CN111019012A - 具有溶致液晶行为的壳聚糖氨基酸衍生物 - Google Patents
具有溶致液晶行为的壳聚糖氨基酸衍生物 Download PDFInfo
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Abstract
本发明属于材料领域，通过简单的酰胺反应，利用不同氨基酸对壳聚糖进行接枝改性，得到了一系列氨基酸改性的壳聚糖，本发明的改性机理和改性手段简单，原料简单易得。通过进一步研究发现，部分氨基酸改性的壳聚糖具有良好的溶致液晶性能，且部分壳聚糖氨基酸衍生物的组合具有令人意外的溶致液晶性能，其在材料、医药领域有广阔的应用前景。
Description
技术领域
本发明属于材料领域，具体地，本发明涉及氨基酸改性壳聚糖的制备及其液晶性能研究。
背景技术
液晶(liquid crystal)为由固态向液态转化过程中存在的取向有序的流体。目前，市面上常见的液晶高分子材料分为热致型和溶致型。其中前者呈现液晶状态时的影响变量是温度，即在加热后在某一温度下会呈现液晶形态，目前在市场上占绝大多数；后者的影响变量是溶剂和浓度，其在某一溶剂下、特定浓度下可呈现液晶态。物质的液晶性质使得其在材料、医药等领域具有广泛的用途，除了大家熟知的新材料领域之外，欧阳钟灿曾深入研究了生物膜的液晶行为，认为生物膜自发排列的磷脂双分子层结构类似于溶致液晶行为；王德华曾研究了液晶态生物膜与癌症及其治疗之间的关系，指出治愈癌症的关键在于癌细胞的生物膜从液晶态到液态的可逆相变；另外，由于溶致液晶的非牛顿流体性能，使得其在化妆品中也有广泛的应用。
壳聚糖(chitosan)是甲壳素的N-脱乙酰产物，材料来源广泛且较为经济，生物相容性好，可降解且无毒，在材料、食品、医药领域均有广泛的应用。随着研究的深入，壳聚糖及其衍生物潜在的液晶性能也逐渐被人们所广泛关注：专利CN102766222A公开了一种含磷改性的壳聚糖溶致液晶及其制备工艺，通过在壳聚糖主链接枝磷酸分子，并用不同结构的单体对其进行修饰得到了含磷壳聚糖，经测试其具备溶致液晶性。CN1176141A公开了壳聚糖接枝聚乳酸溶液的方法，通过将壳聚糖和丙交酯的开环聚合，生成了壳聚糖和乳酸的接枝共聚物，经过测试，所得产物具有溶致液晶行为。赵雅青等人指出壳聚糖及其衍生物一般能在合适的溶液中形成胆甾液晶，即具有溶致液晶性，并采用圆二色谱等方法研究了N-邻苯二甲酰化壳聚糖在不同溶剂中的溶致液晶行为。汪剑炜等研究了分子量对壳聚糖溶致液晶性的影响，得出了三种不同分子量的壳聚糖在二氯乙酸溶液中都呈现胆甾型溶致液晶相，且临界浓度随分子量增加而降低的结论。
由此可见，越来越多的人逐渐关注到了壳聚糖及其衍生物的溶致液晶行为。但是上述具有溶致液晶性的壳聚糖衍生物其要么制备工艺复杂，要么未细致研究其溶致液晶行为。故依旧存在开发结构简单且溶致液晶行为突出的壳聚糖衍生物的需求。本发明便是基于目前的研究现状所作出。
发明内容
基于上述背景技术中所提到的技术问题，发明人经过进一步的技术调研发现，目前已经有部分学者研究了利用氨基酸对壳聚糖衍生物进行结构改造。如张毅等人曾研究了氨基酸改性壳聚糖基金属离子吸附材料的制备和性能，并研究了其成膜性、膜厚度、拉伸强力及抗菌性能；冯芳等人研究了壳聚糖异相接枝L－谷氨酸甲酯的合成，重点研究的是其不同以往的制备工艺。但是现有技术均为明确研究氨基酸改性壳聚糖的溶致液晶行为。故发明人以以上研究为基础，通过尝试将不同的氨基酸或氨基酸衍生物与壳聚糖进行接枝，然后研究其溶致液晶行为。
本发明选用的氨基酸均为常见的氨基酸，其具体种类如下：甘氨酸、丙氨酸、缬氨酸、苯丙氨酸、脯氨酸、亮氨酸、异亮氨酸、精氨酸、天冬氨酸、谷氨酸、丝氨酸、苏氨酸、半胱氨酸、天冬酰胺、谷氨酰胺、组氨酸、赖氨酸、酪氨酸、甲硫氨酸、色氨酸。
材料准备：
壳聚糖，脱乙酰度≥75％，低粘度，购自上海阿拉丁生化科技股份有限公司，以下其使用物质的量的计算为按照其最小重复单元的分子量进行计算，氨基酸购自南京红杉生物科技有限公司，EDC和NHS均购自上海阿拉丁生化科技股份有限公司，其他所用试剂均为分析纯。
制备工艺：
(1)将氨基酸、EDC和NHS在一定温度下溶于双蒸水中搅拌以活化氨基酸；(2)将壳聚糖在一定温度下搅拌溶解于pH为5左右的盐酸溶液中备用；(3)将活化的氨基酸溶液和壳聚糖溶液混合形成均一体系，随后在一定温度下反应12h；(4)反应结束后，用氢氧化钠调节溶液的pH至7-9附近，析出产物后将其装入透析袋中用水透析3-7日，每日换水3-5次；(5)将所获得的透析产物冻干，得到氨基酸改性的壳聚糖。
其中，以物质的量计算，氨基酸、EDC、NHS、壳聚糖的用量比为(0.2-1)：(0.2-1)：(0.2-1)：(0.05-0.5)，优选地，上述物质的摩尔用量比为(0.5-1)：(0.5-1)：(0.5-1)：(0.1-0.5)，更优选地，上述物质的摩尔用量比为(0.8-1)：(0.8-1)：(0.8-1)：(0.2-0.5)；
其中，优选地，步骤(1)、(2)中的溶解温度为25-35℃；步骤(3)中的反应温度为30-60℃；
优选地，步骤(4)中的pH值为7.5-8.5；
优选地，步骤(4)中的透析袋截留分子量为3000-10000Da，透析天数为5-6天，每日换水4次；
接枝率测试：
通常是否接枝成功可通过红外、元素分析等方式测试，但是红外仅仅能定性测试是否接枝成功，而元素分析可基本确定接枝率。故采用元素分析法测试各个氨基酸的接枝率。元素分析步骤：首先通过元素分析确定壳聚糖中的N含量，经过测试，所购买的脱乙酰度≥75％的壳聚糖其N元素含量为7.83。由于所采用的氨基酸其均有特定的N元素含量，如丙氨酸为15.7、苏氨酸为11.7、组氨酸为27.1。故由于大部分氨基酸中N元素的含量均高于壳聚糖中的N元素含量，且差距较为明显，故可通过元素含量测定并计算获得较为准确的接枝率。
溶致液晶行为分析
由于溶致液晶行为的有无与大分子的结构密切相关，如大分子的分子量，旋光度，分子刚性有关，故不同的氨基酸接枝的壳聚糖其所具有的溶致液晶行为各不相同，且由于分子结构和溶致液晶行为之间的关系并不具有可预期性，故通常较难以预期结构和液晶行为之间的关系，往往需要通过实验来证明。而判断溶致液晶行为是否有较大的应用前景，一方面是要看溶致液晶行为的溶剂适用，另一方面则是要看其临界浓度大小。通常溶致液晶行为适用的溶剂范围越广、临界浓度越小，其溶致液晶行为越好，在后续材料、医药领域中适用性就越高，可满足材料领域中不同溶剂、药剂中不同浓度药物载体的适用要求。故本部分对不同氨基酸改性壳聚糖的溶致液晶行为研究中，以临界浓度和适用溶剂范围为研究指标。
研究方法：壳聚糖的氨基酸衍生物的溶致液晶行为采用CD圆二色谱法测试，其依据的机理在于壳聚糖衍生物在达到临界浓度形成溶致液晶行为时，由于分子的定向排布，会导致偏光的显著变化。其中，根据壳聚糖的溶解性，选用的测试溶剂为醋酸水溶液、盐酸水溶液、二甲基甲酰胺(DMF)、二甲亚砜(DMSO)。
样品制备方法，按照赵雅青等人的文献方法进行，主要步骤为：将壳聚糖衍生物在有机溶剂中配置成一系列浓度的溶液，然后置于特制的石英片中，测试其圆二色图谱，然后绘制在400nm左右物质的椭圆度随浓度之间的变化图，记录突变浓度值即得到壳聚糖衍生物的溶致液晶的临界浓度。
附图说明
图1为浓度为25％的壳聚糖的甘氨酸衍生物在pH为5的醋酸水溶液中的CD图谱；
图2为浓度为45％的壳聚糖的甘氨酸衍生物在pH为5的醋酸水溶液中的CD图谱；
图3为壳聚糖的甘氨酸衍生物在pH为5的醋酸水溶液中椭圆度随其浓度的变化趋势图。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1甘氨酸接枝壳聚糖的制备
(1)称取0.01mol甘氨酸、0.01mol EDC和0.005mol NHS，在30℃加入50mL双蒸水中搅拌15min，以活化氨基酸；(2)将1.8g壳聚糖在30℃下搅拌溶解于pH为5的100mL盐酸溶液中备用；(3)将活化的氨基酸溶液和壳聚糖溶液混合形成均一体系，随后升温至50℃，搅拌下反应12h；(4)反应结束后，降至室温，用0.1M的氢氧化钠溶液调节溶液的pH至8，析出产物，待析出完全后将其装入3500Da的透析袋中用双蒸水透析7日，每日换水4次；(5)将所获得的透析产物冻干，得到氨基酸改性的壳聚糖。
接枝率测试：
甘氨酸的N元素含量为18.6％，壳聚糖其N元素含量为7.83％，实施例1的改性壳聚糖其N元素含量为8.61％，经过计算，甘氨酸的接枝率为15.35％。
实施例2-20
按照实施例1的步骤，分别将原料氨基酸进行替换，其他步骤和参数不变，得到即实施例2-20，其中实施例2-20所采用的的氨基酸均为L-氨基酸。其接枝率参见表1。
表1
其中，**的数据由于酪氨酸和接枝壳聚糖的N元素含量差距较小，考虑到实际误差，故接枝数据准确度较低。
由此可见，不同氨基酸在相同制备工艺下的接枝率有很大不同。其中脯氨酸的接枝率可达近30％。然而部分氨基酸的接枝率仅有7％左右，分析可知，天冬氨酸和谷氨酸具有两个羧基，故消耗的活化配体量大，可能导致接枝率相对较低。
试验例1：氨基酸接枝的壳聚糖的溶致液晶行为研究
按照前述方法，进行氨基酸壳聚糖衍生物的溶致液晶行为测试，其主要步骤为：将壳聚糖衍生物在四种不同的溶剂中配置成一系列浓度的溶液，然后置于特制的石英片中，测试其圆二色图谱，然后绘制在400nm左右物质的椭圆度随浓度之间的变化图，记录突变浓度值即得到壳聚糖衍生物的溶致液晶的临界浓度。由于共有20个衍生物，且共4种溶剂(pH为5的醋酸水溶液、pH为5的盐酸水溶液、DMF、DMSO)，故为了快速获得结果，以甘氨酸衍生的壳聚糖为例，首先设计5％、25％、45％、65％四个较大跨度浓度的甘氨酸壳聚糖的醋酸水溶液，测试得到其在25％和45％的浓度下其CD图谱呈现完全不同的两种状态。其中25％浓度下CD图谱见图1，45％的浓度下的图谱见图2，由此可知在45％浓度附近存在其临界浓度，故继续配制其前后10％的浓度范围进行测试，并利用类似二分法进行精准浓度的配制并绘制在410nm处的椭圆度突变曲线，进而测得其临界浓度，其中甘氨酸接枝的壳聚糖其椭圆度突变曲线见图3。由图3可知，甘氨酸衍生的壳聚糖在pH为5的醋酸水溶液中的溶致液晶行为的临界浓度为42％。
按照类似的方法分别测试所有实施例的壳聚糖衍生物在四种溶剂中的溶致液晶行为临界浓度，结果见表2。
表2
由表2可知，不同氨基酸接枝壳聚糖获得的壳聚糖的衍生物其溶致液晶行为有所不同，其中，溶致液晶行为较好的是苯丙氨酸、脯氨酸、组氨酸、酪氨酸、色氨酸。
试验例2
考虑到溶致液晶行为本质上由分子结构决定，主要和分子极性、旋光度、与溶剂分子之间的相互作用等相关。而若将不同的溶质分子混合后其分子和分子之间也存在相互作用的可能，故尝试将上述得到的5种壳聚糖衍生物两两以质量比1:1的比例混合，然后按照试验例1中所述的方法测试其混合后在pH为5的醋酸水溶液中的溶致行为临界浓度，结果如表3所示。
表3
结果可知，简单混合后发现10种组合中明显可降低临界浓度的有两组，即色氨酸/酪氨酸组(这里的色氨酸和酪氨酸组指的是壳聚糖的色氨酸衍生物和壳聚糖的酪氨酸衍生物组，分别对应实施例20和18，以下类似)，以及色氨酸和苯丙氨酸组。故选用上述两种组合，分别混合两种不同的壳聚糖氨基酸衍生物，并将其配制质量比分别为为5:1、4:1、3:1、2:1、1:2、1:3、1:4、1:5共8×2(色氨酸/酪氨酸组、色氨酸/苯丙氨酸组各8组)组固体粉末，然后分别测试上述不同配比的物质其临界浓度。结果如表4所示：
表4
综上可知，壳聚糖的色氨酸/酪氨酸组合物在3:1-1:2的配比范围内，可组成一种临界浓度小的溶致型组合物；壳聚糖的色氨酸/苯丙氨酸组合物在3:1-1:1的范围内，可组成一种临界浓度小的溶致型组合物。
基于以上分析，按照本发明的制备工艺所获得的壳聚糖的苯丙氨酸、脯氨酸、组氨酸、酪氨酸、色氨酸衍生物，尤其是壳聚糖的色氨酸/酪氨酸组合物在3:1-1:2的配比范围内，壳聚糖的色氨酸/苯丙氨酸组合物在3:1-1:1的范围内组成的组合物具有优良的溶致液晶行为，其可在至少四种溶剂(pH为5的醋酸水溶液、pH为5的盐酸水溶液、DMF、DMSO)中在较低的浓度下形成溶致液晶，在材料、医药领域具有广阔的应用前景。
Claims (9)
1.一种具有溶致液晶行为的壳聚糖的氨基酸衍生物的制备工艺，具体步骤如下：
(1)将氨基酸、EDC和NHS在一定温度下溶于双蒸水中搅拌以活化氨基酸；(2)将壳聚糖在一定温度下搅拌溶解于pH为5的盐酸溶液中备用；(3)将活化的氨基酸溶液和壳聚糖溶液混合形成均一体系，随后在一定温度下反应12h；(4)反应结束后，用氢氧化钠调节溶液的pH至7-9附近，析出产物后将其装入透析袋中用水透析3-7日，每日换水3-5次；(5)将所获得的透析产物冻干，即得壳聚糖的氨基酸衍生物。
2.根据权利要求1所述的制备工艺，其中，以物质的量计算，氨基酸、EDC、NHS、壳聚糖的用量比为(0.2-1)：(0.2-1)：(0.2-1)：(0.05-0.5)，优选地，上述物质的摩尔用量比为(0.5-1)：(0.5-1)：(0.5-1)：(0.1-0.5)，更优选地，上述物质的摩尔用量比为(0.8-1)：(0.8-1)：(0.8-1)：(0.2-0.5)。
3.根据权利要求2所述的制备工艺，其中步骤(1)、(2)中的溶解温度为25-35℃；步骤(3)中的反应温度为30-60℃。
4.根据权利要求3所述的制备工艺，其中步骤(4)中的pH值为7.5-8.5。
5.根据权利要求4所述的制备工艺，其中步骤(4)中的透析袋截留分子量为3000-10000Da，透析天数为5-6天，每日换水4次。
6.根据权利要求4所述的制备工艺，其中氨基酸选自甘氨酸、丙氨酸、缬氨酸、苯丙氨酸、脯氨酸、亮氨酸、异亮氨酸、精氨酸、天冬氨酸、谷氨酸、丝氨酸、苏氨酸、半胱氨酸、天冬酰胺、谷氨酰胺、组氨酸、赖氨酸、酪氨酸、甲硫氨酸、色氨酸中的一种。
7.根据权利要求4所述的制备工艺，其中氨基酸为苯丙氨酸、脯氨酸、组氨酸、酪氨酸、色氨酸中的一种。
8.一种具有良好溶致液晶行为的组合物，其由壳聚糖的色氨酸衍生物，以及壳聚糖的酪氨酸衍生物以3:1-1:2的质量比组成，其中壳聚糖的色氨酸衍生物和壳聚糖的酪氨酸衍生物均采用如权利要求4所述的工艺制备得到。
9.一种具有良好溶致液晶行为的组合物，其由壳聚糖的色氨酸衍生物，以及壳聚糖的苯丙氨酸衍生物以3:1-1:1的质量比组成，其中壳聚糖的色氨酸衍生物和壳聚糖的苯丙氨酸衍生物均采用如权利要求4所述的工艺制备得到。
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| CN114437248A (zh) * | 2022-02-15 | 2022-05-06 | 内蒙古农业大学 | 一种壳寡糖非极性氨基酰胺类衍生物及其制备方法 |
| CN114437250A (zh) * | 2022-03-15 | 2022-05-06 | 内蒙古农业大学 | 一种壳寡糖氨基羟基丙酰胺类衍生物及其制备方法 |
| CN116675785A (zh) * | 2023-05-22 | 2023-09-01 | 中国海洋大学 | 巯基改性壳聚糖微球的制备方法及在益生菌包埋中的应用 |
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| CN114437248A (zh) * | 2022-02-15 | 2022-05-06 | 内蒙古农业大学 | 一种壳寡糖非极性氨基酰胺类衍生物及其制备方法 |
| CN114437250A (zh) * | 2022-03-15 | 2022-05-06 | 内蒙古农业大学 | 一种壳寡糖氨基羟基丙酰胺类衍生物及其制备方法 |
| CN116675785A (zh) * | 2023-05-22 | 2023-09-01 | 中国海洋大学 | 巯基改性壳聚糖微球的制备方法及在益生菌包埋中的应用 |
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