Department of Materials Science and Bioengineering, Graduate School of Engineering, Nagaoka University of Technology, Kamitomioka 1603-1, Nagaoka, Niigata 940-2188, Japan.
Research Fellow of the Japan Society for the Promotion of Science (DC), 5-3-1 Koji-machi, Chiyoda-ku, Tokyo 102-0083, Japan.
ACS Biomater Sci Eng. 2024 Oct 14;10(10):6615-6624. doi: 10.1021/acsbiomaterials.4c01146. Epub 2024 Sep 4.
We successfully synthesized folic acid (FA) immobilized hydroxyapatite (HA) nanoparticles without using a mediative reagent (e.g., silane coupling agent), and the immobilization states were evaluated and discussed. The HA nanoparticles with higher biocompatibility have two different planes, namely, - and -planes. These plane surfaces are rich in phosphate groups (P-site) and Ca ions (C-site), respectively. We suggested that during the synthesis of the HA nanoparticles, the P-site substitution and C-site coordination with the addition of organic molecules containing -COO ions can occur. Thus, it is possible to simultaneously immobilize two molecules to one HA nanoparticle. In this study, we successfully synthesized FA-immobilized HA nanoparticles by P-site substitution and C-site coordination reactions, which were named as substitution type and coordination type. In the substitution type, when FA was reacted with HA during the nucleation stage, the PO ions of HA decreased as the FA ratio of coverage surface area increased, and the crystalline phase was changed significantly from the Ca deficient HA to the carbonated HA phase. Accordingly, it was indicated that FA was immobilized on HA by the P-site substitution. In the coordination type, since FA was reacted with HA after the completion of crystal growth, the crystalline phase was changed slightly as the FA ratio of coverage surface area increased, indicating that FA was immobilized on HA by the C-site coordination. From the above, we controlled the FA immobilization states on the HA nanoparticles by the P-site substitution and the C-site coordination through the FA addition timing in the synthesis. Since the -COO ions in FA could be selectively substituted with the P-site in HA, it is possible to directly coordinate the foreign organic molecules to the Ca ions in HA. Therefore, the immobilization technique of this study is expected to achieve two different drug molecules with diagnosis and therapy functions (i.e., theranostics) on one nanoparticle.
我们成功地合成了叶酸（FA）固定化羟基磷灰石（HA）纳米粒子，而无需使用介导试剂（例如硅烷偶联剂），并对固定化状态进行了评估和讨论。具有更高生物相容性的 HA 纳米粒子具有两种不同的平面，即-和-平面。这些平面表面分别富含磷酸基团（P 位）和 Ca 离子（C 位）。我们提出，在 HA 纳米粒子的合成过程中，可能会发生 P 位取代和 C 位与含有-COO 离子的有机分子的配位。因此，有可能将两个分子同时固定到一个 HA 纳米粒子上。在这项研究中，我们通过 P 位取代和 C 位配位反应成功合成了 FA 固定化 HA 纳米粒子，分别命名为取代型和配位型。在取代型中，当 FA 与 HA 在成核阶段反应时，随着 FA 覆盖表面积比的增加，HA 的 PO 离子减少，晶体相从缺 Ca 的 HA 明显转变为碳酸化 HA 相。因此，表明 FA 通过 P 位取代固定在 HA 上。在配位型中，由于 FA 在晶体生长完成后与 HA 反应，随着 FA 覆盖表面积比的增加，晶体相略有变化，表明 FA 通过 C 位配位固定在 HA 上。综上所述，我们通过在合成中添加 FA 的时间控制了 FA 在 HA 纳米粒子上的固定状态，通过 P 位取代和 C 位配位。由于 FA 中的-COO 离子可以被 HA 中的 P 位选择性取代，因此可以将外来有机分子直接配位到 HA 中的 Ca 离子上。因此，本研究的固定化技术有望在一个纳米粒子上实现具有诊断和治疗功能（即治疗学）的两种不同药物分子。
