Discovery of novel tumor-targeted near-infrared probes with 6-substituted pyrrolo[2,3-d]pyrimidines as targeting ligands.

Since the overexpression of folate receptors (FRs) in certain types of cancers, a variety of FR-targeted fluorescent probes for tumor detection have been developed. However, the reported probes almost all have the same targeting ligand of folic acid with various fluorophores and/or linkers. In the present study, a series of novel tumor-targeted near-infrared (NIR) molecular fluorescent probes were designed and synthesized based on previously reported 6-substituted pyrrolo[2,3-d]pyrimidine antifolates. All newly synthesized probes showed specific FR binding in vitro, whereas GT-NIR-4 and GT-NIR-5 with a benzene and a thiophene ring, respectively, on the side chain of pyrrolo[2,3-d]pyrimidine exhibited better FR binding affinity than that of GT-NIR-6 with folic acid as targeting ligand. GT-NIR-4 also showed high tumor uptake in KB tumor-bearing mice with good pharmacokinetic properties and biological safety. This work demonstrates the first attempt to replace folic acid with antifolates as targeting ligands for tumor-targeted NIR probes.

Improving the solubility of melanin nanoparticles from apricot kernels is a potent drug delivery system.

BACKGROUND: Melanin can be used in biomedical nanomaterials, but its solubility in water and bioavailability are low. AIM: Melanin nanoparticles were prepared and then PEG-natural melanin nanoparticles (NMNP-PEG) were obtained with good performance and optimize their (water solubility, dispersion stability, chelating metal ions, photothermal stability, drug delivery, and biocompatibility), therefore improve the water solubility of melanin and broaden its application scope in biology, medicine, food, and other fields. METHODS: MFAK (melanin from apricot kernels) and NMNP-PEG were prepared and characterized using ultraviolet-visible spectrophotometry (UV-Vis), high-performance liquid chromatography (HPLC), Fourier-transform infrared spectroscopy (FTIR), 1H nuclear magnetic resonance (NMR), and electron microscopy. The chelation rate of metal ions, photothermal effect, doxorubicin loading, and cytotoxicity (MCF-7 cells) were examined. RESULTS: UV-Vis, HPLC, FTIR, and NMR indicated that NMNPs contained melanin. NMNPs could be successfully modified using PEG. Under physiological pH conditions (pH 7.4), the metal ion chelation rate of NMNP-PEG increased with time and peaked at 12 h. The photothermal assay showed a temperature enhancement of 26.3°C with 1 mg/mL NMNP-PEG, compared with 1.9℃ with water. The NMNP-PEGs had a typical peak for doxorubicin in the FTIR spectrum, and the peak intensity was proportional to the drug loading. The release of doxorubicin in an acidic buffer was 40.8% at 24 h, almost threefold that in a neutral buffer (11.9%). There was no obvious cytotoxicity from NMNP-PEG. CONCLUSION: NMNP-PEG displays good stability, high metal ion chelation ability, efficient photothermal conversion potential, drug-retaining capability, sustained controlled drug release, and biocompatibility. This study provides a theoretical basis for NMNP-PEG applications in medicine (targeting specific sites to diagnose and treat diseases), food (extending the shelf life of food), and biology (as metal ion chelating agents to remove heavy metals from wastewater).

Study on public acceptance of decommissioning of a uranium mining and metallurgy facility in Hunan Province.

The decommissioning of uranium mining and metallurgy facilities involves sensitive issues of the local government and the public, which is related to the vital interests of the surrounding residents. Improper disposal may lead to negative emotions among the public and affect the process of uranium mining and metallurgy facilities decommissioning projects. In order to explore the acceptance of uranium mining and metallurgy decommissioning projects by nearby residents and its influencing factors, a hypothesis model of influencing factors of public acceptance was constructed through literature survey. Taking the public around a uranium mining and metallurgy in Hunan Province as an example, a questionnaire survey was carried out. Using the AMOS21.0 tool, the fitting test of the structural equation model was carried out on 506 valid sample data and the hypothetical model, and the key factors affecting the public acceptance of the uranium mining and metallurgy decommissioning project were analyzed. The findings show that public perceived risk (-0.28), familiarity (0.26) and trust (0.175) are key factors influencing acceptance. The research results provide a methodological basis for improving the public acceptance of uranium mining and metallurgy decommissioning projects.

Chain conformation transition induced host-guest assembly between triple helical curdlan and ß-CD for drug delivery.

The unique conformation transition from a triple helix to single coils for the triple helical ß-d-glucans has paved the way to fabricate various functional nanocomposites through the denaturing-renaturing process. This study firstly reports a novel kind of naturally derived supramolecular polymer micelle consisting of single-stranded chains of curdlan (CUR) and ß-CDs. It is proposed that ß-CDs as the host molecules were threaded onto single ß-glucan chains (denatured triplex CUR) via the host-guest interaction, thereby forming supramolecular micelles. The results from the 1H NMR, FT-IR, XRD and 2D 1H NOESY NMR studies confirmed the formation of the inclusion complex and the existence of the core-shell structure of the supramolecular assembly. TEM images and DLS revealed that the self-organized micelles displayed a regular spherical shape with an average diameter of ∼27 nm. Furthermore, the hydrophobic anticancer drug camptothecin (CPT) was selected as a model drug and successfully encapsulated into the CUR/ß-CD micelles. The drug-loaded micelles exhibited a steady sustained-release pattern regardless of the environmental pH. The flow cytometry and confocal laser scanning microscopy measurements confirmed that the CPT-loaded micelles could be well internalized into HepG 2 cells and continuously release the drug molecules inside the tumor cells. Meanwhile, the in vivo experiments demonstrated that CPT-loaded micelles could effectively inhibit tumor growth in comparison to free drugs. This concept will give a favorable platform to construct intelligent drug delivery systems for potential use.

Chelidonine enhances the antitumor effect of lenvatinib on hepatocellular carcinoma cells.

BACKGROUND: Lenvatinib is a newly approved molecular targeted drug for the treatment of advanced hepatocellular carcinoma (HCC). However, the high cost associated with this treatment poses a huge financial burden on patients and the entire public health system. Therefore, there is an urgent need to develop novel strategies that enhance the antitumor effect of lenvatinib. METHODS: The antitumor effects of chelidonine or/and lenvatinib on HCC cell lines MHCC97-H and LM-3 were examined using the 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2- H-tetrazolium bromide (MTT) assay. For the in-vivo investigation, the effect on subcutaneous or intrahepatic tumor growth in nude mice was also determined. The mRNA levels of epithelial mesenchymal transition (EMT)-related factors were examined through quantitative polymerase chain reaction or Western blot. RESULTS: In the present study, we found that treatment with chelidonine enhanced the apoptotic effect of lenvatinib on HCC cells and the in-vivo growth of HCC tumors in nude mice. Mechanistically, treatment with chelidonine increased the expression of epithelial indicator E-cadherin, whereas it decreased the expression of mesenchymal indicators N-cadherin and Vimentin. These findings suggest that chelidonine restricted the EMT in HCC cells. CONCLUSION: Chelidonine inhibits the process of EMT and enhances the antitumor effect of lenvatinib on HCC cells.

[Study on difference of chemical constituents of Qiai in different harvest periods].

Artemisiae Argyi Folium,the dried leaves of Artemisia argyi,has been widely used in traditional Chinese and folk medicines for a long time. Qiai is one of the top-geoherb of Artemisiae Argyi Folium. Trying to investigate dynamic changes of chemical components of Qiai in different harvest periods and explore the optimum harvest time of Qiai,in this study,the contents of total flavonoids and total phenolic acids of 36 batches of Qiai collected in 6 different harvest periods were analyzed by ultraviolet-visible spectrophotometry. Furthermore,an HPLC method was applied for simultaneous determination of eight bioactive compounds including six phenolic acids( 5-caffeoylquinic acid,3-caffeoylquinic acid,4-caffeoylquinic acid,3,4-di-O-caffeoylquinic acid,3,5-di-O-caffeoylquinic acid and 4,5-di-O-caffeoylquinic acid) and two flavonoids( jaceosidin and eupatilin) in Qiai samples. The quantitative results indicated that there were some differences in the contents of total flavonoids,total phenolic acids and bioactive compounds of Qiai samples in different harvest periods. The dynamic changes of total flavonoids and total phenolic acids of Qiai in different harvest periods were consistent. The contents of total flavonoids and total phenolic acids of Qiai samples were higher in the third harvest period( around the Dragon Boat Festival),which is basically consistent with the traditional harvest periods. This present study can provide the basis for determining the suitable harvest time of Qiai,and might be useful for the quality evaluation of this herbal medicine.