Pioglitazone-Loaded Cartilage-Targeted Nanomicelles (Pio@C-HA-DOs) for Osteoarthritis Treatment

BACKGROUND: Hyaluronic acid (HA) is a popular biological material for osteoarthritis (OA) treatment. Pioglitazone, a PPAR-γ agonist, has been found to inhibit OA, but its use is limited because achieving the desired local drug concentration after administration is challenging. PURPOSE: Herein, we constructed HA-based cartilage-targeted nanomicelles (C-HA-DOs) to deliver pioglitazone in a sustained manner and evaluated their efficacy in vitro and in vivo. METHODS: C-HA-DOs were chemically synthesized with HA and the WYRGRL peptide and dodecylamine. The products were characterized by FT-IR, (1)H NMR, zeta potential and TEM. The drug loading rate and cumulative, sustained drug release from Pio@C-HA-DOs were determined, and their biocompatibility and effect on oxidative stress in chondrocytes were evaluated. The uptake of C-HA-DOs by chondrocytes and their effect on OA-related genes were examined in vitro. The nanomicelle distribution in the joint cavity was observed by in vivo small animal fluorescence imaging (IVIS). The therapeutic effects of C-HA-DOs and Pio@C-HA-DOs in OA rats were analysed histologically. RESULTS: The C-HA-DOs had a particle size of 198.4±2.431 nm, a surface charge of −8.290±0.308 mV, and a critical micelle concentration of 25.66 mg/Land were stable in solution. The cumulative drug release from the Pio@C-HA-DOs was approximately 40% at pH 7.4 over 24 hours and approximately 50% at pH 6.4 over 4 hours. Chondrocytes rapidly take up C-HA-DOs, and the uptake efficiency is higher under oxidative stress. In chondrocytes, C-HA-DOs, and Pio@C-HA-DOs inhibited H(2)O(2)-induced death, reduced intracellular ROS levels, and restored the mitochondrial membrane potential. The IVIS images confirmed that the micelles target cartilage. Pio@C-HA-DOs reduced the degradation of collagen II and proteoglycans by inhibiting the expression of MMP and ADAMTS, ultimately delaying OA progression in vitro and in vivo. CONCLUSION: Herein, C-HA-DOs provided targeted drug delivery to articular cartilage and improved the role of pioglitazone in the treatment of OA.