CN115040496A - 中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法 - Google Patents
中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法 Download PDFInfo
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Abstract
本发明涉及纳米材料技术领域,公开了一种中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,该纳米粒包括质量比为45~48:9~14:6~11的介孔聚多巴胺纳米粒、脂溶性色素和聚乙二醇改性壳聚糖,介孔聚多巴胺纳米粒作为载体,通过物理和化学吸附吸附脂溶性色素,聚乙二醇改性壳聚糖包裹在最外层。中空介孔聚多巴胺具有较高的比表面积、纳米孔道结构及内部中空结构,可吸附疏水性药物,大幅度提高脂溶性色素的负载效率,具有pH敏感性及门控作用,响应肿瘤部位的pH值,提高肿瘤胞内的有效脂溶性色素浓度,延缓脂溶性色素有效作用时间;提高脂溶性色素的生物利用率及体内外稳定性,提高肿瘤治疗效果。
Description
分案说明
本发明为申请日为2020年12月31日,申请号为2020116179981,发明名称为“中空介孔聚多巴胺载脂溶性色素纳米粒及其制备方法”的分案申请。
技术领域
本发明涉及纳米材料技术领域,具体涉及一种中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法。
背景技术
姜黄素是从姜科姜黄属植物姜黄、莪术、郁金等的根茎中提取的一种多酚类物质。研究报道姜黄素具有抗肿瘤、抗纤维化、抗氧化、抗炎、抑菌、降血脂和护肝等广泛的药理作用,且毒性非常低,越来越受国内外专家学者的重视。番茄红素是从番茄、西瓜等植物中提取的一种类胡萝卜素,是一种脂溶性天然红色素,属于碳氢化合物,其抗氧化功能很强,具有保护心脑血管、增强免疫力、抗肿瘤等作用,对帕金森、癫痫、抑郁症等精神退行性疾病和精神疾病有预防或治疗作用,并且其在剂量范围内基本无毒性,其保健价值备受青睐,已经成为国内外研究的热点。姜黄素和番茄红素均属于脂溶性色素,脂溶性色素难溶于水,口服不易吸收,存在严重的肝脏首过效应,在体内的新陈代谢及清除速率较快,所以生物利用率较低,稳定性差,见光易分解,因此需要制备合适的药物递送系统以解决上述问题,以改善脂溶性色素的水溶性及稳定性,防止药物进入生物体后被水解、氧化而失活,并延长其体内释放时间。
聚多巴胺(PDA)是天然生物色素-黑色素的主要成分,可通过多巴胺的氧化自聚合反应得到,具有良好的稳定性、生物可降解性、生物相容性和光热转换特性,是一种比较理想的载体材料。聚多巴胺表面具有大量邻苯二酚和氨基功能基团,具有很强粘附性,可包覆在多种材料表面。聚多巴胺还具有pH敏感性,可在肿瘤的微酸性环境中解聚。通过硬模板法可以制备得到中空介孔聚多巴胺纳米粒,中空介孔聚多巴胺纳米粒(HPDA)因其具有较高比表面积、孔道结构及内部中空结构,可以高效负载药物,还具有良好的光热转换性能。壳聚糖是一类由氨基葡萄糖组成的阳离子聚合物,具有很好的生物相容性、低毒性和可生物降解性,且具有肠粘膜粘附的特性,作为药物辅料有利于药物的口服吸收。对壳聚糖进行聚乙二醇修饰,可以减少血浆蛋白对壳聚糖包衣介孔聚多巴胺纳米粒的吸附作用,从而减少巨噬细胞对壳聚糖包衣介孔聚多巴胺纳米粒的摄取,延缓载药纳米粒从血浆中被清除的过程,并通过“增强的透过及滞留效应”,进一步提高壳聚糖介孔聚多巴胺纳米粒的被动靶向功能。
发明内容
发明目的:针对现有技术中存在的问题,本发明提供一种中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,可提高脂溶性色素生物利用率,改善了脂溶性色素的水溶性及稳定性,提高了脂溶性色素的生物利用率,该载药纳米粒有望达到肿瘤渗透和定向缓释的目的。
技术方案:本发明提供了一种中空介孔聚多巴胺载脂溶性色素纳米粒,其特征在于,包括质量比为45~48:9~14:6~11介孔聚多巴胺纳米粒、脂溶性色素和聚乙二醇改性壳聚糖,所述介孔聚多巴胺纳米粒作为载体,通过物理和化学吸附吸附所述脂溶性色素,所述聚乙二醇改性壳聚糖包裹在最外层。
优选地,所述脂溶性色素为姜黄素或番茄红素。
本发明还提供了一种中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,具体包括以下步骤实施:(1)向乙醇水溶液中加入盐酸多巴胺和Pluronic F127,室温搅拌均匀后加入二氧化硅颗粒,然后再逐滴加入TMB,形成白色乳液,然后加入氨水溶液搅拌,离心后将沉淀用乙醇和水超声洗涤数次,再将沉淀加入氢氟酸水溶液中蚀刻,离心得到中空介孔聚多巴胺纳米粒,标记为HPDA;其中,盐酸多巴胺、Pluronic F127、二氧化硅、TMB以及氨水溶液的质量体积比为0.3~0.5 g:1.0~1.2 g:20~30 mg:0.6~1.0 mL:4.0~5.0 mL;(2)将步骤(1)所得中空介孔聚多巴胺纳米粒与脂溶性色素粉末加至无水DMSO中,在室温搅拌反应,离心,用DMSO和去离子水的混合溶液冲洗及用去离子水冲洗数次,即得到载脂溶性色素纳米粒;其中,中空介孔聚多巴胺纳米粒与脂溶性色素粉末的质量比为5~8:1;(3)称取一定量壳聚糖和聚乙二醇,溶解于稀乙酸溶液中混合均匀,在室温下搅拌过夜,即得到聚乙二醇改性壳聚糖溶液;(4)将步骤(2)得到的所得载脂溶性色素纳米粒溶于乙酸水溶液中,逐滴加入步骤(3)所得聚乙二醇改性壳聚糖溶液,在室温下搅拌,离心,冷冻干燥,即得中空介孔聚多巴胺载脂溶性色素纳米粒。
优选地,步骤(1)中,乙醇水溶液中,乙醇和水的体积比为1:1。
优选地,步骤(1)中,氢氟酸水溶液的质量分数为3~5%。
优选地,步骤(2)中,所述DMSO和去离子水的混合溶液中,DMSO和去离子水的体积比为3~4:7~8。
优选地,步骤(3)中,壳聚糖与聚乙二醇的质量比为1:0.2~0.3。
优选地,步骤(3)中,稀乙酸水溶液的质量分数为1~2%。
优选地,步骤(4)中,乙酸水溶液的质量分数为0.5~1%。
优选地,步骤(4)中,冷冻干燥温度为-40~-70 ℃,冷冻干燥时间为12~24 h。
有益效果:与现有技术相比,本发明具有以下有益效果:
(1)本发明以聚多巴胺为基础材料,通过中空介孔聚多巴胺纳米粒的合成、脂溶性色素的负载、改性壳聚糖分子的包覆,构建了一种可提高脂溶性色素生物利用率的以改性壳聚糖为包衣的载药中空介孔聚多巴胺纳米粒,改善了脂溶性色素的水溶性及稳定性,提高了脂溶性色素的生物利用率,该载药纳米粒有望达到肿瘤渗透和定向缓释的目的。
(2)载体中空介孔聚多巴胺(HPDA),具有比介孔聚多巴胺更高的比表面积、纳米孔道结构及内部中空结构,且自身具有很强的吸附能力,可将疏水性药物脂溶性色素吸附在中空介孔聚多巴胺的表面和中空内壁,且能产生π-π*电子跃迁,并与脂溶性色素分子形成羰基键(脂溶性色素为姜黄素)或发生michael加成反应(脂溶性色素为番茄红素),物理吸附和化学吸附结合,可以大幅度提高聚多巴胺对脂溶性色素的负载效率。
(3)本发明的中空介孔聚多巴胺载脂溶性色素纳米粒,使脂溶性色素释放具有pH响应性及门控作用,可以有效响应肿瘤部位的pH值,提高肿瘤胞内的有效脂溶性色素浓度,延缓脂溶性色素有效作用时间,并且可改善脂溶性色素的不良口感,避免了有些脂溶性色素的苦味成分溶于口中。
(4)改性壳聚糖能被人体吸收利用,具有良好的生物相容性,可生物降解,降解过程中产生的壳寡糖在体内不积累,几乎无免疫原性,同时具有较好的水溶性,通过壳聚糖修饰将中空介孔聚多巴胺纳米载体表面电性改变为正电,增加中空介孔聚多巴胺载体对肿瘤细胞的粘附性。壳聚糖可以吸附在肠道,延缓排出体外,使得人体吸收的脂溶性色素较多,提高生物利用率,且外表包裹壳聚糖可以提高颗粒储藏稳定性。
(5)本发明构建的中空介孔聚多巴胺载体安全,无毒性,且制备简单,成分单一,能够提高脂溶性色素的稳定性,便于贮存。
附图说明
图1中空介孔聚多巴胺载体及中空介孔聚多巴胺载姜黄素纳米粒的粒径分布图;
图2中空介孔聚多巴胺载体及中空介孔聚多巴胺载姜黄素纳米粒的透射电镜图;
图3姜黄素、介孔聚多巴胺载体及介孔聚多巴胺载姜黄素纳米粒的FTIR谱图;
图4中空介孔聚多巴胺HPDA的氮气吸附/脱附曲线图;
图5空白载体对人正常肝细胞LO2的生物安全性考察;
图6中空介孔聚多巴胺载姜黄素纳米粒在模拟胃液、肠液中的缓释曲线图;
图7中空介孔聚多巴胺纳米粒对人结肠癌细胞HCT-116的细胞毒性作用;
图8中空介孔聚多巴胺载体及中空介孔聚多巴胺载番茄红素纳米粒的粒径分布图;
图9中空介孔聚多巴胺载体及中空介孔聚多巴胺载番茄红素纳米粒的透射电镜图;
图10番茄红素、介孔聚多巴胺载番茄红素纳米粒的光稳定性曲线图;
图11中空介孔聚多巴胺载番茄红素纳米粒在模拟胃液、肠液中的缓释曲线图;
图12中空介孔聚多巴胺纳米粒对肝癌细胞HepG2的细胞毒性作用。
具体实施方式
下面结合附图对本发明进行详细的介绍。
实施方式1:
本实施方式提供了一种中空介孔聚多巴胺载姜黄素纳米粒PEG-CS@HPDA@CUR的制备方法,具体按以下步骤实施:
步骤1,HPDA的合成
向乙醇水(1:1,v/v)的混合溶液中加入0.4 g盐酸多巴胺和1.0 g PluronicF127,室温搅拌,搅拌均匀后加入20 mg二氧化硅颗粒,然后逐滴加入0.8 mL TMB,形成白色乳液;加入4.0 mL氨水溶液,50 ℃搅拌30 min,离心后将沉淀用乙醇和水超声洗涤3次,再将沉淀加入3%氢氟酸水溶液中蚀刻,离心后用去离子水洗涤数次即得到中空介孔聚多巴胺纳米粒,标记为HPDA。
步骤2,HPDA@CUR的合成
将中空介孔聚多巴胺纳米粒与姜黄素粉末按质量比为7:1的比例加至无水DMSO中,在室温搅拌反应24 h,离心,用DMSO和去离子水(3:7,v/v)的混合溶液冲洗一次及用去离子水冲洗3次,即得到载姜黄素纳米粒,标记为HPDA@CUR;
步骤3,PEG-CS@HPDA@CUR的合成
称取1 g壳聚糖和0.25 g聚乙二醇,溶解于1%稀乙酸溶液中混合均匀,在室温下搅拌过夜,即得到聚乙二醇改性壳聚糖溶液;将载姜黄素纳米粒溶于100 mL 0.5%乙酸水中,逐滴加入20 mL聚乙二醇改性壳聚糖溶液,在室温下搅拌,离心,-70 ℃冷冻干燥12 h,即得到中空介孔聚多巴胺载姜黄素纳米粒PEG-CS@HPDA@CUR。
制得的中空介孔聚多巴胺载姜黄素纳米粒PEG-CS@HPDA@CUR,包括质量比为50:9:6的中空介孔聚多巴胺纳米粒、姜黄素和聚乙二醇改性壳聚糖,中空介孔聚多巴胺纳米粒作为载体,通过物理和化学吸附姜黄素,聚乙二醇改性壳聚糖包裹在最外层。
实施方式2:
一种介孔聚多巴胺载姜黄素纳米粒的制备方法,具体按以下步骤实施:
步骤1,HPDA的合成
向乙醇水(1:1,v/v)的混合溶液中加入0.5 g盐酸多巴胺和1.2 g PluronicF127,室温搅拌,搅拌均匀后加入25 mg二氧化硅颗粒,然后逐滴加入1.0 mL TMB,形成白色乳液,加入4.0 mL氨水溶液,50 ℃搅拌30 min,离心后将沉淀用乙醇和水超声洗涤5次,再将沉淀加入4%氢氟酸水溶液中蚀刻,离心后用去离子水洗涤数次即得到中空介孔聚多巴胺纳米粒,标记为HPDA。
步骤2,HPDA@CUR的合成
将中空介孔聚多巴胺纳米粒与姜黄素粉末按质量比为8:1的比例加至无水DMSO中,在室温搅拌反应12 h,离心,用DMSO和去离子水(4:7,v/v)混合溶液冲洗一次及用去离子水冲洗5次,即得到载姜黄素纳米粒,标记为HPDA@CUR;
步骤3,PEG-CS@HPDA@CUR的合成
称取1 g壳聚糖和0.3 g聚乙二醇,溶解于2%稀乙酸溶液中混合均匀,在室温下搅拌过夜,即得到聚乙二醇改性壳聚糖溶液;将载姜黄素纳米粒溶于100 mL 0.5%乙酸水中,逐滴加入20 mL聚乙二醇改性壳聚糖溶液,在室温下搅拌,离心,-40 ℃冷冻干燥24 h,即得到中空介孔聚多巴胺载姜黄素纳米粒PEG-CS@HPDA@CUR。
制得的中空介孔聚多巴胺载姜黄素纳米粒PEG-CS@HPDA@CUR,包括质量比为50:10:7的中空介孔聚多巴胺纳米粒、姜黄素和聚乙二醇改性壳聚糖,中空介孔聚多巴胺纳米粒作为载体,通过物理和化学吸附姜黄素,聚乙二醇改性壳聚糖包裹在最外层。
实施方式3:
一种中空介孔聚多巴胺载姜黄素纳米粒的制备方法,具体按以下步骤实施:
步骤1,HPDA的合成
向乙醇水(1:1,v/v)的混合溶液中加入0.3 g盐酸多巴胺和0.5 g PluronicF127,室温搅拌,搅拌均匀后加入30 mg二氧化硅颗粒,然后逐滴加入0.8 mL TMB形成白色乳液,加入3 mL氨水溶液,40 ℃搅拌30 min,离心后将沉淀用乙醇和水超声洗涤5次,再将沉淀加入5%氢氟酸水溶液中蚀刻,离心后用去离子水洗涤数次即得到中空介孔聚多巴胺纳米粒,标记为HPDA。
步骤2,HPDA@CUR的合成
将介孔聚多巴胺纳米粒与姜黄素粉末按质量比为9:1的比例加至无水DMSO中,在室温搅拌反应24 h,离心,用DMSO和去离子水(4:9,v/v)混合溶液冲洗一次及用去离子水冲洗5次,即得到载姜黄素纳米粒,标记为HPDA@CUR;
步骤3,PEG-CS@HPDA@CUR的合成
称取1 g壳聚糖和0.2 g聚乙二醇,溶解于1%稀乙酸溶液中混合均匀,在室温下搅拌过夜,即得到聚乙二醇改性壳聚糖溶液;将载姜黄素纳米粒溶于100 mL 0.5%乙酸水中,逐滴加入20 mL聚乙二醇改性壳聚糖溶液,在室温下搅拌,离心,-40 ℃冷冻干燥24 h,即得到中空介孔聚多巴胺载姜黄素纳米粒PEG-CS@HPDA@CUR。
制得的中空介孔聚多巴胺载姜黄素纳米粒PEG-CS@HPDA@CUR,包括质量比为49:9:8的中空介孔聚多巴胺纳米粒、姜黄素和聚乙二醇改性壳聚糖,中空介孔聚多巴胺纳米粒作为载体,通过物理和化学吸附姜黄素,聚乙二醇改性壳聚糖包裹在最外层。
采用马尔文激光粒度仪对实施方式1至3中中空介孔聚多巴胺载体和中空介孔聚多巴胺载姜黄素纳米粒的粒径分布进行分析。将中空介孔聚多巴胺载体和中空介孔聚多巴胺载姜黄素纳米粒分散于水中,测定其粒径分布,如图1所示,其水动力直径大小分别为140± 10 nm和150 ± 10 nm。
透射电镜(TEM)观察实施方式1至3中中空介孔聚多巴胺载体和中空介孔聚多巴胺载姜黄素纳米粒的形貌:取10 μL溶液,滴加在表面碳涂层铜网上,室温条件下自然风干。200KV电压条件下,透射电子显微镜观察纳米颗粒的形貌、粒径和分散情况。载体透射电镜图片如图2所示,制得的HPDA粒径分布范围较窄,粒径均一且表面有明显的孔道结构。
红外光谱测定采用溴化钾(KBr)压片法,称取适量介孔聚多巴胺载体、姜黄素、载姜黄素纳米粒与溴化钾按1:50比例混合,在500-4000 cm-1范围内进行红外扫描。如图3所示,载姜黄素纳米粒的FTIR谱图上出现了与壳聚糖有关的峰(1591,2918 cm-1)和姜黄素的主峰(1281,1510,2931 cm-1)。这些结果证实壳聚糖和姜黄素已经结合到介孔聚多巴胺载体上。
HPDA氮气吸附/脱附曲线测定:取烘干的80 mg HPDA样品,仪器测定氮气吸附/脱附曲线,如图4所示,利用BJH法计算出制备的HPDA纳米粒子的比表面积为48.4940 m²/g。
用MTT法考察空白载体对人正常肝细胞LO2的生长抑制作用。使用人正常肝细胞LO2,实验组加入200 μL/孔的不同浓度的空白载体溶液,对照组则加入200 μL培养液,在两种pH条件下,以相对细胞存活率作为考察指标,考察人正常肝细胞LO2在不同浓度条件下的细胞活力。如图5所示,当空白纳米粒浓度达到1000 μg/mL时,人正常肝细胞LO2细胞存活率也均在80%以上,说明载体材料在浓度0.98~1000 μg/mL内具有良好的生物相容性。
采用透析袋法考察实施方式1至3中中空介孔聚多巴胺载姜黄素纳米粒在模拟胃液和模拟肠液中的释放情况。将1 mL中空介孔聚多巴胺载姜黄素纳米粒混悬液置于透析袋中,释放介质为模拟人工胃液和人工肠液,于37 ℃下恒温振荡,于不同时间点取样,绘制累计药物释放曲线。实验结果如图6所示,从图中可以看出中空介孔聚多巴胺载姜黄素纳米粒在模拟胃液中释药速率高于在模拟肠液中释药速率,累计释放率大于80%,释放较为完全。且中空介孔聚多巴胺载姜黄素纳米粒从实验一开始就缓慢释放,并随着时间的推移逐渐稳定,说明中空介孔聚多巴胺载姜黄素纳米粒在姜黄素控释方面的确有显著效果。
通过MTT试验考察了游离姜黄素、PEG-CS@HPDA@CUR对人结肠癌细胞HCT-116的毒性作用。结果如图7所示,在两种pH条件下姜黄素对人结肠癌细胞HCT-116表现出明显的剂量依赖性抑制作用。载于载体上后姜黄素的这种增强的抗肿瘤作用可能是由于螯合的姜黄素具有优异的抗增殖活性以及姜黄素和表面改性壳聚糖包衣的协同抗肿瘤作用。
实施方式4:
本实施方式提供了一种中空介孔聚多巴胺载番茄红素纳米粒PEG-CS@HPDA@LYC的制备方法,具体按以下步骤实施:
步骤1,HPDA的合成
向乙醇水(1:1,v/v)的混合溶液中加入0.5 g盐酸多巴胺和1.1 g PluronicF127,室温搅拌,搅拌均匀后加入25 mg二氧化硅颗粒,然后逐滴加入0.8 mL TMB,形成白色乳液;加入4.0 mL氨水溶液,50 ℃搅拌30 min,离心后将沉淀用乙醇和水超声洗涤3次,再将沉淀加入4%氢氟酸水溶液中蚀刻,离心后用去离子水洗涤数次即得到中空介孔聚多巴胺纳米粒,标记为HPDA。
步骤2,HPDA@LYC的合成
将中空介孔聚多巴胺纳米粒与番茄红素粉末按质量比为8:1的比例加至无水DMSO中,在室温搅拌反应24 h,离心,用DMSO和去离子水(4:7,v/v)的混合溶液冲洗一次及用去离子水冲洗3次,即得到载番茄红素纳米粒,标记为HPDA@LYC;
步骤3,PEG-CS@HPDA@LYC的合成
称取1 g壳聚糖和0.2 g聚乙二醇,溶解于1%稀乙酸溶液中混合均匀,在室温下搅拌过夜,即得到聚乙二醇改性壳聚糖溶液;将载番茄红素纳米粒溶于100 mL 0.5%乙酸水中,逐滴加入20 mL聚乙二醇改性壳聚糖溶液,在室温下搅拌,离心,-40 ℃冷冻干燥24 h,即得到中空介孔聚多巴胺载番茄红素纳米粒PEG-CS@HPDA@LYC。
制得的中空介孔聚多巴胺载番茄红素纳米粒PEG-CS@HPDA@LYC,包括质量比为50:9:8的中空介孔聚多巴胺纳米粒、番茄红素和聚乙二醇改性壳聚糖,中空介孔聚多巴胺纳米粒作为载体,通过物理和化学吸附番茄红素,聚乙二醇改性壳聚糖包裹在最外层。
实施方式5:
一种介孔聚多巴胺载番茄红素纳米粒的制备方法,具体按以下步骤实施:
步骤1,HPDA的合成
向乙醇水(1:1,v/v)的混合溶液中加入0.5 g盐酸多巴胺和1.0 g PluronicF127,室温搅拌,搅拌均匀后加入25 mg二氧化硅颗粒,然后逐滴加入1.0 mL TMB,形成白色乳液,加入4.0 mL氨水溶液,50 ℃搅拌30 min,离心后将沉淀用乙醇和水超声洗涤5次,再将沉淀加入3%氢氟酸水溶液中蚀刻,离心后用去离子水洗涤数次即得到中空介孔聚多巴胺纳米粒,标记为HPDA。
步骤2,HPDA@LYC的合成
将中空介孔聚多巴胺纳米粒与番茄红素粉末按质量比为8:1的比例加至无水DMSO中,在室温搅拌反应12 h,离心,用DMSO和去离子水(3:8,v/v)混合溶液冲洗一次及用去离子水冲洗5次,即得到载番茄红素纳米粒,标记为HPDA@LYC;
步骤3,PEG-CS@HPDA@LYC的合成
称取1 g壳聚糖和0.25 g聚乙二醇,溶解于2%稀乙酸溶液中混合均匀,在室温下搅拌过夜,即得到聚乙二醇改性壳聚糖溶液;将载番茄红素纳米粒溶于100 mL 0.5%乙酸水中,逐滴加入20 mL聚乙二醇改性壳聚糖溶液,在室温下搅拌,离心,-60 ℃冷冻干燥16 h,即得到中空介孔聚多巴胺载番茄红素纳米粒PEG-CS@HPDA@LYC。
制得的中空介孔聚多巴胺载番茄红素纳米粒PEG-CS@HPDA@LYC,包括质量比为55:10:9的中空介孔聚多巴胺纳米粒、番茄红素和聚乙二醇改性壳聚糖,中空介孔聚多巴胺纳米粒作为载体,通过物理和化学吸附番茄红素,聚乙二醇改性壳聚糖包裹在最外层。
实施方式6:
一种中空介孔聚多巴胺载番茄红素纳米粒的制备方法,具体按以下步骤实施:
步骤1,HPDA的合成
向乙醇水(1:1,v/v)的混合溶液中加入0.3 g盐酸多巴胺和1.2 g PluronicF127,室温搅拌,搅拌均匀后加入30 mg二氧化硅颗粒,然后逐滴加入1.0 mL TMB形成白色乳液,加入3 mL氨水溶液,40 ℃搅拌30 min,离心后将沉淀用乙醇和水超声洗涤5次,再将沉淀加入5%氢氟酸水溶液中蚀刻,离心后用去离子水洗涤数次即得到中空介孔聚多巴胺纳米粒,标记为HPDA。
步骤2,HPDA@LYC的合成
将介孔聚多巴胺纳米粒与番茄红素粉末按质量比为7:1的比例加至无水DMSO中,在室温搅拌反应24 h,离心,用DMSO和去离子水(4:9,v/v)混合溶液冲洗一次及用去离子水冲洗5次,即得到载番茄红素纳米粒,标记为HPDA@LYC;
步骤3,PEG-CS@HPDA@LYC的合成
称取1 g壳聚糖和0.25 g聚乙二醇,溶解于1%稀乙酸溶液中混合均匀,在室温下搅拌过夜,即得到聚乙二醇改性壳聚糖溶液;将载番茄红素纳米粒溶于100 mL 0.5%乙酸水中,逐滴加入20 mL聚乙二醇改性壳聚糖溶液,在室温下搅拌,离心,-40 ℃冷冻干燥24 h,即得到中空介孔聚多巴胺载番茄红素纳米粒PEG-CS@HPDA@LYC。
制得的中空介孔聚多巴胺载番茄红素纳米粒PEG-CS@HPDA@LYC,包括质量比为54:11:9的中空介孔聚多巴胺纳米粒、番茄红素和聚乙二醇改性壳聚糖,中空介孔聚多巴胺纳米粒作为载体,通过物理和化学吸附番茄红素,聚乙二醇改性壳聚糖包裹在最外层。
采用马尔文激光粒度仪对实施方式4至6中中空介孔聚多巴胺载体和中空介孔聚多巴胺载番茄红素纳米粒的粒径分布进行分析。将中空介孔聚多巴胺载体和中空介孔聚多巴胺载番茄红素纳米粒分散于水中,测定其粒径分布,如图8所示,其水动力直径大小分别为140 ± 10 nm和163 ± 10 nm。
透射电镜(TEM)观察实施方式4至6中中空介孔聚多巴胺载体和中空介孔聚多巴胺载番茄红素纳米粒的形貌:取10 μL溶液,滴加在表面碳涂层铜网上,室温条件下自然风干。200KV电压条件下,透射电子显微镜观察纳米颗粒的形貌、粒径和分散情况。载体透射电镜图片如图9a所示,制得的HPDA粒径分布范围较窄,粒径均一且表面有明显的孔道结构。中空介孔聚多巴胺载番茄红素纳米粒如图9b所示,可以看出纳米粒子粒径均一,形状为球形,由于表面番茄红素的吸附及壳聚糖的修饰,规则分布的孔道变得模糊。
将一定量的载番茄红素纳米粒和番茄红素粉末置于室内散射光环境中铺平进行全光照射使光能与番茄红素每个表面接触,25 ℃的条件下,分别在0 h、2 h、4 h、6 h、8 h、10 h和12 h称取一定量的粉末加入10 mL DMSO充分溶解,超声10 min,重复3次取平均值,用紫外分光光度计方法分别测定含量。如图10所示,通过对番茄红素进行纳米胶囊的制备,其稳定性有明显的提高,12 h后番茄红素含量由原来未吸附包埋前的83.75%提高到97.98%左右。
采用透析袋法考察实施方式4至6中中空介孔聚多巴胺载番茄红素纳米粒在模拟胃液和模拟肠液中的释放情况。将1 mL中空介孔聚多巴胺载番茄红素纳米粒混悬液置于透析袋中,释放介质为模拟人工胃液和人工肠液,于37 ℃下恒温振荡,于不同时间点取样,绘制累计药物释放曲线。实验结果如图11所示,从图中可以看出中空介孔聚多巴胺载番茄红素纳米粒在模拟胃液中释药速率高于在模拟肠液中释药速率,累计释放率大于80%,释放较为完全。且中空介孔聚多巴胺载番茄红素纳米粒从实验一开始就缓慢释放,并随着时间的推移逐渐稳定,说明中空介孔聚多巴胺载番茄红素纳米粒在番茄红素控释方面的确有显著效果。
通过MTT试验考察了游离番茄红素、PEG-CS@HPDA@LYC对人肝癌细胞HepG2的毒性作用。结果如图12所示,在两种pH条件下番茄红素对人肝癌细胞HepG2表现出明显的剂量依赖性抑制作用。载于载体上后番茄红素的这种增强的抗肿瘤作用可能是由于螯合的番茄红素具有优异的抗增殖活性以及番茄红素和表面改性壳聚糖包衣的协同抗肿瘤作用。
上述实施方式只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所做的等效变换或修饰,都应涵盖在本发明的保护范围之内。
Claims (8)
1.一种中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,其特征在于,具体包括以下步骤实施:
(1)向乙醇水溶液中加入盐酸多巴胺和Pluronic F127,室温搅拌均匀后加入二氧化硅颗粒,然后再逐滴加入TMB,形成白色乳液,然后加入氨水溶液搅拌,离心后将沉淀用乙醇和水超声洗涤数次,再将沉淀加入氢氟酸水溶液中蚀刻,离心得到中空介孔聚多巴胺纳米粒,标记为HPDA;
其中,盐酸多巴胺、Pluronic F127、二氧化硅、TMB以及氨水溶液的质量体积比为0.3~0.5 g:1.0~1.2 g:20~30 mg:0.6~1.0 mL:4.0~5.0 mL;
(2)将步骤(1)所得中空介孔聚多巴胺纳米粒与脂溶性色素粉末加至无水DMSO中,在室温搅拌反应,离心,用DMSO和去离子水的混合溶液冲洗及用去离子水冲洗数次,即得到载脂溶性色素纳米粒;
其中,中空介孔聚多巴胺纳米粒与脂溶性色素粉末的质量比为5~8:1;
(3)称取一定量壳聚糖和聚乙二醇,溶解于稀乙酸溶液中混合均匀,在室温下搅拌过夜,即得到聚乙二醇改性壳聚糖溶液;
(4)将步骤(2)得到的所得载脂溶性色素纳米粒溶于乙酸水溶液中,逐滴加入步骤(3)所得聚乙二醇改性壳聚糖溶液,在室温下搅拌,离心,冷冻干燥,即得中空介孔聚多巴胺载脂溶性色素纳米粒。
2.如权利要求1所述的中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,其特征在于,步骤(1)中,乙醇水溶液中,乙醇和水的体积比为1:1。
3.如权利要求1所述的中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,其特征在于,步骤(1)中,氢氟酸水溶液的质量分数为3~5%。
4.如权利要求1所述的中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,其特征在于,步骤(2)中,所述DMSO和去离子水的混合溶液中,DMSO和去离子水的体积比为3~4:7~8。
5.如权利要求1所述的中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,其特征在于,步骤(3)中,壳聚糖与聚乙二醇的质量比为1:0.2~0.3。
6.如权利要求5所述的中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,其特征在于,步骤(3)中,稀乙酸水溶液的质量分数为1~2%。
7.如权利要求1所述的中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,其特征在于,步骤(4)中,乙酸水溶液的质量分数为0.5~1%。
8. 如权利要求1至7中任意一项所述的中空介孔聚多巴胺载脂溶性色素纳米粒的制备方法,其特征在于,步骤(4)中,冷冻干燥温度为-40~-70 ℃,冷冻干燥时间为12~24 h。
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