Hyaluronate-coated TPGS-g-chitosan nanoparticles for rheumatoid arthritis therapy: pharmaceutical development, anti-inflammatory activities, and bone regeneration studies.

Rheumatoid arthritis (RA) is a commonly occurring chronic autoimmune disorder and causes synovial inflammation and bone degradation/osteoclast in bone joints. The aim of this study was to develop the hyaluronate functionalized d-α-tocopherol polyethylene glycol 1000 succinate-grafted-chitosan (TPGS-g-chitosan) nanoparticles for effective delivery of tofacitinib citrate (TCE) to treat tissue inflammation and bone degradation in RA. TPGS-g-chitosan was synthesized and characterized through Fourier Transform Infrared Spectroscopy (FTIR) and 1H/13C Nuclear Magnetic Resonance (NMR) Spectroscopy and Electrospray Ionization Mass Spectrometry (ESI-MS) techniques. Nanoparticles were developed through slightly modified-ionic gelation method. Nanoparticles were developed and optimized through a 33 Box-Behnken design (BBD) approach for their physicochemical characteristics. The optimized TCTN and TCTN-HA nanoparticles showed particle sizes of 380.8 ± 10.4 nm and 432.2 ± 8.3 nm, zeta potentials of -4.34 ± 0.09 mV and - 16.19 ± 0.10 mV, and PDI values of 0.462 ± 0.01 and 0.453 ± 0.01, respectively, with entrapment efficiencies of 73.54 ± 2.4 % and 70.75 ± 2.1 %. TCTN-HA exhibited a more sustained drug release (79.64 %) than TCTN (80 %) at 72 h. Hemolysis study has confirmed the biocompatibility of nanoparticles with red blood cells (RBCs). Pharmacokinetic studies showed 4.1- and 4.5-fold higher AUC₀-t for TCTN and TCTN-HA, respectively, compared to free TCE. Both formulations markedly reduced paw volume (1.13 ± 0.05 and 1.41 ± 0.09) and diameter (4.13 ± 0.20 and 5.19 ± 0.35) after 28 days of RA treatment. Both TCTN and TCTN-HA significantly reduced TNF-α and RF levels, restored haemoglobin concentration, and promoted CD44-mediated bone regeneration as confirmed by X-ray, SEM, and histopathological analyses. The developed TCTN-HA offers an effective, targeted, and safe delivery system for RA therapy.