Engineering responsive polymeric drug delivery systems via bioorthogonal and click chemistry: From molecular design to function.

Stimuli-responsive polymer systems have been rapidly gaining attention for the targeted release of therapeutics. Such systems often require the construction of complex, multi-functional materials. Advancements in click and bioorthogonal reactions have therefore been increasingly used to prepare these polymeric materials, both through their synthesis in the lab as well as in their assembly in vivo at the target site. Furthermore, such reactions can even be used to trigger therapeutic release. This review will cover the main bioorthogonal and click reactions used for polymeric delivery systems including copper(I)-catalyzed azide-alkyne cycloaddition, strain-promoted cycloadditions, inverse electron demand Diels-Alder reactions, imine and hydrazone formation, and reactions of thiols such as thiol-ene, thiol-yne, thiol-Michael, and disulfide exchange. It will also provide an overview of the most important stimuli used to actuate drug release including changes in pH or redox status, enzymes, and external stimuli such as heat and light. The applications of this chemistry in a range of polymeric systems including polymer-drug conjugates, nanoparticles, polyion complexes, hydrogels, and nanogels will then be discussed. Finally a perspective of the current status of the field, challenges and areas for future exploration will be presented.