Self-assembling prodrugs

The terms self-assembled prodrug and supramolecular prodrug are largely overlapping, the latter being the most comprehensive. They represent multi- and plurimolecular systems intended for the delivery of prodrug molecules. In contrast to the classic unimolecular prodrugs, they act as unimers capable of self-assembly due to their peculiar prodrug moiety which is prone to supramolecular aggregation by means of noncovalent interactions. From a taxonomic point of view, three classes of supramolecular prodrugs can be defined: the host-guest complexes, the dynamic assemblies, and the structured nanoentities. In terms of pharmacological mechanisms of action, there is a diffuse border between supramolecular prodrugs and the supramolecular drug delivery systems. Both of them are biophase selective and release specific, but the prodrug ones supplementary protect and assist the parent drug throughout its transport and delivery, including during its bioconversion from the prodrug conjugate. Our review was focused not on presenting spectacular initiatives in the field of the supramolecular prodrugs, but on feasible solutions, even if they are still at the theoretical or preclinical stage of study. In the final section, we discuss two of the very specific details related to supramolecular/self-assembled prodrugs: their reproducibility issues and the philosophy of the prodrug strategy.