Guizhou Medical University, Guiyang, 550025, People's Republic of China.
Department of Orthopaedics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, People's Republic of China.
Int J Nanomedicine. 2023 Oct 18;18:5871-5890. doi: 10.2147/IJN.S428938. eCollection 2023.
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.
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.
C-HA-DOs were chemically synthesized with HA and the WYRGRL peptide and dodecylamine. The products were characterized by FT-IR, 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.
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 HO-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.
Herein, C-HA-DOs provided targeted drug delivery to articular cartilage and improved the role of pioglitazone in the treatment of OA.
透明质酸（HA）是治疗骨关节炎（OA）的常用生物材料。过氧化物酶体增殖物激活受体-γ（PPAR-γ）激动剂吡格列酮已被发现可抑制 OA，但由于给药后难以达到所需的局部药物浓度，其应用受到限制。
本研究构建了基于 HA 的软骨靶向纳米胶束（C-HA-DO），以持续递药，并评估其在体外和体内的疗效。
通过 HA 与 WYRGRL 肽和十二胺化学合成 C-HA-DO。采用傅里叶变换红外光谱（FT-IR）、核磁共振氢谱（H NMR）、Zeta 电位和透射电子显微镜（TEM）对产物进行表征。测定 Pio@C-HA-DO 的载药率和累积、持续药物释放，并评估其生物相容性和对软骨细胞氧化应激的影响。检测 C-HA-DO 被软骨细胞摄取及其对 OA 相关基因的影响。通过小动物体内荧光成像（IVIS）观察纳米胶束在关节腔中的分布。分析 C-HA-DO 和 Pio@C-HA-DO 治疗 OA 大鼠的组织学疗效。
C-HA-DO 的粒径为 198.4±2.431nm，表面电荷为-8.290±0.308mV，临界胶束浓度为 25.66mg/L，在溶液中稳定。Pio@C-HA-DO 在 pH7.4 下 24 小时累积药物释放约 40%，在 pH6.4 下 4 小时累积药物释放约 50%。软骨细胞能快速摄取 C-HA-DO，氧化应激下摄取效率更高。在软骨细胞中，C-HA-DO 和 Pio@C-HA-DO 抑制 HO 诱导的细胞死亡，降低细胞内 ROS 水平，恢复线粒体膜电位。IVIS 图像证实了胶束对软骨的靶向性。Pio@C-HA-DO 通过抑制 MMP 和 ADAMTS 的表达减少了胶原 II 和糖胺聚糖的降解，最终在体外和体内延缓了 OA 的进展。
本研究构建的 C-HA-DO 为关节软骨提供了靶向药物递送，提高了吡格列酮治疗 OA 的作用。
