CN115368516A - 一种紫外光控缓释硫化氢的水凝胶及其制备与应用 - Google Patents
一种紫外光控缓释硫化氢的水凝胶及其制备与应用 Download PDFInfo
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Abstract
本发明提供一种紫外光控缓释硫化氢的水凝胶及其制备与应用,所述水凝胶具有如式(I)所示的化学结构。本发明的水凝胶制备方法简单,反应条件温和,具有良好的稳定性和生物兼容性;在紫外光照射下,水凝胶可以生成活性中间体苯甲硫醛,苯甲硫醛与氨基酸或胺反应会释放硫化氢;通过控制光照时间,可以有效调控硫化氢的释放速度和浓度;释放硫化氢后,凝胶残余保持原态,可以移去,对生物细胞没有毒性。
Description
技术领域
本发明涉及硫化氢缓释技术领域,特别是涉及一种紫外光控缓释硫化氢的水凝胶及其制备与应用。
背景技术
硫化氢(H2S)是一种新近发现的细胞信号分子,其在生物体内的含量非常低,但是广泛参与各种生理(如神经信号传导、血管舒张、细胞增殖、细胞凋亡等)、病理(如癌症、糖尿病、心血管病)过程。获得安全、可控的硫化氢供体是研究其生理效应的基础,同时也可以为硫化氢相关的疾病治疗提供材料。
由于高浓度的硫化氢往往导致严重的细胞毒性,所以直接使用硫化氢气体面临着难以控制浓度与用量的问题。使用硫化钠(Na2S)或者硫氢化钠(NaHS)作为硫化氢供体,则无法模拟生理条件下硫化氢缓慢、持续的释放过程。近年来,研究人员开发了基于化学反应、酶促反应的硫化氢供体,如GYY4137、HSD-R等,可以满足一些缓释的要求,但是,这些硫化氢供体还面临着释放效率低、浓度难以控制、副产物毒性、生物兼容性差等问题。
发明内容
鉴于现有技术的缺点,本发明的目的在于提供一种紫外光控缓释硫化氢的水凝胶及其制备与应用,用于解决现有技术中硫化氢供体释放效率低、浓度难以控制、生物兼容性差等问题。
为实现上述目的及其他相关目的,本发明第一方面提供一种水凝胶,所述水凝胶含有如式(Ⅰ)所示的化学结构:
其中,x,y,z,m,n为重复单元数,m为5~100,n为1~100,x:y:z=10:1:1。
进一步,所述水凝胶能在紫外光照下,分解产生如式(II)所示的活性中间体苯甲硫醛,分解过程如下:
其中,x,y,z,m,n为重复单元数,m为5~100,n为1~100,x:y:z=10:1:1。
进一步,所述紫外光波长为300~375纳米,优选为365纳米。
进一步,紫外光照时长≥1分钟。
进一步,紫外光照强度为0.5~10mW cm-2。
进一步,所述中间体与氨基酸或者胺反应会释放硫化氢,并得到如式(III)所示的化合物:
其中,x,y,z,m,n为重复单元数,m为5~100,n为1~100,x:y:z=10:1:1。
进一步,所述氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸(蛋氨酸)、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天门冬酰胺、谷氨酰胺、苏氨酸、天冬氨酸、谷氨酸、赖氨酸、精氨酸、组氨酸中的任意一种。
进一步,所述胺选自正丁胺、叔丁胺、正戊胺、异戊胺、正己胺、正辛胺中的任意一种……。
本发明第二方面提供根据第一方面所述的水凝胶的制备方法,包括如下步骤:
将化合物1、化合物2与化合物3按配比溶解于反应溶剂中,加入聚合引发剂,通入保护气体,在避光条件下,加热搅拌反应得到凝胶体系;去除反应溶剂,水洗后在PBS缓冲溶液中溶胀,得到所述水凝胶;
所述化合物1为甲氧基聚乙二醇丙烯酸酯,所述化合物2的分子结构如下所示,所述化合物3为交联剂;反应过程如下:
其中,x,y,z,m,n为重复单元数,m为5~100,n为1~100,x:y:z=10:1:1。
进一步,所述化合物1甲氧基聚乙二醇丙烯酸酯的数均分子量(Mn)为500。
进一步,所述化合物3交联剂选自乙二醇二丙烯酸酯、二-(乙二醇)二丙烯酸酯、三-(乙二醇)二丙烯酸酯中的至少一种。
进一步,所述反应溶剂选自四氢呋喃、乙腈、四氢呋喃-水混合体系中的任意一种,所述四氢呋喃-水混合体系中,四氢呋喃与水的体积比范围为1:3~3:1。
进一步,所述聚合引发剂选自偶氮二异丁腈(AIBN)、过氧化苯甲酰、过氧化二碳酸二环己酯中的任意一种。
进一步,所述保护气体选自氮气。
进一步,加热反应温度为50~70℃。
进一步,加热反应时间≥12小时,优选为12~48小时,更优选为24小时。
本发明第三方面提供根据第一方面所述的水凝胶或根据第二方面所述的方法制得水凝胶在硫化氢缓释中的应用。
本发明第四方面提供一种硫化氢供体,为第一方面所述的水凝胶或根据第二方面所述的方法制得水凝胶。
如上所述,本发明的紫外光控缓释硫化氢的水凝胶及其制备与应用,具有以下有益效果:
本发明的水凝胶,制备方法简单,反应条件温和,具有稳定性好、生物兼容性好等优点,同时表现出通过紫外光控制释放硫化氢,缓释过程可控性好、无残留等特点,在研究硫化氢信号分子的生理作用、制备基于硫化氢缓释的药物等方面具有巨大的应用潜力与价值。
附图说明
图1显示为本发明实施例2中水凝胶的合成路线图。
图2显示为本发明实施例2中制备得到的水凝胶的实物图。
图3显示为本发明实施例4中加入水凝胶后,紫外光照释放硫化氢后的细胞培养图。
图4显示为本发明实施例4的流式细胞分析数据图。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。
将光作为响应因子,控制硫化氢的释放,可以实现瞬时和远程控制,同时满足低浓度、缓释硫化氢、无残留的优点。
基于此,本发明一实施例提供了一类可通过紫外光控制释放硫化氢的水凝胶,其含有如式(Ⅰ)所示的化学结构:
其中,x,y,z,m,n为重复单元数,m为5~100,n为1~100,x:y:z=10:1:1。
本发明提供的水凝胶稳定性好,无紫外光条件下,可长期保存;在紫外光照下,会分解产生如式(II)所示的活性中间体苯甲硫醛,其分解过程如下所示:
其中,x,y,z,m,n为重复单元数,m为5~100,n为1~100,x:y:z=10:1:1。
其中,紫外光波长为300~375纳米,优选为365纳米。紫外光源可采用长波紫外灯,例如菲利普斯8瓦长波紫外灯。
其中,紫外光照时长≥1分钟,紫外光照强度为0.5~10mW cm-2。在紫外光照下,控制紫外光照时间或者紫外光照强度(0.5-10mW cm-2),可以控制中间体(II)的生成,进而有效调控硫化氢的释放速度和浓度。
进一步地,将活性中间体苯甲硫醛与氨基酸或者胺反应,会释放硫化氢,并得到如式(III)所示的化合物:
其中,x,y,z,m,n为重复单元数,m为5~100,n为1~100,x:y:z=10:1:1。
释放硫化氢后的凝胶保持原态,可以移除,无残留影响酶,且生成的副产物无毒害。因此,本发明提供的水凝胶具有无残留的优点,还具有良好的生物兼容性,对生物细胞没有毒性。
其中,所述氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸(蛋氨酸)、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天门冬酰胺、谷氨酰胺、苏氨酸、天冬氨酸、谷氨酸、赖氨酸、精氨酸、组氨酸中的任意一种。
其中,所述胺为正丁胺、叔丁胺、正戊胺、异戊胺、正己胺、正辛胺等,但不局限于此。
本发明另一实施例提供如上所述的水凝胶的制备方法,包括如下步骤:
将化合物1甲氧基聚乙二醇丙烯酸酯、化合物2与化合物3交联剂)按配比溶解于反应溶剂中,加入聚合引发剂,通入保护气体,在避光条件下,加热搅拌反应得到凝胶体系;去除反应溶剂,水洗后在PBS缓冲溶液中溶胀,得到水凝胶;反应过程如下:
其中,x,y,z,m,n为重复单元数,m为5~100,n为1~100,x:y:z=10:1:1。
其中,所述化合物1甲氧基聚乙二醇丙烯酸酯的数均分子量(Mn)为500。
其中,所述化合物3交联剂选自乙二醇二丙烯酸酯、二-(乙二醇)二丙烯酸酯、三-(乙二醇)二丙烯酸酯中的至少一种。
其中,所述反应溶剂选自四氢呋喃、乙腈、四氢呋喃-水混合体系中的任意一种,所述四氢呋喃-水混合体系中,四氢呋喃与水的体积比范围为1:3到3:1。
其中,所述聚合引发剂选自偶氮二异丁腈(AIBN)、过氧化苯甲酰、过氧化二碳酸二环己酯中的任意一种。
其中,所述保护气体选自氮气。
其中,加热反应温度为50~70℃,优选为60℃;加热反应时间≥12小时,优选为12~48小时,更优选为24小时。
下面具体的例举实施例是为了进一步详细说明本发明。应理解,以下实施例只用于对本发明进行具体的说明,不能理解为对本发明保护范围的限制,本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。下述示例具体的工艺参数等也仅是合适范围中的一个示例,即本领域技术人员可以通过本文的说明做合适的范围内选择,而并非要限定于下文示例的具体数值。
以下实施例中,甲氧基聚乙二醇丙烯酸酯(Mn 480,CAS号32171-39-4),乙二醇二丙烯酸酯(CAS号2274-11-5),偶氮二异丁腈(AIBN,CAS号78-67-1)购买自Aldrich公司。
以下实施例中,化合物2为实验室合成。
实施例1
化合物2的合成
尿素(1.52g,20mmol)溶于50mL 95%的乙醇中,搅拌下加入4-氯甲基苯乙烯(3.05g,20mmol),溶解后加热到沸腾,反应5小时。冷却至室温后,减压蒸除溶剂,加入氢氧化钠(2.0g,50mmol)水溶液30mL。然后加入四丁基溴化铵(161mg,0.5mmol)以及溴苯乙酮(4.0g,20mmol)。继续在60℃,氮气环境下搅拌反应3小时。冷却至室温后,过滤,收集固体。固体用二氯甲烷萃取,有机相减压蒸除溶剂后得到淡黄色固体。此固体在二氯甲烷/甲醇中重结晶得到化合物2(4.70g,88%)。反应过程如下所示:
化合物2的表征数据如下:1H NMR(400MHz,CDCl3):d=7.92(d,J=7.2Hz,2H),7.57(t,J=7.2Hz,1H),7.45(t,J=7.2Hz,2H),7.35(d,J=7.2Hz,2H),7.31(d,J=7.2Hz,2H),6.69(dd,J1=17.4Hz,J2=10.8Hz,1H),5.73(d,J=17.4Hz,1H),5.23(d,J=10.8Hz,1H),3.74(s,2H),3.66(s,2H);13C NMR(400MHz,CDCl3):d=194.4,136.8,136.6,136.4,135.4,133.3,129.4,128.7,128.6,126.3,113.8,35.8,35.7;HRMS calculated for C17H17OS:269.1000;found:269.0994[M+H]+。
实施例2
水凝胶的制备
如图1所示,化合物1-甲氧基聚乙二醇丙烯酸酯(Mn 480,1.0g)(化合物1),化合物2(0.1g),化合物3-交联剂乙二醇二丙烯酸酯(0.1g)溶解于10mL四氢呋喃中,加入聚合引发剂偶氮二异丁腈(5mg),通氮气鼓泡10分钟。加热到60℃,在黑暗中搅拌反应24小时。除去溶剂后,先用水洗,然后在PBS缓冲液中溶胀,获得水凝胶,如图2所示。
实施例3
硫化氢缓释
剪切20mg实施例2制得的水凝胶,置于PBS缓冲液中,加入25mg丙氨酸,用8瓦菲利普斯紫外灯长波照射(紫外光波峰355纳米,0.5厘米处紫外光照强度为2.3mW cm-2)。2分钟后,6分钟,10分钟,15分钟后,分别取样分析。体系中取20μL PBS缓冲液加入新制亚甲基蓝混合体系中(含0.1mL 1%w/v的Zn(OAc)2水溶液,0.2mL 30mM FeCl3的盐酸(1.2M)溶液,0.2mL 20mM N,N-二甲基-P-苯基二胺硫酸盐溶液),反应体系在室温保存30分钟后,通过对比670纳米处紫外吸收,测定硫化氢浓度。2分钟,6分钟,10分钟,15分钟后,PBS缓冲液中硫化氢浓度分别为3.1μM,6.3μM,8.8μM,10.5μM。
上述结果表明,本发明提供的水凝胶可通过紫外光控制释放硫化氢,并且实现了微摩级别、生理浓度的硫化氢控制释放。
实施例4
细胞培养
将实施例2制得的水凝胶用80%的乙醇消毒2次,每次5分钟。然后用PBS缓冲液冲洗3次后,置于富含葡萄糖以及10%牛血清蛋白的达尔伯克改良伊格尔培养基(Dulbecco’sModified Eagle’s Medium)中。3T3纤维原细胞按照1.5×104个/cm2的密度种植在96孔板中后,加入水凝胶;以培养基不加水凝胶为参照条件。1天,2天,3天后,分别用紫外光照5分钟。3天后,移除水凝胶,进行CCK-8细胞毒性测试。100μL新鲜培养基及10μL CCK-8溶液加入细胞培氧孔板中。培氧4小时后,酶标仪在450纳米处计数,进行流式细胞分析数据。
图3显示了加入水凝胶后,紫外光照释放硫化氢后的细胞培养图。图4显示了所得的流式细胞分析数据图。生物细胞培养实验表明,水凝胶的加入不影响细胞的活性,在水凝胶上培养细胞可实现硫化氢的高效定向释放,有利于研究硫化氢的生理作用,也可用于基于硫化氢的药物开发。
上述实施例仅例示性说明本发明的原理及其功效,而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下,对上述实施例进行修饰或改变。因此,举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变,仍应由本发明的权利要求所涵盖。
Claims (10)
3.根据权利要求2所述的水凝胶,其特征在于,所述紫外光波长为300~375纳米;
和/或,紫外光照时长≥1分钟。
5.根据权利要求4所述的水凝胶,其特征在于,其中,x,y,z,m,n为重复单元数,m为5~100,n为1~100,x:y:z=10:1:1;
和/或,所述氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸(蛋氨酸)、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天门冬酰胺、谷氨酰胺、苏氨酸、天冬氨酸、谷氨酸、赖氨酸、精氨酸、组氨酸中的任意一种;所述胺为正丁胺、叔丁胺、正戊胺、异戊胺、正己胺、正辛胺等;所述胺选自正丁胺、叔丁胺、正戊胺、异戊胺、正己胺、正辛胺中的任意一种。
7.根据权利要求6所述的水凝胶的制备方法,其特征在于,所述化合物1甲氧基聚乙二醇丙烯酸酯的数均分子量为500;
和/或,所述化合物3交联剂选自乙二醇二丙烯酸酯、二-(乙二醇)二丙烯酸酯、三-(乙二醇)二丙烯酸酯中的至少一种;
和/或,所述反应溶剂选自四氢呋喃、乙腈、四氢呋喃-水混合体系中的任意一种;
和/或,所述聚合引发剂选自偶氮二异丁腈、过氧化苯甲酰、过氧化二碳酸二环己酯中的任意一种。
8.根据权利要求6所述的水凝胶的制备方法,其特征在于,所述保护气体选自氮气;
和/或,加热反应温度为50~70℃;
和/或,加热反应时间≥12小时。
9.根据权利要求1~5任一项所述的水凝胶或根据权利要求6~8任一项所述的方法制得的水凝胶在硫化氢缓释中的应用。
10.一种硫化氢供体,其特征在于,为权利要求1~5任一项所述的水凝胶或根据权利要求6~8任一项所述的方法制得的水凝胶。
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