Latest ArticlesChemodynamic therapy (CDT) is a promising therapeutic approach for in situ cancer treatment, but it is still hindered by inefficient single-modality treatment and the weak targeted delivery of reagents into mitochondria (the main site of intracellular ROS production). Herein, to obtain a multimodal strategy, peptide-assembled siRNA nanomicelles were prepared to confine ultrasmall MnO in small silica cages (silicages), which is convenient for synergistic chemical and gene-regulated cancer therapy. Given the free energy and versatility of small silicages, as well as the excellent Fenton-like activity of ultrasmall MnO, MnO-inside-loaded silicages (10 nm) were prepared for CDT delivery to mitochondria. Subsequently, to obtain a synergistic CDT and gene silencing treatment, the peptide-mediated assembly of siRNA and MnO-loaded silicages were employed to obtain silicage@MnO-siRNA nanomicelles (SMS NMs). After multiple modifications, sequential cancer cell-targeted delivery, GSH-controlled reagent release of siRNA and mitochondria-targeted delivery of MnO-loaded silicages were successfully achieved. Finally, by both in vitro and in vivo experiments, SMS NMs were confirmed to be effective for synergistic chemical and gene-regulated cancer therapy. Our findings expand the applications of silicages and initiate the development of multimodal CDT.
A novel series of CHOR-HEPT non-nucleoside HIV-1 reverse transcriptase inhibitors were developed by means of structure-based design strategy based on compound 6 reported previously by our group. Most of these compounds showed moderate to good activity toward wild-type HIV-1 strain with EC50 values in the range of 0.18–51.88 µmol/L and SI values in the range of 4–907. The compound 14aj with a CHOH linker and compound 13i with a CHOTMS linker in this series exhibited improved anti-HIV-1 activity (EC50 = 0.18 µmol/L, and 0.20 µmol/L) with higher selectivity (SI = 907, and 665) as comparison with the lead compound 6 (EC50 = 0.59 µmol/L, SI = 9). These two compounds 14aj and 13i were more sensitive than 6 toward clinically relevant mutant L100I, K103N and E138K viruses, which were further evaluated for their activity against wild-type reverse transcriptase and displayed a good correlation with the cell-based activity. Preliminary molecular modeling investigations provided insight for further structural optimization of HEPT.
Hypoxic tumor microenvironment is a major challenge for photodynamic therapy (PDT). To overcome this problem, PDT combined hypoxia-activated chemotherapy is a promising strategy for hypoxic cancer therapy. Herein, a multifunctional liposome (AQ4N-Ir1-sorafenib-liposome) is prepared by encapsulating a hypoxia-activated prodrug AQ4N, a photosensitizer iridium(Ⅲ) complex and hepatocellular carcinoma (HCC) targeting drug sorafenib, for synergistic therapy of HCC. Ir1-mediated PDT upon irradiation induces ROS generation and hypoxic environment, which leads to the disassembly of the liposome and activates the antitumor activity of AQ4N. Meantime, the co-delivered sorafenib could effectively target therapy of HCC. It is noted that ferroptosis mechanism is proved during the treatment. This work contributes to the design of hypoxia-responsive multifunctional liposome for combination of chemotherapy, targeting therapy and PDT. It is a promising strategy for hypoxic HCC therapy.
Phthalates esters (PAEs) are extensively used as additives for polymers in plastic, particularly in polyvinyl chloride (PVC) and polyethylene terephthalate (PET). These compounds are not part of the polymer chains and can be released easily from products and migrate into beverages and foods that come into direct contact, causing environmental and human health impacts. Simple and rapid detection of such substances is of great significance for ensuring environmental food safety and consumer health. At present, optical sensor and electrochemical sensor detection technologies have been applied to PAEs detection due to their advantages, such as simple, rapid, low cost, high sensitivity, simple operation, portability and high specificity. They can make up for the shortcomings of chromatographic detection technology, such as expensive equipment, cumbersome operation, the need for professional and technical personnel, and difficulty in achieving a large number of sample screening objectives. In this paper, research progress on optical sensors and electrochemical sensors for the detection of phthalates in recent ten years is reviewed and discussed. This is helpful to better understand preparation methods for sensors and their detection mechanisms for phthalates. The review will also be used in developing a more effective trace detection sensor for phthalates.
Inspired by the indolopyridoquinazoline scaffold of natural products evodiamine and rutaecarpine, novel triple G4 and Top1/2 ligands were rationally designed and synthesized. Systematic structure–activity relationship (SAR) studies led to the discovery of compound 15g, which effectively induced and stabilized G4 and inhibited Top1/2 with potent antitumor activity. Compound 15g represents a valuable chemical tool or lead compound for antitumor drug discovery. This proof-of-concept study also validated the feasibility of using planar natural products scaffold as templates to design new G4 ligands.
T4 polynucleotide kinase (T4 PNK) is a pivotal enzyme for DNA replication, recombination, and DNA damage repair. Herein, a robust single particle counting-based assay has been developed for the high-sensitive determination of T4 PNK activity through only a simple one-step reaction. Taking benefit of the exceptional space-confined enzymatic property of T4 PNK towards DNA substrates on a single nanoparticle, the T4 PNK activity can be precisely determined by counting the fluorescence-positive nanoparticles in a digital manner with a total internal reflection fluorescent microscope (TIRFM). Due to the featured spatial-confined enzymatic property of T4 PNK and the single particle counting-based signal readout, T4 PNK can be effectively differentiated from other interfering enzymes. This facile strategy has been also successfully applied to screen T4 PNK inhibitor and accurately determine T4 PNK activity in complex biological samples, paving a potential avenue for the digital analysis of biomarkers.
Based on the coumarin skeleton, we deliberately designed two groups of fluorophores, termed as Coum-R and Naph-Coum-R, using the diphenylamino group as the electron donor, which displayed long-wavelength emissions (red spectral region), large Stokes shift (up to 204 nm), superior AIE performance, and large two-photon absorbance cross-sections (as high as 365 GM). The electron-withdrawing substituents at the 3-position of these dyes could induce a significant red-shift in their emission spectra. Preliminary imaging experiments demonstrated the capability of these dyes as two-photon fluorophores for specifically staining lipid droplets in living cells.
Chiral glycosyl lactone is an important class of bioactive compound and pharmaceutical intermediate in nature, especially for chiral lactones with 4 carbon atoms, which are very useful building blocks for synthesis of biologically interesting compounds. Herein, a selective dehydrogenation and solvent matched catalytic system under oxygen-free conditions was developed to try to achieve the one-step direct conversion of cyclic hemiacetal sugars toward their chiral glycosyl lactones. During the process, the inherent structural characteristics of sugar was efficiently utilized, and the transfer of its chiral centers was realized. Under the optimum condition, the corresponding lactones were successfully prepared from C4-C6 sugars with cyclic hemiacetal structure in acetonitrile. The reaction mechanism in acetonitrile was explored by the first principle density functional theory calculations and tracking reaction process. It was found that the high lactone yield in acetonitrile was due to the high proportion of α-conformation form among multiple tautomers in it. This selective dehydrogenation process may further extend the possibility of the preparation of chiral synthons from carbohydrates directly.
Staphylococcus aureus wall teichoic acids (WTAs) are attractive targets for antibacterial vaccine development. In this study, three core glycosylated WTA structure, including α-1,4-GlcNAc, β-1,4-GlcNAc and β-1,3-GlcNAc modified ribitol phosphates containing a linker are chemically synthesized and conjugated with tetanus toxin (TT) carrier protein as vaccine candidates. In vivo immunological studies demonstrate that the synthesized glycosylated WTAs display high immunogenicity and all conjugates provoke strong immune responses and elicit high levels of specific IgG antibodies against the GlcNAc-modified WTA. Furthermore, antibodies elicited by the vaccine candidates remain the capability to recognize S. aureus cells and display significant opsonophagocytic activity to clear S. aureus. This study demonstrates that the core structure of glycosylated WTAs are effective antigens for constructing anti-S. aureus vaccines to prevent and control S. aureus infections.
Erythrocyte membrane (EM)-camouflaged chemotherapeutic delivery nanovehicles hold promise for solid tumor therapy because of their excellent biostability and biocompatibility. However, it is accompanied with insufficient targeting effect and deficient pharmacokinetic behavior due to the lack of a regulated biointerface to navigate and overcome biological transportation obstacles in solid tumor therapy. Herein, an anti-epidermal growth factor receptor (EGFR) aptamer (EApt) modified and EM-cloaked chemotherapeutic nanomissile delivery system was constructed. The anchored-EApt acting as a specific EGFR suppressor promotes to inhibit the overexpression of EGFR and initiate the cell apoptosis. Importantly, the resulting PLGA-DOX@EM-EApt orchestrated the bioactivity of each component and provided synergistic cell apoptosis and antitumor effects by precisely suppressing EGFR expression levels and delivering DOX. The in vitro and in vivo experimental results confirmed that the immune escape and active targeting behaviors of PLGA-DOX@EM-EApt could significantly promote its drug retention and tumor inhibition abilities. Our findings propose a novel strategy using the biointerface functionalization technique, demonstrating a promising therapeutic platform via a biomimetic drug delivery system for precise solid tumor recognition and synergistic therapy.
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