Latest ArticlesChemodynamic therapy (CDT) relying on the transformation of endogenous hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (•OH) based on the catalysis of Fenton/Fenton-type reactions exhibits great potentiality for cancer treatment. However, the inadequate H2O2 supply and intricate redox homeostasis in tumor microenvironment (TME) severely impair the efficacy of CDT. Herein, we design self-assembled 1,2-distearoyl-sn-glycero-3-phosphoethanolamine conjugated polyethylene glycol (DSPE-PEG)-modified Fe(Ⅲ)-juglone nanoscale coordination polymers (FJP NCPs) as redox homeostasis disruptors for juglone-enhanced CDT. Responding to glutathione (GSH)-rich and acidic TME, the Fe2+/Fe3+-guided CDT and GSH consumption by Fe3+ are activated, resulting in •OH downstream and up-regulation of lipid peroxidation (LPO). In addition, the released juglone not only depletes GSH through Michael addition, but also elevates intracellular H2O2 level for achieving •OH further bursting. With the impressive efficiency of GSH exhaustion and reactive oxygen species (ROS) storm generation, ferroptosis and apoptosis are significantly enhanced by FJP NCPs in vivo. In brief, this facile and efficient design for versatile nanoscale coordination polymers presents a novel paradigm for effectively elevating CDT efficiency and tumor synergistic therapy.
The low drug bioavailability of eye drops challenges the therapy of ocular disorders with high efficacy. One of solutions is to extend the corneal retention and enhance the penetration of drug into cornea. Here we synthesize two fluorophore-conjugated peptide based analogs rich in positive charges (i.e., NBD-FFKK) and with a specific ligand (i.e., NBD-FFRGD), respectively, to visualize their performances in vitro and in vivo. The peptides both can self-assemble into supramolecular hydrogels with the microstructure of nanofibers. The in vitro experiments exhibit that two peptides are both uniformly distributed in cytoplasm, and the intracellular amount of peptide rich in positive charges is significantly larger than that of peptide with a specific ligand. The living corneal fluorescence shows that two peptides enter the corneal stroma within 15 min, and the peptide rich in positive charges is accumulated more extensively throughout the entire cornea, revealing that the supramolecular hydrogel eye drops penetrate the cornea more efficiently via electrostatic interaction than that via ligand-receptor interaction. This work, as a comparative study of supramolecular hydrogel eye drops on penetrating efficiency, indicates a possible direction for the design of eye drops with efficient corneal penetration.
Developing natural nano-platforms with high biocompatibility and natural targeting ability represents great significance for drug delivery. High-density lipoprotein (HDL), a natural lipid-protein complex, plays important roles in physiological activities, particularly in reverse cholesterol transport (RCT) and be closely associated with atherosclerotic cardiovascular diseases. Recent studies have demonstrated that HDLs have the potential to serve as ideal drug carriers. Recombinant HDLs (rHDLs) have been used to encapsulate substances such as small interfering RNA (siRNA), drugs, and contrast agents, fully utilizing the biocompatibility and targeting ability of rHDL in the body and providing new strategies for drug delivery and disease treatment. In this review, we discussed in detail the basic principles of HDL as a drug delivery system, the mechanisms of targeted drug delivery, and several methods for preparing HDL nanoparticles. Afterward, we comprehensively reviewed the applications of HDL as a drug carrier in cardiovascular diseases, cancer treatment (such as glioblastoma, breast cancer, hepatocellular carcinoma and urologic cancers) and some other fields. Finally, we reviewed the therapeutic effects and safety of HDL nanoparticles in clinical studies. Through a review and summary of these research advances, we aim to fully understand the potential of HDL as a drug carrier in clinical applications, providing valuable references and guidance for future research and expedites the translational application of HDL as drug carriers.
Nanoparticles that employ stimuli-responsive polymeric delivery carriers have emerged as intelligent nanoplatforms with great potential in cancer theranostics, mainly including cancer diagnosis, controlled/triggered drug delivery, and real-time monitoring of therapeutic response. Particularly, tumor microenvironment (TME)-responsive polymeric nanocarriers in response to weak acidity, hypoxia, reactive oxygen species (ROS), glutathione (GSH), or tumor enzymes in the TME show great promise in facilitating tumor accumulation, enhancing tumor penetration, prolonging tumor retention, and achieving controlled drug release, thereby improving the efficiency of tumor therapy. Besides, the combination of chemotherapy and phototherapy presents a promising endeavor for the treatment of tumors, which allows for the integration of the advantages of each treatment modality, addressing the shortcomings of the two methods, and amplifying the efficacy of tumor treatment while reducing adverse reactions. This review focuses on the latest progress in the development of TME-responsive polymeric nanoparticles for synergetic chemo-photo therapy, and discusses the critical challenges and future considerations involved in the fabrication of TME-responsive nanocarriers.
This article reviews the latest research advances of tetrahedral framework nucleic acid (tFNA)-based systems in their fabrication, modification, and the potential applications in biomedicine. TFNA arises from the synthesis of four single-stranded DNA chains. Each chain contains brief sequences that complement those found in the other three, culminating in the creation of a pyramid-shaped nanostructure of approximately 10 nanometers in size. The first generation of tFNA demonstrates inherent compatibility with biological systems and the ability to permeate cell membrane effectively. These attributes translate into remarkable capabilities for regulating various cellular biological processes, fostering tissue regeneration, and modulating immune responses. The subsequent evolution of tFNA introduces enhanced adaptability and a relatively higher degree of biological stability. This advancement encompasses structural modifications, such as the addition of functional domains at the vertices or side arms, integration of low molecular weight pharmaceuticals, and the implementation of diverse strategies aimed at reversing multi-drug resistance in tumor cells or microorganisms. These augmentations empower tFNA-based systems to be utilized in different scenarios, thus broadening their potential applications in various biomedical fields.
α1-Adrenergic receptor (AR) blockers can be effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature or low selectivity of many current drugs. We previously reported that phenylpiperazine analogues with amide and propane linker were moderate α1D/1A adrenoceptor antagonists and exhibited better anti-BPH effect than lead compound naftopidil (NAF) in vivo, however, with modest α1D/1A-subtype selectivity. Herein, we replaced propane moiety with 2-hydroxypropanol linker and synthesized twenty-seven racemic derivatives with modified aromatic and hetero aromatic groups. Of these new compounds, quinoline surrogate 17 exhibited extremely weak antagonistic affinity on α1B in both cell-based calcium assay and tissue-based functional assay, so that elicited significant α1A/1B and α1D/1B selectivity. Intriguingly, the R enantiomer of 17 preferentially displayed superior anti-BPH effect in rat model compared with S-17, supporting ligand regulates the receptor in a highly stereospecific manner. Finally, the computer-aided modelling research was also performed in order to deeply understand the unique binding mode of R-17 in complex with α1A and the subtype receptor selectivity for R-17 was also rationalized in this study. Taken together, our work enriched the diversity of phenylpiperazines for the treatment of BPH/LUTS, and provided a basis for discovery of α1D/1A-selective ligands.
The development of enantioselective C-H macrocyclizations to efficiently access structurally diversified macrocycles is highly desirable, but remain a big challenge. Herein, we reported the first rhodium(Ⅲ)-catalyzed asymmetric intramolecular C-H macrocyclization, enabling the efficient synthesis of structurally diverse enantioenriched macrocycles. This robust enantioselective C-H macrocyclization has a broad functional group tolerance, excellent enantioselectivities (up to 98.5:1.5 e.r.) and a mild reaction condition, releasing CO2 as the single by-product. More significantly, the resulting unique enantioenriched 19-membered macrocycle 2f was found to demonstrate a potent in vitro anti-Zika virus (ZIKV) activity without obvious cytotoxicity. Further investigation revealed that the anti-ZIKV activity is presumably attributed to an autophagy inhibition in the early stage of viral infection by down-regulating the expression of autophagy related gene Atg12.
Chronic kidney disease (CKD) is an increasingly prevalent medical condition associated with high mortality and cardiovascular complications. The intricate interplay between kidney dysfunction and subsequent metabolic disturbances may provide insights into the underlying mechanisms driving CKD onset and progression. Herein, we proposed a large-scale plasma metabolite identification and quantification system that combines the strengths of targeted and untargeted metabolomics technologies, i.e., widely-targeted metabolomics (WT-Met) approach. WT-Met method enables large-scale identification and accurate quantification of thousands of metabolites. We collected plasma samples from 21 healthy controls and 62 CKD patients, categorized into different stages (22 in stages 1–3, 20 in stage 4, and 20 in stage 5). Using LC-MS-based WT-Met approach, we were able to effectively annotate and quantify a total of 1431 metabolites from the plasma samples. Focusing on the 539 endogenous metabolites, we identified 399 significantly altered metabolites and depicted their changing patterns from healthy controls to end-stage CKD. Furthermore, we employed machine-learning to identify the optimal combination of metabolites for predicting different stages of CKD. We generated a multiclass classifier consisting of 7 metabolites by machine-learning, which exhibited an average AUC of 0.99 for the test set. In general, amino acids, nucleotides, organic acids, and their metabolites emerged as the most significantly altered metabolites. However, their patterns of change varied across different stages of CKD. The 7-metabolite panel demonstrates promising potential as biomarker candidates for CKD. Further exploration of these metabolites can provide valuable insights into their roles in the etiology and progression of CKD.
Water splitting with proton exchange membrane water electrolyzers (PEMWE) is regarded as a promising pathway for sustainable hydrogen conversion. Additionally, oxygen evolution reaction (OER) is considered as the dominant factor during the whole process due to the sluggish kinetics. Among the catalysts, Ru-based catalysts draw special attention because of their excellent activity and relatively low price. However, the limited stability impedes their further commercialization and tremendous efforts have been devoted to overcome this challenge. This review firstly introduces the basic mechanisms of OER. Then the evaluation protocols and techniques to investigate the stability of Ru-based catalysts are summarized. A detailed elucidation of the possible degradation mechanisms is also critically analyzed. Furthermore, effective strategies to design durable Ru-based catalysts for acidic OER are discussed. Such as heteroatom doping, phase and facet engineering, heterostructure building and support optimization. Finally, promises, perspectives and challenges in developing highly durable Ru-based catalysts for acidic OER are outlined.
Lithium argyrodites Li6PS5X (X = Cl, Br, I) show great potential as solid electrolytes for solid-state lithium batteries due to their high Li-ion conductivities and excellent electrode compatibility. However, the relatively low conductivity of Li6PS5I (10−6 mS/cm) compared to the other two compositions limits its applications. Herein, Si-doped Li6.5P0.5Si0.5S5I electrolyte is designed and synthesized with superior high conductivity of 3.6 mS/cm. Structural characterization proves the increase due to the anion disorder and volume expansion caused by Si-doping. However, the poor interfacial stability between layered oxide cathode LiNi0.6Co0.2Mn0.2O2 and Li6.5P0.5Si0.5S5I inhibits its battery performance. By introducing Li3InCl6 electrolyte in the configuration, the corresponding battery delivers high initial discharge capacity of 150.2 mAh/g and superior cyclability during 250 cycles at 0.5 C. This work offers design strategy to obtain Li6PS5I-based electrolytes for high performance solid-state batteries.
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