聚乙二醇偶联羟基喜树碱的合成、 表征及聚集行为

doi:10.7503/cjcu20150895

高等学校化学学报 ›› 2016, Vol. 37 ›› Issue (8): 1535.doi: 10.7503/cjcu20150895

聚乙二醇偶联羟基喜树碱的合成、表征及聚集行为

邱传龙¹, 李春芳¹, 李东祥¹, 侯万国²()

1. 青岛科技大学化学与分子工程学院, 生态化工国家重点实验室培育基地, 青岛 266042
2. 山东大学胶体与界面化学教育部重点实验室, 济南 250100

收稿日期:2015-11-23 出版日期:2016-07-14 发布日期:2016-07-14
作者简介:
联系人简介: 侯万国, 男, 博士, 教授, 主要从事胶体与表面化学研究. E-mail: wghou@sdu.edu.cn
基金资助:
国家自然科学基金(批准号: 21273123, 21573133)资助

Synthesis, Characterization and Aggregation Behavior of Polyethylene Glycol-conjugated Hydroxycamptothecin^†

QIU Chuanlong¹, LI Chunfang¹, LI Dongxiang¹, HOU Wanguo^2,^*()

1. College of Chemistry and Molecular Engineering, State Key Laboratory Base of Eco-chemical Engineering,Qingdao University of Science and Technology, Qingdao 266042, China
2. Key Laboratory of Colloid and Interface Chemistry(Ministry of Education), Shandong University, Jinan 250100, China

Received:2015-11-23 Online:2016-07-14 Published:2016-07-14
Contact: HOU Wanguo E-mail:wghou@sdu.edu.cn
Supported by:
Supported by the National Natural Science Foundation of China(Nos.21273123, 21573133)

摘要/Abstract

摘要：

通过羟基喜树碱(HCPT)的10位羟基与聚乙二醇单甲醚(MPEG)之间的成醚反应, 制备了MPEG化学偶联的HCPT(MPEG-HCPT); 采用¹H NMR和FTIR等进行了结构表征. 考察了MPEG偶联后对HCPT药物的水溶性和内酯环稳定性的影响, 研究了MPEG-HCPT在水溶液中的聚集行为. 结果表明, MPEG-HCPT中HCPT原药的质量分数约为33%, 在37 ℃, pH=4.8和7.2的缓冲溶液中的溶解度分别为5.23和7.90 mmol/L, 明显高于HCPT原药(0.0026和0.035 mmol/L). 该偶联药物在37 ℃下的pK_ah=7.12(K_ah为表观水解反应平衡常数), 高于HCPT原药(6.67), 说明MPEG的偶联对HCPT内酯环结构具有一定的稳定作用. 研究还发现, 该偶联药物具有明显的表面活性, 在水溶液中可形成疏水药物为内核、亲水聚乙二醇为外壳的聚集体, 其临界聚集浓度约为0.46 mmol/L.

关键词: 羟基喜树碱, 聚乙二醇, 溶解度, 内酯环稳定性

Abstract:

Methoxypolyethylene glycol(MPEG)-conjugated hydroxycamptothecin(HCPT), denoted as MPEG-HCPT, was synthesized via etherification reaction between terminal hydroxyl of MPEG and 10-hydroxy of HCPT, and they were characterized via ¹H NMR and FTIR. The effect of MPEG conjugation on the solubility and lactone-ring stability of HCPT was investigated, as well as its aggregation behavior. The mass fraction of HCPT in the derivative was approximately 33% and the solubility of the MPEG-HCPT in buffer solutions of pH 4.8 and 7.2 at 37 ℃ were respectively 5.23 and 7.90 mmol/L, significantly higher than those of pristine HCPT(0.0026 and 0.035 mmol/L). The pK_ah(K_ah, the apparent hydrolysis equilibrium constant) of MPEG-HCPT at 37 ℃ was determined to be approximately 7.12, higher than that of pristine HCPT(ca. 6.67), indicating that the MPEG conjugation could enhance the lactone-ring stability of HCPT. The MPEG-HCPT exhibited obvious surface activity, and could form aggregates in water with a aggregation micelle concentration of 0.46 mmol/L.

Key words: Hydroxycamptothecin, Polyethylene glycol, Solubility, Lactone ring stability

中图分类号:

O648
O629.3

TrendMD:

邱传龙, 李春芳, 李东祥, 侯万国. 聚乙二醇偶联羟基喜树碱的合成、表征及聚集行为. 高等学校化学学报, 2016, 37(8): 1535.

QIU Chuanlong,LI Chunfang,LI Dongxiang,HOU Wanguo. Synthesis, Characterization and Aggregation Behavior of Polyethylene Glycol-conjugated Hydroxycamptothecin^†. Chem. J. Chinese Universities, 2016, 37(8): 1535.

图/表 5

Fig.1 Hydrolysis reaction of HCPT

Fig.2 Synthetic route of MPEG-HCPT

Fig.3 1H NMR(A) and FTIR(B) spectra of HCPT(a), MPEG-HCPT(b) and MPEG(c)

Fig.4 UV-Vis spectra of HCPT(A) and MPEG-HCPT(B) in buffer solutions with various pH values and variation of relative percentages of lactone form and carboxylate form vs. pH for HCPT(C) and MPEG-HCPT(D) pH: (A) a—k. 3.5, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9.5; (B) a—j. 4, 5, 6, 6.5, 7, 7.5, 8, 9, 10, 11.

Fig.5 Variation of surface tension(A), I5/I1 value(B), and dynamic radius(Rh)(C) of MPEG-HCPT aggregates vs. concentration with different pH values

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聚乙二醇偶联羟基喜树碱的合成、表征及聚集行为

Synthesis, Characterization and Aggregation Behavior of Polyethylene Glycol-conjugated Hydroxycamptothecin^†

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聚乙二醇偶联羟基喜树碱的合成、 表征及聚集行为

Synthesis, Characterization and Aggregation Behavior of Polyethylene Glycol-conjugated Hydroxycamptothecin†

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聚乙二醇偶联羟基喜树碱的合成、表征及聚集行为

Synthesis, Characterization and Aggregation Behavior of Polyethylene Glycol-conjugated Hydroxycamptothecin^†