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

PurposeUp-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.MethodsA 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.ResultsThe 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.ConclusionBased on these outcomes, the formulated IA delivery system of ATV can be presented as an excellent candidate for ameliorating OA.