Quantitative Factors Introduced in the Feasibility Analysis of Reactive Oxygen Species (ROS)‐Sensitive Triggers

Reactive oxygen species (ROS) are critical for cellular signaling. Various pathophysiological conditions are also associated with elevated levels of ROS. Hence, ROS‐sensitive triggers have been extensively used for selective payload delivery. Such applications are predicated on two key functions: (1) a sufficient magnitude of concentration difference for the interested ROS between normal tissue/cells and intended sites and (2) appropriate reaction kinetics to ensure a sufficient level of selectivity for payload release. Further, ROS refers to a group of species with varying reactivity, which should not be viewed as a uniform group. In this review, we critically analyze data on the concentrations of different ROS species under various pathophysiological conditions and examine how reaction kinetics affect the success of ROS‐sensitive linker chemistry. Further, we discuss different ROS linker chemistry in the context of their applications in drug delivery and imaging. This review brings new insights into research in ROS‐triggered delivery, highlights factors to consider in maximizing the chance for success and discusses pitfalls to avoid. Success of Reactive Oxygen Species (ROS) triggered prodrug activation relies on two key functions: (1) sufficient magnitude of concentration difference for the interested ROS between normal tissue/cells and the intended site of delivery, (2) appropriate reaction kinetics to ensure a sufficient level of payload release. Herein, we examine ROS concentrations under various pathophysiological conditions and critically analyze ROS‐triggered prodrug.