Recent Advances in Smart Linkage Strategies for Developing Drug Conjugates for Targeted Delivery.

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.