly luciferase (fLuc) mRNA-loaded lipid nanoparticles (LNPs). LNPs could efficiently deliver fLuc mRNA into living cells and in vivo, expressing abundant luciferase in the cytoplasm in situ. In the presence of ClO-, probe ClO-Luc locked by formylhydrazine could release cage-free d-luciferin through oxidation and follow-up hydrolysis reactions, further allowing for bioluminescence imaging. Moreover, based on the luciferase-luciferin system, it was able to sensitively and selectively detect ClO- in vitro with a limit of detection of 0.59 µM and successfully monitor the endogenous hypochlorite generation in the DILI mouse model for the first time. We postulate that this work provides a new method to elucidate the roles of ClO- in related diseases via bioluminescence imaging.

Real-time fluorescence imaging with indocyanine green during laparoscopic duodenum-preserving pancreatic head resection.

BACKGROUND: Laparoscopic duodenum-preserving pancreatic head resection (LDPPHR) is a surgical method used to treat benign and low-grade malignant pancreatic head tumors. This study aimed to determine the protective effect of common bile duct in LDPPHR using indocyanine green (ICG) fluorescence imaging. METHODS: A retrospective analysis of 30 patients treated with LDPPHR at the Second Affiliated Hospital of Nanchang University between January 2015 and November 2022 was performed. Patients were divided into two groups based on ICG use: ICG and non-ICG. RESULTS: Thirty patients received LDPPHR, 11 males and 19 females, and the age was 50.50 (M (IQR)) years (range: 19-76 years). LDPPHR was successfully performed in 27 (90 %) patients, LPD was performed in 1 (3 %) patient, and laparotomy conversion was performed in 2 (7 %) patients. One patient (3 %) died 21 days after surgery. The incidence of intraoperative bile duct injury in the ICG group was lower than that in the non-ICG group (10 % vs 60 %, P = 0.009), and the operation time in the ICG group was shorter than that in the non-ICG group (311.9 ± 14.97 vs 338.05 ± 18.75 min, P < 0.05). Postoperative pancreatic fistula occurred in 16 patients (53 %), including 10 with biochemical leakage (62.5 %), four with grade B (25 %), and two with grade C (12.5 %). Postoperative bile leakage occurred in four patients (13 %). CONCLUSIONS: The ICG fluorescence imaging technology in LDPPHR helps protect the integrity of the common bile duct and reduce the occurrence of intraoperative bile duct injury, postoperative bile leakage, and bile duct stenosis.

Electron-Withdrawing Substituents Allow Boosted NIR-II Fluorescence in J-Type Aggregates for Bioimaging and Information Encryption.

Developing molecular fluorophores with enhanced fluorescence in aggregate state for the second near-infrared (NIR-II) imaging is highly desirable but remains a tremendous challenge due to the lack of reliable design guidelines. Herein, we report an aromatic substituent strategy to construct highly bright NIR-II J-aggregates. Introduction of electron-withdrawing substituents at 3,5-aryl and meso positions of classic boron dipyrromethene (BODIPY) skeleton can promote slip-stacked J-type arrangement and further boost NIR-II fluorescence of J-aggregates via increased electrostatic repulsion and intermolecular hydrogen bond interaction. Notably, NOBDP-NO2 with three nitro groups (-NO2 ) shows intense NIR-II fluorescence at 1065 nm and high absolute quantum yield of 3.21 % in solid state, which can be successfully applied in bioimaging, high-level encoding encryption, and information storage. Moreover, guided by this electron-withdrawing substituent strategy, other skeletons (thieno-fused BODIPY, aza-BODIPY, and heptamethine cyanine) modified with -NO2 are converted into J-type aggregates with enhanced NIR-II fluorescence, showing great potential to convert aggregation caused emission quenching (ACQ) dyes into brilliant J-aggregates. This study provides a universal method for construction of strong NIR-II emissive J-aggregates by rationally manipulating molecular packing and establishing relationships among molecular structures, intermolecular interactions, and fluorescence properties.

Laparoscopic anatomical left hemihepatectomy guided by middle hepatic vein in the treatment of left hepatolithiasis with a history of upper abdominal surgery.

BACKGROUND: This study aimed to investigate the safety and efficacy of laparoscopic anatomical left hemihepatectomy guided by the middle hepatic vein (MHV) for the treatment of patients with hepatolithiasis who had a history of upper abdominal surgery. METHODS: Retrospective data analysis was performed on patients who underwent laparoscopic left hepatectomy for hepatolithiasis and with previous upper abdominal surgery at the Second Affiliated Hospital of Nanchang University from January 2018 to April 2022. According to the different surgical approaches, patients were divided into laparoscopic anatomical left hepatectomy guided by the MHV group (MHV-AH group) and laparoscopic traditional anatomical left hepatectomy not guided by the MHV group (non-MHV-AH group). RESULTS: This study included 81 patients, with 37 and 44 patients in the MHV-AH and non-MHV-AH groups, respectively. There was no significant difference in the basic information between the two groups. Five cases were converted to laparotomy, and the remaining were successfully completed under laparoscopy. Compared to the non-MHV-AH group, the MHV-AH group had a slightly longer operation time (319.30 min vs 273.93 min, P = 0.032), lower bile leakage rate (5.4% vs 20.5%, P = 0.047), stone residual rate (2.7% vs 20.5%, P = 0.015), stone recurrence rate (5.4% vs 22.7%, P = 0.028), and cholangitis recurrence rate (2.7% vs 22.7%, P = 0.008).There were no significant differences in the results of other observation indices between the groups. CONCLUSIONS: Laparoscopic anatomical left hepatectomy guided by the MHV is safe and effective in the treatment of left hepatolithiasis with a history of upper abdominal surgery. It does not increase intraoperative bleeding and reduces the risk of postoperative bile leakage, residual stones, stone recurrence, and cholangitis recurrence.

Modular Design of Biodegradable Ionizable Lipids for Improved mRNA Delivery and Precise Cancer Metastasis Delineation In Vivo.

Lipid nanoparticles (LNPs) represent the most clinically advanced nonviral mRNA delivery vehicles; however, the full potential of the LNP platform is greatly hampered by inadequate endosomal escape capability. Herein, we rationally introduce a disulfide bond-bridged ester linker to modularly synthesize a library of 96 linker-degradable ionizable lipids (LDILs) for improved mRNA delivery in vivo. The top-performing LDILs are composed of one 4A3 amino headgroup, four disulfide bond-bridged linkers, and four 10-carbon tail chains, whose unique GSH-responsive cone-shaped architectures endow optimized 4A3-SCC-10 and 4A3-SCC-PH lipids with superior endosomal escape and rapid mRNA release abilities, outperforming their parent lipids 4A3-SC-10/PH without a disulfide bond and control lipids 4A3-SSC-10/PH with a disulfide bond in the tail. Notably, compared to DLin-MC3-DMA via systematic administration, 4A3-SCC-10- and 4A3-SCC-PH-formulated LNPs significantly improved mRNA delivery in livers by 87-fold and 176-fold, respectively. Moreover, 4A3-SCC-PH LNPs enabled the highly efficient gene editing of 99% hepatocytes at a low Cre mRNA dose in tdTomato mice following intravenous administration. Meanwhile, 4A3-SCC-PH LNPs were able to selectively deliver firefly luciferase mRNA and facilitate luciferase expression in tumor cells after intraperitoneal injection, further improving cancer metastasis delineation and surgery via bioluminescence imaging. We envision that the chemistry adopted here can be further extended to develop new biodegradable ionizable lipids for broad applications such as gene editing and cancer immunotherapy.

Traceable Attribute-Based Encryption With Equality Test for Cloud Enabled E-Health System.

The emerging Internet of Things (IoTs) and cloud technologies spark dramatic growth in efficiency and productivity for the conventional e-health sector. However, the extensive applications of the communication network also expose the sensitive medical data to the unprecedented cyber threats. To protect the data privacy in IoTs-based e-health cloud environments, we propose an adaptively secure data sharing scheme with traceability and equality test (T-ABEET). The T-ABEET not only allows flexible access control to the massive data but also provides the functionality of traitor tracing to identity the users who leak their decryption keys. Meanwhile, through carrying out the equality test, the target ciphertext can be retrieved efficiently without revealing anything about the plaintext. Particularly, distinct from previous traceable ABE works, the tracing cost in our T-ABEET scheme keeps constant even with the increasing number of users. Also, by introducing the multi-authority mechanism, our T-ABEET can avoid the inherent key escrow problem of ABE. Furthermore, our T-ABEET is demonstrated adaptively secure under subgroup decision assumption. Finally, performance comparison reveals that our T-ABEET has superior practicality, efficiency, and security in cloud-enabled e-health systems.

Non-Solvatochromic Cell Membrane-Targeted NIR Fluorescent Probe for Visualization of Polarity Abnormality in Drug-Induced Liver Injury Mice.

Noninvasive visualization of liver polarity by using fluorescence imaging technology is helpful to better understand drug-induced liver injury (DILI). However, cell membrane-targeted polarity-sensitive near-infrared (NIR) fluorescent probes are still scarce. Herein, we report a non-solvatochromic cell membrane-targeted NIR small molecular probe (N-BPM-C10) for monitoring the polarity changes on cell membranes in living cells and in vivo. N-BPM-C10 exhibits polarity-dependent fluorescence around 655 nm without an obvious solvatochromic effect, which endows it with good capability for the in vivo imaging study. Moreover, it can rapidly and selectively light up the cell membranes as well as distinguish tumor cells from normal cells due to its excellent polarity-sensitive ability. More importantly, N-BPM-C10 has been successfully applied to visualize liver polarity changes in vivo, revealing the reduction of liver polarity in DILI mice. We believe that N-BPM-C10 provides a new way for the diagnosis of DILI.

"Dual-Key-and-Lock" NIR-II NSCyanines Enable High-Contrast Activatable Phototheranostics in Extrahepatic Diseases.

Conventional cyanine dyes with a symmetric structure are "always-on", which can easily accumulate in the liver and display high liver background fluorescence, inevitably interfering the accurate diagnosis and therapy in extrahepatic diseases. We herein report a platform of NIR-II non-symmetric cyanine (NSCyanine) dyes by harnessing a non-symmetric strategy, which are extremely sensitive to pH/viscosity and can be activated via a "dual-key-and-lock" strategy. These NSCyanine dyes with a low pKa (<4.0) only show weak fluorescence at lysosome pH (key1), however, the fluorescence can be completely switched on and significantly enhanced by intracellular viscosity (key2) in disease tissues, exhibiting high target-to-liver ratios up to 19.5/1. Notably, high-contrast phototheranostics in extrahepatic diseases are achieved, including intestinal metastasis-imaging, acute gastritis-imaging, bacteria infected wound healing, and tumor ablation via targeted combined photothermal therapy and chemotherapy.

Effect of different lymph node dissection methods on the number of lymph nodes detected and prognosis in gallbladder cancer.

At present, the extent of lymph node dissection (LND) for radical gallbladder cancer (GBC) is still controversial, and there is no evidence that LND improves prognosis, however, the latest guidelines for GBC recommend that removal of more than 6 lymph nodes facilitates staging of regional lymph nodes. The aim of this study is to investigate the effect of different LND methods on the number of lymph nodes detected and assess the prognostic factors during radical resection of GBC. This study retrospectively analyzed 133 patients (46 men and 87 women; average age: 64.01, range: 40-83 years) who underwent radical resection of GBC in a single center between July 2017 and July 2022, of which 41 underwent fusion lymph node dissection (FLND) and 92 underwent standard lymph node dissection (SLND). Baseline data, surgical results, number of LNDs, and follow-up data were analyzed. Each patient was followed up every 3 months. The total number of lymph nodes detected after the operation was 12.00 ± 6.95 versus 6.10 ± 4.71 (P < .05). The number of positive lymph nodes detected was (mean) 1.85 versus 0.78 and (percentage) 15.45% versus 12.83% (P < .05). Postoperative complications (8 vs 23, P > .05). The progression-free survival was 13 versus 8 months, the median survival time was 17 versus 9 months (P < .05). This study concluded that FLND can increase the detection rate of total lymph nodes and positive lymph nodes after surgery, which can prolong the survival time of patients.

Case report: Preliminary response to tislelizumab plus S-1 in patients with metastatic gallbladder carcinoma: A report of five cases and a literature review.

Gallbladder cancer (GBC) and cholangiocarcinoma are common cancers of the biliary system and are associated with a poor prognosis. Surgery and chemotherapy provide limited benefit to patients with advanced biliary tract carcinoma. Novel immunotherapies and molecularly targeted therapies are more effective options; however, few patients benefit and drug resistance is a concern. Here, we report five cases of advanced GBC with either high programmed death-ligand 1 (PD-L1) expression or a high tumor mutation burden (TMB-H). The patients were treated with a combination therapy of tislelizumab and S-1. The tumors were effectively controlled in most patients. One patient developed immune-related pneumonia (irP) during treatment, which resolved after hormone therapy, and the patient underwent surgery. Tislelizumab and S-1 were administered again after surgery; however, recurrent irP required discontinuation, and the tumor progressed after drug withdrawal. These cases demonstrate that combined therapy of anti-programmed cell death protein-1 (PD-1) antibodies and S-1 is a safe and effective regimen with few side effects for GBC patients, especially for sensitive populations (patients with TMB-H, microsatellite instability, deficient mismatch repair, or high expression of PD-L1). To our knowledge, this is the first time that tislelizumab in combination with S-1 has been used to treat patients with advanced GBC.

Laparoscopic Transcystic Common Bile Duct Exploration: 8-Year Experience at a Single Institution.

BACKGROUND: Laparoscopic transcystic common bile duct exploration (LTCBDE) is used to treat cholecystolithiasis and choledocholithiasis. This study aimed to investigate the safety, effectiveness and generalisability of LTCBDE in patients with cholecystolithiasis and choledocholithiasis based on our LTCBDE experience within 8 years. METHODS: Four hundred patients with cholecystolithiasis and choledocholithiasis (including 62 of cholecystolithiasis and choledocholithiasis with common bile duct no-dilatation) treated with LTCBDE at a single centre from January 2014 to February 2022 were retrospectively evaluated. They were divided into the first 200 and last 200 LTCBDE cases. The disease characteristics, cystic duct incision methods, surgical outcomes and follow-up data were analysed retrospectively. Each patient was followed up for > 3 months. RESULTS: Four hundred patients underwent LTCBDE, including 188 males and 212 females aged from 15 to 91 years (average age: 56 years). LTCBDE was successful in 377 (94.3%) patients, while treatment was converted to laparoscopic choledocholithotomy with T-tube drainage in 23 (5.8%), owing to intraoperative choledochoscope insertion failure. The CBD diameter (10.89 ± 1.76 vs 9.97 ± 2.39, P < 0.05), cystic duct diameter (4.62 ± 1.03 vs 5.03 ± 1.29, P < 0.05), and operation time (164.60 ± 24.30 vs 135.34 ± 30.00, P < 0.05). Residual stones were found in six (1.5%) patients and removed during the second operation; post-operative bile leakage was found in one (0.3%) patient, who was discharged safely after the second operation. CONCLUSIONS: Phase I LTCBDE is safe and effective in treating cholecystolithiasis and choledocholithiasis. With continuous technological advances, LTCBDE has been effectively promoted and applied.

BOIMPY-Based NIR-II Fluorophore with High Brightness and Long Absorption beyond 1000 nm for In Vivo Bioimaging: Synergistic Steric Regulation Strategy.

Fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) region holds great promise for in vivo bioimaging. However, it is challenging to develop a brilliant donor-acceptor-donor (D-A-D) type NIR-II fluorophore with maximal absorption beyond 1000 nm in aqueous solution. Herein, we report a bright D-A-D type BOIMPY-based NIR-II dye (NK1143) with peak absorption/emission at 1005/1143 nm for in vivo bioimaging. Co-assembly of NK1143, SC12 (intermolecular steric hindrance modulator), and DSPE-PEG2000 effectively inhibits H-aggregation of NK1143 in aqueous solution and enhances the brightness simultaneously up to 53-fold by leveraging synergistic steric regulation strategy. Notably, this strategy allows for deep optical penetration of 8 mm and high-resolution blood vessels imaging in vivo, displaying high signal-to-background ratio of 7.8/1 under 980 nm excitation. More importantly, the BOIMPY-based nanoprobe can passively target and clearly visualize broad types of tumor xenografts, further improving intraoperative NIR-II fluorescence-guided resection of tiny metastases of less than 1 mm. This work provides an effective strategy for the development of BOIMPY-based NIR-II organic fluorophores with broad applications.

Three Birds with One Stone: Acceptor Engineering of Hemicyanine Dye with NIR-II Emission for Synergistic Photodynamic and Photothermal Anticancer Therapy.

It is challenging to develop a near-infrared (NIR) small molecular photosensitizer for synergistic phototherapy in deep tissues. Herein, first, a heavy-atom-free NIR hemicyanine photosensitizer (BHcy) for 808 nm light-mediated synergistic photodynamic therapy/photothermal therapy (PDT/PTT) anticancer therapy by leveraging the acceptor engineering strategy is reported. This strategy endows BHcy with a more planar and larger π-conjugated structure, resulting in long NIR absorption/emission at 770/915-1200 nm as well as enhanced singlet oxygen (1 O2 ) generation ability and photothermal effect, which is ascribed to the reduced energy levels of excited singlet/triplet states and the promoted intersystem crossing process. Notably, BHcy-based nanoparticles (BHcy-NPs) exhibit efficient 1 O2 yield (12.9%) and high photothermal conversion efficiency (55.1%). More importantly, BHcy-NPs are able to significantly kill cancer cells by destroying main organelles and inhibit tumor growth in vivo after a single irradiation. Overall, this study provides a strategy to design new heavy-atom-free PDT/PTT agents for potential clinical applications.

Remission from the 5-Fu-Based Chemotherapy to Gemcitabine-Based Chemotherapy-Based on the Pathological Classification of Periampullary Carcinoma: A Case Report and Literature Review.

Background: Periampullary carcinoma, which includes ampullary carcinoma, pancreatic head cancer, distal common bile duct cancer, and duodenal papillary cancer, is a relatively rare malignancy with uncertain therapeutic options. Although several studies have investigated the efficacy of multiple adjuvant chemotherapy regimens for periampullary carcinoma treatment, the optimal regimen remains to be determined. The inherent heterogeneity of the mucosal origin divides periampullary carcinoma into intestinal and pancreaticobiliary types. Therefore, the selection of chemotherapy regimens based on pathological type may have potential therapeutic significance. Case Presentation: A 72-year-old woman with moderately differentiated periampullary adenocarcinoma experienced disease progression after receiving FOLFOX regimen. Subsequently, the sample was subtyped first by H&E evaluation and then by the evaluation of an IHC panel composed of CK20, CDX2, MUC1, MUC2, and MUC5AC. The pathologists concluded that the patient's sample was of the pancreaticobiliary (PB) subtype. The subsequent change to gemcitabine plus S-1 adjuvant therapy achieved remission of liver metastases based on the pathological classification of the cancer. Conclusion: Based on the pathological classification, adjuvant chemotherapy with gemcitabine may be beneficial for patients with PB subtype periampullary carcinoma. 5-Fu-based adjuvant chemotherapy may be beneficial for patients with intestinal subtype periampullary carcinoma.

Bichromatic Imaging with Hemicyanine Fluorophores Enables Simultaneous Visualization of Non-alcoholic Fatty Liver Disease and Metastatic Intestinal Cancer.

Simultaneous detection of different diseases via a single fluorophore is challenging. We herein report a bichromatic fluorophore named Cy-914 for the simultaneous diagnosis of non-alcoholic fatty liver disease (NAFLD) and metastatic intestinal cancer by leveraging its NIR-I/NIR-II dual-color imaging capability. Cy-914 with a pKa of 6.98 exhibits high sensitivity to pH and viscosity, showing turn-on NIR-I fluorescence at 795 nm in an acidic tumor microenvironment, meanwhile displaying intense NIR-II fluorescence at 914/1030 nm under neutral to slightly basic viscous conditions. Notably, Cy-914 could sensitively and noninvasively monitor viscosity variations in the progression of NAFLD. More importantly, it was able to simultaneously visualize NAFLD (ex/em = 808/1000-1700 nm) and intestinal metastases (ex/em = 570/810-875 nm) in two independent channels without spectral cross interference after topical spraying, further improving fluorescence-guided surgery of tiny metastases less than 3 mm. This strategy may provide an understanding for developing multi-color fluorophores for multi-disease diagnosis.

H2O2-Activated NIR-II Fluorescent Probe with a Large Stokes Shift for High-Contrast Imaging in Drug-Induced Liver Injury Mice.

Drug-induced liver injury (DILI) is the most common clinical adverse drug reaction, which is closely associated with the oxidative stress caused by overproduced reactive oxygen species. Hepatic H2O2, as an important biomarker of DILI, plays a crucial role in the progression of DILI. However, there remains a challenge to develop H2O2-activatable second near-infrared (NIR-II, 1000-1700 nm) small molecular probes with both a large Stokes shift and a long emission wavelength beyond 950 nm. Herein, we developed an activatable NIR-II fluorescent probe (IR-990) with an acceptor-π-acceptor (A-π-A) skeleton for real-time detection of H2O2 in vivo. In the presence of H2O2, nonfluorescent probe IR-990 was successfully unlocked by generating a donor-π-acceptor (D-π-A) structure and switched on intense NIR-II fluorescence, exhibiting a peak emission wavelength at 990 nm and a large Stokes shift of 200 nm. Moreover, it was able to detect H2O2 with high sensitivity and selectivity in vitro (LOD = 0.59 µM) and monitor the behavior of endogenous H2O2 in the HepG2 cell model of DILI for the first time. Notably, probe IR-990 was successfully applied in real-time imaging of endogenous H2O2 generation in the DILI mouse model, showing a high signal-to-background ratio of 11.3/1. We envision that IR-990 holds great potential as a powerful diagnosis tool for real-time visualization of H2O2 in vivo and revealing the mechanism of DILI in the future.

An acid-enhanced OFF-ON fluorescent probe for the detection of hypochlorous acid in rheumatoid arthritis.

Excessive production of hypochlorite acid (HClO) and lactic acid are general hallmarks in the microenvironment of rheumatoid arthritis (RA). Here, we, for the first time, report an acid-enhanced "OFF-ON" fluorescent probe PPS for the detection of HClO in vivo. The probe PPS showed good water solubility, large Stokes shift (143 nm), and fast response toward HClO within 100 s. In the presence of HClO, the sulfur atom in the core of phenothiazine would be oxidized into sulfoxide, triggering intense fluorescence at 580 nm, whose fluorescence intensity could be further enhanced under acidic conditions. Moreover, the exogenous and endogenous HClO in living cells could be sensitively and selectively detected by PPS with a low LOD of 24 nM. Notably, PPS was able to rapidly visualize endogenous HClO generation in a RA mouse model, exhibiting a 2.3-fold higher fluorescence intensity than it in normal joint and 4.1-fold enhanced fluorescence intensity at acidic pH.