CN114652743A - 一种基于海藻酸钠的一氧化氮供体及其合成方法和应用 - Google Patents
一种基于海藻酸钠的一氧化氮供体及其合成方法和应用 Download PDFInfo
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- sodium alginate
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 title claims abstract description 92
- 235000010413 sodium alginate Nutrition 0.000 title claims abstract description 92
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- 229940005550 sodium alginate Drugs 0.000 title claims abstract description 92
- 239000002840 nitric oxide donor Substances 0.000 title claims abstract description 62
- 238000001308 synthesis method Methods 0.000 title claims abstract description 12
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- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims abstract description 21
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Abstract
本发明公开了一种基于海藻酸钠的一氧化氮供体及其合成方法和应用,该合成包括如下步骤:将海藻酸钠溶于超纯水中,加入活化剂进行反应,加入L‑半胱胺酸盐酸盐或者胱胺二盐酸盐,继续反应;将反应液透析后,加入亚硝酸叔丁酯,继续反应,得到溶液透析冻干得到海藻酸钠一氧化氮供体。本发明合成的海藻酸钠一氧化氮供体是S‑亚硝基化海藻酸钠,通过在海藻酸钠上接枝巯基,再通过亚硝基化形成SNO基团,本发明合成方法简单易行、无毒且成本低,且制备的一氧化氮供体释放时间长,可稳定存在,有望于和其他聚合物材料应用于制备多功能的一氧化氮释放复合材料。
Description
技术领域
本发明属于一氧化氮供体,具体涉及一种基于海藻酸钠的一氧化氮供体及其合成方法和应用。
背景技术
一氧化氮是人体内一种重要的气体信号小分子,一直是科学界和医学界众多研究者关注的焦点。NO参与人体内众多生理系统,例如:免疫系统,心血管系统,中枢神经系统和外循环生理系统。另外,一氧化氮具有抗菌,抗血小板粘附,促进血管生成,促进伤口愈合,抑制平滑肌细胞过度增殖和抗癌等功效。在人体内,一氧化氮主要由一氧化氮合酶(NOS)合成,但是一氧化氮的半衰期较短且不稳定,仅1-5s,从而限制了一氧化氮在生物医学方面的众多应用。因此,众多科研工作者将研究重点放在了合成外源性一氧化氮供体和催化释放一氧化氮的材料。外源性一氧化氮供体包含很多种类,其中一种为S-亚硝基硫醇类,可通过Cu2+,抗坏血酸和光照催化断裂S-NO键释放出一氧化氮气体。其中S-亚硝基血清白蛋白(Alb-SNO)和亚硝基谷胱甘肽(GSNO)是人体血液循环内广泛存在的两种天然一氧化氮供体。
海藻酸钠,是一种从褐藻类植物当中提取出来的天然多糖,它是由β-D-甘露糖醛酸和α-L-古罗糖醛酸通过1-4糖苷键连接而成的一种线性聚合物。由于海藻酸钠具有低毒性、较好的生物相容性、生物可降解性、增稠性和易成凝胶特性,因此它在药物载体、组织工程支架材料、抗菌材料和创伤敷料等方面的应用具有较多探索和研究,但是目前关于采用海藻酸钠作为一氧化氮供体没有相关报道。
发明内容
发明目的:针对现有技术存在的问题,本发明提供一种基于海藻酸钠的一氧化氮供体的合成方法。本发明合成的基于海藻酸钠的一氧化氮供体延长了一氧化氮释放的时间,解决了小分子供体溶解性差和一氧化氮释放过快的问题。
本发明还提供所述的基于海藻酸钠的一氧化氮供体及其应用。
技术方案:为了实现上述目的,本发明所述一种基于海藻酸钠的一氧化氮供体的合成方法,包括如下步骤:
(1)将海藻酸钠溶于超纯水中,加入活化剂,进行反应得到溶液A;
(2)将L-半胱胺酸盐酸盐或者胱胺二盐酸盐入到溶液A中,继续反应得反应液B;
(3)将反应液B透析后,加入亚硝酸叔丁酯,继续反应,得到溶液C,透析冻干得到海藻酸钠一氧化氮供体;
当步骤(2)中采用胱胺二盐酸盐时,步骤(3)中将反应液B透析后,然后加入DTT,继续反应得到溶液C;将得到溶液C透析后,加入亚硝酸叔丁酯,继续反应,得到溶液D,透析冻干得到海藻酸钠一氧化氮供体。
其中,步骤(1)所述活化剂为EDC·HCl,反应条件为20-30℃反应0.5-1h。
其中,步骤(2)中按L-半胱胺酸盐酸盐或者胱胺二盐酸盐与海藻酸钠摩尔比为1:1-5:1,将L-半胱胺酸盐酸盐或者胱胺二盐酸盐加入到溶液A中。
其中,步骤(2)中L-半胱胺酸盐酸盐或者胱胺二盐酸盐入到溶液A中调节pH为5-7,在20-30℃,继续反应3-12h。
作为优选,步骤(2)调节pH为5,所述L-半胱胺酸盐酸盐或者胱胺二盐酸盐与海藻酸钠摩尔比为2:1。
其中,步骤(3)中透析采用透析袋透析48-60h,截留分子量为3500Da。
其中,步骤(3)中加入亚硝酸叔丁酯调节pH为7-9。
作为优选,步骤(3)中调节pH为8。
其中,步骤(3)中溶液C透析后测定其巯基含量,加入亚硝酸叔丁酯,所加入的亚硝酸叔丁酯的量为巯基含量的5-10倍。
作为优选,所加入的亚硝酸叔丁酯的量为巯基含量的5倍。
其中,步骤(3)所述检测巯基含量的方法为Ellman法。
其中,步骤(3)中加入亚硝酸叔丁酯在室温氮气保护避光反应6-12h。
其中,步骤(3)中所述透析采用透析袋透析透析24h,截留分子量为3500Da。
本发明所述的合成方法所合成的基于海藻酸钠的一氧化氮供体。
本发明所述的基于海藻酸钠的一氧化氮供体在制备心血管支架、人造血管或治疗心肌细胞缺血性损伤的药物或材料中的应用。
本发明合成的海藻酸钠一氧化氮供体是S-亚硝基化海藻酸钠,通过在海藻酸钠上接枝巯基,再通过亚硝基化形成-SNO基团,图2处的紫外吸收峰即为-SNO键的吸收峰,可证明-SNO键的合成。本发明合成方法简单易行、无毒且成本低,且制备的一氧化氮供体释放时间长,可稳定存在。有望于和其他聚合物材料应用于制备多功能的一氧化氮释放复合材料。
本发明将海藻酸钠上丰富的羧基通过酰胺化反应接枝上巯基,巯基再与亚硝酸叔丁酯反应生成硫亚硝基键SNO,此化学键的断裂可以释放出一氧化氮。本发明使用的海藻酸钠是一种应用广泛的生物长链大分子,具有保湿性,生物相容改性等优点。由于其存在很多活泼的羧基官能团,易化学改性在上面接枝巯基合成SNO化学键,从而使其可以释放一氧化氮,增加海藻酸钠的功能性,拓展其应用领域。本发明首次选用海藻酸钠来合成一氧化氮供体,主要是因为长链大分子羧基多,可接枝更多的巯基,合成更多-SNO键,提高一氧化氮释放量。而目前临床上应用的一氧化氮供体主要为亚硝酸盐,小分子,释放周期短,应用方式有限,而本发明的海藻酸钠一氧化氮供体为长链大分子,合成的-SNO键稳定,可以延长一氧化氮的释放时间,增加海藻酸钠的生物利用度,可以纺丝成纳米纤维,可以制成水凝胶,海绵等形式。
本发明制备的全新的基于海藻酸钠的一氧化氮供体有效解决了体内一氧化氮供体含量少,可以对于伤口处这种特定部位进行外源一氧化氮进行治疗。此外,现有很多生物大分子溶水性差,例如明胶等,而制备得到的海藻酸钠一氧化氮供体具有良好的水溶性,使得其使用更加方便。同时本发明的一氧化氮供体中的SNO化学键在不被Asc等物质作用下是不释放一氧化氮的,就和普通的海藻酸钠一样。而普通的海藻酸钠一般只具有普通的保湿作用,有一定的生物相容性,本发明通过特定的方法将其改性成一氧化氮供体后,不仅可以释放一氧化氮,并且其很稳定,在没有催化的情况下不释放一氧化氮,而现有的一氧化氮供体例如亚硝酸盐不稳定,会收到受pH,光照等因素就释放一氧化氮了。本发明的一氧化氮供可以应用在肿瘤部位,杀死肿瘤细胞,同时其在正常细胞周围是稳定的,不能释放一氧化氮,当加入Asc后可以长时间持续释放一氧化氮。
有益效果:与现有技术相比,本发明具有如下优点:
(1)本发明合成制备的基于海藻酸钠的一氧化氮供体具有良好的水溶性,且供体稳定性好,生物毒性低。
(2)本发明合成制备的基于海藻酸钠的一氧化氮供体延长了一氧化氮释放的时间,解决了一氧化氮半衰期短的问题。
(3)本发明所采用的方法操作简便,反应条件温和,易于实现,对海藻酸钠的结构不造成破坏。
(4)本发明制备的基于海藻酸钠的一氧化氮供体具有SNO活性基团,可以在一定条件下被分解并缓慢释放出NO;海藻酸钠在一定条件下可以制成凝胶,有望于制备多功能的一氧化氮释放复合材料,如制备心血管支架、人造血管或作为伤口敷料的药物或材料。
附图说明
图1是本发明实施例1合成的海藻酸钠一氧化氮供体一氧化氮释放曲线示意图;
图2是本发明实施例1合成的海藻酸钠一氧化氮供体紫外吸收光谱图(Alg为海藻酸钠,Alg-SNO为海藻酸钠一氧化氮供体);
图3是合成的巯基接枝海藻酸钠的红外光谱图(Alg为海藻酸钠,Alg-SH为巯基化海藻酸钠);
图4是合成的海藻酸钠一氧化氮供体促进L929细胞增殖的示意图。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
实施例1
(1)将0.2g的海藻酸钠溶于20mL的超纯水中,加入终浓度为50mMEDC·HCl室温下反应1h得到溶液A。
(2)鼓吹N2 5min,称取海藻酸钠两倍摩尔量的L-半胱胺酸盐酸盐加入到步骤(1)的溶液A中,用1M NaOH将溶液的pH调为5,25℃避光反应12h得到反应液B。
(3)步骤(2)的反应液B置于MWCO=3500Da的透析袋中,每隔12h换超纯水一次,室温透析48h,透析结束后得到溶液C。
采用Ellman法测得溶液C中海藻酸钠上的巯基接枝率,将溶液C冷冻干燥得到巯基化的海藻酸钠。通过红外固体压片操作实验,如图3所示,红外光谱表征证明了海藻酸钠巯基改性成功。将0.1g巯基化的海藻酸钠溶于10ml超纯水中,采用Ellman法测得海藻酸钠上的巯基接枝率。
(4)向溶液C中加入巯基五倍摩尔量的亚硝酸叔丁酯,1M的氢氧化钠溶液调节溶液pH为8,氮气保护避光室温反应12h,采用截留分子量为3500Da的透析袋用超纯水透析48h,冷冻干燥得到海藻酸钠一氧化氮供体。
通过紫外分光光度计检测,证明巯基化的海藻酸钠成功与硝酸叔丁酯反应生成了-SNO官能团,如图2所示。
将制备得到的25mg海藻酸钠一氧化氮供体溶于5mL的抗坏血酸Asc(250μg/mL)溶液中,定点取样用Griess试剂溶液进行检测,并根据标准曲线计算得到一氧化氮释放曲线,如图1所示,释放时间可达16h以上,比亚硝酸盐等一氧化氮供体更稳定,释放时间长。
实施例2
(1)将0.2g的海藻酸钠溶于20mL的超纯水中,加入终浓度为50mMEDC·HCl室温下反应1h得到溶液A。
(2)鼓吹N2 5min,称取海藻酸钠两倍摩尔量的L-半胱胺酸盐酸盐加入到步骤(1)的溶液A中,用1M NaOH将溶液的pH调为6,25℃避光反应12h得到反应液B。
(3)步骤(2)的反应液B置于MWCO=3500Da的透析袋中,每隔12h换超纯水一次,透析48h,透析结束后得到溶液C,采用Ellman法测得海藻酸钠上的巯基接枝率。
(4)在溶液C中直接加入五倍巯基摩尔量的亚硝酸叔丁酯,调节溶液pH为9,氮气保护避光室温反应12h,采用截留分子量为3500Da的透析袋用超纯水透析48h,冷冻干燥得到海藻酸钠一氧化氮供体。
实施例3
(1)将0.2g的海藻酸钠溶于20mL的超纯水中,加入终浓度为50mMEDC·HCl室温下反应1h得到溶液A。(2)鼓吹N2 5min,称取海藻酸钠两倍摩尔量的胱胺二盐酸盐加入到步骤(1)的溶液A中,用1M NaOH将溶液的pH调为6,25℃避光反应12h得到反应液B。
(3)步骤(2)的反应液B置于MWCO=3500Da的透析袋中,每隔12h换水一次,透析48h,透析结束后得到溶液C。
(4)向溶液C中加入终浓度10mM的DTT,将溶液pH调为7.5,反应12h后采用超纯水透析48h,每隔12h换一次水,透析结束后得到溶液D。
(5)采用Ellman法测得溶液D中的巯基含量,加入其巯基五倍摩尔量的亚硝酸叔丁酯,调节溶液pH为9,氮气保护避光室温反应12h,采用截留分子量为3500Da的透析袋用超纯水透析48h,冷冻干燥得到海藻酸钠一氧化氮供体。
实施例4
(1)将0.2g的海藻酸钠溶于20mL的超纯水中,加入终浓度为50mMEDC·HCl室温下反应1h得到溶液A。(2)鼓吹N2 5min,称取海藻酸钠两倍摩尔量的L-半胱胺酸盐酸盐加入到步骤(1)的溶液A中,用1M NaOH将溶液的pH调为6,25℃避光反应12h得到反应液B。
(3)步骤(2)的反应液B置于MWCO=3500Da的透析袋中,每隔12h换水一次,透析48h,透析结束后得到溶液C。
(4)向溶液C中加入五倍摩尔量的亚硝酸叔丁酯,调节溶液pH为9,氮气保护避光室温反应12h,采用截留分子量为3500Da的透析袋用超纯水透析48h,冷冻干燥得到海藻酸钠一氧化氮供体。
实施例5
实施例5和实施例1的合成方法相同,不同之处在于,步骤(3)中透析采用0.1M的HCl溶液透析24h,再用0.1M的HCl和1%的NaCl透析24h。透析结束后用Ellman法测得海藻酸钠上接枝的巯基含量后加入五倍摩尔量的亚硝酸叔丁酯,并将溶液pH调到9,N2保护,避光温室反应12h,反应结束后用超纯水透析48h,冷冻干燥得到海藻酸钠一氧化氮供体。
实施例6
实施例6与实施例1的合成方法相同,不同之处在于,步骤(1)反应条件为20℃反应1h;步骤(2)中按L-半胱胺酸盐酸盐与海藻酸钠摩尔比为1:1加入到溶液A中调节pH为7,在30℃,避光继续反应3h;步骤(3)中透析采用透析袋透析60h,截留分子量为3500Da;步骤(4)中加入亚硝酸叔丁酯调节pH为9,入的亚硝酸叔丁酯的量为巯基含量的10倍,室温氮气避光反应6h。
实施例7
取对数生长期中的L-929细胞,用胰蛋白酶消化后,配成1×104cells/mL的细胞悬液。取100μL细胞悬浮液分别接种于96孔板。将用上述实施例1制备的海藻酸钠一氧化氮供体溶于培养液,用0.22μm无菌滤头过滤后,配成不同浓度的供体溶液(10μg/mL-500μg/mL)。将孔板中的细胞培养基替换为100μL供体溶液,并加入15μL抗坏血酸溶液(250μg/mL),阴性对照组不加抗坏血酸溶液。将96孔板放入37℃、5%CO2的培养箱中培养2天,然后每孔加入10μL CCK8溶液,培养箱中继续培养1h,用酶标仪测其细胞活力(450nm)。如图4所示,海藻酸钠一氧化氮供体在抗坏血酸Asc的作用下可以有效释放一氧化氮,从而促进L-929细胞的生长,且促进作用随着供体浓度递增,而不存在Asc的实验组,细胞生长行为无显著差异。综上,制备得到的海藻酸能够一氧化氮供体具有良好的生物相容性,有明显促进细胞生长的作用,可以用于制备伤口敷料等生物组织工程领域。
Claims (10)
1.一种基于海藻酸钠的一氧化氮供体的合成方法,其特征在于,包括如下步骤:
(1)将海藻酸钠溶于超纯水中,加入活化剂,进行反应得到溶液A;
(2)将L-半胱胺酸盐酸盐或者胱胺二盐酸盐加入到溶液A中,继续反应得反应液B;
(3)将反应液B透析后,加入亚硝酸叔丁酯,继续反应,得到溶液C,透析冻干得到海藻酸钠一氧化氮供体;
当步骤(2)中采用胱胺二盐酸盐时,步骤(3)中将反应液B透析后,然后加入DTT,继续反应得到溶液C;将得到溶液C透析后,加入亚硝酸叔丁酯,继续反应,得到溶液D,透析冻干得到海藻酸钠一氧化氮供体。
2.根据权利要求1所述的基于海藻酸钠的一氧化氮供体的合成方法,其特征在于,步骤(1)所述活化剂优选为EDC·HCl,反应条件为20-30℃反应0.5-1h。
3.根据权利要求1所述的基于海藻酸钠的一氧化氮供体的合成方法,其特征在于,步骤(2)中按L-半胱胺酸盐酸盐或者胱胺二盐酸盐与海藻酸钠摩尔比为1:1-5:1,将L-半胱胺酸盐酸盐或者胱胺二盐酸盐加入到溶液A中。
4.根据权利要求1所述的基于海藻酸钠的一氧化氮供体的合成方法,其特征在于,步骤(2)中L-半胱胺酸盐酸盐或者胱胺二盐酸盐加入到溶液A中调节pH为5-7,在20-30℃,继续反应3-12h。
5.根据权利要求1所述的基于海藻酸钠的一氧化氮供体的合成方法,其特征在于,步骤(3)中透析采用透析袋透析48-60h,截留分子量为3500Da。
6.根据权利要求1所述的基于海藻酸钠的一氧化氮供体的合成方法,其特征在于,步骤(3)中加入亚硝酸叔丁酯调节pH为7-9。
7.根据权利要求1所述的基于海藻酸钠的一氧化氮供体的合成方法,其特征在于,步骤(3)中溶液C透析后测定其巯基含量,加入亚硝酸叔丁酯,所加入的亚硝酸叔丁酯的量为巯基含量的5-10倍。
8.根据权利要求1所述的基于海藻酸钠的一氧化氮供体的合成方法,其特征在于,步骤(3)中加入亚硝酸叔丁酯后在室温氮气避光反应6-12h。
9.一种权利要求1所述的合成方法所合成的基于海藻酸钠的一氧化氮供体。
10.一种权利要求9所述的基于海藻酸钠的一氧化氮供体在制备心血管支架、人造血管或治疗心肌细胞缺血性损伤的药物或材料中的应用。
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