CN101431983A - 作为生物材料的多功能的超分子水凝胶 - Google Patents
作为生物材料的多功能的超分子水凝胶 Download PDFInfo
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- CN101431983A CN101431983A CNA2005800329075A CN200580032907A CN101431983A CN 101431983 A CN101431983 A CN 101431983A CN A2005800329075 A CNA2005800329075 A CN A2005800329075A CN 200580032907 A CN200580032907 A CN 200580032907A CN 101431983 A CN101431983 A CN 101431983A
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Abstract
本发明涉及具有三维的自组装的弹性的网状结构的超分子水凝胶的设计和应用,该网状结构中含有非聚合的功能分子和液体介质,由此功能分子是非共价交联的。例如,功能分子可以是抗炎分子、抗生素、金属螯合剂、抗癌剂、小肽、表面修饰的纳米颗粒或其组合。水凝胶的设计包括:1)修饰功能分子,使其转化成水凝胶因子,同时增强或保持它们的治疗性质,和2)通过物理、化学或酶处理,触发-水凝胶化过程,由此通过形成功能分子的非共价交联而导致产生超分子水凝胶。本发明的应用包括超分子水凝胶用作例如伤口愈合、组织工程学、药物传送和药物/抑制剂筛选的生物材料。
Description
技术领域
本申请要求受益于2004年9月28日提交的美国系列号60/613,413,其内容在此以其全文并入本文作为参考。
遍及本申请,引用了多种参考文献且这些出版物的公开内容在此以其全文并入本申请作为参考,以便更充分地描述本发明所属现有技术的状态。
背景技术
由三维、其间隙空间充满液体的弹性的网络(networks)形成的水凝胶具有多种有用的性质(例如,对外部刺激的反应,适应剪切力的流动等)。因为其有用的性质,水凝胶已经应用于很多领域如生物分析、化学传感、食品加工、化妆品、药物传送和组织工程学。
在以聚合物为基础的水凝胶在生物医学工程学的成功应用和对低分子量的有机凝胶的成功研究之后,由小分子的自组装(self-assembly)形成的超分子水凝胶,最近已作为新型的生物材料出现,其预示重要的生物医学应用(例如,基于寡肽自组装的水凝胶已经用作生长神经元的支架)。然而,这些基于寡肽的水凝胶仅仅是单功能的,而且它们的成本依然高。
相反,本发明涉及一种新型的超分子水凝胶,其中功能性的小分子(或实体)的自组装的纳米纤维(nanofibers)或纳米-网络用作封装水和形成水凝胶的基质。另外地,甚至当其用作超分子水凝胶的结构组件时,这些小分子保持它们的治疗效果。因为它们与细胞外基质的相似性、它们的生物相容性和它们的生物可降解性,这种类型水凝胶可以用作一种新的和广泛性的平台,用于生物医学领域的不同应用,如除去毒素、伤口愈合、组织工程学和药物传送。
发明概述
本发明涉及一种新的超分子水凝胶的一般设计和应用,其自组装网络包含一种或多种类型的功能分子(例如,抗炎分子、抗生素、金属螯合剂、抗癌剂、小肽和/或表面修饰的纳米颗粒(nanoparticles)),所述超分子水凝胶作为生物材料用于多种应用如伤口愈合、组织工程学、药物传送、抗癌治疗、传染病的治疗、药物/抑制剂筛选和毒素的清除。
超分子水凝胶的设计包括:1)修饰功能分子使它们转变成水凝胶因子(hydrogelators),同时增强或保持它们的治疗活性,和2)通过物理、化学或酶的处理触发水凝胶化过程,借此通过形成功能分子的非共价交联导致产生超分子水凝胶。值得注意地,甚至当其用作超分子水凝胶的结构组件时,功能分子维持它们的治疗效果。
附图简述
图1、说明三个小分子的结构:N-(芴基-9-甲氧羰基)-L-亮氨酸、N-(芴基-9-甲氧羰基)-L-赖氨酸和氨羟二磷酸二钠。N-(芴基-9-甲氧羰基)-L-亮氨酸1和N-(芴基-9-甲氧羰基)-L-赖氨酸2属于Burch等人报道的一类新抗炎剂1,且1在动物模型中显示有效的抗炎活性。在中性水性溶液中,1或2都不用作水凝胶因子。在pH=9时,向1和2的混悬液中加入氨羟二磷酸二钠(3)导致形成水凝胶,其中3作为促进水凝胶化的氢键的供体和受体起作用。此外,3是临床上用的药物并与UO2 2+形成稳定的络合物,减少铀酰离子引起的毒害。
图2、(2A)小鼠体重的变化(原始体重被标准化为1;0表示死亡的小鼠)。在组内N只小鼠中获得的数据是平均值+SD,其中N=7、7、5,分别关于(-)、(+)和愈合组。
(2B)说明了水凝胶和模拟的铀伤口之间的似乎可能的相互作用。
图3、(3A)配体、万古霉素4及受体5、6和7的衍生物的分子结构。
(3B)5和5+4的水凝胶分别在1%和0.1%应变时的线性粘弹性的频率扫描响应。
(3C)6、7、6+4和7+4的水凝胶在1%的应变时的线性粘弹性的频率扫描响应。4、5、6和7的浓度全是30mM。
图4、8的结构和8的水凝胶的光学图像(0.36wt%)(当管形瓶水平放置时,用平面扫描器取得)。
图5、用于形成水凝胶的两种化合物的分子结构和示意的胶凝化过程。胶凝化的条件:(i)Na2CO3、缓冲液;(ii)酶,37℃;(iii)Na2CO3,缓冲液;和(iv)酶,60℃(缓冲液:pH~9.6,50mM的Tris-HCl加上1mM的MgCl2)。
图6、说明通过水凝胶化鉴别酶的抑制剂的设计。
图7、三种抑制剂的活性的结果:行1)左到右:9的溶解;9和酶的溶解;9+氨羟二磷酸二钠的溶解;9+Zn2+的溶解;和9+Na3VO4([氨羟二磷酸二钠]=[Zn2+]=[Na3VO4]=33mM)的溶解;行2)氨羟二磷酸二钠;行3)Zn2+;和行4)Na3VO4。(左到右,浓度=33;3.3;0.33;0.033;0.0033mM)。
图8、(8A)低浓度水凝胶因子的溶液。
(8B)加入表面修饰磁性纳米颗粒,简写为“NP”后的水凝胶
的形成。
(8C)向水凝胶应用磁场1小时之后,磁场表示“H”。
(8D)向水凝胶应用磁场H4小时之后。
(8E)向水凝胶应用磁场H10小时之后。
图9、作为生物相容的水凝胶因子的含有二肽衍生物的萘的化学结构。
图11、由0.5wt%浓度的化合物11(11A)、化合物12(11B)、化合物13(11C)和化合物14(11D)形成的水凝胶的TEM影象。
图12、五肽衍生物15、16、17、18、19和20的化学结构。
图13、β-氨基酸衍生物21和22的化学结构。
图14、21(14A)和22(14B)的水凝胶的光学图像。
图15、五肽15(SEQ.ID No.1)、16(SEQ.ID No.2)、17(SEQ.ID No.3)、18(SEQ.ID No.4)、19(SEQ.ID No.5)和20(SEQ.ID No.6)的胶凝化性质。
发明详述
本发明涉及一种新型的具有三维的自组装的弹性的网状结构的超分子水凝胶的设计和应用,网状结构包含非聚合的功能分子和液体介质,由此所述功能分子是非共价交联的。功能分子(或实体)可以例如是抗炎分子、抗生素、金属螯合剂、抗癌剂、小肽、表面修饰的纳米颗粒或其组合。
抗生素可以是例如万古霉素、青霉素、阿莫西林、头孢菌素、苯唑西林、萘夫西林、克林霉素、红霉素、环丙沙星、利福平、两性霉素和/或磺胺甲噁唑。金属螯合剂可以是放射性同位素的螯合剂,如铀螯合剂、铯螯合剂、碘螯合剂、锶(stronium)螯合剂和/或镅螯合剂。
在一个实施方案中,该液体介质是保留在该结构的间隙空间内。液体介质,包括但不限于水、生理盐水或其他液体介质。已经鉴别了适合的液体介质的实例,以便促进以后水凝胶的使用。
超分子水凝胶的设计包括:1)修饰功能分子使它们转变成水凝胶因子,同时增强或保持它们的治疗性质,和2)触发水凝胶化过程,借此通过形成功能分子的非共价交联来导致产生超分子水凝胶。
步骤1)的修饰包括附着或除去功能分子中的一个或多个基团。
在步骤2)中,水凝胶化过程可以是通过物理、化学或酶处理触发的。
本发明进一步提供了由以上方法制得的超分子水凝胶。
本发明的应用包括超分子水凝胶例如作为生物材料用于伤口愈合、组织工程学、药物传送、细胞培养及药物/抑制剂筛选的用途。
例如,在一个实施方案中,多功能的超分子水凝胶是这样设计的,以便把三个小分子1、2和3(如图1所示)用作其结构组件;两个可减少炎症的氨基酸衍生物;和一个配位UO2 2+并降低UO2 2+毒性的二膦酸盐(bisphosphonate)。这些分子自组装成作为水凝胶基质的纳米纤维的网络。为了证明超分子水凝胶的体内活性,水凝胶局部给药于已被硝酸双氧铀污染的小鼠的皮肤上的伤口位点。在用水凝胶处理之后,小鼠恢复正常,而对照组的小鼠(其伤口受到污染并未被处理)称重减少35%或断气(如图2A所示)。值得注意地,结果表明,甚至当这些小分子用作超分子水凝胶的结构组件时,它们保持其治疗性质,因此证明超分子水凝胶可以作为一种新型的生物材料用于广泛的应用。
本发明提供了一种治疗创伤的方法,该方法包含给予以上讨论的水凝胶至有此需要的患者的外部或内部伤口的步骤。在这个实例中,可以使用适于治疗创伤的特定的介质。
本领域已经开发了很多以聚合的水凝胶因子为基础的水凝胶,这样的水凝胶通常是与治疗分子混合以便用作药物传送装置。然而,一些缺点是与聚合的水凝胶本质上有关的:1)聚合的水凝胶因子,它们自己通常是不活泼的(即,聚合物不具有治疗的性质);2)聚合物必须是生物可降解的;3)治疗剂和聚合物的混合物不是完全均质的(即,可能存在不需要的相分离),其可能导致药物分子不受控制的释放;和4)由于使用聚合物,治疗剂的量可能受限。
在另一方面,本发明直接使用治疗性或功能性的(非聚合的)分子作为水凝胶因子,可以容易地特制期望性质的水凝胶。术语“非聚合的”指的是分子不具有共价连接的重复单元。然而,本发明不排除在非聚合物的组合中使用聚合物。
因此,例如,生物可降解性和生物相容性可以构建到分子中;药物分子可以制成更均质地分布于水凝胶中;大量的药物分子可以掺合入水凝胶中。本发明的水凝胶还可以形成与磁性纳米颗粒的复合材料。这样的复合材料表现出磁反应,其可以通过磁场或磁调节器(actuator)进行受控的药物释放。
本发明还提供了一种由筛选方法得到的酶抑制剂,其是以前没有描述过的。
本发明另外提供一种培养细胞的方法,该方法包含利用以前讨论的水凝胶作为细胞生长的三维基质。
除了以上简要提及的实施例之外,以下是详细描述本发明的另外的实施例。
本文描述的实施例仅仅是用作说明的,不是意欲限制本发明至这样的范围。本领域的普通技术人员将能够理解本发明的全部范围及根据在此教导的其等同物。
具体实施方式
实施例1.伤口愈合
为了说明本发明的超分子水凝胶的生物活性,包含如图1所示的功能分子的水凝胶被用于处理铀创伤,所述铀创伤是通过擦伤小鼠背部的皮肤并向伤口外表上给予硝酸双氧铀造成的。然后,水凝胶后来局部地给药于阴性对照组的伤口上20分钟,但是不给予阳性对照组。实验的结果是如图2A所示的。由于创伤的作用,全部组中的小鼠在第二天表现出原始体重的减轻。阴性对照组在经历轻微的原始体重减轻之后很快恢复了伤口,并在第二天就恢复至正常的生长。与之相反地,阳性对照组表现出持续的体重减轻直到约第5天时死亡或在接下来的十天内35%的体重减轻。因此,当水凝胶局部地给药于阴性对照组的小鼠的硝酸双氧铀的伤口时,小鼠经历了很少的体重减轻和良好的恢复,在小鼠的日常行为中没有观察到硝酸双氧铀的毒性作用。
图2B描述了图1中所示的功能分子似乎可能的传送过程。1和2移进伤口,通过阻断中性粒细胞(neutropils)募集至发炎的位点来减少炎症,并且3通过与UO2 2+螯合来减少UO2 2+的毒性。此外,因为水凝胶能够从硝酸双氧铀溶液中“摄取”UO2 2+,水凝胶从创伤位点吸收一些UO2 2+,因此进一步地减轻了UO2 2+引起的损害。
尽管对于其他放射性元素引起的创伤的作用尚需试验,但是与基因液体的治疗相比,本发明的水凝胶可以有利地用于吸持(confinement)放射性的铀,因为水凝胶很好地吸收UO2 2+并具有很少流动性。因此,本发明的水凝胶作为铀创伤的急诊治疗是有用的。于是,以上实施例证明了选自药物分子库(pool)的水凝胶因子的其他组合可以用于产生其他有用的生物材料。
实施例2.非共价交联的超分子水凝胶
虽然原位聚合反应允许增强小分子凝胶的稳定性,但是这样的共价交联的方法通常需要另外的化学合成,其改变了水凝胶因子的性质,并可能导致丧失生物相容性和生物可降解性。因此,使用分子识别(非共价交联)来增强小分子水凝胶的弹性是优选的。例如,向受体衍生物的机械性差的水凝胶中加入配体,导致直到水凝胶储能模量百万倍地增加。术语“非共价交联”指的是交联通过氢键、疏水的力或离子力实现。
在一个实施方案中,万古霉素(Van)被选作为配体4,D-Ala-D-Ala衍生物被选作为受体5,因为在水性溶液中4和5之间很好地建立分子识别(图3A)。
化合物5在~30mM的最低胶凝化浓度和pH=9.5下凝胶水。与之相反,4和5的混合物(摩尔比=1:1)在5mM的最低胶凝化浓度和pH=9.5下形成水凝胶。
动态振动测量用于评估这两种水凝胶在相同的浓度(30mM)下的粘弹性能行为。为了确保当施加剪切力时水凝胶是可逆的,所有的频率扫描测量法是跟随在应变扫描测定线性粘弹性的方案之后。如在水凝胶的线性粘弹性的频率扫描的响应中所示的(图3B),5的水凝胶的储能模量(G′)在0.1rad/s时是0.12Pa。频率依赖性对络合物粘度(η*∝(频率)n-1,n=0.47±0.006),而非线性频率响应在100rad/s下启动,表明5仅可以形成液体样的水凝胶。在30mM的浓度下,5+4的水凝胶的G′在0.1 rad/s时是1.6x105Pa,而其频率依赖性对络合物粘度((ηl*∝(频率)n-1,n=0.15±0.006)表明水凝胶的固体样和高度弹性特征。增加4(与5相比)的摩尔比从0至1,增加了5+4的水凝胶的G′,接着幂定律(power law)(G′∝[4]n,n=5.93±0.31)表明4用作交联剂。
实施例3.抗生素超分子水凝胺
图4A显示了8的化学结构(当R=芘基时),图4B显示了把6.5mg的8加入1.8ml的水中形成水凝胶的照片,相当于~0.36wt%(2.2mM)的凝胶因子(gelator)和~23000的水分子/凝胶因子分子。8意外地有效力(0.125-2μg/ml,比对应的万古霉素低8-11倍稀释度),抑制VRE(2vanA-阳性粪肠球菌、4 vanA-阳性粪链球菌,4 vanB-阳性屎肠球菌)。8的自组装的强的倾向和意外的效力还让我们推测,当8局部浓度高时,其可能在细胞表面聚集成超分子结构。
实施例4.超分子水凝胶的酶的形成
最近,Messersmith等人2报道了使用一种酶交联聚合物来引起水凝胶化,而且Mooney等人3证实使用细胞作为聚合物的交联剂来促进凝胶化。据认为,两种方法在水凝胶的生物医学应用上是有利的。然而,相似的方法已经用于探究小分子形成的水凝胶。术语“小分子”指的是没有共价交联重复单元的分子,而且包括小肽(例如,单个氨基酸、二肽、三肽、β-氨基酸和五肽的衍生物,借此该衍生物的分子量是低于3.0KD)。如目前公开中所用的,“小分子”可以是与“非聚合”分子互换使用。
在本发明中,酶反应是用于把氨基酸衍生物上的离子基团转变成中性基团,其创造了小分子水凝胶因子并导致形成超分子水凝胶。这个胶凝化过程利用了碱性磷酸酶在碱性条件下脱磷酸化去N-(芴基-甲氧羰基)酪氨酸磷酸酯(tyrosine phosphate)(9)的PO4 3-,碱性磷酸酶是调节蛋白质活性的激酶/磷酸酶开关的一个组件。和先前报道酶促凝胶化过程不同,此过程,涉及键断裂而不是键形成,调节前体即氨基酸的普通的两亲的衍生物,的疏水性和亲水性的平衡,获得水凝胶因子。因为脱磷酸作用是存在于很多有机体中的普通而重要的生物反应,所以其与水凝胶化作用(hydrogelation)偶联提供了一种产生和利用基于超分子水凝胶的生物材料的有利方法。
图5说明了两种典型的操作,通过9的脱磷酸诱发凝胶化。在第一种情况下,9和一当量的Na2CO3溶解于磷酸盐缓冲液(pH=9.6)形成澄清的溶液。在37℃下30分钟内,加入碱性磷酸酶使9的溶液转变成10的不透明的水凝胶,pH为9.6。
在第二种情况下,等摩尔的9和2以及两当量的Na2CO3在磷酸盐缓冲液(pH=9.6)中混合,在温和的加热下形成混悬液。然后,混悬液中加入碱性磷酸酶,在~60℃下保持3分钟。混悬液变成澄清的溶液,当冷却至室温时其形成澄清的水凝胶。当没有加碱性磷酸酶而重复相同的两个操作时,两个步骤都不导致形成水凝胶。
实施例5.使用超分子水凝胶筛选酶的抑制剂
图6说明了看得见的分析的设计。前体,其作为酶的底物,当酶催化其转化时转变成水凝胶因子。然后,在水中水凝胶因子的自组装引起水凝胶的形成。当抑制剂竞争性地结合酶的活性位点并阻止酶催化的前体的转化时,无水凝胶形成。因此,前体的溶液的肉眼可见(macroscopic)的溶液向凝胶的转变(其可以目视观察到)报告了由于抑制剂所致的酶的失活。
这个方法具有唯一的特征-其征募水分子作为报告系统的部分。此外,无需用分光计来观察溶液至凝胶相的转化。当使用适合的前体时,这种简单且价廉的方法不但可用于筛选抑制剂,而且还可用于检测酶的存在。
为了证实图6所示的设计的可行性,一种简单的氨基酸衍生物(9)用于筛选酸性磷酸酶的抑制剂,该氨基酸衍生物(9)通过脱磷酸作用可以转化成水凝胶因子(10)。
因为酸性磷酸酶催化9转化成10并在37℃和pH=6.0下产生水凝胶化,水凝胶化的结果可以表明用于酸性磷酸酶自身的抑制剂的活性。选用氨羟二磷酸二钠、Zn2+和原钒酸钠(Na3VO4)来评价它们对于酸性磷酸酶的最低抑制浓度。三种化合物首先分别与酶在一系列的浓度下混合,接着在混合之后10分钟内把9加入到溶液10中。在另外孵育30分钟后,溶液至凝胶相转化表明化合物的最低抑制浓度。从图7中行2、3和4的变化,对于酸性磷酸酶的氨羟二磷酸二钠、Zn2+和原钒酸钠(Na3VO4)的最低抑制浓度分别测定为33mM、0.33mM和3.3mM。这个结果紧密地接近这种的酶的文献值,因此确认我们的设计。
实施例6.超分子水凝胺的磁反应
图8显示了向稀释的水凝胶因子的溶液(图8A)中加入表面修饰磁性纳米颗粒之后,磁反应的水凝胶(图8B)的形成。对水凝胶持续施加小磁场10小时之后(图8E),水凝胶转化成溶液和磁性纳米颗粒的聚集体(例如,氧化铁)。这个过程可以通过磁力用以触发水凝胶中药物的释放。
实施例7.含萘的二肽的水凝胺因子
水凝胶因子可以制成是更生物相容的,通过含有萘基团,其是一种药物分子中的常见片段。
图9显示了为水凝胶因子的含萘的二肽的化学结构.化合物11、12、13和14的合成是以2-(萘-2-基氧基)乙酸为基础的。11-14的合成是非常简单的,仅需使用N-羟基琥珀亚胺(succinimine)的活性酯与不同的氨基酸反应,而且总产率是相当高(60-80%)。
化合物11-14表现出在pH~2下凝胶(gel)水的极好的能力,而且可以形成浓度小于0.10wt%的凝胶。化合物12和13是最好的凝胶因子,而且可以在0.07wt%的浓度时凝胶(gel)水。化合物11和14同2和3相比表现出相似的凝胶化行为,除了在较高的浓度([11]=0.10wt%和[14]=0.08wt%)。图10显示了四种如此配制的水凝胶的线性粘弹性的频率扫描响应。所有的它们表现出非常差的0.1-100rad/s的频率依赖性,G′支配G",其指的是它们是有效的水凝胶。图11显示了水凝胶的电子透射显微照片(TEM),其揭示了由12(图11B)或13(图11C)制得的水凝胶,其含有螺旋状的结构,具有均匀的约30nm的大小和约60nm的螺距。这些结果证实萘部分是有效的水凝胶化的促进剂。
实施例8.五肽衍生物的水凝胶因子
为了探究基于五肽的水凝胶作为潜在的生物材料,三种芳香部分(芘(P)、芴(F)和萘(N))共价连接于一系列的五肽:
GAGAS,SEQ ID No.1,(15),GVPVP,SEQ ID No.2,(16),VPGVG,SEQ ID No.3,(17),VTEEI,SEQ ID No.4(16),VYGGG,SEQ ID No.5,(19),and YGFGG,SEQ ID No.5(20).
分子间的芳香族-芳香族的相互作用和这些分子的氢键之间的平衡可以导致它们在水中的自组装,其提供了用于水凝胶化的纳米纤维的基质。
所有的五肽(结构如图12所示)通过采用2-氯三苯甲游基树脂和相应的Nα-Fmoc保护的氨基酸的固相合成制得,Nα-Fmoc保护的氨基酸具有采用叔丁基适当保护的侧链。
把C-末端的第一个氨基酸装在树脂上,接着除去Fmoc基团。然后,使用TBTU/HOBt作为偶联剂,把下一个Fmoc-保护的氨基酸与游离的氨基偶合。最后,五肽的N-末端用Fmoc保护或者与1-芘丁酸或1-萘乙酸偶合来提供疏水基团。当完成所有的偶合之后,用含2.5%三异丙基甲硅烷和2.5%水的三氟乙酸(TFA)作为清除剂把五肽从树脂上裂解下来,再用反相HPLC纯化。五肽的胶凝化的性质如图15所示。
在适当的pH下,绝大多数的化合物可以凝胶水。当pH变得比列出的值更高时,凝胶倾向于变成澄清的溶液,而较低的pH总是产生沉淀而不是形成均质的凝胶。GAGAS,表位具有最小体积的侧链,似乎是非常亲水的。萘似乎不是足够的疏水以维持Naph-GAGAS凝胶水所需的疏水/亲水平衡,因为Naph-GAGAS是溶于水的,甚至在低pH和高浓度下。
具有一个更疏水的基团,Fmoc-GAGAS和芘-GAGAS变成为可以在非常酸性条件下凝胶水的水凝胶因子。GVGVP,缬氨酸中具有较大的侧链并在肽链末端具有一个脯氨酸,其在水中表现出差的溶解性。
然而,作为水凝胶因子亲水的尾部其仍然不是好的候选对象。仅有芘-GVGVP可以容易地形成凝胶。
借助于Fmoc-GVGVP的水凝胶可以是通过小心地调整pH至4.8获得,水凝胶不是热可逆的。Naph-GVGVP溶解于pH高于4的水中,或者在较低的pH时变成为混悬液。一旦加热,其还可以熔化.采用VPGVG作为亲水部分的所有三个化合物,未能在试验的条件下凝胶水。它们对pH的变化和低熔点都显示出敏锐的溶解度变化。VTEEI,其中所有五个氨基酸具有大的侧链,当连接Fmoc、芘或萘时显示了令人满意的凝胶水的能力。值得注意地,表位VYGGG、Fmoc和萘是用于形成水凝胶的适合的疏水基团,同时芘还表现出是如此疏水的,甚至在碱性条件下芘-VYGGG是不溶于水的。这些实施例证明,五肽可以被转化成极好的水凝胶因子,用于产生作为潜在的生物材料的超分子水凝胶。
实施例9.β-氨基酸衍生物的水凝胶因子
在体内使用时,基于寡肽的支架是可生物降解的,因为生物系统中的蛋白水解酶将催化其水解4。当需要长期的生物利用度时,对酶而言,这种的固有的敏感性(suseptibiity)缩短了这些基于肽的水凝胶在体内的寿命,减少它们的效力,并限制其应用范围。
在另一方面,对于基于肽的治疗剂而言,蛋白水解的缺点是常见的特征。因此,许多努力集中在设计和合成非肽分子,其模拟肽或蛋白质的功能来实现这些分子延长的或受控的稳定性和生物利用度4。
在肽模拟物中5,因为其改善的生物稳定性,含有β-氨基酸的β-肽受到密切的关注4,6-10。尽管β-肽的设计和合成的快速发展,应用β-氨基酸来控制超分子水凝胶的生物利用度仍然是未探索的,因为不知道是否β-氨基酸衍生物将能用作水凝胶因子。图13说明了两种水凝胶因子21和22的化学结构,其是通过酰胺键连接萘基团的二肽模拟物。两个化合物的合成是简单和简明的:N-羟基琥珀酰亚胺(NHS)活化的2-(萘-2-基氧基)乙酸或2-(萘-2-基)乙酸的酯同甘氨酸或β3-苯丙氨酸反应分别得到2-(2-(萘-2-基氧基)乙酰氨基)乙酸或3-(2-(萘-2-基)乙酰氨基)-3-苯基丙酸。以后的NHS辅助的偶合给出收率为67%的21,以及收率72%的22。
把5mg的1悬浮在1.0mL的水中后,调整混悬液的pH值至4.8,产生澄清的溶液,其提供了透明的水凝胶(图14A)。相似地,通过调整pH或温度,含5mg的2的1.0mL的水也可以形成轻微不透明的水凝胶(图14B)。证实基于β-氨基酸的水凝胶因子将要提供一种的新方法来调制(tailor)水凝胶在生物学环境中的稳定性,并最终扩展作为生物材料的水凝胶的应用范围。
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Claims (26)
1、一种具有三维的自组装的弹性的网状结构的超分子水凝胶,所述的网状结构包含非聚合的功能分子和液体介质,借此所述功能分子是非共价交联的。
2、权利要求1的水凝胶,其中功能分子选自抗炎分子、抗生素、金属螯合剂、抗癌剂、小肽、表面修饰的磁性纳米颗粒及其组合。
3、权利要求2的水凝胶,其中小肽选自单个氨基酸、二肽、三肽、β-氨基酸和五肽的衍生物,借此所述衍生物的分子量小于3.0KD。
4、权利要求2的水凝胶,其中抗炎分子选自N-(芴基-9-甲氧羰基)-L-亮氨酸和N-(芴基-9-甲氧羰基)-L-赖氨酸。
5、权利要求2的水凝胶,其中抗生素选自万古霉素,青霉素、阿莫西林、头孢菌素、苯唑西林、萘夫西林、克林霉素、红霉素、环丙沙星、利福平、两性霉素和磺胺甲噁唑。
6、权利要求2的水凝胶,其中金属螯合剂是放射性同位素的螯合剂。
7、权利要求6的水凝胶,其中螯合剂选自铀螯合剂、铯螯合剂、碘螯合剂、锶螯合剂和镅螯合剂。
8、权利要求7的水凝胶,其中铀螯合剂是二膦酸盐。
9、权利要求8的水凝胶,其中二膦酸盐是氨羟二磷酸二钠。
10、权利要求1的水凝胶,其中非共价交联是通过配体-受体相互作用实现的。
11、权利要求10的水凝胶,其中配体-受体相互作用包含选自氢键、疏水力和离子力的力。
12、权利要求10的水凝胶,其中配体是万古霉素而受体是D-Ala-D-Ala衍生物。
13、权利要求1的水凝胶,其中液体介质是水。
14、一种治疗创伤的方法,该方法包含给予权利要求1的水凝胶至有此需要的患者的外部或内部伤口的步骤。
15、权利要求14的方法,其中该伤口是被放射性同位素污染的。
16、权利要求15的方法,其中放射性同位素选自硝酸双氧铀、氧化铀和铀。
17、一种制备超分子水凝胶的方法,该方法包含使用水凝胶因子的前体,该前体接着在适当的条件下用水解酶水解,由此导致形成所述水凝胶。
18、权利要求17的方法,其包含在碱性条件下用碱性磷酸酶脱磷酸N-(芴基甲氧羰基)酪氨酸磷酸酯,由此导致形成所述水凝胶。
19、权利要求18的方法,其中脱磷酸包含以下步骤:
a.把N-(芴基甲氧羰基)酪氨酸磷酸酯和一当量的Na2CO3溶解在磷酸盐缓冲剂中,以形成溶液;
b.向此溶液中加入碱性磷酸酶;和
c.维持溶液在约37℃的温度。
20、权利要求18的方法,其中脱磷酸包含以下步骤:
a.在磷酸盐缓冲液中混合等摩尔的N-(芴基甲氧羰基)酪氨酸磷酸酯和N-(芴基-9-甲氧羰基)-L-赖氨酸与两当量的Na2CO3,在加热下形成混悬液;
b.向此混悬液中加入碱性磷酸酶;和
c.维持混悬液在约60℃的温度。
21、权利要求19或20的方法,其中缓冲剂具有约9.6的pH。
22、一种制造超分子水凝胶的方法,该方法包含以下步骤:
a.修饰功能分子使其转化成水凝胶因子,同时增强或保持其治疗性质;和
b.通过酶处理触发水凝胶化过程,借此通过形成由所述功能分子的非共价交联导致产生超分子水凝胶。
23、超分子水凝胶,其由权利要求17-22任一项的方法制造。
24、一种筛选酶抑制剂的方法,该方法包含以下步骤:
a.提供在酶存在下转化成水凝胶因子的前体;和
b.通过观察不形成/形成水凝胶,确定存在/不存在酶抑制剂,借此,不形成水凝胶表明存在酶抑制剂。
25、酶抑制剂,其由权利要求24的筛选方法获得。
26、一种培养细胞的方法,该方法包含使用权利要求1的水凝胶作为细胞生长的三维基质。
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CN102585267A (zh) * | 2012-02-23 | 2012-07-18 | 上海交通大学 | 细胞培养用的智能凝胶三维支架材料 |
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CN113024844B (zh) * | 2021-03-16 | 2021-09-24 | 盐城工学院 | 一种小分子交联剂增韧水凝胶及其制备方法 |
CN113145030A (zh) * | 2021-04-06 | 2021-07-23 | 南京医科大学 | 超分子水凝胶及其制备方法 |
CN115105627A (zh) * | 2022-05-12 | 2022-09-27 | 江苏大学 | 一种基于天然受体配体识别作用的动态抗菌水凝胶、制备方法及应用 |
CN115105627B (zh) * | 2022-05-12 | 2023-10-10 | 江苏大学 | 一种基于天然受体配体识别作用的动态抗菌水凝胶、制备方法及应用 |
WO2023216495A1 (zh) * | 2022-05-12 | 2023-11-16 | 江苏大学 | 一种基于天然受体配体识别作用的动态抗菌水凝胶、制备方法及应用 |
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WO2006037113A2 (en) | 2006-04-06 |
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WO2006037113A3 (en) | 2009-04-23 |
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