Design and Synthesis of Nanofibers of Self-assembled de novo Glycoconjugates towards Mucosal Lining Restoration and Anti-Inflammatory Drug Delivery

Abstract

The medical practice for IBD is solely based on anti-inflammatory drugs, but the outcome is far from ideal. Our long-term research goal is to seek a better clinical outcome by combining the anti-inflammatory therapy with physical mucus layer restoration. As the first step towards that objective, we choose to develop self-assembled hydrogels of de novo glycoconjugates that consist of anti-inflammatory drugs and glycopeptides. By covalently linking peptides (e.g., nap-phe-phe-lys), saccharides (e.g., glucosamine), and an anti-inflammatory drug (i.e., olsalazine), we have demonstrated that the obtained molecules self-assemble in water to form hydrogels composed of 3D networks of the nanofibers under acidic conditions. We also confirmed that the resulting glycoconjugates are cell compatible. However, the preliminary assessment of the efficacy of the hydrogels on the murine model is inconclusive, which warrants further investigation and molecular engineering.

Keywords: Inflammatory bowel disease (IBD); anti-inflammatory therapy; glycopeptide; nanofibers; self-assembled hydrogel.

Figure 1

TEM images show the matrices of the hydrogels formed by 1–6 at the concentration of 1.0 wt% and pH of 5. The scale bar is 100 nm. Inset is the optical image of the hydrogels

Figure 2

Rheological characterization of hydrogels formed by 4, 5, or 6, at the concentration of 1.0 wt% and pH of 5.0. The frequency (A) and strain (B) dependence of the dynamic storage.

Figure 3

Cell viability (determined by MTT cell viability/proliferation assay) of HeLa cells treated by 1–6 at different concentrations.

Figure 4

Illustration of experiment protocol. DSS is administered ad libitum for 5 days (3% DSS (w/v)), with a 2-day recovery period with water. Compounds 6 is administered on Day 4 and Day 6. Mice were sacrificed on Day 7 for scoring disease activity index.

Figure 5

(A) The changes of the body weights of DSS mice during the treatment. (B) The weight percentages of DSS mice treated with 6 at different dosages on the ending day (7th day) compared with that on the starting day. (C) The colon lengths of DSS mice treated with 6 at different dosages on the ending day. (D) The fecal blood score of DSS mice treated with 6 at different dosages on the ending day. (E) The disease activity index (DAI) of DSS mice treated with 6 at different dosages. The DAI is calculated based on hunching, wasting, stool consistency and thickness of the colon.

Scheme 1

Conceptual illustration of the use of self-assembled glycoconjugates (e.g., 6) on the disrupted mucosal surfaces for the treatment of IBD.

Scheme 2

Molecular structures and synthetic route of the glycoconjugates and the relevant control compounds.