载吡格列酮的靶向软骨纳米胶束（Pio@C-HA-DOs）治疗骨关节炎。
Pioglitazone-Loaded Cartilage-Targeted Nanomicelles (Pio@C-HA-DOs) for Osteoarthritis Treatment.
机构信息
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.
出版信息
Int J Nanomedicine. 2023 Oct 18;18:5871-5890. doi: 10.2147/IJN.S428938. eCollection 2023.
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, 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 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.
CONCLUSION
Herein, C-HA-DOs provided targeted drug delivery to articular cartilage and improved the role of pioglitazone in the treatment of OA.
背景
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。
目的
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。
方法
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。
结果
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。
结论
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。
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