Recent advances in targeted drug delivery for treatment of osteoarthritis

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02790723 NCT04119687 NCT03203330.

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

FIGURE 1.

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).

FIGURE 2.

(a, I) Multiarm Avidin conjugated to Dex (mAv-Dex) via controlled release ester linkers. (ii) Confocal imaging showing full thickness penetration from superficial zone (SZ) to deep zone (DZ) of mAv-Dex in healthy and GAG-depleted cartilage explants within 24 h. (iii) A single low dose of mAv-Dex suppressed IL-1-induced GAG loss significantly greater than free Dex at 16 days as shown by Safranin-O/fast green staining of cartilage explants. Adapted with permission from reference [40▪▪]. (b, I) X-ray crystallography showing structure ribbon (top) and molecular surface representations (bottom) of CDP-11R (α-helices: red; β-strands: yellow; random coil: green; disulfide bonds: gold). Positive (blue) and negative (red) electrostatic potentials are also shown. (ii) Mouse knee joint stained with Toluidine Blue (left). Cy5.5 and DAPI channel fluorescent images of CDP-11R-Cy5.5 (red) localized to articular cartilage following intravenous injection. (iii) Suppression of CIA rat ankle joint swelling following intravenous injection of CDP-11R–DMA–TCA on treatment day 4. Adapted with permission from reference [44▪▪]. (c, I) IVIS imaging showing collagen II-binding Avimer (CII-M26) being retained within rat knee joint for 28 days after intra-articular injection compared with negative control (NC), which was cleared within 1 day. Region of interest of each image is plotted as fluorescence vs. time. DAPI (nucleus: blue) and AF657 staining (Avimer: red) of articular cartilage confirms intra-tissue presence of CII-M26 for 28 days through confocal imaging. (ii) IL-1Ra-M26 [given either at the same time as (day 0) or 7 days prior to IL-1β intra-articular injection) suppresses IL-6 expression in synovial fluid of rat knees at 4 h following treatment. ***P 0.001 or less. Adapted with permission from from reference [57▪▪].