Atorvastatin loaded lecithin-coated zein nanoparticles based thermogel for the intra-articular management of osteoarthritis: in-silico, in-vitro, and in-vivo studies

Abstract

Purpose: Up-to-date literature offers limited data about utilizing atorvastatin calcium (ATV) as a promising chondroprotective agent in osteoarthritis (OA). So, this study aims to develop a depot intra-articular (IA) delivery system for ATV to enhance its deposition in the articular joint. Methods: A 33 D-optimal design was implemented to prepare ATV-loaded lecithin-coated zein nanoparticles. The optimized formulation (Opt-LCZN) was selected and imaged using a transmission electron microscope according to the desirability value. Various in-vitro and in-silico studies were conducted to evaluate the features of Opt-LCZN. Additionally, it was loaded into an injectable thermogel (Opt-LCZN-thermogel) and evaluated in-vivo in OA-induced Sprague Dawley rats. Results: The Opt-LCZN showed entrapment efficiency of 70.00 ± 2.96%, particle size of 191.95 ± 17.42 nm, zeta potential of − 20.12 ± 0.79 mV, and polydispersity index of 0.25 ± 0.01. The docking studies revealed favorable binding of zein and ATV, confirmed by molecular dynamics simulation. The morphological examination displayed a bilayer spherical structure formed of a zein core enclosed by a lecithin coat. Furthermore, the formulated Opt-LCZN-thermogel achieved a remarkable sustained release profile, with nearly 50% of the drug being released over 144 h. Opt-LCZN-thermogel showed a significant reduction in inflammation in OA-induced rats, confirmed by knee joint swelling and knee bend test results, in addition to the pro-inflammatory and anti-inflammatory mediators’ levels. The protective effect of ATV can be markedly observed through histopathological examination. Conclusion: Based on these outcomes, the formulated IA delivery system of ATV can be presented as an excellent candidate for ameliorating OA. Graphical abstract: (Figure presented.)