Journal of Chinese Pharmaceutical Sciences

Berberine enhances the activity of Sunitinib by targeting telomere G-quadruplex

Haitao Hou, Zibing Song, Jieqin Ding, Dengguo Wei, Sheng Hu, Qianqian Zhai, Xiali Yue

2019, 28(5): 289-297. DOI: 10.5246/jcps.2019.05.029

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G-quadruplexes are stable secondary structures formed with guanine rich sequences, which are widely distributed in genome. Chemical compounds stabilizing G-quadruplexes exhibited inhibition on tumor cells. However, the feasibility of G-quadruplex structures as drug targets needs to be validated. In this study, Sunitinib, an antitumor drug targeting tyrosine kinases was found to stabilize telomere G-quadruplex. The stabilization was further enhanced by the combined usage with Berberine, an isoquinoline alkaloid. Circular dichroism spectra showed the synergistic effect comes from inducing the conformation conversion of telomere G-quadruplex. The combination of Berberine with Sunitinib resulted in 1.7-fold enhancement in cell apoptosis rate with the percentageof apoptotic cells reaching about 70%. The confocal microscopy immunofluorescence images showed the combination of Berberine and Sunitinib induced the formation of G-quadruplex at the telomere in A549 cancer cells. This study suggested that more clinic drugs could work by targeting G-quadruplex structures.

Design and synthesis of nitrogen-fused pyridazinone fluorescent probes and their application in biological imaging

Hui Liu, Lei Liang, Lan Yuan, Fengrong Xu, Yan Niu, Chao Wang, Ping Xu

2019, 28(5): 298-315. DOI: 10.5246/jcps.2019.05.030

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A series of small-molecular fluorescent probes based on nitrogen-fused pyridazinone scaffold were developed in this report. The design strategy involved two steps: 1) enhancing the electron-withdrawing ability of the acceptor by incorporatingan N-heterocyclic aromatic ring (pyridine or pyrazine) at the C₄ and C₅ positions of the pyridazinone skeleton and 2) anchoring a triphenylphosphine or morpholine tail as the subcellular targeting group. These fluorescent probes displayed excellent properties in live cell and brain tissue imaging.

Synthesis of poly(amidoamine)-poly(ethyleneglycol)-poly(amidoamine) and preparation of its hydrogel solution containing doxorubicin

Zhantao Li, Ai Liao, Man Liu, Shuang Zhang, Zhenhan Feng, Guangxue Wang, Jingru Wang, Meiqi Xu, Zhuoyue Li, Xiaochuan Duan, Yanli Hao, Xiuchai Zheng, Hui Li, Qin Na, Hua Zhang, Bilin Liu, Xuan Zhang

2019, 28(5): 316-328. DOI: 10.5246/jcps.2019.05.031

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Many pH- and temperature-responsive polymers have been designed for preparing hydrogel. In the present study, in order to decrease the pH sensitivity of reported poly(amidoamine)-poly(ethyleneglycol)-poly(amidoamine) (PAA₁₅₈₀-PEG₄₆₀₀-PAA₁₅₈₀), we designed and synthesized poly(amidoamine)-poly(ethyleneglycol)-poly(amidoamine) (PAA-PEG-PAA) with shorter length of PAA chain by decreasing reaction temperature for preparing PAA-PEG-PAA hydrogel solution containing doxorubicin (DOX). The PAA-PEG-PAA was synthesized via the Michael-addition polymerization. The characteristic of PAA-PEG-PAA was evaluated.The PAA-PEG-PAA hydrogel solution was prepared and investigated. DOX-loaded PAA-PEG-PAA hydrogel solution was prepared, and its in vitro DOX release and in vitro anti-tumor activity were evaluated. Our results indicated that the viscosity of PAA-PEG-PAA hydrogel solution was concentration- and temperature-dependent. The sol-gel transition temperature of PAA-PEG-PAA hydrogel solution (12 %, w/w) ranged from 35 to 29 ºC, and its pH ranged from 6.0 to 7.4. The released DOX from DOX-loaded PAA-PEG-PAA hydrogel showed sustained release characteristics. The in vitro anti-tumor activity of DOX-loaded PAA-PEG-PAA hydrogel was confirmed in B16F10 cell line. Considering the acidic tumor microenvironment, this DOX-loaded PAA-PEG-PAA hydrogel solution would be easy in situ administration for intra-tumor injection or para-tumor injection forming hydrogel at body temperature. We suggested that this DOX-loaded PAA-PEG-PAAhydrogel solution, if containing photothermal conversion agents, would have a potential further use for photothermal therapy.

In vitro dissolution and oral bioavailability study of fenofibrate nanomatrix system prepared by hot-melt extrusion

Yajie Yin, Xiaofei Zhang, Zheng Cui, Wei Qu, Bing He, Wenbing Dai, Hua Zhang, Xueqing Wang, Qiang Zhang

2019, 28(5): 329-338. DOI: 10.5246/jcps.2019.05.032

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Solvent evaporation method for preparation of nanomatrix has the disadvantages, such as residual organic solvent, environmental pollution, explosion-proofing and so on. To overcome these shortcomings, a series of fenofibrate nanomatrix drug delivery system (NDDS) consisting of nano-porous silica Sylysia^®350 (S350) and pH sensitive material Eudragit^®L100-55 (EL100-55) were prepared using hot-melt extrusion (HME), and their in vitro dissolution and in vivo bioavailability were compared. Finally, the formulation with the highest in vivo bioavailability was selected as the optimized formulation for DSC and PXRD characterization. The results showed that the optimized NDDS showed a higher bioavailability than the reference formulation, although there was crystalline form drug remaining in NDDS. The relative bioavailability of the optimized formulation was 157.1% compared with the commercial product Lipanthyl^®. In addition, the relative bioavailability of the optimized formulation was 124.8% in comparison with the formulation prepared by solvent evaporation method, showing that the NDDS prepared by the HME method was effective in improving the bioavailability of fenofibrate. In conclusion, HME was a promising method to prepare NDDS.

Effects of harvesting time and processing on the contents of five alkaloids in the herbaceous stems of Ephedra sinica

Wen Zhang, Kangfei Duan, Mingying Shang, Meng Guan, Deyun Li, Zongli Bai, Zhiyong Le, Shaoqing Cai

2019, 28(5): 339-347. DOI: 10.5246/jcps.2019.05.033

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In the present study, we studied the changes of the contents of alkaloids in the herbaceous stems of Ephedra sinicaduring different harvest periods as well as before and after processing. The alkaloid contents of 39 batches of ephedra herb, prepared slices ephedra and honey-fried ephedra, 24 batches of ephedra herb with different harvesting periods, which were all collected from cultivation base in Inner Mongolia, and 38 batches of prepared slices ephedra purchased from the market were detected by taking norephedrine (NE), norpseudoephedrine (NPE), ephedrine (E), pseudoephedrine (PE) and methylephedrine (ME) as indicators by using HPLC method. The content of total alkaloid in prepared slices ephedra (1.71%–3.14%) was higher than that in ephedra herb (1.20%–2.53%) and honey-fried ephedra (1.52%–2.99%). Contents of different alkaloids in these three types of samples were significantly different. Prepared slices ephedra and honey-fried ephedra showed significant differences in the contents of NE, NPE and ME (P<0.05), and the contents of E were significantly different between ephedra herb and honey-fried ephedra (P<0.05). The total alkaloid content of ephedra herb was the highest in September (3.10%). Alkaloid contents of prepared slices ephedra collected in the market were uneven and 13%–91% lower than those collected from cultivation base. The results provided a basis for the quality evaluation of ephedra herb and its processed products, and had certain guiding significance for the selection of processed ephedra according to different drug purposes in clinical application. It also provided data support for the harvesting time of ephedra herb.

A new simple and reliable high-performance liquid chromatography-diode array detection method for the simultaneous quantitative and fingerprint analyses of Salvia przewalskii

Yuanyuan Jiang, Tao Wang, Hui Zhang, Huan Chen, Long Wang, Li Zhang, Yonghong Zhou

2019, 28(5): 348-359. DOI: 10.5246/jcps.2019.05.034

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In the present study, we developed a novel high-performance liquid chromatography-diode array detection (HPLC-DAD) method for the simultaneous determination and fingerprinting of 15 components in Salvia przewalskii. The method had good linearity, precision, stability and recovery. Chromatographic fingerprints were determined by HPLC-DAD using rosmarinic acid peaks as references, and 17 common peaks were selected. The similarity indexes calculated based on similarity system theory of the 10 samples were higher than 0.948, indicating good correlation among the common peaks. The chromatograms distinguished S. przewalskii from Salvia miltiorrhiza and identified the origins of S. przewalskii. These results suggested that the proposed method was suitable for S. przewalskii quality control.

Bioactivity of compounds isolated from the leaves of the Lantana camara Linn plant

Suryati, Elida Mardiah, Mai Efdi, Kartika MZ, Yuni Mala Sari

2019, 28(5): 360-368. DOI: 10.5246/jcps.2019.05.035

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Two compounds with different bioactivitieswere isolated from the leaves of the Lantana camara Linn plant. Compound 1wastriterpenoid (Lantadene B)(22β-dimethylacroyloxy-3-oxoolean-12-en-28-oic-acid, C₃₅H₅₂O₅), which was isolatedfrom n-hexane fraction and obtained as white solid (amorphous). Compound 2was glycosideflavonoid (5-hydroxy-6,4′-dimethoxyflavon-7-O-glucopyranose, C₂₃H₂₄O₁₁), which was isolated from ethyl acetate and obtained as pale yellow solid (amorphous). Extraction was performed withmaceration method using methanol solvent. Subsequently, fractionation was carried out using n-hexane and ethyl acetate solvents. Isolation and purification of both fractions were conductedusing chromatography method. The structure of the isolated compounds was determined throughspectralanalyses of ultraviolet (UV), infrared (IR), and nuclear magnetic resonance (¹H NMR and ¹³C NMR), distortionless enhancement by polarization transfer (DEPT), heteronuclear multiple bond connectivity (HMBC), heteronuclear single quantum correlation (HSQC), and H-H COSY (¹H-¹H homonuclear correlatedspectroscopy). The cytotoxic activity of compound 1 was tested against MCF-7 breast cancer cellsin vitro using MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), showing very strong cytotoxic activity in inhibiting the growth of MCF-7 breast cancer cells, and the IC₅₀ value was 1.1336 µM. The antioxidant activity of compound 2 was tested using DPPH assay (1,1-diphenyl-2-picrylhydrazyl), showing strong activity in inhibiting free radicals, and its IC₅₀ value was 71.03 mg/L.

The team of Prof. Qiang Zhang has important research progress in ACS Nano

School of Pharmaceutical Sciences, Peking University Health Science Center

2019, 28(5): 369-370.

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