新型可用于荧光标记的α-氰基丙烯酸酯单体的合成及在小鼠活体成像中的应用

doi:10.7503/cjcu20160079

高等学校化学学报 ›› 2016, Vol. 37 ›› Issue (6): 1168.doi: 10.7503/cjcu20160079

新型可用于荧光标记的α-氰基丙烯酸酯单体的合成及在小鼠活体成像中的应用

张涛, 汤永嘉, 徐亮(), 刘克良()

军事医学科学院毒物药物研究所, 抗毒药物与毒理学国家重点实验室, 北京 100850

收稿日期:2016-01-30 出版日期:2016-06-10 发布日期:2016-05-26
作者简介:联系人简介: 刘克良, 男, 博士, 研究员, 博士生导师, 主要从事多肽药物、核酸化学和医药用高分子材料的研究. E-mail:keliangliu55@126.com;徐亮, 男, 博士, 副研究员, 主要从事核酸化学和医药用高分子材料的研究. E-mail:wj24998@163.com
基金资助:
国家自然科学基金(批准号: 81573345)和国家科学和技术重大专项(批准号: 2012ZX09301003)资助

Synthesis of a New Cyanoacrylate Monomer and Its Application in Fluorescence Imaging in vivo^†

ZHANG Tao, TANG Yongjia, XU Liang^*(), LIU Keliang^*()

Beijing Institute of Pharmacology and Toxicology,State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China

Received:2016-01-30 Online:2016-06-10 Published:2016-05-26
Contact: XU Liang,LIU Keliang E-mail:wj24998@163.com;keliangliu55@126.com
Supported by:
† Supported by the Natural Science Foundation of China(No.81573345) and the National Science and Technology Major Projects of China(No.2012ZX09301003)

摘要/Abstract

摘要：

设计合成了新型含有荧光基团的α-氰基丙烯酸酯单体, 并与其它α-氰基丙烯酸酯单体共聚, 得到产生荧光的聚氰基丙烯酸酯材料. 将其包埋在小鼠背部肌肉层, 可获得良好的荧光成像效果. 通过对荧光强度的监测, 初步研究了聚氰基丙烯酸酯材料中的侧链酯基在小鼠体内的降解情况. 单体合成是以蒽合氰基丙烯酸和4,4'-二甲氧基三苯基-氨基己醇为原料, 得到蒽合氰基丙烯酸(4,4'-二甲氧基三苯基-氨基己醇)酯, 脱保护后再将异硫氰酸荧光素以化学键合的方式标记在末端氨基上, 脱蒽还原烯双键后, 得到可用于荧光标记的α-氰基丙烯酸(异硫氰酸荧光素-氨基己醇)酯单体. 反应中间体及单体结构采用核磁共振氢谱和质谱进行表征. 该单体及其高聚物均可在激发光(488 nm)和发射光(525 nm)条件下观察到明显荧光.

关键词: α-氰基丙烯酸酯, 异硫氰酸荧光素, 活体荧光成像

Abstract:

A new cyanoacrylate monomer with fluorescein isothiocyanate(FITC) labeling was synthesized. It could copolymerize with any other cyanoacrylate monomers and result in copolymer being able to produce fluorescence. Well fluorescence imaging could be got when the copolymer was embedded in subcutaneous tissue of Sprague-Dawley(SD) mice. We also discussed the degradation pattern of polycyanoacrylate by monitoring the fluorescence intensity with time. The synthesis was started with anthracene /cyanoacrylate acid adduct and 6-(4,4'-dimethoxytriphenylmethyl)-amino-1-hexanol. After deprotection of 4,4'-dimethoxytriphenylmethyl group from intermediate anthracene/6-(4,4'-dimethoxytriphenylmethyl)-amino-1-hexanol cyanoacrylate adduct, FITC was labeled onto the amino group. The target product was finally got by reduction of the ethylenic bond. Structure of intermediates and target compound were identified by ¹H NMR and MS spectroscopy. Both the monomer and polymer could be observed fluorescence around 525 nm wavelength by an exciting light at 488 nm.

Key words: Cyanoacrylate, Fluorescein isothiocyanate(FITC), Fluorescence imaging in vivo

中图分类号:

O632.1

TrendMD:

张涛, 汤永嘉, 徐亮, 刘克良. 新型可用于荧光标记的α-氰基丙烯酸酯单体的合成及在小鼠活体成像中的应用. 高等学校化学学报, 2016, 37(6): 1168.

ZHANG Tao, TANG Yongjia, XU Liang, LIU Keliang. Synthesis of a New Cyanoacrylate Monomer and Its Application in Fluorescence Imaging in vivo^†. Chem. J. Chinese Universities, 2016, 37(6): 1168.

图/表 7

Scheme 1 Synthesis of 6-DMT-amino-1-hexanolConditions: C3H9ClSi, pyridine, r.t., 12 h.

Scheme 2 Synthesis of FITC-labeling 6-amino-1-hexanol cyanoacrylatei. DIC, DMAP, DCM, r.t., 6 h; ii. CH3COOH, DCM, r.t.; iii. FITC, DCM, EtOH, r.t.; iv. Maleic anhydride, dimethylbenzene, EtOH, r.t., 5 h.

Fig.1 In vitro fluorescence imaging of poly(FITC-labeling cyanoacrylate)a. Control group: poly(N-butyl cyanoacrylate); b. experimental group A: poly(FITC-labeling cyanoacrylate); c. experimental group B: poly[(FITC-labeling cyanoacrylate)∶N-butyl cyanoacrylate(mass ratio=1∶5)].

Fig.2 In vivo fluorescence imaging of poly(FITC-labeling cyanoacrylate)a. Control group∶poly(N-butyl cyanoacrylate); b. experimental group: poly[(FITC-labeling cyanoacrylate)∶N-butyl cyanoacrylate(mass ratio=1∶5)].

Fig.3 In vivo fluorescence intensity test of poly(FITC-labeling cyanoarylate)(A) Fluorescence imaging; (B) fluorescence intensity.

Fig.4 Residue of poly(FITC-labeling cyanoacrylate) embedded in SD mice after 14 d

Fig.5 GPC analysis of the residual solid embedded in SD mice after 14 d(A) Poly[(FITC-labeling cyanoacrylate)∶N-butyl cyanoacrylate(mass ratio=1∶5)] before degradation; (B) residual solid of poly[(FITC-labeling cyanoacrylate)∶N-butyl cyanoacrylate(mass ratio=1∶5)] after 14 d.

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新型可用于荧光标记的α-氰基丙烯酸酯单体的合成及在小鼠活体成像中的应用

Synthesis of a New Cyanoacrylate Monomer and Its Application in Fluorescence Imaging in vivo^†

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新型可用于荧光标记的α-氰基丙烯酸酯单体的合成及在小鼠活体成像中的应用

Synthesis of a New Cyanoacrylate Monomer and Its Application in Fluorescence Imaging in vivo†

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Synthesis of a New Cyanoacrylate Monomer and Its Application in Fluorescence Imaging in vivo^†