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北京大学学报（医学版） ›› 2018, Vol. 50 ›› Issue (6): 1070-1077. doi: 10.3969/j.issn.1671-167X.2018.06.023

• 论著 • 上一篇    下一篇

空白及载阿霉素的聚丙烯酸栓塞微球的制备与评价

郭李盈1,刘晓昕1,李子圆1,覃小雅1,范则杨2,李真真2,关海涛2,宋莉2,邹英华2,范田园1,△()   

  1. 1. 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　100191
    2. 北京大学第一医院介入血管外科, 北京　100034
  • 收稿日期:2018-05-02 出版日期:2018-12-18 发布日期:2018-12-18
  • 通讯作者: 范田园 E-mail:tianyuan_fan@bjmu.edu.cn
  • 基金资助:
    国家自然科学基金(81571779)

Preparation and evaluation of blank and doxorubicin loaded poly (acrylic acid) microspheres for embolization

Li-ying GUO1,Xiao-xin LIU1,Zi-yuan LI1,Xiao-ya QIN1,Ze-yang FAN2,Zhen-zhen LI2,Hai-tao GUAN2,Li SONG2,Ying-hua ZOU2,Tian-yuan FAN1,△()   

  1. 1. The State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Peking University School of Pharmaceutical Sciences, Beijing 100191, China
    2. Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital, Beijing 100034, China
  • Received:2018-05-02 Online:2018-12-18 Published:2018-12-18
  • Contact: Tian-yuan FAN E-mail:tianyuan_fan@bjmu.edu.cn
  • Supported by:
    Supported by the National Natural Science Foundation of China(81571779)

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摘要：

目的: 研究离子交换型载阿霉素聚丙烯酸栓塞微球的制备方法与性质评价。方法: 采用反相悬浮聚合法制备空白聚丙烯酸栓塞微球[poly (acrylic acid) microspheres,PMs],通过离子交换原理将阿霉素载入该微球,制备载阿霉素的聚丙烯酸栓塞微球[doxorubicin-loaded poly (acrylic acid) microspheres,DPMs]。采用光学显微镜考察两种微球的形态和粒径分布,荧光显微镜和激光扫描共聚焦显微镜考察载药微球中阿霉素的分布,物性测定仪测定PMs和DPMs的弹性,HPLC法测定PMs的载药性质和DPMs的释药性质。以0.1 mL的DPMs栓塞家兔肝动脉评价其在动物体内的栓塞效果。结果: 制备的PMs和DPMs形态圆整、表面光滑,能够均匀分散,阿霉素主要分布在靠近微球表面的区域且分布均匀。PMs和DPMs的平均粒径分别为(283±136) μm和(248±149) μm,杨氏模量分别为(62.63±1.65) kPa和(93.94±1.10) kPa,空白和载药微球均具有良好的抗压缩能力。PMs在12 h时达到载药平衡,包封率大于99%,在浓度为5.0 g/L和12.5 g/L的阿霉素溶液中微球的载药量分别为(19.78±0.27) g/L和(49.45±0.37) g/L;DPMs在磷酸盐缓冲液(phosphate buffered saline,PBS)中缓慢释放阿霉素,载药量为(19.78±0.27) g/L和(49.45±0.37) g/L的微球24 h体外累积释放百分数分别为6.82%±0.02%和2.83%±0.10%。影像学结果显示,DPMs成功地栓塞了家兔的肝动脉。结论: 聚丙烯酸微球具有良好的载阿霉素性能,DPMs是一种潜在的可用于动脉化疗栓塞的新型药物递送系统。

关键词: 微球, 化学栓塞, 治疗性, 离子交换, 阿霉素, 缓释

Abstract:

Objective: To prepare ion exchange doxorubicin-loaded poly (acrylic acid) microspheres (DPMs) and evaluate the properties of these chemoembolic agents.Methods:Poly (acrylic acid) microspheres (PMs) without drug were prepared by inverse suspension polymerization method and then doxorubicin was loaded by ion exchange mechanism to prepare DPMs. Optical microscope was used to investigate the morphology and particle size distribution of PMs and DPMs; fluorescence microscope and confocal microscope were used to observe the distribution of doxorubicin after drug loading. Elasticities of both the microspheres were evaluated by texture analyzer. High performance liquid chromatography (HPLC) method was established to determine the drug loading behavior of PMs and releasing behavior of DPMs. The in vivo embolic property was evaluated by embolizing the hepatic artery of a rabbit with 0.1 mL of DPMs.Results:PMs and DPMs were both spherical in shape, smooth in surface and dispersed well. Doxorubicin was mainly in the outer area inside of DPMs and distributed evenly. The average particle size of PMs and DPMs were (283±136) μm and (248±149) μm, respectively. PMs and DPMs both had good compression ability with the Young’s modulus of (62.63±1.65) kPa and (93.94±1.10) kPa separately. PMs reached the drug loading balance at 12 h, and the entrapment efficiency was greater than 99%. Drug loading of PMs in doxorubicin solution at the concentration of 5.0 g/L and 12.5 g/L was (19.78±0.27) g/L and (49.45±0.37) g/L, respectively. Doxorubicin released slowly from DPMs in PBS and the accumulative release percentages of DPMs with corresponding drug loading were 6.82%±0.02% and 2.83%±0.10% after 24 h, respectively. Arterial angiograms showed that the hepatic artery of the rabbit was successfully embolized with DPMs.Conclusion:DPMs with good performance of loading doxorubicin could be a potential embolic agent for transcatheter arterial chemoembolization.

Key words: Microspheres, Chemoembolization, therapeutic, Ion exchange, Doxorubicin, Sustained release

中图分类号: 

  • R94

图1

PMs在不同浓度阿霉素溶液中的载药量(A)和包封率(B)"

图2

光学显微镜下的PMs(A)和DPMs(B)(×64)"

图3

荧光显微镜下的DPMs(×100)"

图4

激光扫描共聚焦显微镜下的DPMs,A~D依次为顶端到最大截面处的横向扫描图(×100)"

图5

PMs和DPMs的粒径分布"

表1

PMs和DPMs的杨氏模量、半松弛时间、残余应力、破裂形变、破裂应力、粘弹性、凝聚性和回复性(n=3)"

Microspheres PMs DPMs
Young’s modulus/kPa 62.63±1.65 93.94±1.10#
RHT/s 37.45±1.90 15.42±0.71#
Residual force/% 71.68±6.15 41.54±3.73#
Percentage of failure deformation/% 94.0±1.7 99.4±0.31#
Failure stress/N 0.43±0.13 0.70±0.04*
Springiness 0.73±0.02 0.69±0.02
Cohesiveness 0.74±0.04 0.61±0.08
Resilience 0.51±0.04 0.35±0.06*

图6

不同载药量的DPMs随时间的药物累积释放百分数(n=3)"

图7

家兔肝动脉栓塞前(A)和栓塞后(B)的血管造影图像"

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