叶酸修饰硬脂酸接枝白芨共聚物的合成及作为抗肿瘤药物载体的研究

doi:10.7503/cjcu20180021

高等学校化学学报 ›› 2018, Vol. 39 ›› Issue (8): 1815.doi: 10.7503/cjcu20180021

叶酸修饰硬脂酸接枝白芨共聚物的合成及作为抗肿瘤药物载体的研究

管清香¹, 纪丹阳¹, 孙波¹, 乔瑾¹, 何彤¹, 张广远¹, 虞振静¹, 尹建元¹(), 杨薇²()

1. 吉林大学药学院, 长春 130021
2. 吉林大学第二医院, 长春 130041

收稿日期:2018-01-08 出版日期:2018-08-10 发布日期:2018-03-26
作者简介:联系人简介: 尹建元, 男, 博士, 教授, 主要从事天然药物活性及载体材料研究. E-mail: yinjy@jlu.edu.cn;杨薇, 女, 博士, 教授, 主要从事载体材料的研究. E-mail: wei88linda@yahoo.com
基金资助:
国家自然科学基金(批准号: 81401513)和吉林卫生厅项目(批准号: 2017J056)资助.

Synthesis of Folate-conjugated Stearic Acid Grafted Bletilla striata Polysaccharides Copolymers and Application for Delivering Antitumor Drugs as a Drug Delivery Carrier^†

GUAN Qingxiang¹, JI Danyang¹, SUN Bo¹, QIAO Jin¹, HE Tong¹, ZHANG Guangyuan¹, YU Zhenjing¹, YIN Jianyuan^1,^*(), YANG Wei^2,^*()

1. School of Pharmacy, Jilin University, Changchun 130021, China
2. The Second Hospital of Jilin University, Changchun 130041, China

Received:2018-01-08 Online:2018-08-10 Published:2018-03-26
Contact: YIN Jianyuan,YANG Wei E-mail:yinjy@jlu.edu.cn;wei88linda@yahoo.com
Supported by:
† Supported by the National Natural Science Foundation of China(No.81401513) and the Project of Health Department of Jilin Province, China(No.2017J056).

摘要/Abstract

摘要：

制备了叶酸修饰硬脂酸接枝白芨(FA-BSPs-SA)的共聚物, 通过氢核磁光谱(¹H NMR)、紫外-可见分光光度法(UV)及红外光谱法(IR)对其进行结构表征. 以乳化-溶剂挥发法制备了载多西他赛胶束并对其进行表征, 并采用噻唑蓝(MTT)法测定了共聚物及其载药胶束的细胞毒性. 结果证实硬脂酸和叶酸均已接枝在白芨多糖上. 疏水性药物多西他赛可被包嵌于FA-BSPs-SA的胶束内. 叶酸取代度增加, 胶束粒径减小, 载药量与包封率均增加. 载药胶束体外释药具有pH依赖性(pH=5.0~7.4). 共聚物FA-BSPs-SA和BSPs-SA浓度为40 μg/mL时, 细胞存活率均在80%以上. 与多西他赛溶液相比, 相同药物浓度的FA-BSPs-SA和BSPs-SA载药胶束抗肿瘤效果更佳, 且载药FA-BSPs-SA胶束对有叶酸受体表达的肿瘤细胞的抑制作用较载药BSPs-SA胶束更强. FA-BSPs-SA共聚物有望作为难溶性抗肿瘤药物的纳米载体材料.

关键词: 叶酸, 硬脂酸, 白芨, 胶束, 自组装, 抗肿瘤药物

Abstract:

Folate-conjugated stearic acid-grafted Bletilla striata polysaccharides copolymers(FA-BSPs-SA) were prepared and characterized using ¹H nuclear magnetic resonance spectroscopy(¹H NMR), ultraviolet visible spectrophotometry(UV) and infrared spectroscopy(IR). Docetaxel-loaded FA-BSPs-SA(DTX-loaded FA-BSPs-SA) micelles were prepared by an emulsion-solvent evaporation method and characterized. The cytotoxicity of copolymers and DTX-loaded micelles was evaluated by MTT assay. The results of ¹H NMR and IR demonstrated that stearic acid and folic acid have been grafted on Bletilla striata polysaccharide. Docetaxel could be entrapped into micelles of FA-BSPs-SA copolymer. DTX-loaded BSPs-SA copolymer micelles displayed pH-dependent properties in the respects of in vitro release behavior ranging from pH=5.0 to pH=7.4. The particle sizes of DTX-loaded micelles decreased whereas encapsulation efficiency and loading capacity increased with the substitution degree increase of folic acid. The cell survival rates subjected to FA-BSPs-SA and BSPs-SA were still above 80% at the concentration of 40 μg/mL. The anti-tumor effect in vitro of DTX-loaded FA-BSPs-SA and DTX-loaded BSPs-SA micelles were superior to that of DTX solution at the same concentration. More-over, DTX-loaded FA-BSPs-SA micelles exhibited stronger inhibitory effects on tumor cells with folate receptor expression in comparison to DTX-loaded BSPs-SA micelles. FA-BSPs-SA polymers are expected to be nanoscale materials for hydrophobic antitumor drugs.

Key words: Folic acid, Stearic acid, Bletilla striata, Micelle, Self-assembly, Antitumor drug

中图分类号:

O636

TrendMD:

管清香, 纪丹阳, 孙波, 乔瑾, 何彤, 张广远, 虞振静, 尹建元, 杨薇. 叶酸修饰硬脂酸接枝白芨共聚物的合成及作为抗肿瘤药物载体的研究. 高等学校化学学报, 2018, 39(8): 1815.

GUAN Qingxiang, JI Danyang, SUN Bo, QIAO Jin, HE Tong, ZHANG Guangyuan, YU Zhenjing, YIN Jianyuan, YANG Wei. Synthesis of Folate-conjugated Stearic Acid Grafted Bletilla striata Polysaccharides Copolymers and Application for Delivering Antitumor Drugs as a Drug Delivery Carrier^†. Chem. J. Chinese Universities, 2018, 39(8): 1815.

图/表 11

Scheme 1 Preparation of drug loading and intracellar release of DTX/FA-BSPs-SA copolymer micelles

Fig.1 1H NMR spectra of BSPs-SA(a) and FA-BSPs-SA(b) in DMSO-d6

Fig.2 FTIR spectra of BSPs(a), BSPs-SA(b), FA(c) and FA-BSPs-SA(d)

Fig.3 UV-Vis spectra of FA(a), BSPs-SA(b) and FA-BSPs-SA(c) in DMSO

Fig.4 Plots of the intensity ratio of I374/I385 from emission spectra vs. lgc of FA-BSPs-SA copolymer micelles with different FA substituted degrees

Fig.5 Particle size and zeta potential of DTX/FA-BSPs-SA micelles(A) and DTX/FA-BSPs-SA micelles within 48 h at 4 ℃(B)

Fig.6 Transmission electron microscopy image of DTX/FA-BSPs-SA copolymer micelles

Fig.7 Encapsulation efficiency and drug loaded capacity of DTX/FA-BSPs-SA micelles

Fig.8 Release profiles of DTX solution and DTX/FA-BSPs-SA copolymer micelles in different pH values media at 37 ℃(n=3)

Fig.9 Cell viability of BSPs-SA and FA-BSPs-SA copolymers of different FA substitution at different concentrations after 48 h incubation(n=6)

Fig.10 Viability of HepG2(A) and HeLa(B) cells incubated with DTX solution(), DTX/BSPs-SA() and DTX/FA-BSPs-SA copolymer micelles() at different DTX concentrationsData were expressed as mean ±S.D.(n=6)(* P<0.05; ** P<0.01).

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叶酸修饰硬脂酸接枝白芨共聚物的合成及作为抗肿瘤药物载体的研究

Synthesis of Folate-conjugated Stearic Acid Grafted Bletilla striata Polysaccharides Copolymers and Application for Delivering Antitumor Drugs as a Drug Delivery Carrier^†

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叶酸修饰硬脂酸接枝白芨共聚物的合成及作为抗肿瘤药物载体的研究

Synthesis of Folate-conjugated Stearic Acid Grafted Bletilla striata Polysaccharides Copolymers and Application for Delivering Antitumor Drugs as a Drug Delivery Carrier†

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Synthesis of Folate-conjugated Stearic Acid Grafted Bletilla striata Polysaccharides Copolymers and Application for Delivering Antitumor Drugs as a Drug Delivery Carrier^†