Halting hyaluronidase activity with hyaluronan-based nanohydrogels: development of versatile injectable formulations

TL;DR

This study develops biocompatible hyaluronan-cholesterol nanohydrogels that effectively inhibit hyaluronidase activity, enhancing the stability and longevity of HA-based injectable formulations for medical and cosmetic use.

Contribution

The paper introduces self-assembled hyaluronan-cholesterol nanohydrogels that bind and inhibit hyaluronidase more effectively than existing formulations, offering a new approach to improve HA stability.

Findings

HA-CH nanohydrogels inhibit hyaluronidase activity more efficiently than marketed formulations.

The nanohydrogels bind to the enzyme's active site with high affinity.

Engineered into injectable hydrogels, they prevent HA degradation in vitro.

Abstract

Hyaluronan (HA) is among the most used biopolymers for viscosupplementation and cosmetic applications. However, the current injectable HA-based formulations present relevant limitations: I) unmodified HA is quickly degraded by endogenous hyaluronidases (HAase), resulting in short lasting properties; II) cross-linked HA, although shows enhanced stability against HAase, often contains toxic chemical cross-linkers. As such, herein, we present biocompatible self-assembled hyaluronan-cholesterol nanohydrogels (HA-CH NHs) able to bind to HAase and inhibit the enzyme activity in vitro, more efficiently than currently marketed HA-based cross-linked formulations (e.g. JonexaTM). HA-CH NHs inhibit HAase through a mixed mechanism, by which NHs bind to HAase with an affinity constant 7-fold higher than that of HA. Similar NHs, based on gellan-cholesterol, evidenced no binding to HAase, neither inhibition of the enzyme activity, suggesting this effect might be due to the specific binding of HA-CH to the active site of the enzyme. Therefore, HA-CH NHs were engineered into injectable hybrid HA mixtures or physical hydrogels, able to halt the enzymatic degradation of HA.