Dynamic Glycopeptide Dendrimers: Synthesis and Their Controllable Self-Assembly into Varied Glyco-Nanostructures for the Biomimicry of Glycans.

Abstract

A library of 14 dynamic glycopeptide amphiphilic dendrimers composed of 14 hydrophilic and bioactive saccharides (seven kinds) as dendrons and 7 hydrophobic peptides (di- and tetrapeptides) as arms with β-cyclodextrin (CD) as a core were facially designed and synthesized in several steps. Fourteen saccharides were first conjugated to the C-2 and C-3 positions of CD, forming glycodendrons. Subsequently, seven oligopeptide arms were introduced at the C-6 positions of a CD moiety by an acylhydrazone dynamic covalent bond, resulting in unique Janus amphiphilic glycopeptide dendrimers with precise and varied molecular structures. The kinds of hydrophilic parts of saccharides and hydrophobic parts of peptides were easily varied to prepare a series of amphiphilic Janus glycopeptide dendrimers. Intriguingly, these obtained amphiphilic glycopeptide dendrimers showcased very different self-assembly behaviors from the traditional amphiphilic linear block-copolymers and self-assembled into different glyco-nanostructures with controllable morphologies including glycospheres, worm-like micelles, and fibers depending upon the repeat unit ratio of saccharides and phenylalanine. Both glycodendrons and glycopeptide assemblies displayed strong and specific recognitions with C-type mannose-specific lectin. Moreover, these glycopeptide nanomaterials can encapsulate exemplary hydrophobic molecules such as Nile red (NR). The dye-loaded glycopeptide nanostructures showed a pH-controllable release behavior around the physiological and acidic tumor environment. Furthermore, cell experiments demonstrated that such glyco-nanostructures can further facilitate the functions of a model drug of the pyridone agent to reduce the expression of monocyte chemotactic protein-1 (MCP-1) and interleukin -1beta (IL-1β) in the primary peritoneal macrophages via encapsulating drugs. Considering all the abovementioned advantages including unique and precise structures, bioactivity, targeting, and controllable cargo release, we believe that these findings can not only enrich the library of glycopeptides but also provide a new avenue to the fabrication of smart and structure-controllable glyco-nanomaterials which hold great potential biological applications such as targeted delivery and release of therapeutic and bioactive molecules.