Bioconjugate Chemistry最新文献

Colon cancer (COAD) is one of the common malignant tumors in the gastrointestinal tract; it is urgent to deeply study the mechanism of COAD and develop new therapeutic agents, which will provide new hope for improving the therapeutic efficacy and prolonging the survival of patients. Mitochondria are crucial organelles that play an important role in COAD, participating in cellular energy and material metabolism and playing a key role in the regulation of cell death, making mitochondria a potential target for COAD therapy. In this study, we designed an antimicrobial peptide (AMP) that can target tumor cells and act on mitochondria. The AMP is taken up by tumor cells and can achieve colocalization with mitochondria, reducing the mitochondrial membrane potential levels in tumor cells and inducing ferroptosis. The AMP affects N6-methyladenosine (m6A) methylation modification in cells and participates in the regulation of ferroptosis. During in vivo experiments on COAD, the AMP demonstrated a strong ability to inhibit tumor growth and good biosafety. Unlike peptide–drug conjugates that rely on toxin release, the synthetic AMP exerts direct targeted activity with improved biosafety and efficiency. The AMP effectively suppresses the development of COAD, providing a new reference method for the treatment of COAD.

Click reactions exhibit remarkable selectivity within biological systems, making them powerful and useful tools for synthesizing various novel anticancer drugs in biomedical fields. Utilizing the overexpressed enzyme in a tumor microenvironment to trigger click reactions between nontoxic or low-toxicity precursors provides an effective solution to the high toxicity of conventional chemotherapeutic agents. However, small-molecule drugs tend to undergo rapid metabolism within biological environments; therefore, an effective drug delivery system was needed. In this study, a hollow covalent organic framework (HCOF) was introduced, prodrug molecules were loaded, and finally, an anticancer drug was formed via the click reaction with the help of nitroreductase (NTR). Both in vitro and in vivo studies confirmed the excellent antitumor efficacy of the resulting therapeutic platform. This work further expands the biomedical applications of HCOF via click chemistry.

In modern pharmacology, obtaining an in-depth understanding of the interaction of chemical drugs with their target proteins is essential for drug discovery and the advancement of precision medicine. However, detecting these drug–protein interactions in living cells remains challenging owing to the lack of reliable methodologies. The current study presents a robust strategy involving the redistribution of target proteins in cells and applying a cotranslocation-based cellular assay for monitoring drug–target interactions in living cells. This technique utilizes an enhanced green fluorescent protein (EGFP)-tagged drug target protein that is translocated from the cytoplasm to the plasma membrane when exposed to a biotin-conjugated drug and phorbol 12-myristate 13-acetate (PMA). This movement is facilitated by the membrane-translocation properties of the C1A–mRFP–streptavidin fusion protein, which anchors the biotinylated small-molecule drug and facilitates the spatial redistribution of its target proteins. This system provides a dynamic tool for the real-time observations of drug–protein binding events within cellular environments.

Gastric cancer is a malignant tumor that seriously threatens human health. Its high mortality is mainly due to delayed diagnosis, which makes early detection important for improving patient prognosis. Near-infrared (NIR) fluorescence imaging, with its high signal-to-noise ratio and good sensitivity, has been widely applied in biomedical research and clinical diagnosis. NOTCH2 is often overexpressed in gastric cancer and may serve as a useful target for diagnosis and treatment. In this study, we constructed a NOTCH2-targeted single-chain variable fragment (scFv) conjugated with indocyanine green (ICG) and evaluated its application in gastric cancer imaging in vitro and in vivo. The ICG-scFv probe showed similar photophysical properties to free ICG and was specifically taken up by MKN45 gastric cancer cells. In NIR imaging, ICG-scFv selectively accumulated in tumor tissue, achieved tumor-specific imaging, and maintained fluorescence signals for a longer time, which was further confirmed by colocalization analysis. These results indicate that the targeted fluorescent probe ICG-scFv may have potential value in the diagnosis and treatment of gastric cancer.

Efficient delivery of therapeutic antibodies into the central nervous system (CNS) remains severely limited by the restrictive nature of the blood–brain barrier (BBB). Receptor-mediated transcytosis (RMT) has emerged as a promising strategy to enhance antibody transport across the BBB. In this Viewpoint, we highlight recent advances in RMT-based antibody delivery, focusing specifically on three representative BBB receptors: transferrin receptor (TfR), insulin receptor (InsR), and neonatal Fc receptor (FcRn). By comparing antibody engineering strategies that target these receptors, we summarize current progress, discuss critical limitations, and suggest directions for advancing CNS-targeted therapeutic antibodies. This Viewpoint provides valuable insights for selecting appropriate RMT targets and optimizing antibody-based therapies for CNS diseases.

The development of fluorescent probes that target the tumor stroma to help surgeons detect and remove malignant lesions using near-infrared fluorescence (NIRF)-guided surgery is advancing rapidly. Such advancements show promise for a range of malignancies, expanding the eligibility of patients for surgical intervention and offering improved surgical outcomes. Fibroblast activation protein (FAP), expressed by cancer-associated fibroblasts (CAFs), is highly upregulated within the tumor stroma of nearly all solid tumors. It is a promising tumor target for NIRF-guided surgery, especially in solid tumors with dense tumor stroma, such as pancreatic cancer. In this study, we aimed to develop FAP-targeting fluorescent probes with enhanced pharmacokinetics for the NIRF-guided surgery of pancreatic cancer. Three novel FAP-targeted probes (eFAPs) based on a (4-quinolinoyl)-glycyl-2-cyanopyrrolidine (QCP) structure equipped with the NIRF dye IRDye800CW were designed and synthesized. All of the probes displayed excellent inhibition potency and selectivity to FAP. The probes consistently exhibited strong inhibition and specific uptake in FAP-expressing U87 glioblastoma cells. In in vivo optical imaging studies, eFAP-24 showed a tumor-to-background ratio (TBR) of 3.1 ± 0.6 at 24 h postinjection, enabling the clear delineation of tumors using the clinical Quest Spectrum NIRF imaging system. A strong fluorescence signal in the tumor and a negligible uptake in nontarget tissues were confirmed by biodistribution analyses. The successful development and validation of FAP-targeting fluorescent probes, especially eFAP-24, offers promising prospects for enhancing the visualization of FAP-rich stromal compartments improving surgical outcomes through NIRF-guided surgery, particularly in solid tumors with dense stroma such as pancreatic cancer.

Photothermal and chemodynamic therapies (PTT and CDT) have gained traction as viable adjunct anti-cancer treatments. However, they remain restricted by the low efficiency of photothermal conversion and the inefficiency of the Fenton reaction. Kaempferol (Kae), a naturally occurring bioactive flavonoid, can induce apoptotic signaling pathways by reducing the expression or activity of many proteins involved in the initiation and execution phases of apoptosis. In this study, we fabricated Kae–iron-assembled nanoparticles (Kae-Fe NPs) for synergistic PTT and CDT in breast cancer treatment. Under 808 nm laser irradiation, the Kae-Fe NPs not only facilitated the photon-to-heat energy conversion for PTT but also enhanced CDT by improving the efficiency of the Fenton reaction. Additionally, treatment with Kae-Fe NPs induced the release of immunostimulatory signals from breast cancer cells, leading to the migration of HMGB1 and CRT protein expression, and the release of ATP into the extracellular space, thereby triggering immunogenic cell death (ICD) and macrophage polarization toward the M1 type. The implications of these results are that Kae-Fe NPs have a dual effect: reprogramming macrophage phenotypes and inducing ICD. Furthermore, this study lays a firm foundation for utilizing Kae-Fe NPs in breast cancer management.

The misuse of antibiotics has intensified the emergence of drug-resistant bacteria. The diversity of chemical structures offers a crucial foundation for developing novel small-molecule antibacterials. New chemical scaffolds may hold significant potential for combating drug-resistant bacteria. In this study, a series of benzoic acid derivatives featuring a tetraphenylethylene (TPE) core were designed to modulate their pK_a by incorporating various electron-donating and electron-withdrawing groups. This approach led to the development of a series of effective Staphylococcus aureus therapeutic agents. Among these compounds, the nitro-substituted tetraphenylethylene benzoic acid derivative (NOA) exhibits an ultralow minimum inhibitory concentration (MIC = 0.04 μg/mL) against S. aureus, while MIC of the traditional antibiotic vancomycin was 0.13 μg/mL. NOA achieved a 99% elimination rate of S. aureus at a 0.16 μg/mL and displayed antibacterial activity against S. aureus biofilm at 0.32 μg/mL. NOA could effectively treat wound infections caused by S. aureus in infected mouse models. This study provides valuable advice about the chemical substituents for designing new antibacterial agents.

Highly selective and fast reactions at the thiol group of a cysteine-containing peptide or protein, giving a reduction-resistant linkage, are highly desirable for anchoring a paramagnetic label that enables structure determination with electron paramagnetic resonance and/or nuclear magnetic resonance spectroscopy. One possibility is the Michael addition of the thiol group onto a 4-vinylpyridine, which is a structural subunit of the labeling agent, e.g., of the complex 4-vinyl-PyMTA-Gd. This reaction, however, turned out to be too slow for broad applicability. If pyridine is exchanged for pyrimidine, this reaction becomes very fast while still being sufficiently chemoselective, as is demonstrated with reactions of the complexes 4-vinyl-PymiMTA-Ln with Ln = Gd and/or La, which contain a 4-vinylpyrimidine subunit, with cysteine, cysteine-containing oligoproline, and cysteine-containing thioredoxin. Furthermore, it was found that the complex PymiMTA-Gd is a suitable spin label for distance determination via double electron electron resonance spectroscopy. Interestingly, the EPR spectra of PyMTA-Gd and PymiMTA-Gd and their relaxation times are very similar. Obviously, the exchange of pyridine for pyrimidine has little effect on these relevant EPR spectroscopical properties. This indicates that other pyridine-containing Gd³⁺ complexes may be convertible in the same way to fast-reacting, ready-made spin labels while keeping their favorable EPR spectroscopical properties.

Dynamic regulation of cell–cell adhesion is fundamental to numerous biological processes and is the key to engineering multicellular structures. Optogenetic tools offer precise spatiotemporal control over cell–cell adhesions, but current methods often require the genetic modification of each participating cell type. To address this limitation, we engineered a single-component synthetic cell adhesion molecule based on the blue-light-responsive, plasma membrane-binding protein BcLOV4. We tagged BcLOV4 with a transmembrane domain to display it on the outer plasma membrane (BcLOV4-PM). Under blue light but not in the dark, BcLOV4-PM cells formed both homotypic adhesions with other BcLOV4-PM cells and heterotypic adhesions with a range of unmodified wild-type cells. While these adhesions were not reversed in the dark, they could be efficiently disrupted by increasing the temperature to 37 °C, leveraging BcLOV4’s thermosensitivity. Using BcLOV4-PM-based adhesions, we demonstrated light-controlled compaction of spheroids in both monocultures and cocultures with wild-type cells. Altogether, BcLOV4-PM enables promiscuous, modular, light-dependent control of cell–cell adhesions without requiring genetic modification of all cell types involved, offering promising applications in tissue engineering and the study of multicellular process.