Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan; Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo, Tokyo 113-8549, Japan.
Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan.
Int J Pharm. 2018 Aug 25;547(1-2):53-60. doi: 10.1016/j.ijpharm.2018.05.063. Epub 2018 May 24.
Melatonin (MLT), a hormone secreted from the pineal gland, is recognized as a potential candidate for stimulation of bone regeneration. However, because of its hydrophobicity, the administration of MLT to stimulate bone regeneration is difficult. In this study, an inclusion complex of MLT with 2-hydroxypropyl β-cyclodextrin (HP-β-CD) was prepared to improve the water solubility, and the osteogenic differentiation ability of the inclusion complex was investigated in MC3T3-E1 cells. The formation of HP-β-CD/MLT inclusion complex was confirmed by H and C nuclear magnetic resonance spectroscopy and wide-angle X-ray diffraction. The water solubility of MLT increased linearly upon addition of HP-β-CD because of the formation of the inclusion complex. Additionally, treatment of the cells with HP-β-CD/MLT inclusion complex showed higher uptake amount of MLT than that treated with free MLT. In addition, treatment of MC3T3-E1 cells with HP-β-CD/MLT inclusion complex increased alkaline phosphatase activity and mineralized matrix deposition, compared to that in free MLT-treated and untreated cells. Furthermore, cells treated with HP-β-CD/MLT inclusion complex exhibited higher expression levels of osteogenic differentiation genes than those in the untreated and free MLT-treated cells. Accordingly, these results suggested that inclusion complexation of MLT with HP-β-CD would be a potential formulation for bone regeneration because of its improved solubility and enhanced osteogenic differentiation efficiency.
褪黑素（MLT）是一种由松果体分泌的激素，被认为是刺激骨再生的潜在候选药物。然而，由于其疏水性，将 MLT 用于刺激骨再生的给药较为困难。在这项研究中，我们制备了 MLT 与 2-羟丙基-β-环糊精（HP-β-CD）的包合物，以提高其水溶性，并在 MC3T3-E1 细胞中研究了包合物的成骨分化能力。通过 1H 和 13C 核磁共振波谱和广角 X 射线衍射证实了 HP-β-CD/MLT 包合物的形成。由于形成了包合物，MLT 的水溶性随 HP-β-CD 的加入而呈线性增加。此外，与游离 MLT 处理的细胞相比，用 HP-β-CD/MLT 包合物处理的细胞摄取 MLT 的量更多。此外，与游离 MLT 处理和未处理的细胞相比，用 HP-β-CD/MLT 包合物处理 MC3T3-E1 细胞可增加碱性磷酸酶活性和矿化基质沉积。此外，与未处理和游离 MLT 处理的细胞相比，用 HP-β-CD/MLT 包合物处理的细胞中骨分化基因的表达水平更高。因此，这些结果表明，由于其提高的水溶性和增强的成骨分化效率，将 MLT 与 HP-β-CD 包合将成为骨再生的一种潜在制剂。
