Nobiletin-loaded micelles reduce ovariectomy-induced bone loss by suppressing osteoclastogenesis
Nobiletin-loaded micelles reduce ovariectomy-induced bone loss by suppressing osteoclastogenesis
复制标题
负载川陈皮素的胶束通过抑制破骨细胞生成减少卵巢切除术引起的骨质流失
DOI：
10.2147/ijn.s213724
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发表时间：
2019-01-01
影响因子：
8
通讯作者：
Su, Jiansheng
中科院分区：
文献类型：
--
作者：
Wang, Yabing;Xie, Jian;Su, Jiansheng
背景诺比莱汀(Nobiletin，NOB)是一种多甲氧基黄酮类化合物，具有抗癌、抗炎等活性，已有报道在抗骨质疏松治疗中发挥作用。然而，由于在高浓度下缺乏亲水性和细胞毒性，以往的研究并没有集中在实际应用上。本研究的目的是开发一种基于NOB利用的治疗骨质疏松症的处方。方法采用透析法制备负载型聚乙二醇聚己内酯嵌段聚己内酯(NOB-PEG-PCL)。在RANKL诱导的细胞模型和去卵巢(OVX)小鼠中观察其对破骨细胞和抗骨质疏松功能的影响。结果动态光散射和透射电子显微镜观察结果表明，所制得的聚乙二醇聚乙二醇酯为圆形，平均直径约为124 nm。包封率为76.34±3.25%，载药量为7.60±0.48%。NOB-PEG-PCL体外释药显示出明显的缓释特征，在pH 7.4PBS中可保持至少48小时。抗破骨细胞实验表明，Nob-PEG-PCL能显著抑制RANKL刺激的抗酒石酸酸性磷酸酶(TRAP)阳性多核细胞的形成。此外，Nob-PEG-PCL对骨髓来源的巨噬细胞(BMMS)没有细胞毒作用。在NOB-fi-PCL存在下，破骨细胞遗传标志物TRAP和组织蛋白酶K的基因表达显著降低。此外，Nob-PEG-PCL通过RANKL诱导的MAPK信号通路抑制BMMS的OC分化。给予NOB-PEG-PCL后，NOB-PEG-PCL可防止去卵巢小鼠的骨丢失并改善骨密度。提示Nob-PEG-PCL在治疗骨质疏松症方面有很大的潜力。结论NOB-PEG-PCL胶束能有效阻止NOB从胶束中快速释放，延长循环时间。Nob-PEG-PCL给药系统有望成为防治骨质疏松症的一种有效途径。
Background Nobiletin (NOB), a polymethoxy flavonoid, possesses anti-cancer and anti-inflammatory activities, has been reported that it played role in anti-osteoporosis treatment. However, previous research did not focus on practical use due to lack of hydrophilicity and cytotoxicity at high concentrations. The aim of this study was to develop a therapeutic formulation for osteoporosis based on the utilization of NOB. Methods In this study, NOB-loaded poly(ethylene glycol)-block-poly(e-caprolactone) (NOB-PEG-PCL) was prepared by dialysis method. The effects on osteoclasts and anti-osteoporosis functions were investigated in a RANKL-induced cell model and ovariectomized (OVX) mice. Results Dynamic light scattering and transmission electron microscopy examination results revealed that the NOB-PEG-PCL had a round shape, with a mean diameter around 124 nm. The encapsulation efficiency and drug loading were 76.34±3.25% and 7.60±0.48%, respectively. The in vitro release of NOB from NOB-PEG-PCL showed a remarkably sustained releasing characteristic and could be retained at least 48 hrs in pH 7.4 PBS. Anti-osteoclasts effects demonstrated that the NOB-PEG-PCL significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells stimulated by RANKL. Furthermore, the NOB-PEG-PCL did not produce cytotoxicity on bone marrow-derived macrophages (BMMs). The mRNA expressions of genetic markers of osteoclasts including TRAP and cathepsin K were significantly decreased in the presence of NOB-PEG-PCL. In addition, the NOB-PEG-PCL inhibited OC differentiation of BMMs through RANKL-induced MAPK signal pathway. After administration of the NOB-PEG-PCL, NOB-PEG-PCL prevented bone loss and improved bone density in OVX mice. These findings suggest that NOB-PEG-PCL might have great potential in the treatment of osteoporosis. Conclusion The results suggested that NOB-PEG-PCL micelles could effectively prevent NOB fast release from micelles and extend circulation time. The NOB-PEG-PCL delivery system may be a promising way to prevent and treat osteoporosis.