Development of Dual-Action Nanoparticle-Loaded Microparticles for Osteoarthritis Treatment

ABSTRACT Osteoarthritis (OA) is a painful and debilitating joint disease and a leading cause of disability in the US. It is preliminarily characterized by cartilage degeneration. Previous drug discovery efforts predominantly focused on monotherapy (the use of a single therapeutic drug) targeting a single joint tissue (predominantly cartilage). However, rapid clearance of these potential drugs from the joint space requires repeated administrations and high doses, which increase the risk of treatment-related toxicity, escalate healthcare expenditures, and diminish patient quality of life. To date, there are no disease-modifying drugs available to halt disease progression or reverse its course. In healthy joints, articular cartilage is maintained through a fine balance between anabolic and catabolic activities of chondrocytes. In OA joints, this balance is tipped toward increased catabolic activity and diminished anabolic activity, leading to cell death and matrix degradation. We recently developed two innovative nanoparticle (NP)-based therapeutics, transforming growth factor alpha ( TGFα) -conjugated polymeric micellar nanoparticles (TGFα-NPs) and superoxide dismutase (SOD)-loaded porous polymersome nanoparticles (SOD-NPs), with independent intervention mechanisms for OA treatment. Our preliminary in vitro and in vivo data demonstrated that TGFα-NPs stimulate the anabolic activity via enhancing epidermal growth factor receptor (EGFR) signaling in chondroprogenitors, and SOD-NPs block the inflammation-mediated catabolic activity via reducing oxidative stress in the synovium. Despite encouraging and proof-of-principle results in a mouse model of OA induced by destabilization of the medial meniscus (DMM), neither of them restored the joints to a fully healthy state, and the injection frequency used in the pilot studies (once every 2-3 weeks) falls short of clinical practicality. We hypothesize that a combination treatment, using an advanced drug delivery system that targets distinct joint tissues to simultaneously enhance anabolic activity and reduce catabolic activity, can more effectively restore cartilage integrity and achieve better therapeutic outcomes than single treatments. The overall goal of this proposal is to engineer and optimize dual-action, nanoparticle-loaded microparticles (NMPs) for OA treatment with clinically relevant injection frequencies, using both injury- and age-induced animal OA models. The specific aims for the proposal are 1) Synthesize and characterize physical-chemical properties of NMPs; 2) Evaluate the efficacy of combination therapy in a mouse OA injury model; and 3) Evaluate the efficacy of MRI- guided combination therapy in a spontaneous OA model. In the short-term, this proposal will demonstrate for the first time that a two-pronged approach using advanced drug delivery system is feasible for OA treatment. In the long-term, data from this proposal will pave the foundation for future clinical trials. Thus, the success of this project will greatly benefit patients with disabilities caused by OA as well as other forms of degenerative joint disease.