CN113402628A - 一种两亲性高生物活性改性透明质酸 - Google Patents
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Abstract
本发明公开了一种两亲性高生物活性改性透明质酸。本发明以透明质酸为主链,以具有促进组织修复和再生功能的高活性短肽为生物活性接枝基团,以亲脂基团为促进透皮能力的接枝基团。通过接枝改性,制备同时具有亲水及亲脂的两亲性和高生物活性的透明质酸材料。通过用不同分子量的透明质酸主链,制备不同用途的透明质酸衍生物生物材料,小分子量改性透明质酸可作为化妆品功能性原料,通过涂抹透皮吸收。大分子量的改性多糖材料可通过注射用于医美材料或组织再生或关节腔润滑。本发明克服了透明质酸材料单一的物理填充作用的缺陷,在透明质酸材料固有的高保湿特性上,增加了多糖类生物材料透明质酸促进细胞再生、胶原再生等生物学功能。
Description
技术领域
本发明涉及一种两亲性高生物活性改性透明质酸,属于生物医用材料技术领域。
背景技术
透明质酸(Hyaluronic acid,HA)又叫玻尿酸,是一种重要的天然多糖高分子生物医用材料,其基本结构是由双糖单位D-葡萄糖醛酸及N-乙酰葡糖胺组成的多糖类高分子,具有优异的保水性、润滑性、黏弹性、生物相容性等特性,在医药、化妆品及功能性食品领域应用广泛,特别是作为组织填充剂、关节润滑剂及功能保湿成分时,HA尚无天然可替代品。目前常规HA使用中面临的挑战包括:(1)半衰期短,易被机体内HA酶降解;(2)功能单一,缺乏细胞粘附和增殖位点。虽通过交联、共混改性(与生长因子、胶原、壳聚糖等混合和交联)等手段可提高HA的抗酶解能力并赋予其功能性,但这些方法极易引起免疫排异、透皮吸收难等问题。
HA广泛分布于哺乳动物骨髓细胞、眼部玻璃体以及软组织的细胞外基质中,在细胞应答,如增殖、变异、迁移、黏附和基因表达等方面发挥重要作用。相对分子质量高的HA可以保证细胞外基质的含水量和细胞的完整性;低分子量的HA则可以诱发受体介导的细胞内吞作用。高活性短肽(Bioactive Short Peptides,BSP)是一类可模拟体内活性蛋白质生理功能且无免疫源性的小分子肽链,可实现单位密度内有效成份的高表达,如抗菌、促组织再生和免疫调节等。BSP合成路径清晰,具有活性位点丰富、构象稳定、易于合成、方便保存等优势,是当前国际功能生物材料领域的研究与产业热点。目前关于采用生物活性功能的材料对HA进行改性从而获得新型HA材料的相关技术还未见报道。
发明内容
本发明所要解决的技术问题是:如何利用生物活性功能材料BSP对HA进行改性从而获得功能多样性的HA材料。
为了解决上述技术问题,本发明提供了一种两亲性高生物活性改性透明质酸,以透明质酸HA为主链,以活性短肽为生物活性接枝基团,以亲脂基团为促进透皮接枝基团,其化学结构式如式I所示:
其中,式I中的R1为活性短肽、R2为亲脂基团,或者式I中的R1为亲脂基团、R2为活性短肽,n=1~7000。
优选地,所述的活性短肽包括氨基酸序列为RXDX的短肽,其中,X为E、G、V或S。
优选地,所述亲脂基团包括C4~C20的羰基、聚氧丙烯基、长链全氟烷基、聚硅氧烷基以及含有芳基、酯基、醚基、胺基、酰胺基、环烷基或双键的烃基中的任意一种基团或多种基团的组合。
优选地,所述透明质酸HA主链的分子量为1K-2500KDa。
优选地,所述的如式I所示的改性透明质酸的亲疏水性和生物活性可通过改变活性短肽和亲脂基团的接枝比例来调节,所述活性短肽和亲脂基团的接枝比例之比为1000:1~1:1000。。
优选地,所述活性短肽和透明质酸HA主链之间为直接共价结合或通过短肽链接剂结合。
更优选地,所述的短肽链接剂为WGRGDSP、GWGLGPAGK或CCRR。
与现有技术相比,本发明的有益效果在于:
1.本发明的两亲性高生物活性改性透明质酸利用具有生物活性功能的BSP,接枝于HA表面,赋予HA促组织再生等生物活性功能,同时接枝亲脂疏水基团,增强其透皮吸收效果,并可以通过调节活性短肽和亲脂基团的接枝比例获得功能多样性的改性透明质酸;
2.本发明利用不同分子量的透明质酸主链进行改性后,小分子量改性透明质酸可作为化妆品功能性原料,通过涂抹透皮吸收,其具有的亲脂基团能够大大促进皮肤的吸收;大分子量的改性透明质酸可通过注射用于医美材料或组织再生或关节腔润滑,其具有良好的生物相容性和促进细胞再生的功能,本发明克服了透明质酸材料单一的物理填充功能的缺陷。
附图说明
图1为实施例1的改性透明质酸与普通透明质酸HA对成纤细胞的培养结果;其中,A:普通透明质酸HA对成纤细胞的培养结果,B:实施例1的改性透明质酸对成纤细胞的培养结果;
图2为实施例2的低分子量改性透明质酸和普通透明质酸HA涂抹后透皮吸收对比图;其中,(A):普通透明质酸HA涂抹后透皮吸收情况;(B):实施例2的低分子量改性透明质酸涂抹后透皮吸收情况。
具体实施方式
为使本发明更明显易懂,兹以优选实施例,并配合附图作详细说明如下。
实施例1
一种两亲性高生物活性改性透明质酸的制备方法,包括如下步骤:
将大于800KDa的高分子量的HA(n=6500,或n=2500)在水浴中加热到80℃,并在该温度下维持1小时。37℃下,在pH=6.8的含有碳化二亚胺和1-羟基苯并三唑(HOBt)的二甲基亚砜(DMSO)中反应1小时,将多肽RXDX(其中X可以是E或G、V和S,本实施例中的多肽为REDG)通过WGRGDSP(linker)接枝到HA的羧基上。利用十六烷基三甲基溴化铵(CTA)与HA的6位伯醇羟基在37℃下,在二甲基亚砜(DMSO)中反应1小时,生成HA-CTA后,再与二(对硝基苯)碳酸酯(4-NPBC)在pH=8.0的磷酸盐-DMSO缓冲体系中反应1小时,形成活化酯后,再与苯胺在65℃条件下反应24小时,反应结束后,用乙醚沉淀并洗涤产品,得到一种高分子量的具有促进组织修复生物活性功能的改性透明质酸,为化合物1~2。
所得化合物1中,n=6500,R1=WGRGDSPREDG,R2=C6H5NH;
所得化合物2中,n=2000,R1=WGRGDSPREDG,R2=C6H5NH。
测试上述具有促进组织修复生物活性功能的改性透明质酸中的化合物1或2的生物活性:以普通透明质酸HA为对照组,将成纤细胞加入含透明质酸的培养皿中培养24h,观察成纤细胞的贴附与增殖情况,如图1所示,由图1可知,上述改性透明质酸与成纤细胞之间贴附良好且有效促进成纤细胞的增殖,其具有良好的生物相容性和高生物活性。
实施例2
一种两亲性高生物活性改性透明质酸的制备方法,包括如下步骤:
将分子量为2.5KDa左右的HA(n=8)在水浴加热到80℃,并在该温度下在pH=4.6的极性溶剂磷酸盐-DMSO中搅拌1小时。37℃下,在pH=6.8的含有碳化二亚胺和1-羟基苯并三唑(HOBt)的二甲基亚砜(DMSO)中反应1小时,将多肽RXDX(其中X可以是E或G、V和S,本实施例中的多肽为REDG)接聚到HA的羧基衍生物上。在HA主链的6位伯醇羟基进行修饰(其活性比其他位点的羟基高),和丁酸酐在pH=8.0的DMSO中搅拌1小时进行酯化反应,从而引入相应的丁酸酯。得到一种低分子量的具有促进组织修复生物活性功能的改性透明质酸,为化合物3。
所得化合物3中,n=8,R1=REDG,R2=CH3CH2CH2C=O。
其中,低分子量改性透明质酸中的化合物3可涂抹后透皮吸收,涂抹后可在3秒内完全吸收,而普通透明质酸HA涂抹后在3分钟仍未完全吸收,如图2所示。
实施例3
一种两亲性高生物活性改性透明质酸的制备方法,包括如下步骤:
将分子量为80kDa左右的HA(n=250)在水浴中加热到80℃,并在该温度下维持1小时。37℃下,在pH=6.8的含有碳化二亚胺和1-羟基苯并三唑(HOBt)的二甲基亚砜(DMSO)中反应1小时,将多肽RXDX(其中X可以是E或G、V和S,本实施例中的多肽为REDG)通过GWGLGPAGK(linker)接枝到HA的羧基上。将此改性HA溶解在含棕榈酸的pH为6.0的磷酸盐-DMSO环境中,室温下搅拌24小时,得到一种中分子量的具有促进组织修复生物活性功能的改性透明质酸,为化合物4。
所得化合物4中,n=250,R1=GWGLGPAGKREDG,R2=CH3(CH2)14C=O。
实施例4
一种两亲性高生物活性改性透明质酸的制备方法,包括如下步骤:
将分子量为10kDa左右的HA(n=30)在水浴中加热到80℃,并在该温度下维持1小时。将多肽RXDX(其中X可以是E或G、V和S,本实施例中的多肽为REDG)通过CCRR(linker)接枝到制备的HA的羧基上(接枝方法同实施例3)。在HA主链的6位伯醇羟基进行修饰(其活性比其他位点的羟基高),具体地,采用棕榈酸与HA分子上的OH在pH=8.0的DMSO中搅拌1小时进行酯化反应,生成酯,从而引入亲脂基团,得到一种具有促进组织修复生物活性功能的改性透明质酸,为化合物5。
所得化合物5中,n=30,R1=CCRRREDG,R2=CH3(CH2)14C=O。
上述实施例仅为本发明的优选实施例,并非对本发明任何形式上和实质上的限制,应当指出,对于本技术领域的普通技术人员,在不脱离本发明的前提下,还将可以做出若干改进和补充,这些改进和补充也应视为本发明的保护范围。
Claims (7)
2.如权利要求1所述的两亲性高生物活性改性透明质酸,其特征在于,所述的活性短肽包括氨基酸序列为RXDX的短肽,其中,X为E、G、V或S。
3.如权利要求1所述的两亲性高生物活性改性透明质酸,其特征在于,所述亲脂基团包括C4~C20的羰基、聚氧丙烯基、长链全氟烷基、聚硅氧烷基以及含有芳基、酯基、醚基、胺基、酰胺基、环烷基或双键的烃基中的任意一种基团或多种基团的组合。
4.如权利要求1所述的两亲性高生物活性改性透明质酸,其特征在于,所述透明质酸HA主链的分子量为1K-2500KDa。
5.如权利要求1所述的两亲性高生物活性改性透明质酸,其特征在于,所述的如式I所示的改性透明质酸的亲疏水性和生物活性可通过改变活性短肽和亲脂基团的接枝比例来调节,所述活性短肽和亲脂基团的接枝比例之比为1000:1~1:1000。
6.如权利要求1所述的两亲性高生物活性改性透明质酸,其特征在于,所述活性短肽和透明质酸HA主链之间为直接共价结合或通过短肽链接剂结合。
7.如权利要求6所述的两亲性高生物活性改性透明质酸,其特征在于,所述的短肽链接剂为WGRGDSP、GWGLGPAGK或CCRR。
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