Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
ACS Nano. 2023 Sep 26;17(18):17740-17750. doi: 10.1021/acsnano.3c01955. Epub 2023 Sep 1.
Site-specific chemical conjugation has long been a challenging endeavor in the field of ligand-directed modification to produce homogeneous conjugates for precision medicine. Here, we develop a chemical amplification-enabled topological modification (Chem-ATM) methodology to establish a versatile platform for the programmable modification of nucleic acid aptamers with designated functionalities. Differing from conventional conjugation strategies, a three-dimensional artificial base is designed in Chem-ATM as a chemical amplifier, giving access to structurally and functionally diversified conjugation of aptamers, with precise control over loading capacity but in a sequence-independent manner. Meanwhile, the sp hybridized atom-containing amplifier enables planar-to-stereo conformational transformation of the entire conjugate, eliciting high steric hindrance against enzymatic degradation in complex biological environments. The versatility of Chem-ATM is successfully demonstrated by its delivery of anticancer drugs and imaging agents for enhanced therapy and high-contrast noninvasive tumor imaging in xenograft and orthotopic tumor models. This study offers a different perspective for ligand-directed chemical conjugation to enrich the molecular toolbox for bioimaging and drug development.
靶向特定部位的化学偶联在配体导向修饰领域一直是一项具有挑战性的工作，因为需要生成用于精准医学的同质性缀合物。在这里，我们开发了一种化学放大的拓扑修饰（Chem-ATM）方法，为具有指定功能的核酸适体的可编程修饰建立了一个通用平台。与传统的偶联策略不同，Chem-ATM 中设计了一个三维人工碱基作为化学放大器，使适体能够进行结构和功能多样化的偶联，精确控制载药量，但不依赖于序列。同时，含有 sp 杂化原子的放大器使整个缀合物发生平面到立体的构象转变，在复杂的生物环境中产生高空间位阻，从而抵御酶的降解。Chem-ATM 的多功能性通过其递送至癌症药物和成像剂以增强治疗效果以及在异种移植和原位肿瘤模型中的高对比度非侵入性肿瘤成像得到了成功验证。这项研究为配体导向的化学偶联提供了一个不同的视角，丰富了生物成像和药物开发的分子工具包。
