ABSTRACT
Rheumatoid arthritis (RA), an autoimmune inflammatory disorder is currently incurable. Methotrexate and Teriflunomide are routinely prescribed drugs but their uses are limited due to severe hepatotoxicity. Hyaluronic acid (HYA) is a targeting ligand for CD44 receptors overexpressed on inflamed macrophages. The present investigation aimed at design and fabrication of HYA coated hydroxyapatite nanoparticles (HA-NPs) loaded with Methotrexate (MTX) and Teriflunomide (TEF) (HAMT-NPs) to form HYA-HAMT-NPs for the treatment of RA. HYA-HAMT-NPs showed the nanoscale size of 274.9 ± 64 nm along with a zeta potential value of -26.80 ± 6.08 mV. FTIR spectra of HYA and HYA-HAMT-NPs proved the coating of HYA on HYA-HAMT-NPs. HYA-HAMT-NPs showed less cell viability compared to drugs on RAW 264.7 macrophage cells. A biodistribution study by gamma scintigraphy imaging further strengthened the results by revealing significantly higher (p<0.05) percentage radioactivity (76.76%) of HYA-HAMT-NPs in the synovial region. The results obtained by pharmacodynamic studies ensured the better efficacy of HYA-HAMT-NPs in preventing disease progression and promoting articular regeneration. Under hepatotoxicity evaluation, liver histopathology and liver enzyme assay revealed ~29% hepatotoxicity was reduced by HYA-HAMT-NPs when compared to conventional FOLITRAX-10 and AUBAGIO oral treatments. Overall, the results suggest that HYA-HAMT-NP is a promising delivery system to avoid drug-induced hepatotoxicity in RA.
Subject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Crotonates/administration & dosage , Drug Carriers/administration & dosage , Durapatite/chemistry , Hyaluronic Acid/chemistry , Methotrexate/administration & dosage , Nanoparticles/administration & dosage , Toluidines/administration & dosage , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/toxicity , Arthritis, Experimental/pathology , Crotonates/pharmacokinetics , Crotonates/therapeutic use , Crotonates/toxicity , Cytokines/blood , Drug Carriers/pharmacokinetics , Drug Carriers/toxicity , Drug Evaluation, Preclinical , Drug Liberation , Hydroxybutyrates , Liver/drug effects , Liver/enzymology , Liver/pathology , Methotrexate/pharmacokinetics , Methotrexate/therapeutic use , Methotrexate/toxicity , Mice , Nanoparticles/toxicity , Nitriles , RAW 264.7 Cells , Rats , Rats, Wistar , Spectroscopy, Fourier Transform Infrared , Tissue Distribution , Toluidines/pharmacokinetics , Toluidines/therapeutic use , Toluidines/toxicityABSTRACT
This research aims to coat Teriflunomide (TEF) loaded conventional nanoliposomes (CON-TEF-LIPO) with Chondroitin sulphate (CS) to produce CS-TEF-LIPO for the effective treatment of Rheumatoid arthritis (RA). Both CON-TEF-LIPO and CS-TEF-LIPO were produced, characterized and evaluated for their active targeting potential towards CD44 receptors. Cell cytotoxicity, cell viability and intracellular uptake study on differentiated U937 and MG-63 cells demonstrated the active targeting of CS-TEF-LIPO towards CD44 receptors. Furthermore, in vivo pharmacodynamic, biochemical, radiological and histopathological studies performed in adjuvant induced arthritic (AIA) rat model showed a significant (P < 0.05) reduction in inflammation in arthritic rat paw in CS-TEF-LIPO group compared to TEF and CON-TEF-LIPO groups. Moreover, liver toxicity study revealed that CS-TEF-LIPO showed no signs of toxicity and biodistribution study revealed the accumulation of CS-TEF-LIPO in synovial region of arthritic rat. Taken together, results suggest that CS-TEF-LIPO could provide a new insight for an effective treatment of RA.