Extracellular pH-manipulated in situ reconfiguration of aptamer functionalized DNA monomer enables specifically improved affinity, detection and drug delivery,Analyst

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Extracellular pH-manipulated in situ reconfiguration of aptamer functionalized DNA monomer enables specifically improved affinity, detection and drug delivery
Analyst ( IF 3.6 ) Pub Date : 2020/03/05 , DOI: 10.1039/d0an00101e
Shanzi Zou _{1,

2,

3,

4,

5} , Yanli Lei _{1,

2,

3,

4,

5} , Wenjie Ma _{1,

2,

3,

4,

5} , Biao Chen _{1,

2,

3,

4,

5} , Hong Cheng _{1,

2,

3,

4,

5} , Ruichen Jia _{1,

2,

3,

4,

5} , Zenghui Li _{1,

2,

3,

4,

5} , Xiaoxiao He _{1,

2,

3,

4,

5} , Kemin Wang _{1,

2,

3,

4,

5}

Affiliation

Aptamers are promising in cancer diagnosis and therapy, but their poor affinity under physiological conditions is a challenge. In view of the acidic microenvironment of solid tumors, we herein developed an extracellular pH-manipulated multivalent approach to exclusively improve the affinity to target cells at physiological temperature. Specifically, an aptamer based DNA monomer (AptDM) with split i-motif fragments overhanging was rationally designed, it possessed pH-responsiveness and doxorubicin loading capacity. At neutral pH, AptDMs existed as well dispersed small units, showing weakly undesired binding and internalization. In acidic extracellular conditions, AptDMs tended to crosslink of each other into multivalent DNA assemblies (MDAs) via formation of an intermolecular i-motif structure. Due to the multivalent effect, the resulting MDAs showed greatly enhanced affinity (K_d = 9.96 ± 1.06 nM) and stable binding ability at 37 °C, thus allowing highly sensitive diagnosis, efficient drug delivery, and improved inhibition to target tumor cells, but decreased cytotoxicity to nontarget cells. It is believed that this multivalent approach may boost the development of novel aptamer functionalized nanodevices for clinical validation.

中文翻译：

适体功能化的DNA单体的细胞外pH值原位重构可实现特异性改善的亲和力，检测和药物递送

适体在癌症诊断和治疗中很有前途，但是它们在生理条件下的亲和力差是一个挑战。考虑到实体瘤的酸性微环境，我们在本文中开发了一种细胞外pH操纵的多价方法来专门提高在生理温度下对靶细胞的亲和力。具体而言，合理设计了以适配子为基础的DNA单体（AptDM），其带有i-基序片段的片段突出端，具有pH响应能力和阿霉素负载能力。在中性pH下，AptDM存在分散的小单元，显示出微弱的不良结合和内在化。在酸性条件下的胞外，AptDMs倾向于交联彼此成多价DNA组件（MDA的）经由分子间i-基序结构的形成。由于具有多价效应，所得的MDA在37°C时显示出极大的亲和力（K _d = 9.96±1.06 nM）和稳定的结合能力，因此可以实现高度灵敏的诊断，有效的药物递送以及对靶肿瘤细胞的抑制作用，降低了对非靶细胞的细胞毒性。相信这种多价方法可以促进用于临床验证的新型适体功能化纳米装置的开发。

更新日期：2020-03-31

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