CN106539092B - 一种绿藻多糖化纳米硒及其制备方法与应用 - Google Patents
一种绿藻多糖化纳米硒及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开一种绿藻多糖化纳米硒及其制备方法与应用，属于生物技术领域。本发明建立简便的天然绿藻多糖化纳米硒(PSSNP)是人体必需微量营养元素，多糖对机体具有免疫调节作用。本发明研发出一种安全有效的新的多糖化纳米硒，实现纳米尺寸均一性、液相保存稳定性和多糖化高效率。本发明的绿藻多糖化纳米硒(PSSNP)制品，主要适用于辅助治疗肠炎和炎症性肠病，也可用于高脂血症、动脉粥样硬化、糖尿病和其它炎症相关疾病的辅助预防治疗；其使用简便，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
本发明属于生物技术领域，特别涉及一种绿藻多糖化纳米硒及其制备方法与应用。
背景技术
炎症性肠病(Inflammation bowel disease，IBD)是一类肠道慢性复发性炎症性疾病，其中溃疡性结肠炎(Ulcerative colitis，UC)和克罗恩病(Crohn’sDisease，CD)最为普遍。近年来其发病率在我国有逐渐升高趋势，但传统治疗主要依赖的类固醇激素和柳氮磺吡啶(SASP)，疗效不理想，复发率高，副作用多，在疾病的慢性期治疗及在预防复发方面也受到限制；因而IBD被认为是临床上顽固的疾病，易于复发，常使患者丧失劳动能力和严重影响患者生活质量。
炎症性肠炎的一大标志就是肠道免疫炎症细胞浸润，以及肠黏膜上皮细胞的促炎细胞因子和趋化因子的过表达，包括IL-1β，IL-6，TNF-α，MCP-1等。肠黏膜上皮细胞位于绒毛表面，形成了第一道天然免疫屏障。通过释放促炎细胞因子和趋化因子，以及持续的抗原暴露启动了白细胞的粘膜浸润。因此，肠道上皮在IBD的发病机理中扮演了关键的角色，它可以通过肠道免疫系统各部分的相互作用调节局部的炎症和免疫反应。有研究发现，随着外来病菌的入浸，加速了肠道上皮细胞释放IL-1β，IL-6，TNF-α和某些趋化因子，招募并激活循环系统中的免疫细胞至粘膜的炎症位点上，并且持续释放更多细胞因子，最终刺激诱发和维持IBD的炎症性。纵观国内外一个多世纪以来对炎症性肠病的研究，众多科学家已从多方面阐述了炎症性肠病与多种因素的关系，包括免疫、遗传、环境等。尽管有大量证据证实免疫调节异常在炎症性肠病的发病中处于关键作用，但至今仍无法全面阐明IBD确切的发病机制。普遍认为IBD与粘膜免疫系统的持续激活有关，结果导致T细胞被激活并分泌NF-κB依赖的趋化因子和细胞因子。而这些得益于人类的IBD和动物的结肠炎模型研究。早在1996年，Nuerhat等在TNBs诱发的结肠炎动物模型中发现炎症肠道组织中NF-κB被激活，诱导调控基因转录。且研究表明炎症性肠炎患者的白介素IL-1、IL-6和TNF-α提高。此外，NF-κB在激活辅助T细胞1(Th1)和辅助T细胞2(Th2)细胞中起着至关重要的作用，这两者均参与调控炎症的促进和持续。由此可见，NF-κB信号通路在IBD发生进展中扮演着非常重要角色，因此我们针对这个信号通路开发免疫调节生物制剂具有切实的科学理论依据。
人体必需微量元素硒(selenium，Se)在体内以硒代半胱氨酸(selenocysteine，Se-Cys)形式，通过构成25种重要硒蛋白(selenoprotein)或硒酶(selenoenzyme)的功能活性中心而发挥作用。现今发现硒蛋白参与调控机体内氧化还原平衡、激素和代谢稳态、先天和获得性免疫应答、炎症反应，从而参与调控肿瘤发生、心血管疾病和病毒感染等众多疾病病理生理过程。已经阐明的硒和硒蛋白抗炎症作用机制提示，其对氧化还原信号和免疫应答的调节与NF-κB信号通路和Th1/Th2细胞因子平衡有关。另外，在肠炎和IBD发展过程中，会造成低硒营养状态，加重肠道炎症和肠道微生态紊乱，对IBD炎症起负反馈效应。因此，合理利用硒的营养，发挥硒蛋白质的功能，是拮抗和治疗IBD炎症的有效策略。近些年来，随着纳米硒生物活性的发现，纳米硒的研制和它们在生化和医学领域中的应用前景引起了不同领域科研人员的关注。我们课题组长期致力于活性硒形态的制备、功能发掘和应用开发，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。
绿藻多糖是一种纯天然富硫酸酯多糖，有较好的抗氧化、免疫调节和抗肿瘤活性，且对纳米硒的稳定性和生物活性具有增强作用。研究发现硒多糖的生物活性普遍高于多糖和硒，硒多糖的研究具有一定的开发价值。我们研制出新型绿藻多糖化纳米硒(PSSNP)基础上，发现其拮抗肠道炎症反应的新作用和对实验性小鼠炎症性肠病(IBD)具有治疗效果。
发明内容
为了克服现有技术的缺点与不足，本发明的首要目的在于提供一种绿藻多糖化纳米硒。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，目前主要存在纳米硒尺寸调控、稳定性和活性分子富载效率等问题。本发明建立简便的天然绿藻多糖化纳米硒(PSSNP)是人体必需微量营养元素，多糖对机体具有免疫调节作用。本发明研发出一种安全有效的新的多糖化纳米硒，实现纳米尺寸均一性、液相保存稳定性和多糖化高效率。
本发明的另一目的在于提供所述的绿藻多糖化纳米硒的制备方法。
本发明的再一目的在于提供所述的绿藻多糖化纳米硒的应用。
证明多糖化纳米硒PSSNP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。欧美发达国家IBD发病率高，我国人群近年来IBD发生呈上升趋势，其中仅溃疡性结肠炎(UC)的发病率已达6‰，IBD被WHO认定为临床疑难病症，尚无根治方法，目前主要治疗措施存在严重副作用。为此，观察经口服补充PSSNP后对小鼠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PSSNP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技术方案实现：
一种绿藻多糖化纳米硒，该纳米硒形貌规则、分散均匀、粒径适中，且表现出良好的稳定性，4℃下在水相中稳定保存1个月。
所述的绿藻多糖化纳米硒的制备方法，包括如下步骤：
利用绿藻多糖作为调控剂，在简单的氧化还原体系(还原型Vc和亚硒酸钠)中，制备得到绿藻多糖化纳米硒(PSSNP)。
具体包括如下步骤：
在含有10mg/mL的绿藻多糖水溶液中加入亚硒酸钠溶液，终浓度为1mM，混合均匀，然后滴加还原性维生素C溶液，终浓度为4mM，边滴加边混匀，定容后待产物中所出现的红色不再加深，即可得到功能化纳米硒溶胶；溶胶经过透析后，获得绿藻多糖化纳米硒(PSSNP)。
所述的绿藻多糖化纳米硒作为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肠炎和炎症性肠病，也可用于高脂血症、动脉粥样硬化、糖尿病和其它炎症相关疾病的辅助预防治疗。
证明绿藻多糖修饰纳米硒具有较好缓解肠炎症状和抗炎症效果：利用DSS诱导建立的小鼠肠炎模型，观察经口补充绿藻多糖修饰纳米硒后对模型小鼠体重和临床症状的影响，并检测PSSNP对IBD小鼠血液生化、炎症指标和肠道组织炎症病理变化的治疗作用。结果发现补充PSSNP，按其中含硒量计算，补充硒0.8ppm体重剂量组对DSS诱导的小鼠慢性IBD具有明显疗效，可显著降低小鼠血浆中IL-6和TNF-α等炎症因子的水平，上调小鼠血浆中IL-10抗炎症因子的水平。分子机制研究进一步阐明PSSNP主要通过抑制NF-κB介导的炎症信号转导，发挥其抗炎症作用。
目前技术研发进度：研制的绿藻多糖修饰纳米硒是一种生物利用度高、毒性低制品；同时，已完成其成药性实验评价和急性毒性试验，正在进行临床前实验申报和组合药物成分研发。
本发明相对于现有技术，具有如下的优点及效果：
由于炎症性肠病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。本项目研发的绿藻多糖化纳米硒(PSSNP)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是实施例制备的绿藻多糖化纳米硒的形貌图和实施例制备的绿藻多糖化纳米硒的纳米粒度图。
图2是实施例中急性肠炎模型组的体重变化情况。
图3是实施例中急性肠炎模型组的DAI(疾病活动指数)变化情况。
图4是实施例中病理组织切片的结果图；其中，A为空白组(Control)；B为DSS组；C为DSS+PSSNP(0.08ppm)；D为DSS+PSSNP(0.4ppm)；E为DSS+PSSNP(0.8ppm)。
图5是实施例中急性肠炎模型组血清中的IL-6、TNF-α和IL-10的变化情况；其中；A为IL-6；B为TNF-α；C为IL-10。
具体实施方式
下面结合实施例及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1
1)绿藻多糖修饰纳米硒制备：常温常压下，在含有10mg/mL的绿藻多糖水溶液中加入亚硒酸钠溶液，亚硒酸钠的终浓度为1mM，混合均匀，然后滴加还原性维生素C溶液，维生素C的终浓度为4mM，边滴加边混匀，定容后待产物中所出现的红色不再加深，即可得到功能化纳米硒溶胶(即绿藻多糖化纳米硒)。溶胶经过24h透析后(截留分子量8000kDa)。通过用透射电子显微镜(TEM)观察功能化纳米硒形貌，纳米粒度仪，测定PSSNP的纳米尺寸。结果见图1-A和图1-B所示。结果表明，本发明制备出形貌规则、分散均匀、粒径适中(在100nm左右)的纳米硒PSSNP硒表现出良好的稳定性，4℃下在水相中稳定保存1个月。
2)绿藻多糖修饰纳米硒拮抗肠炎作用和抗炎症效果：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40只，随机分为5组，每组8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％DSS饮水诱导小鼠肠炎模型持续6天，同时(3)～(5)组小鼠经口补充不同剂量的PSSNP(按给硒量分别为0.08ppm、0.4ppm和0.8ppm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。结果见图2～5所示。结果发现补充PSSNP(硒0.8ppm体重)对DSS诱导的小鼠慢性IBD具有明显疗效，可显著降低小鼠血浆中IL-6和TNF-α等炎症因子的水平，上调小鼠血浆中IL-10炎症因子的水平。进一步还证明PSSNP主要通过抑制NF-κB介导的炎症信号转导，发挥其抗炎症作用。
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 (5)
1.一种绿藻多糖化纳米硒的应用，其特征在于：
所述的绿藻多糖化纳米硒在制备生物功能制品中的应用；
所述的生物功能制品适用于辅助治疗肠炎；
所述的绿藻多糖化纳米硒的制备方法，包括如下步骤：
利用绿藻多糖作为调控剂，在简单的氧化还原体系中，制备得到绿藻多糖化纳米硒；
具体包括如下步骤：
在含有10mg/mL的绿藻多糖水溶液中加入亚硒酸钠溶液，终浓度为1mM，混合均匀，然后滴加还原性维生素C溶液，终浓度为4mM，边滴加边混匀，定容后待产物中所出现的红色不再加深，即得到功能化纳米硒溶胶；溶胶经过透析后，获得绿藻多糖化纳米硒。
2.根据权利要求1所述的应用，其特征在于：
所述的纳米硒形貌规则、分散均匀、粒径适中，且表现出良好的稳定性，4℃下在水相中稳定保存1个月。
3.根据权利要求1或2所述的应用，其特征在于：
所述的生物功能制品为复方药物成分或候选药物。
4.根据权利要求1或2所述的应用，其特征在于：
所述的生物功能制品适用于辅助治疗炎症性肠病。
5.根据权利要求3所述的应用，其特征在于：
所述的生物功能制品适用于辅助治疗炎症性肠病。
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