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Hyaluronic-Acid-Functionalized Tofacitinib Loaded Transethosomes for Targeted Drug Delivery in Rheumatoid Arthritis
Pavani Chowdary1,2, Eswara Rao Puppala3, Chandra Lekha Putta1
1Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi 502284, Telangana, India.
Abstract:
The Janus kinase inhibitor tofacitinib (TOF) is an FDA-approved drug for rheumatoid arthritis (RA) treatment, but its long-term oral use leads to significant systemic side effects. The present research aimed to conquer these challenges by formulating hyaluronic-acid-coated transethosomes (HA-TOF-TE), a novel system for targeted, topical delivery of TOF to reduce systemic toxicity and improve therapeutic efficacy. Transethosomes were synthesized via the cold sonication technique with HA functionalization enabling CD44 receptor-mediated targeting of inflamed synovial tissue. Optimized TOF-TE and HA-TOF-TE formulations showed particle sizes of 199.08 ± 4.2 and 151.5 ± 5.4 nm, zeta potentials of -27.1 ± 0.75 and -34.10 ± 0.89 mV, and entrapment efficiencies of 81.16 ± 0.84% and 79.19 ± 2.65%, respectively. The gels were assessed through in vitro drug release, ex vivo permeability, and in vivo effectiveness experiments using Freund's complete adjuvant (CFA) model. Ex vivo studies showed 2.02-fold and 1.61-fold increments in flux for TOF-TE and HA-TOF-TE, respectively, with superior skin retention for HA-TOF-TE. In vivo efficacy confirmed HA-TOF-TE's significant (P < 0.001) anti-inflammatory effect on arthritic rat paws, outperforming TOF-TE and FD gels. Cytokine analysis showed notable reductions in serum IL-1, IL-6, and PGE-2 levels after HA-TOF-TE treatment, closely approximating control values. Additionally, mRNA analysis demonstrated marked decreases in IL-6, CD44, and collagen II expression, indicating HA-TOF-TE's potential as an effective, targeted RA treatment, addressing the challenges of conventional TOF therapy and minimizing systemic side effects.
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