Latest ArticlesChemotherapy is the cornerstone of cancer treatment, and paclitaxel (PTX), as a first-line broad-spectrum chemotherapy drug, is widely used in the treatment of multiple tumors in the clinic. However, unsatisfactory efficacy and drug resistance of single chemotherapy have severely hampered the clinical progress of PTX. Herein, three-in-one naringenin (NAR)-loaded PTX polymer prodrug micelles were constructed for efficient and synergistic antitumor therapy. Firstly, the polymer prodrug micelles could simultaneously act as nanoreservoirs for two hydrophobic drugs, PTX and NAR. Secondly, the polymer prodrug micelles enabled dual-responsive intelligent release of PTX and NAR triggered by reduction and acid. Finally, released PTX and NAR exerted synergistic antitumor effects for reversing tumor resistance, while NAR enhanced the immune and anti-inflammatory functions of polymer prodrug micelles. Due to the cascade-enhanced chemotherapeutic augmentation, the intelligent-responsive nanoreservoir proved to be an excellent antitumor therapeutic platform. This work was of great interest for designing superior chemotherapeutic augmentation regimens.
Early recognition is key to improving the prognosis of ischemic stroke (IS), while available imaging methods tend to target events that have already undergone ischemia. A new method to detect early IS is urgently needed, as well as further study of its mechanisms. Viscosity and cysteine (Cys) levels of mitochondria have been associated with ferroptosis and IS. It is possible to identify IS and ferroptosis accurately and early by monitoring changes in mitochondrial Cys and viscosity simultaneously. In this work, a viscosity/Cys dual-responsive mitochondrial-targeted near-infrared (NIR) fluorescent probe (NVCP) was constructed for the precise tracking of IS using a two-dimensional design strategy. NVCP consists of a chromophore dyad containing diethylaminostyrene quinolinium rotor and chloro-sulfonylbenzoxadiazole (SBD-Cl) derivative with two easily distinguished emission bands (λem = 592 and 670 nm). NVCP performs the way of killing two birds with one stone, that is, the probe exhibits excellent selectivity and sensitivity for detecting viscosity and Cys in living cells with excellent biocompatibility and accurate mitochondrial targeting capability by dual channel imaging mode. In addition, NVCP recognized that the viscosity increases and Cys level decreases in cells when undergoing ferroptosis and oxygen-glucose deprivation (OGD) stress by confocal imaging, flow cytometry, and Western blot experiments. Treatment of ferroptosis inhibitors (ferrostatin-1 (Fer-1) and deferoxamine (DFO)) could reverse the variation tendency of viscosity and Cys. This is the first time that the relationship between ferroptosis and IS was identified through an analysis of Cys and viscosity. More importantly, the ischemic area was also instantly distinguished from normal tissues through fluorescence imaging of NVCP in vivo. The developed NIR dual-responsive probe NVCP toward viscosity and Cys could serve as a sensitive and reliable tool for tracking ferroptosis-related pathological processes during IS.
Photocatalytic overall water splitting is a promising method for producing clean hydrogen energy, but faces challenges such as low light utilization efficiency and high charge carrier recombination rates. This study demonstrates that dielectric Mie resonance in TiO2 hollow nanoshells can enhance electric field intensity and increase light absorption through resonant energy transfer, compared to crushed TiO2 nanoparticles. The Mie resonance effect was confirmed through fluorescence spectra, photo-response current measurements, photocatalytic water splitting experiments, and Mie calculation. The incident electric-field amplitude was doubled in hollow nanoshells, allowing for increased light trapping. Additionally, the spatially separated Pt and RuO2 cocatalysts on the inner and outer surfaces facilitated the separation of photoinduced electrons and holes. Pt@TiO2@RuO2 hollow nanoshells exhibited superior photocatalytic water splitting performance, with a stable H2 generation rate of 50.1 µmol g−1 h−1 and O2 evolution rate of 25.1 µmol g−1 h−1, outperforming other nanostructures such as TiO2, Pt@TiO2, and TiO2@RuO2 hollow nanoshells. This study suggests that dielectric Mie resonance and spatially-separated cocatalysts offer a new approach to simultaneously enhance light absorption and charge carrier transfer in photocatalysis.
Recent advances in drug development and bioactive molecules that covalently target lysine residues have shown substantial progress. Both reversible and irreversible covalent inhibitors are developed for targeting lysine residues. The identification of protein targets and binding sites of these lysine-targeting molecules in the whole proteome is crucial to understand their proteome-wide selectivity. For covalent inhibitors, the pull down-based methods including activity-based protein profiling (ABPP) are commonly used to profile their target proteins. For covalent reversible inhibitors, it is not easy to pull down the potential protein targets as the captured proteins may get off beads because of the reversible manner. Here, we report a pair of isotope-labelled click-free probes to competitively identify the protein targets of lysine-targeting covalent reversible small molecules. This pair of isotopic probes consists of a lysine-reactive warhead, a desthiobiotin moiety and isotopicable linker. This integrated probe could eliminate the background proteins induced by the click chemistry during the pull-down process. To demonstrate the feasibility of our newly-developed probes for the protein target identification, we selected the natural product Gossypol in that we proved for the first time that it could modify the lysine residue in a covalent reversible manner. Finally, we confirmed that this pair of integrated probes can be used in a competitive manner to precisely identify the protein target as well as binding sites of Gossypol. Interestingly, pretreatment of Gossypol could stop the antibody from recognizing Gossypol-binding proteins. Together, our isotope-labeled click-free probes could be used for whole-proteome profiling of lysine-targeting covalent reversible small molecules.
The aggressive nature and high mortality rate of lung cancer underscore the imperative need for early diagnosis of the disease. Thus, aminopeptidase N (APN), a potential biomarker for lung cancer, should be thoroughly investigated in this context. This report describes the development of HA-apn, a novel near-infrared fluorescent probe, specifically engineered for the sensitive detection of endogenous APN. Characterized by its high selectivity, straightforward molecular architecture, and suitable optical properties, including a long-wavelength emission at 835 nm and a large Stokes shift of 285 nm, HA-apn had high efficacy in identifying overexpressed APN in tumor cells, which shows its potential in pinpointing malignancies. To further validate its applicability and effectiveness in facilitating the direct and enhanced visualization of pulmonary alterations, an in situ lung cancer mouse model was employed. Notably, HA-apn was applied for in vivo imaging of APN activity in the lung cancer mouse model receiving the probe through aerosol inhalation, and rapid and precise diagnostic results were achieved within 30 min post-administration. Overall, HA-apn can be applied as an effective, non-intrusive tool for the rapid and accurate detection of pulmonary conditions.
Gallstones are a common disease worldwide, often leading to obstruction and inflammatory complications, which seriously affect the quality of life of patients. Research has shown that gallstone disease is associated with ferroptosis, lipid droplets (LDs), and abnormal levels of nitric oxide (NO). Fluorescent probes provide a sensitive and convenient method for detecting important substances in life systems and diseases. However, so far, no fluorescent probes for NO and LDs in gallstone disease have been reported. In this work, an effective ratiometric fluorescent probe LR-NH was designed for the detection of NO in LDs. With an anthracimide fluorophore and a secondary amine as a response site for NO, LR-NH exhibits high selectivity, sensitivity, and attractive ratiometric capability in detecting NO. Importantly, it can target LDs and shows excellent imaging ability for NO in cells and ferroptosis. Moreover, LR-NH can target the gallbladder and image NO in gallstone disease models, providing a unique and unprecedented tool for studying NO in LDs and gallbladder.
Boron neutron capture therapy (BNCT) has emerged as a promising treatment for cancers, offering a unique approach to selectively target tumor cells while sparing healthy tissues. Despite its clinical utility, the widespread use of fructose-BPA (F-BPA) has been hampered by its limited ability to penetrate the blood-brain barrier (BBB) and potential risks for patients with certain complications such as diabetes, hyperuricemia, and gout, particularly with substantial dosages. Herein, a series of novel BPA derivatives were synthesized. After the primary screening, geniposide-BPA (G-BPA) and salidroside-BPA (S-BPA) exhibited high water solubility, low cytotoxicity and safe profiles for intravenous injection. Furthermore, both G-BPA and S-BPA had demonstrated superior efficacy in vitro against the 4T1 cell line compared with F-BPA. Notably, S-BPA displayed optimal BBB penetration capability, as evidenced by in vitro BBB models and glioblastoma models in vivo, surpassing all other BPA derivative candidates. Meanwhile, G-BPA also exhibited enhanced performance relative to the clinical drug F-BPA. In brief, G-BPA and S-BPA, as novel BPA derivatives, demonstrated notable safety profiles and remarkable boron delivery capabilities, thereby offering promising therapeutic options for BNCT in the clinic.
Photodynamic therapy (PDT) has received much attention in recent years. However, traditional photosensitizers (PSs) applied in PDT usually suffer from aggregation-caused quenching (ACQ) effect in H2O, single and inefficient photochemical mechanism of action (MoA), poor cancer targeting ability, etc. In this work, two novel Ru(Ⅱ)-based aggregation-induced emission (AIE) agents (Ru1 and Ru2) were developed. Both complexes exhibited long triplet excited lifetimes and nearly 100% singlet oxygen quantum yields in H2O. In addition, Ru1 and Ru2 displayed potent photo-catalytic reduced nicotinamide adenine dinucleotide (NADH) oxidation activity with turnover frequency (TOF) values of about 1779 and 2000 h−1, respectively. Therefore, both Ru1 and Ru2 showed efficient PDT activity towards a series of cancer cells. Moreover, Ru2 was further loaded in bovine serum albumin (BSA) to enhance the tumor targeting ability in vivo, and the obtained Ru2@BSA could selectively accumulate in tumor tissues and effectively inhibit tumor growth on a 4T1 tumor-bearing mouse model. So far as we know, this work represents the first report about Ru(Ⅱ) AIE agents that possess high singlet oxygen quantum yields and also potent photo-catalytic NADH oxidation activity, and may provide new ideas for rational design of novel PSs with efficient PDT activity.
Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients, oxygen, and biomolecules from the surrounding microenvironments. Inspired by natural processes, tumor biomineralization has evolved due to its biocompatibility, self-reinforcing capability, and penetration-independent mechanism. However, the selective induction of tumor biomineralization using synthetic tools presents a significant challenge. Herein, a metabolic glycoengineering-assistant tumor biomineralization strategy was developed. Specifically, the azido group (N3) was introduced onto the cytomembrane by incubating tumor cells with glycose analog Ac4ManNAz. In addition, a bisphosphonate-containing polymer, dibenzocyclooctyne-poly(ethylene glycol)-alendronate (DBCO-PEG-ALN, DBPA) was synthesized, which attached to the tumor cell surface via "click chemistry" reaction between DBCO and N3. Subsequently, the bisphosphonate group on the cell surface chelated with positively charged ions in the microenvironments, triggering a consecutive process of biomineralization. This physical barrier significantly reduced tumor cell viability and mobility in a calcium ion concentration-dependent manner, suggesting its potential as an effective anti-tumor strategy for in vivo applications.
Lipids serve as fundamental constituents of cell membranes and organelles. Recent studies have highlighted the significance of lipids as biomarkers in the diagnosis of breast cancer. Although liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is widely employed for lipid analysis in complex samples, it suffers from limitations such as complexity and time-consuming procedures. In this study, we have developed dopamine-modified TiO2 nanoparticles (TiO2-DA) and applied the materials to assist the analysis of lipids by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The TiO2-DA can provide large specific surface area and acidic environment, well suited for lipid analysis. The method was initially validated using standard lipid molecules. Good sensitivity, reproducibility and quantification performance was observed. Then, the method was applied to the analysis of 90 serum samples from 30 patients with breast cancer, 30 patients with benign breast disease and 30 healthy controls. Five lipid molecules were identified as potential biomarkers for breast cancer. We constructed a classification model based on the MALDI-TOF MS signal of the 5 lipid molecules, and achieved high sensitivity, specificity and accuracy for the differentiation of breast cancer from benign breast disease and healthy control. We further collected another 60 serum samples from 20 healthy controls, 20 patients with benign breast disease and 20 patients with breast cancer for MALDI-TOF MS analysis to verify the accuracy of the classification model. This advancement holds great promise for the development of diagnostic models for other lipid metabolism-related diseases.
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