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

作　　者：任玉双 郭园园 刘学怡 宋杰 张川 REN Yushuang;GUO Yuanyuan;LIU Xueyi;SONG Jie;ZHANG Chuan(School of Chemistry and Chemical Engineering,Frontiers Science Center for Transformative Molecules,State Key Laboratory of Metal Matrix Composites;School of Electronic Information and Electrical Engineering,Shanghai Jiao Tong University,Shanghai 200240,China)

机构地区：[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

出　　处：《高等学校化学学报》2020年第8期1721-1730,共10页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金(批准号:21661162001,21673139,51973112)资助。

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.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.

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 

分 类 号：O626.413[理学—有机化学]