Design of chondroitin sulphate coated proglycosomes for localized delivery of tofacitinib for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease under the category of musculoskeletal condition that affects joints and causes pain, swelling, limitation in mobility, and damage all over your body, commonly the wrist and fingers [1], [2]. According to a recent assessment of Global Burden of Disease (GBD) data, worldwide 1.71 billion individuals suffer from musculoskeletal disorders. Among these up to 14 million people around the world suffer from rheumatoid arthritis [3], [4]. This indicated the need for effective treatment to improve the quality of life and minimize the disease burden.

In RA pathogenesis, macrophages play a crucial role by generating cytokines that enhance inflammation and contribute to the destruction of cartilage and bone [5]. In addition, the thorough literature survey revealed that continuous activation of Janus kinase (JAK) / signal transducers and activators of transcription (STAT) pathway plays a crucial role in the pathogenesis and progression of inflammation in rheumatoid arthritis [6], [7]. Tofacitinib (TOF) is a potent inhibitor of JAK 1 and JAK 3 approved by the United State Food and Drug Administration (USFDA) in 2012 for the treatment of moderate to severe arthritis [6]. Regardless of its significant efficacy to treat RA, concerns about TOF dose-dependent adverse effects cause hyperlipidemia, and long-term safety studies showed higher rates of pulmonary embolism and death when using high doses [8].

During these conditions, the topical administration with appropriate delivery vehicles can provide optimized delivery to inflamed synovium. Topical administration can be efficacious over oral therapy, however the outermost stratum corneum acts as a physiological barrier and limits the drug penetration [9]. Skin permeability and retention were more with modified liposomes i.e., reported ethosomes when compared to the conventional liposomal formulations. The vesicular carriers can exhibit high permeation profile because the Phospholipid molecules and propylene glycol improve molecular transport over the skin by changing lipid tight packing. In general, modified liposomes that is proglycosomes (PG) take the trans appendageal and intercellular pathway to permeate into the skin [10]. These TOF loaded PG have proved their efficacy in permeating through the skin layers in preclinical study conducted by Kathuria et al [10]. In consideration of above points, the targeted delivery of TOF via ligands in RA condition could be a better approach to achieve better efficacy. During inflammatory condition, the macrophages exhibit cluster determinants (CD44) on surface of macrophages and fibroblasts [11]. It has been investigated that CD44 can recognize and bind glycosaminoglycan-based biomaterials. CD44 consists of variant stem fibrin region as a binding site for chondroitin sulphate (CS). CS is a water soluble, unbranched sulphated anionic glycosaminoglycan with virtuous biodegradability, biocompatibility and less toxicity [12]. It is present in cartilage, ligament and it is well recognized to decrease the joint space's discomfort and narrowing [13], [14]. Considering the above benefits, we hypothesize that glycosaminoglycan coated drug-incorporated nanocarrier-loaded hydrogels could be an effective approach to treat the patients suffering with the RA. In the current research work, we aimed of active targeted drug delivery via CS coated TOF-loaded to target the CD44 receptors can be an effective approach to RA therapy.

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