Redox-Sensitive Materials for Drug Delivery: Targeting the Correct Intracellular Environment, Tuning Release Rates, and Appropriate Predictive Systems

Significance: The development of responsive drug delivery systems (DDS) holds great promise as a tool for improving the pharmacokinetic properties of drug compounds. Redox-sensitive systems are particularly attractive given the rich variety of redox gradients present in vivo. These gradients, where the circulation is generally considered oxidizing and the cellular environment is substantially more reducing, provide attractive options for targeted, specific cargo delivery. Recent Advances: Experimental evidence suggests that a one size fits all redox gradient does not exist. Rather, there are subtle differences in redox potential within a cell, while the chemical nature of reducing agents in these microenvironments varies. Recent works have demonstrated an ability to modulate the degradation rate of redox-susceptible groups and, hence, provide new tools to engineer precision-targeted DDS. Critical Issues: Modern synthetic and macromolecular chemistry provides access to a wide range of redox-susceptible architectures. However, in order to utilize these in real applications, the actual chemical nature of the redox-susceptible group, the sub-cellular location being targeted, and the redox microenvironment being encountered should be considered in detail. This is critical to avoid the over-simplification possible when using non-biological reducing agents, which may provide inaccurate kinetic information, and to ensure these materials can be advanced beyond simple on/off systems. Furthermore, a strong case can be made for the use of biorelevant reducing agents such as glutathione when demonstrating a materials redox response. Future Directions: A further understanding of the complexities of the extra-and intracellular microenvironments would greatly assist with the design and application of DDS.