Novel Delivery Platform For Controlled Release Of Bacterial Metabolites To Modulate The Immune System

SUMMARY

• Conditioning of the immune system by the microbiome has received substantial attention for the scientific community in recent years. Microbial metabolites are being assessed as novel therapeutic tools for various diseases, including cancer and immune disorders.

• Butyrate is a key bacterial metabolite that plays an important and complex role in modulation of immunity and maintenance of epithelial barriers. Its translation to clinic is limited by poor bioavailability, pungent smell, and the need for high doses, and effective delivery strategies have yet to realize clinical potential.

• The faculty inventor developed a novel polymeric delivery platform for tunable and sustainable release of butyrate consisting of a methacrylamide backbone with butyryl ester or phenyl ester side chains as well as mannosyl side chains, which is also applicable to other therapeutically relevant metabolites.

• The butyrate-containing material modulates immune cell activation in vitro and induces striking changes in the milieu of soluble cytokine and chemokine signals present within the diabetic wound microenvironment in vivo. This novel therapy shows efficacy in the treatment of non-healing wounds through the modulation of the soluble signals present within the wound, and importantly accommodates the critical temporal regulation associated with the wound healing process.

FIGURE

In vivo wound closure efficacy of butyrate polymer. Male db/db mice had four 6 mm wounds excised from dorsal cutaneous tissue and were subsequently treated with PBS, 1% HA, or 1% HA + pMan-But at a concentration of 12.5 mg mL⁻¹ butyrate equivalent. After 7 or 11 days mice were sacrificed and their wounds excised for histological analysis. A) Wound closure percentage after 7 days. B) Percent of wounds within each bin of closure after 7 days. C) Percent wound closure after 11 days, experiment was repeated a total of two times and pooled. D) Percent of wounds within each bin of closure after 11 days. E) Representative H&E images after 11 days. The black arrowheads indicate the margin of the original wound and red arrowheads indicate the tips of epithelium tongue. F) Representative CD31⁺ IHC images after 11 days. Statistical analysis was performed using a) ordinary one-way analysis of variance with Tukey's multiple comparison test against all groups or b) Kruskal–Wallis test with Dunn's multiple comparison with respect to PBS control. *p < 0.05, **p < 0.01, and ns, not significant.

ADVANTAGES

ADVANTAGES

• The platform can be extended to other payloads/bacterial metabolites

• Accelerates the closure of diabetic or non-healing wounds

• Masks the smell and taste of butyrate

APPLICATIONS

• Drug delivery
• Wound healing

PUBLICATIONS

• Lauterbach, A. L., Slezak, A. J., Wang, R., Cao, S., Raczy, M. M., Watkins, E. A., Jimenez, C. J. M., Hubbell, J. A., Mannose-Decorated Co-Polymer Facilitates Controlled Release of Butyrate to Accelerate Chronic Wound Healing. Adv. Healthcare Mater. 2023, 12, 2300515

November 3, 2023

Proof of concept

Patent Pending

Licensing,Co-development

Jeffrey Hubbell