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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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MRI"可视化"载药栓塞微球的制备及其体外评价

MRI"可视化"载药栓塞微球的制备及其体外评价

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2017年中国药学大会暨第十七届中国药师周

作者：刘晓昕郭李盈李子圆覃小雅关海涛宋莉邹英华郑卓肇范田园北京大学药学院天然及仿生药物国家重点实验室北京 100191 北京大学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 北京大学第一医院介入血管外科北京 100034 北京清华长庚医院核医学科北京 100044

目的：为了发挥栓塞治疗与药物化疗的双重功效,同时能够利用MRI 监测栓塞进程及效果,我们制备了包载舒尼替尼和磁性氧化铁纳米簇的MRI"可视化" 载药栓塞微球,并对其进行了体外的初步评价.方法：前期我们采用微波辅助溶剂热法... 详细信息

目的：为了发挥栓塞治疗与药物化疗的双重功效,同时能够利用MRI 监测栓塞进程及效果,我们制备了包载舒尼替尼和磁性氧化铁纳米簇的MRI"可视化" 载药栓塞微球,并对其进行了体外的初步评价.方法：前期我们采用微波辅助溶剂热法制备了磁性氧化铁纳米簇,将其作为MRI 显影材料包载到聚丙烯酸微球中;并考察了该微球的理化性质、栓塞性质和MRI 可视性.本研究进一步将化疗药物舒尼替尼载入该微球,制备了同时包载舒尼替尼和磁性氧化铁纳米簇的栓塞微球,考察了微球的形态、粒径分布以及100-300,300-500,500-700,700-900 和900-1200 μm 不同粒径组的载药量、包封率和体外释药性质.结果：所得微球形态圆整,药物和磁性氧化铁纳米簇分布在微球中,粒径均在100-1200 μm 范围内.微球在体外MRI T2加权成像扫描下可被检测到.微球载药量可达到40 mg/mL;48 h 包封率可达到98％以上.舒尼替尼在磷酸盐缓冲液(PBS)中缓慢释放,各粒径组微球7 天的平均累计释放率为36.07±7.47％.结论：本研究所制备的包载磁性氧化铁纳米簇和舒尼替尼的栓塞微球,是一种同时具有MRI 下"可视"和缓释作用的新型栓塞给药系统,有望提高经动脉栓塞治疗的疗效和安全性.

关键词：栓塞微球磁共振成像磁性氧化铁纳米簇舒尼替尼缓释

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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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新型多功能磁性纳米簇的制备及体外表征

新型多功能磁性纳米簇的制备及体外表征

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2016年中国药学大会暨第十六届中国药师周

作者：李子圆郭李盈覃小雅郑卓肇范田园北京大学药学院天然及仿生药物国家重点实验室北京大学药学院分子药剂学与新释药系统北京市重点实验室北京清华长庚医院核医学科

目的:磁性纳米簇是由纳米粒装配而成的纳米聚集体,具有磁靶向、热疗和磁共振成像的多功能性质,并且这些能力高于磁性纳米粒,是磁性物质的研究热点。本研究制备和评价了三种材料修饰的磁性氧化铁纳米簇(Fe3O4 magnetite colloid nanocrys... 详细信息

目的:磁性纳米簇是由纳米粒装配而成的纳米聚集体,具有磁靶向、热疗和磁共振成像的多功能性质,并且这些能力高于磁性纳米粒,是磁性物质的研究热点。本研究制备和评价了三种材料修饰的磁性氧化铁纳米簇(Fe3O4 magnetite colloid nanocrystal clusters,MCNCs)的性质。方法:通过溶剂热法分别制备了由柠檬酸(CA)、聚丙烯酸(PAA)和聚乙烯吡咯烷酮(PVP)修饰的MCNCs,并通过磁铁吸引、透射电子显微镜(TEM)、动态光散射(DLS)粒度测定仪、傅里叶转换红外(FT-IR)光谱仪、振动样品磁强计(VSM)、X射线衍射仪(XRD)分别对三种MCNCs的磁响应性、形态、粒径、红外特征、磁学性质、X射线衍射图谱等进行表征;通过高频感应加热机分别对三种MCNCs的发热性能进行考察;通过3.0 T磁共振成像(MRI)扫描仪对三种MCNCs的横向弛豫效能(r2)进行评价。结果:按CA-MCNCs、PAA-MCNCs和PVP-MCNCs顺序,三种MCNCs在水中分别呈棕、深棕和深黑色;其磁响应性由弱到强(被磁铁吸引的速度由慢到快);电镜结果显示其分散性均较好,大小均一,平均粒径分别为在150 nm、400 nm和600 nm左右;DLS测得水力学平均粒径分别为274 nm、443 nm和658 nm;FT-IR和电镜表明其均被使用的材料成功修饰;VSM证明其均具有良好的超顺磁性,饱和磁化强度分别为57.9 emu/g、68.2 emu/g和77.6 emu/g;XRD说明其均为反尖晶石型结构;在9A、45-50kHz的交变电磁场下,三种MCNCs均呈现出良好的发热性能,经测定其比吸收率(specific absorption rate,SAR)值分别为30、38和48W/g;在MRI下均可显影。结论:三种磁性纳米簇均有磁靶向、热疗和MRI诊断的多功能性质,以PVP-MCNCs的性质为最佳,可望用于相关的医学和药学领域。

关键词：磁性纳米簇磁靶向热疗磁共振成像

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MRI“可视化”载药栓塞微球的制备及其体内外评价

MRI“可视化”载药栓塞微球的制备及其体内外评价

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2016年中国药学大会暨第十六届中国药师周

作者：郭李盈李子圆覃小雅李真真关海涛宋莉邹英华郑卓肇范田园北京大学药学院天然及仿生药物国家重点实验室北京大学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介入血管外科北京清华长庚医院核医学科

目的:MRI"可视化"栓塞剂可以提高栓塞治疗的疗效和安全性,已成为目前栓塞剂研究的前沿;载化疗药物的栓塞剂具有化疗与栓塞治疗的双重功效。为此,我们研制了载磁性纳米簇和阿霉素的栓塞微球,并评价其被MRI检测及用于化疗栓塞... 详细信息

目的:MRI"可视化"栓塞剂可以提高栓塞治疗的疗效和安全性,已成为目前栓塞剂研究的前沿;载化疗药物的栓塞剂具有化疗与栓塞治疗的双重功效。为此,我们研制了载磁性纳米簇和阿霉素的栓塞微球,并评价其被MRI检测及用于化疗栓塞的体内外性质。方法:前期我们采用微波辅助-溶剂热法制备了磁性纳米簇,并将其包载到聚丙烯酸微球中。本研究进一步将阿霉素载入该微球,制成载磁性纳米簇和阿霉素的栓塞微球。在前期工作的基础上(证明了载簇微球具有MRI"可视"、理化性质和栓塞性质良好),本研究以HPLC分别考察了100-300,300-500,500-700,700-900和900-1200μm粒径组微球的载药量、包封率、体外释药性质和MRI下的"可视"性。利用高效液相质谱联用技术,研究和比较了家兔肝动脉微球栓塞组(0.1 mL, 50 mg/mL;100-300μm;n=5)和阿霉素溶液灌注组(1 mL, 5mg/mL;n=5)的药物动力学性质,并进行了微球体内外相关性评价。结果:微球载药量可达到50 mg/mL;24 h包封率达到99%以上;阿霉素在磷酸盐缓冲液(PBS)中缓慢释放,各粒径组48h平均累积释放率为3.83±1.32%。体外MRI扫描下各粒径组微球均可被检测到。微球被成功地栓塞到家兔的肝动脉。微球栓塞组的Cmax为34.74±3.92ng/mL,AUC0-24h为176.84±43.16ng/mL·h;灌注组的Cmax为318.04±48.55ng/mL,AUC0-24h为303.05±48.54ng/mL·h,说明药物在动物体内栓塞后缓释。栓塞组的AUC与药物体外累计释放量呈线性相关,且相关性良好(r=0.9932)。结论:研制的载磁性纳米簇和阿霉素的栓塞微球,同时具有MRI下"可视"和缓释药物的性质,是一种能够提高疗效和安全性的用于经动脉化疗栓塞的新型栓塞给药系统。

关键词：栓塞微球磁共振成像磁性纳米簇阿霉素缓释药物动力学

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The targeting effect of H_7K(R_2)_2-modified pH-sensitive liposomes on U87-MG cells

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Journal of Chinese Pharmaceutical Sciences 2015年第10期24卷 660-665页

作者：赵阳任伟钟婷王超张卫强黄丹张爽郭阳姚鑫张烜张强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

The present study aimed to investigate the targeting effect of H7K（R2）2-modified pH -sensitive liposomes on U87-MG cells. Using coumarin-6 as a fluorescence probe, we prepared H7K（R2）2-modified p H-sensitive liposomes（designated as coumarin-6-PSL-H7K（R2）2）. The flow cytometry assay was used to evaluate the effect of H7K（R2）2 proportions on the cellular uptake and endocytosis pathways of coumarin--6--PSL--H7K（R2）2 on U87-MG cells. The circular dichroism（CD） spectroscopy assay was used to investigate the secondary structures of H7K（R2）2 peptide at pH 7.4 and H 6.8, respectively. Our results indicated that the 2.5% proportion of H7K（R2）2 in the coumarin-6--PSL-H7K（R2）2 was superior to those of 1% and 3.5% of H7K（R2）2. The uptake of coumarin--6-PSL--H7K（R2）2 on U87--MG cells was not inhibited by filipin, M-β--CD or chlorpromazine. The secondary structure of H7K（R2）2 at pH 6.8 was mostly presented as β--turn. In conclusion, we suggested that the appropriate proportion of H7K（R2）2 in the H7K（R2）2--modified pH--sensitive liposomes could be set at 2.5%. The cellular uptake pathway for H7K（R2）2-modified pH--sensitive liposomes was via the cell penetrating capacity of H7K（R2）2 which responded to acidic condition. The secondary structure of H7K（R2）2 at pH 6.8, which was presented as the shape of hairpin, might be mainly responsible for its targeting and cell penetrating effect.

关键词： H7K（R2）2-modified pH-sensitive liposomes Cellular uptake pathway Secondary structure U87-MG cells

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Development and validation of a liquid chromatography with tandem mass spectrometry(LC-MS/MS) method for the determination of sunitinib in rabbit plasma

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Journal of Chinese Pharmaceutical Sciences 2015年第11期24卷 721-725页

作者：杨勇杰李佳林王欢覃小雅卢晓静张兰馨张悦顾梦洁范田园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

A liquid chromatography with tandem mass spectrometry（LC-MS/MS） method has been developed and validated for the measurement of sunitinib in rabbit plasma. After protein precipitation with acetonitrile, samples were analyzed on a Zorbax Extend-C18 column（150 mm×4.6 mm, 5μm）. The mobile phase consisted of a mixture of acetonitrile and deionized water（containing 0.05% formic acid） at a ratio of 27：73（v/v）, and the flow rate was set at 0.8 mL /min. The column temperature was maintained at 30 oC. The LC eluate was detected by an electrospray ionization（ESI） source operated in the positive ion mode, and quantification was conducted using MRM of the transitions m/z 399.24→283.01 and m/z 415.19→178.00 for sunitinib and internal standard（IS, diltiazem hydrochloride）, respectively. The calibration curve was linear in the range of 2–600 ng/m L. The lower limit of quantification was 2 ng/mL. The method also exhibited satisfactory results in terms of sensitivity, specificity, accuracy（with relative error ranging from –4.0% to 1.1%）, precision（with intra- and inter-day relative standard deviations ranging from 2.8% to 9.5%）, matrix effect, recovery as well as stability. Taken together, our newly developed method was reliable to monitor sunitinib concentrations in rabbit plasma.

关键词： Sunitinib LC-MS/MS Rabbit plasma

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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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Preparation and anti-MDR tumors study of folate and TPGS dual-modified DSPE-PEG micelles loaded with docetaxel

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Journal of Chinese Pharmaceutical Sciences 2015年第7期24卷 419-426页

作者：王爱婷佟淑文胡新齐宪荣北京大学医学部药学院药剂学系北京100191 北京泰德制药股份有限公司北京100176 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 北京大学医学部天然药物及仿生药物国家重点实验室北京100191

Multidrug resistance （MDR） operated by P-glycoprotein （P-gp） is one of the major causes in the treatment failure of cancers. In this work, docetaxel-loaded mixed micelles comprised of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy （polyethylene-glycol）2000 （DSPE-PEG2000）, D-α-Tocopherylpolyethylene glycol 1000 succinate （TPGSIooo） and DSPE-PEG2000-folate were developed to overcome MDR and reduce the side effect of docetaxel in cancer therapy. The diameters of micelles ranged from 13 to 26 nm and the encapsulation efficiencies were all above 85%. The influences of DSPE-PEG2000 and TPGSIooo ratios on the micellar characteristics and anti-resistant tumors effects were evaluated. Micelles with high TPGS1000 amount showed an increased cellular uptake and stronger cytotoxicity against MDR KBv cells. Moreover, the micelles modified by targeting ligand of folic acid exhibited better antitumor effect on folate receptor over-expressing KBv cells. The study provides a method for overcoming MDR in cancer therapy.

关键词： Micelles Multidrug resistance Preparation DSPE-PEG TPGS Folate

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