Template-Free Self-Assembly of Hollow Microtubular Covalent Organic Frameworks for Oral Delivery of Insulin.

Covalent organic frameworks (COFs) have demonstrated versatile application potential since their discovery. Although the structure of COFs is orderly arranged, the synthesis of controllable macrostructures still faces challenges. Herein, we report, to our knowledge, the first template-free self-assembled COF-18 Å hollow microtubule (MT-COF-18 Å) structure and its use for insulin delivery that exhibits high loading capacity, gastroresistance, and glucose-responsive properties. The hollow MT-COF-18 Å was achieved by a template-free method benefiting from the mixed solvents of mesitylene and dioxane. The formation mechanism and morphology changes with insulin loading and release were observed. In Caco-2 cells, the transferrin-coated system demonstrated enhanced insulin cellular uptake and transcellular transport, which indicated great potential for oral applications. Additionally, the composites presented sustained glycemic control and effective insulin blood concentrations without noticeable toxicity in diabetic rats. This work shows that hollow microtubular COFs hold great promise in loading and delivery of biomolecules.

An MMP-2 sensitive and reduction-responsive prodrug amphiphile for actively targeted therapy of cancer by hierarchical cleavage.

A hierarchically cleaved amphiphile, mPEG-pep-etcSS-CPT, was synthesized to pursue actively targeted cancer therapy through self-assembly. This micelle can respond to MMP-2 achieving dePEGylation and releasing RGD peptides to be internalized into targetable tumor cells. Inside the cell, free CPT could be released by reduction-response leading to cytotoxicity.

The correlation factors and prognostic significance of coagulation disorders after chimeric antigen receptor T cell therapy in hematological malignancies: a cohort study.

Background: Along with cytokine release syndrome (CRS) and neurotoxicity, coagulation disorder is a common early complication of chimeric antigen receptor (CAR)-T cell therapy. However, the mechanisms and prognostic significance of CAR-T-related coagulation disorders are not fully known. This study explored the possible correlation factors and prognostic significance of coagulation disorders after CAR-T cell infusion in patients with relapsed/refractory hematological malignancies. Methods: This cohort study included 56 patients with relapsed/refractory hematological malignancies who were treated with CAR-T cells between April 2017 and February 2022. The median follow-up was 26.8 months. Coagulation disorders were defined as the abnormality in at least one coagulation parameters, including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, and D-dimer. The correlation factors of coagulation disorders were analyzed using Wilcoxon rank-sum test, Fisher's exact test, paired t-test and Spearman correlation coefficient. The prognostic significance of coagulation disorders was analyzed using Kaplan-Meier method and stepwise multivariate Cox regression model. Results: The incidence of coagulation disorders was 59% within 1 month of CAR-T cell infusion. PT prolongation, APTT prolongation, TT prolongation, and D-dimer increase peaked at a median of 6-9 days, and fibrinogen decreased to its lowest value at a median of 12 days. Coagulation disorders in patients with severe CRS were more significant (P<0.001). Abnormality of coagulation parameters was closely related to cytokines, CAR-T cells, liver function parameters, and von Willebrand Factor (VWF) in both peak level and peak time (P<0.05). Statistical analysis showed that coagulation disorders were associated with higher initial response rates (TT, P=0.006; D-dimer, P=0.010) and also longer progression-free survival (PFS) (PT, P=0.017; APTT, P=0.018; TT, P=0.001; Fibrinogen, P=0.003; D-dimer, P<0.001) in CAR-T therapy, with TT prolongation (HR =0.279, 95% CI: 0.099-0.782, P=0.015) and D-dimer increase (HR =0.218, 95% CI: 0.087-0.548, P=0.001) independent predictors for PFS. Conclusions: The protection of liver and endothelial cells may reduce CAR-T-related coagulation disorders. Further, coagulation disorders occurring within 1 month of CAR-T cell infusion can serve as a new predictor for prognosis in patients with hematological malignancies.

A novel coumarin-based fluorescent probe with fine selectivity and sensitivity for hypochlorite and its application in cell imaging.

It is necessary to develop simple and highly sensitive methods for the detection of hypochlorous acid (HOCl)/hypochlorite (ClO-) to ravel its relationship with disease. In this paper, a novel bio-compatible fluorescent (Z)-8-(hydrazonomethyl)-7-hydroxy-4-methyl-2H-chromen-2-one (probe 1b) based on coumarin was synthesized and used for detecting ClO- in PBS buffer (pH = 7.2, 10 mM, 60% C2H5OH). Probe 1b showed a remarkable fluorescence change from yellow to blue with the limit of detection as low as 2.4 × 10-9 M-1 when ClO- was added. The coexisted anions, metal ions and reactive oxygen species (•OH, 1O2, H2O2, KO2) showed any competitiveness towards ClO-. In response to ClO-, the fluorescence emission intensity of probe 1b was obviously enhanced within 20 s. The mechanism was confirmed by the ESI - MS and density functional theory calculations (DFT) to reveal that the coumarin lactone bonds C - O was cleavaged by oxidation of ClO-. What's more, probe 1b could be used in practical water samples and showed well recovery. Additionally, the cell imaging experiment was demonstrated that probe 1b could be effectively exploited to imaging exogenous ClO- in vitro.

Modulation of fluorescence sensing properties of coumarin-based fluorescent probe for H2S and its application in cell imaging.

A coumarin-based turn on probe, named 3-((E)-3-(1H-indol-3-yl)acryloyl)-2H-chromen-2-one(IAC) was designed and synthesized for the detection of H2S in aqueous medium. IAC showed no obvious red fluorescence in Tris-HCl(pH = 7.2, 60% DMF), a 28.2-fold fluorescence enhancement was found when 40 equiv. H2S was added. Other analytes such as anions, metal ions and GSH, Cys, Gly did no significant fluorescence enhancement at 580 nm to IAC. The red fluorescence enhancement mechanism between IAC and H2S was considered by DFT and ESI-MS. Overall, IAC was successfully applied in cell imaging.

Two coumarin-based turn-on fluorescent probes based on for hypochlorous acid detection and imaging in living cells.

This work, two turn-on fluorescent probes (3-acetyl-2H-chromen-2-one (ACO) & (1E)-1-(1-(2-oxo-2H-chromen-3-yl)ethylidene)thiosemicarbazide (CETC)) based on coumarin have been designed and synthesized, which could selectively and sensitively recognize ClO- with fast response time. ACO &CETC were almost non fluorescent possibly due to both the lacton form of coumarin and unbridged CN bonds which can undergo a nonradiative decay process in the excited state. Upon the addition of ClO-, ACO &CETC were oxidized to ring - opened by cleavage the CO and CN and the fluorescence intensity were increased considerably. Fluorescence titration experiments showed that the detection limit ACO &CETC is as low as 22 nm and 51 nm respectively. In particular, some relevant reactive species, including OH, 1O2, H2O2, KO2, some anions and cations cannot be interference with the test. In live cell experiments, ACO &CETC were successfully applied to image exogenous ClO- in HepG2 cells. Therefore, ACO &CETC not only could image ClO- in living cells but also proved that CO and CN can be cleavage by ClO-.

A highly specific and sensitive turn-on fluorescence probe for hypochlorite detection and its bioimaging applications.

Development of high performance fluorescent chemosensors for the detection of ClO- in vitro and in vivo is very desirable, because many human diseases are caused by ClO-. In this paper, a highly selectivity and sensitive fluorescent probe, EDPC, based on 3-acetylcoumarin, was synthesized, which could respond to ClO- and exhibit an "off-on" mode in Tris-HCl buffer (pH = 7.2, 10 mM, 50% C2H5OH) solutions. The detection limit of the EDPC probe for ClO- was as low as 1.2 × 10-8 M. Moreover, the high selectivity and high sensitivity of EDPC towards ClO- are attributed to the oxidation reaction between the C-O of the coumarin lactone and the C[double bond, length as m-dash]C formed by aldol condensation and the mechanism was further verified using ESI-MS and DFT. Additionally, the concentrations of ClO- in real water were also calculated using the EDPC probe and showed good recovery. Finally, the distribution of intracellular endogenous ClO- was gained by confocal fluorescence microscopy in living HEK293T cells.

Synthesis, X-ray crystal structure, DNA/BSA binding, DNA cleavage and cytotoxicity studies of phenanthroline based copper(II)/zinc(II) complexes.

Research on copperII 1,10-phenanththroline (phen) derivatives continues to attract interest in the context of structure and biological properties. In this paper, two metal complexes [Cu2(phen)2(µ-Cl)2]Cl2 (1), [Zn(phen)2(H2O)Cl]Cl·4H2O (2) were synthesized and characterized. The crystal structures of 1 and 2 were determined by X-ray diffraction. In order to investigate the biological properties of the prepared complexes, spectroscopic and biological studies were performed. Results of X-ray diffraction showed that 1 and 2 form two types of crystal structures in a given system: dinuclear and mono-nuclear complex. The preliminary study on the DNA cleavage activity has shown that 1 under study behaved as the chemical nucleases. The DNA binding interaction of 1 & 2 with CT-DNA has been investigated by UV-Visible and fluorescence emission spectrometry and the apparent binding constant (K app) values are 5.1 × 104 and 1.2 × 104 M-1, respectively. In addition, fluorescence spectrometry of bovine serum albumin (BSA) with 1 & 2 showed that the quenching mechanism might be a static quenching procedure with one binding sites for BSA. In addition, the cytotoxicity of 1 in vitro on tumor cells lines (MCF-7, HepG2 and HT29) was examined by MTT and showed better antitumor effect on the tested cells.