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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2017, Vol. 37 Issue (10): 33-41    DOI: 10.13523/j.cb.20171005
研究报告     
共价连接BODIPY光敏剂的聚合物纳米胶束及其靶向光动力疗效的研究
周忠厅1, 张权1,2, 王胜涛1, 蔡颖1, 中西秀树1,2, 尹健1,2
1. 糖化学与生物技术教育部重点实验室 无锡 214122;
2. 江南大学生物工程学院 无锡 214122
Polymeric Nanomicelles Conjugated with BODIPY-based Photosensitizers for Targeted Photodynamic Therapy
ZHOU Zhong-ting1, ZHANG Quan1,2, WANG Sheng-tao1, CAI Yin1, NAKANISHI Hideki1,2, YIN Jian1,2
1. Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China;
2. School of Biotechnology, Jiangnan University, Wuxi 214122, China
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摘要： 目的：利用聚合物纳米胶束靶向输送光敏剂分子已经成为光动力治疗癌症的研究热点。方法：采用原子转移自由基聚合反应合成嵌段聚合物聚丙烯酸叔丁酯-聚甲基丙烯酸缩水甘油酯（PtBA-b-PGMA），共聚物的一端脱除叔丁基，通过缩合反应共价键连接甘露糖分子，另一端环氧基开环引入叠氮基，并通过"click"反应共价连接氟硼二吡咯光敏剂分子，最后制备得到表面甘露糖修饰的负载光敏剂聚合物胶束。利用核磁共振氢谱仪和傅立叶变换红外光谱仪进行结构确认；通过透射电镜和动态光散射等考察其理化性质；经激光共聚焦显微镜和MTT细胞毒性实验对其甘露糖受体靶向性及光动力疗效进行考察和评价。结果：聚合物PtBA-b-PGMA的相对分子量为16 924，其分散系数为1.36。聚合物中环氧基开环引入叠氮后在2 106 cm-1处出现叠氮基特征峰。经过"click"反应引入氟硼二吡咯光敏剂分子后，叠氮基特征峰消失，在1 637 cm-1处出现三氮唑特征峰。聚合物胶束粒径分布均一，稳定性良好。胶束平均流体力学直径为178 nm，在水溶液中粒度分布较窄（PDI=0.298）。聚合物胶束对人乳腺癌MDA-MB-231细胞和HEK293正常细胞均无暗毒性，在535 nm LED光照下对乳腺癌MDA-MB-231细胞具有较好的光动力治疗效果。结论：聚合物胶束能被MDA-MB-231癌细胞表面高表达的甘露糖受体特异性识别，并被内吞进入癌细胞内，具有较好的光动力杀伤作用。
关键词： 聚合物纳米胶束;  细胞内吞;  光毒性;  光动力治疗;  靶向输送    
Abstract: Objectives:Polymeric nanomicelles have attracted more attention since it could become a targeted delivery system of photosensitizers for cancer photodynamic therapy (PDT). Methods:The poly(butyl acrylate)-block-poly(glycidyl methacrylate) (PtBA-b-PGMA) copolymer was first synthesized by atom transfer radical polymerization. After the tert-butyl group was removed from PtBA-b-PGMA, mannose was covalently linked via amide reaction. Finally, BODIPY-based photosensitizers were introduced by the "click" reaction to obtain polymeric nanomicelles (Man-PAA-b-PGMA-BPDIPY). Structure of Man-PAA-b-PGMA-BPDIPY was confirmed by 1H NMR and FT-IR. The size and morphology of Man-PAA-b-PGMA-BODIPY was characterized by transmission electron microscopy and dynamic light scattering. The cytotoxicity, cellular uptake and PDT effects of Man-PAA-b-PGMA-BODIPY were investigated by MTT assay and confocal laster scanning microscope. Results:The relative molecular weight of PtBA-b-PGMA is 16 924, and the dispersion coefficient is 1.36. The appearance of a peak at 2 106 cm-1 in the FTIR spectrum of Man-PAA-b-PGMA-N3 indicates successful grafting of azide groups onto the polymer. This peak disappeared and a new peak at 1 637 cm-1 was observed after azide-alkyne cycloaddition "click" chemistry, indicating the formation of triazole bonds in Man-PAA-b-PGMA-BODIPY. Polymeric nanomicelles have uniform size distribution and excellent stability in aqueous solution. The average hydrodynamic diameter of polymeric nanomicelles is 178 nm with a narrow size distribution (PDI=0.298). Man-PAA-b-PGMA-BODIPY did not exhibit toxicity against MDA-MB-231 and HEK293 cells in the dark, while the enhanced phototoxicity was observed on MDA-MB-231 cancer cells under 535 nm LED irradiation. Conclusions:Man-PAA-b-PGMA-BODIPY was efficiently internalized by MDA-MB-231 cancer cells through receptor-mediated endocytosis, while HEK293 normal cells showed much lower endocytosis towards micelles under the same conditions. Thus, Man-PAA-b-PGMA-BODIPY shows its potential for targeted PDT of cancer.
Key words: Polymeric nanomicelles    Targeted delivery    Endocytosis    Phototoxicity    Photodynamic therapy
收稿日期: 2017-04-07 出版日期: 2017-10-25
ZTFLH:  Q819  
基金资助: 国家自然科学基金（51403081）、江苏省自然科学基金（BK20140137）资助项目
通讯作者: 中西秀树,hideki@jiangnan.edu.cn;尹健,jianyin@jiangnan.edu.cn     E-mail: hideki@jiangnan.edu.cn;jianyin@jiangnan.edu.cn
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引用本文:

周忠厅, 张权, 王胜涛, 蔡颖, 中西秀树, 尹健. 共价连接BODIPY光敏剂的聚合物纳米胶束及其靶向光动力疗效的研究[J]. 中国生物工程杂志, 2017, 37(10): 33-41.

ZHOU Zhong-ting, ZHANG Quan, WANG Sheng-tao, CAI Yin, NAKANISHI Hideki, YIN Jian. Polymeric Nanomicelles Conjugated with BODIPY-based Photosensitizers for Targeted Photodynamic Therapy. China Biotechnology, 2017, 37(10): 33-41.

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https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20171005    或    https://manu60.magtech.com.cn/biotech/CN/Y2017/V37/I10/33

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