Inflammation plays an essential role in arthritis development and progression. Despite the advances in the pharmaceutical field, current treatments still present low efficacy and severe side effects. Considering the high activity of the glutathione reductase (GR) enzyme in inflamed joints, a distinctive drug delivery system sensitive to the GR enzyme was designed for efficient drug delivery on arthritic diseases. A linear amphiphilic polymer composed of methoxypolyethylene glycol amine-glutathione-palmitic acid (mPEG-GSH<sub><i>n</i></sub>-PA) was synthesized and the intermolecular oxidation of the thiol groups from GSHs retain the drug inside the resulting micelles. Stable polymeric micelles of 100 nm of size presented a loading capacity of dexamethasone (Dex) up to 65%. Although in physiological conditions the Dex release presented slow and sustained kinetics, in the presence of the GR enzyme, there was a burst release (stimuli-responsive properties). Biological assays demonstrated their cytocompatibility in contact with human articular chondrocytes, macrophages, and endothelial cells as well as their hemocompatibility. Importantly, in an in vitro model of inflammation, the polymeric micelles promoted a controlled drug release in the presence of GR, exhibiting a higher efficacy than the free Dex while reducing the negative effects of the drug into normal cells. In conclusion, this formulation is a promising approach to treat arthritic diseases and other inflammatory conditions.
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