Fabrication of self-assembled nanostructures for intracellular drug delivery from diphenylalanine analogues with rigid or flexible chemical linkers

Abstract

Self-assembly of molecular building blocks is a simple and useful approach to generate supramolecular structures with varied morphologies and functions. By studying the chemical properties of the building blocks and tuning the parameters of their self-assembly process, the resultant supramolecular assemblies can be optimized for the required downstream applications. To this end, in the present study we have designed and synthesized three different molecular building blocks composed of two diphenylalanine (FF) units connected to each other through three different linkers: ethylenediamine, succinic acid, or terephthalaldehyde. Under identical conditions, all the three building blocks self-assemble into supramolecular architectures with distinct morphologies. However, by varying the polarity of the self-assembly medium, the nature of the non-covalent interactions changes in such a way as to generate additional self-assembled structures unique to each building block. Utilizing microscopic and spectroscopic techniques, we characterized the morphological variety generated by each building block/linker combination. These data represent the first report analysing the diversity of nanostructures that can be generated from identical dipeptide-based molecular backbones simply by varying the chemical linker. We also demonstrate that the spherical assemblies and nanorod structures fabricated from these dipeptide/linker pairs can act as drug delivery systems. More specifically, the spherical assembly generated by two FF dipeptides linked via ethylenediamine and nanorods fabricated from terephthalaldehyde linked FF dipeptides were able to encapsulate the cancer chemotherapeutic agent doxorubicin (DOX) and chaperone the drug into cells. Thus, these supramolecular assemblies represent a new platform for the development of efficient and effective intracellular drug delivery systems.