International Journal of Nanomedicine (Mar 2024)
Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis
Abstract
Sushmita Negi,1,2,* Nikunj Tandel,3,* Neeraj K Garg,4 Prakriti Sharma,1 Rajinder Kumar,1 Praveen Sharma,1 Reetesh Kumar,5 Sheetal Saini,1 Aman Sharma,6 Rajeev K Tyagi1,2 1Biomedical Parasitology and Translational-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh, 160036, India; 2Academy of Scientific and Innovation Research (Acsir), Ghaziabad, 201002, India; 3Institute of Science, Nirma University, Ahmedabad, Gujarat, India; 4University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India; 5Faculty of Agricultural Sciences, Institute of Applied Sciences and Humanities, GLA University, Mathura, Uttar Pradesh, India; 6Clinical Immunology and Rheumatology Wing, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India*These authors contributed equally to this workCorrespondence: Rajeev K Tyagi, Biomedical Parasitology and Translational-immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Sec-39a, Chandigarh, 160036, India, Tel +91-172-6665278; +91-172-6665279, Email [email protected]; [email protected]: Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events.Methods: We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)-loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund’s adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA.Results: Higher permeation of ACE-NLCs/CE across skin layers confirming the greater “therapeutic index” of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations.Conclusion: Our findings confirmed the use of co-delivery of drug nanoformulations as the “combination drug regimen” to treat RA.Keywords: methotrexate, aceclofenac, lipid polymer hybrid nanoparticles, nanostructured lipid nanocarriers, rheumatoid arthritis, MMP-1
