Abstract and Introduction
Purpose of Review: Osteoarthritis is associated with severe joint pain, inflammation, and cartilage degeneration. Drugs injected directly into intra-articular joint space clear out rapidly providing only short-term benefit. Their transport into cartilage to reach cellular targets is hindered by the tissue's dense, negatively charged extracellular matrix. This has limited, despite strong preclinical data, the clinical translation of osteoarthritis drugs. Recent work has focused on developing intra-joint and intra-cartilage targeting drug delivery systems (DDS) to enable long-term therapeutic response, which is presented here.
Recent Findings: Synovial joint targeting hybrid systems utilizing combinations of hydrogels, liposomes, and particle-based carriers are in consideration for pain-inflammation relief. Cartilage penetrating DDS target intra-cartilage constituents like aggrecans, collagen II, and chondrocytes such that drugs can reach their cellular and intra-cellular targets, which can enable clinical translation of disease-modifying osteoarthritis drugs including gene therapy.
Summary: Recent years have witnessed significant increase in both fundamental and clinical studies evaluating DDS for osteoarthritis. Steroid encapsulating polymeric microparticles for longer lasting pain relief were recently approved for clinical use. Electrically charged biomaterials for intra-cartilage targeting have shown promising disease-modifying response in preclinical models. Clinical trials evaluating safety of viral vectors are ongoing whose success can pave the way for gene therapy as osteoarthritis treatment.
Musculoskeletal diseases, such as osteoarthritis (OA), rheumatoid arthritis (RA), and low back pain represent the second leading cause of disability globally, imposing a significant physiologic and economic burden on society.[1,2] Such diseases are characterized by tissue degeneration and inflammatory activity that can cause chronic pain and severe joint damage. Specifically, osteoarthritic joints are most affected by articular cartilage degradation and synovial inflammation because of their load-bearing nature, which over time result in loss of joint function and mobility. Overexpression of biological factors, such as inflammatory cytokines [e.g. interleukin (IL)-1, IL-6, tumor necrosis factor α (TNFα)] and degradative enzymes [e.g. matrix metalloproteinase (MMP)13, a disintegrin metalloproteinase with thrombospondin motifs 5 (ADAMTS5)] accelerate progression to osteoarthritis, especially in case of joint injury. The avascular nature of cartilage limits its self-regenerative capacity; timely therapeutic intervention is thus needed to repair the tissue and inhibit further disease progression.
In the early stages of osteoarthritis, patients usually experience mild pain and stiffness after performing routine activities, which is typically treated by either topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics. As the disease progresses to its mid-stage, joint space begins to narrow and shows signs of osteophyte formation and cartilage damage whereas chondrocytes begin to experience a hypertrophic state in an effort to restore tissue damage. At this stage, interventions, such as intra-articular (IA) injections of high-dose corticosteroids or viscosupplements like hyaluronic acid are often recommended for relieving some of the pain and inflammation. However, the aforementioned methods only provide temporary relief and fail to initiate any disease-modifying effect. As the disease progresses to end-stage osteoarthritis, surgical interventions using tissue engineering approaches, microfracture, and joint arthroplasty may be considered but eventually total joint replacement is required. Early-stage intervention with disease-modifying osteoarthritis drugs (DMOADs) has the potential to slow down osteoarthritis progression and restore joint structure and function but no such drugs have translated to clinical practice, in part because of a lack of effective delivery systems that can penetrate through the dense meshwork of cartilage to target chondrocytes and provide controlled low drug doses over a period of time with minimal off target effects.[10,11]
Most small molecule drugs clear out rapidly from the synovial joint (with half-lives of 1–4 h) following their intra-articular administration because of fast exchange of synovial fluid requiring multiple injections of high drug doses that cause toxicity. In order to prolong joint residence times and provide sustained drug release intended for pain and inflammation relief, delivery systems like hydrogels, micelles, polymeric particles are in consideration owing to their large size or viscous nature (Figure 1). These systems can only target the synovium or the synovial fluid and use high drug doses, thus are only useful for providing pain relief. To achieve cartilage protection – that is to inhibit catabolism and stimulate regeneration, DMOADs must penetrate through the full thickness of cartilage and reach chondrocytes and other matrix target sites, a majority of which lie within the tissue deep zone. Therefore, nanosized carriers that can penetrate into the cartilage and bind within to provide sustained drug release are under consideration.
Schematic showing healthy and mid-stage osteoarthritis of the knee. In osteoarthritis, the synovium undergoes hypertrophy with an increase in synovial macrophages and fibroblast-like synoviocytes (FLS) accompanied by an outgrowth of blood and lymphatic vessels (angiogenesis), which contribute towards significant pain and inflammation. The environment of the synovial fluid becomes acidic and infiltrated by macrophages and cartilage degradation products. Cartilage and its matrix components (aggrecan and collagen II) begin to degrade, while chondrocytes enter a hypertrophic and apoptotic state. To prolong drug residence and provide long-term osteoarthritis therapy, drugs can be administered via intra-articular injection and modified in the form of drug delivery systems (DDS) to specifically target intra-joint components as shown in the synovium (top), synovial fluid (middle) and cartilage (bottom) insets. DDS can be designed for targeting the synovium (FLS, macrophages, microvasculature endothelium), prolonging synovial fluid residence or targeting the cartilage (aggrecan, collagen II, chondrocytes).
This review presents recent basic science and clinical developments in nanoparticle-based delivery systems for prolonging drug residence time within the joint space for pain-inflammation relief and targeting specific intra-cartilage components to restore joint structure and function for osteoarthritis therapy.
Curr Opin Rheumatol. 2021;33(1):94-109. © 2021 Lippincott Williams & Wilkins