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2018年中国药理学会定量药理学专业委员会学术年会

作者：薛钧升姚烨卢炜田秀云郝纯毅周田彦北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室北京大学肿瘤医院肝胆胰外二科

运用第三代芳香化酶抑制剂来曲唑(Letrozole,LTZ)抑制体内雌激素水平,进而抑制肿瘤生长的内分泌疗法已在乳腺癌中成功运用,然而其在胰腺癌中的药效尚属未知。核苷类似物吉西他滨(Gemcitabine,GEM)是临床上胰腺癌的一线化疗药物。临床实... 详细信息

运用第三代芳香化酶抑制剂来曲唑(Letrozole,LTZ)抑制体内雌激素水平,进而抑制肿瘤生长的内分泌疗法已在乳腺癌中成功运用,然而其在胰腺癌中的药效尚属未知。核苷类似物吉西他滨(Gemcitabine,GEM)是临床上胰腺癌的一线化疗药物。临床实践中,内分泌治疗与化疗是否应该同时应用存在争议。本研究通过构建LTZ与GEM联合治疗胰腺癌的临床前PK/PD模型,引入联用指数φ定量描述两药的相互作用,并仿真不同给药方案下的

关键词：胰腺癌来曲唑吉西他滨动力学研究联合治疗

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A novel type of functional epirubicin liposomes modified with DSPE-PEG_(2000)-cyclopamine conjugate for eliminating heterogeneous breast cancer cells

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Journal of Chinese Pharmaceutical Sciences 2017年第4期26卷 255-264页

作者：胡英杰张靖莹刘磊阎妍沐黎敏白婧吴佳栓吕万良北京大学医学部药学院天然药物及仿生药物国家重点实验室分子药剂学与新释药系统北京市重点实验室北京100191

Common chemotherapy is unable to eliminate the heterogeneous side population of cancer cells （such as cancer stem-like cells）, resulting in poor prognosis. The heterogeneity of cancer cells causes an extensive multidrug resistance through the aberrantly active Hedgehog （Hh） signaling pathway. Cyclopamine is a chemical compound that can block Hh signaling pathway, and a combination use of cyclopamine with anticancer drug would be beneficial for killing heterogeneous cancer cells. In the present study, we aimed to develop a kind type of fimctional drug liposomes for eliminating heterogeneous cancer, The study was performed on human breast cancer cells. A distearoylphosphoethanolamine polyethylene glycol （DSPE-PEG2000）-cyclopamine conjugate was newly synthesized by a nucleophilic substitution reaction, and confirmed by MALDI-TOF mass. An HPLC method was established and validated for qualification of epirubicin. Functional epimbicin liposomes were successful constructed by modifying with DSPE-PEG2o00-cyclopamine, displaying a particle size in nano-scale （approximately 98 nm） and a high epirubicin encapsulation （〉97%）. The CD44＋/CD24-side population was characterized in defining heterogeneous breast cancer cells. As compared with regular epirubicin liposomes, fimctional epirubicin liposomes exhibited an evidently enhanced cellular drug uptake and a significant killing effect in overall breast cancer cells. In conclusion, the functional epirubicin liposomes could be a useful drug delivery carrier for eliminating heterogeneous breast cancer cells.

关键词： Cyclopamine conjugate Epirubin Liposomes Heterogeneity Breast cancer

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The use of a new functional glucose conjugate material, TPGS_(1000)-Glu, in treatment of brain glioma by incorporating into epirubicin liposomes

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Journal of Chinese Pharmaceutical Sciences 2016年第4期25卷 266-274页

作者：沐黎敏吴佳栓谢红军刘磊曾凡阎妍赵曜胡英杰卜英子吕万良北京大学医学部药学院天然药物与仿生药物国家重点实验室分子药剂学与新释药系统北京市重点实验室北京100191

Most of antieancer agents can not be used for treatment of brain glioma due to the existence of the blood brain barrier （BBB）. The over-expression of glucose transporters （GLUTs） on the BBB and brain glioma cells enables the possibility that the GLUTs ligand modified drug carrier transports across the BBB, and targets to the brain glioma cells. The objectives of the present study were to synthesize a new glucose conjugate material, TPGS1000-Glu, develop a kind of TPGSI00o-Glu modified epirubicin liposomes, and evaluate their efficacy. The studies were performed on the BBB co-culture model and brain glioma cells in vitro. TPGS 1000-Glu was synthesized by conjugating TPGSlo00_COOH with 4-aminophenyl-[3-D-glucopyranoside （Glu）, and confirmed by MALDI-TOF-MS spectrum. TPGS^0oo-GIu modified epirubicin liposomes were prepared with a high drug encapsulation efficiency （〉97%）, a nanosize （approximately 90 nm）, and a minimal drug leakage in fetal bovine serum （FBS）-containing buffer system. The BBB co-culture model was established, and after applying TPGSl0oo-Glu modified epirubicin liposomes to the model, transport of liposomal drug across the BBB was evidenced. Besides, TPGS1000-Glu modified epirubicin liposomes showed the strongest cellular drug uptake and anti-glioma efficacy after transport across the BBB in vitro. The synthesized TPGS1000-Glu material could offer a new targeting ligand for the BBB, while the developed TPGS1000-Glu modified epirubicin liposomes might provide a potential anticancer formulation for treatment of brain glioma.

关键词： TPGS1000-Glu Epirubicin Liposomes Glucose transporters Brain glioma

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The preparation and characteristics of sterically stabilized liposomes containing paclitaxel and super-paramagnetic iron oxide nanoparticles

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Journal of Chinese Pharmaceutical Sciences 2016年第8期25卷 570-575页

作者：任伟张爽钟婷黄丹姚鑫郭阳段晓川殷一凡张漱石张烜北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室北京100191 北京大学医学部天然药物及仿生药物国家重点实验室北京100191

Theranostics, combining therapy and diagnosis, is an appealing approach for chemotherapy. In the present study, we selected paclitaxel （PTX） as a therapeutic agent, super-paramagnetic iron oxide nanoparticles （SPIO） as a diagnostic agent and sterically stabilized liposomes as a carrier to prepare theranostic liposomes. The SPIO were prepared and characterized. Moreover, the sterically stabilized liposomes containing PTX and SPIO （PTX/SPIO-SSL） were prepared. The characteristics of PTX/SPIO-SSL were investigated. The results indicated that prepared SPIO exhibited super-paramagnetic and could be used for MRI. The average particle size of PTX/SPIO-SSL was about 170 rim, with a polydispersity index （PDI） less than 0.3. The zeta potential of PTX/SPIO-SSL was negative. The PTX entrapment efficiency of PTX/SPIO-SSL was more than 98%. The TEM results indicated the spherical structure and dense SPIO content in PTX/SPIO-SSL. The in vitro release of PTX from PTX/SPIO-SSL and PTX-SSL was almost identical at both pH 6.8 and 7.4. In conclusion, the PTX/SPIO-SSL were prepared and characterized in vitro. The anti-tumor and diagnostic activity of PTX/SPIO-SSL should be investigated deeply in future study.

关键词： Paclitaxel Super-paramagnetic iron oxide nanoparticles Sterically stabilized liposomes Theranostics

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A liquid chromatography-tandem mass spectrometric method for the determination of axitinib in nude mouse plasma: development, validation and application to a pharmacokinetic study

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Journal of Chinese Pharmaceutical Sciences 2016年第5期25卷 342-350页

作者：马元亨李健苏清虹陈文君卢炜周田彦北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室北京100191 北京大学医学部天然药物及仿生药物国家重点实验室北京100191

In the present study, a simple, rapid, and sensitive liquid chromatography-tandem mass spectrometric method for the determination of axitinib in nude mouse plasma was developed, validated, and applied to a pharmacokinetic study. Plasma samples were pre-treated by protein precipitation with acetonitrile spiked with erlotinib as an internal standard. The chromatographic separation was accomplished by using a reversed phase C18 column （50 mm×2 mm, 5 μm） with a simple mobile phase system composed of methanol and water （60：40, v/v） at an isocratic flow rate of 0.4 mL/min. The analyte was detected by a triple-quadrupole tandem mass spectrometer via electrospray ionization and multiple reaction monitoring was employed to select both axitinib and erlotinib in the positive ion mode. The calibration curves were linear （r〉0.99） ranging from 1 to 1000 ng/mL, and the lowest level of this range was the lower limit of quantification. The intra- and inter-day precision were 7.7%-12.0%, and the accuracies ranged from 88.6% to 110.4%. This method was successfully applied to a preclinical pharmacokinetic study on female nu/nu nude mice administrated with a single oral dose of axitinib at 120 mg/kg, and the pharmacokinetics was characterized by a one-compartment model with first-order absorption.

关键词： Axitinib LC-MS/MS Nude mice Pharmacokinetics

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抗耐药长春瑞滨脂质体及其抗耐药性乳腺癌的效应与机制研究（英文）

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Journal of Chinese Pharmaceutical Sciences 2016年第7期25卷 489-501页

作者：谢红军刘磊曾凡沐黎敏赵曜阎妍胡英杰吴佳栓卜英子张婧莹吕万良北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室天然药物及仿生药物国家重点实验室

在乳腺癌的综合治疗策略中,化疗药物对于清除癌细胞起关键作用。但是,抗癌药物的多药耐药性是化疗成功的主要障碍之一。本研究旨在构建一种抗耐药长春瑞滨脂质体并考察其抗耐药性乳腺癌的效应与机制。以耐药性人乳腺癌MCF-7/adr细胞为... 详细信息

在乳腺癌的综合治疗策略中,化疗药物对于清除癌细胞起关键作用。但是,抗癌药物的多药耐药性是化疗成功的主要障碍之一。本研究旨在构建一种抗耐药长春瑞滨脂质体并考察其抗耐药性乳腺癌的效应与机制。以耐药性人乳腺癌MCF-7/adr细胞为模型进行效应和机制研究;将长春瑞滨包封于脂质体内核、将他莫昔芬和地喹氯铵修饰脂质体表面,制备了抗耐药长春瑞滨脂质体,其平均粒径约100 nm。该脂质体表现出较强的体外杀伤耐药性乳腺癌效果,其作用机制与如下因素有关:增加耐药性癌细胞中药物摄取;降低耐药性癌细胞膜转运蛋白ABCB1和ABCC10的表达;载药脂质体靶向性作用于线粒体并诱导癌细胞凋亡。诱导凋亡信号通路包括:激活凋亡酶caspase(8,9,3);诱导线粒体释放细胞色素c;激活Bax活性并抑制Mcl-1活性;诱导产生活性氧ROS。因此,本研究构建了一种新的抗耐药长春瑞滨脂质体,可望用于耐药性乳腺癌的治疗,并为耐药性乳腺癌的治疗提供一种备选策略。

关键词：抗耐药长春瑞滨脂质体线粒体靶向凋亡信号通路疗效耐药性乳腺

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Augmented efficacy and the mechanism of a combined use of daunorubicin with rofecoxib in treatment of triple-negative breast cancer

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Journal of Chinese Pharmaceutical Sciences 2016年第6期25卷 438-447页

作者：赵曜张婧莹胡英杰吴佳栓卜英子吕万良北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室天然药物及仿生药物国家重点实验室北京100191

Triple-negative breast cancer is the tumor that lacks expressions of estrogen receptor（ER）, progesterone receptor（PR） and human epidermal growth factor receptor-2（HER2）. A regular chemotherapy cannot eradicate triple-negative breast cancer. In the present study, we aimed to develop a combined use of daunorubicin and rofecoxib to treat triple-negative breast cancer, and reveal the underlying mechanisms. A gradient elution HPLC-UV method was developed for quantification, and the evaluations were performed on the triple-negative breast cancer MDA-MB-231 cells using a high content screening system. The results demonstrated that daunorubicin alone was insensitive to the triple negative breast cancer cells, while the combined use of daunorubicin and rofecoxib was able to effectively kill these triple-negative cancer cells, exhibiting a rofecoxib concentration-dependent manner. The mechanism revealed that the augmented anticancer efficacy was associated with direct killing effect, inducing apoptosis and inducing autophagy by the combination treatment. Besides, the apoptosis signaling pathways were correlated to a cascade of reactions by activating apoptotic enzyme caspase family and by suppressing anti-apoptotic gene expressed protein Bcl-2 family. In conclusion, this study provided a fundamental evidence for further developing the combined use of daunorubicin and rofecoxib formulation, hence offering a promising strategy for eradicating the triple negative breast cancer.

关键词： Daunorubicin Rofecoxib Triple-negative breast cancer Apoptosis Autophagy

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TM208治疗非小细胞肺癌移植瘤的药物动力学-药效动力学模型（英文）

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Journal of Chinese Pharmaceutical Sciences 2016年第7期25卷 502-511页

作者：花明冀希炜李润涛季双敏李健姚庆宇王丽杰郝方然卢炜周田彦北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室北京大学第一医院临床药理研究所北京大学医学部天然药物及仿生药物国家重点实验室

本文旨在研究一种新的抗癌化合物TM208在非小细胞肺癌（NSCLC）移植瘤中的治疗效果,并建立药物动力学-药效动力学（PK-PD）模型,描述和仿真给药之后肿瘤体积随着时间的变化情况。首先,比较了TM208治疗组（TM208 100 mg/kg和TM208 150 mg... 详细信息

本文旨在研究一种新的抗癌化合物TM208在非小细胞肺癌（NSCLC）移植瘤中的治疗效果,并建立药物动力学-药效动力学（PK-PD）模型,描述和仿真给药之后肿瘤体积随着时间的变化情况。首先,比较了TM208治疗组（TM208 100 mg/kg和TM208 150 mg/kg）和对照组（空白对照,吉西他滨阳性对照）之间的肿瘤生长情况;其次,建立了肿瘤自然生长模型和基于空白对照以及TM208治疗组数据的PK-PD模型;最后,对模型进行了评价和验证并仿真不同给药方案下的药效。结果表明,NSCLC可能是TM208的一种潜在适应症,TM208 150 mg/kg QD可以作为有效剂量;模型参数中肿瘤的初始体积为0.134 cm3,生长速率为0.0869 day;;而PK/PD模型显示药物对NSCLC细胞的直接杀伤系数为0.174 mL/μg/d,其导致的隔室间传导速率为0.173 day;。不同给药方案的仿真结果表明,TM208 900 mg/kg QW与TM208 150 mg/kg QD的肿瘤抑制作用相当。总之,TM208在NSCLC移植瘤中的抗癌疗效得以证实,所建立的PK-PD模型能定量地描述和预测血浆药物浓度和药效之间的关系,该研究对今后TM208的转化研究具有参考作用。

关键词：药物动力学-药效动力学模型 TM208 非小细胞肺癌

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Folate and cell penetrating peptide modification effects on penetration behavior of nanostructured lipid carriers using multicellular tumor spheroids

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Journal of Chinese Pharmaceutical Sciences 2015年第10期24卷 666-672页

作者：庄鸿蒙孟婷婷高玮袁兰齐宪荣北京大学医学部药学院分子药剂学和新释药系统北京重点实验室北京100191 北京大学医学部药学院药剂学系北京100191 北京大学医学部药学院药剂学系北京100191 北京大学医学部医学分析中心北京100191

Surface modification may have important influences on the penetration behavior of nanoscale drug delivery system. In the present study, we mainly focused on whether cell targeting or cell penetration could affect penetration abilities of nanostructured lipid carriers（NLC）. Real--time penetration of folate--or cell penetrating peptide（CPP）-modified NLC was evaluated using a multicellular tumor spheroid（MTS） established by stacking culture method as an in vitro testing platform. The results suggested that CPP modification had a better penetration behavior both on penetration depth and intensity compared with folate-modified NLC at the early stage of penetration process.

关键词： Nanostructured lipid carriers Multicellular tumor spheroids Stacking method Folate Cell penetrating peptide

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Preparation and characterization of mesoporous silica nanoparticles with enlarged pores capped with crosslinked PEI

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Journal of Chinese Pharmaceutical Sciences 2015年第11期24卷 712-720页

作者：孙璐刘瑜洁仰浈臻齐宪荣北京大学医学部分子药剂学与新释药系统北京市重点实验室北京100191 北京大学医学部药学院药剂学系北京100191 北京大学医学部天然药物及仿生药物国家重点实验室北京100191

The epidemiological statistics reveals the striking patterns of cancer in women and highlights the need for novel therapeutic strategies. In this work, mesoporous silica nanoparticles（MSNs） as representative of inorganic nanoparticles were prepared for loading si RNA that plays a role of gene silencing to treat breast carcinoma（MCF-7） cells. The critical processes of synthesis were optimized for the nanoparticles with desired quality attributes that have the enlarged pores for elevated loading capacity. After si RNA loading into mesoporous, crosslinked-polyethylenimine was employed as the cap to coat the enlarged MSN pores and protect the cargo from leakage. The elevated quantity of si RNA（35 μg si RNA/mg MSNs） were loaded in the MSNs. The as-synthesized MSNs were further evaluated on MCF-7 cells in vitro and shown negligible cytotoxicity. As expected, the si RNA loaded in the as-synthesized MSNs was readily internalized into MCF-7 cells and displayed 420 times higher intake than that of naked si RNA. The MSNs may be exploited to become an effective si RNA cell delivery strategy and further studied for the anti-tumor efficacy.

关键词： Mesoporous silica nanoparticle Preparation Polyethylenimine MCF-7 cells

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