| خلاصه مقاله | Rheumatoid arthritis (RA) is one of the most common intricate chronic autoimmune diseases affecting diverse organs and tissues, especially synovial joints. Due to the lack of definite
cures for RA by available therapeutic strategies, the goal of medication is to achieve
symptomatic relief and limit the advancement of the disease. Drug administration by intraarticular (IA) injection is an emerging popular treatment for RA, which provides localized
drugs accumulation and reduces undesirable side effects such as systemic toxicity and
gastrointestinal problems. In this regard, biomaterials such as chitosan hydrogels have gained more attention for intra-articular injection because of their perfect biocompatibility and biodegradability, resulting in extended drug retention time and high loading capacity.
Besides, cartilage degradation and RA flares are attributed to metalloproteinases (MMPs) enzymes that belong to extracellular matrix metalloproteinase produced by inflamed joint
tissues. The objective of the current study was to design an enzyme-responsive drug delivery system based on natural chitosan/gelatin containing diclofenac sodium as a model drug, which could titrate drug release to match the disease activity, resulting in optimal therapeutic
efficacy. Chitosan/gelatin hydrogels were prepared using gelatin and chitosan at different -glycerophosphate as an ionic crosslinking agent. Gelation time was determined by the test tube inversion method. The synthesized hydrogels were
characterized by FT-IR and scanning electron microscopy. The cytotoxicity of the synthesized hydrogels was investigated on the Huvec cell line by MTT assay. Enzymeresponsive release of diclofenac sodium from prepared hydrogels was investigated in PBS
buffer (pH 7.4), with or without collagenase I with incubation at 37 °C and 150 rpm during ten consecutive days. An aliquot of sink medium was removed and replenished with the same volume of fresh PBS at specific time intervals. Drug release was determined by UV-VIS spectrophotometry at 276 nm and the drugs calibration equation. Based on the optimization procedures, the gelation time of the final drug-loaded hydrogel was adjusted to 8 minutes. The cell viability assay of the final formulation revealed that the hydrogels are
cytocompatible and exert no/negligible cytotoxicity on Huvec cells. Drug release study showed that the amount of released diclofenac sodium was related to the rate of gelatin
degradation, which confirmed the sustained and controlled release in the presence of
different concentrations of collagenase. This study develops a novel drug-releasing hydrogel that can effectively respond to arthritis flares. Designed hydrogels can encapsulate a wide
range of therapeutic agents, containing enzyme-cleavable sites to facilitate hydrogel disassembly in response to enzymes present in inflammatory environments. The designed hydrogel will be liquid below or at room temperature and indicate fast response thermogelling behavior at the body temperature. |