Spontaneous assembly of a class of small molecule prodrugs directed by SN38

Abstract

Small molecule self-assembling prodrugs (SAPDs) are an emerging class of amphiphilic monomers that can aggregate into supramolecular nanostructures with high drug loading identical to that of the individual prodrug. Despite great progress in creating nanodrugs via nanoprecipitation, the direct self-assembly of small molecule SAPDs in aqueous solution remains challenging, as the proper hydrophilic–hydrophobic balance and intermolecular interactions have to be rationally considered. We report a class of small molecule SAPDs by conjugating the anticancer drug SN38 as the structure-directing component with various hydrophilic auxiliaries (i.e., oligo ethylene glycol (OEG) of different lengths, amino, and carboxyl groups) via a self-immolative disulfanyl-ethyl carbonate linker. Driven by π–π interactions between SN38 units, these SAPDs spontaneously assembled into well-defined fibrous nanostructures. Variations in hydrophilic domains can robustly regulate the hydrophobicity of SAPDs, as well as the morphologies and surface features of supramolecular filaments, subsequently influencing cellular internalization behaviors. Furthermore, our study also reveals that the parent drug can be efficiently and controllably released in the presence of glutathione (GSH), exhibiting high in vitro toxicity against colorectal cancer cells. In this work, we present a delicate platform to design small molecule SAPDs that can spontaneously self-assemble into supramolecular filamentous assemblies directed by aromatic interaction of the parent drugs, providing a new strategy to optimize supramolecular drug delivery systems.