Journal of Chinese Pharmaceutical Sciences

Structure-based design and biological evaluation of novel mTOR inhibitors as potential anti-cervical agents

Peili Jiao, Yiyan Li, Xing Wu, Yuxi Wang, Beibei Mao, Hongwei Jin, Lihe Zhang, Liangren Zhang, Zhenming Liu

2020, 29(9): 603-616. DOI: 10.5246/jcps.2020.09.056

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The mammalian target of rapamycin (mTOR) is a critical component of the PI3K-AKT signaling pathway. It is highly activated in cervical cancer, which continues to pose an important clinical challenge with an urgent need for new and improved therapeutic approaches. Herein, we describe the structure-based drug discovery and biological evaluation of a series of mTOR kinase inhibitors as potential anti-cervical cancer agents. The results of enzymatic activity assays supported C3 as a potential mTOR inhibitor, which exhibited high inhibitory activity with an IC₅₀ of 1.57 μM. Molecular docking and dynamics simulation were conducted to predict the binding patterns, suggesting relationships between structure and activity. The anti-proliferative assay against diverse cancer cell lines was displayed subsequently, revealing that C3 exhibited significant proliferation inhibition against cervical cancer cell HeLa (IC₅₀ = 0.38 μM) compared with other cell lines. Moreover, C3 could effectively reduce the expression of phospho-ribosomal S6 protein (p-S6) in HeLa cells in a dose-dependent manner. Noteworthily, mTOR signaling and other cellular pathways might contribute to the significant effect of C3 against cervical cancer simultaneously. These data indicated that C3 represented a good lead molecule for further development as a therapeutic agent for cervical cancer treatment.

Preparation and characterization of zinc oxide nanoparticles

Man Liu, Shuang Zhang, Zhuoyue Li, Guangxue Wang, Jingru Wang, Xuan Zhang

2020, 29(9): 617-625. DOI: 10.5246/jcps.2020.09.057

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In the present study, the zinc oxide nanoparticles (ZnO NPs) were prepared by using a sol-gel method. The characterizationof ZnO NPs, such as particle size, morphology, crystal form, optical properties and pH-responsive behavior, was carried out. The in vitro anti-tumor activity of ZnO NPs was evaluated on PC-3M and 4T1 cell lines. The results indicated that ZnO NPs were spherical NPs with uniform particle size, excellent fluorescence properties, and pH-responsive behavior. The in vitro anti-tumor activity of ZnO NPs was observed on PC-3M and 4T1 cell lines. Considering to above characteristics, ZnO NPs could be used as drug delivery carries for loading active compound performing therapeutic and diagnostic effect.

Enhanced tumor-targeted delivery of anticancer drugs by folic acid-conjugated pH-sensitive polymeric micelles

Chuhang Zhou, Xinping Hu, Qi Liu, Leqi Wang, Yuanhang Zhou, Yao Jin, Yan Liu

2020, 29(9): 626-636. DOI: 10.5246/jcps.2020.09.058

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In order to enhance the targeted delivery of anticancer drugs by polymeric micelles, folic acid (FA), the ligand of folate receptor (FR) over-expressed in the most cancer cells, modified pH-sensitive polymeric micelles were designed and fabricated to encapsulate doxorubicin (DOX) by combination of pH-sensitive amphiphilic polymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) with FA-conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide). The prepared micelles were characterized to have about 36 nm in diameter with narrow distribution, well-defined spherical shape observed under TEM and pH-responsive drug release behavior. Moreover, the tumor targeting ability of the FA-modified pH-sensitive polymeric micelles was demonstrated by the cellular uptake, in vitro cytotoxicity to FR-positive KB cells and in vivo real time near-infrared fluorescence imaging in KB tumor-bearing nude mice. The efficient drug delivery by the micelles was ascribed to the synergistic effects of FR-mediated targeting and pH-triggered drug release. In conclusion, the designed FR-targeted pH-sensitive polymeric micelles might be of great potential in tumor targeted delivery of water-insoluble anticancer drugs.

Development and validation of an HPLC-UV method for routine trough plasma concentration monitoring of imatinib in Chinese patients with gastrointestinal stromal tumor

Yi Zhou, Junli Lai, Feng Qiu, Jun Zhang

2020, 29(9): 637-648. DOI: 10.5246/jcps.2020.09.059

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Imatinib is the first-line medication for the treatment of advanced gastrointestinal stromal tumor (GIST). Due to the large inter-individual variability, it is recommended to monitor the trough plasma concentration of imatinib to ensure the efficacy and safety of imatinib therapy. In the present study, an HPLC-UV method was developed and validated for quantitating imatinib in the plasma of Chinese GIST patients. The samples were processed by protein precipitation and then mixed with a neutralizing agent (1.4 g K₂CO₃ and 0.65 g KCl dissolved in 5 mL ultrapure water). The chromatographic separation was performed on an InertSustain C₁₈ column (250 mm×4.6 mm, 5 µM) maintained at 40 ºC utilizing the mobile phase consisted of 25 mM NH₄H₂PO₄ (pH 8.0)–acetonitrile (61:39, v/v) at a flow rate of 1 mL/min, with an ultraviolet detector set at 265 nm. The method was fully validated according to the published guidelines. The plotted calibration curves were all linear within the range of 50 to 10 000 ng/mL. The validation results of the intra-day and inter-day accuracies and precisions ranged from –5.81% to 6.33%. The extraction recoveries were within the range of 92.38% to 97.86%. All the results of stability studies were all consistent with the acceptance criteria of within ±15%. Finally, the method was successfully applied to trough plasma concentration monitoring of imatinib in 150 Chinese GIST patients orally administrated with imatinib. Incurred sample reanalysis was conducted, results of which were also in accordance with the acceptance criteria of within ±20%.

Study on drug retention in menopausal women with sequential hormone therapy and tibolone

Shurong Shao, Xiaoqing Shao, Yi Chen

2020, 29(9): 649-655. DOI: 10.5246/jcps.2020.09.060

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In the present study, we aimed to retrospectively analyze the medication prescriptions of menopausal women diagnosed with menopausal syndrome in our hospital from 2015 to 2018, and compare the retention rate of estrogen and progesterone sequential therapy and hormone continuous therapy in menopausal women. The rational drug management system of Ningbo Women and Children's hospital was used to screen the prescriptions of menopausal syndrome in 4 years. After the age, year included in the study, and prescription cost were adjusted, Kaplan-Meier regression analysis was performed to compare the prescription retention rates of the two drug regimens. The distribution of the two HRT regimens in the 4 years showed an increasing trend year by year, and the age groups of the two HRT regimens were mainly distributed between 41 and 60 years old, accounting for 97.1% and 87.06%, respectively. The cost distribution for the other two HRT regimens was approximately the same. Compared with the two HRT regimens, the drug retention rate of hormone continuous regimens was higher than that of hormone sequential regimens within 4 years. Kaplan-Meier regression analysis showed that the trend was significant (Tarone-Ware, Chi-square value=3.857, P = 0.050). This study found that the median retention time of HRT therapy in menopausal women in our hospital was about half a year, which was significantly lower than that reported in previous studies of 1 year or longer. In addition, the present study found that compared with Femoston, the tibolone regimen significantly increased retention time in the treatment of menopausal syndrome.

Microscale thermophoresis in the investigation of biomolecular interactions

Qian Wang, Jing Wang, Shuxiang Song, Guiwang Zhu, Ze Cao, Zhenming Liu

2020, 29(9): 656-665. DOI: 10.5246/jcps.2020.09.061

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Accurate characterization of the interactions between biomolecules not only provides fundamental insights into cellular processes but also paves the way for drug discovery and development. With recent increases in throughput and sensitivity, biophysical technologies have become prominent tools for studying biomolecular interactions. Biophysical techniques that can reduce costs, shorten detection time, simplify the complexity of the system under analysis, and simultaneously provide high-quality data content are particularly favored. Here, we summarize the qualitative and quantitative analysis of biomolecular interactions using MicroScale Thermophoresis (MST), as well as extend the application of MST functions to explore thermodynamics, enzyme kinetics and protein folding-unfolding processes. MST has emerged as a simple and powerful biophysical approach for identifying and quantifying binding events based on the movement of molecules along microscopic temperature gradients. The advantages of MST over other competitive biophysical techniques include freedom from immobilization, rapid analysis times, lower sample consumption, and the ability to analyze binding affinities in cell lysates. This article discusses the instrumental setups, principles, experimental workflows, and examples of MST application in practice.

Analysis of treatment regimen in a pregnant patient with ornithine transcarbamylase deficiency

Lixia Li, Yingxiu Liu, Junming Du

2020, 29(9): 666-670. DOI: 10.5246/jcps.2020.09.062

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As a common urea-cycle disorder, ornithine transcarbamylase deficiency (OTCD) disables the conversion of ammonia into non-toxic urea, and its subsequent excretion results in hyperammonemia. We reported a 28-year-old woman who was diagnosedwith OTCD during her first pregnancy. She was treated with arginine, citrulline and sodium benzoate for complications associated with hyperammonemia, and her protein intake was restricted. The patient’s condition was stabilized, and she delivered a baby boy via cesarean section. However, the baby died 2 d later. During her second pregnancy, prenatal screening suggested that the fetus had OTCD, and an induced abortion was performed. During her third pregnancy, fetal OTCD was ruled out, and the patient was treated with oral sodium benzoate. Her blood ammonia level was stabilized, and a baby boy was successfully deliveredvia cesarean section. This case described the treatment process of the pregnant patient with OTCD, and the safety and efficacy of sodium benzoate were evaluated. Collectively, our findings provided the experience and evidence for the drug selection and treatment of these rare diseases.