CN107007555A - 酰基化葡甘聚糖纳米颗粒的制备及应用 - Google Patents
酰基化葡甘聚糖纳米颗粒的制备及应用 Download PDFInfo
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Abstract
本发明公开了酰基化葡甘聚糖纳米颗粒的制备及应用。一种酰基化葡甘聚糖纳米颗粒，是对葡甘聚糖进行酰基化得到的粒径为10nm–100nm的纳米颗粒；所述的酰基化为甲酰化、乙酰化或丙酰化。本发明从纳米医学角度出发，通过研究纳米生物界面特异性作用方式，将两种葡甘聚糖进行特定的酰基化得到预期的纳米多糖颗粒，大小均一，在水溶液中均匀分散。通过研究发现酰基化葡甘聚糖纳米颗粒较单纯的多糖能够显著提高其抗炎和促进伤口愈合的活性；能够在制备治疗炎症性疾病、胃溃疡、创伤愈合的药物和/或敷料中应用。
Description
技术领域：
本发明属于生物医药技术领域，具体涉及酰基化葡甘聚糖纳米颗粒的制备及应用。
背景技术：
巨噬细胞(Macrophage)是在各类慢性炎症疾病的发生发展中起到重要作用的免疫细胞,包括动脉粥样硬化，哮喘，炎症性胃肠炎，类风湿性关节炎及组织修复等。活化的巨噬细胞刺激促炎因子的大量分泌，从而促进炎症反应的发生发展。当机体内组织发生炎症时，血液中的单核细胞被招募至炎症部位，并分化成活化的巨噬细胞，浸润粘膜层，分泌促炎细胞因子，从而导致上皮细胞及腺体凋亡、屏障功能丧失、组织坏死、肉芽肿形成和纤维化。例如炎症性肠病(Inflammatory bowel disease)和胃溃疡(Gastric ulcer)是典型慢性的，易复发的炎症性疾病，其病因和发病机制比较复杂，诊断和治疗也相当棘手，但针对巨噬细胞的治疗是当今热门研究方向之一，通过新型分子治疗策略来抑制巨噬细胞的活化状态，降低炎症因子的表达水平，从而缓解炎症性疾病的发展；创伤愈合(wound healing)是一个复杂的生物学过程，创伤后愈合的各个阶段均有大量的蛋白分子进行诱导和调控，这些因子在合成和分泌后，通过作用于机体细胞及细胞间质，调控组织愈合的均衡发展。既刺激组织修复，又限制组织的过度增生，以维持愈合的动态平衡。巨噬细胞通过表型转换及相关细胞因子的表达，参与整个组织修复、再生(tissue repair,regeneration)的过程。
白芨多糖(Bletilla Striata polysaccharide)是一种从传统中药白芨提取而得的葡甘聚糖，由4分子甘露糖和1分子葡萄糖组成的中性非离子型线形甘露聚糖，具有抗炎、促凝血、抗病毒、抗肿瘤，抗氧化等生物学活性。白芨多糖是安全高效的医药原料，具有优良的理化性质，相当具有发展前景的生物材料。魔芋多糖(Konjac polysaccharide,KGM)，是一种天然的高分子多糖，广泛应用于包装、涂料、食品及化妆品等领域。除此之外，KGM还具备促免疫功能、抗癌、改善肠道功能、减肥、降脂、降血糖作用、抗皮肤炎症因子等生物活性，现已被应用于临床、医药等领域，对KGM的进一步研究和深度开发利用已经引起人们的广泛关注。
多糖的酰基化是对其羟基进行酰基化修饰，改变其理化性质以便形成一定的形态结构，更好的研究对生命体的活性。通过醋酐引入乙酰基降低了白芨多糖的溶解性，疏水基团的加入使高分子量的多糖自发形成纳米颗粒，多糖的这种酰基化方法作为多糖改性的一种方法得到人们的广泛关注和深入研究，并已在医药、食品及化工等领域取得重要进展。目前，有关白芨多糖在生物医药上的研究局限于药物载体、黏附剂及血管栓塞剂。
多糖酰基化的制备方法及弊端
发明内容：
本发明的目的是提供一种酰基化葡甘聚糖纳米颗粒。
本发明的另一目的是提供该酰基化葡甘聚糖纳米颗粒的制备方法。
本发明的又一目的是提供该酰基化葡甘聚糖纳米颗粒的应用。这也是本发明的核心。
本发明的目的通过以下技术方案实现：
一种酰基化葡甘聚糖纳米颗粒，是对葡甘聚糖进行酰基化得到的粒径为10nm–100nm的纳米颗粒；所述的酰基化为甲酰化、乙酰化或丙酰化。
所述的一种酰基化葡甘聚糖纳米颗粒优选为对葡甘聚糖进行乙酰化得到的粒径为25-35nm的纳米颗粒；进一步优选对葡甘聚糖进行乙酰化得到的粒径为30nm的纳米颗粒。发明人在研究过程中发现只有甲酰化、乙酰化或丙酰化的葡甘聚糖能够形成均一分散的纳米颗粒，并且较之单纯的葡甘聚糖具备更好的抗炎活性，其中尤其以乙酰化的葡甘聚糖的抗炎活性及促进伤口愈合的活性最佳。
所述的葡甘聚糖进一步优选白芨多糖或魔芋多糖中的任意一种。
所述的乙酰化葡甘聚糖纳米颗粒，优选主要通过以下步骤制备得到：
(1)白芨多糖或魔芋多糖加入到吡啶中分散，反应温度40℃～90℃，搅拌时间15min～1h；白芨多糖或魔芋多糖与吡啶的质量体积比为(15-5)mg:1mL；
(2)加入吡啶和醋酐的混合液混合，混合温度50～95℃，反应时间4～24h；吡啶与醋酐的体积比1：1～1：30；吡啶和醋酐的混合液加入量与步骤(1)中加入的吡啶等体积；
(3)加入蒸馏水，醋酐和水的摩尔比是1：1～1：3；
(4)向反应液中加入过量的无水乙醇，保持4～8℃沉淀过夜，无水乙醇与步骤(3)反应体系的体积比为4:1～10:1；
(5)滤出沉淀，并用无水乙醇或丙酮清洗；
(6)将沉淀分散于蒸馏水中，冻干抽真空即得酰基化的白芨多糖或魔芋多糖。
一种酰基化的葡甘聚糖纳米颗粒的制备方法，其包含如下步骤：
(1)白芨多糖或魔芋多糖加入到吡啶中分散，反应温度40℃～90℃，搅拌时间15min～1h；白芨多糖或魔芋多糖与吡啶的质量体积比为(15-5)mg:1mL；
(2)加入吡啶和醋酐的混合液混合，混合温度50～95℃，反应时间4～24h；吡啶与醋酐的体积比1：1～1：30；吡啶和醋酐的混合液加入量与步骤(1)中加入的吡啶等体积；
(3)加入蒸馏水，醋酐和水的摩尔比是1：1～1：3；
(4)向反应液中加入过量的无水乙醇，保持4～8℃沉淀过夜，无水乙醇与步骤(3)反应体系的体积比为4:1～10:1；
(5)滤出沉淀，并用无水乙醇或丙酮清洗；
(6)将沉淀分散于蒸馏水中，冻干抽真空即得酰基化的白芨多糖或魔芋多糖。
所述的步骤(2)温度优选90℃。
所述的步骤(4)温度优选4℃。
所述的酰基化的葡甘聚糖纳米颗粒在制备治疗结肠炎等炎症性疾病、胃溃疡、创伤愈合的药物和/或敷料中的应用。
这项发明通过对炎症性肠病疾病，胃溃疡模型以及全层皮肤切除创伤模型进行例证。此处的动物包括但是不限于：小鼠，大鼠，驯养动物包括但是不限于猫，狗，以及其它一些动物例如但是不限于牛，羊，猪，马，灵长类动物例如但是不限于猴子和人。小鼠炎症性肠病疾病模型，的体内检测是被广泛认可和接受的体内药物活性检测的模型，同时也可以为其它生物例如但是不限于人提供参考。
有益效果：
我们将白芨多糖、魔芋多糖与甲酸酐、醋酐或丙酸酐发生酰基化反应，使其形成均一的纳米结构在制备相关炎症性疾病的治疗药物及加速伤口愈合的敷料中应用作为本发明保护的关键。
本发明从纳米医学角度出发，通过研究纳米生物界面特异性作用方式，将两种葡甘聚糖进行特定的酰基化得到预期的纳米多糖颗粒，大小均一，在水溶液中均匀分散。通过研究其与巨噬细胞作用机制，明确作用机理，较单纯的多糖能够显著提高其抗炎和促进伤口愈合的活性。
本发明提供了酰基化葡甘聚糖纳米颗粒在制备治疗炎症性疾病、胃溃疡、创伤愈合的药物和/或敷料中的应用。含有大量葡甘聚糖的白芨多糖和魔芋多糖酰基化后通过疏水基团形成纳米结构，可以激活巨噬细胞的表型变化，进而引起新的生物学效应，如分泌大量抑制性因子IL-10，改善胃肠道的炎症状态；同时在创伤愈合过程中，通过调控巨噬细胞的表型，形成组织修复型巨噬细胞，通过TGF-β1和VEGF来调节并加速组织修复、再生。为进一步研究葡甘聚糖的生物活性奠定基础；与小分子药物相比，具有极高的原料选择性，成本较低，纳米化产物单一，分离简单，具备一定的工业化前景；与纯多糖比，在治疗效果上突出的是更具有靶向性，药效更佳。
附图说明
图1为AC-BSP以及AC-KGM的形貌结构及大小分布
图2为通过动态光散射检测两种酰基化多糖的粒径和电位
图3为AC-BSP对小鼠炎症性疾病的疗效考核
图4为AC-BSP(A图)以及AC-KGM(B图)对小鼠全层皮肤切除创伤愈合率曲线变化
具体实施方式
为了进一步理解本发明，下面结合实施例对本发明优选实施方案进行描述，但是应当理解，这些描述只是为进一步说明本发明的特征和优点，而不是对本发明权利要求的限制。
实施例1：AC-BSP/AC-KGM溶液的制备
(1)称取200mg的白芨多糖或魔芋多糖加入到20mL吡啶中分散，反应温度80℃，搅拌时间30min；
(2)加入20mL吡啶&醋酐的混合液(吡啶：醋酐1：1,V/V)，混合温度90℃，反应时间6h；
(3)加入蒸馏水反应掉多余的醋酐，按加入总酸酐的摩尔量计算，醋酸酐和水的摩尔比是1：1。
(4)向反应液中加入过量的无水乙醇，保持4℃沉淀过夜，加入无水乙醇的量与上述总反应体系的体积比为4:1。
(5)滤出沉淀，并用无水乙醇或丙酮等清洗三次以上。
(6)将沉淀分散于蒸馏水中，冻干抽真空即得白芨多糖或魔芋多糖酰基化。
称取一定量的制备的乙酰化白芨多糖纳米颗粒(以下简称AC-BSP)和乙酰化魔芋多糖纳米颗粒(以下简称AC-KGM)，紫外照射灭菌，制备方式通过先用乙醇：dd water＝4：1清洗三遍，再用生理盐水配制成一定浓度(使用浓度为50mg/kg)。对合成的酰基化纳米多糖进行理化表征分析。
通过透射电镜观测AC-BSP以及AC-KGM的形貌结构及大小分布，如图1，形成的纳米颗粒近似球形，尺寸均一，粒径约为30nm，表明酰基化的多糖能够形成均一纳米颗粒，初步制备的酰基化多糖达到预期。
通过动态光散射检测两种酰基化多糖的粒径和电位，如图2，纳米颗粒的粒径均一，尺寸接近30nm,测得电位酰基化后多糖纳米颗粒带负电荷。
实施例2：AC-BSP对小鼠TNBS肠炎的治疗作用
按照文献报道方法建立小鼠TNBS肠炎模型，即取雌性BALB/C小鼠40只，体重16-18g，鼠禁食24小时，除空白对照组外灌肠给药TNBS溶液建立TNBS肠炎小鼠模型。模型建立12小时后灌肠给药将药物注入小鼠结肠内。
将小鼠随机分为4组，分组如下：
空白对照组：模型建立时灌入50％的乙醇溶液，灌肠给药时给入生理盐水；
模型组：模型建立时灌入3mg/ml的TNBS，灌肠给药时给入生理盐水；
BSP/KGM组：模型建立时灌入3mg/ml的TNBS，灌肠给药时给入BSP溶液作为对照；
AC-BSP/AC-KGM组：模型建立时灌入3mg/ml的TNBS，灌肠给药时给入AC-BSP(50mg/kg)
TNBS模型中均为三次给药，给药体积均为100μl。给药后每天观察小鼠毛发状况，粪便性状，称量小鼠体重，并详细记录，共计三天。DAI评分标准如下表。如果观测小鼠体重，小鼠饲养到模型建立第8天。
(1)疾病活动度(DAI)评分
给药后每天观察小鼠毛发状况，粪便性状，称量小鼠体重，并详细记录，共计三天。DAI评分标准如下表。
表1DAI积分计分法
DAI评分＝(体重丢失积分+粪便连续积分+隐血肉眼血积分)/3
(2)结肠HE病理切片评分
模型建立后3天处死动物，取小鼠结肠，4％甲醛固定12小时，包埋切片，H&E染色，显微镜观察其病理变化，并进行评分。评分标准如下：
表2小鼠结肠HE病理切片评分标准：
TNBS灌肠造模后，小鼠出现明显腹泻，体重降低，便血等症状，DAI评分可以综合上述指标评价小鼠结肠炎的疾病严重程度。如表3所示，TNBS模型小鼠的DAI评分与正常健康小鼠对比显著上升，而魔芋多糖纳米颗粒治疗可以有效缓解肠炎症状，降低DAI评分，此外BSP/KGM处理对DAI评分没有影响。通过组织学评分我们可以发现治疗组中仅见少量炎症细胞浸润，组织学评分显著低于TNBS模型组；而白芨多糖单独处理对结肠的病理学评分并无影响。由此可见AC-BSP/AC-KGM的治疗可以有效缓解TNBS诱导的肠道炎症。其中AC-BSP的治疗图片见图3。设立正常对照组，肠炎模型组，治疗组给小鼠灌入TNBS溶液后给相应药物。3天后处死小鼠取结肠，拍照结果如图3，从图3可以看出，对照小鼠结肠长度较长，无红肿现象，无明显其他炎症症状。TNBS组炎症症状明显，有红肿，结肠变短的现象。BSP组的炎症症状存在，但没有TNBS组炎症明显，可能是由于BSP有改善肠道内环境的作用。多糖纳米颗粒组(AC-BSP组)与正常相似，无明显红肿现象。由此可见多糖纳米颗粒确有缓解炎症的作用,且效果明显优越于BSP组。
表3 AC-BSP治疗TNBS肠炎模型小鼠疗效
数据均以平均值±标准差的形式加以显示，显著性差异通过ANOVA检验加以确定。与模型组相比较，*代表P≤0.05
实施例3：AC-BSP/AC-KGM对小鼠酒精性胃溃疡模型的治疗作用
按照文献报道方法建立小鼠酒精性胃溃疡模型，即取ICR雄性小鼠40只，体重20-22g，将小鼠随机分为4组，基于酒精性胃溃疡模型灌胃给药。
ICR小鼠经24小时禁食，分别灌胃给药，分组如下：
空白对照组：灌胃给药时给入生理盐水；
模型组：灌胃给药时给入生理盐水；
BSP/KGM组：灌胃给药时给入BSP溶液作为对照；
AC-BSP/AC-KGM组：灌胃给药时给入AC-BSP(50mg/kg)
给药4小时后，除空白对照组外，其余各组0.2ml/只无水乙醇灌胃，观察小鼠状态并记录，随后处死小鼠；处死后结扎贲门，取出全胃，固定1小时，用生理盐水清洗，肉眼观察胃溃疡情况，记录溃疡指数。模型组半数小鼠出现俯卧、震颤、运动失调症状；胃体出有较大点状出血或出血带，少部分出现点状出血，可见腺胃部黏膜深红色，有明显允血症状。AC-BSP/AC-KGM在所用剂量下对小鼠无水乙醇模型有良好的保护作用，与空白对照组比较对溃疡有较好的抑制率，能够减轻乙醇对胃黏膜的损伤作用，溃疡指数明显低于对照组。结果见表4。
表4 AC-BSP对小鼠酒精性胃溃疡的影响
数据均以平均值±标准差的形式加以显示，显著性差异通过ANOVA检验加以确定。与模型组相比较，*代表P≤0.05
实施例4：AC-BSP/AC-KGM对小鼠全层皮肤切除创伤模型的治疗作用
a.按照文献报道方法建立小鼠皮肤创伤愈合：
b.取C57小鼠，戊巴比妥钠腹腔麻醉，背部去毛，消毒，用特制打孔器在鼠背上打一圆孔，切取直径7mm、面积平均为mm2的皮肤，深至皮下,止血后，拍照记为Day1，对照组以一次性无菌敷料贴包扎,单笼喂养。
c.实验组将药物涂抹在伤口处，再用涂上红霉素药膏的纱布包扎，单笼喂养。
d.在创伤后3天、5天、7天、9天以及12天照相，然后使用美国Image-Pro○R PlusVersion6(IPP)图像分析软件测量小鼠和的伤口面积。愈合率＝[(原始创面面积-未愈合创面面积)÷原始创面面积]×100％。
取伤口组织，固定，石蜡包埋切片，HE染色和天狼猩红染色，观察创面的病理学和细胞学特征
实验随机分为四组：
对照组：涂抹给药时给入生理盐水；
BSP/KGM组：涂抹给药时给入BSP溶液作为对照；
AC-BSP/AC-KGM组：涂抹给药时给入AC-BSP/AC-KGM(5mg/ml)
涂抹给药后，红霉素软膏涂抹伤口，一次性无菌敷料贴包扎，单笼饲养，观察小鼠造模前、后体重，皮毛，运动及进食的变化。通过创面愈合率、创面愈合时间和组织病理学分析作为直接而有效的创面愈合评价指标。创面愈合率见图4。通过对小鼠定时拍照记录伤口愈合的图片，分别在1、3、6、9、12统计愈合面积，酰基化的多糖能够促进早期的伤口愈合，减少愈合过程中感染的风险。
Claims (9)
1.一种酰基化葡甘聚糖纳米颗粒，其特征在于是对葡甘聚糖进行酰基化得到的粒径为10nm–100nm的纳米颗粒；所述的酰基化为甲酰化、乙酰化或丙酰化。
2.根据权利要求1所述的一种酰基化葡甘聚糖纳米颗粒，其特征在于对葡甘聚糖进行乙酰化得到的粒径为25-35nm的纳米颗粒；优选对葡甘聚糖进行乙酰化得到的粒径为30nm的纳米颗粒。
3.根据权利要求2所述的一种酰基化葡甘聚糖纳米颗粒，其特征在于所述的葡甘聚糖选自白芨多糖或魔芋多糖中的任意一种。
4.根据权利要求3所述的酰基化葡甘聚糖纳米颗粒，其特征在于主要通过以下步骤制备得到：
(1)白芨多糖或魔芋多糖加入到吡啶中分散，反应温度40℃～90℃，搅拌时间15min～1h；白芨多糖或魔芋多糖与吡啶的质量体积比为(15-5)mg:1mL；
(2)加入吡啶和醋酐的混合液混合，混合温度50～95℃，反应时间4～24h；吡啶与醋酐的体积比1：1～1：30；吡啶和醋酐的混合液加入量与步骤(1)中加入的吡啶等体积；
(3)加入蒸馏水，醋酐和水的摩尔比是1：1～1：3；
(4)向反应液中加入过量的无水乙醇，保持4～8℃沉淀过夜，无水乙醇与步骤(3)反应体系的体积比为4:1～10:1；
(5)滤出沉淀，并用无水乙醇或丙酮清洗；
(6)将沉淀分散于蒸馏水中，冻干抽真空即得乙酰化的白芨多糖或魔芋多糖。
5.权利要求3所述的酰基化葡甘聚糖纳米颗粒的制备方法，其特征在于包括以下步骤：
(1)白芨多糖或魔芋多糖加入到吡啶中分散，反应温度40℃～90℃，搅拌时间15min～1h；白芨多糖或魔芋多糖与吡啶的质量体积比为(15-5)mg:1mL；
(2)加入吡啶和醋酐的混合液混合，混合温度50～95℃，反应时间4～24h；吡啶与醋酐的体积比1：1～1：30；吡啶和醋酐的混合液加入量与步骤(1)中加入的吡啶等体积；
(3)加入蒸馏水，醋酐和水的摩尔比是1：1～1：3；
(4)向反应液中加入过量的无水乙醇，保持4～8℃沉淀过夜，无水乙醇与步骤(3)反应体系的体积比为4:1～10:1；
(5)滤出沉淀，并用无水乙醇或丙酮清洗；
(6)将沉淀分散于蒸馏水中，冻干抽真空即得乙酰化的白芨多糖或魔芋多糖。
6.根据权利要求5所述的制备方法，其特征在于步骤(2)中所述的混合温度为90℃。
7.根据权利要求5所述的制备方法，其特征在于步骤(4)中保持4℃沉淀过夜。
8.权利要求1所述的酰基化葡甘聚糖纳米颗粒在制备治疗炎症性疾病、胃溃疡、创伤愈合的药物和/或敷料中的应用。
9.根据权利要求8所述的应用，其特征在于所述的炎症性疾病选自结肠炎、慢性胃炎或关节炎。
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