CN112933242B - 儿茶酚与胶原三肽自组装纳米复合物及制备和应用 - Google Patents
儿茶酚与胶原三肽自组装纳米复合物及制备和应用 Download PDFInfo
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Abstract
本发明提供儿茶酚与胶原三肽自组装纳米复合物及制备和应用,该纳米复合物由天然多酚、胶原三肽和高分子聚合物组成。先通过氢键作用自发组装形成EGCG/CTP纳米粒子,再利用树枝状大分子聚合物将EGCG/CTP纳米粒子在静电吸附相互作用下压缩形成粒径大小更为均一、形态更为规则的GECNs纳米复合物。本发明纳米复合物对细胞造成的毒性小,具有良好的生物相容性,并且在经皮递送治疗特异性皮炎和银屑病方面显示出与市售的他克莫司软膏和丙酸氯倍他索乳膏相当的治疗效果。本发明提供的一种新型的经皮递送系统,具有皮肤病治疗的临床转化应用价值。
Description
技术领域
本发明属于药剂学、生物材料学和皮肤医学等领域,涉及一种儿茶酚与胶原三肽自组装纳米复合物及制备和应用。具体是将一种天然化合物儿茶酚分子表没食子儿茶素没食子酸酯(EGCG)与人工合成胶原三肽胶原三肽(CTP)自发组装形成纳米粒子,再利用树枝状大分子聚合物G5-PAMAM将EGCG/CTP纳米粒子压缩形成GECNs(G5-PAMAM/EGCG/CTP)纳米复合物用于特异性皮炎和银屑病的皮肤炎症治疗。
背景技术
皮肤为人体最大的器官。主要承担的作用为:保护人体内各器官和组织免受外界机械性、物理性、化学性和病原微生物的侵入。人体的皮肤组织由表皮、真皮、皮下组织三个部分组成。表皮层从上到下分为5层,分别为角质层,透明层,颗粒层,棘层,基底层。角质层位于表皮层的最外层,由已经死亡的角质形成细胞组成,其厚度大约在15~20um。人体表皮层的厚度大约50~150um。角质层将人体外内环境分隔开,起到主要的物理屏障作用。角质层的脂质主要包括游离脂肪酸、神经酰胺类和胆固醇三大类。角质层能够阻碍亲水性药物和相对分子质量大于500Da的生物大分子渗透进入皮肤。角化细胞和数量不多但却发挥着重要作用的朗格汉斯细胞、黑色素细胞等组成表皮内的细胞。真皮层位于表皮层的下方,真皮层内的细胞主要有真皮树突状细胞、成纤维细胞、肥大细胞等,还包含有大量的胶原蛋白纤维,神经组织,血管组织和淋巴组织。丰富的脂肪细胞通过大量的胶原蛋纤维连接组成真皮层下方的皮下脂肪组织,其功能有维持热量和储存热量,能发挥缓冲保护作用当机体受到外界机械碰撞时。皮肤真皮层或者皮下脂肪层还含有大量的附属器官如皮脂腺,汗腺,毛囊等,皮肤表面pH为3~5的酸性环境与皮脂腺分泌的皮脂中含有脂肪酸和乳酸有关,从而抑制微生物的生长。所以,虽然人体皮肤表面随时随地都会接触大量的病菌及微生物,但是由于皮肤天然的屏障功能存在保护了人体的健康。对于经皮给药递送系统,通过局部给药可以使药物定位于皮肤进行靶向治疗,可绕过口服后的第一次代谢(肝脏首过效应)提高生物利用度。
纳米技术的出现彻底改变了口服、外用和肠外药物的给药方式。纳米粒子作为药物载体可以潜在地提高药物的靶向性性、生物利用度和治疗效果,同时提高患者在治疗期间的依从性。此外,纳米颗粒为基础的药物递送增强其滞留,并可在皮肤内疾病部位调节释放动力学。
特应性皮炎(AD)是一种慢性复发性皮肤病,伴有湿疹和剧烈瘙痒。AD的标志特征是表皮上层屏障功能的破坏,导致皮肤干燥和IgE介导的对各种过敏原的致敏效应。事实上,AD的致病机制很复杂,包括抗微生物防御能力受损,皮肤屏障功能的改变,对过敏原的适应性免疫反应和先天性免疫反应失调,多个易感基因之间复杂的相互作用以及免疫系统失调所涉及的环境因素。特应性皮炎与异常的免疫平衡有关,2型辅助T细胞的免疫反应高于1型辅助T细胞的免疫反应。在特应性皮炎中,Th2细胞因子(如IL-4和IL-5)的产生增加,而Th1细胞因子(如IFN-γ)的表达下调,导致免疫状态不平衡,倾向于2型免疫反应。因此,目前治疗特应性皮炎最有效的方法之一是通过增强Th1和下调Th2来恢复Th1和Th2免疫之间的免疫平衡。
银屑病是一种最常见的以多基因为主的慢性免疫介导炎症性红斑皮肤病,影响着全世界大约2%的人口。其病理特征是角质形成细胞过度增殖、表皮增生以及炎症性白细胞在表皮层和真皮层中大量浸润。目前银屑病确切的发病机制仍不清楚,主要是环境和遗传因素之间的相互作用,一些机体内部和环境的刺激,包括创伤、感染或某些药物,可以触发银屑病的进展。一般认为,银屑病发病机制的启动因素是皮肤中树突状细胞的异常活化导致了免疫系统相关细胞与角质形成细胞之间复杂的相互作用。IL-23/IL-17细胞因子轴在牛皮癣的发病机理中起关键作用。皮肤中活化的树突状细胞释放IL-12和IL-23,导致T细胞分化成为1型辅助T细胞和Th 17细胞,释放包括IL-17和IL-23的Th1和Th17细胞因子。在此过程中,IL-23,IL-17,IL-22,IL-1β,IL-6和TNF-α作为网络相互作用,随后进一步激活角质形成细胞并诱导角质形成细胞增殖。
截止目前,特异性皮炎和银屑病的治疗策略包括多种选择,从局部用药(局部皮质类固醇和维生素D类似物)、全身用药(甲氨蝶呤、环孢素a和维甲酸)、日光疗法(广谱、窄谱紫外线UVA)到免疫疗法(特异性siRNA、IL-12/23拮抗剂)。尽管有多种治疗选择,但是有效的皮肤病治疗仍然具有挑战性,因为该类疾病是多因素的和多基因的。大多数患有轻度至中度疾病的特异性皮炎和银屑病的患者经常接受基于类固醇的局部制剂治疗。由于潜在的副作用,例如皮肤萎缩,速激肽的过表达和停药后的症状反弹即反跳现象,因此不建议长期使用类固醇。相较于全身治疗,局部治疗又具有较低的全身毒性和对受影响皮肤的潜在靶向性,其仍是目前临床治疗银屑病的重要手段。
另外,药物的渗透性差也是目前皮肤病局部治疗的一个瓶颈。由于皮肤病的生理病理,炎症皮损导致角质层增厚和异常成熟,天然皮肤保湿剂缺乏,脂质失衡,阻碍药物的渗透,减少药物在皮肤中的滞留,从而降低治疗效果。目前仍然缺乏安全有效的局部治疗。因此,开发一个创新的经皮给药系统,以加强药物渗透至皮肤层对于局部治疗特异性皮炎和银屑病是至关重要的。
表没食子儿茶素没食子酸酯(EGCG)是从绿茶儿茶素中提取的多酚化合物,具有很强的螯合作用和抗氧化活性,因为其有两个没食子甲酚环,能高效直接清除氧自由基。EGCG已证明对多种疾病具有治疗效果,例如唐氏综合症、癌症和阿尔兹海默症等疾病,被认为是一种安全有效的小分子。虽然EGCG具有水溶性和抗氧化活性,但其固有的不稳定性限制了其生物利用度和有效性。然而,关于EGCG对特应性皮炎和银屑病的治疗较少被报道。EGCG可以通过氢键与RNA、蛋白质或其他生物大分子结合,鉴于其高效和无毒的特性,可用于药物递送系统。先前已经发现EGCG对皮肤炎症具有抗炎作用,研究表明局部应用EGCG可通过抑制迁移抑制因子和其他与1型T细胞免疫调节有关的细胞因子来改善特应性皮炎(AD)的皮肤病变。
此外,胶原三肽(CTP)是一种纯度高、低过敏性、非抗原且具有生物活性的胶原蛋白,其平均分子量为280道尔顿。CTP的结构简单的表示为Gly-X-Y,Gly是甘氨酸,X和Y是脯氨酸、羟脯氨酸或丙氨酸三种氨基酸中的任意一种。这三种氨基酸成分使胶原蛋白更能抵抗一般蛋白酶的降解。CTP和皮肤的胶原蛋白有相同的基本结构,可透过角质层与皮肤上皮细胞结合,参与和改善皮肤细胞的代谢,使皮肤中的胶原蛋白活性加强,保持角质层水分及纤维结构的完整性,达到修复皮肤屏障功能的目的。多项研究表明,CTP可通过调节Th2型炎症因子和趋化因子,不仅对皮肤屏障有修复作用,对Th2型免疫反应也有一定抑制作用。
发明内容
本发明的目的是提供一种儿茶酚与胶原三肽自组装纳米复合物(GECNs纳米复合物),使用树枝状大分子聚合物G5-PAMAM将EGCG/CTP纳米粒子进行压缩整合形成一种新型GECNs纳米复合物。
本发明提供的一种儿茶酚与胶原三肽自组装纳米复合物,由天然多酚、胶原三肽和高分子聚合物组成,所述的天然多酚是儿茶酚小分子,选自表没食子儿茶素没食子酸酯(EGCG)、单宁酸(TA)、阿魏酸(FA)和槲皮素(QU)中的至少一种或几种,其能够与蛋白质产生较强的相互作用,通过疏水、氢键等作用力形成纳米粒子,或通过氨基与苯甲醛形成席夫碱,使蛋白质表面修饰苯二酚基团。所述胶原三肽(collagen tripeptide,CTP)是胶原三肽,是胶原蛋白的最小结构单位,平均分子量为280Da,其结构简单的表示为Gly-X-Y,Gly是甘氨酸,X和Y是脯氨酸、羟脯氨酸或丙氨酸三种氨基酸中的任意一种。
表没食子儿茶素没食子酸酯(EGCG)的分子结构式:
单宁酸(TA)的分子结构式:
阿魏酸(FA)的分子结构式:
槲皮素(QU)的分子结构式:
所述的阳离子聚合物包括结构式(1)所示的末端为氨基、内核为乙二胺的第五代聚酰胺树枝状高分子聚合物G5-PAMAM,结构式(2)所示的线性化的聚乙酰亚胺PEI和结构式(3)所示的树枝状的聚乙酰亚胺PEI和结构式(4)、式(5)、式(6)所示的含苯硼酸修饰的高分子阳离子聚合物P4包括阳离子聚合物中的至少一种或几种。
聚酰胺树枝状高分子聚合物G5-PAMAM的分子结构式如下:
式(1)中,n为1-10之间的整数;m为2-4之间的整数;M是聚酰胺-胺树形高分子的核心;核心为乙二胺、丁二胺、己二胺、辛二胺、癸二胺和1,12-十二烷二胺时,m=4;核心为氨时,m=3;核心为甲胺、乙胺、正丙胺、正丁胺、正戊胺、正己胺、正辛胺、正癸胺、正十二胺时,m=2。
聚乙酰亚胺PEI的分子结构式如下:
式(2)中,n为2-100之间的整数。
树枝状聚乙酰亚胺PEI的分子结构式如下:
式(3)中,n为20-1500之间的整数。
含苯硼酸修饰的高分子阳离子聚合物P4的分子结构式如下:
式(4)~式(6)中,R1为阳离子聚合物;R2为连接键;R3、R4、R5、R6分别为化学官能团,分别独立地选自H、卤素、C1~C5烷基、C1~C5甲氧基、硝基;X为含苯硼酸功能基团的连接数,为1~256之间的整数。
本发明提供的儿茶酚与胶原三肽自组装(EGCG/CTP)纳米复合物,选择最优化的处方是表没食子儿茶素没食子酸酯(EGCG)与胶原三肽(CTP)自发组装形成EGCG/CTP纳米粒子,之后树枝状大分子聚合物G5-PAMAM将EGCG/CTP纳米粒子在静电吸附相互作用下压缩形成GECNs(G5-PAMAM/EGCG/CTP)新纳米复合物。这种新型GECNs纳米复合物既可改善EGCG本身的不稳定性,又可其加强清除ROS的效果,从而提高抗炎作用,也能高效地递送CTP进入表皮层进行屏障功能修复并抑制过度表达的Th2型免疫反应等。
本发明的另一个目的是提供所述的一种儿茶酚与胶原三肽自组装纳米复合物的制备方法,通过以下步骤实现:
(1)在去离子水体系或者磷酸缓冲盐溶液体系中,将天然多酚(表没食子儿茶素没食子酸酯EGCG)和胶原三肽CTP按质量比为1:4~4:1比例吹打均匀混合,静置孵育30min可得到EGCG/CTP纳米复合物。
EGCG/CTP纳米复合物粒子分散度(PDI)范围为0.079~0.349,当EGCG和CTP最佳质量比为1:1时,其形成的EGCG/CTP纳米复合物粒径范围是78.82nm~141.8nm,最佳粒径为111.73nm,最佳PDI为0.079,电势电位为负电荷。
(2)在去离子水体系或者磷酸缓冲盐溶液体系中,再将EGCG/CTP纳米复合物按其中的胶原三肽CTP质量与树枝状高分子聚合物G5-PAMAM的质量比为4:1~1:8比例吹打均匀混合,再次静置孵育30min可得到GECNs(G5-PAMAM/EGCG/CTP)新纳米复合物。
GECNs(G5-PAMAM/EGCG/CTP)纳米复合物分散度(PDI)范围为0.09~0.418;当EGCG/CTP纳米复合物按其中的胶原三肽CTP质量和树枝状高分子聚合物G5-PAMAM最佳质量比为4:1时,其形成的GECNs(G5-PAMAM/EGCG/CTP)纳米复合物粒径范围是91.28nm~122.4nm,最佳粒径大小为105.7nm,最佳PDI为0.09,电势电位为正电荷。
本发明的再一个目的是提供所述儿茶酚与胶原三肽自组装纳米复合物作为经皮给药递送系统在制备治疗炎症性皮肤疾病药物中的应用。所述炎症性皮肤疾病是指特异性皮炎和银屑病。本发明提供的ECGN纳米复合物在体外实验中验证了其低毒性高效性的作用,更重要的是在体内实验的炎症性皮肤疾病中证明,改善延缓皮肤炎症的损伤,在临床转化方面具有极大的应用潜力。
由于炎症性皮肤疾病(ISDs)是最持久的疾病之一,通常以产生促炎细胞因子激活固有和适应性免疫反应为特征。银屑病和特应性皮炎(AD)等ISDs正日益成为威胁公众健康的主要问题。这些疾病通常被认为是皮肤上皮屏障对抗过敏原和病原体的炎症反应的结果。例如,银屑病的发病机制通常表现为树突状细胞的异常激活和T细胞介导的复杂细胞网络自身免疫反应。AD作为另一种典型的炎症性皮肤病,其发病机制一般以Th2介导的异常炎症反应为主,嗜酸性粒细胞和血清免疫球蛋白E(IgE)水平升高为特征。目前,患有这些疾病的患者只有几种被批准的治疗方案。虽然局部糖皮质激素和免疫抑制剂仍是一线治疗方式,但由于糖皮质激素抵抗,大多数患者往往对局部或全身糖皮质激素治疗反应不良,特别是对长期治疗。这表明寻找新型经皮递送系统的局部治疗方案对于炎症性皮肤疾病治疗至关重要。
为了缓解目前炎症性皮肤病的症状,使用纳米技术解决这一难题也许是一种可行的方案。然而,皮肤使得纳米颗粒几乎不可能通过。但纳米颗粒可通过跨附属途径进入皮肤,包括毛囊、汗腺、皮脂腺和毛囊皮脂腺。这使得纳米颗粒能够穿透角质层的浅层,即皮肤最外层的保护层。所以,它对大分子和纳米颗粒进入皮肤疾病层有一定的限制。因此,开发一个创新的经皮给药递送系统,以加强药物渗透至皮肤层对于局部治疗特异性皮炎和银屑病是至关重要的。
本发明首次提出利用天然化合物EGCG和人工合成肽CTP自组装形成纳米复合物,两种化合物通过氢键作用力进行复合且两种化合物无毒对炎症性皮肤疾病治疗都有一定的治疗效果。另外,EGCG本身具有极其不稳定性,通过自组装提高其抗炎作用;CTP在皮肤屏障修复方面一直处于较为优越,将其制备成纳米粒子形式可提升CTP的生物利用度,可发挥纳米技术在经皮给药递送系统中的优势。
本发明的创新点在于皮肤作为人体的八大系统之一对大分子和纳米颗粒进入皮肤疾病层有一定的限制。当皮肤正常的生理模式发生改变,如内外在因素的影响产生炎症,这使得纳米粒子渗透至病理的皮肤层内部更加容易。对于特异性皮炎和银屑病两种炎症性皮肤疾病,在临床上通常表现为强烈的瘙痒,过度抓挠,发红,表皮屏障功能受损。这些表现可能导致极度不适,睡眠不足和生活质量下降,因此本发明最终提供的GECNs纳米复合物可有效地经皮递送至表皮层和真皮层,这些纳米颗粒可以进一步将EGCG和CTP转运至细胞内发挥各自的功能。这样的逐步递送策略在透皮水平最大化的协同治疗效果。GECNs纳米复合物的治疗效果与临床一线药物他克莫司软膏和丙酸氯倍他索乳膏相当。总的来说,本发明提出的自组装纳米复合物在经皮给药递送系统中可以达到高效低毒并缓解炎症损伤的效果,经济成本低,,能够有效且安全地将儿茶酚小分子和胶原三肽分子递送到皮肤层内部。
因此,在这里我们首次提供一种EGCG与CTP通过氢键的相互作用可自组装形成纳米粒子,再使用树支状大分子聚合物G5-PAMAM通过静电相互作用将其压缩,既可改善EGCG的不稳定性,加强清除ROS的效果,从而提高抗炎作用,也能高效地递送CTP进入表皮层进行屏障功能修复并抑制过度表达的Th2型免疫反应。整体来说,我们开发了一种新型的经皮治疗策略,在局部治疗特异性皮炎和银屑病方面可达到协同皮肤屏障修复和加强炎症抑制的作用,具有皮肤病治疗的临床转化应用价值。
附图说明
图1是实施例1中儿茶酚分子与胶原三肽CTP氢键作用下自组装形成纳米粒子以及阳离子聚合物与其静电吸附相互作用形成新型GECNs纳米复合物在特异性皮炎及银屑病皮肤炎症中的应用示意图。
图2为实施例1中儿茶酚分子与胶原三肽CTP氢键作用下自组装形成纳米粒子的示意图。
图3为实施例1中单宁酸(TA)、阿魏酸(FA)和槲皮素(QU)依次与胶原三肽CTP自组装形成纳米复合物,再利用G5-PAMAM树枝状大分子聚合物形成的一系列纳米复合物的粒径分布图。
图4为实施例1中表没食子儿茶素没食子酸酯(EGCG)与胶原三肽CTP自组装形成纳米复合物,再利用线性化的聚乙酰亚胺PEI、树枝状的聚乙酰亚胺PEI和含苯硼酸修饰的高分子阳离子聚合物P4形成的一系列纳米复合物的粒径分布图。
图5为实施例3和4中自组装形成的一系列纳米复合物的电势电位图。
图6为实施例1中EGCG与CTP按不同质量比(w/w)分别为1:4~4:1;采用动态光散射法(Zetasizer Nano ZS90,Malvern)测定了制备的EGCG/CTP纳米复合物的粒径分布和粒子分散度。
图7为实施例1中EGCG/CTP纳米颗粒,通过透射电子显微镜(TEM)(HT7700,日立,日本)进一步观察了EGCG/CTP纳米颗粒的形貌特征。
图8为实施例1中将EGCG/CTP纳米复合物按其中的胶原三肽CTP质量与树枝状高分子聚合物G5-PAMAM的质量比为4:1~1:8比例,采用动态光散射法(Zetasizer Nano ZS90,Malvern)测定了制备的GECNs纳米复合物的粒径分布和粒子分散度。
图9为实施例1中GECNs纳米颗粒,通过透射电子显微镜(TEM)(HT7700,日立,日本)进一步观察了GECNs纳米颗粒的形貌特征。
图10为实施例2中G5-PAMAM树状大分子直接与CTP进行孵育,采用动态光散射法(Zetasizer Nano ZS90,Malvern)测定了其粒径分布和通过透射电子显微镜(TEM)(HT7700,日立,日本)观察其形貌特征。
图11为实施例1中是三种体系的zeta电位分析统计图,其中G5-PAMAM与CTP水溶液体系是带正电荷的;EGCG/CTP纳米复合物是带负电荷的;ECGNs纳米复合物是带正电荷的。
图12为实施例3中是荧光淬灭检测,使用荧光光度分度计检测蛋白质的荧光光谱,激发波长和发射波长分别为Hex=280nm和Aem=300-450nm。
图13为实施例4中是利用CD圆二色谱检测CTP与EGCG自组装纳米复合物过程中的二级结构的变化情况。
图14为实施例5中是利用等温滴定量热法(ITC)检测EGCG与CTP的相互作用过程中的吸放热行为。
图15为实施例6中是荧光共振能量转移(FRET)分析:EGCG/CTP纳米颗粒和ECGNs也通过能量色散X射线光谱(EDX)元素图谱(Talos F200C,FEI)进行了分析。
图16为实施例7中是在HaCaT细胞、NIT 3T3细胞和DC2.4细胞上体外检测EGCG/CTP纳米复合物以及EGCNs纳米复合物消除ROS的相对荧光强度。
图17为实施例8中是GECN纳米复合物的稳定性研究和细胞毒性测定。
图18为实施例9中测定GECNs纳米复合物使用后的皮肤水分流失(TEWL)和皮肤水合作用。
图19为实施例10中将GECNs纳米复合物在DNCB(2,4-二硝基氯苯)诱导的特应性皮炎小鼠模型耳朵及背部进行涂抹,然后进行特异性皮炎严重程度评分(SCORAD)评估。
图20为实施例11中是将GECNs纳米复合物在咪喹莫特诱导的银屑病模型小鼠耳朵及背部进行涂抹治疗,然后进行银屑病面积区域严重程度指数(PASI)评估评价。
具体实施方式
本发明结合附图和实施例作进一步的说明,本发明的保护内容不局限于以下实施例。在不违背本发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公共常识,本发明没有特别限制内容。
实施例1:将儿茶酚分子与胶原三肽CTP自组装形成纳米粒子,再利用阳离子聚合物形成的一系列新纳米复合物的粒径分布图和电势电位图。
具体方法如下:一种儿茶酚与胶原三肽自组装纳米复合物,其主要的制备过程是①一般将EGCG(10mg/mL)和CTP(10mg/mL)按质量比为1:4~4:1溶解于2ml体积的Milli-Q水中,通过旋涡振荡器快速混合溶解,在室温其可不搅拌并且静置30分钟的情况下自发聚集形成纳米颗粒;②然后,在EP管中加入800μL G5-PAMAM枝状高分子聚合物(浓度为12mg/mL)和200μL EGCG/CTP纳米颗粒,将EGCG/CTP纳米复合物按其中的胶原三肽CTP质量与树枝状高分子聚合物G5-PAMAM的质量比为4:1~1:8比例吹打均匀混合,再次静置孵育30min,可得到GECNs(G5-PAMAM/EGCG/CTP)新纳米复合物;③采用动态光散射法(Zetasizer NanoZS90,Malvern)测定了制备的EGCG/CTP纳米颗粒和ECGNs复合物的尺寸和zeta电位;④通过透射电子显微镜(TEM)进一步观察了EGCG/CTP纳米颗粒和ECGNs纳米复合物的形貌。用DLS法测定EGCG/CTP纳米粒和ECGNs在水溶液、150毫摩尔盐溶液和细胞培养液中培养的稳定性。
注释:儿茶酚分子优选表没食子儿茶素没食子酸酯(EGCG),但也包括单宁酸(TA)、阿魏酸(FA)和槲皮素(QU);阳离子聚合物优选树枝状大分子聚合物G5-PAMAM,但也包括线性化的聚乙酰亚胺PEI、树枝状的聚乙酰亚胺PEI和含苯硼酸修饰的高分子阳离子聚合物P4。
实验结果:图1~图9表明:
通过测定粒径分布和zeta电位,发现EGCG/CTP纳米复合物粒子分散度(PDI)范围为0.079~0.349,;当EGCG和CTP最佳质量比为1:1,其形成的EGCG/CTP纳米复合物粒径范围是78.82nm~141.8nm,最佳粒径大小为111.73nm,最佳PDI为0.079,电势电位为负电荷。通过透射电子显微镜(TEM)进一步观察了EGCG/CTP纳米颗粒的形貌特征,我们发现其纳米粒子形状圆形较为均一规整。
通过测定粒径分布和zeta电位,发现GECNs(G5-PAMAM/EGCG/CTP)纳米复合物分散度(PDI)范围为0.09~0.418;当EGCG/CTP纳米复合物按其中的胶原三肽CTP质量和树枝状高分子聚合物G5-PAMAM最佳质量比为4:1,其形成的GECNs(G5-PAMAM/EGCG/CTP)纳米复合物粒径范围是91.28nm~122.4nm,最佳粒径大小为105.7nm,最佳PDI为0.09,电势电位为正电荷。通过透射电子显微镜(TEM)进一步观察了ECGNs纳米复合物的形貌特征,我们发现相较于上述的EGCG/CTP纳米颗粒,ECGNs纳米复合物形状圆形且大小非常均一规整。
实施例2:将儿茶酚分子直接与阳离子聚合物形成的一系列混合体系的粒径分布图和电势电位图。
具体方法如下:G5-PAMAM树枝状大分子聚合物直接与CTP按质量比1:4~8:1比例吹打均匀混合,静置孵育30min,再采用动态光散射法(Zetasizer Nano ZS90,Malvern)测定了制备其尺寸和zeta电位。
实验结果:图10表明:
通过测定粒径分布,发现粒径分布无规律,此外其粒子分散度PDI接近1;另外,G5-PAMAM与CTP水溶液体系通过负染制备透射电镜的TEM样品发现该G5-PAMAM与CTP水溶液体系未有纳米粒子的形成,因此,我们发现ECGNs纳米粒子中EGCG对于自组装体系的重要性。
图11为实施例1和实施例2三种体系(即EGCG/CTP纳米粒子、ECGNs纳米复合物和G5-PAMAM/CTP混合体系)的zeta电位分析统计图,其中G5-PAMAM与CTP水溶液体系是带正电荷的;EGCG/CTP纳米颗粒是带负电荷的;ECGNs纳米颗粒是带正电荷的,图中1代表:树枝状分子/胶原三肽复合;2代表儿茶酚分子/胶原三肽复合;3代表树枝状分子/儿茶酚分子/胶原三肽复合。
实施例3:使用荧光光度分度计检测四种体系(即单一CTP溶液体系、EGCG/CTP纳米粒子、ECGNs纳米复合物和G5-PAMAM/CTP混合体系)中CTP的荧光光谱,激发波长和发射波长分别为Hex=280nm和Aem=300-450nm。
具体方法如下:所使用的荧光光度分度计型号为HitachiF4500(日本Hitachi公司)。按照不同的摩尔比,将EGCG溶液滴加入CTP溶液中,充分吹打均匀,室温静置,使EGCG与CTP充分混合。使用去离子水将混合溶液稀释到1mL,稳定1分钟后,检查溶液的荧光光谱。使用牛血清白蛋白(BSA)作为模型对照蛋白质,检测时溶液中的终浓度为0.3μM。
实验结果:图12表明:
通过荧光光度分度计检测CTP的荧光光谱,我们发现EGCG/CTP纳米粒子、ECGNs纳米复合物和G5-PAMAM/CTP混合体系相较于单一CTP溶液体系,荧光强度曲线明显降低。
实施例4:利用CD圆二色谱检测四种体系(即单一CTP溶液体系、EGCG/CTP纳米粒子、ECGNs纳米复合物和G5-PAMAM/CTP混合体系)自组装过程中的CTP二级结构的变化情况。
具体方法如下:检测所用的仪器设备是CD圆二色谱J-815.将BSA牛血清白蛋白以及CTP与EGCG室温下孵育复合30分钟,检测是使用去离子水稀释至1mL,最终CTP浓度为1微摩尔。同时,检测不含EGCG的CTP溶液的CD圆二色谱作为阳性对照。
实验结果:图13表明:
通过CD圆二色谱检测,我们发现EGCG/CTP纳米粒子、ECGNs纳米复合物和G5-PAMAM/CTP混合体系相较于单一CTP溶液体系,CTP二级结构的无明显变化。
实施例5:利用等温滴定量热法(ITC)检测EGCG与CTP的相互作用过程中的吸放热行为。
具体方法如下:ITC是在Microcal ITC200(GE Healthcare,Milwaukee)上进行的,容量为200微升。每隔2分钟,将EGCG溶液(50mm)(每次注射2微升)注射到10mm CTP溶液中,使每次注射之间的聚电解质体系完全平衡。将EGCG注射到不含CTP的缓冲液中,测量EGCG的稀释热,作为参考。原始的实验数据以每秒产生的总热量作为时间的函数,而每次喷射产生的热量则通过积分微热源上单个峰下的面积来计算。减去EGCG的稀释热后,将实验数据拟合成理论滴定曲线,计算出摩尔焓变(H)、熵变(S)、结合位点数(N)和结合亲和力(K)。所得到的ITC数据为检测时间内每秒所产生的热量的总和。
实验结果:图14表明:
通过等温滴定量热法(ITC)检测,我们发现EGCG与CTP的相互作用过程为放热行为。
实施例6:利用荧光共振能量转移(FRET)分析:四种体系(即单一CTP溶液体系、EGCG/CTP纳米粒子、ECGNs纳米复合物和G5-PAMAM/CTP混合体系)通过能量色散X射线光谱(EDX)元素图谱(Talos F200C,FEI)进行了分析。
具体方法如下:为了进行荧光共振能量转移(FRET)分析,将具有EGCG(EGCG与CTP重量比为1:1)的CTP-FAM溶液(10mg/mL,1mL)与若丹明标记的G5-PAMAM树状聚合物(GP-Rho)混合在室温下,用荧光分光光度计(在420nm激发,在450-700nm发射)测量10分钟的EGCG与GP-Rho重量比为1:1。如上所述制备不含EGCG的G5-PAMAM树状聚合物/CTP多聚体并通过FRET表征。
实验结果:图15表明:
通过荧光共振能量转移(FRET)分析,我们发现EGCG/CTP纳米粒子、ECGNs纳米复合物和G5-PAMAM/CTP混合体系相较于单一CTP溶液体系,次级荧光光发生红移。
实施例7:利用活性氧检测试剂盒在HaCaT细胞、NIT 3T3细胞和DC2.4细胞上体外检测四种体系(即单一CTP溶液体系、EGCG/CTP纳米粒子、ECGNs纳米复合物和G5-PAMAM/CTP混合体系)消除ROS的相对荧光强度。
具体方法如下:因二氯荧光素二乙酸盐(DCFH-DA)是自身没有荧光的化学物质,能够自由穿过细胞膜。当其进入细胞内,可以被被酯酶水解去掉两个乙基,形成DCFH,而DCFH不能自由穿过细胞膜,从而能使荧光探针装载在细胞内。当细胞产生活性氧可以使无荧光的DCFH被氧化形成具有荧光的DCF,首先通过激光共聚焦显微镜测观察细胞内DCF的荧光分布,同时通过多功能酶标仪测定细胞内荧光强度,从而对细胞内活性氧的水平进行检测,判断EGCG/CTP纳米粒子以及EGCNs的抗氧化作用。
实验结果:图16表明:
通过活性氧检测试剂盒检测以及激光共聚焦Confocal拍照,我们发现EGCG/CTP纳米粒子和ECGNs纳米复合物具有一定消耗ROS能力,且ECGNs纳米复合物消耗ROS能力更为优越。
实施例8:利用MTT细胞增殖及细胞毒性检测试剂盒,检测GECN纳米复合物的稳定性研究和细胞毒性测定。
具体方法如下:一般将GECNs纳米复合物对HaCaT细胞、NIH 3T3细胞和DC2.4细胞活力的影响是根据制造商的试剂盒说明通过CCK-8分析确定的。通常,将HaCaT细胞、NIH3T3细胞和DC2.4细胞以约104个细胞/孔的密度接种到96孔板中过夜。将细胞与不同体积的组(对照组,1μL,2μL,4μL和10μLECGN纳米颗粒)孵育4小时。将细胞培养24小时,然后用MTT处理。每个样品进行五次重复。
实验结果:图17表明:
通过MTT细胞增殖及细胞毒性检测,我们发现四种体系(即单一CTP溶液体系、EGCG/CTP纳米粒子、ECGNs纳米复合物和G5-PAMAM/CTP混合体系)在HaCaT细胞、NIT 3T3细胞和DC2.4细胞上的相对存活率都在80%以上,说明该一系列纳米复合物的生物安全性较高。
实施例9:测定GECNs纳米复合物使用后的皮肤水分流失(TEWL)和皮肤水合作用。
具体方法如下:皮肤水分流失TEWL对评估皮肤水分保护层的功能是非常重要的参数,皮肤保护层越完好,水份的含量就会越高,皮肤水份流失TEWL的数值就越低,TEWL的单位为:g/hm2。用Tewmeter TM 210测量水分流失率,以评估皮肤屏障的破坏情况。皮肤水合作用指的是皮肤外层角蛋白或其降解产物具有的与水结合的能力。皮肤水合性是用CM820corneometer测定的,它可以测量任意单位(a.u)的皮肤电容。在应用ECGN纳米复合物和市售药物丙酸氯倍他索(阳性对照)治疗前的第0、7、14、21、28和35天测量皮肤经皮水分流失和水合作用。
实验结果:图18表明:
通过测定治疗小鼠的皮肤水分流失(TEWL)和皮肤水合作用,我们发现与皮肤屏障功能相关的经表皮失水(TEWL)值的降低。与阴性对照组相比,治疗组局部处理TEWL水平下降。这些结果表明含有CTP的纳米复合物有利于加速修复皮肤的自然屏障功能。此外,皮肤电容是定量评价AD治疗效果的重要参数,也是AD的主要症状之一。与阴性对照组相比,治疗组小鼠皮肤增加了水化。
实施例10:将GECNs纳米复合物在DNCB(2,4-二硝基氯苯)诱导的特应性皮炎小鼠模型耳朵及背部进行涂抹,然后进行特异性皮炎严重程度评分(SCORAD)评估。
具体方法如下:在第0天、第7天、第14天、第21天、第28天对小鼠称重,并在第0天、7天、14天、21天、28天根据小鼠的红斑/出血、疤痕/干燥、水肿、背部皮肤浸润/糜烂情况进行特异性皮炎临床严重程度评分。按病情轻重采用0-4分进行评分:无为0分;轻度为1分;中度为2分;重度为3分;极重度为4分。同时在第29天后,取耳朵测定每一组小鼠的耳朵重量与厚度。同时每只小鼠取脾脏,测定脾脏与身体重量比。
实验结果:图19表明:
通过特异性皮炎严重程度评分(SCORAD)评估,我们发现由于炎症因子的释放是一种较强的免疫反应指标,使DNCB诱导的小鼠脾脏随着体重的增加而明显增大,可见DNCB诱导的小鼠脾脏体积和重量明显增加。相比之下,治疗组的DNCB诱导小鼠的脾脏与重量和大小与身体重量比明显下降以及严重程度评分(出血、疤痕/干燥、水肿和表皮脱落/侵蚀)也明显下降。
实施例11:将GECNs纳米复合物在咪喹莫特诱导的银屑病模型小鼠耳朵及背部进行涂抹治疗,然后进行银屑病面积区域严重程度指数(PASI)评估评价。
具体方法如下:PASI评分(Psoriasis Area and Severity Index)是开发了一种客观评分系统来评估小鼠背部皮肤和耳朵发炎的严重程度,综合银屑病患者的皮损严重程度(包括红斑、浸润、鳞屑)及皮损面积对其进行评分。通过特定公式计算出最终分数,常常用来对寻常型银屑病的严重程度进行评估。PASI是国际上通用于银屑病皮损程度的评分标准。基于临床牛皮癣面积和严重程度指数(PASI),三个因素即红斑,鳞屑和增厚可显示ECGN纳米复合物对银屑病治疗的效果。按病情轻重采用0-4分进行评分:无为0分;轻度为1分;中度为2分;重度为3分;极重度为4分。累计评分(红斑+标度+增厚)显示炎症严重程度(0-12分)。每24小时进行一次评分,共7天。注释:银屑病的临床表现进行三类评分:1、红斑(erythema,E)指红色及暗红色的炎性斑块,压之颜色可消退;2、浸润(infiltration,I)指皮损的边界相对模糊,逐渐向周围扩散,压之有一定的实质感;3、鳞屑(desquamation,D)指表皮细胞的大片状剥落现象。
实验结果:图20表明:
通过银屑病面积区域严重程度指数(PASI)评估评价,我们发现咪喹莫特乳膏诱导的银屑病小鼠连续7天背皮肤红斑等引起的皮肤损伤、硬化、皮肤褶厚度增加等。与未给予任何治疗的小鼠相比,治疗组均能显著改善咪喹莫特乳膏所致的临床症状和银屑病症状的严重程度。PASI评分显示,其中治疗组的抗炎作用最显著。
Claims (7)
1.一种儿茶酚与胶原三肽自组装纳米复合物,其特征在于,该纳米复合物由天然多酚、胶原三肽和高分子聚合物组成;
所述的天然多酚选用表没食子儿茶素没食子酸酯;所述的胶原三肽的平均分子量为280 Da,其结构表示为Gly-X-Y,其中Gly是甘氨酸,X和Y是脯氨酸、羟脯氨酸二种氨基酸中的任意一种;所述的高分子聚合物选用末端为氨基、内核为乙二胺的第五代聚酰胺树枝状高分子聚合物G5-PAMAM,其分子结构式(1)如下:式(1)中,n为1-10之间的整数;m为4;M是聚酰胺-胺树形高分子的核心,为乙二胺。
2.权利要求1所述的一种儿茶酚与胶原三肽自组装纳米复合物的制备方法,其特征在于,通过以下步骤实现:
(1)在去离子水体系或者磷酸缓冲盐溶液体系中,将天然多酚和胶原三肽CTP按质量比为1:4 ~ 4:1比例吹打均匀混合,静置孵育30min得到EGCG/CTP纳米复合物;
(2)在去离子水体系或者磷酸缓冲盐溶液体系中,再将EGCG/CTP纳米复合物按其中的胶原三肽CTP质量与树枝状高分子聚合物G5-PAMAM的质量比为4:1 ~ 1:8比例吹打均匀混合,再次静置孵育30min得到GECNs复合纳米复合物。
3.根据权利要求2所述的制备方法,其特征在于,步骤(1)EGCG/CTP纳米复合物粒子分散度范围为0.079~0.349。
4.根据权利要求2所述的制备方法,其特征在于,当EGCG和CTP质量比为1:1时,其形成的EGCG/CTP纳米复合物粒径范围是78.82nm~141.8nm,电势电位为负电荷。
5.根据权利要求2所述的制备方法,其特征在于,步骤(2)GECNs纳米复合物分散度范围为0.09~0.418。
6.根据权利要求2所述的制备方法,其特征在于,当EGCG/CTP纳米复合物按其中的胶原三肽CTP质量和树枝状高分子聚合物G5-PAMAM质量比为4:1时,其形成的GECNs纳米复合物粒径范围是91.28nm~122.4nm,电势电位为正电荷。
7.权利要求1所述的儿茶酚与胶原三肽自组装纳米复合物作为经皮给药递送系统在制备治疗炎症性皮肤疾病药物中的应用,其特征在于,所述炎症性皮肤疾病为特异性皮炎和银屑病。
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