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 dyeloaded 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.

Properties and Bioapplications of Amphiphilic Janus Dendrimers: A Review

“…Other exceptional Janus amphiphilic glycopeptide dendrimers for the biomimicry of glycans exhibited strong and specific recognitions with C-type mannose-specific lectin [ 144 ].…”

“…They were self-assembled into different controllable nanostructures such as glycospheres, worm-like micelles, and fibers conditioned by the repeating unit fraction of saccharides and phenylalanine. These nanomaterials were successfully encapsulated with Nile red dye and fluorofenidone, an anti-inflammatory agent [ 144 ].…”

Complexation of Fluorofenidone by Cucurbit[7]uril and β-Cyclodextrin: Keto–Enol Tautomerization to Enhance the Solubility

“…25−28 Biomedical applications of AKF-PD are limited by its poor solubility. 29 Previous studies have provided evidence that the solubility of AKF-PD is notably enhanced by β-CD. 30 Therefore, the application of macrocyclic molecules to improve drug aqueous solubility and bioavailability could be a suitable approach for AKF-PD.…”

“…AKF-PD was approved for clinical trials by China Food and Drug Administration in 2016 (approval number: 2016L09979) and the phase I clinical trial was finished in 2019 . AKF-PD enters phase II clinical trials (ChiCTR2200065008) for hepatic fibrosis in China after its antifibrotic effects were demonstrated in various experimental models of liver, kidney, and lung fibrosis. , Furthermore, the drug has antioxidant, anti-apoptotic, and anti-inflammatory properties. − Biomedical applications of AKF-PD are limited by its poor solubility . Previous studies have provided evidence that the solubility of AKF-PD is notably enhanced by β-CD .…”

Adenosine Triphosphate-Responsive Glyconanorods through Self-Assembly of β-Cyclodextrin-Based Glycoconjugates for Targeted and Effective Bacterial Sensing and Killing

“…CDMan and CDEG were synthesized following our previous work. 61 Synthesis of Rh-NH 2 . Rhodamine B (3.83 g, 8 mmol) and triethylenetetramine (6 mL, 40 mmol) were dissolved in EtOH (50 mL).…”