CN109528757A - 一种茯苓寡糖功能化纳米硒及其制备和应用 - Google Patents
一种茯苓寡糖功能化纳米硒及其制备和应用 Download PDFInfo
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- CN109528757A CN109528757A CN201811511421.5A CN201811511421A CN109528757A CN 109528757 A CN109528757 A CN 109528757A CN 201811511421 A CN201811511421 A CN 201811511421A CN 109528757 A CN109528757 A CN 109528757A
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Abstract
本发明属于生物医药中成药和功能性食品生物技术领域，公开了一种茯苓寡糖功能化纳米硒(POS‑SeNPs)的制备方法和应用。所述茯苓寡糖是利用茯苓多糖经β‑甘露聚糖酶水解所得到的水溶性富含甘露糖的葡萄甘露寡聚糖。采用茯苓寡糖作为调控剂，在维生素C还原亚硒酸钠体系中，制备得到茯苓寡糖功能化修饰纳米硒POS‑SeNPs，实现了纳米尺寸均一性、液相保存稳定性和寡糖修饰高效率。本发明的茯苓寡糖功能化纳米硒制品主要适用于辅助治疗炎症性肠病，也可用于高脂血症、动脉粥样硬化、糖尿病、肠道肿瘤和其它炎症相关疾病的辅助预防治疗。使用简便，绿色安全，价格低廉，不仅可减轻病患痛苦，而且极大减少经济负担。
Description
技术领域
本发明属于生物医药中成药和功能性食品技术领域，特别涉及一种茯苓寡糖功能化纳米硒及其制备方法和应用。
背景技术
中药茯苓(Poriacocos Wolf)为多孔菌科卧孔菌属真菌茯苓的干燥菌核。茯苓是中国名贵中药材，性平，味甘、淡，入心、肺、脾、肾经，用于水肿尿少，痰咳眩悸，脾虚食少，便溏泄泻，心神不安，惊悸失眠。茯苓的主要活性成分是茯苓多糖(Poria cocospolysaccharides，PPS)，茯苓多糖有较好的抗肿瘤、抗感染、抗衰老及调理免疫和代谢的作用。茯苓多糖PPS的单糖组成、糖链结构及生化特性与其它物种来源的多糖显著不同，为提高其水溶性和生物利用度，PPS经酶水解后产生的茯苓寡糖(Poria oligosaccharides，POS)富含甘露糖残基，具有更好的生物活性。
人体必需微量元素硒(selenium,Se)可掺入生物分子形成活性硒蛋白、硒代氨基酸和硒多糖等功能有机硒形态，对调节机体氧化还原平衡、激素与代谢稳态、免疫应答及炎症反应均发挥重要作用。因此，强化硒营养和生物有机硒的功能，对调治炎症性疾病、代谢性疾病、慢性老年病和肿瘤具有较好的应用价值。
近年来，随着纳米医药技术的快速发展，新型纳米硒制备及其生物活性被不断发现和挖掘。纳米硒引起生物医学与食品保健领域广大研发人员的关注。我们课题组长期致力于活性硒形态制备、功能发掘和应用开发，系列实验证明纳米硒是一种高效低毒的硒形态，在体内具有药物载运、溶解缓释和免疫细胞亲嗜等良好特性。
但是，利用茯苓寡糖、硒营养和纳米硒优化组合研制功能产品尚无报道，茯苓寡糖功能化纳米硒也未见应用于生物医药中成药和功能性食品技术领域。
随人口老龄化及生活方式转变，动脉粥样硬化(AS)、炎症性肠病(IBD)、阿茨海默症(AD)、糖尿病(DM)、骨质疏松(OP)和肿瘤等慢性非感染性疾病(简称慢病)严重威胁人类健康。大量研究支持炎症微环境是调控慢病过程的关键因素，这一认识被Science杂志评为新世纪初“十大科学卓见”之一。炎症性肠病是一种慢性复发性炎症性疾病，包括溃疡性结肠炎(UC)和克罗恩病(CD)，目前IBD治疗的主要措施包括：皮质类固醇；非类固醇抗炎药物如抗生素、硫唑嘌呤和甲氨蝶呤；以及抗炎症细胞因子的单克隆抗体如肿瘤坏死因子α(TNF-α)、干扰素γ(IFN-γ)、抗白细胞介素12(IL-12)和IL-23。但临床药物治疗效果并不满意，且长期应用副作用严重。
本发明基于发现茯苓寡糖POS对纳米硒的稳定性和生物活性具有增强作用，建立了新型茯苓寡糖功能化修饰的纳米硒(POS-SeNPs)制备方法，进而发现其拮抗肠道炎症反应的新作用和对化学诱导小鼠结肠炎具有治疗效果。
发明内容
为了克服上述现有技术的缺点与不足，本发明的首要目的在于提供一种茯苓寡糖功能化纳米硒(POS-SeNPs)的制备方法。纳米硒制备技术和活性分子的协同掺入对相关创新医药研发具有广泛用途，本发明解决纳米硒尺寸调控、稳定性和活性分子富载效率问题，应用本发明的方法能够批量制备POS-SeNPs。
本发明的再一目的在于提供一种由上述方法制备得到的POS-SeNPs，它是一种新的安全有效的茯苓寡糖化纳米硒，能够协同增效营养元素硒的功能与茯苓寡糖的生理活性。
本发明另一目的在于提供上述茯苓寡糖功能化纳米硒的应用。
证明茯苓寡糖化纳米硒POS-SeNPs拮抗肠道炎症反应的新作用和对化学诱导小鼠炎症性肠病(IBD)具有治疗效果。通过观察小鼠灌胃补充POS-SeNPs后对实验性肠炎症状的影响，并检测其对IBD小鼠炎症因子和肠道组织炎症病理的调治作用，为开发POS-SeNPs辅助治疗肠炎和其它炎症相关疾病提供科学实验依据。
本发明的目的通过下述方案实现：
一种茯苓寡糖功能化纳米硒的制备方法，包括以下步骤：利用茯苓寡糖作为功能化修饰调控剂，在优化的氧化还原体系(还原型维生素C和亚硒酸钠)中，制备得到茯苓寡糖功能化纳米硒(POS-SeNPs)。
具体包括以下步骤：
(1)向茯苓多糖PPS水溶液中加入β-甘露聚糖酶，37℃水浴搅拌反应2小时，凝胶过滤层析分离收集寡糖组分，即为茯苓寡糖(POS)；
(2)将茯苓寡糖POS的水溶液与等体积的亚硒酸钠水溶液混合，搅拌使混合均匀，然后在搅拌条件下向其中加入还原性维生素C(VitC)溶液形成反应溶液，观察到反应溶液变红，继续搅拌反应直至产物中所出现的红色不再加深时，停止反应，将所得反应产物经过透析后即得茯苓多糖功能化纳米硒POS-SeNPs。
步骤(1)中所述的茯苓多糖PPS水溶液优选为浓度为10～50mg/mL的茯苓多糖水溶液；步骤(1)中所述的β-甘露聚糖酶的用量满足每10mg的茯苓多糖对应加入5单位(U)的β-甘露聚糖酶；
步骤(1)中所制备的茯苓寡糖POS优选为富含甘露糖的葡萄甘露寡聚糖，其糖组构成为葡萄糖和甘露糖，两者质量比为2:1，其平均分子量为3.24kDa；
步骤(2)中所述的茯苓寡糖POS水溶液是指其中茯苓寡糖浓度为0.2～1.0mg/mL的水溶液；步骤(2)中所述的亚硒酸钠溶液是指硒浓度为0.4～2.0mg/mL的亚硒酸钠水溶液；步骤(2)中反应溶液中茯苓寡糖和硒的质量比为1:2；
步骤(2)中所述的还原性维生素C溶液是指浓度为100～500mmol/L的还原性维生素C溶液。
步骤(2)中所述的还原性维生素C溶液的用量满足加入还原性维生素C溶液以后反应溶液中维生素C的终浓度为4～5mmol/L；
步骤(2)中所述的维生素C溶液的加入优选为采用自动加液泵进行加入，加入的速度满足：每1L的反应溶液每分钟向其中加入4～5mL的维生素C溶液；
步骤(2)中所述的透析是指透析袋的截留分子量为8kDa，温和磁力搅拌(120rpm)条件下透析时间超过15小时，每3-6小时换去离子水1次，每次换水超过透析袋内体积20倍。
由上述方法制备得到的茯苓寡糖功能化纳米硒，其形貌规则、分散均匀、粒径适中(<100nm)，具有良好的稳定性，4℃下在水相中可稳定保存50天。
本发明的茯苓寡糖功能化纳米硒是一种生物利用度高、毒性低制品，硒含量符合国家食品安全标准，可应用为功能食品、营养保健品、复方药物成分或候选药物等生物功能制品。该生物功能制品主要适用于辅助治疗炎症性肠病，也可用于高脂血症、动脉粥样硬化、糖尿病、肠道肿瘤和其它炎症相关疾病的辅助预防治疗。
本发明相对于现有技术，具有如下的优点及有益效果：
本发明建立硫酸葡聚糖(DSS)诱导小鼠结肠炎模型，通过灌胃补充POS-SeNPs，对DSS诱导的小鼠急性结肠炎具有明显疗效，可明显提升化学诱导结肠炎组织中硒营养累积，升高还原型谷胱甘肽GSH水平和谷胱甘肽过氧化物酶GPX活性，相应地显著降低结肠组织中脂质过氧化产物丙二醛MDA的生成和髓过氧化物酶MPO水平；进一步检测化学诱导结肠炎小鼠补充POS-SeNPs后，血清中促炎因子IL-1β、TNF-α、IL-6、IL-12和MCP-1表达水平明显下降，抑炎症因子IL-10表达水平明显升高。上述结果表明，POS-SeNPs可通过平抑肠炎组织氧化应激和炎症因子释放水平，缓解结肠炎病变。
由于慢性炎症病理生理机制的复杂性，致使相关疾病仍无有效治疗措施，大多采用综合对症治疗策略。尽管甾体抗炎药(即糖皮质激素氢化可的松及其人工合成的衍生物)沿用至今，以及大量非甾体抗炎药如解热镇痛药阿司匹林、保泰松、塞来昔布等在医疗实践中广泛使用，但这些药物长期大量使用均有严重副作用。本发明研发的茯苓寡糖功能化纳米硒(POS-SeNPs)制品，使用简便，绿色安全，价格低廉，不仅可减轻病患痛苦，而且极大减少经济负担。
附图说明
图1为茯苓多糖经β-甘露聚糖酶水解前后的糖组构成图以及标准糖谱图，其中A为标准糖谱，B为茯苓多糖经酶水解前的糖组构成，C为茯苓多糖水解后的茯苓寡糖的糖组构成；
图2为实施例1中不同浓度的茯苓寡糖水溶液在相同实验条件下得到的茯苓寡糖功能化纳米硒(POS-SeNPs)的粒径图；
图3为实施例1中反应溶液中茯苓寡糖终浓度为0.18mg/mL时制备的POS-SeNPs在4℃、在水相中的粒径大小随着时间的变化图；
图4为实施例1中反应溶液中茯苓寡糖终浓度为0.18mg/mL时制备的POS-SeNPs及空载纳米硒SeNPs的粒径分布图，其中A为SeNPs，B为POS-SeNPs；
图5为实施例1中反应溶液中茯苓寡糖终浓度为0.18mg/mL时制备的POS-SeNPs及空载纳米硒SeNPs的透射电子显微镜(TEM)形貌图，其中A为SeNPs，B为POS-SeNPs；
图6为实施例1中反应溶液中茯苓寡糖终浓度为0.18mg/mL时制备的POS-SeNPs及空载纳米硒SeNPs的红外谱图；
图7为实施例1中反应溶液中茯苓寡糖终浓度为0.18mg/mL时制备的POS-SeNPs的EDX能谱图。
图8为实施例2中空白对照组、肠炎模型组以及POS-SeNPs剂量为0.4mg/kg体重时的实验剂量组对结肠炎氧化应激的调节作用数据图，其中，A为MDA水平；B为GSH水平；C为MPO活性；D为GPx酶活性；E为结肠组织中硒含量；F为肝脏组织中硒含量；
图9为实施例2中空白对照组、肠炎模型组以及POS-SeNPs剂量为0.4mg/kg体重时的实验剂量组对小鼠结肠炎血清炎症因子的影响数据图，其中，A为血清IL-1β水平；B为血清IL-6水平；C为血清TNF-α水平；D为血清IL-12水平；E为血清MCP-1水平；F为血清IL-10水平。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例中所用试剂如无特殊说明均可从市场常规购得。
实施例1：茯苓寡糖功能化纳米硒的制备
(1)常温常压下，向质量浓度为10.0mg/mL的茯苓多糖(PPS)(购自上海源叶生物科技有限公司，产品编号：S25585)水溶液中加入β-甘露聚糖酶，加入后β-甘露聚糖酶的浓度为5单位(U)/mL，37℃水浴搅拌反应2小时，凝胶过滤层析分离收集寡糖组分，即为茯苓寡糖(POS)。
步骤(1)中茯苓多糖经β-甘露聚糖酶水解前后的糖组成以及标准糖谱如图1所示，从图1中可以看出，茯苓多糖(购自上海源叶生物科技有限公司，产品编号：S25585)主要含有岩藻糖、半乳糖、葡萄糖和甘露糖，经β-甘露聚糖酶水解后分离收集得到的水溶性寡糖组份为葡萄甘露寡聚糖，HPLC测得其平均分子量为3.24kDa，离子色谱测得其糖组构成为葡萄糖和甘露糖，两者比例为2:1，表明制备的茯苓寡糖为富含甘露糖的葡萄甘露寡聚糖。
(2)将步骤(1)中收集的茯苓寡糖(POS)配制成不同浓度系列(寡糖浓度依次为：0、0.05、0.1、0.2、0.4和0.8mg/mL)的水溶液，然后向其中加入等体积的亚硒酸钠溶液(对应硒浓度分别为：0.16、0.1、0.2、0.4、0.8和1.6mg/mL)，温和磁力搅拌(120rpm)混合均匀，然后搅拌条件下缓慢加入500mM的维生素C溶液形成反应溶液，反应溶液中维生素C的终浓度为5mM，继续搅拌反应2小时，待产物中所出现的红色不再加深，将所得产物透析15小时换水3次后(截留分子量8kDa)，通过ICP-MS检测透析袋外液体中硒浓度低于1ng/mL，收集透析袋内所得产物进行后续的实验。上述方法中，反应体系中加有茯苓寡糖所得功能化纳米硒，命名为POS-SeNPs，未加茯苓寡糖所得为空载纳米硒，命名为SeNPs。
步骤(2)中不同浓度的茯苓寡糖功能化修饰纳米硒的粒径如图2所示，从图2中可以看出在0～0.8mg/mL浓度范围内，当反应体系中茯苓寡糖POS的终浓度为0.18mg/mL时(图2中为0.2mg/mL，加入维生素C溶液后实际浓度为0.18mg/mL)，所生成的POS修饰功能化纳米硒(POS-SeNPs)不仅粒径最小，分散性良好，大小也最均匀。以这一条件制备的POS-SeNPs，悬在水溶液中贮存于4℃条件下，粒径大小随着时间的变化如图3所示，表明所制备的POS-SeNPs具有良好的稳定性，4℃下在水相中可稳定保存超过50天。
将步骤(2)中反应溶液中茯苓寡糖终浓度为0.18mg/mL时(即茯苓寡糖水溶液浓度为0.2mg/mL时)制备的POS-SeNPs与不含茯苓寡糖生成的空载纳米硒SeNPs，采用粒度散射分析仪进行平均粒径测定及大小分布分析，结果如图4所示，从图4中可以看出POS-SeNPs平均粒径明显小于SeNPs，纳米尺寸分布区间更集中，表明茯苓寡糖可调控功能化修饰纳米硒的大小及均一性。进而通过透射电子显微镜(TEM)观测其纳米形态，结果从图5中可以看出POS-SeNPs比SeNPs形貌更规则均匀，呈100nm以下圆球形。
将步骤(2)中反应体系茯苓寡糖终浓度为0.18mg/mL时制备的POS-SeNPs与不含茯苓寡糖生成的空载纳米硒SeNPs冷冻干燥得到干粉，将干粉置于铜台后利用傅立叶变换红外光谱法(FT-IR)测定其特征性红外光谱图，同时进行EDX扫描，测定其中碳、氧、硒元素的EDX能谱图，结果分别如图6、图7所示，可以看出POS-SeNPs中不仅含有相应的POS红外信号，而且有硒元素能谱峰。
综合图1～7的结果证明，本发明成功制备了富甘露糖的茯苓寡糖，进而研制出形貌规则、分散均匀、粒径适中(<100nm)的茯苓寡糖修饰功能化纳米硒POS-SeNPs，该种茯苓寡糖修饰功能化纳米硒表现出良好的稳定性，4℃下在水相中可稳定保存50天。
实施例2：茯苓寡糖功能化纳米硒拮抗肠炎作用
小鼠分组实验，在暨南大学医学院国家许可动物实验室进行。取雄性C57BL/6小鼠50只，随机分为5组，每组10只，分别为(1)空白对照组、(2)肠炎模型组、(3)-(5)实验剂量组。分笼正常饲喂1周后，(2)-(5)组小鼠按标准方法用含4％的DSS饮水诱导小鼠急性结肠炎模型持续5天，同时(3)-(5)组小鼠灌胃补充不同剂量的POS-SeNPs(按给硒量分别为0.08、0.4和1.0mg/kg体重)。每天对各组小鼠体重、腹泻、便血和其它症状进行详细记录，检测粪便潜血实验。实验结束处死小鼠，取各组小鼠血液、结肠组织和其它组织，进行炎症指标和肠道组织炎症病理变化的分析检测。
空白对照组、肠炎模型组以及POS-SeNPs补充硒剂量为0.4mg/kg体重的实验组对化学诱导结肠炎小鼠肠组织氧化应激的影响如图8所示，其中，A为MDA水平；B为GSH水平；C为MPO活性；D为GPx酶活性；E为结肠组织中硒含量；F为肝脏组织中硒含量。
空白对照组、肠炎模型组以及POS-SeNPs补充硒剂量为0.4mg/kg体重的实验组对化学诱导结肠炎小鼠血清中炎症因子水平的影响如图9所示，其中，A为血清IL-1β水平；B为血清IL-6水平；C为血清TNF-α水平；D为血清IL-12水平；E为血清MCP-1水平；F为血清IL-10水平。
从图8-9结果中可以看出，补充POS-SeNPs(硒0.4mg/kg体重)对DSS诱导的小鼠结肠炎具有明显缓解效果，可显著提升小鼠肠炎组织中硒营养积累，降低肠炎组织氧化应激水平和血清中炎症因子的表达释放水平。表明POS-SeNPs可协同增强硒抗氧化和POS免疫调节功能，平抑肠炎组织氧化应激和炎症因子释放，达到缓解结肠炎病变的作用。
实施例3：茯苓寡糖功能化纳米硒应用预测
将本发明实施例1制备的茯苓寡糖功能化纳米硒(POS-SeNPs)转化成辅助治疗肠炎和其它炎症性疾病的功能食品或保健品制剂，产生较大规模的社会经济效益。以我国为例，目前肠炎患者约600万人，以3个月疗程每人每天用本产品20元估算，产业化总市场规模可达104亿元，保守估计1/100市场占有率则可为达1亿元以上。本发明专利的应用转化将促进食品和药用多糖和硒粉原料工业，并生成片剂、胶囊和口服液系列产品，辅助治疗其它炎症性疾病，形成自有专利技术池和转化应用产业链。每天使用该制剂20元，使用疗程3个月，该产品可创造1.8亿产值，按20％计利税，年利税可达3600万元。产品使用方便，安全无毒，可减轻患病痛苦，提高生活质量，经济负担较少。产品具有良好成药性。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (10)
1.一种茯苓寡糖功能化纳米硒的制备方法，其特征在于包括以下步骤：利用茯苓寡糖组分作为调控剂，在还原型维生素C和亚硒酸钠组成的氧化还原体系中，制备得到茯苓寡糖功能化纳米硒POS-SeNPs。
2.根据权利要求1所述的茯苓寡糖功能化纳米硒的制备方法，其特征在于具体包括以下步骤：
(1)向茯苓多糖水溶液中加入β-甘露聚糖酶，37℃水浴搅拌反应2小时，凝胶过滤层析分离收集寡糖组分，即为茯苓寡糖；
(2)将茯苓寡糖的水溶液与等体积的亚硒酸钠水溶液混合，搅拌使混合均匀，然后在搅拌条件下向其中加入还原性维生素C溶液形成反应溶液，观察到反应溶液变红，继续搅拌反应直至产物中所出现的红色不再加深时，停止反应，将所得反应产物经过透析后即得茯苓多糖功能化纳米硒POS-SeNPs。
3.根据权利要求2所述的茯苓寡糖功能化纳米硒的制备方法，其特征在于：
步骤(1)中所述的茯苓多糖水溶液为浓度为10～50mg/mL的茯苓多糖水溶液；步骤(1)中所述的β-甘露聚糖酶的用量满足每10mg的茯苓多糖对应加入5单位(U)的β-甘露聚糖酶。
4.根据权利要求2所述的茯苓寡糖功能化纳米硒的制备方法，其特征在于：
步骤(1)中所制备的茯苓寡糖为富含甘露糖的葡萄甘露寡聚糖，其糖组构成为葡萄糖和甘露糖，两者质量比为2:1，其平均分子量为3.24kDa。
5.根据权利要求2所述的茯苓寡糖功能化纳米硒的制备方法，其特征在于：
步骤(2)中所述的茯苓寡糖的水溶液是指其中茯苓寡糖浓度为0.2～1.0mg/mL的水溶液；步骤(2)中所述的亚硒酸钠溶液是指硒浓度为0.4～2.0mg/mL的亚硒酸钠水溶液；步骤(2)中反应溶液中茯苓寡糖和硒的质量比为1:2；
步骤(2)中所述的还原性维生素C溶液是指浓度为100～500mmol/L的还原性维生素C溶液；步骤(2)中所述的还原性维生素C溶液的用量满足加入还原性维生素C溶液以后反应溶液中维生素C的终浓度为4～5mmol/L；
步骤(2)中所述的透析是指透析袋的截留分子量为8kDa。
6.一种根据权利要求1～5任一项方法制备得到的茯苓寡糖功能化纳米硒。
7.根据权利要求6所述的茯苓寡糖功能化纳米硒，其特征在于：
所述的茯苓寡糖功能化纳米硒形貌规则、分散均匀、粒径<100nm，具有良好的稳定性，4℃下在水相中稳定保存50天。
8.根据权利要求6或7所述的茯苓寡糖功能化纳米硒作为生物功能制品中的应用。
9.根据权利要求8所述的应用，其特征在于：
所述的生物功能制品为功能食品、营养保健品、复方药物成分或候选药物。
10.根据权利要求8所述的应用，其特征在于：
所述的生物功能制品是指适用于炎症性肠病、高脂血症、动脉粥样硬化、糖尿病、肠道肿瘤的辅助治疗的生物功能制品。
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