中国组织工程研究

中国组织工程研究 ›› 2019, Vol. 23 ›› Issue (22): 3536-3541.doi: 10.3969/j.issn.2095-4344.1280

• 药物控释材料 drug delivery materials • 上一篇    下一篇

羟丙基壳聚糖/肝素纳米载药体系的制备、释放及抗肿瘤特性分析

杜建红1，范春水1，杜月莲1，孙笑宇1，王庆峰2
  

  1. 1山西药科职业学院制药工程系，山西省太原市  030031；2辽宁中医药大学基础医学院，辽宁省沈阳市  110032
  • 通讯作者: 杜建红，山西药科职业学院制药工程系，山西省太原市 030031
  • 作者简介:杜建红，女，1976年生，山西省太谷县人，汉族，山西医科大学毕业，硕士，讲师，主要从事制药及相关新剂型的研发研究。

Preparation, sustained release and anti-tumor characteristics of hydroxypropyl chitosan/heparin nano-drug system

Du Jianhong1, Fan Chunshui1, Du Yuelian1, Sun Xiaoyu1, Wang Qingfeng2
  

  1. 1Department of Pharmaceutical Engineering, ShanXi Pharmaceutical College, Taiyuan 030031, Shanxi Province, China; 2Basic Medical School of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, Liaoning Province, China
  • Contact: Du Jianhong, Department of Pharmaceutical Engineering, ShanXi Pharmaceutical College, Taiyuan 030031, Shanxi Province, China
  • About author:Du Jianhong, Master, Lectuner, Department of Pharmaceutical Engineering, ShanXi Pharmaceutical College, Taiyuan 030031, Shanxi Province, China

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摘要：

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文题释义：
羟丙基壳聚糖：作为常见的纳米载药材料，壳聚糖有着较好的生物相容性，可以和血液、器官等相容，且安全性较高，亦有较好的生物降解性。然而，在实际的应用中，壳聚糖的水溶性往往不足，因此，可以在壳聚糖上引入羟丙基，从而增加其水溶性。
肝素抗癌：作为一种抗凝剂，肝素是由二种多糖交替连接而成的多聚体，在体内外都有抗凝血作用。然而，随着现代的研究发现，肝素也有较好的抗癌活性，其可抑制肿瘤血管的生成，通过对选择素的抑制，直接抑制肿瘤的转移，同时抑制肝素酶的活性，从而起到抗癌的作用。
 
 
背景：肝素类药物在人体内使用时，存在毒性大、代谢时间短等临床问题。
目的：制备羟丙基壳聚糖/肝素纳米载药体系，考察其载药量、微观形貌、粒径分布、体外释放及对肝癌细胞的抑制效果。
方法：设置肝素溶液与羟丙基壳聚糖溶液体积比为3∶10，6∶10和9∶10，以电荷吸引制备获得羟丙基壳聚糖/肝素纳米颗粒，考察所制备颗粒的性质。考察该颗粒在pH=2.1，4.6，7.4的PBS中的24 h释放率；培养肝癌SMMC-7721细胞株，接种于96孔板内。同时向平板内添加2.5，5，10，20 mg/L的肝素、羟丙基壳聚糖及制备的羟丙基壳聚糖/肝素纳米颗粒混悬液，分析细胞培养24 h后的细胞抑制率。
结果与结论：①肝素溶液与羟丙基壳聚糖体积比为3∶10，6∶10和9∶10时，载药量分别为(27.13±0.79)%，(36.39±1.12)%及(43.68±1.45)%；②肝素溶液与羟丙基壳聚糖体积比为6∶10时制备的纳米颗粒在pH=7.4的条件下释放肝素的速度，远快于pH=2.1或4.6时，且该颗粒在6 h可释放95%以上的肝素。同时释放速率同肝素的负载量成正比；③羟丙基壳聚糖溶液对肝癌SMMC-7721细胞株没有明显的抑制作用；而随着溶液浓度的增加，肝素对肝癌SMMC-7721细胞株的抑制率显著增加，且肝素溶液与羟丙基壳聚糖体积比为  6∶10时制备的羟丙基壳聚糖/肝素颗粒的抑制率高于单独使用肝素时；④结果表明，以肝素溶液与羟丙基壳聚糖体积比为6∶10时制备羟丙基壳聚糖/肝素纳米载药体系具有pH选择性缓释作用，且对肿瘤的抑制效果明显。

关键词: 载药体系, 纳米粒子, pH敏感性, 羟丙基壳聚糖, 肝素, SMMC-7721, 克隆形成, 肝癌, 缓释特性 

Abstract:

BACKGROUND: When heparin drugs are used in human body, there are some clinical problems such as high toxicity and short-term metabolism.
OBJECTIVE: To prepare hydroxypropyl chitosan/heparin nano-drug system, and to investigate its drug loading, micromorphology, particle size distribution, in vitro release and inhibitory effect on hepatocellular carcinoma cells.
METHODS: The volume ratios of heparin solution and hydroxypropyl chitosan solution were set as 3:10, 6:10 and 9:10, and the hydroxypropyl chitosan/heparin nanoparticles were prepared by charge attraction method and to detect its property. The 24-hour release rate of the particle in PBS with pH=2.1, 4.6 and 7.4 was investigated. The SMMC-7721 cell lines were inoculated in 96-well plate. Meanwhile, heparin (2.5, 5, 10, and 20 mg/L), and hydroxypropyl chitosan/heparin nanoparticles were added. After cultured for 24 hours, the cell inhibition rate was measured.
RESULTS AND CONCLUSION: (1) When the volume ratio of heparin solution and hydroxypropyl chitosan was 3:10, 6:10 and 9:10, the corresponding drug loads were (27.13±0.79)%, (36.39±1.12)% and (43.68±1.45)%, respectively. (2) The release rate for heparin of the nanoparticles prepared by the volume ratio of heparin solution and hydroxypropyl chitosan of 6:10 under the condition of pH=7.4 was faster than that under the condition of pH=2.1 or 4.6, which could release more than 95% heparin at 6 hours. At the same time, the release rate was proportional to the heparin load. (3) Hydroxypropyl chitosan solution showed no significant inhibition on the SMMC-7721 cell lines. With the increase of solution concentration, the inhibition of heparin on the SMMC-7721 cell lines increased significantly. In addition, the inhibitory effect of hydroxypropyl chitosan/heparin granules prepared when the volume ratio of heparin solution and hydroxypropyl chitosan was 6:10 was better than that of heparin alone. (4) These results indicate that the hydroxypropyl chitosan/heparin nano-loaded drug system with the 6:10 volume ratio of heparin solution and hydroxypropyl chitosan can achieve sustained release of pH sensitivity, and exerts significant inhibition on the tumor.

Key words: drug load, nanoparticles, pH sensitivity, hydroxypropyl chitosan, heparin, SMMC-7721, clonogenesis, liver cancer, sustained-release characteristics

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