Table of Content

    22 August 2015, Volume 24 Issue 8
    Advances in the formulation and delivery technology of paclitaxel for injection
    Jing Sun, Wenbing Dai, Zhe Liang, Zhaoyang Wang, Changsheng Huang, Bing He, Hua Zhang, Xueqing Wang, Qiang Zhang
    2015, 24(8):  487-500.  DOI: 10.5246/jcps.2015.08.063
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    Paclitaxel is a promising antineoplastic agent against a variety of human solid tumors, such as ovary, breast, lung, head and neck tumors, and melanoma. Owing to its poor solubility, the first available formulation of paclitaxel (Taxol®) exists as a non-aqueous concentrate composed of Cremophor EL (polyethoxylated castor oil) and ethanol. It must be diluted to a suitable aqueous solution prior to long time intravenous infusion. Based on the components and usage, Taxol® has serious adverse effects and is inconvenient for clinical use. To address these problems, the development of a less-toxic, better-tolerated, Cremophor EL-free formulation of paclitaxel has been attempted. In recent years, new drug delivery systems (DDS) including albumin-based nanoparticles, micelles, liposomes, etc. have been investigated. In this review, we present the formulations and delivery technologies of paclitaxel for injection and focus on some of preclinical and clinical experience on the formulations which are already on the market or under clinical stages. Finally, possible nanotechnology advantages, existing challenges and future perspectives of paclitaxel delivery are highlighted.

    Original articles
    Vapreotide-modified nanomicelle as a targeted nanocarrier for delivering paclitaxel to the tumors with overexpression of somatostatin receptors
    Wenjie Hou, Hua Zheng, Jiancheng Wang
    2015, 24(8):  501-513.  DOI: 10.5246/jcps.2015.08.064
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    Somatostatin receptors (SSTRs) were widely expressed in many tumor cells. As a somatostatin analogue, vapreotide (VAP) can be exploited as a modifier for targeting tumor therapy based on its high affinity to SSTR. In this study, we conjugated α-NH2 of exocyclic D-phenylalanine (D-Phe) of vapreotide to N-hydroxysuccinimidyl-PEG2000-DSPE (NHS-PEG-DSPE), and the resulted DSPE-PEG-VAP was used as a targeting component to construct the targeted micelles for delivering paclitaxel (VAP-M-PTX) through a thin-film hydration method. Similar particle size, zeta potential, drug encapsulation efficiencies, drug release behaviors and hemolysis effects were observed between the targeted micelles (VAP-M-PTX) and the non-targeted micelles (M-PTX). In MCF-7 cells, significantly higher intracellular fluorescence intensity (1.5-fold) was determined by flow cytometry after incubation of coumarin-6 loaded targeted micelles (VAP-M-Cou) for 3 h compared with non-targeted micelles (M-Cou), and similar finding was observed confocal microscopy. Furthermore, in comparison with non-targeted formulations, higher antitumorefficacy and higher drug accumulation were found in MCF-7 tumors in nude mice after intravenous injection of the targeted micelles. In conclusion, we believed that the vapreotide-modified nanomicelles could be a promising targeted nanocarrier for delivering anticancer drugs to the tumors with overexpression of somatostatin receptors.

    Investigation of the effect of 2'-substitution of NMN analogues on CD38 NADase inhibitory activity
    Jianguo Li, Fen Pei, Wenjie Zhu, Hongwei Jin, Yongjuan Zhao, Liangren Zhang, Honcheung Lee, Lihe Zhang
    2015, 24(8):  514-523.  DOI: 10.5246/jcps.2015.08.065
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    CD38 is a nicotinamide adenine dinucleotide (NAD)-metabolizing enzyme responsible for catalyzing the synthesis of Ca2+ messengers. Its inhibitor plays an important role in probing the regulatory pathway and physiological function of CD38. For clearly understanding the effect of 2'-substitution of nicotinamide mononucleotide (NMN) analogues on CD38 NADase inhibitory activity, a new kind of NMN analogues with two substituents at C-2' was investigated. Molecular dynamics (MD) simulation and quantum chemical calculation were used to investigate the mechanism by which 2'-substitution affects the inhibitory activity. The results showed that two substituents at C-2' interfered the formation of covalent bond between C-1' of NMN analogues and CD38. The findings of this study will be helpful for comprehensively clarifying the structure-activity relationships of NMN- related CD38 NADase’s inhibitor.

    Synthesis and anticancer activity study of curcumin-related compounds containing benzyl piperidone
    Daiying Zhou, Suqing Zhao, Xi Zheng, Zhiyun Du, Kun Zhang
    2015, 24(8):  524-529.  DOI: 10.5246/jcps.2015.08.066
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    Sixteen curcumin-related compounds containing benzyl piperidonewere synthesized and evaluated for their anticancer activity by the MTT assay towards cultured prostate cancer (PC-3), pancreatic cancer (BxPC-3), colon cancer (HT-29), and lung cancer (H1299) cells. Compounds A1 and B3 exhibited potent growth inhibitory effects againstthese cells in culture. The IC50 values of these compounds were lower than 1 µM in all four cell lines.

    Simultaneous determination of seven principal constituents in Asari Radix et Rhizoma by HPLC
    Chen Cao, Jingzhe Wang, Lu Wang, Mingying Shang, Guangxue Liu, Feng Xu, Xuan Wang, Shaoqing Cai
    2015, 24(8):  530-537.  DOI: 10.5246/jcps.2015.08.067
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    A method using high-performance liquid chromatography for the simultaneous determination of seven principal constituentsincluding xanthoxylol, kakuol, methyleugenol, l-sesamin, safrole, sarisan, and l-asarinin in Asari Radix et Rhizoma (Xixin in Chinese) was developed. Fifty five samples of Asari Radix et Rhizoma from different sources (35 samples from Asarum heterotropoides var. mandshuricum, 3 samples from Asarum sieboldii var. seoulense, and 17 samples from Asarum sieboldii) were analyzed with this method. Chromatographic separation was achieved on an Agilent Zorbax SB-C18 column (4.6 mm×25 cm, 5 μm) using a gradient elution with mobile phase of aqueous (A) and acetonitrile (B). The assay was carried out at 20 °C and with detection at 287 nm. All calibration curves showed good linearity (r2>0.999) within the tested ranges. The average recoveries were in the range of 96.0%-103.1% with relative standard deviation (RSD) less than 2.54%. The developed method was accurate with high sensitivity and good reproducibility. The content of volatile methyleugenol in LiaoXixin(the root and rhizome of A. heterotropoides var. mandshuricum and A. sieboldii var. seoulense) was (6.17±5.13) mg/g, which was higher than (0.58±0.40) mg/g in HuaXixin (the root and rhizome of A. sieboldii). The toxic safrole in LiaoXixin was (2.66±2.16) mg/g, which was lower than (6.44±3.89) mg/g in HuaXixin. This is the first report on the simultaneous and quantitative determination of anthoxylol and sarisan in Asari Radix et Rhizoma.

    Hepatoprotective and antioxidant effects of baicalin against CCl4-induced hepatotoxicity
    Song Liu, Xiaohui Lv, Zongxi Sun, Ruiqiang Su
    2015, 24(8):  538-544.  DOI: 10.5246/jcps.2015.08.068
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    Scutellaria baicalensis is widely cultivated in eastern Asia, particularly in China. In the present study, we isolated baicalin from this plant and studied for its hepatoprotective activity against CCl4-induced oxidative damage in rats. Our findings revealed that baicalin exhibited strong antioxidant activity in vitro. In established in vivo tests, baicalin showed effective protective effects by reducing the elevated levels of glutamate pyruvate transaminase(ALT), aspartate aminotransferase(AST), alkaline phosphatase (ALP), total bilirubin (TB) and malondialdehyde (MDA) against CCl4-induced damage, and it restored the activities antioxidant defense substances, such as superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH), toward their normal levels. These data were supplemented with histopathological examination of rat liver sections. The results demonstrated that baicalin could be proposed to protect the liver against CCl4-induced oxidative damage in rats, and the possible underlying mechanism of the activity could be due to its free radical-scavenging and antioxidant activity.

    Inhibiting calcium-activated chloride channel ANO1/TMEM16A suppresses migration of tumor epithelial cells
    Linghan Jia, Wen Liu, KeWei Wang
    2015, 24(8):  545-551.  DOI: 10.5246/jcps.2015.08.069
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    Uncontrolled cell migration is a common feature of tumor metastasis and formation. Understanding the molecular targetscritically involved in cell migration process can lead to the development of potentially novel therapeutic strategies for controlling invasion of tumor cells. In this study, we showed that calcium-activated chloride channel ANO1/TMEM16A played an important role in cell migration and inhibition of ANO1 channel function suppressed the migration of tumor epithelial cells. Silencing ANO1 by small hairpin RNA (shRNA) resulted in suppression of cell migration and invasiveness in cancer cell lines. In addition, pharmacological inhibition of ANO1 by the channel specific inhibitor T16Ain-A01 significantly slowed down the migration andinvasion of tumor epithelial cells in a dose-dependent manner. Taken together, our findings have demonstrated that calcium-activated chloride channel ANO1 contributes to cell migration, and specific ANO1/TMEM16A inhibitors can be the promising candidate to develop new therapies for cancer metastasis.

    Drug administration column
    Stakeholder analysis of clinical trials in China: a structural equation model
    Xiaoyuan Zheng, Linguang Zhou, Bo Gao, Song Yang, Bin Jiang
    2015, 24(8):  552-556.  DOI: 10.5246/jcps.2015.08.070
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    Stakeholder analysis was conducted to define stakeholders and their role in clinical trials; a conceptual model and hypotheses regarding the relationship of each stakeholder were then constructed based on pharmaceutical regulations in China and interviews with experts; Amos 17.0 was utilized to test the model and path analysis. We found that government and hospital are the most powerful stakeholders, while the public and sponsor have little impact on clinical trials. Further measures should be taken by sponsors to promote the development of clinical trials, and the public should be more involved in clinical research.

    Short communication
    Pharmacokinetics, tissue distribution and excretion study of tetrandrine in rats
    Aixia Ju, Yuhong Kang, Qingdan Xue, Qiuhong Li
    2015, 24(8):  557-562.  DOI: 10.5246/jcps.2015.08.071
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    As an important bis-benzylisoquinoline alkaloid isolated from the bulbous root of Stephania tetrandra S. Moore, tetrandrine (Tet) is widely used for the treatment of malignant tumor due to its properties of reversing the multidrug resistance and apoptosis induction. In the present study, we aimed to evaluate the pharmacokinetics, tissue distribution and excretion of Tet in rats. Drug concentration in plasma and tissues was measured by high performance liquid chromatography (HPLC), and the experimental data were analyzed using pharmacokinetic software DAS 2.0. The results showed that the plasma protein binding rate of Tet was 68.7%, indicating a higher protein binding drug. Tissue distribution was found in a descending order as follows: lung>heart>liver>kidney>spleen. Renal excretion was a major route of excretion, and the urine, bile and fecal excretion accounted for 25.73% of the administered dose. AUC0 of Tet in the liver was 20 times greater than that in plasma, indicating that Tet had a higher affinity for the liver. Moreover, CL in the liver was the lowest among all tissues, indicating that Tet with slow elimination might result in the accumulation. Therefore, we need to adjust the dose for patients who have dysfunction in liver and kidney. In addition, therapeutic drug monitoring in long-term clinical treatment, if necessary, should be carried out.