Fe_3O_4-CMC-5FU纳米载体药物的制备及其对胃癌细胞抗肿瘤作用的电镜研究
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摘要
目的：以多面体磁性Fe3O4为纳米颗粒核心,构建载有5-氟尿嘧啶的纳米药物；体外干预胃癌SGC-7901细胞,联合分子生物学方法和电子显微镜技术对纳米药物抗肿瘤效果进行观察,从而为纳米药物的开发、应用提供理论依据。
方法：利用高温液相法合成形状、大小可控的Fe3O4纳米颗粒,羧甲基壳聚糖(CMC)对Fe304纳米颗粒进行表面包裹、改善生物相容性,进一步结合5-Fu；外加使用外加磁场将Fe3O4-CMC-5-FU纳米药物分离。VSM进行纳米药物磁性检测。采用红外光谱对Fe3O4-CMC纳米颗粒和Fe3O4-CMC-5-FU纳米药物中的化学键进行分析。用CCK-8(cell counting kit-8)试剂盒检测5-Fu和Fe3O4-CMC-5FU对胃癌细胞增殖抑制率的变化。Annexin-V-FITC/PI双染法检测不同浓度药物诱导胃癌细胞凋亡率的变化。采用装备有EDX能谱分析仪和高角暗场像的场发射高分辨率透射电镜对单个的Fe3O4, Fe3O4-CMC, Fe3O4-CMC-5-FU纳米药物,SGC-7901细胞(分别经5FU, Fe3O4纳米颗粒和Fe3O4-CMC-5-FU纳米药物干预后)在纳米／原子尺度进行形态、晶体结构、化学表征的检测。综合超微结构观察的结果,可以对纳米药物抗肿瘤有效性进行推断,并且绘制相应的模拟图示。
结果：合成直径10nm的多边形Fe304纳米颗粒用于本研究；HAADF-STEM和TEM观察合成的Fe3O4NPs为单体均匀分散。Fe3O4-CMC纳米颗粒平均直径为12nm, Fe3O4-CMC-5FU纳米药物直径为13nm,均匀分散,基本接近理想化的纳米药物直径。Fe3O4-CMC-5FU较单纯5-Fu抑制SGC-7901细胞的增殖的作用增强,呈时间-剂量依赖性。Fe3O4-CMC-5FU纳米药物诱导细胞凋亡、坏死的能力较单纯5-Fu增强,同样呈时间-剂量依赖性。研究中发现,Fe3O4-CMC-5FU干预胃癌细胞24小时后,仍有大量的5FU同Fe3O4-CMC粘附,提示5FU经过一个持续、缓慢的释放过程,从而在细胞质局部形成高浓度。通过透射电镜对加入Fe3O4-CMC-5FU (50μg/ml)纳米药物进行培养的218个胃癌细胞观察发现,其中161个细胞由于纳米药物导致线粒体死亡从而诱导细胞凋亡,占总数的74%。EDX元素分布显示了属于Fe3O4NPS和5FU药物的五种元素C、N、O、 F、Fe在细胞内的分布。
结论：Fe3O4-CMC-5FU纳米药物对胃癌细胞抗肿瘤效果明显增强。抗肿瘤效果的增强归结于细胞质内局部的纳米药物的高浓度。线粒体途径不仅是纳米药物抗肿瘤活性增强的主要原因,而且也是纳米药物抗肿瘤的新证据。
Objective:The present research was to conduct5-fluorouracil loaded nanodrugs which used polyhedral Fe3O4nanoparticle as core treated gastric cancer cells. Electron-microscopy techniques was used in vitro experiment in order to explore the antitumor mechanism of nano-dugs and provide theory basis for development and application of nanodrug.
METHODS:Size-and shape-controlled Fe3O4nanoparticles were prepared by using a high temperature liquid phase method. Fe3O4nanoparticles was coated by CMC in order to improve biocompatibility, further immobilize5-Fu onto the CMC coated Fe3O4-CMC NPs. The Fe3O4-CMC-5FU nanomedicine was then collected from the reaction mixture by using a magnet. The chemical bonding of the conjugated Fe3O4-CMC and Fe3O4-CMC-5-FU nanomedicine were investigated by an infrared spectroscopy (IR). A cell counting kit-8(CCK-8) was used to determine the inhibition of drugs (Fe3O4NPs,5FU and Fe3O4-CMC-5FU) against SGC-7901cells. Annexin-V-FITC/PI double staining assay was performed to detect apoptosis of SGC-7901cells. The morphology, crystal structure and chemical characterization of individual Fe3O4, Fe3O4-CMC, Fe3O4-CMC-5-FU, SGC-7901cells incubated with5FU, Fe3O4NPs and Fe3O4-CMC-5-FU nanomedicine were analyzed at the nano/atomic-scale using field emission high-resolution transmission electron microscopywhich is equipped with energy-dispersive x-ray analysis (EDAX), high angle annular dark and scanning transmission electron microscope (HAADF-STEM). The results of ultra-structure changes were Composited to make a deduce which leaded us to draw a analogue map which displayed antitumor effectiveness by nanomedicines.
Results:Fe3O4NPs with10nm diameter and polyhedral shape were therefore chosen in this study.Both HAADF-STEM and TEM images reveal that individual Fe3O4NPs are fairly uniform and monodispersed. The Fe3O4-CMC hybrids had a mean size of approximately12nm. The average diameter of the Fe3O4-CMC-5FU nanomedicine is about13nm, nearly an ideal diameter of nanomedicines. The data demonstrate that the Fe3O4-CMC-5FU nanomedicine has a much better effect in inhibiting SGC-7901proliferation at all tested concentrations than the traditional pure5FU. The data demonstrate that the Fe3O4-CMC-5FU nanomedicine has a much better effect in inhibiting SGC-7901proliferation at all tested concentrations than the traditional pure5FU. Apoptosis rate detected by flow cytometry reveals that the Fe3O4-CMC-5FU nanomedicine promotes the apoptosis and necrosis of SGC-7901cells much better than the traditional pure5FU. The intensity of apotosis also indicates that the apotosis-inducing effect of the Fe3O4-CMC-5FU nanomedicine on SGC-7901cells is also dose-and time-dependent. We examined218SGC-7901cells incubated with50μg-ml-1Fe3O4-CMC-5FU nanomedicine under transmission electron microscope and found that161cells promoted apotosis due to the mitochondrial death, taking up about74%of the apotosis cases. It is clearly evident that a large amount of5FU was still retained to conjugate with Fe Fe3O4-CMC after24h incubation and5FU should be slowly and continuously released from the surface of the Fe Fe3O4-CMC-5FU nanomedicine agglomerates, thus forming a localized high concentration of5FU in the cytoplasm of SGC-7901cancer cells may induce an acute injury of mitochondrial membrane structure including mitochondria death.
Conclusions:Fe3O4-CMC-5FU nanomedicine apparently enhances antitumor effect on gastric cancer cells. The enhanced therapeutic efficacy derives from the localized high-concentration of the magnetic nanomedicine in the cytoplasm. Mitochondrial pathway is not only the main reason which enhanced antitumor activity of nanomedicine, but also the new evidence for nanomedicine treating tumour.
方法：利用高温液相法合成形状、大小可控的Fe3O4纳米颗粒,羧甲基壳聚糖(CMC)对Fe304纳米颗粒进行表面包裹、改善生物相容性,进一步结合5-Fu；外加使用外加磁场将Fe3O4-CMC-5-FU纳米药物分离。VSM进行纳米药物磁性检测。采用红外光谱对Fe3O4-CMC纳米颗粒和Fe3O4-CMC-5-FU纳米药物中的化学键进行分析。用CCK-8(cell counting kit-8)试剂盒检测5-Fu和Fe3O4-CMC-5FU对胃癌细胞增殖抑制率的变化。Annexin-V-FITC/PI双染法检测不同浓度药物诱导胃癌细胞凋亡率的变化。采用装备有EDX能谱分析仪和高角暗场像的场发射高分辨率透射电镜对单个的Fe3O4, Fe3O4-CMC, Fe3O4-CMC-5-FU纳米药物,SGC-7901细胞(分别经5FU, Fe3O4纳米颗粒和Fe3O4-CMC-5-FU纳米药物干预后)在纳米／原子尺度进行形态、晶体结构、化学表征的检测。综合超微结构观察的结果,可以对纳米药物抗肿瘤有效性进行推断,并且绘制相应的模拟图示。
结果：合成直径10nm的多边形Fe304纳米颗粒用于本研究；HAADF-STEM和TEM观察合成的Fe3O4NPs为单体均匀分散。Fe3O4-CMC纳米颗粒平均直径为12nm, Fe3O4-CMC-5FU纳米药物直径为13nm,均匀分散,基本接近理想化的纳米药物直径。Fe3O4-CMC-5FU较单纯5-Fu抑制SGC-7901细胞的增殖的作用增强,呈时间-剂量依赖性。Fe3O4-CMC-5FU纳米药物诱导细胞凋亡、坏死的能力较单纯5-Fu增强,同样呈时间-剂量依赖性。研究中发现,Fe3O4-CMC-5FU干预胃癌细胞24小时后,仍有大量的5FU同Fe3O4-CMC粘附,提示5FU经过一个持续、缓慢的释放过程,从而在细胞质局部形成高浓度。通过透射电镜对加入Fe3O4-CMC-5FU (50μg/ml)纳米药物进行培养的218个胃癌细胞观察发现,其中161个细胞由于纳米药物导致线粒体死亡从而诱导细胞凋亡,占总数的74%。EDX元素分布显示了属于Fe3O4NPS和5FU药物的五种元素C、N、O、 F、Fe在细胞内的分布。
结论：Fe3O4-CMC-5FU纳米药物对胃癌细胞抗肿瘤效果明显增强。抗肿瘤效果的增强归结于细胞质内局部的纳米药物的高浓度。线粒体途径不仅是纳米药物抗肿瘤活性增强的主要原因,而且也是纳米药物抗肿瘤的新证据。
Objective:The present research was to conduct5-fluorouracil loaded nanodrugs which used polyhedral Fe3O4nanoparticle as core treated gastric cancer cells. Electron-microscopy techniques was used in vitro experiment in order to explore the antitumor mechanism of nano-dugs and provide theory basis for development and application of nanodrug.
METHODS:Size-and shape-controlled Fe3O4nanoparticles were prepared by using a high temperature liquid phase method. Fe3O4nanoparticles was coated by CMC in order to improve biocompatibility, further immobilize5-Fu onto the CMC coated Fe3O4-CMC NPs. The Fe3O4-CMC-5FU nanomedicine was then collected from the reaction mixture by using a magnet. The chemical bonding of the conjugated Fe3O4-CMC and Fe3O4-CMC-5-FU nanomedicine were investigated by an infrared spectroscopy (IR). A cell counting kit-8(CCK-8) was used to determine the inhibition of drugs (Fe3O4NPs,5FU and Fe3O4-CMC-5FU) against SGC-7901cells. Annexin-V-FITC/PI double staining assay was performed to detect apoptosis of SGC-7901cells. The morphology, crystal structure and chemical characterization of individual Fe3O4, Fe3O4-CMC, Fe3O4-CMC-5-FU, SGC-7901cells incubated with5FU, Fe3O4NPs and Fe3O4-CMC-5-FU nanomedicine were analyzed at the nano/atomic-scale using field emission high-resolution transmission electron microscopywhich is equipped with energy-dispersive x-ray analysis (EDAX), high angle annular dark and scanning transmission electron microscope (HAADF-STEM). The results of ultra-structure changes were Composited to make a deduce which leaded us to draw a analogue map which displayed antitumor effectiveness by nanomedicines.
Results:Fe3O4NPs with10nm diameter and polyhedral shape were therefore chosen in this study.Both HAADF-STEM and TEM images reveal that individual Fe3O4NPs are fairly uniform and monodispersed. The Fe3O4-CMC hybrids had a mean size of approximately12nm. The average diameter of the Fe3O4-CMC-5FU nanomedicine is about13nm, nearly an ideal diameter of nanomedicines. The data demonstrate that the Fe3O4-CMC-5FU nanomedicine has a much better effect in inhibiting SGC-7901proliferation at all tested concentrations than the traditional pure5FU. The data demonstrate that the Fe3O4-CMC-5FU nanomedicine has a much better effect in inhibiting SGC-7901proliferation at all tested concentrations than the traditional pure5FU. Apoptosis rate detected by flow cytometry reveals that the Fe3O4-CMC-5FU nanomedicine promotes the apoptosis and necrosis of SGC-7901cells much better than the traditional pure5FU. The intensity of apotosis also indicates that the apotosis-inducing effect of the Fe3O4-CMC-5FU nanomedicine on SGC-7901cells is also dose-and time-dependent. We examined218SGC-7901cells incubated with50μg-ml-1Fe3O4-CMC-5FU nanomedicine under transmission electron microscope and found that161cells promoted apotosis due to the mitochondrial death, taking up about74%of the apotosis cases. It is clearly evident that a large amount of5FU was still retained to conjugate with Fe Fe3O4-CMC after24h incubation and5FU should be slowly and continuously released from the surface of the Fe Fe3O4-CMC-5FU nanomedicine agglomerates, thus forming a localized high concentration of5FU in the cytoplasm of SGC-7901cancer cells may induce an acute injury of mitochondrial membrane structure including mitochondria death.
Conclusions:Fe3O4-CMC-5FU nanomedicine apparently enhances antitumor effect on gastric cancer cells. The enhanced therapeutic efficacy derives from the localized high-concentration of the magnetic nanomedicine in the cytoplasm. Mitochondrial pathway is not only the main reason which enhanced antitumor activity of nanomedicine, but also the new evidence for nanomedicine treating tumour.
引文
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