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

E Montanari; N Zoratto; L Mosca; L Cervoni; E Lallana; R Angelini; R Matassa; T Coviello; C Di Meo; P Matricardi

doi:10.1016/j.carbpol.2019.06.004

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

Carbohydr Polym. 2019 Oct 1:221:209-220. doi: 10.1016/j.carbpol.2019.06.004. Epub 2019 Jun 5.

Authors

E Montanari¹, N Zoratto¹, L Mosca², L Cervoni², E Lallana³, R Angelini⁴, R Matassa⁵, T Coviello¹, C Di Meo⁶, P Matricardi¹

Affiliations

¹ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo Moro 5, Rome 00185, Italy.
² Department of Biochemical Sciences, Sapienza University of Rome, P.le Aldo Moro 5, Rome 00185, Italy.
³ Faculty of Biology, Medicine and Health, The University of Manchester, Oxford road, M13 9PT Manchester, UK.
⁴ Istituto dei Sistemi Complessi del Consiglio Nazionale delle Ricerche (ISC-CNR), P.le Aldo Moro 5, Rome I-00185, Italy; Department of Physics, Sapienza University of Rome, P.le Aldo Moro 5, Rome 00185, Italy.
⁵ Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Via A. Borelli, Rome 00161, Italy.
⁶ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo Moro 5, Rome 00185, Italy. Electronic address: chiara.dimeo@uniroma1.it.

PMID: 31227160
DOI: 10.1016/j.carbpol.2019.06.004

Abstract

Hyaluronan (HA) is among the most used biopolymers for viscosupplementation and dermocosmetics. 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. Jonexa™). 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 native HA. Similar NHs, based on gellan-CH, 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.

Keywords: Dermal filler; Hyaluronan-cholesterol; Hyaluronidase inhibitor; Nanohydrogels; Viscosupplementation.

MeSH terms

Biocompatible Materials / chemical synthesis
Biocompatible Materials / chemistry
Biocompatible Materials / toxicity
Cell Line
Cholesterol / analogs & derivatives*
Cholesterol / chemical synthesis
Cholesterol / toxicity
Drug Compounding
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / toxicity
Humans
Hyaluronic Acid / analogs & derivatives*
Hyaluronic Acid / chemical synthesis
Hyaluronic Acid / toxicity
Hyaluronoglucosaminidase / antagonists & inhibitors*
Hyaluronoglucosaminidase / chemistry
Hydrogels / chemical synthesis
Hydrogels / chemistry*
Hydrogels / toxicity
Nanostructures / chemistry
Nanostructures / toxicity

Substances

Biocompatible Materials
Enzyme Inhibitors
Hydrogels
Hyaluronic Acid
Cholesterol
Hyaluronoglucosaminidase