Prodrug Nanomedicine for Synovium Targeted Therapy of Inflammatory Arthritis: Insights from Animal Model and Human Synovial Joint Fluid

Abstract

Many patients cannot tolerate low‐dose weekly methotrexate (MTX) therapy for inflammatory arthritis treatment due to life‐threatening toxicity. Although biologics offer a target‐specific therapy, it raises the risk of serious infections and even cancer due to immune system suppression. We introduce an anti‐inflammatory arthritis MTX ester prodrug using a long‐circulating biocompatible polymeric macromolecule: folic acid (FA) functionalized hyperbranched polyglycerol (HPG). In vitro the drug MTX is incrementally released through pH and enzymatic degradation over 2 weeks. The role of matrix metalloproteinases (MMPs) in site‐specific prodrug activation was verified using synovial fluid (SF) of 26 rheumatology patients and 4 healthy controls. Elevated levels of specific MMPs‐markers of joint inflammation‐positively correlated with enhanced prodrug release explained by acid‐catalyzed hydrolysis of esters by proteases. Intravenously administered 111In‐radiolabeled prodrug confirmed by SPECT/CT imaging that it accumulated preferentially in inflamed joints while reducing off‐target side‐effects in a mouse model of rheumatoid arthritis (RA). Added FA as a targeting vector prolonged prodrug action; prodrug with 4x less MTX applied every 2 weeks was as effective as weekly MTX therapy. The preclinical results suggest a prodrug‐based strategy for the treatment of inflammatory joint diseases, with potential for other chronic inflammatory diseases and cancer.