Synergistic and receptor-mediated targeting of arthritic joints via intra-articular injectable smart hydrogels containing leflunomide-loaded lipid nanocarriers

Intra-articular drug delivery represents a tempting strategy for local treatment of rheumatoid arthritis. Targeting drugs to inflamed joints bypasses systemic-related side effects. Albeit, rapid drug clearance and short joint residence limit intra-articular administration. Herein, injectable smart hydrogels comprising free/nanoencapsulated leflunomide (LEF) were developed. Nanostructured lipid carriers (NLCs), 200-300 nm, were coated with either chondroitin sulfate (CHS), hyaluronic acid (HA), or chitosan (CS) to provide joint targetability. Coated NLCs were incorporated in either hyaluronic/pluronic (HP) or chitosan/β-glycerophosphate (CS/βGP) hydrogels. Optimized systems ensured convenient gelation time (14-100 s), injectability (5-15 s), formulation-dependent mechanical strength, and extended LEF release up to 51 days. In vivo intra-articular injection in induced arthritis rat model revealed that rats treated with HA-coated NLCs showed the fastest recovery. Histopathological examination demonstrated perfect joint healing in case of HA-coated LEF-NLCs in CS/βGP thermogel manifested as minor erosion of subchondral bone, improved intensity of extracellular matrix, cartilage thickness, and chondrocyte number. Both HA- and CHS-coated NLCs reduced TNF-α level 4-5-fold relative to positive control. The feat would be achieved via active targeting to CD44 receptors overexpressed in the articular tissue, limiting chondrocyte apoptosis together with innate synergistic targetability by promoting chondrocyte proliferation and neovascularization, inhibiting the production of pro-inflammatory cytokines, thus enhancing cartilaginous tissue repair.