Ultra-Stable Linker Strategies in Antibody–Drug Conjugates: Balancing Plasma Stability with Controlled Cytotoxic Payload Release

Abstract

Targeted drug delivery has emerged as a transformative approach in cancer therapy, allowing selective destruction of malignant cells while minimizing systemic toxicity. Antibody-drug conjugates (ADCs) and other targeted delivery systems rely heavily on chemical linkers that connect highly potent cytotoxic agents to targeting ligands. Among these, ultra-stable chemical linkers have gained significant attention due to their ability to remain intact during systemic circulation while ensuring precise intracellular release of therapeutic payloads. The physicochemical properties of linkers directly influence pharmacokinetics, therapeutic index, efficacy, and safety. Recent advances in linker chemistry have enabled the development of enzyme-responsive, pH-sensitive, reduction-sensitive, and bio orthogonal cleavage mechanisms, improving payload release specificity. This review discusses the chemistry, design principles, mechanisms of action, recent advances, clinical applications, challenges, and future perspectives of ultra-stable chemical linkers used for controlled cytotoxic payload delivery.