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浙江大学学报（医学版）
浙江大学学报（医学版）  2017, Vol. 46 Issue (2): 135-143    DOI: 10.3785/j.issn.1008-9292.2017.04.04
专题报道     
氟硼二吡咯类光敏剂的制备及对肿瘤细胞的光动力学影响
刘馨刚(),吴敏,李素莹,李忠宝,胡青莲,周峻,汤谷平*()
浙江大学化学系, 浙江 杭州 310028
Synthesis of BODIPY photosensitizers and their photodynamic effect on cancer cells
LIU Xingang(),WU Min,LI Suying,Li Zhongbao,HU Qinglian,ZHOU Jun,TANG Guping*()
Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310003, China
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摘要：

目的：设计合成两种不同极性取代基的氟硼二吡咯类光敏剂，观察其理化特性和在不同极性条件下的光动力学效应。方法：通过苯甲醛与吡咯活泼氢的缩合反应以及亲电取代反应制备氟硼二吡咯类光敏剂碘代羟基氟硼二吡咯（BPOI）和碘代甲酸甲酯氟硼二吡咯（BPCI）。通过核磁共振氢谱、傅里叶红外光谱和紫外可见吸收光谱、荧光发射光谱对该光敏剂进行理化性质表征。通过1，3-二苯基异苯并呋喃与2'，7'-二氯荧光黄双乙酸盐检测该光敏剂活性氧产生能力，并采用MTT法检测其对肿瘤细胞的光动力学效应。结果：核磁共振氢谱和傅里叶红外光谱证实成功合成了两种不同取代基的氟硼二吡咯类光敏剂BPOI和BPCI。两种材料具有低毒性，且易被细胞摄取。meso位为给电子取代基的氟硼二吡咯类光敏剂BPOI产生活性氧的能力受溶剂极性影响大，而meso位为吸电子取代基的氟硼二吡咯类光敏剂BPCI则不受溶剂极性影响。结论：给电子取代基的氟硼二吡咯类光敏剂BPOI在高极性环境中产生活性氧速率慢，而在低极性环境中产生活性氧的能力大大增强，有望用于肿瘤细胞内的环境选择性光动力治疗。
关键词： 光化学疗法;  光敏感药/药代动力学;  光敏感药/治疗应用;  肿瘤/治疗;  肿瘤细胞，培养的/药物作用;  光谱法，荧光;  光谱分析;  吡咯类/药理学    
Abstract:

Objective: To design and synthesize photosensitizers with different substituents and to identify its physicochemical characteritics and photodynamic effect on cancer cells. Methods: Two kinds of BODIPY photosensitizers BPOI and BPCI were synthesized through condensation reaction between aldehyde and reactive hydrogen of pyrrole, followed with electrophilic substitution reaction. Physicochemical properties were characterized by 1H NMR, FT-IR and UV-visible absorption spectra and fluorescence emission spectra. The ability to produce reactive oxygen species was detected by BPDF and DCFH-DA. Photodynamic therapy effect on rat glioma C6 cells in vitro was determined by MTT method. Results: Two kinds of BODIPY photosensitizers BPOI and BPCI were successfully synthesized with different substituents, which were confirmed by 1H NMR, FT-IR. Both materials had low toxicity and could be readily taken up by tumor cells. The ability of synthesized photosensitizers to produce reactive oxygen species was strongly influenced by solvent polarity when the substituent was electron-donating group, while no effect was found when the substituent was electron-withdrawing group. Conclusion: Photosensitizer BPOI with electron-donating substituent produces reactive oxygen species with a slow rate in a highly polar environment, while greatly enhanced this effect in a low polarity environment, which is expected to be used for environmental-selective photodynamic therapy in tumor cells.
Key words: Photochemotherapy    Photosensitizing agents/pharmacokinetics    Photosensitizing agents/therapeutic use    Neoplasms/therapy    Tumor cells, cultured/drug effects    Spectrometry, fluorescence    Spectrum analysis    Pyrroles/pharmacology
收稿日期: 2016-11-02 出版日期: 2017-08-07
基金资助: 国家自然科学基金（21374098）
通讯作者: 汤谷平     E-mail: liuxg@zju.edu.cn;tangguping@zju.edu.cn
作者简介: 刘馨刚(1989—)，男，博士研究生，主要从事生物化学研究；E-mail: liuxg@zju.edu.cn；https://orcid.org/0000-0001-7071-0209
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引用本文:

刘馨刚,吴敏,李素莹,李忠宝,胡青莲,周峻,汤谷平. 氟硼二吡咯类光敏剂的制备及对肿瘤细胞的光动力学影响[J]. 浙江大学学报（医学版）, 2017, 46(2): 135-143.

LIU Xingang,WU Min,LI Suying,Li Zhongbao,HU Qinglian,ZHOU Jun,TANG Guping. Synthesis of BODIPY photosensitizers and their photodynamic effect on cancer cells. J Zhejiang Univ (Med Sci), 2017, 46(2): 135-143.

链接本文:

http://www.zjujournals.com/xueshu/med/CN/10.3785/j.issn.1008-9292.2017.04.04    或    http://www.zjujournals.com/xueshu/med/CN/Y2017/V46/I2/135

图 1  碘代羟基氟硼二吡咯(BPOI)和碘代甲酸甲酯氟硼二吡咯(BPCI)的合成路线图
图 2  中间体BPO、BPC和光敏剂BPOI、BPCI的核磁共振氢谱图
图 3  光敏剂BPOI和BPCI的傅里叶红外光谱图
图 4  中间体BPO、BPI以及光敏剂BPOI、BPCI的紫外可见吸收光谱图和荧光发射光谱图
图 5  C6细胞经BPOI和BPCI孵育4 h后的激光共聚焦扫描显微镜图像
图 6  含有BPOI或BPCI的不同极性溶剂中DPBF在415 nm处紫外吸收特征峰强度变化曲线
图 7  数据归一化处理后DPBF在415 nm波长处紫外可见吸收强度变化趋势
图 8  以DCFH-DA为活性氧指示剂检测光敏剂BPOI和BPCI在细胞内产生单线态氧能力的激光共聚焦扫描显微镜图像
图 9  光敏剂BPOI或BPCI共孵育的C6细胞生存曲线
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