Nanocomposite hydrogel to deliver the immunomodulator lenalidomide and anti-inflammatory hesperidin locally to joints affected by rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disease characterized by inflammatory cell infiltration, neo-vascularization in the synovial tissue, and progressive joint destruction. The immunomodulatory drug lenalidomide and anti-inflammatory anti-oxidant hesperidin show therapeutic potential against the disease as two complementary drugs, but they also show poor oral bioavailability and solubility as well as a short time in circulation. To overcome these disadvantages, the two drugs were loaded into polymeric micelles in their native forms and also, they were conjugated to polyethylene glycol to create acid-activated prodrugs. Lastly, the micelles alone or with the prodrugs were formulated into an injectable hydrogel. Of all formulations, the hydrogel containing micelles and prodrugs led to the greatest drug uptake by Raw264.7 macrophages in culture and inhibition of angiogenesis in a chick chorioallantoic membrane assay. In rats with collagen-induced arthritis, the hydrogel released the two drugs in a sustained manner, preferentially in joints with acidic pH. They dampened inflammatory responses, mitigating bone injury. This biocompatible, pH-responsive formulation based on two complementary drugs may provide a new strategy for treating rheumatoid arthritis.