Challenges and Opportunities for Cleavable Linkers Used in Polymer-Drug Conjugates

Polymer-drug conjugates with cleavable linkers show excellent promise as controlled-release drug delivery systems for a range of diseases; however, several cleavage strategies fall short in their specificity or require additional complexities that pose significant challenges for clinical adoption. This Perspective outlines the advantages and pitfalls of various linker types in terms of their responsiveness to their target cleavage stimuli. Aside from overcoming efficacy and biocompatibility challenges, we critically discuss other key challenges in the translation of these materials and highlight the latest clinical developments. Taking inspiration from other areas of prodrug chemistry and polymer science, new opportunities for this field are proposed, which aim to overcome the current barriers and may be the key to the clinical adoption of this exciting class of therapeutics.