CN115353555A - 季铵化壳寡糖-μ-芋螺毒素结合物及其制备方法与应用 - Google Patents
季铵化壳寡糖-μ-芋螺毒素结合物及其制备方法与应用 Download PDFInfo
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- CN115353555A CN115353555A CN202211008463.3A CN202211008463A CN115353555A CN 115353555 A CN115353555 A CN 115353555A CN 202211008463 A CN202211008463 A CN 202211008463A CN 115353555 A CN115353555 A CN 115353555A
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- chitosan oligosaccharide
- conotoxin
- quaternized chitosan
- conjugate
- oil
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Abstract
本发明属于生物医药及化妆品技术领域，涉及季铵化壳寡糖‑μ‑芋螺毒素结合物及其制备方法与应用。季铵化壳寡糖‑μ‑芋螺毒素结合物中，季铵化壳寡糖分子通过酰胺键与至少一个μ‑芋螺毒素连接。其制备方法为，季铵化壳寡糖与μ‑芋螺毒素CnIIIC经过1‑(3‑二甲氨基丙基)‑3‑乙基碳二亚胺盐酸盐、N‑羟基琥珀酰亚胺的活化，进行酰胺化反应，即得。本发明提供的季铵化壳寡糖‑μ‑芋螺毒素结合物能够提高μ‑芋螺毒素CnIIIC的稳定性。另外，通过实验研究，本发明意外地发现，本发明提供的季铵化壳寡糖‑μ‑芋螺毒素结合物具有更为显著的抗皱效果以及更好的吸湿性和保湿性。
Description
技术领域
本发明属于生物医药及化妆品技术领域，涉及季铵化壳寡糖-μ-芋螺毒素结合物及其制备方法与应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
μ-芋螺毒素CnIIIC由22个氨基酸组成，是一种非常有效、具有选择性和持久性的骨骼肌NaV1.4钠通道拮抗剂，可以作为一种具有祛皱效果的肌肉松弛剂，在美容方面具有巨大的应用价值。但是，μ-芋螺毒素CnIIIC作为一种多肽类药物，具有半衰期短、稳定性差、抗原性强、易被蛋白酶降解等缺点。
发明内容
为了解决现有技术的不足，本发明的目的是提供季铵化壳寡糖-μ-芋螺毒素结合物及其制备方法与应用，本发明提供的季铵化壳寡糖-μ-芋螺毒素结合物能够提高μ-芋螺毒素CnIIIC的稳定性。另外，通过实验研究，本发明意外地发现，与μ-芋螺毒素CnIIIC相比，本发明提供的季铵化壳寡糖-μ-芋螺毒素结合物具有更为显著的抗皱效果；与季铵化壳寡糖相比，本发明提供的季铵化壳寡糖-μ-芋螺毒素结合物具有更好的吸湿性和保湿性。
为了实现上述目的，本发明的技术方案为：
一方面，一种季铵化壳寡糖-μ-芋螺毒素结合物，季铵化壳寡糖分子通过酰胺键与至少一个μ-芋螺毒素连接。
相比壳聚糖，壳寡糖是一种低聚壳聚糖，具有更好的水溶性，由于其具有较低的分子量，更有利于渗透至皮肤内。增加其保湿性，将壳寡糖进行季铵化改性，使其具有更多的亲水基团，从而增加与水的结合能力，从而实现吸湿性和保湿性的增加。另外，季铵化壳聚糖不仅具有优良的保湿性，由于其存在的季铵基团，有利于消毒杀菌，因而本发明采用季铵化壳聚糖与μ-芋螺毒素进行结合，使形成的结合物不仅具有抗皱效果，而且具有良好的保湿性、抗氧化活性和抗菌活性等。
在实验验证本发明提供的季铵化壳寡糖-μ-芋螺毒素结合物的保湿性和抗皱活性的过程中，意外地发现，该结合物比μ-芋螺毒素具有更优异的抗皱性能，且比季铵化壳聚糖具有更好的吸湿性和保湿性，说明季铵化壳寡糖与μ-芋螺毒素结合后形成的季铵化壳寡糖-μ-芋螺毒素结合物产生了协同增效的效果。
另一方面，一种季铵化壳寡糖-μ-芋螺毒素结合物的制备方法，季铵化壳寡糖(QCOS)与μ-芋螺毒素CnIIIC(μ-CnIIIC)经过1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、N-羟基琥珀酰亚胺(NHS)的活化，进行酰胺化反应，即得。
第三方面，一种组合物，包括上述季铵化壳寡糖-μ-芋螺毒素结合物和载体。
第四方面，一种上述季铵化壳寡糖-μ-芋螺毒素结合物或组合物在制备抗皱纹美容产品中的应用。
本发明的有益效果为：
本发明提供的季铵化壳寡糖-μ-芋螺毒素结合物，将季铵化壳寡糖连接到μ-芋螺毒素CnIIIC上，改变了μ-芋螺毒素CnIIIC分子量大小，在保留其最大生物活性的同时提高稳定性，延长半衰期。
本发明提供的季铵化壳寡糖-μ-芋螺毒素结合物具有良好的保湿、抗皱、抗氧化、抗菌、抗炎、促进皮肤愈合等效果，应用于功效性的化妆品、皮肤外用药物领域可有效的发挥保湿、抗氧化、抗皱、消除疤印和痘痕、祛斑等功效。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1为本发明实施例2中利用实施例1制备的季铵化壳寡糖-μ-芋螺毒素的结合物的吸湿性曲线，A在硫酸铵饱和溶液(RH＝81％)中，B在碳酸钾饱和溶液(RH＝43％)中；
图2为本发明实施例2中利用实施例1制备的季铵化壳寡糖-μ-芋螺毒素的结合物的保湿性曲线；
图3为本发明实施例5中利用实施例1制备的季铵化壳寡糖-μ-芋螺毒素的结合物的抗皱活性评价柱状图。
具体实施方式
应该指出，以下详细说明都是示例性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与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。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本发明的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
正如背景技术所介绍的，μ-芋螺毒素CnIIIC是一种有效的、具有祛皱效果的肌肉松弛剂，但是其存在自身稳定性差、半衰期短等缺点，本发明提出了季铵化壳寡糖-μ-芋螺毒素结合物及其制备方法与应用。
本发明的一种典型实施方式，提供了一种季铵化壳寡糖-μ-芋螺毒素结合物，季铵化壳寡糖分子通过酰胺键与至少一个μ-芋螺毒素连接。
在一些实施例中，一个季铵化壳寡糖分子连接1～10个μ-芋螺毒素，即QCOS-(μ-CnIIIC)n，n为1～10中的自然数。
本发明的另一种实施方式，提供了一种季铵化壳寡糖-μ-芋螺毒素结合物的制备方法，季铵化壳寡糖与μ-芋螺毒素CnIIIC经过1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺的活化，进行酰胺化反应，即得。
在一些实施例中，操作过程为：将μ-芋螺毒素CnIIIC加入至双蒸水中，再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺混合均匀，调节pH至7.0～7.5，然后加入季铵化壳寡糖的溶液，室温反应12～36h。
在一种或多种实施例中，反应后进行透析除杂，然后冷冻干燥。
在一些实施例中，所述季铵化壳寡糖的制备方法为：先采用苯甲醛对壳寡糖C2位的氨基进行保护的反应获得B-COS，再采用缩水甘油三甲基氯化铵(GTMAC)与B-COS反应，使得B-COS的C6位羟基上引入季铵基团获得B-QCOS，然后对B-QCOS的C2位进行氨基脱保护的反应，即得。
在一种或多种实施例中，壳寡糖的分子量为1kDa～2kDa。该分子量更有利于形成的结合物在皮肤外用制剂或生物医药领域的应用。
在一种或多种实施例中，采用苯甲醛对壳寡糖C2位的氨基进行保护的反应的过程为：将壳寡糖加入至醋酸水溶液，混合均匀后添加无水乙醇和苯甲醛，加热反应，采用碱溶液调节pH产生沉淀，将沉淀洗涤干燥即可。该过程中，加热反应的温度优选为45～55℃，反应时间为0.5～1.5h。洗涤采用的溶剂为甲醇。
在一种或多种实施例中，采用缩水甘油三甲基氯化铵与B-COS反应的过程为：将B-COS溶于异丙醇，混合均匀，加入缩水甘油三甲基氯化铵，加热反应，反应后收集沉淀，将沉淀洗涤干燥。该过程中，加热反应的温度为65～75℃，反应时间为15～20h。洗涤采用甲醇和丙酮多次交替洗涤。
在一种或多种实施例中，对B-QCOS的C2位进行氨基脱保护的反应的过程为：将B-QCOS加入至盐酸乙醇溶液中，室温搅拌12～36h，去除溶剂，加入双蒸水和丙酮沉淀，将沉淀进行透析、冷冻干燥。该过程中，盐酸乙醇溶液的浓度为0.20～0.30M。去除溶剂采用旋蒸。双蒸水和丙酮的体积比为1:8.5～9.5。透析过程中的透析袋中的MWCO为1000Da。
本发明的第三种实施方式，提供了一种组合物，包括上述季铵化壳寡糖-μ-芋螺毒素结合物和载体。
本发明所述的载体为皮肤外用产品的辅料，主要包括油相、水相、赋形剂等。
其中，所述油相为烃、酯、动植物油和脂肪、蜡、虾虎油、高级脂肪酸、高级醇、硅酮类物质、固醇和树脂、以及通过酶(例如，水解和酯交换)或化学(例如，酯交换和氢化)处理的上述物质；具体地，如杏仁油、坚果油、鳄梨油、猴面包树油、茶花油、胡萝卜油、蓖麻油、香茅油、椰子油、酸果蔓籽油、葡萄籽油、大麻籽油、霍霍巴油、澳洲坚果油、草甸泡沫种子油、燕麦润肤剂、红树莓种子油、玫瑰果油、大豆油、菜籽油、玉米油、芝麻籽油、棉籽油、红花油、葵花籽油、花生油、胚芽油、夏威夷果油、大蒜油、山茶油、棕榈油、橄榄油、亚麻籽油、桉树油、月见草油、乌龟油、貂油、猪油、牛脂、马油、蛇油、鱼油、蛋黄油；液体石蜡、异链烷烃、凡士林、角鲨烷、角鲨烯、松节油、聚乙二醇、肉豆蔻酸异丙酯、肉豆蔻酸异棕榈酰酯、2-肉豆蔻酸辛基十二烷基酯、2-乙基己酸十六烷基酯、三-2-乙基甘油酯己酸、甘油三辛酸酯、辛酸和癸酸的混合脂肪酸甘油三酸酯、新戊二醇二-2-乙基己酸酯、苹果酸二异硬脂基酯、异壬酸异壬酸酯(3,5,5-三甲基己基-3',5',5'-三甲基己酸)、胆固醇12-羟基硬脂酸酯、二季戊四醇和异硬脂酸和/或高级脂肪酸的单酯至六酯、对甲氧基肉桂酸和2-己酸的甘油酯、对甲氧基肉桂酸异辛酯、三硬脂酸甘油酯、松香、胆固醇、植物甾醇、羊毛脂、肉豆蔻酸、棕榈酸、异棕榈酸、硬脂酸、异硬脂酸、油酸、亚油酸、亚油酸、蓖麻油酸、12-羟基硬脂酸酸、10-羟基硬脂酸、山嵛酸、芥酸、花生四烯酸、二十碳五烯酸、二十二碳六烯酸、肉豆蔻醇、鲸蜡醇、硬脂醇、异硬脂醇、山嵛醇、羊毛脂醇、石蜡、微晶蜡、蜜蜂蜡、乳木果油、硬脂、巴西棕榈蜡、小烛树蜡、米糠蜡、向日葵蜡、浆果蜡、杨梅果蜡、月桂树蜡、日本蜡、虫胶、二甲基聚硅氧烷、甲基苯基聚硅氧烷。
上述载体中成分的具体选择根据组合物的制剂形式决定，其中的制剂形式可以为乳液、糊剂、溶液、粉剂、悬浮液、泡沫、霜剂、擦剂、硬膏、软膏、凝胶、贴剂、膏药等。制剂形式为硬膏等固体形式，其油相成分可从上述原料中选择羊毛脂、凡士林、石蜡等进行组合。制剂形式为软膏形式时，其至少包括一种聚乙二醇类成分。
所述赋形剂包括但不限于抗氧化剂、缓冲剂、增硬剂、填充剂、乳化剂、助乳化剂、润肤剂、溶剂、助悬剂、粘合剂、pH调节剂、稳定剂、增溶剂、增稠剂、增塑剂、胶凝剂、增粘剂、中和剂、防腐剂、螯合剂、吸留性、崩解剂、湿润剂、香料、渗透促进剂等。其中，所述抗氧化剂例如抗坏血酸(维生素C)、谷胱甘肽、硫辛酸、尿酸、生育酚(维生素E)、丁基化羟基甲苯(BHT)、丁基化羟基茴香醚(BHA)、胡萝卜素或泛醇(辅酶Q)等。所述凝胶剂例如西黄蓍胶、海藻酸钠、果胶、硅酸盐(例如气相二氧化硅)、明胶、纤维素衍生物(例如甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素)、卡波姆、瓜尔豆胶、聚乙烯醇粘土等。所述渗透促进剂例如油酸、卵磷脂、尿素、丁香油、肉豆蔻酸异丙酯、薄荷醇、香芹酚、芳樟醇、柠檬烯、香叶醇、橙花醇、丙二醇双戊四酸酯或环糊精。所述防腐剂例如羟基苯甲酸甲酯、羟基苯甲酸丙酯、氯化苯扎氯铵、乙酸洗必太、苄醇、汞、氯甲酚、苯甲酸、硝酸苯汞等。所述螯合剂例如柠檬酸、马来酸等。所述香料例如薰衣草油、玫瑰油、柠檬油、石灰油、佛手柑油、橙油、petgragrain油、橘油、洋甘菊油、肉桂油、鼠尾草精油、柏树油、天竺葵油、姜油、杜松油、马郁兰精油、桃金娘油、橙花油、松木油、紫檀木油、依兰油、雪松木油、茉莉花油、乳香油、没药油、广藿香油、檀香油、刺五加油等。所述乳化剂例如烷基硫酸盐、肥皂、十二烷基苯磺酸盐、乳酸酯、磺基琥珀酸酯、单酸甘油酯磺酸盐、磷酸酯、硅氧烷、牛磺酸盐等。
本发明的第四方面，提供了一种上述季铵化壳寡糖-μ-芋螺毒素结合物或组合物在制备抗皱纹美容产品中的应用。
本发明所述的抗皱纹美容产品包括但不限于皮肤外用制剂、洗护产品、化妆品或皮具护理剂。所述皮肤外用制剂用于干燥、辐射相关、炎症的皮肤症状，如晒伤、皮炎、皮肤干燥综合症、放射性皮肤病等。所述洗护产品包括但不限于清洁产品、护理产品；所述清洁产品例如香皂、洗发水、洗面奶、剃须膏、洗手液、沐浴露等；所述护理产品例如限于护手霜、身体乳、面霜等。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将结合具体的实施例详细说明本发明的技术方案。
实施例1
一种季铵化壳寡糖-μ-芋螺毒素结合物(QCOS-μ-CnIIIC结合物)的制备方法：
S1、COS中C2位氨基保护：
取1g COS(1kDa)溶于40mL10％醋酸水溶液，于室温下搅拌40min，再加入20mL无水乙醇和5mL苯甲醛，50℃搅拌反应1h，用2M的NaOH溶液调节反应液pH至大量沉淀析出，收集沉淀，甲醇多次抽滤洗涤，60℃烘箱干燥，得到产物B-COS。
S2、B-COS中C6位羟基连接季铵基团：
取1g B-COS溶于20mL异丙醇中，于室温下搅拌40min，再加入3g 2,3-环氧丙基三甲基氯化铵(GTMAC)，70℃下搅拌反应16h，收集沉淀，甲醇、丙酮多次交替洗涤，60℃烘箱干燥，得到产物B-QCOS。
S3、B-QCOS中C2位氨基脱保护：
取1g B-QCOS溶于20mL 0.25M的盐酸乙醇溶液中，于室温下搅拌24h，旋转蒸发除去溶剂，加入5mL双蒸水，加入45mL丙酮沉淀过夜，收集沉淀，少量双蒸水溶解后转移到MWCO为1000Da的透析袋中用双蒸水透析两天，除去杂质。透析完成后，收集反应液放入冷冻干燥机中冻干，得到产物QCOS。
S4、制备QCOS-μ-CnIIIC结合物：
取10mgμ-CnIIIC溶于10mL双蒸水中，加入EDCI和NHS催化剂，比例为2：1，混匀，于室温条件下缓慢搅拌，搅拌完成后调pH值至7.2～7.5。用10mL双蒸水溶解10mg QCOS，加入到上述溶液中，缓慢搅拌反应24h，将反应液转移到MWCO为1000Da的透析袋中用双蒸水透析两天，除去杂质。透析完成后，收集反应液放入冷冻干燥机中冻干，获得QCOS-μ-CnIIIC结合物。
实施例2
本实施例中，针对实施例1制备的季铵化壳寡糖-μ-芋螺毒素结合物的吸湿和保湿性进行了评价：
(1)QCOS-μ-CnIIIC吸湿性评价：准确称取50mg干燥的COS、QCOS和QCOS-μ-CnIIIC结合物，分别放入锥形瓶中。在25℃下，将锥形瓶分别放置在含有硫酸铵饱和溶液(相对湿度RH＝81％)和含有饱和碳酸钠溶液(相对湿度RH＝43％)的干燥器中，在12h、24h、36h、48h时称量样品质量，并根据以下公式计算吸湿率，实验重复三次。
式中：m0为样品和锥形瓶放置前的质量，m1为样品和锥形瓶在各时间点称重质量，W为样品质量。
(2)QCOS-μ-CnIIIC保湿性评价：将上述在硫酸铵饱和溶液的干燥器中吸湿达到48h样品放置在装有干燥硅胶的干燥器中，放置24h，期间每2h称量样品质量，并根据以下公式计算保湿率，实验重复三次。
式中：m2为样品和锥形瓶放置前的质量，m3为样品和锥形瓶在各时间点称重质量。
结果如图1～2所示，相较于壳寡糖原料，季铵化壳寡糖的吸湿性和保湿性显著增加。此外，季铵化壳寡糖-μ-芋螺毒素结合物具有比季铵化壳寡糖更好的吸湿性和保湿性。
实施例3
本实施例中，针对实施例1制备的季铵化壳寡糖-μ-芋螺毒素结合物的抗氧化活性进行了评价：
(1)QCOS-μ-CnIIIC对ABTS自由基清除活性评价：配制2.6mM的过硫酸钾溶液，7.4mM的ABTS溶液，然后各取5mL摇晃均匀，在避光下放置4℃反应过夜，得到ABTS自由基溶液。用无水乙醇稀释ABTS自由基溶液，并检测其在734nm出吸光度值为0.70±0.02。取浓度为0.5，1.0，1.5，2.0，2.5，3.0mg/mL的COS、QCOS、μ-CnIIIC和QCOS-μ-CnIIIC结合物于试管中，与稀释后的ABTS自由基溶液按照1:1的比例混合，空白对照组用双蒸水代替样品，避光反应20min，记录各组在734nm下测定吸光度，并根据以下公式计算样品对ABTS自由基的清除率，实验重复3次，取平均值。
式中：A0为空白对照组的吸光度，A1为样品组的吸光度。
(2)QCOS-μ-CnIIIC对DPPH自由基清除活性评价：取浓度为0.5，1.0，1.5，2.0，2.5，3.0mg/mL的COS、QCOS、μ-CnIIIC和QCOS-μ-CnIIIC结合物于试管中，每管分别加入等量的0.1mmol/L的DPPH溶液，空白对照组用双蒸水代替样品，记录各组在517nm的吸光值，并根据以下公式计算样品对DPPH自由基的清除率，实验重复3次，取平均值。
式中：A0为空白对照组的吸光度，A1为样品组的吸光度。
结果表明季铵化壳寡糖-μ-芋螺毒素结合物具有较高的抗氧化性能。
实施例4
本实施例中，针对实施例1制备的季铵化壳寡糖-μ-芋螺毒素结合物的抗菌活性进行了评价：
将活化好的金黄色葡萄球菌和大肠杆菌，分别放入适量无菌的生理盐水中，振荡摇匀，制成一系列菌悬液，浓度约为107cfu/mL备用。以2mg/mL的青霉素钠作为阳性对照组，双蒸水做空白对照组，以20mg/mL的COS、QCOS、μ-CnIIIC和QCOS-μ-CnIIIC结合物为实验组。取100μL菌悬液均匀涂布于平板培养基上，将蘸取样品的直径为6mm的圆形滤纸片均匀摆放在上述平板培养基上，每个平板培养基放5个纸片，置于37℃培养箱中培养24h，用游标卡尺测定抑菌圈直径，实验重复三次，取平均值。
结果表明季铵化壳寡糖-μ-芋螺毒素结合物具有较高的抗菌性能。
实施例5
本实施例中，针对实施例1制备的季铵化壳寡糖-μ-芋螺毒素结合物的抗皱效果进行了评价：
采用细胞收缩检测试剂盒来评估QCOS-μ-CnIIIC结合物对肌肉细胞收缩性的影响。在37℃，5％CO2条件下，用骨骼肌细胞培养基培养人骨骼肌细胞(HSMC)至生长到对数期，收集细胞进行重悬，使细胞终浓度为5×106个细胞/mL培养基。将细胞悬液和预冷的胶原凝胶溶液以1:4的比例混合制成胶原晶格。在24孔板的每个孔中加入500μL的细胞-胶原混合液，在培养箱中孵育1h。当胶原聚合后，向凝胶晶格中添加1mL培养基。培养48h，期间观察胶原的收缩变化。在释放收缩基质之前，用浓度为100μmol/L的COS、QCOS、μ-CnIIIC和QCOS-μ-CnIIIC溶液处理细胞1h。24h后用直尺测量胶原凝胶大小的变化。使用细胞培养基作为阴性对照，实验重复3次，取平均值。
收缩率(mm)＝释放前胶原凝胶的直径-释放24h后胶原凝胶的直径。
结果如图3所示，相较于空白对照组来说，COS组和QCOS组的胶原直径有所减少，但是没有显著性差异，而μ-CnIIIC组胶原直径则显著降低，这表明μ-芋螺毒素本身具有良好的抗皱活性。更令人意外的是，QCOS-μ-CnIIIC结合物的胶原直径最小，且与μ-CnIIIC组之间存在极显著性差异，这表明经过季铵化壳寡糖修饰后，μ-芋螺毒素的抗皱活性显著提升，具有更好的抗皱活性。
实施例6
本实施例中，针对实施例1制备的季铵化壳寡糖-μ-芋螺毒素结合物的稳定性进行了评价：
采用细胞收缩检测试剂盒来评估制备保存一定时间的μ-CnIIIC和QCOS-μ-CnIIIC结合物的抗皱活性，以此来评价QCOS-μ-CnIIIC结合物的稳定性。在37℃，5％CO2条件下，用骨骼肌细胞培养基培养人骨骼肌细胞(HSMC)至生长到对数期，收集细胞进行重悬，使细胞终浓度为5×106个细胞/mL培养基。将细胞悬液和预冷的胶原凝胶溶液以1:4的比例混合制成胶原晶格。在24孔板的每个孔中加入500μL的细胞-胶原混合液，在培养箱中孵育1h。当胶原聚合后，向凝胶晶格中添加1mL培养基。培养48h，期间观察胶原的收缩变化。在释放收缩基质之前，用新鲜制备的、在不同条件下保存1个月和保存3个月的μ-CnIIIC以及QCOS-μ-CnIIIC(100μmol/L)溶液处理细胞1h。24h后用直尺测量胶原凝胶大小的变化。使用细胞培养基作为阴性对照，实验重复3次，取平均值。
收缩率(mm)＝释放前胶原凝胶的直径-释放24h后胶原凝胶的直径。
结果表明季铵化壳寡糖-μ-芋螺毒素结合物具有较好的稳定性。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种季铵化壳寡糖-μ-芋螺毒素结合物，其特征是，季铵化壳寡糖分子通过酰胺键与至少一个μ-芋螺毒素连接。
2.如权利要求1所述的季铵化壳寡糖-μ-芋螺毒素结合物，其特征是，一个季铵化壳寡糖分子连接1～10个μ-芋螺毒素。
3.一种季铵化壳寡糖-μ-芋螺毒素结合物的制备方法，其特征是，季铵化壳寡糖与μ-芋螺毒素CnIIIC经过1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺的活化，进行酰胺化反应，即得。
4.如权利要求3所述的制备方法，其特征是，操作过程为：将μ-芋螺毒素CnIIIC加入至双蒸水中，再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺混合均匀，调节pH至7.0～7.5，然后加入季铵化壳寡糖的溶液，室温反应12～36h。
5.如权利要求3所述的制备方法，其特征是，所述季铵化壳寡糖的制备方法为：先采用苯加氢对壳寡糖C2位的氨基进行保护的反应获得B-COS，再采用缩水甘油三甲基氯化铵(GTMAC)与B-COS反应，使得B-COS的C6位羟基上引入季铵基团获得B-QCOS，然后对B-QCOS的C2位进行氨基脱保护的反应，即得。
6.如权利要求5所述的制备方法，其特征是，壳寡糖的分子量为1kDa～2kDa。
7.如权利要求5所述的制备方法，其特征是，采用苯加氢对壳寡糖C2位的氨基进行保护的反应的过程为：将壳寡糖加入至醋酸水溶液，混合均匀后添加无水乙醇和苯甲醛，加热反应，采用碱溶液调节pH产生沉淀，将沉淀洗涤干燥即可。
8.如权利要求5所述的制备方法，其特征是，采用缩水甘油三甲基氯化铵与B-COS反应的过程为：将B-COS溶于异丙醇，混合均匀，加入缩水甘油三甲基氯化铵，加热反应，反应后收集沉淀，将沉淀洗涤干燥。
9.一种组合物，其特征是，包括权利要求1或2所述的季铵化壳寡糖-μ-芋螺毒素结合物或权利要求3～8任一所述的制备方法获得的季铵化壳寡糖-μ-芋螺毒素结合物和载体。
10.一种权利要求1或2所述的季铵化壳寡糖-μ-芋螺毒素结合物或权利要求3～8任一所述的制备方法获得的季铵化壳寡糖-μ-芋螺毒素结合物或权利要求9所述的组合物在制备抗皱纹美容产品中的应用。
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