高等学校化学学报

高等学校化学学报 ›› 2012, Vol. 33 ›› Issue (12): 2809.doi: 10.7503/cjcu20120137

• 高分子化学 • 上一篇    下一篇

肿瘤酸度响应性聚(L-赖氨酸)-阿霉素键合药的制备与表征

张建成1,2, 丁建勋2,3, 肖春生2, 贺超良2, 庄秀丽2, 杨亚楠1, 陈学思2   

  1. 1. 长春工业大学化学工程学院, 长春 130012;
    2. 中国科学院长春应用化学研究所, 生态环境高分子材料重点实验室, 长春 130022;
    3. 中国科学院研究生院, 北京 100049
  • 收稿日期:2012-02-16 出版日期:2012-12-10 发布日期:2012-11-20
  • 通讯作者: 杨亚楠,女,博士,教授,主要从事功能高分子研究.E-mail:yangyanan@ccut.edu.cn庄秀丽,女,博士,研究员,主要从事生物医用材料研究.E-mail:zhuangxl@ciac.jl.cn E-mail:yangyanan@ccut.edu.cn;zhuangxl@ciac.jl.cn
  • 基金资助:

    国家自然科学基金(批准号: 51103015, 50733003, 20904053, 51003103, 21174142和50973108)资助.

Synthesis and Characterization of Tumor-acidity-sensitive Poly(L-lysine)-doxorubicin Conjugates

ZHANG Jian-Cheng1,2, DING Jian-Xun2,3, XIAO Chun-Sheng2, HE Chao-Liang2, ZHUANG Xiu-Li2, YANG Ya-Nan1, CHEN Xue-Si2   

  1. 1. Department of Chemical Engineering, Changchun University of Technology, Changchun 130012, China;
    2. Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Changchun 130022, China;
    3. Graduate University of Chinese Academy of Sciences, Beijing 100049, China
  • Received:2012-02-16 Online:2012-12-10 Published:2012-11-20

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摘要：

用丁二酸酐(SA)和顺式乌头酸酐(CA)分别对阿霉素(DOX)进行修饰, 得到非酸响应的SA-DOX(SAD)和酸响应的CA-DOX(CAD). 通过SAD或CAD、端羧基化的聚乙二醇单甲醚(mPEG-COOH)与聚(L-赖氨酸)(PLL)的缩合反应, 制得非酸响应的PLL-g-mPEG/SAD和酸响应的PLL-g-mPEG/CAD键合药. 通过核磁共振氢谱和红外光谱表征键合药的化学结构, 并通过紫外-可见分光光度计测定药物键合量. 动态激光光散射研究结果表明, 两亲性的PLL-DOX键合药可以在pH=7.4的磷酸缓冲溶液中自组装形成稳定的纳米微粒. 体外释放实验及噻唑蓝检测结果表明, PLL-g-mPEG/SAD在实验pH范围和时间段内只释放出少量DOX, 不具有酸响应特性, 且对HeLa细胞增殖抑制作用较小. 而PLL-g-mPEG/CAD在生理条件(pH=7.4)下相对稳定, 在弱酸性条件(pH=5.3, 6.8)下, CAD中酸响应的酰胺键能快速水解并释放出DOX, 表现出较强的HeLa细胞增殖抑制效果.

关键词: 阿霉素, 聚(L-赖氨酸), 肿瘤酸度响应性, 肿瘤细胞增殖抑制

Abstract:

Succinic anhydride(SA) and cis-aconitic anhydride(CA) were used to modify doxorubicin(DOX), obtaining acid-insensitive SA-DOX(SAD) and acid-sensitive CA-DOX(CAD), respectively. SAD or CAD, and carboxyl group terminated monomethoxyl poly(ethylene glycol)(mPEG-COOH) were conjugated onto poly(L-lysine)(PLL), yielding acid-insensitive PLL-g-mPEG/SAD and acid-sensitive PLL-g-mPEG/CAD, respectively. The chemical structures of PLL-DOX conjugates were characterized by 1H NMR and FTIR. The drug conjugating content was determined with UV-Vis spectrophotometer. Dynamic laser scattering(DLS) measurements revealed that the amphiphilic PLL-DOX conjugates could self-assemble into nanoparticles in phosphate buffer(PB) at pH=7.4. In vitro release profiles revealed that the DOX release from PLL-g-mPEG/CAD could be accelerated at acid conditions(pH=5.3 and 6.8), while that from PLL-g-mPEG/SAD was slow at all test pH(5.3, 6.8 and 7.4). The acid-sensitive DOX release from PLL-g-mPEG/CAD conjugates ensured higher concentration of free DOX in tumor and more pronounced antitumor efficacy. In vitro methyl thiazolyl tetrazolium assay demonstrated that PLL-g-mPEG/CAD had enhanced tumor proliferation inhibition activity comparing with acid-insensitive PLL-g-mPEG/SAD. Therefore, PLL-g-mPEG/CAD conjugates might be further developed as potential smart antitumor drugs with controlled DOX release.

Key words: Doxorubicin, Poly(L-lysine), Tumor-acidity-sensitive, Tumor cell proliferation inhibition

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