顺铂前药接枝修饰硫代DNA及其自组装靶向纳米药物研究

doi:10.7503/cjcu20200283

高等学校化学学报 ›› 2020, Vol. 41 ›› Issue (8): 1721.doi: 10.7503/cjcu20200283

• 庆祝《高等学校化学学报》复刊40周年专栏 • 上一篇下一篇

顺铂前药接枝修饰硫代DNA及其自组装靶向纳米药物研究

任玉双¹, 郭园园¹, 刘学怡¹, 宋杰², 张川¹

1. 上海交通大学化学化工学院, 上海交通大学变革性分子前沿科学中心, 金属基复合材料国家重点实验室;
2. 电子信息与电气工程学院, 上海 200240

收稿日期:2020-05-25 出版日期:2020-08-10 发布日期:2020-06-11
通讯作者: 张川,男,博士,特别研究员,主要从事核酸纳米技术研究.E-mail:chuanzhang@sjtu.edu.cn E-mail:chuanzhang@sjtu.edu.cn
基金资助:
国家自然科学基金（批准号：21661162001，21673139，51973112）资助.

Platinum(Ⅳ) Prodrug-grafted Phosphorothioate DNA and Its Self-assembled Nanostructure for Targeted Drug Delivery

REN Yushuang¹, GUO Yuanyuan¹, LIU Xueyi¹, SONG Jie², ZHANG Chuan¹

1. School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240, China;
2. School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China

Received:2020-05-25 Online:2020-08-10 Published:2020-06-11
Supported by:
Supported by the National Natural Science Foundation of China(Nos.21661162001, 21673139, 51973112).

1. ESM to 1721-1730.pdf(764KB)

摘要/Abstract

摘要： 选用具有良好生物相容性的硫代修饰嵌段核酸为载体，将其非硫代修饰部分设计为靶向MUC-1蛋白的核酸适配体序列，同时在其硫代修饰部分通过硫代磷酸酯基团（Phosphorothioate，PS）接枝修饰四价顺铂前药，制备了两亲性核酸-顺铂前药缀合物MUC-1/^PODNA-b-（^PSDNA-g-Pt），并进一步自组装成类似球形核酸（Spherical nucleic acid，SNA）的含铂靶向纳米药物（MUC-1/Pt-SNAs）.结果表明，该纳米药物递送体系载药率高、形貌稳定、分散性好，能够高效靶向MUC-1蛋白过表达的MCF-7乳腺癌细胞，并在体内外实验中表现出优异的抗肿瘤效果和极低的毒副作用.

关键词: 顺铂前药, 硫代修饰DNA, 靶向药物递送, 球形核酸, MUC-1核酸适配体

Abstract: cis-Platin drugs play a vital role in the clinical treatment of various cancers. However, its poor water solubility, non-targeting capability and severe side effects result in limited antitumor efficacy and greatly impede its clinic practices. To address these challenges, we successfully graft a multitude of Pt(Ⅳ) prodrugs on a diblock DNA that consists of a regular phosphodiester DNA segment with MUC-1 aptamer sequence and a phosphorothioate(PS) ploy T segment. After being modified with iodoacetate moiety, the prodrug can efficiently react with PS groups and grafted onto the backbone of PS segment, resulting in the formation of an MUC-1/^PODNA-b-(^PSDNA-g-Pt) conjugate. Owing to its amphiphilic feature, the obtained DNA-drug conjugate(DDC) could further self-assembled into spherical nucleic acid like nanostructure(MUC-1/Pt-SNAs) to serve as a new drug delivery system. With the presence of MUC-1 aptamer on particle surface, MUC-1/Pt-SNAs can actively target the tumor cells overexpressed MUC-1 proteins and internalize into cells with high efficiency. Together with a high drug loading ratio(39.6%) achieved by simple and convenient conjugation method, the obtained DNA-based targeted delivery system shows substantial antitumor effect and low side effects both in vitro and in vivo.

Key words: Platinum prodrug, Phosphorothioate DNA, Targeted drug delivery, Spherical nucleic acid, MUC-1 aptamer

中图分类号:

O626.413

TrendMD:

任玉双, 郭园园, 刘学怡, 宋杰, 张川. 顺铂前药接枝修饰硫代DNA及其自组装靶向纳米药物研究. 高等学校化学学报, 2020, 41(8): 1721.

REN Yushuang, GUO Yuanyuan, LIU Xueyi, SONG Jie, ZHANG Chuan. Platinum(Ⅳ) Prodrug-grafted Phosphorothioate DNA and Its Self-assembled Nanostructure for Targeted Drug Delivery. Chem. J. Chinese Universities, 2020, 41(8): 1721.

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顺铂前药接枝修饰硫代DNA及其自组装靶向纳米药物研究

Platinum(Ⅳ) Prodrug-grafted Phosphorothioate DNA and Its Self-assembled Nanostructure for Targeted Drug Delivery

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