Injectable Click-Crosslinked Hyaluronic Acid Depot To Prolong Therapeutic Activity in Articular Joints Affected by Rheumatoid Arthritis

Abstract

The aim of this study was to design a click-crosslinked hyaluronic acid (HA) (Cx-HA) depot via a click crosslinking reaction between tetrazine-modified HA and trans-cyclooctene-modified HA for direct intra-articular injection into joints affected by rheumatoid arthritis (RA). The Cx-HA depot had significantly more hydrogel-like features and a longer in vivo residence time than the HA depot. Methotrexate (MTX)loaded Cx-HA (MTX-Cx-HA)easily prepared as an injectable formulationquickly formed an MTX-Cx-HA depot that persisted at the injection site for an extended period. In vivo MTX biodistribution in MTX-Cx-HA depots showed that a high concentration of MTX persisted at the intra-articular injection site for an extended period, with little distribution of MTX to normal tissues. In contrast, direct intra-articular injection of MTX alone or MTX-HA resulted in rapid clearance from the injection site. After intra-articular injection of MTX-Cx-HA into rats with RA, we noted the most significant RA reversal, measured by an articular index score, increased cartilage thickness, extensive generation of chondrocytes and glycosaminoglycan deposits, extensive new bone formation in the RA region, and suppression of tumor necrosis factor-α or interleukin-6 expression. Therefore, MTX-Cx-HA injected intra-articularly persists at the joint site in therapeutic MTX concentrations for an extended period, thus increasing the duration of RA treatment, resulting in an improved relief of RA.

Hyaluronic Acid Hydrogels Crosslinked in Physiological Conditions: Synthesis and Biomedical Applications

“…Biomedicines 2021, 9, x FOR PEER REVIEW 11 HA hydrogels are also formed by inverse electron demand Diels-Alder (IEDDA cloaddition reaction using tetrazine groups as the diene to react with alkenes or alky under physiological conditions (see Figure 8). The material formulations can be "in s injected into the area to be treated and rapidly form the crosslinked network, due to "click" properties of the reaction and do not require an external reagent [98][99][100][101][102]. H tetrazine (Tet) can react with PEG-norbornene to form DA hydrogels.…”

<p>Intraarticular Injection of Infliximab-Loaded Thermosensitive Hydrogel Alleviates Pain and Protects Cartilage in Rheumatoid Arthritis</p>

“…18 In particular, HA, a linear polysaccharide composed of D-glucuronic acid and N-acetylglucosamine, is an attractive natural polymer material owing to its high biocompatibility and controlled degradability. 19 Moreover, HA is also a key component of articular cartilage and can lubricate the joint after its intraarticular injection. Furthermore, note that HA intraarticular injection could significantly moderate the inflammatory response of synovial tissue, promote the healing and regeneration of articular cartilage, and alleviate pain, thus contributing to the recovery of disease-affected tissue.…”

“…also been reported to inhibit the secretion of enzymes, free radicals, and inflammatory mediators in arthritis as well as hinder the destruction of articular cartilage induced by these substances and accelerate the synthesis and repair of articular cartilage. 19,[28][29][30] Based on these findings, it could be assumed that intraarticular injection therapy using an IFX-incorporated HA-based hydrogel could significantly alleviate clinical symptoms.…”

In Vivo Imaging of Click-Crosslinked Hydrogel Depots Following Intratympanic Injection

“…When HA-TET and HA-TCO are mixed, they form a crosslinked HA (Cx-HA) depot. This technique has the advantages of facile handling and reproducibility, and the residence times of Cx-HA depots are comparatively long [ 23 , 24 , 25 ].…”