CN116139291B - 一种广谱活性物质清除功能胶束及其制备方法和应用 - Google Patents
一种广谱活性物质清除功能胶束及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种广谱活性物质清除功能胶束及其制备方法和应用,涉及抗炎药物技术领域,本发明所述胶束由如下质量份的组分组成:TSPBA 2~50份、EGCG 2~46份、Na2SeO31~12份、维生素C 3~44份。本发明通过EGCG中的儿茶酚基团与TSPBA中的苯硼酸基团形成两个可逆的硼酸酯键,进而形成EGCG‑TSPBA胶束,增加了EGCG的稳定性。本发明利用胶束的疏水空腔和EGCG中羟基的氢键作用包裹经维生素C还原Na2SeO3而原位成的硒纳米粒子,有效避免因硒纳米粒子聚集而丧失活性的问题,制得的EGCG‑TSPBA‑Se胶束含EGCG、硒两种功能物质,从而具有广谱活性物质清除功能。
Description
技术领域
本发明涉及抗炎药物技术领域,具体涉及一种广谱活性物质清除功能胶束及其制备方法和应用。
背景技术
非酒精性脂肪肝病(NAFLD)是指酒精外和其他明确的损肝因素导致的肝细胞内脂肪过度沉积的临床病理综合征,包括单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)。随着社会进步和经济发展,NAFLD已经成为全球性慢性肝病的重要病因。NAFLD相关并发症主要包括高脂血症、肥胖和II型糖尿病。目前还没有明确的治疗NAFLD的药物上市。因此,对NAFLD的治疗药物一直是研究的热点。
非酒精脂肪性肝疾病的发病机制较为复杂,目前较为公认的关键发病因素为“二次打击”学说。其中胰岛素耐受引发的第一次打击会引起组织脂肪的分解并且能够抑制肝脏内甘油三酯的利用,使其沉积在肝脏内,引发肝脏脂肪变性。脂肪变性一旦发生,肝脏就更易受到第二次打击。二次打击是由多种因素引起的损伤,主要包括氧化应激、脂质过氧化、自由基的大量产生等。其中,氧化应激与其引起的脂质过氧化是二次打击引发NAFLD恶化的重要因素。因此,抗炎在治疗非酒精性脂肪肝病及其相关疾病中非常重要。
在炎症部位中,往往存在多种活性氧,如:双氧水、羟基自由基、超氧阴离子自由基等。然而,当前的天然酶和人工纳米酶虽然对某些特定的活性氧有高效的清除能力,但是对疾病过程中产生的多种活性氧的抗氧化作用不足。因此急需开发一种具有广谱活性氧清除能力的材料。
表没食子儿茶素没食子酸酯(EGCG)是绿茶中含量最丰富的多酚类化合物,与其他儿茶素相比,因其含有更多的酚羟基和没食子酰基,对活性氧(ROS)产生的抑制作用和自由基清除活性更强。然而,由于其稳定性差和多羟基结构,EGCG的靶向细胞摄取效率和生物利用度相当低,这限制了其生物利用。黄龙月的学位论文《新型微米复合物提高茶叶活性成分EGCG稳定性及抗炎效果的研究》中也有提到,EGCG在摄入人体后在胃肠道消化过程中破坏严重,因此制约了EGCG在功能食品和医药领域中的应用,其采用的米糠白蛋白提取物RBAI负载EGCG,借此提高EGCG的稳定性和抗炎效果,虽然最终相对于未负载在RBAI上的EGCG而言,取得了明显的进步,但就其数据上看,EGCG保留量从7.6%提升到18.9%。但在功能上,仍然不能实现多种活性物质的清除,功能比较单一。
发明内容
针对现有技术中的上述问题,本发明提供一种广谱活性物质清除功能胶束及其制备方法,以解决现有技术无法清楚多种活性物质的技术问题。本发明还提供了该胶束的应用,除了抗炎症,还提供了降低总胆固醇、甘油三酯等应用。
本发明采用的技术方案如下:
一种广谱活性物质清除功能胶束,由如下质量份的组分组成:TSPBA 2~50份、EGCG2~46份、Na2SeO3 1~12份、维生素C 3~44份。
广谱活性物质清除功能胶束的制备方法,包括如下步骤:
(1)制备EGCG-TSPBA胶束:分别将TSPBA、EGCG溶入水中形成溶液,而后将EGCG水溶液滴加至TSPBA水溶液中,涡旋混合,静置30min,即可得到EGCG-TSPBA胶束;
(2)制备EGCG-TSPBA-Se胶束:向EGCG-TSPBA胶束中缓慢滴加Na2SeO3水溶液,室温搅拌4h,再缓慢滴加维生素C,继续室温搅拌反应60min;反应结束后,离心弃去上清液以去除游离药,收集沉淀,即得到具有广谱活性氧清除功能的EGCG-TSPBA-Se胶束。
作为优选地,所述TSPBA的合成过程为:将N,N,N’,N’-四甲基-1,3-丙二胺和4-(溴甲基)苯硼酸加入到二甲基甲酰胺中,60℃搅拌12h,然后放入四氢呋喃中浸泡4h,过滤后用四氢呋喃清洗若干次,真空干燥24h即得TSPBA。
广谱活性物质清除功能胶束在清除生物体中活性氧、DPPH自由基、羟基自由基、超氧阴离子自由基的药物中的应用。
广谱活性物质清除功能胶束在制备抗炎药物中的应用。
广谱活性物质清除功能胶束在降总胆固醇、甘油三酯的药物中的应用。
广谱活性物质清除功能胶束在治疗非酒精性脂肪肝病及其相关疾病的药物中的应用。
综上所述,相比于现有技术,本发明具有如下优点及有益效果:
1、本发明通过EGCG中的儿茶酚基团与TSPBA中的苯硼酸基团形成两个可逆的硼酸酯键,进而形成EGCG-TSPBA胶束,增加了EGCG的稳定性。
2、本发明利用胶束的疏水空腔和EGCG中羟基的氢键作用包裹经维生素C还原Na2SeO3而原位形成的硒纳米粒子,有效避免因硒纳米粒子聚集而丧失活性的问题,制得的EGCG-TSPBA-Se胶束含EGCG、硒两种功能物质,从而具有广谱活性物质清除功能。硒(Se)是一种对哺乳动物具有重要营养价值的必需微量元素,它可以帮助细胞抵抗氧化损伤,具有良好的生物相容性和清除羟基自由基(·OH)的能力。本发明通过胶束的束绑作用解决了硒的低反应性和不稳定性问题,为Se作为抗氧化剂的临床应用提供了新思路。
3、本发明原料来源广泛,制备方法简单,制备的EGCG-TSPBA-Se胶束粒径较为均一,为50-200nm;对于活性氧以及其他自由基等活性物质均具有清除功能,且对多种活性物质均有良好的清除效果,能够有效治疗非酒精性脂肪肝病及其相关疾病;具有较好的稳定性,能够在4℃长久保存。
附图说明
为了更清楚地说明本发明实施例中的技术方案,下面将对实施例描述中所需要使用的附图作一简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其它的附图。
图1是本发明实施例1制备的EGCG-TSPBA-Se胶束的TEM图。
图2是各物质清除双氧水能力对比图。
图3是各物质清除DPPH自由基能力对比图。
图4是各物质清除羟基自由基能力对比图。
图5是各物质清除超氧阴离子自由基能力对比图。
图6是各物质在细胞中的活性氧清除能力对比图。
图7是各物质经尾静脉注射后,小鼠肝组织中总胆固醇、甘油三酯的水平对比图。
图8是各物质经尾静脉注射后,小鼠肝指数(肝脏重量mg/体重g)对比图。
图9是各物质经尾静脉注射后,小鼠肝组织H&E染色对比图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图以及各实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明,即所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
在这里专用的词“实施例”,作为“示例性”所说明的任何实施例不必解释为优于或好于其它实施例。本法实施例中性能指标测试,除非特别说明,采用本领域常规试验方法。本发明中所述的术语仅仅是为描述特别的实施方式,并非用于限制本发明公开的内容。
除非另有说明,否则本文使用的技术和科学术语具有本发明所属技术领域的普通技术人员通常理解的相同含义;作为本发明中的其它未特别注明的原材料、试剂、试验方法和技术手段均指本领域内普通技术人员通常使用的原材料和试剂,以及通常采用的实验方法和技术手段。
实施例1
本实施例提供的EGCG-TSPBA-Se胶束按照如下制备过程制备:
(1)EGCG-TSPBA的合成:将14.61mg的TSPBA(市购)加入到3ml水中,13.74mg的EGCG加入到3ml水中,超声溶解;再将EGCG水溶液滴加至TSPBA水溶液中,涡旋混合,静置30min,驱动复合物形成EGCG-TSPBA胶束。
(2)EGCG-TSPBA-Se的合成:向步骤(2)的EGCG-TSPBA胶束中,缓慢滴加3.46mg/ml的亚硒酸钠水溶液1ml,室温搅拌4h;缓慢滴加7mg/ml的抗坏血酸2ml,继续室温搅拌反应60min;反应结束后,12000r/min离心15min,弃去上清液,得沉淀,即为具有广谱活性氧清除功能的EGCG-TSPBA-Se胶束,其透射电镜图与实施例1所得胶束的透射电镜图区别不大,此处省略电镜图,本实施例制备得到的EGCG-TSPBA-Se胶束,其纳米制剂粒径均一,平均粒径为50-200nm。
将实施例1所得胶束进行功能性试验,具体如下:
1、清除双氧水能力的检测
胶束清除双氧水能力检测见图2。图2分别是TSPBA,Se,EGCG,EGCG-TSPBA,EGCG-TSPBA-Se清除双氧水情况。其中各组制剂浓度均为50μM,与1mmol/L双氧水反应30min后,在240nm处测得紫外吸光度。从图中可以看出,TSPBA几乎没有双氧水清除能力,Se,EGCG,EGCG-TSPBA有一定的清除能力,而EGCG-TSPBA-Se的双氧水清除能力能达到83.12%,远优于其他各组。说明按上述方法制备的具有广谱活性氧清除功能的胶束表现出高效的双氧水清除能力。
2、清除DPPH自由基能力的检测
图3分别是TSPBA,Se,EGCG,EGCG-TSPBA,EGCG-TSPBA-Se清除DPPH情况。其中各组制剂浓度均为50μM,与0.1mg/ml DPPH避光反应30min,在517nm处测得紫外吸光度。从图中可以看出,EGCG-TSPBA-Se清除DPPH能力最强,远优于其他各组。说明按上述方法制备的具有广谱活性氧清除功能的胶束表现出高效的DPPH清除能力。
3、清除羟基自由基能力的检测
通过ESR评估胶束清除羟基自由基的能力见图4。使用5,5-二甲基-1-吡咯啉-N-氧化物(DMPO)作为捕获剂。配置浓度为5mg/ml的FeSO4溶液,取200μL该溶液先加入20μLDMPO,再分别加入160μL去离子水和胶束溶液,最后加入20μL 30%浓度的双氧水,混匀反应10min后取样测试。从图中可以看出,加入EGCG-TSPBA-Se后峰强度显著降低。说明按上述方法制备的具有广谱活性氧清除功能的胶束能够高效清除羟基自由基。
4、清除超氧阴离子自由基能力的检测
通过ESR评估胶束清除超氧阴离子自由基的能力见图5。使用5,5-二甲基-1-吡咯啉-N-氧化物(DMPO)作为捕获剂。用PBS缓冲液作为溶剂,配置浓度为10mM的黄嘌呤溶液和浓度为1U/ml的黄嘌呤氧化酶溶液,取100μL黄嘌呤溶液和100μL黄嘌呤氧化酶溶液,先加入20μL DMPO,再分别加入180μL缓冲液和胶束溶液,反应孕育10min后取样测试。从图中可以看出,加入EGCG-TSPBA-Se后峰强度显著降低。说明按上述方法制备的具有广谱活性氧清除功能的胶束能够高效清除超氧阴离子自由基。
从图2、3、4、5中可以看出,本发明方法制得的胶束能够高效清除多种活性氧,包括双氧水、羟基自由基、超氧阴离子自由基,并用DPPH代替其他活性氧自由基进行检测,同样具有高效清除能力,可以证明胶束具有广谱的活性物质清除功能。
5、在细胞中的活性氧清除能力的检测
检测该胶束在Raw264.7细胞中清除活性氧能力见图6,分别将TSPBA,Se,EGCG,EGCG-TSPBA,EGCG-TSPBA-Se与细胞共培养6h后,用300μmol/L的双氧水处理细胞3h作为实验组。只用培养基培养细胞作为空白对照组,不加制剂与细胞共培养只用双氧水处理作为阳性对照组,所有组再用活性氧探针(DCFH-DA)检测细胞内活性氧。其中,培养基中制剂浓度均为100μmol/L,活性氧探针(DCFH-DA)用不加血清的培养基1:1000稀释,避光处理细胞30min。Raw264.7在6孔板中2×105/孔。从图中可知,双氧水刺激细胞3h再用活性氧探针检测细胞内活性氧水平,可以看到细胞呈现出明显的绿色荧光,即双氧水刺激细胞3h可以使细胞内的活性氧水平上升;若先加入胶束与细胞共培养6h再加入双氧水刺激,细胞内并不会产生明显的活性氧水平上升。证明在细胞层面上,本发明方法制得的胶束可以有效降低细胞内的活性氧水平。
6、对非酒精性脂肪肝病的治疗作用试验
本实验使用高脂肪含量的饲料喂养C57小鼠,设置非酒精性脂肪肝模型组(HFD)、静脉注射给药组(TSPBA,Se,EGCG,EGCG-TSPBA,EGCG-TSPBA-Se,以及静脉给药+低脂饮食组(EGCG-TSPBA-Se+LFD)和正常饮食组(NC)来探究该胶束对非酒精性脂肪肝病的治疗作用。其中,制剂给药量均为5mg/kg。实验结束以后,去小鼠肝组织,进行H&E染色,并对其进行病理分析。此外,研究小鼠肝组织中总胆固醇、甘油三酯的水平以及肝指数(肝脏重量mg/体重g)的变化。
结果表明,静脉注射EGCG-TSPBA-Se后,小鼠肝组织中总胆固醇、甘油三酯的水平明显低于其他各组(图7),且肝指数恢复到正常饮食组水平(图8)。H&E染色结果显示,HFD组小鼠肝组织出现大量大小不等的脂滴,即肝脏脂质积聚所致的肝脂肪变性;静脉注射EGCG-TSPBA-Se后,小鼠肝组织脂滴数量显著减少,恢复到正常饮食组水平(图9)。因此,EGCG-TSPBA-Se胶束对非酒精性脂肪肝病具有显著的治疗作用。
以上所述实施例仅表达了本申请的具体实施方式,其描述较为具体和详细,但并不能因此而理解为对本申请保护范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本申请技术方案构思的前提下,还可以做出若干变形和改进,这些都属于本申请的保护范围。
Claims (4)
1.一种广谱活性物质清除功能胶束,其特征在于,由如下质量份的组分组成: TSPBA 2~50份、EGCG 2~46份、Na2SeO3 1~12份、维生素C 3~44份;所述胶束的制备过程包括如下步骤:
(1)制备EGCG-TSPBA胶束:分别将TSPBA、EGCG溶入水中形成溶液,而后将EGCG水溶液滴加至TSPBA水溶液中,涡旋混合,静置30 min,即可得到EGCG-TSPBA胶束;
(2)制备EGCG-TSPBA-Se胶束:向EGCG-TSPBA胶束中缓慢滴加Na2SeO3水溶液,室温搅拌4h,再缓慢滴加维生素C,继续室温搅拌反应60 min;反应结束后,离心弃去上清液以去除游离药,收集沉淀,即得到具有广谱活性氧清除功能的EGCG-TSPBA-Se胶束。
2.如权利要求1所述的广谱活性物质清除功能胶束的制备方法,其特征在于,包括如下步骤:
(1)制备EGCG-TSPBA胶束:分别将TSPBA、EGCG溶入水中形成溶液,而后将EGCG水溶液滴加至TSPBA水溶液中,涡旋混合,静置30 min,即可得到EGCG-TSPBA胶束;
(2)制备EGCG-TSPBA-Se胶束:向EGCG-TSPBA胶束中缓慢滴加Na2SeO3水溶液,室温搅拌4h,再缓慢滴加维生素C,继续室温搅拌反应60 min;反应结束后,离心弃去上清液以去除游离药,收集沉淀,即得到具有广谱活性氧清除功能的EGCG-TSPBA-Se胶束。
3.如权利要求2所述的制备方法,其特征在于,所述TSPBA的合成过程为:将 N,N,N’,N’-四甲基-1,3-丙二胺和4-(溴甲基)苯硼酸加入到二甲基甲酰胺中,60 ℃搅拌12 h,然后放入四氢呋喃中浸泡4h,过滤后用四氢呋喃清洗若干次,真空干燥24h即得TSPBA。
4.如权利要求1所述的广谱活性物质清除功能胶束在制备治疗非酒精性脂肪肝病的药物中的应用。
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