CN112169013B - 一种粒子堆垛型生物胶黏剂及其制备与应用 - Google Patents
一种粒子堆垛型生物胶黏剂及其制备与应用 Download PDFInfo
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Abstract
本发明公开了一种粒子堆垛型生物胶黏剂及其制备与应用。该粒子堆垛型生物胶黏剂以UPy‑PEI微粒堆垛而成;所述UPy‑PEI微粒为:聚乙烯亚胺PEI通过二异氰酸酯在其氨基端连接上脲基嘧啶酮UPy。本发明设计并制备的基于微粒自堆垛形成的生物胶黏剂具备在伤口处强力粘附、对分泌液响应、透明以及能长久并高效捕获杀菌的能力,对于开发并应用新型的抗菌敷料具有指导意义以及良好应用前景。
Description
技术领域
本发明属于生物医药技术领域,特别涉及一种粒子堆垛型生物胶黏剂及其制备与应用。
背景技术
抗生素滥用已经严重影响了全球经济和公众健康,这极大地加速了细菌的新生突变或从外部获得抵抗基因的能力,用以抵抗几乎所有类型的传统抗生素。然而,细菌对一些固有机制(如结构活性或阳离子基团)的抵抗力微乎其微。在这些抗菌材料中,具有防治细菌感染能力的伤口材料近年来尤其受欢迎。
在生物医疗领域,抗菌敷料的发现对患者细菌感染伤口的愈合提供了极大的帮助。全球每年死于微生物感染的患者约为1600万人,占死亡患者的1/3,因此对于能促进细菌感染伤口愈合的抗菌敷料的需求是保持增长态势的。然而,因为目前许多种类的细菌对于绝大部分抗生素具有极强的抗药性,所以能开发一种不用抗生素便可高效杀死细菌的抗菌敷料显得尤为重要。有研究表明,广泛使用具有抗菌效果的、不含抗生素的伤口敷料,能有助于伤口愈合、降低其他副作用,进而帮助节省相关的医疗开支(Nat.Commun.,2018,9,2784.)。
聚乙烯亚胺(PEI),一种众所周知的阳离子聚合物,已被报道在生物体内可高效地递送DNA或RNA。利用质子化的铵基基团,阳离子PEI及其衍生物的抗菌性能得到了广泛的研究。然而,目前可用于生物体伤口愈合的PEI基生物材料尚处于产品开发初期,市场化的实际应用还很少。这可能是因为基于PEI的抗菌敷料,其最大的挑战在于如何克服PEI的流体特性,使其在伤口上实现长期的生物粘附能力,同时保持有效的抗菌活性。特别地,脲基嘧啶酮(UPy)基超分子材料因其动态可逆的四重氢键,在机械和温度以及水响应性能上已经展现出巨大的优势(WO2015067569A1);同时基于UPy构造的生物医学材料也被应用于治疗心血管疾病(US20180153717A1)。因此,为了应对这一挑战,本发明引入UPy来极大地提高PEI的力学性能,设计并制备了一种以UPy-PEI微粒为基本单元的透明生物胶黏剂。
发明内容
基于以上背景技术,本发明提供一种粒子堆垛型生物胶黏剂及其制备与应用,该生物胶黏剂以UPy-PEI微粒为基本单元,可捕获杀菌且对伤口分泌液响应。
为了实现以上目的,本发明采用以下技术方案:
本发明一方面提供一种粒子堆垛型生物胶黏剂,以UPy-PEI微粒堆垛而成;
所述UPy-PEI微粒为:聚乙烯亚胺PEI通过二异氰酸酯在其氨基端连接上脲基嘧啶酮UPy。
优选地,所述PEI为支化的聚乙烯亚胺,其数均分子量为10KD。
优选地,所述UPy-PEI微粒通过以下方法制备:
S1、UPy与二异氰酸酯在吡啶溶剂中进行反应,UPy的氨基与二异氰酸酯中的一个-NCO偶联得到UPy-NCO;
S2、UPy-NCO与PEI进行反应,PEI中的氨基与UPy-NCO中的-NCO偶联形成所述UPy-PEI微粒。
优选地,S1具体包括:将UPy、二异氰酸酯和吡啶混合;保护气氛围下加热反应;反应结束后滴入戊烷或石油醚,过滤出白色固体粉末并收集;用丙酮洗涤白色粉末去除未反应的二异氰酸酯后,干燥粉末得到所述UPy-NCO。
优选地,S1中,所述二异氰酸酯为1,6-己二异氰酸酯(HMDI)、1,5-戊二异氰酸酯或1,4-丁二异氰酸酯;更有选为1,6-己二异氰酸酯。
优选地,S1中,所述UPy与二异氰酸酯的摩尔比为(0.5-1):1。为了确保UPy中的-NH2均连接上二异氰酸酯,投料中二异氰酸酯为过量即可。
优选地,S1中,所述保护气为氮气、氦气或氩气;更有选为氮气,在常用的保护气中,氮气的价格最为便宜。
优选地,S1中,所述加热的温度为70-120℃,反应时间为12-36小时。S1中的加热反应条件在此范围内均可,例如本发明实施例中,加热的温度为100℃,反应时间为24小时。
优选地,S1中,所述干燥的条件为30-70℃真空干燥12-36小时;在此干燥条件范围内均可实现干燥目的,例如本发明实施例中,干燥的条件为60℃真空干燥24小时。
本发明一个优选方案中的S1的反应式如下:
优选地,S2具体包括:将UPy-NCO和PEI分散于二甲基亚砜(DMSO)溶剂中,将混合物搅拌进行反应,然后,在水中透析以除去DMSO,同时在此过程中会得到自组装形成的UPy-PEI微粒;最后,离心得到所述UPy-PEI微粒。
优选地,S2中,搅拌进行反应6-12小时。
优选地,S2中,所述UPy-NCO和PEI的摩尔比为(3-5):1。
本发明一个优选方案中的S2的反应式如下:
优选地,所述UPy-PEI微粒的堆垛过程包括:
S3、将UPy-PEI微粒的水分散液干燥数天去除水分,获得透明的粒子堆垛型生物胶黏剂(UPy-PEI胶黏剂)。
优选地,S3中,所述干燥的温度为30-70℃;更有选为60℃。
本发明另一方面提供一种粒子堆垛型生物胶黏剂的制备方法,包括以下步骤:
S1、UPy与二异氰酸酯在吡啶溶剂中进行反应,UPy的氨基与二异氰酸酯中的一个-NCO偶联得到UPy-NCO;
S2、UPy-NCO与PEI进行反应,PEI中的氨基与UPy-NCO中的-NCO偶联形成所述UPy-PEI微粒;
S3、将UPy-PEI微粒的水分散液干燥数天去除水分,获得透明的UPy-PEI胶黏剂。
优选地,S1具体包括:将UPy、二异氰酸酯和吡啶混合;保护气氛围下加热反应;反应结束后滴入戊烷或石油醚,过滤出白色固体粉末并收集;用丙酮洗涤白色粉末去除未反应的二异氰酸酯后,干燥粉末得到所述UPy-NCO。
优选地,S1中,所述二异氰酸酯为1,6-己二异氰酸酯(HMDI)、1,5-戊二异氰酸酯或1,4-丁二异氰酸酯;更有选为1,6-己二异氰酸酯。
优选地,S1中,所述UPy与二异氰酸酯的摩尔比为(0.5-1):1。
优选地,S1中,所述保护气为氮气、氦气或氩气;更有选为氮气。
优选地,S1中,所述加热的温度为70-120℃,反应时间为12-36小时。S1中的加热反应条件在此范围内均可,例如本发明实施例中,加热的温度为100℃,反应时间为24小时。
优选地,S1中,所述干燥的条件为30-70℃真空干燥12-36小时;在此干燥条件范围内均可实现干燥目的,例如本发明实施例中,干燥的条件为60℃真空干燥24小时。
本发明一个优选方案中的S1的反应式如下:
优选地,S2具体包括:将UPy-NCO和PEI分散于二甲基亚砜(DMSO)溶剂中,将混合物搅拌进行反应,然后,在水中透析以除去DMSO,同时在此过程中会得到自组装形成的UPy-PEI微粒;最后,离心得到所述UPy-PEI微粒。
优选地,所述PEI为支化的聚乙烯亚胺,其数均分子量为10KD。
优选地,S2中,搅拌进行反应6-12小时。
优选地,S2中,所述UPy-NCO和PEI的摩尔比为(3-5):1。
本发明一个优选方案中的S2的反应式如下:
优选地,所述UPy-PEI微粒的堆垛过程包括:
S3、将UPy-PEI微粒的水分散液干燥数天去除水分,获得透明的粒子堆垛型生物胶黏剂(UPy-PEI胶黏剂)。
优选地,S3中,所述干燥的温度为30-70℃;更优选为60℃。
本发明设计并制备了一种以UPy-PEI微粒为基本单元的透明生物胶黏剂。疏水保护的UPy硬相处于微粒内腔,提高了外侧亲水PEI的机械性能;外侧的PEI则同时起到抗菌和生物粘附的作用。通过表面氨基氢键的相互作用,UPy-PEI微粒可以进一步堆垛成生物胶黏剂,降低流动性,便于储存和伤口涂覆。同时,得益于水分子对氢键的瓦解作用,该生物胶黏剂会在伤口分泌液等含水环境下,缓慢解离,持续释放UPy-PEI微粒并使之均匀分散在伤口处,持续提供捕杀细菌的效果。与此同时,该生物胶黏剂在皮肤上显示出强的自支撑和附着能力,它高度透明的特性便于对伤口状况的实时观察,这些都将为其在抗菌伤口敷料领域的应用提供了有力的帮助。
本发明再一方面提供以上粒子堆垛型生物胶黏剂在抗菌伤口敷料中的应用。
目前,几乎所有用于伤口愈合的微/纳米颗粒都必须直接喷洒在受感染的伤口上,或用水凝胶或纱布作为载体敷料来施用。因此,上述现有方法无法保证治疗严重感染伤口时所需长期有效的药物浓度。而本申请制备的具有生物粘附性的智能微粒可用作伤口分泌液响应的敷料,并展现出持久的自支撑能力解决了上述问题。而且,目前还未有任何报道关于微粒自堆垛形成的敷料以促进细菌感染伤口的愈合。
附图说明
图1为优选实施例中透析后UPy-PEI微粒分散液的离心情况。
图2为优选实施例中UPy-PEI微粒分散液的静置稳定情况。
图3为优选实施例中UPy-PEI生物胶黏剂附着于玻璃基底的情况。
图4为优选实施例中UPy-PEI生物胶黏剂的透明特性图。
图5为优选实施例中UPy-PEI生物胶黏剂在光学显微镜下的内部组成图。
图6为优选实施例中UPy-PEI生物胶黏剂在无水条件下的性状。
图7为优选实施例中UPy-PEI生物胶黏剂在水接触条件下的性状。
图8为优选实施例中UPy-PEI生物胶黏剂在水接触和无水条件下的剪切速率-粘度曲线图。
图9为优选实施例中荧光素标记的UPy-PEI生物胶黏剂在琼脂板上随时间增长的扩散行为。
图10为优选实施例中UPy-PEI微粒对金黄色葡萄球菌的作用。
图11为优选实施例中UPy-PEI微粒对大肠杆球菌的作用。
图12为优选实施例中UPy-PEI生物胶黏剂对细菌存活率的减少和时间的关系图。
图13为优选实施例中扫描电镜观测UPy-PEI胶黏剂处理前金黄色葡萄球菌的形貌。
图14为优选实施例中扫描电镜观测UPy-PEI胶黏剂处理后金黄色葡萄球菌的形貌。
图15为优选实施例中扫描电镜观测UPy-PEI胶黏剂处理前大肠杆菌的形貌。
图16为优选实施例中扫描电镜观测UPy-PEI胶黏剂处理前大肠杆菌的形貌。
图17为金黄色葡萄球菌(革兰氏阳性)对老鼠全皮厚度伤口的感染对照组(未使用UPy-PEI胶黏剂)。
图18为金黄色葡萄球菌(革兰氏阳性)对老鼠全皮厚度伤口的感染试验组(使用UPy-PEI胶黏剂)。
图19为大肠杆菌(革兰氏阴性)对老鼠全皮厚度伤口的感染对照组(未使用UPy-PEI胶黏剂)。
图20为大肠杆菌(革兰氏阴性)对老鼠全皮厚度伤口的感染试验组(使用UPy-PEI胶黏剂)。
具体实施方式
为了更清楚地说明本发明,下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
本发明通过以下优选实施例对以上方案进行详细说明,本优选实施例合成一种粒子堆垛型生物胶黏剂,具体包括以下步骤:
(1)首先,将10gUPy、100mLHMDI和7mL吡啶添加到250mL圆底烧瓶中。然后,用冷凝回流装置固定的烧瓶在100℃以及在氮气保护下加热反应24小时。滴入30mL戊烷或石油醚,过滤出白色固体粉末并收集。最后,用大量丙酮清洗白色粉末数次。去除未反应的HMDI后,在真空干燥箱(60℃)下干燥粉末24小时得到UPy-NCO。反应式如下:
(2)25mgUPy-NCO和100mgPEI分散于DMSO溶剂中,将混合物搅拌12小时。然后,在水中透析以除去DMSO,同时在此过程中会得到自组装形成的UPy-PEI微粒。最后,用高速离心机对UPy-PEI微粒进行分离,收集沉积物。其中,UPy-NCO与PEI的反应式如下:
(3)在60℃下将UPy-PEI微粒分散液干燥数天去除水分,获得透明的UPy-PEI胶黏剂。
图1给出了透析后UPy-PEI微粒(100毫克/毫升)分散液在离心后完全沉淀,而用手轻微晃动约1分钟便可重新使得UPy-PEI微粒分散于水中。
图2表明了UPy-PEI微粒在水中的稳定性,在五天的静置后仍然保持较好的分散性。
图3和图4展现了UPy-PEI生物胶黏剂(120微米)附着于玻璃基底上的透光度,证实了其具有良好的透明特性。
图5说明了生物胶黏剂中的构造,是由大量UPy-PEI微粒堆垛形成。同时,UPy-PEI微粒粒径大约为2-5微米。
图6-图8给出了UPy-PEI生物胶黏剂在水接触和无水条件下的粘度和性状(无水:透明堆垛态;含水:白色分散态);同时具有明显的剪切变稀行为,水含量越多使胶黏剂的粘度下降的越明显。
图9给出了荧光素标记的胶黏剂在琼脂板上随时间增长的扩散行为。UPy-PEI生物胶黏剂从琼脂板中吸收水分,从而逐渐瓦解胶黏剂中的氨基氢键形成分散的UPy-PEI微粒,可以持续近10个小时。
图10中箭头表示了绿色荧光素标记的UPy-PEI微粒和红色荧光素标记的金黄色葡萄球菌的结合,绿色的UPy-PEI微粒与红色的金黄色葡萄球菌完全重叠结合。图11中箭头给出了绿色荧光素标记的UPy-PEI微粒和红色荧光素标记的大肠杆球菌的结合,绿色的UPy-PEI微粒与红色的大肠杆球菌部分重叠结合。图10和图11证明了UPy-PEI颗粒可以高效地捕获细菌。
图12为UPy-PEI胶黏剂对细菌存活率的减少和时间的关系。图13-图16为扫描电镜观测UPy-PEI胶黏剂处理前后的细菌形貌变化。从图13-图16中可以清晰观测到UPy-PEI胶黏剂处理后,金黄色葡萄球菌发生了严重地萎缩,大肠杆菌的表面则出现了严重地褶皱。
图17-图20为金黄色葡萄球菌(革兰氏阳性)和大肠杆菌(革兰氏阴性)对老鼠全皮厚度伤口的感染。在第2天将UPy-PEI胶黏剂附着于伤口处,可以清晰地看出此胶黏剂可以强力地粘附于伤口至5天,而胶黏剂含量的减少是由于伤口分泌液对胶黏剂的逐渐瓦解造成的。另外,相比于对照组,可以发现UPy-PEI胶黏剂处理的伤口的愈合速率比对照组更快。
以上实施例中,1,6-己二异氰酸酯作为连接分子将UPy和PEI连接在一起,将以上制备方法中原料1,6-己二异氰酸酯替换为其他常用的二异氰酸酯同样可以实现连接分子的作用,例如1,5-戊二异氰酸酯或1,4-丁二异氰酸酯;其中的两个-NCO分别与UPy中的-NH2和PEI中的-NH2连接。
本发明设计制备的基于UPy-PEI微粒的新型生物胶黏剂可以在细菌感染的伤口处进行强力地粘附,从而实现对伤口分泌液的响应,进一步将UPy-PEI微粒持续地释放出来对伤口处的细菌进行捕杀达到促进伤口愈合的目的。同时,该生物胶黏剂的透明性质提供了可以实时观测伤口愈合情况的条件。
显然,本发明的上述实施例仅仅是为清楚地说明本发明所作的举例,而并非是对本发明的实施方式的限定,对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动,这里无法对所有的实施方式予以穷举,凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。
Claims (17)
1.一种粒子堆垛型生物胶黏剂,其特征在于,该粒子堆垛型生物胶黏剂以UPy-PEI微粒堆垛而成;
所述UPy-PEI微粒为:聚乙烯亚胺PEI通过二异氰酸酯在其氨基端连接上脲基嘧啶酮UPy。
2.根据权利要求1所述的粒子堆垛型生物胶黏剂,其特征在于,所述UPy-PEI微粒通过以下方法制备:
S1、UPy与二异氰酸酯在吡啶溶剂中进行反应,得到UPy-NCO;
S2、UPy-NCO与PEI进行反应,得到所述UPy-PEI微粒。
3.根据权利要求2所述的粒子堆垛型生物胶黏剂,其特征在于,S1具体包括:将UPy、二异氰酸酯和吡啶溶剂混合;保护气氛围下加热反应;反应结束后滴入戊烷或石油醚,过滤出白色固体粉末并收集;用丙酮洗涤白色粉末去除未反应的二异氰酸酯后,干燥粉末得到所述UPy-NCO。
4.根据权利要求2或3所述的粒子堆垛型生物胶黏剂,其特征在于,所述二异氰酸酯为1,6-己二异氰酸酯、1,5-戊二异氰酸酯或1,4-丁二异氰酸酯。
5.根据权利要求4所述的粒子堆垛型生物胶黏剂,其特征在于,所述二异氰酸酯为1,6-己二异氰酸酯。
6.根据权利要求2或3所述的粒子堆垛型生物胶黏剂,其特征在于,所述UPy与二异氰酸酯的摩尔比为(0.5-1):1。
7.根据权利要求3所述的粒子堆垛型生物胶黏剂,其特征在于,所述保护气为氮气、氦气或氩气。
8.根据权利要求7所述的粒子堆垛型生物胶黏剂,其特征在于,所述保护气为氮气。
9.根据权利要求3所述的粒子堆垛型生物胶黏剂,其特征在于,S1中,所述加热的温度为70-120℃,反应时间为12-36小时。
10.根据权利要求3所述的粒子堆垛型生物胶黏剂,其特征在于,S1中,所述干燥的条件为30-70℃真空干燥12-36小时。
11.根据权利要求2所述的粒子堆垛型生物胶黏剂,其特征在于,S2具体包括:将UPy-NCO和PEI分散于二甲基亚砜溶剂中,将混合物搅拌进行反应,然后,在水中透析以除去DMSO,同时在此过程中会得到自组装形成的UPy-PEI微粒;最后,离心得到所述UPy-PEI微粒。
12.根据权利要求11所述的粒子堆垛型生物胶黏剂,其特征在于,S2中,搅拌进行反应6-18小时。
13.根据权利要求11所述的粒子堆垛型生物胶黏剂,其特征在于,S2中,所述UPy-NCO和PEI的摩尔比为(3-5):1。
14.根据权利要求1所述的粒子堆垛型生物胶黏剂,其特征在于,所述UPy-PEI微粒的堆垛过程包括:
S3、将UPy-PEI微粒的水分散液干燥数天去除水分,获得透明的粒子堆垛型生物胶黏剂。
15.根据权利要求14所述的粒子堆垛型生物胶黏剂,其特征在于,S3中,所述干燥的温度为30-70℃。
16.一种权利要求1-15任一项所述的粒子堆垛型生物胶黏剂的制备方法,其特征在于,包括以下步骤:
S1、UPy与二异氰酸酯在吡啶溶剂中进行反应,UPy的氨基与二异氰酸酯中的一个-NCO偶联得到UPy-NCO;
S2、UPy-NCO与PEI进行反应,PEI中的氨基与UPy-NCO中的-NCO偶联形成所述UPy-PEI微粒;
S3、将UPy-PEI微粒的水分散液干燥数天去除水分,获得透明的UPy-PEI胶黏剂。
17.权利要求1-15任一项所述粒子堆垛型生物胶黏剂在抗菌伤口敷料中的应用。
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FR2948669A1 (fr) * | 2009-07-28 | 2011-02-04 | Arkema France | Polymeres olefiniques porteurs de groupes associatifs et adhesifs les comprenant |
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