Growing Prospects of Dynamic Covalent Chemistry in Delivery Applications

Delivery remains a major obstacle restricting the potential action of small molecular drugs as well as novel biologics which cannot readily enter cells without the help of a vector. A successful active delivery process involves three steps: (a) tagging the drug with a vector, (b) effective trafficking of this [drug–vector] conjugate through biological barriers, and finally (c) controlled drug release. While covalent bond formation and/or supramolecular association is involved in the making of the [drug–vector] conjugate, the final step requires precisely a controlled dissociation in order to trigger drug release. Therefore, in pursuit of smart, effective, and nontoxic delivery systems, it has become widely recognized that control over dynamic self-assembly could unleash the efficacy of artificial vectors. In this Account, I discuss our endeavors, and those of colleagues, in the recent implementation of Dynamic Covalent Chemistry (DCvC) in delivery applications. DCvC exploits reversible covalent reactions to generate covalent systems that can self-fabricate, adapt, respond, and fall apart in a controlled fashion. A privileged set of reversible covalent reactions has emerged in the community working on delivery applications and is based on condensation reactions (imine, acylhydrazone, oxime), and disulfide and boronate ester formations. The latest developments making this chemistry particularly attractive for such a DCvC approach are discussed. The rational justifying the potential of DCvC in delivery is based on the principle that using such reversible covalent reactions afford transient [drug-vector] conjugates which form spontaneously and chemoselectively, then adapt and self-correct their structure during self-assembly and trafficking thanks to the dynamic nature of the reversible covalent bonds, and finally respond to physicochemical stimuli such as pH and redox changes, thereby enabling controlled dissociation and concomitant drug release. For these reasons, DCvC has recently emerged as a leverage tool with growing prospects for advancing toward smarter delivery systems. The implementation of DCvC can follow three approaches that are discussed herein: (1) dynamic covalent bioconjugates, involving the transient covalent conjugation with a vector, (2) dynamic covalent vectors, involving the controlled dynamic and adaptive assembly and disassembly of vectors that complex drugs through supramolecular association, and (3) dynamic covalent targeting, involving the transient chemoselective formation of covalent bonds with the constituents of cell