两亲性多糖基胶束改善疏水性功能物质性能的研究进展

李双红，叶发银，雷琳，赵国华,2*

1(西南大学 食品科学学院，重庆, 400715) 2(重庆市特色食品工程技术研究中心， 重庆,400175)

两亲性多糖基胶束改善疏水性功能物质性能的研究进展

李双红1，叶发银1，雷琳1，赵国华1,2*

1(西南大学 食品科学学院，重庆, 400715) 2(重庆市特色食品工程技术研究中心， 重庆,400175)

两亲性多糖往往是亲水性多糖适度疏水化改性而获得的一类低毒、生物相容性和可降解性良好的半合成聚合物，其在水相中能自发聚集组装成为具有疏水核-亲水壳结构的胶束。最近，这类胶束受到食品科学、药学、生物医学工程乃至材料学相关科学家的广泛重视，其研究急剧升温，且主要集中在利用其改善疏水性物质生物活性方面。论文主要以近5年文献为基础，全面综述了两亲性多糖基胶束在疏水物质分散增溶、靶向递送、延缓释放、生物利用度提升及稳定性增强等方面的应用，并在此基础上对该领域存在的问题及今后的发展方向进行了探讨。

两亲性；多糖；自聚集；胶束；疏水活性物质

一些生物活性物质(β-胡萝卜素、番茄红素、维生素D3、姜黄素、槲皮素、紫杉醇、喜树碱和α-生育酚等)或药物(左旋溶肉瘤素和两性霉素B等)由于不溶或微溶于水，致使其在生物体内出现分散性差和生物利用率低等缺点，这极大降低了疏水活性物质的临床应用效能[1-3]。最近发现两亲性分子(表面活性剂)在水相中集聚形成的胶束是解决这一问题的有效工具。两亲性分子在水中达到一定浓度后在疏水相互作用的推动下，分子疏水基团相互缔合形成内核并被亲水链形成的外壳所包围，进而形成的有序分子集聚体结构称为胶束。通常将两亲性分子能够形成胶束的最低浓度称为其临界胶束浓度。高于该浓度时聚合物可自发聚集形成胶束，将天然亲水性多糖分子经过适度疏水化修饰后可赋予其两亲性，即形成两亲性多糖。该类多糖在水相中能自发集聚形成具有核-壳结构的胶束，其内核由疏水性基团组成而外壳则由亲水性糖链构成[4]。这一结构特征使该类胶束具有在内核装载疏水小分子物质的特殊能力，而通过外壳实现其水相分散、生物相容等优点[5]。截至目前，约有上百种两亲性多糖聚合物被合成，对应胶束的理化特性及应用特性，已成为近期食品科学、药学、生物医学工程乃至材料学等的重要研究热点之一。尽管如此，笔者在查阅文献资料的过程中发现，绝大部分的研究侧重于新型多糖聚合物胶束载体的开发研究，而对于其应用特性方面进行系统性梳理的报道少之又少，为了给国内从事该领域的学者提供参考，本文在重点查阅近5年文献的基础上，结合国内外研究现状，对两亲性多糖基胶束在疏水物质分散增溶、靶向递送、控制释放、生物利用度提升及稳态化等方面的应用进行综述。

1 两亲性多糖基胶束对疏水性物质的增溶作用

两亲性多糖基胶束对疏水性物质的增溶方式主要分为2种，一种是多糖基胶束通过其内核与目标物质之间的疏水相互作用实现对难溶或不溶性物质增溶[6]，其本质仍遵循相似相溶的基本原理。两亲性多糖基胶束对疏水活性物质的增溶过程与常见的反胶束萃取过程十分相似，是被增溶物质从固相(不溶)到液相(极低浓度)再到胶束内相(高浓度富集)的定向传质过程(图1-a)。第二种方式是通过共聚[7-8](如酯化反应等)将待增溶的目标物质直接连接到多糖链上形成两亲性多糖聚合物，该聚合物在水溶液中自聚集将目标物质以内核形式载入胶束中，由此达到难溶物质在水相中的分散(图1-b)。增溶过程中常用的方法有薄膜水化法[2]、微相分离法[6]、透析法[9]、水包油法[10]以及乳液溶剂蒸发法[11]等。对增溶效果的评价常以特定浓度的两亲性多糖胶束溶液，荷载目标物质的含量来表示。除增溶方法之外，多糖聚合物的临界胶束浓度、疏水基团的取代度和疏水性能以及环境参数(时间、温度、搅拌强度)等都是影响增溶效果的重要因素。表1给出了两亲性多糖基胶束增溶疏水性物质的一些案例。

图1 两亲性多糖基胶束增溶疏水性物质的主要方式Fig.1 The main ways of amphiphilic polysaccharide-based micelles in solubilizing hydrophobic compounds

2 两亲性多糖基胶束对疏水性物质的靶向递送作用

生物活性物质只有能抵达特定的器官或细胞才能发挥其特定的生物活性。但对大多数生物活性物质来说，被吸收进入机体后随着血液循环分布到全身。这不仅影响其生物活性发挥，且易造成正常组织细胞损伤，引发系统毒性[5]。因此，生物活性物质的靶向递送具有十分重要的意义。根据靶向机制，可分为组织特异性靶向与环境响应性靶向。

组织特异性靶向又可分为被动靶向和配体耦合靶向。被动靶向主要依赖于靶向组织的高通透性和滞留效应以及两亲性多糖基胶束的尺寸[17]。肿瘤组织血管壁的孔径一般为几百纳米到几微米，明显大于正常组织血管壁孔径(2～6 nm)，这为肿瘤组织吸收和滞留大分子物质或颗粒提供了通道[18]，从而生物活性物质被动实现靶向递送。配体耦合靶向是指在胶束载体上连接能特异性识别肿瘤表面过表达抗原物质的配体，这些配体与目标位点特异性结合，从而使药物载体在肿瘤组织中选择性积累。常用的配体包括透明质酸、硫酸软骨素、叶酸、β-D-半乳糖残基、生长激素抑制素、转铁蛋白、生物素、α2-糖蛋白及表皮生长因子等[19]。显而易见，不同配体具有不同的靶向性，应根据具体靶向组织选择使用配体。表2给出了一些多糖基胶束载体靶向运输的应用案例。

注：增溶效果以水中溶解度→胶束中溶解度表示。

环境响应性靶向主要是根据靶向部位特定的生理环境条件设计的，如常见的pH响应性靶向、氧化还原响应性靶向和温度响应性靶向。pH响应性靶向的基本原理是人体正常组织环境的pH值(7.4)明显高于病变部位(如肿瘤细胞外pH值为6.8左右，细胞核内体则为5.5～6.5)[20]。当含有酸可降解基团的多糖基胶束接触肿瘤组织时，其酸可降解基团发生质子化或解离，导致胶束结构松散甚至解体并释放活性物质[21-22]。氧化还原响应性靶向常常在多糖基胶束中引入二硫键而得以实现。其基本原理为人体正常细胞内谷胱甘肽的含量(2～10 mmol/L)要显著低于病变组织(如肿瘤细胞中谷胱甘肽的含量约为正常组织中的4倍)。当含有二硫键的多糖基胶束接触肿瘤组织时，在高浓度谷胱甘肽的还原作用下，二硫键被打开，导致胶束结构松散甚至解体并释放活性物质[23]。温度响应性靶向依据病变部位的温度高于正常生理温度(>37 ℃)，一旦环境温度高于热敏性胶束载体的低临界溶解温度，载体发生相变迫使聚合物链崩解，加速内容物释放[24]。表3给出了一些多糖基胶束载体环境响应性靶向的应用案例。

表2 两亲性多糖基胶束载体对疏水性物质的组织特异性靶向应用案例

表3 两亲性多糖基胶束载体对疏水性物质环境响应性靶向应用案列

注：1. 响应效果：载体胶束对不同响应环境的敏感程度以包载物质释放量的百分数表示；2.CGSH：谷胱甘肽浓度；CDTT：二硫苏糖醇浓度。

3 两亲性多糖基胶束对疏水性物质的缓释作用

活性制剂以口服或者静脉注射的方式进入人体，在组织或血液中富集短时间内浓度达到高峰并被机体快速清除，这直接导致活性物质在组织或血液中维持有效浓度的时间过短，造成浪费[29]。多糖基聚合物胶束的疏水基团与活性成分之间存在相互作用，可延长制剂释放时间并改善治疗效果。活性成分释放率通常以胶束在特定体系(缓冲溶液、模拟胃液、模拟肠液等)中保温后，漏出的疏水物质质量百分比表示[23]。疏水内核材料的种类、胶束的降解能力、活性制剂的含量及胶束疏水区域与包载物质之间的亲和力的强弱等因素影响活性制剂释放率[19]，具体作用结果见表4。

4 两亲性多糖基胶束提高疏水性物质的生物利用度

活性物质自身的强电荷、高分子质量也是限制其临床应用的重要因素之一[44]。正如前所述，两亲性多糖基胶束特殊的结构将该类物质包裹其中，能大幅度提升其生物利用价值。 常用于衡量活性物质生物利用度的参数包括药-时量曲线下面积(AUC)、平均滞留时间(MRT)等，AUC也代表生物活性成分进入全身血液循环的相对量，MRT是活性物质在血浆中总保留时间的平均值，AUC和MRT的值越大表示生物活性物质的生理有效性越高[45]，具体案例见表5。研究发现[1]，利用槲皮素单体及透明质酸-槲皮素共聚物载药胶束分别对大鼠进行体内药物动力学试验，得到了两者的AUC(3.69→18.07 mg/(L·h))和MRT(0.185→4.30 h)值，表明聚合物胶束可以提高单体药物的生物利用率。此外，半数抑制浓度(IC50)指用药后活细胞数量减少一半时所需的药物浓度，能间接反应活性物质的利用程度，该值越小表示活性物质的效能越大。表6给出了两亲性多糖基胶束载体降低疏水物质IC50值的案例。

表4 两亲性多糖基胶束载体对疏水性物质缓释作用案例

表5 两亲性多糖基胶束载体对疏水物质AUC和MRT的影响案例

表6 两亲性多糖基胶束载体降低疏水物质半数抑制浓度(IC50)的应用案例

5 两亲性多糖基胶束增强疏水物质的稳定性

某些活性成分的稳定性差，容易随着生理环境pH值的改变而发生降解反应，严重影响其临床疗效。列如：姜黄素在中性或偏碱性环境中快速水解成阿魏酰甲烷、香草酸和阿魏酸等小分子片段物[48]。两亲性多糖基聚合物胶束的核-壳结构有效的避免了活性成分直接与外界环境接触，显著提高其稳定性。SARIKA[13]等发现在中性环境中(pH 7.4)，37 ℃培育5 h后姜黄素-阿拉伯胶共聚物胶束(GA-Cur)的吸光度值变化不明显而游离姜黄素25 min时就全部降解。而在酸性条件下(pH 4.0～6.0)，游离姜黄素稳定性明显提升，但仍显著低于GA-Cur。同样，与海藻酸或透明质酸共聚形成胶束后也能大幅度提升姜黄素在生理环境中的稳定性[7,14]。β-胡萝卜素结构中含有共轭多烯链和不饱和键，对光、热、氧气敏感，易发生降解。将β-胡萝卜素(β-C)包埋于几丁质-聚乳酸接枝共聚物胶束中分别在4 ℃和25 ℃下保存15 d后，检测发现其保留率分别达到95.45%和91.85%，表明该聚合物胶束载体能明显提高β-C的稳定性[6]。此外，利用多糖基胶束作为载体提高紫杉醇在运载过程中理化稳定性的研究也有报道[36]。

6 小结与展望

两亲性多糖基胶束具有生物可降解性和良好的生物相容性，被广泛应用于活性物质运载体系，但其应用过程中仍存在诸多问题：(1) 多糖基外壳与包载的药物活性成分之间是否会发生相互作用并改变了活性成分的化学性质尚不清楚；(2) 多糖本身具有特殊的功能作用如：透明质酸、菊粉、壳聚糖等，作为运载体系与活性成分之间是否存在协同作用或抑制作用尚不明确；(3) 多糖基胶束仍存在装载量低、包封率差等问题，为了提高胶束载体的稳定性，疏水内核与亲水外壳之间的交联过于紧密造成胶束内的物质释放受到束缚，探究胶束疏水-亲水片段之间的交联形式仍需深入；(4)口服利用率也是多糖基胶束难于克服的问题之一，极端的胃肠环境对胶束载体的稳定性提出了较高要求，有必要继续寻找无毒、可降解且稳定性好的载体材料。此外，多糖基胶束的应用主要集中在药物运载体系方面，尤其是抗癌药物的传输研究诸多，而其他方面的研究相对较少。所以未来结合医药、食品、化工等多领域的需求设计、开发多功能型多糖基胶束必将拥有广阔的发展前景和巨大的经济效益。

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Researchdevelopmentofhydrophobicfunctionimprovementbyamphiphilicpolysaccharide-basedmicelles

LI Shuang-hong1，YE Fa-yin1，LEI Lin1，ZHAO Guo-hua1,2*

1(College of Food Science, Southwest University, Chongqing 400715, China) 2(Chongqing Engineering Research Centre of Regional Foods, Chongqing 400715,China)

Amphiphilic polysaccharides is a class of semisynthetic polymer with low toxicity, good biocompatibility and degradable. It can form self- assembled hydrophobic- hydrophilic core-shell structure in aqueous. Recently, this kind of micelles got more attention in the field of food science, medicine, biomedical engineering and even material science. The polysaccharide-based micelles research is mainly focused on improving the bioactivity of hydrophobic compounds. Based on the literatures review of the last five years, this paper reviews the applications of amphiphilic polysaccharide-based micelles on targeted delivery, scattered solubilization, delayed release, as well as bioavailability of hydrophobic substances. Finally, the existing problems and future development in this field are also discussed.

amphiphilicity; polysaccharide; self-aggregation; micelles; hydrophobic bioactive compounds

10.13995/j.cnki.11-1802/ts.013448

硕士研究生(赵国华教授为通讯作者，E-mail：zhaoguohua1971@163.com)。

国家自然科学基金面上项目(31371737)；重庆市特色食品工程技术研究中心能力提升项目(cstc2014pt-gc8001)

2016-11-21，改回日期：2017-01-18