Innovative approach for the treatment and the diagnosis of rheumatoid arthritis exploiting polymeric biodegradable nanoparticles targeting synovial endothelium

Rheumatoid arthritis (RA) is an autoimmune disease affecting joints due to the persistent inflammation of the synovial tissue. It affects 1% of the worldwide population with high socioeconomic costs. Patients usually require lifetime treatments in order to prevent late stage of the disease, which leads to a condition of disability and pain. Despite the introduction of biological drugs, Methotrexate (MTX) is still the gold standard. However, it shows some weakness such as inefficacy or adverse events after long term usage. For this reason, there is the need to develop drugs with an improved safety profile and higher therapeutic efficacy. Moreover, it is of primary importance to develop diagnostics with enhanced sensitivity and tissue specificity. In order to meet these needs, the purpose of this work is to develop a nanotechnological agent capable to delivery its content, such as drugs or diagnostic tracers, specifically into pathological joints, avoiding healthy tissues. These aims have been achieved exploiting peculiar features of biodegradable nanoparticles (BNPs), such as improved pharmacokinetic and bioavailability, associated to a peptide specific for the inflamed synovia. Recently, the heterogeneity of the molecules present in the endothelium has allowed to develop peptides capable to target vessels of specific tissues. In this project, a cyclic peptide able to target the microvasculature of the inflamed synovia has been exploited to drive BNPs only into inflamed joints. BNPs have been characterized for their physicochemical features, polymers’ toxicity and drug release. Targeted polymeric nanoparticles (tBNPs) demonstrated, both in vitro and in vivo, to preferentially bind inflamed synovial tissue, and their accumulation depends from the degree of inflammation. Targeted BNPs loaded with MTX showed higher efficacy compared to free MTX in two different animal models of RA. In addition, reduced dose of tBNPs-MTX demonstrated to maintain its efficacy, showing fewer side effects compared with systemic administration of free MTX. This new therapeutic approach provided a new mechanism of action from approved therapy and suggest potential application in non-responding patients. All these evidences highlight the potential use of tBNPs as biocompatible and adaptable tool for the diagnosis and the treatment of RA showing important efficacy, reduced side effects and with the potential to enhance the sensitivity of several imaging technologies.