Zhang Jie, Yang Zeyu, Liu Yu, Liu Yuying, Qu Jingkun, Pan Xiaoyan
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Top Curr Chem (Cham). 2025 Mar 13;383(2):13. doi: 10.1007/s41061-025-00497-w.
Targeted drug delivery systems effectively solve the problem of off-target toxicity of chemotherapeutic drugs by combining chemotherapeutic drugs with antibodies or peptides, thereby promoting drug targeting to the tumor site and bringing further hope for cancer treatment. The development of stimulus-responsive smart linkage technologies has led to the emergence of drug conjugates. Linkage technologies play a crucial role in the design, synthesis, and in vivo circulation of drug conjugates, as they determine the release of cytotoxic drugs from the conjugates and their subsequent therapeutic efficacy. This article reviews some of the smart linkage strategies used in designing drug conjugates, with a focus on the tumor microenvironment and exogenous stimuli as conditions influencing controlled drug release. This review introduces linker classifications and cleavage mechanisms, discusses modular linkers that promote the efficient synthesis of conjugates, and discusses the differences between linkage strategies. Furthermore, this article focuses on the implementation of self-assembly in drug conjugates, which is currently of great interest. Related concepts are introduced and relevant examples of their applications are provided. Furthermore, a comprehensive discourse is presented on the challenges that may arise in the research and clinical implementation of diverse linkage strategies, along with the associated enhancement measures. Finally, the factors that should be considered when designing linkage strategies for drug conjugates are summarized, offering strategies and ideas for scientists involved in drug conjugate research. It is particularly noteworthy that appropriate linkage strategies allow for the intracellular release of drugs after internalization of the conjugates, thereby maximizing their tumor cell-killing effect.
靶向给药系统通过将化疗药物与抗体或肽结合，有效解决了化疗药物的脱靶毒性问题，从而促进药物靶向肿瘤部位，为癌症治疗带来了新的希望。刺激响应型智能连接技术的发展催生了药物偶联物。连接技术在药物偶联物的设计、合成及体内循环中起着关键作用，因为它们决定了细胞毒性药物从偶联物中的释放及其后续的治疗效果。本文综述了用于设计药物偶联物的一些智能连接策略，重点关注肿瘤微环境和外源性刺激作为影响药物控释的条件。本综述介绍了连接子的分类和裂解机制，讨论了促进偶联物高效合成的模块化连接子，并探讨了连接策略之间的差异。此外，本文重点介绍了目前备受关注的药物偶联物中的自组装实现。介绍了相关概念并提供了其应用的相关实例。此外，还全面讨论了不同连接策略在研究和临床应用中可能出现的挑战以及相关的改进措施。最后，总结了设计药物偶联物连接策略时应考虑的因素，为从事药物偶联物研究的科学家提供了策略和思路。特别值得注意的是，合适的连接策略可使偶联物内化后在细胞内释放药物，从而最大化其对肿瘤细胞的杀伤作用。
