Hyaluronic acid-Gd2O3@MSN, nanoparticle probe of MRI for targeted identification of atherosclerosis
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摘要:
目的 探究合成透明质酸（HA）修饰的介孔二氧化硅MR纳米探针HA-Gd2O3@MSN的性能以及成像特点，为动脉粥样硬化疾病提供新的检查技术手段。 方法 以CTAB为模板，正硅酸四乙酯和十六烷基三甲基溴化铵在碱性条件下制备成MSN，滴加GdCl36H2O变成Gd2O3@MSN，在600℃下煅烧2 h去除十六烷基三甲基溴化铵模板，最后制备成分子探针Gd2O3@MSN，再通过酰胺缩合制备成HA-Gd2O3@MSN。运用透射电镜观察其形貌特征，动态光散射法检测其水合粒径和Zeta电位。运用3.0T MR观察其成像效果，并利用ICP-MS数据分析探针的弛豫率。 结果 合成的探针水动力尺寸为223.5±10.5 nm，Zeta电位为-13.04 mV，弛豫率为11.023 mmol· L-1· s-1)；随着分子探针浓度逐渐升高，T1信号也随之增强。体外细胞试验研究显示透明质酸-Gd2O3@MSN以HA依赖的方式靶向巨噬细胞表面受体CD44。在细胞毒性试验中发现HA包被的纳米探针毒性较小。 结论 HA修饰的介孔二氧化硅MR纳米探针HA-Gd2O3@MSN T1弛豫率高，细胞毒性小，靶向效果好，具有较好的MR成像增强效果，为进一步早期识别动脉粥样硬化斑块奠定基础。 Abstract:Objective To synthesize a hyaluronic acid (HA)-modified mesoporous silica nanoprobe (MSN) for MRI, which is HAGd2O3@MSN. Its performance and imaging characteristics were preliminarily studied, so as to provide a new technical tool for the diagnosis of atherosclerosis. Methods The cetyltrimethylammonium bromide (CTAB) was utilized as the template, and tetraethyl orthosilicate and CTAB were formulated into MSN under alkaline conditions. GdCl36H2O was incrementally introduced to produce the Gd2O3@MSN. Subsequently, the CTAB template was eliminated through calcination at 600 ℃ for 2 h, which led to the formation of the molecular probe Gd2O3@MSN. The HA-Gd2O3@MSN was then prepared through amide condensation. The morphology of HA-Gd2O3@MSN was examined by transmission electron microscopy, while its hydrodynamic diameter and zeta potential were measured by dynamic light scattering technique. The imaging results were observed by a 3.0T MR scanner and the relaxation rate of the molecular probe Gd2O3@MSN was analyzed using data from the inductively coupled plasma mass spectrometry testing. Results The hydrodynamic diameter of the synthesized probe HA-Gd2O3@MSN was 223.5±10.5 nm, the zeta potential of HA-Gd2O3@MSN was -13.04 mV, with its relaxation rate being 11.023 mmol· L-1· s-1. As the concentration of the molecular probe increased incrementally, the T1 signal was correspondingly enhanced. Through in vitro cellular studies, we demonstrated that HA-Gd2O3@MSN was capable to bind and target the CD44 receptors on the surface of macrophages in a HA-dependent manner. Furthermore, the HA-coated nanoprobes were found to be less toxic in cytotoxicity assays. Conclusion The nanoprobe HA-Gd2O3@MSN, with its high T1 relaxation rate, low cytotoxicity, excellent targeting capacity and good MR imaging enhancement effects, it lays the foundation for identification of atherosclerotic plaques at earlier stages. -
Key words:
- hyaluronic acid /
- mesoporous silica /
- MR molecular probes /
- nanoparticle probe
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图 2 纳米探针的实物照片及透射电子显微镜图像
Figure 2. Physical photograph of the nanoprobe and transmission electron microscope imag.
A: HA-Gd2O3@MSN; B: TEM image of HA-Gd2O3@MSN.
图 3 纳米探针的水合粒径及Zeta表面电位
Figure 3. Hydrated particle size and Zeta surface potential of nanoprobes.
A: Hydration particle size of HA-Gd2O3@MSN; B: Zeta potential of HA-Gd2O3@MSN.
图 4 纳米探针的高角环形暗场扫描透射及元素mapping分析
Figure 4. High-angle annular dark-field scanning transmission and elemental mapping analysis of nanoprobes.
A: STEM-HAADF analysis of HA-Gd2O3@MSN; B: Mapping analysis of element Gd; C: Mapping analysis of element Si; D: Mapping analysis of element O; E: Merged image of mapping analysis of elements Gd, Si and O.
图 5 纳米探针的氮气吸附等温线和孔径分布图
Figure 5. Nitrogen adsorption isotherm and pore size distribution of nanoprobes.
A: BET nitrogen adsorption isotherm; B: Distribution of BJH pore diameters.
图 6 纳米探针的磁共振成像性能
Figure 6. Magnetic resonance imaging properties of nanoprobes.
A: Magnetic resonance T1-weighted imaging results. The intensities of MR images increase with the incremental increase of the concentration of Gd3+; B: T1 relaxation rate (r1) of nanoprobes.
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