CN102757952A - 两亲结构微球及其制备和应用 - Google Patents
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Abstract
本发明涉及一种含有疏水成分的两亲结构微球产品,其特征在于微球产品为粒径10-4000微米的微球,其结构分为亲水区和疏水区两部分,其中,疏水区在微球亲水区中呈放射状分布,与微球表面形成贯穿通道,通道内径从几十纳米到几微米。这种微球产品可作为酶或者细胞的固定化载体用于非水相生物催化。
Description
技术领域
本发明涉及一种微球产品,具体地说是一种用于酶或细胞固定化的两亲结构微球产品及其在非水相生物催化领域的应用。
背景技术
生物催化的主要挑战是将生理状态下作用的酶转变为工业过程中苛刻条件下执行功能的催化剂,其中非水相生物催化是工业生物催化的一个重要方面。而生物催化剂酶或细胞的活性和稳定性保持是非水相生物催化需要解决的关键问题。
从工程学的角度,固定化技术是一个简单易行且行之有效的手段,可以保持或提高生物催化剂在非水相中活性和稳定性。但传统的亲水性固定化载体应用于非水相介质时,疏水底物或产物难以扩散传递,成为整个生物催化过程的限速步骤。
国际上关于两亲结构固定化载体的研究仅发现两种体系:①在四甲氧基硅烷中添加盐酸或氯铂酸的异丙醇溶液作为催化剂,经过水解或者升温至303K引发反应聚合,得到海藻酸钙凝胶网络包裹硅胶微球形式的亲、疏水骨架结构以包埋细胞或酶,用于生物转化 (Kawakami K and Furukawa SY, Alcohol-oxidation activity of whole cells of Pichia pastoris entrapped in hybrid gels composed of Ca-alginate and organic silicate. Applied Biochemistry and Biotechnology, 1997, 67: 23–31) ;②用聚羟乙基丙烯酸酯和聚硅氧烷复合材料,经紫外引发自由基聚合形成多孔膜,通过浸泡方式将酶吸附在纳米尺度的亲水区,而其中分布的疏水区用于疏水底物的扩散(Yi YY, Kermasha S, Neufeld R. Matrix physicochemical properties affect activity of entrapped chlorophyllase. Journal of Chemical Technology and Biotechnology, 2005, 80(12): 1395-1402)。但是,上述两种体系反应条件苛刻,引入了非生物相容的化学催化剂、溶剂及疏水性成分,破坏了生物催化剂需要的温和水环境,导致其活性和稳定性明显下降。
因此,在传统的固定化载体技术中,如何既提供亲水环境以保持生物催化剂的活性和稳定性,又提供疏水环境以促进疏水底物/产物传递,仍是非水相生物催化研究面临的重要挑战。
发明内容
针对上述问题,本发明提出对传统的固定化水凝胶载体结构进行疏水性改造,在全生理条件下构建新颖的两亲扩散结构微球,即:亲水凝胶骨架中调控形成径向放射状疏水微区,实现亲水、疏水分子“各行其道”,在充分保持生物催化剂活性的前提下,提高疏水分子的传递速率,提高生物催化效率,并应用于非水相生物催化领域。
技术方案:
本发明将疏水高分子材料引入水凝胶体系,发明了一种含有疏水成分的两亲结构微球产品,实现亲水、疏水分子“各行其道”,在充分保持生物催化剂活性的前提下,提高疏水分子的传递速率,提高生物催化效率。
本发明的两亲结构微球产品,其结构分为亲水区和疏水区两部分,以亲水区为形成微球的主体,其中,疏水区从微球的中部向微球的表面呈放射状分布于亲水区中,疏水区从微球的中部至微球表面形成贯穿通道。产品粒径10-4000微米,疏水区通道内径从几十纳米到几微米,便于疏水分子的扩散传递;亲水区提供了保持酶或微生物细胞生物活性的水凝胶环境,酶或微生物细胞引入亲水区中,该微球产品可用于非水相生物催化。
微球产品中的亲水区水凝胶环境由天然高分子材料中的海藻酸盐、卡拉胶、壳聚糖、琼脂、琼脂糖、阿拉伯胶、明胶,合成高分子材料中的聚丙烯酰胺、聚乙烯醇、光硬化树脂、聚丙烯酸,以及上述材料衍生物中的一种或二种以上材料形成的亲水性水凝胶组成;
微球产品中的疏水区由植物油、脂肪酸的酯、脂肪酸类、蔗糖酯类、液体石蜡中的一种或二种以上成分组成。
其中,植物油为大豆油、藏红花油、玉米油、橄榄油、蓖麻油、月见草油、土荆芥油、松节油、薄荷脑、丁香油、香柠檬油、山苍子油、香茅油、迷迭香油、樟脑、麝香草油、苦艾油、桂皮油、茴香油或洋甘菊油;
脂肪酸的酯为油酸乙酯C20H38O2、癸二酸二丁酯、肉豆蔻酸异丙酯IPM:C17H37O2 或6-18个碳原子的脂肪酸甘油酯;
脂肪酸类为油酸或亚麻油酸;蔗糖酯类为单、双或三棕榈酸蔗糖酯。
微球产品的制备按照生物活性酶或微生物细胞的引入方式分为直接包埋法或吸附法;
其中,直接包埋法的制备步骤是:
(1) 将组成亲水性水凝胶的材料在溶液状态下与具有催化功能的酶或微生物细胞混匀;
(2) 将步骤(1)制备的酶或细胞的混悬液与疏水材料混合,二者体积比为2~10:1,形成O/W型乳液;
(3) 将步骤(2)制备的乳液采用挤出或乳化的方式形成球形液滴;
(4) 将步骤(3)制备的球形液滴通过化学交联剂 (例如:海藻酸盐、卡拉胶、壳聚糖、聚丙烯酰胺、聚乙烯醇、聚丙烯酸); 光交联(例如:光硬化树脂);温度或pH交联(例如:卡拉胶、琼脂、琼脂糖、阿拉伯胶、明胶、聚丙烯酸)引发凝胶化反应,形成包埋酶或者微生物细胞的两亲结构微球;
吸附法的制备步骤是:
(1) 将组成亲水性水凝胶的材料与疏水材料混合,二者体积比为2~10:1,形成O/W型乳液;
(2) 将步骤(1)制备的乳液采用挤出或乳化的方式形成球形液滴;
(3) 将步骤(2)制备的球形液滴通过化学交联剂 (例如:海藻酸盐、卡拉胶、壳聚糖、聚丙烯酰胺、聚乙烯醇、聚丙烯酸); 光交联(例如:光硬化树脂);温度或pH交联(例如:卡拉胶、琼脂、琼脂糖、阿拉伯胶、明胶、聚丙烯酸)引发凝胶化反应,形成含有疏水成分的两亲结构微球;
(4) 将步骤(3)制备的微球浸泡在酶或者微生物细胞的混悬液中,吸附酶或微生物细胞,从而制备成包埋酶或者微生物细胞的两亲结构微球。
微球产品作为酶或细胞的固定化载体,酶或微生物细胞生物引入亲水区中,用于非水相生物催化。
上述操作其它参数范围均为公知技术,具体参考文献见实施例。
本发明的有益效果:
1、 本发明产品由于在制备过程中引入了疏水材料,使得产品在凝胶化形成过程中降低了凝胶化速度,从而形成了从微球中心至微球表面的放射状贯穿通道结构。
2、 本发明产品的制备过程条件温和,利于生物催化剂活性和稳定性保持。
3、 与传统的水凝胶微球相比,本发明的这种新型两亲结构微球产品,在作为酶或细胞的固定化载体用于非水相生物催化时,其油溶性底物或产物可快速扩散出微球,减少产物抑制,提高细胞活性。
附图说明
图1为实施例1制备的两亲结构海藻酸钙凝胶微球照片(图中标尺为100μm)。
图2为实施例2制备的亲水结构海藻酸钙凝胶微球照片(图中标尺为100μm)。
图3 为难溶于水的分子(2-苯乙醇)在实施例1制备的两亲结构海藻酸钙凝胶微球和比较例1制备的传统亲水海藻酸钙凝胶微球中的释放行为。
具体实施方式
形成海藻酸盐液滴的方式为静电液滴法(参考文献:In Vivo Culture of Encapsulated Endostatin-Secreting Chinese Hamster Ovary Cells for Systemic Tumor Inhibition. Human Gene Therapy. 2007, 18: 474-481)、
基于琼脂、卡拉胶微球的制备参数综合参考文献(Influence of whole microalgal cell immobilization and organic solvent on the bioconversion of androst-4-en-3,17-dione to testosterone by Nostoc muscorum. Journal of Molecular Catalysis B-Enzymatic. 2010, 62 (3-4): 213-217; Degradation of carbazole by microbial cells immobilized in magnetic gellan gum gel beads. Applied and Environmental Microbiology. 2007, 73, 6421-6428; 琼脂包埋法固定化酪氨酸酶的研究. 食品工业科技, 2010, 9, 188-190; )
实施例1:
[1] 将15g/L海藻酸钠溶液与油酸按体积10:1混合乳化,形成水包油(O/W)乳液;
[2] 将0.8g 2-苯乙醇溶于80mL步骤[1]制备的海藻酸钠乳液中,搅拌均匀后,静置除气泡;
[3] 将步骤[2]制备的混合液在高压静电场作用下,通过注射器泵,滴加到100 mM氯化钙溶液中(具体制备条件参考In Vivo Culture of Encapsulated Endostatin-Secreting Chinese Hamster Ovary Cells for Systemic Tumor Inhibition. Human Gene Therapy. 2007, 18: 474-481),即形成两亲结构海藻酸钙凝胶微球(见附图1);
[4] 将步骤(3)制备出的微球放入去离子水中进行扩散试验,在扩散0分钟、5分钟、15分钟、30分钟、1小时、2小时、4小时、8小时、12小时、24小时各时间点从扩散体系中取样,液相色谱测定溶液中2-苯乙醇含量,色谱条件:流动相:甲醇:水=50:50,检测波长:260nm,柱温:30℃,流速0.8mL/min,进样10μL;
[5] 考察2-苯乙醇向微球内的扩散行为(见附图3),结果显示,微溶于水的2-苯乙醇(2-phenylethanol)在两亲结构微球中的扩散速率明显加快,累积扩散量是亲水结构微球的2倍。
比较例1:
[1] 将0.8g 2-苯乙醇溶于80mL 15g/L海藻酸钠溶液中,搅拌均匀后,静置除气泡;
[2] 将上述混合液在高压静电场作用下,通过注射器泵,滴加到100 mM氯化钙溶液中,制备条件同实施例1,即形成传统亲水结构海藻酸钙凝胶微球(见附图2);
[3] 将步骤[2]制备出的微球5ml置于50mL去离子水中进行2-苯乙醇释放试验,于10min、20min、30min、1h、2h、4h、8h、12h、24h取样1mL;
[4] 液相色谱法测定2-苯乙醇含量,色谱条件同实施例1,结果显示,微溶于水的2-苯乙醇(2-phenylethanol)在传统亲水结构海藻酸钙微球中的释放速率明显低于实施例1中的两亲结构微球,累积释放量是两亲结构微球的一半(见附图3)。
实施例2:
[1] 在40-42摄氏度下,将20 g/L琼脂溶液(部分制备条件参考: Influence of whole microalgal cell immobilization and organic solvent on the bioconversion of androst-4-en-3,17-dione to testosterone by Nostoc muscorum. Journal of Molecular Catalysis B-Enzymatic. 2010, 62 (3-4): 213-217; Degradation of carbazole by microbial cells immobilized in magnetic gellan gum gel beads. Applied and Environmental Microbiology. 2007, 73: 6421-6428; 琼脂包埋法固定化酪氨酸酶的研究. 食品工业科技, 2010, 9: 188-190 )与酵母细胞按照2×109(个/毫升)混合形成细胞悬液;
[2] 步骤[1]制得的细胞悬液与癸二酸二丁酯按体积5:1混合乳化,形成O/W乳液;
[3] 在40-42摄氏度下,将步骤[2]制备的混合液再与液体石蜡按体积1:5混合乳化,形成O/W/O乳液,冷却至室温后即形成含有酵母细胞的两亲结构琼脂凝胶微球;
[4] 将步骤[3]制备出的微球于含有L-苯丙氨酸底物的培养液(葡萄糖20 g/L、蛋白胨20 g/L、酵母膏10 g/L、L-苯丙氨酸6g/L)中发酵,并用癸二酸二丁酯萃取2-苯乙醇产物,在两亲结构微球的保护下,细胞活性保持6天以上,并持续保持生物催化活性,2-苯乙醇产物在4g/L以上。
实施例3:
[1] 在40-42摄氏度下,将20g/L卡拉胶溶液(部分制备条件参考: Influence of whole microalgal cell immobilization and organic solvent on the bioconversion of androst-4-en-3,17-dione to testosterone by Nostoc muscorum. Journal of Molecular Catalysis B-Enzymatic. 2010, 62 (3-4): 213-217; Degradation of carbazole by microbial cells immobilized in magnetic gellan gum gel beads. Applied and Environmental Microbiology. 2007, 73: 6421-6428; 琼脂包埋法固定化酪氨酸酶的研究. 食品工业科技, 2010, 9: 188-190 )与蓖麻油按体积8:1混合乳化,形成水包油乳液;
[2] 在40-42摄氏度下,将步骤[1]制备的混合液再与液体石蜡按体积1:5混合乳化,形成O/W/O乳液,冷却至室温后即形成两亲结构卡拉胶凝胶微球;
[3] 将步骤[2]制备出的微球浸入腈水解酶粗酶提取液中进行酶吸附;
[4] 将150mM的的3- 氰基吡啶溶液加入到步骤[3]得到的吸附有腈水解酶的两亲结构卡拉胶凝胶微球中,用于(R)-4-氰基-3-羟基-丁酸的生产(催化条件参考文献:北京科技大学学报,2007,29:223),生物催化反应在20小时内,底物100%转化。
实施例4:
[1] 将15g/L海藻酸钠溶液与大豆油按体积10:1混合乳化,得到O/W乳液;
[2] 将50 g/L脂肪酶溶液与步骤[1]制备的海藻酸钠乳液混合,搅拌均匀后,静置除气泡;
[3] 将步骤[2]制备的混合液在高压静电场作用下,通过注射器泵,滴加到100 mM氯化钙溶液中,即形成两亲结构海藻酸钙凝胶微球;
[4] 配制5g/L壳聚糖溶液,凝胶微球与壳聚糖溶液按体积1:5混合交联,得到载脂肪酶海藻酸钙-壳聚糖微球;
[5] 将步骤[4]制备出的微球用于催化橄榄油、菜油等油脂(部分反应条件参考: 脂肪酶的固定化及其催化合成生物柴油. 石油化工, 2009, 38: 1336-1341; 固定化脂肪酶性质及其应用研究. 生物加工过程, 2007, 5(1): 45-49 ),其中橄榄油的转化率接近90%,且高于游离酶10%以上;固定化脂肪酶连续使用5次,仍可保持约60%酶活。
实施例5:
[1] 将15g/L海藻酸钠溶液与酵母细胞按照2×109(个/毫升)混合形成细胞悬液;
[2] 步骤[1]制得的细胞悬液与棕榈酸蔗糖酯按体积5:1混合乳化,形成O/W乳液;
[3] 将100g/L聚乙烯醇(PVA)溶液与步骤[1]制备的乳液按体积1:5混合,在高压静电场作用下,通过注射器泵,滴加到硼酸-氯化钙溶液中,即形成含有酵母细胞的两亲结构海藻酸钙-PVA微球;
[4] 将步骤[3]制备出的微球于含有高粱粉的培养液中糖化发酵(部分反应条件参考: 聚乙烯醇固定酵母细胞在液态白酒的应用研究. 酿酒, 2007, 34(3): 37-39),在两亲结构微球的保护下,细胞活性保持7天以上,乙醇产率大于6% (v/v)。
实施例6:
[1] 将15 g/L海藻酸钠溶液与酵母细胞按照每毫升2×109(个/毫升)混合形成细胞悬液;
[2] 步骤[1]制得的细胞悬液与肉豆蔻酸异丙酯按体积5:1混合乳化,形成O/W乳液;
[3] 将步骤[2]制备的O/W乳液在高压静电场作用下,通过注射器泵,滴加到100 mM氯化钙溶液中,即形成含有酵母细胞的两亲结构海藻酸钙微球;
[4] 将步骤[3]制备出的微球用于手性醇(S)-2-己醇的氧化生成2-己酮(反应条件参考: Asymmetric synthesis with immobilized yeast in organic solvents:Equilibrium conversion and effect of reactant partitioning on whole cell biocatalysis. Biotechnology Progress, 2003, 19(2): 389-395),在两亲结构微球的保护下,细胞活性保持良好,反应4小时后(S)-2-己醇的表观转化率可达90%。
Claims (6)
1.两亲结构微球,其特征在于:其结构分为亲水区和疏水区两部分,以亲水区为形成微球的主体,其中,疏水区从微球的中部向微球的表面呈放射状分布于亲水区中,疏水区从微球的中部至微球表面形成贯穿通道。
2.按照权利要求1所述的微球,其特征在于:微球产品为粒径10-4000微米的微球,通道内径从几十纳米到几微米,便于疏水分子的扩散传递;
所述亲水区提供了保持酶或微生物细胞生物活性的水凝胶环境,酶或微生物细胞引入亲水区中,该微球产品可用于非水相生物催化。
3.按照权利要求1或2所述的微球,其特征在于:微球产品中的亲水区水凝胶环境由天然高分子材料中的海藻酸盐、卡拉胶、壳聚糖、琼脂、琼脂糖、阿拉伯胶、明胶,合成高分子材料中的聚丙烯酰胺、聚乙烯醇、光硬化树脂、聚丙烯酸,以及上述材料衍生物中的一种或二种以上材料形成的亲水性水凝胶组成;
微球产品中的疏水区由植物油、脂肪酸的酯、脂肪酸类、蔗糖酯类、液体石蜡中的一种或二种以上成分组成。
4.按照权利要求3所述的微球,其特征在于:所述植物油为大豆油、藏红花油、玉米油、橄榄油、蓖麻油、月见草油、土荆芥油、松节油、薄荷脑、丁香油、香柠檬油、山苍子油、香茅油、迷迭香油、樟脑、麝香草油、苦艾油、桂皮油、茴香油或洋甘菊油;
脂肪酸的酯为油酸乙酯C20H38O2、癸二酸二丁酯、肉豆蔻酸异丙酯IPM:C17H37O2 或6-18个碳原子的脂肪酸甘油酯;
脂肪酸类为油酸或亚麻油酸;蔗糖酯类为单、双或三棕榈酸蔗糖酯。
5.一种权利要求1或2所述微球的制备方法,其特征在于:微球产品的制备按照生物活性酶或微生物细胞的引入方式分为直接包埋法或吸附法;
其中,直接包埋法的制备步骤是:
(1) 将组成亲水性水凝胶的材料在溶液状态下与具有催化功能的酶或微生物细胞混匀;
(2) 将步骤(1)制备的酶或细胞的混悬液与疏水材料混合,二者体积比为2~10:1,形成O/W型乳液;
(3) 将步骤(2)制备的乳液采用挤出或乳化的方式形成球形液滴;
(4) 将步骤(3)制备的球形液滴通过化学交联剂; 光交联;温度或pH交联引发凝胶化反应,形成包埋酶或者微生物细胞的两亲结构微球;
吸附法的制备步骤是:
(1) 将组成亲水性水凝胶的材料与疏水材料混合,二者体积比为2~10:1,形成O/W型乳液;
(2) 将步骤(1)制备的乳液采用挤出或乳化的方式形成球形液滴;
(3) 将步骤(2)制备的球形液滴通过化学交联剂、光交联、温度或pH交联引发凝胶化反应,形成含有疏水成分的两亲结构微球;
(4) 将步骤(3)制备的微球浸泡在酶或者微生物细胞的混悬液中,吸附酶或微生物细胞,从而制备成包埋酶或者微生物细胞的两亲结构微球。
6.一种权利要求1所述微球的应用,其特征在于:微球产品作为酶或细胞的固定化载体,酶或微生物细胞生物引入亲水区中,用于非水相生物催化。
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