Drug in Therapeutic Polymer: Sinomenine-Loaded Oxidation-Responsive Polymeric Nanoparticles for Rheumatoid Arthritis Treatment

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that frequently involves cartilage damage and the destruction of the bone structure, ultimately resulting in disability and long-term pain. It is clear that overexpression of reactive oxygen species (ROS) and the complex inflammatory microenvironment are the main causes of RA pathogenesis; thereby, the efficacy of any single-drug treatment is limited. Herein, we formulated a therapeutic hyaluronic acid derivative (PAM-HA) with adsorption capacity to the subchondral bone, a long retention time within inflamed joints, and ROSscavenging capacity, which was used as a drug carrier for realizing the controlled release of sinomenine (Sin) within arthritic joints. This "drug in therapeutic polymer" design strategy was aimed at realizing antioxidant and anti-inflammatory combination therapy for RA. In vivo experiments suggest that PAM-HA@Sin NPs can be retained in the inflamed joints of rats for a long time compared with commercially available free Sin injections. As expected, therapeutic PAM-HA polymeric carriers can increase joint lubrication and reduce oxidative stress, while the released Sin induces downregulation of proinflammatory factors (TNF-α and IL-1β) and upregulation of anti-inflammatory factors (Arg-1 and IL-10) via the NF-κB pathway. In summary, a ROS-scavenging hyaluronic acid (HA) derivative was developed as the nanocarrier for Sin delivery to simultaneously remodel the oxidative/inflammatory microenvironment in RA, which opens up new horizons for the development of therapeutic polymers and the combined therapeutic strategies.

Precise modulation and use of reactive oxygen species for immunotherapy

“…For example, Shang et al . ( 97 ) developed a biomimetic nanocomplex encapsulating TNF-α siRNA and catalase coated with the macrophage membrane. After systemic administration, the nanocomplex exhibited long circulation time and effective accumulation in joints.…”

“…Catalase in the nanocomplex catalyzed the decomposition of H 2 O 2 into O 2 in the oxidative microenvironment of the inflamed joints. The inner positively charged nanocomplex core was exposed simultaneously to facilitate internalization into synovial macrophages, leading to efficient TNF-α silencing ( 97 ). All the studies above indicate that modulating ROS is a promising strategy for the treatment of RA.…”