新颖光控Dex-H交联胶束药物释放体系的制备及协同抗肿瘤性能

doi:10.7503/cjcu20141102

高等学校化学学报 ›› 2015, Vol. 36 ›› Issue (5): 1004.doi: 10.7503/cjcu20141102

新颖光控Dex-H交联胶束药物释放体系的制备及协同抗肿瘤性能

李宪华¹, 张雷刚¹, 王雪雪¹, 于清波²()

1.安徽理工大学机械工程学院
2. 材料科学与工程学院, 淮南 232001

收稿日期:2014-12-16 出版日期:2015-05-10 发布日期:2015-03-31
作者简介:联系人简介: 于清波, 女, 博士, 副教授, 主要从事功能材料制备与应用研究. E-mail: yuqingbo007@163.com
基金资助:
国家自然科学基金(批准号: 21401001)和安徽省绿色高分子材料重点实验室开放基金资助

Fabrication and Multi-antitumor Effect of Novel Dextran-hemin Crosslinked Micelles Triggered by Photo Conditions^†

LI Xianhua¹, ZHANG Leigang¹, WANG Xuexue¹, YU Qingbo^2,^*()

1. School of Mechanical Engineering and Engineering, 2. Department of Materials Science and Engineering,Anhui University of Science and Technology, Huainan 232001, China
2. Department of Materials Science and Engineering,Anhui University of Science and Technology, Huainan 232001, China

Received:2014-12-16 Online:2015-05-10 Published:2015-03-31
Contact: YU Qingbo E-mail:yuqingbo007@163.com
Supported by:
† Supported by the National Natural Science Foundation of China(No.21401001) and the Open Fund of Anhui Province Key Laboratory of Environment-friendly Polymer Materials, China

摘要/Abstract

摘要：

合成了一种基于血红素中双键交联的葡聚糖(Dex)载药(5-氟尿嘧啶)胶束(Dex-H交联胶束). 接枝在葡聚糖上的血红素不仅可以用作光控开关控制5-氟尿嘧啶在定点部位的快速释放, 而且可以同时在光照下作为光动力学疗法的光敏剂产生单线态氧, 实现协同抗肿瘤作用. 交联后的胶束具有良好生物相容性, 同时, 稳定性也相应增强, 高度稀释后仍能保持稳定, 有望在体内安全运输. 采用3-(4,5-二甲基噻唑-2)-2,5-二甲苯基四氨唑溴盐(MTT)和荧光显微镜观察发现, 激光照射下载药交联胶束表现出高效的抗癌效果, 具有协同抗肿瘤作用.

关键词: Dex-H交联胶束, 5-氟尿嘧啶, 单线态氧, 协同抗肿瘤性能

Abstract:

In order to search for novel candidate drug endowed with better antitumor activities and less neurotoxicities, a novel crosslinked dextran-hemin micelle was synthesized. Hemin grafted to dextran is not only used as a phototriggered switch for the controlled release of the loaded 5-fluorouracil(5FU) quickly, but also simultaneously as a photosensitizer for photodynamic therapy(PDT) under laser irradiation. The prepared micelles exhibit high stability against extensive dilution of solution which can restrain premature drug loss and reduce side effect to human bodies. The micelles possess good biocompatibility as well. More importantly, the 5FU loaded crosslinked dextran-hemin micelles present higher antitumor effect than those of free 5FU or crosslinked micelles under laser irradiation, indicating the excellent synergetic antitumor effect of hemin with 5FU in the as-prepared micelles.

Key words: Dextran-hemin(Dex-H) crosslinked micelle, 5-fluorouracil, Singlet oxygen, Multi-antitumor effect

中图分类号:

O631

TrendMD:

李宪华, 张雷刚, 王雪雪, 于清波. 新颖光控Dex-H交联胶束药物释放体系的制备及协同抗肿瘤性能. 高等学校化学学报, 2015, 36(5): 1004.

LI Xianhua, ZHANG Leigang, WANG Xuexue, YU Qingbo. Fabrication and Multi-antitumor Effect of Novel Dextran-hemin Crosslinked Micelles Triggered by Photo Conditions^†. Chem. J. Chinese Universities, 2015, 36(5): 1004.

图/表 9

Scheme 1 Formation schematic illustration of crosslinked Dex-H micelles and photo-triggered multimodal cancer therapy

Fig.1 UV-Vis spectra of hemin measured at different irradiation time(A) and ESR spectrum of hemin after laser irradiation(B) Time/min: a. 0; b. 5; c. 10.

Fig.2 UV-Vis(A) and FTIR(B) spectra of Dex-H(a) and dextran(b), FTIR difference spectrum(C) and FTIR spectrum of crosslinked micelles(D)

Fig.3 Size distribution of micelles before(a) and after(b) cross-linking(A) and AFM images of micelles before(B) and after(C) cross-linking

Fig.4 Change of I372/I383 of micelles before(a) and after(b) cross-link upon addition of H2O(A), AFM image(B) and dynamic light scattering(DLS)(C) of crosslinked micelles after laser irradiation(5 min) and in vitro cytotoxicity of crosslinked micelles against HeLa cells at different concentrations of polymer after 24 h incubation(D)

Fig.5 Release profiles for 5-FU loaded in crosslinked micelles under different conditions

Fig.6 UV-Vis spectra of crosslinked micelles measured(A) and singlet oxygen produced with crosslinked micelles under laser irradiation(B) t/min: a. 0; b. 6.

Fig.7 Fluorescence images of HeLa cells incubated with free 5FU(A—C), crosslinked micelles(D—F) and 5FU-loaded crosslinked micelles for 3 h(G—I)(H) and (I) are exposed to laser light source for 1 min after 1.5 h incubation. Each series can be classified to cell nucleus dyed in blue by Hoechst 33342(A, D, G), red by PI(B, E, H) and the merged images of both above(C, F, I), respectively.

Fig.8 Cell viability with free 5FU(a), crosslinked micelles(b) and 5FU-loaded crosslinked micelles under laser irradiation for 24 h incubation(c)The cell viability profiles determined by MTT.

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新颖光控Dex-H交联胶束药物释放体系的制备及协同抗肿瘤性能

Fabrication and Multi-antitumor Effect of Novel Dextran-hemin Crosslinked Micelles Triggered by Photo Conditions^†

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新颖光控Dex-H交联胶束药物释放体系的制备及协同抗肿瘤性能

Fabrication and Multi-antitumor Effect of Novel Dextran-hemin Crosslinked Micelles Triggered by Photo Conditions†

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Fabrication and Multi-antitumor Effect of Novel Dextran-hemin Crosslinked Micelles Triggered by Photo Conditions^†