On-demand release of a selective MMP-13 blocker from an enzyme-responsive injectable hydrogel protects cartilage from degenerative progression in osteoarthritis

• Published in: Journal of materials chemistry. B, Materials for biology and medicine Vol. 12; no. 22; p. 5325
• Main Authors: Roy, Himadri Shekhar, Murugesan, Preethi, Kulkarni, Chirag, Arora, Malika, Nagar, Geet Kumar, Guha, Rajdeep, Chattopadhyay, Naibedya, Ghosh, Deepa
• Format: Journal Article
• Language: English
• Published: England 05-06-2024
• Subjects: Animals; Cartilage, Articular - drug effects; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Hydrogels - chemistry; Hydrogels - pharmacology; Male; Matrix Metalloproteinase 13 - metabolism; Matrix Metalloproteinase Inhibitors - chemistry; Matrix Metalloproteinase Inhibitors - pharmacology; Osteoarthritis - drug therapy; Osteoarthritis - metabolism; Osteoarthritis - pathology; Rats; Rats, Sprague-Dawley
• ISSN: 2050-7518
• DOI: 10.1039/d3tb02871b

In osteoarthritis (OA), the degradation of cartilage is primarily driven by matrix metalloprotease-13 (MMP-13). Hence, the inhibition of MMP-13 has emerged as an attractive target for OA treatment. Among the various approaches that are being explored for MMP-13 regulation, blocking of the enzyme with specific binding molecules appears to be a more promising strategy for preventing cartilage degeneration. To enhance effectiveness and ensure patient compliance, it is preferable for the binding molecule to exhibit sustained activity when administered directly into the joint. Herein, we present an enzyme-responsive hydrogel that was designed to exhibit on-demand, the sustained release of BI-4394, a potent and highly selective MMP-13 blocker. The stable and compatible hydrogel was prepared using triglycerol monostearate. The efficacy of the hydrogel to prevent cartilage damage was assessed in a rat model of OA induced by anterior cruciate ligament transection (ACLT). The results revealed that in comparison to the rats administrated weekly with intra-articular BI-4394, the hydrogel implanted rats had reduced levels of inflammation and bone erosion. In comparison to untreated control, the cartilage in animals administered with BI-4394/hydrogel exhibited significant levels of collagen-2 and aggrecan along with reduced MMP-13. Overall, this study confirmed the potential of BI-4394 delivery using an enzyme-responsive hydrogel as a promising treatment option to treat the early stages of OA by preventing further cartilage degradation.