Synthesis of naringenin loaded lipid based nanocarriers and their in-vivo therapeutic potential in a rheumatoid arthritis model

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease of joints with no permanent cure. Although, there are some treatment strategies for RA that can go into remission but a precise treatment strategy is not currently available due to different patient manifestations. In addition, the use of various naturally available anti-inflammatory agents and antioxidants are hampered due to their instability in blood and lack of effective penetration into the synovial fluid. In this study, we aimed to enhance the therapeutic potential of natural but less bioavailable flavonoids by using lipid-based nanocarriers. Three types of lipid nanocarriers including stearic acid (SA), stearic-lauric (SL), and lecithin-chitosan (LC) nanocarriers (with encapsulated naringenin) were prepared by hot melt encapsulation and coprecipitation techniques, respectively. Arthritis in rats was induced by a single injection of complete Freund's adjuvant (CFA) in the sub-planter region of the left hind paw. Thirty six (36) male albino rats were divided into six groups with six animals each. Sole naringenin (NAR) and NAR-loaded lipid NPs (40 mg/kg) were administered orally to treatment groups after 1 h of CFA injection for 28 days continuously. NAR-loaded nanocarriers of spherical shape were synthesized with an average size less than ∼190 nm and zeta potential (<-25 mV for SA and SL, and >+30 mV for LC). We observed the encapsulation efficiency (EE) of 85%, 78% and 81% for LC, SA and SL, respectively. In vitro release of NAR from all nanoformulations showed sustained release behaviour. NAR loaded all lipid nanoformulations significantly (p < 0.001) reduced RA factor, key inflammatory markers, and joint damage than sole NAR. Among all nanocarriers, superior efficacy of SL may be due to synergistic anti-inflammatory effects of the lauric acid. Moreover, HE staining study demonstrated that NAR-loaded NPs significantly suppressed pathological changes of joints and liver tissues. In conclusion, solid lipid nanocarriers and lipid polymer hybrid nanoparticles are proposed here as a safe and effective oral delivery systems to enhance the therapeutic potential of NAR for rheumatoid arthritis treatment. SL carriers were found most effective, followed by LC nanocarriers and SA nanocarriers.