李雙紅，葉發(fā)銀，雷琳，趙國(guó)華,2*

1(西南大學(xué) 食品科學(xué)學(xué)院，重慶, 400715) 2(重慶市特色食品工程技術(shù)研究中心， 重慶,400175)

兩親性多糖基膠束改善疏水性功能物質(zhì)性能的研究進(jìn)展

李雙紅1，葉發(fā)銀1，雷琳1，趙國(guó)華1,2*

1(西南大學(xué) 食品科學(xué)學(xué)院，重慶, 400715) 2(重慶市特色食品工程技術(shù)研究中心， 重慶,400175)

兩親性多糖往往是親水性多糖適度疏水化改性而獲得的一類低毒、生物相容性和可降解性良好的半合成聚合物，其在水相中能自發(fā)聚集組裝成為具有疏水核-親水殼結(jié)構(gòu)的膠束。最近，這類膠束受到食品科學(xué)、藥學(xué)、生物醫(yī)學(xué)工程乃至材料學(xué)相關(guān)科學(xué)家的廣泛重視，其研究急劇升溫，且主要集中在利用其改善疏水性物質(zhì)生物活性方面。論文主要以近5年文獻(xiàn)為基礎(chǔ)，全面綜述了兩親性多糖基膠束在疏水物質(zhì)分散增溶、靶向遞送、延緩釋放、生物利用度提升及穩(wěn)定性增強(qiáng)等方面的應(yīng)用，并在此基礎(chǔ)上對(duì)該領(lǐng)域存在的問題及今后的發(fā)展方向進(jìn)行了探討。

兩親性；多糖；自聚集；膠束；疏水活性物質(zhì)

一些生物活性物質(zhì)(β-胡蘿卜素、番茄紅素、維生素D3、姜黃素、槲皮素、紫杉醇、喜樹堿和α-生育酚等)或藥物(左旋溶肉瘤素和兩性霉素B等)由于不溶或微溶于水，致使其在生物體內(nèi)出現(xiàn)分散性差和生物利用率低等缺點(diǎn)，這極大降低了疏水活性物質(zhì)的臨床應(yīng)用效能[1-3]。最近發(fā)現(xiàn)兩親性分子(表面活性劑)在水相中集聚形成的膠束是解決這一問題的有效工具。兩親性分子在水中達(dá)到一定濃度后在疏水相互作用的推動(dòng)下，分子疏水基團(tuán)相互締合形成內(nèi)核并被親水鏈形成的外殼所包圍，進(jìn)而形成的有序分子集聚體結(jié)構(gòu)稱為膠束。通常將兩親性分子能夠形成膠束的最低濃度稱為其臨界膠束濃度。高于該濃度時(shí)聚合物可自發(fā)聚集形成膠束，將天然親水性多糖分子經(jīng)過適度疏水化修飾后可賦予其兩親性，即形成兩親性多糖。該類多糖在水相中能自發(fā)集聚形成具有核-殼結(jié)構(gòu)的膠束，其內(nèi)核由疏水性基團(tuán)組成而外殼則由親水性糖鏈構(gòu)成[4]。這一結(jié)構(gòu)特征使該類膠束具有在內(nèi)核裝載疏水小分子物質(zhì)的特殊能力，而通過外殼實(shí)現(xiàn)其水相分散、生物相容等優(yōu)點(diǎn)[5]。截至目前，約有上百種兩親性多糖聚合物被合成，對(duì)應(yīng)膠束的理化特性及應(yīng)用特性，已成為近期食品科學(xué)、藥學(xué)、生物醫(yī)學(xué)工程乃至材料學(xué)等的重要研究熱點(diǎn)之一。盡管如此，筆者在查閱文獻(xiàn)資料的過程中發(fā)現(xiàn)，絕大部分的研究側(cè)重于新型多糖聚合物膠束載體的開發(fā)研究，而對(duì)于其應(yīng)用特性方面進(jìn)行系統(tǒng)性梳理的報(bào)道少之又少，為了給國(guó)內(nèi)從事該領(lǐng)域的學(xué)者提供參考，本文在重點(diǎn)查閱近5年文獻(xiàn)的基礎(chǔ)上，結(jié)合國(guó)內(nèi)外研究現(xiàn)狀，對(duì)兩親性多糖基膠束在疏水物質(zhì)分散增溶、靶向遞送、控制釋放、生物利用度提升及穩(wěn)態(tài)化等方面的應(yīng)用進(jìn)行綜述。

1 兩親性多糖基膠束對(duì)疏水性物質(zhì)的增溶作用

兩親性多糖基膠束對(duì)疏水性物質(zhì)的增溶方式主要分為2種，一種是多糖基膠束通過其內(nèi)核與目標(biāo)物質(zhì)之間的疏水相互作用實(shí)現(xiàn)對(duì)難溶或不溶性物質(zhì)增溶[6]，其本質(zhì)仍遵循相似相溶的基本原理。兩親性多糖基膠束對(duì)疏水活性物質(zhì)的增溶過程與常見的反膠束萃取過程十分相似，是被增溶物質(zhì)從固相(不溶)到液相(極低濃度)再到膠束內(nèi)相(高濃度富集)的定向傳質(zhì)過程(圖1-a)。第二種方式是通過共聚[7-8](如酯化反應(yīng)等)將待增溶的目標(biāo)物質(zhì)直接連接到多糖鏈上形成兩親性多糖聚合物，該聚合物在水溶液中自聚集將目標(biāo)物質(zhì)以內(nèi)核形式載入膠束中，由此達(dá)到難溶物質(zhì)在水相中的分散(圖1-b)。增溶過程中常用的方法有薄膜水化法[2]、微相分離法[6]、透析法[9]、水包油法[10]以及乳液溶劑蒸發(fā)法[11]等。對(duì)增溶效果的評(píng)價(jià)常以特定濃度的兩親性多糖膠束溶液，荷載目標(biāo)物質(zhì)的含量來表示。除增溶方法之外，多糖聚合物的臨界膠束濃度、疏水基團(tuán)的取代度和疏水性能以及環(huán)境參數(shù)(時(shí)間、溫度、攪拌強(qiáng)度)等都是影響增溶效果的重要因素。表1給出了兩親性多糖基膠束增溶疏水性物質(zhì)的一些案例。

圖1 兩親性多糖基膠束增溶疏水性物質(zhì)的主要方式Fig.1 The main ways of amphiphilic polysaccharide-based micelles in solubilizing hydrophobic compounds

2 兩親性多糖基膠束對(duì)疏水性物質(zhì)的靶向遞送作用

生物活性物質(zhì)只有能抵達(dá)特定的器官或細(xì)胞才能發(fā)揮其特定的生物活性。但對(duì)大多數(shù)生物活性物質(zhì)來說，被吸收進(jìn)入機(jī)體后隨著血液循環(huán)分布到全身。這不僅影響其生物活性發(fā)揮，且易造成正常組織細(xì)胞損傷，引發(fā)系統(tǒng)毒性[5]。因此，生物活性物質(zhì)的靶向遞送具有十分重要的意義。根據(jù)靶向機(jī)制，可分為組織特異性靶向與環(huán)境響應(yīng)性靶向。

組織特異性靶向又可分為被動(dòng)靶向和配體耦合靶向。被動(dòng)靶向主要依賴于靶向組織的高通透性和滯留效應(yīng)以及兩親性多糖基膠束的尺寸[17]。腫瘤組織血管壁的孔徑一般為幾百納米到幾微米，明顯大于正常組織血管壁孔徑(2～6 nm)，這為腫瘤組織吸收和滯留大分子物質(zhì)或顆粒提供了通道[18]，從而生物活性物質(zhì)被動(dòng)實(shí)現(xiàn)靶向遞送。配體耦合靶向是指在膠束載體上連接能特異性識(shí)別腫瘤表面過表達(dá)抗原物質(zhì)的配體，這些配體與目標(biāo)位點(diǎn)特異性結(jié)合，從而使藥物載體在腫瘤組織中選擇性積累。常用的配體包括透明質(zhì)酸、硫酸軟骨素、葉酸、β-D-半乳糖殘基、生長(zhǎng)激素抑制素、轉(zhuǎn)鐵蛋白、生物素、α2-糖蛋白及表皮生長(zhǎng)因子等[19]。顯而易見，不同配體具有不同的靶向性，應(yīng)根據(jù)具體靶向組織選擇使用配體。表2給出了一些多糖基膠束載體靶向運(yùn)輸?shù)膽?yīng)用案例。

注：增溶效果以水中溶解度→膠束中溶解度表示。

環(huán)境響應(yīng)性靶向主要是根據(jù)靶向部位特定的生理環(huán)境條件設(shè)計(jì)的，如常見的pH響應(yīng)性靶向、氧化還原響應(yīng)性靶向和溫度響應(yīng)性靶向。pH響應(yīng)性靶向的基本原理是人體正常組織環(huán)境的pH值(7.4)明顯高于病變部位(如腫瘤細(xì)胞外pH值為6.8左右，細(xì)胞核內(nèi)體則為5.5～6.5)[20]。當(dāng)含有酸可降解基團(tuán)的多糖基膠束接觸腫瘤組織時(shí)，其酸可降解基團(tuán)發(fā)生質(zhì)子化或解離，導(dǎo)致膠束結(jié)構(gòu)松散甚至解體并釋放活性物質(zhì)[21-22]。氧化還原響應(yīng)性靶向常常在多糖基膠束中引入二硫鍵而得以實(shí)現(xiàn)。其基本原理為人體正常細(xì)胞內(nèi)谷胱甘肽的含量(2～10 mmol/L)要顯著低于病變組織(如腫瘤細(xì)胞中谷胱甘肽的含量約為正常組織中的4倍)。當(dāng)含有二硫鍵的多糖基膠束接觸腫瘤組織時(shí)，在高濃度谷胱甘肽的還原作用下，二硫鍵被打開，導(dǎo)致膠束結(jié)構(gòu)松散甚至解體并釋放活性物質(zhì)[23]。溫度響應(yīng)性靶向依據(jù)病變部位的溫度高于正常生理溫度(>37 ℃)，一旦環(huán)境溫度高于熱敏性膠束載體的低臨界溶解溫度，載體發(fā)生相變迫使聚合物鏈崩解，加速內(nèi)容物釋放[24]。表3給出了一些多糖基膠束載體環(huán)境響應(yīng)性靶向的應(yīng)用案例。

表2 兩親性多糖基膠束載體對(duì)疏水性物質(zhì)的組織特異性靶向應(yīng)用案例

表3 兩親性多糖基膠束載體對(duì)疏水性物質(zhì)環(huán)境響應(yīng)性靶向應(yīng)用案列

注：1. 響應(yīng)效果：載體膠束對(duì)不同響應(yīng)環(huán)境的敏感程度以包載物質(zhì)釋放量的百分?jǐn)?shù)表示；2.CGSH：谷胱甘肽濃度；CDTT：二硫蘇糖醇濃度。

3 兩親性多糖基膠束對(duì)疏水性物質(zhì)的緩釋作用

活性制劑以口服或者靜脈注射的方式進(jìn)入人體，在組織或血液中富集短時(shí)間內(nèi)濃度達(dá)到高峰并被機(jī)體快速清除，這直接導(dǎo)致活性物質(zhì)在組織或血液中維持有效濃度的時(shí)間過短，造成浪費(fèi)[29]。多糖基聚合物膠束的疏水基團(tuán)與活性成分之間存在相互作用，可延長(zhǎng)制劑釋放時(shí)間并改善治療效果?；钚猿煞轴尫怕释ǔＲ阅z束在特定體系(緩沖溶液、模擬胃液、模擬腸液等)中保溫后，漏出的疏水物質(zhì)質(zhì)量百分比表示[23]。疏水內(nèi)核材料的種類、膠束的降解能力、活性制劑的含量及膠束疏水區(qū)域與包載物質(zhì)之間的親和力的強(qiáng)弱等因素影響活性制劑釋放率[19]，具體作用結(jié)果見表4。

4 兩親性多糖基膠束提高疏水性物質(zhì)的生物利用度

活性物質(zhì)自身的強(qiáng)電荷、高分子質(zhì)量也是限制其臨床應(yīng)用的重要因素之一[44]。正如前所述，兩親性多糖基膠束特殊的結(jié)構(gòu)將該類物質(zhì)包裹其中，能大幅度提升其生物利用價(jià)值。 常用于衡量活性物質(zhì)生物利用度的參數(shù)包括藥-時(shí)量曲線下面積(AUC)、平均滯留時(shí)間(MRT)等，AUC也代表生物活性成分進(jìn)入全身血液循環(huán)的相對(duì)量，MRT是活性物質(zhì)在血漿中總保留時(shí)間的平均值，AUC和MRT的值越大表示生物活性物質(zhì)的生理有效性越高[45]，具體案例見表5。研究發(fā)現(xiàn)[1]，利用槲皮素單體及透明質(zhì)酸-槲皮素共聚物載藥膠束分別對(duì)大鼠進(jìn)行體內(nèi)藥物動(dòng)力學(xué)試驗(yàn)，得到了兩者的AUC(3.69→18.07 mg/(L·h))和MRT(0.185→4.30 h)值，表明聚合物膠束可以提高單體藥物的生物利用率。此外，半數(shù)抑制濃度(IC50)指用藥后活細(xì)胞數(shù)量減少一半時(shí)所需的藥物濃度，能間接反應(yīng)活性物質(zhì)的利用程度，該值越小表示活性物質(zhì)的效能越大。表6給出了兩親性多糖基膠束載體降低疏水物質(zhì)IC50值的案例。

表4 兩親性多糖基膠束載體對(duì)疏水性物質(zhì)緩釋作用案例

表5 兩親性多糖基膠束載體對(duì)疏水物質(zhì)AUC和MRT的影響案例

表6 兩親性多糖基膠束載體降低疏水物質(zhì)半數(shù)抑制濃度(IC50)的應(yīng)用案例

5 兩親性多糖基膠束增強(qiáng)疏水物質(zhì)的穩(wěn)定性

某些活性成分的穩(wěn)定性差，容易隨著生理環(huán)境pH值的改變而發(fā)生降解反應(yīng)，嚴(yán)重影響其臨床療效。列如：姜黃素在中性或偏堿性環(huán)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]。兩親性多糖基聚合物膠束的核-殼結(jié)構(gòu)有效的避免了活性成分直接與外界環(huán)境接觸，顯著提高其穩(wěn)定性。SARIKA[13]等發(fā)現(xiàn)在中性環(huán)境中(pH 7.4)，37 ℃培育5 h后姜黃素-阿拉伯膠共聚物膠束(GA-Cur)的吸光度值變化不明顯而游離姜黃素25 min時(shí)就全部降解。而在酸性條件下(pH 4.0～6.0)，游離姜黃素穩(wěn)定性明顯提升，但仍顯著低于GA-Cur。同樣，與海藻酸或透明質(zhì)酸共聚形成膠束后也能大幅度提升姜黃素在生理環(huán)境中的穩(wěn)定性[7,14]。β-胡蘿卜素結(jié)構(gòu)中含有共軛多烯鏈和不飽和鍵，對(duì)光、熱、氧氣敏感，易發(fā)生降解。將β-胡蘿卜素(β-C)包埋于幾丁質(zhì)-聚乳酸接枝共聚物膠束中分別在4 ℃和25 ℃下保存15 d后，檢測(cè)發(fā)現(xiàn)其保留率分別達(dá)到95.45%和91.85%，表明該聚合物膠束載體能明顯提高β-C的穩(wěn)定性[6]。此外，利用多糖基膠束作為載體提高紫杉醇在運(yùn)載過程中理化穩(wěn)定性的研究也有報(bào)道[36]。

6 小結(jié)與展望

兩親性多糖基膠束具有生物可降解性和良好的生物相容性，被廣泛應(yīng)用于活性物質(zhì)運(yùn)載體系，但其應(yīng)用過程中仍存在諸多問題：(1) 多糖基外殼與包載的藥物活性成分之間是否會(huì)發(fā)生相互作用并改變了活性成分的化學(xué)性質(zhì)尚不清楚；(2) 多糖本身具有特殊的功能作用如：透明質(zhì)酸、菊粉、殼聚糖等，作為運(yùn)載體系與活性成分之間是否存在協(xié)同作用或抑制作用尚不明確；(3) 多糖基膠束仍存在裝載量低、包封率差等問題，為了提高膠束載體的穩(wěn)定性，疏水內(nèi)核與親水外殼之間的交聯(lián)過于緊密造成膠束內(nèi)的物質(zhì)釋放受到束縛，探究膠束疏水-親水片段之間的交聯(lián)形式仍需深入；(4)口服利用率也是多糖基膠束難于克服的問題之一，極端的胃腸環(huán)境對(duì)膠束載體的穩(wěn)定性提出了較高要求，有必要繼續(xù)尋找無毒、可降解且穩(wěn)定性好的載體材料。此外，多糖基膠束的應(yīng)用主要集中在藥物運(yùn)載體系方面，尤其是抗癌藥物的傳輸研究諸多，而其他方面的研究相對(duì)較少。所以未來結(jié)合醫(yī)藥、食品、化工等多領(lǐng)域的需求設(shè)計(jì)、開發(fā)多功能型多糖基膠束必將擁有廣闊的發(fā)展前景和巨大的經(jīng)濟(jì)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

碩士研究生(趙國(guó)華教授為通訊作者，E-mail：zhaoguohua1971@163.com)。

國(guó)家自然科學(xué)基金面上項(xiàng)目(31371737)；重慶市特色食品工程技術(shù)研究中心能力提升項(xiàng)目(cstc2014pt-gc8001)

2016-11-21，改回日期：2017-01-18