CN113304311B - 一种环境敏感型聚合物/金杂化敷料的制备方法 - Google Patents
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Abstract
本发明公开了一种环境敏感型聚合物/金杂化敷料的制备方法,所述敷料由聚合物/金杂化膜与水凝胶载体两部分组成,由聚姜黄素前药开始,脱除保护基团暴露主链上大量的巯基,并通过金‑硫键从聚合物链上抓取金纳米粒子,经由界面自组装的方法得到杂化膜,聚乙烯亚胺和六氯三聚磷腈等通过一锅法得到水凝胶载体,水凝胶载体与杂化膜共同组成所述环境敏感型聚合物/金杂化敷料。该环境敏感型聚合物/金杂化敷料的制备方法制备得到的聚合物/金杂化敷料可以达到促进急性伤口愈合和抑制肿瘤生长的目的。
Description
技术领域
本发明涉及凝胶敷料领域,具体涉及一种环境敏感型聚合物/金杂化敷料的制备方法。
背景技术
急性伤口和外科手术中创伤的愈合在当今社会是一个亟需解决的问题,伤口若处理不当其自愈合时间较久,愈合过程中细菌二次感染并且伤口处因细菌感染会出现炎症。为避免细菌入侵伤口,防止因血液流出而增加的被感染的风险,伤口敷料的出现是极其有必要的。目前,提高敷料在伤口处的作用时间,增加其抗菌抗炎性能,促进伤口愈合效果成为国内外研究者关注的重点。这种直接作用于伤口处的敷料应具有生物低毒性甚至无毒性,可降解并且具有一定清洁能力。若能将抗炎抗菌药物协同光热疗法结合,还能进一步加强敷料的各项性能。
姜黄素(curcumin)已被证明具有广泛的生物学和药理学活性,是一种从姜科植物姜黄等的根茎中提取得到的黄色色素,为酸性多酚类物质,兼具抗氧化与抗炎的效果。在药理学方面,姜黄素也是非常安全的,在一期临床试验中,即使日摄入量达12g,姜黄素也没有表现出系统毒性,但生物利用率差。姜黄素对多种癌症有治疗效果,但它仍然不能直接作为药物使用。姜黄素是双-R,α,β-不饱和二酮,其表现出酮-烯醇互变异构,在酸性条件下不能溶于水体系中,而在中性或碱性条件下又快速分解,使得其生物利用率极低。姜黄素水溶性差,不易吸附,代谢快,这些导致其生物利用率低,是临床应用的关键瓶颈。
发明内容
本发明的目的在于提供一种环境敏感型聚合物/金杂化敷料的制备方法,其制备得到的聚合物/金杂化敷料可以达到促进急性伤口愈合和抑制肿瘤生长的目的。
为实现上述目的,本发明提供如下技术方案:
一种环境敏感型聚合物/金杂化敷料的制备方法,所述敷料由聚合物/金杂化膜与水凝胶载体两部分组成,由聚姜黄素前药开始,脱除保护基团暴露主链上大量的巯基,并通过金-硫键从聚合物链上抓取金纳米粒子,经由界面自组装的方法得到杂化膜,聚乙烯亚胺和六氯三聚磷腈等通过一锅法得到水凝胶载体,水凝胶载体与杂化膜共同组成所述环境敏感型聚合物/金杂化敷料。
优选地,所述聚姜黄素前药由疏水性药物姜黄素、疏水性分子三苯甲基硫代甘油、亲水性辅料短链聚乙二醇以及提供草酸酯键的草酰氯单体组成,并通过三氟乙酸脱去三苯基保护基团使聚合物主链上有大量巯基。
优选地,所述金纳米粒子通过柠檬酸钠还原法制得,且金纳米粒子直径为21nm,所述金纳米粒子均匀分散在去离子水中,聚合物上亲水性辅料为分子量为300-500的短链聚乙二醇,可一定程度提高杂化膜的韧性。
优选地,所述六氯三聚磷腈在酸性环境下分解,使得水凝胶载体在伤口酸性环境下发生解离,释放出药物分子PEI与姜黄素。
优选地,所述杂化膜的具体制备方法包括以下步骤:
(1)三苯基保护巯基单体合成:将硫代甘油与三苯基氯甲烷用四氢呋喃溶解,加入三乙胺,在室温下搅拌反应过夜,然后过滤、萃取、洗涤、分离并干燥得到产物Ⅰ,产物Ⅰ的结构式为:
其合成路线为:
(2)姜黄素聚合物合成:产物Ⅰ与姜黄素、聚乙二醇用干燥除水的四氢呋喃溶解,充入氮气置换反应瓶中的空气并且置于冰浴中,用一次性注射器加入干燥除水的三乙胺,搅拌5min,再将溶有草酰氯的四氢呋喃溶液缓慢滴加到反应体系中,在室温下反应8-10h,过滤、浓缩,沉淀,干燥得到聚合物Ⅱ,聚合物Ⅱ的结构式为:
其合成路线为:
(3)姜黄素聚合物保护基团脱除:将聚合物Ⅱ、三乙基硅烷加入反应瓶中,充入氮气置换空气并置于冰浴中,用一次性注射器加入溶解了三氟乙酸的无水二氯甲烷,完全溶解后于室温下反应0.5小时,反应完成后用冰甲醇沉淀聚合物,过滤、干燥得到聚合物Ⅲ,聚合物Ⅲ的结构式为:
其合成路线为:
(4)金纳米粒子合成:次氯金酸用去离子水溶解,搅拌并加热,待将要沸腾时快速加入柠檬酸钠水溶液,继续搅拌20min后停止加热,自然冷却至室温并通过离心纯化产物,收集离心后下层黑色固体并重新分散在去离子水中,得到产物Ⅳ金纳米粒子水溶液;
(5)聚合物/金杂化膜合成:聚合物Ⅲ用无水三氯甲烷溶解并加入到螺口瓶中,将产物Ⅳ金纳米粒子水溶液逐滴加入到螺口瓶中,在室温下静置48小时自然成膜。
所述杂化膜的结构式如下所示:
优选地,所述水凝胶载体的具体制备方法包括以下步骤:将聚乙烯亚胺、丙三醇用去离子水溶解,姜黄素用N,N-二甲基甲酰胺溶解并一起加入到反应皿中,加入六氯三聚磷腈十秒反应体系失去流动性开始凝胶化,6h后将完全凝胶化的凝胶取出并浸泡在去离子水中去除未反应完的单体与溶剂,冷冻干燥即得所述水凝胶载体,将水凝胶载体保存于室温下。
其合成路线为:
优选地,所述杂化膜和水凝胶均可用于处于伤口抗菌消炎。由于短链聚乙二醇的存在,极大提高了界面自组装后杂化膜的韧性。姜黄素作为杂化膜的一部分,可在活性氧环境刺激下断链释放出来。当杂化膜处于伤口部位高活性氧(过氧化氢:H2O2)的环境中时,草酸酯键断裂,聚合物链完全解离,致使杂化膜完全降解,释放出姜黄素药物,达到抗菌消炎的目的。同时,聚合物主链上通过巯基抓取的大量金纳米粒子,可被808nm处的近红外光激发产生热量升高温度,光热协同姜黄素药物分子对细菌达到更高的杀伤效果。作为杂化膜的载体,水凝胶具有一定的机械性能和力学性能。其含有酸敏感的分子六氯三聚磷腈,使得水凝胶可在伤口酸性环境条件下降解释放药物。同时水凝胶在室温下具有较好的稳定性,此特性使得水凝胶敷料得以长时间保存,降低了储存成本。
与现有技术相比,本发明的有益效果是:
1)将姜黄素与金纳米粒子结合,并依附在水凝胶上作为伤口敷料,便可同时把姜黄素的抗菌抗炎作用和金的光热效应结合起来,起到协同抗菌作用。
2)将姜黄素作为共聚单体,通过缩聚反应制备含姜黄素和硫醇的聚合物(聚姜黄素前药)。姜黄素单元作为载体的一部分掺入聚姜黄素前药骨架中,导致高姜黄素负载量和效率,而不会过早释放爆发。引入的PEG增强了姜黄素的水溶性和稳定性,延长在伤口处的作用时间。与此同时,聚姜黄素前药骨架上的多个巯基可与金纳米粒子通过硫-金键结合,并在两相液面中形成柔软的杂化膜。另一方面,将抗菌分子聚乙烯亚胺(PEI)和酸敏感的聚磷腈协同姜黄素结合,制备了酸降解的水凝胶。杂化膜和水凝胶制备的伤口敷料具有多种抗菌分子并且协同光热效应起到很高的抗菌抗炎作用,促进伤口愈合。
2)姜黄素药物是聚合物链上的一部分,极大提高了姜黄素载药量。同时还可以物理包裹DOX、CPT、PTX等抗癌药物,与姜黄素起到协同治疗的效果;姜黄素药物通过共价键连接在聚合物链上,使得抗炎抗菌药物姜黄素能够在伤口处精准控释,提高了药物的利用率。姜黄素单体不需进行纯化处理,酰氯选择草酰氯。姜黄素,三苯甲基硫代甘油与聚乙二醇的比例为1:1:1,所得到的聚合物杂化膜具有一定的韧性,只对高浓度过氧化氢响应,具有较好的稳定性。搭载水凝胶载体后作为伤口敷料敷在伤口处,伤口处酸性环境与高浓度过氧化氢使得水凝胶载体与聚合物杂化膜解离,释放药物达到化学治疗的效果。
3)聚合物主链上含有大量巯基位点,使得形成的杂化膜上含有大量金纳米粒子,在近红外光的辐射下局部温度可迅速升高,起到光热治疗的效果。
4)水凝胶载体由安全无毒的原料制成,且对酸性环境敏感,在伤口处酸性环境下降解释放药物。
5)聚合物/金杂化敷料易于从伤口处清除,不会对人体造成二次伤害。
6)本敷料协同药物的化学治疗和金纳米粒子的光热治疗,有更好的治疗效果。
附图说明
图1为本发明实施实例1中的三苯甲基巯基甘油单体的合成路线以及1H NMR(DMSO,600M Hz)图;
图2a为本发明实施实例2和实施实例3中的聚姜黄素前药(聚合物Ⅱ)和聚合物Ⅲ的合成路线以及1H NMR(DMSO,600M Hz)图;图2b为聚合物Ⅱ和聚合物Ⅲ的荧光谱图、GPC、红外谱图和紫外吸收光谱图;
图3为本发明实施实例4中金纳米粒子的DLS图与透射电镜图;
图4为本发明实施实例5中的聚合物/金杂化膜的紫外吸收光谱图和透射电镜图;
图5为本发明实施实例6中的水凝胶形成过程,加入六氯三聚磷腈约10秒后,溶液失去流动性开始凝胶化;
图6为本发明实施实例7中的聚合物/金杂化膜在808nm近红外光辐射10min的体外光热图;由图可以看到当808nm的近红外光辐射300秒之后,温度已经超过50℃,表明具有很好的光热治疗效果;
图7a为本发明实施实例8中的水凝胶具有高粘附力特性,图7b显示在甘油水溶液的作用下凝胶会迅速失去粘附力,易于清除;
图8为本发明实施实例9中的水凝胶在不同pH值下的体外降解速率对比图;图8为本发明实施实例9中的水凝胶载体在酸性环境下的姜黄素药物释放速率图;
图9为聚合物/金杂化敷料的抗菌特性图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1三苯甲基巯基甘油单体的合成
硫代甘油:三苯基氯甲烷:三乙胺按摩尔比1.05:1:1.1加入两口瓶中,以四氢呋喃为溶剂,室温反应过夜。TLC显示反应完全后,用去离子水洗3次,饱和碳酸氢钠溶液洗3次,饱和氯化钠溶液洗3次,收集有机相,加无水硫酸钠干燥3h,抽滤除去无水硫酸钠,旋蒸除去溶剂,过硅胶柱提纯(洗脱剂为石油醚:乙酸乙酯=1:1),收集产物,除去溶剂,真空干燥。得产物Ⅰ,结构式为:
实施例2聚姜黄素前药(聚合物Ⅱ)合成
姜黄素:聚乙二醇:产物Ⅰ按摩尔比1:1:1加入两口瓶中,以无水四氢呋喃为溶剂溶解,再将溶有草酰氯的无水四氢呋喃溶液置于恒压滴液漏斗中,密封,充N2保护并且置于冰浴中,用注射器向两口瓶中加入3.5份无水三乙胺,搅拌5min,然后打开恒压滴液漏斗将草酰氯四氢呋喃溶液缓慢滴加到反应体系中,室温下磁力搅拌反应过夜。反应完后,过滤、浓缩,用二氯甲烷重新溶解,并用去离子水洗2次,饱和碳酸氢钠溶液洗2次,饱和氯化钠溶液洗2次,收集有机相,用无水硫酸钠干燥3h。抽滤除去无水硫酸钠,滤液浓缩并在冷甲醇中沉析,除去未反应的单体,真空干燥,得到聚合物Ⅱ。结构式为:
实施例3聚姜黄素前药保护基团脱除(聚合物Ⅲ)
聚合物Ⅱ与三乙基硅烷加入反应瓶中,密封,充N2保护并且置于冰浴中。用一次性注射器加入溶解在无水二氯甲烷中的三氟乙酸(TFA:DCM=1:10,体积比),室温下磁力搅拌反应0.5小时。反应完后将聚合物溶液直接在提前氮气鼓泡的冷甲醇中沉析,除去脱除的保护基团三苯基甲烷,真空干燥,得到聚合物Ⅲ。结构式为:
实施例4金纳米粒子合成
称取30mg次氯金酸用200ml去离子水溶解,搅拌并加热。待将要沸腾时快速加入102mg柠檬酸钠水溶液,继续搅拌20min后停止加热,自然冷却至室温并通过离心纯化产物。收集离心后下层黑色固体并重新分散在去离子水中,得到产物Ⅳ金纳米粒子水溶液。
实施实例5:聚合物/金杂化膜合成
聚合物Ⅲ用无水三氯甲烷溶解并加入到螺口瓶中,将产物Ⅳ金纳米粒子水溶液逐滴加入到螺口瓶中,在室温下静置48小时自然成膜。
实施例6pH响应性可降解水凝胶合成
将1g聚乙烯亚胺、63mg丙三醇用去离子水溶解,14mg姜黄素用N,N-二甲基甲酰胺溶解并一起加入到反应皿中,加入80mg六氯三聚磷腈约十秒反应体系失去流动性开始凝胶化。6小时后将完全凝胶化的凝胶取出并浸泡在去离子水中去除未反应完的单体与溶剂。冷冻干燥并保存于室温下。
实施例7聚合物/金杂化膜的化学-光热协同治疗特性
本发明合成的杂化膜中包含了具有近红外光吸收特性的金纳米粒子,当聚合物/金杂化膜作用在伤口处后,在近红外光的辐射下,伤口处的局部温度会明显上升,不仅起到了光热治疗的效果,同时伤口处的高浓度过氧化氢也会促进药物分子姜黄素的释放,从而起到了化学治疗的效果,实现了化学-光热协同治疗的特性。因此该聚合物/金杂化膜具有明显的化学-光热协同治疗的特征。
实施例8水凝胶载体的高粘附特性
本发明合成的水凝胶具有较高的粘附力,可对不同材料诸如塑料、玻璃、金属、皮肤、纤维素等产生强的黏附作用,并且在水下湿润环境也可以保持一定黏附作用。水凝胶在用甘油水溶液浸泡处理后,粘附力会迅速降低,从而达到快速从人体剥离的目的,且不会留下凝胶残留。
实施例9水凝胶载体在体外降解和释放药物的特性
本发明合成的水凝胶中含有酸敏感的分子六氯三聚磷腈,因此凝胶在酸性环境下会发生解离,在pH=5.0的磷酸缓冲液中约16小时即可降解完毕。通过计算水凝胶重量来监测降解速率。水凝胶降解释放出药物分子姜黄素,随着时间延长姜黄素分子释放的量也逐渐增多,通过紫外吸收光谱计算药物释放效率。
实施实例10:聚合物/金杂化敷料的抗菌特性
聚合物/金杂化敷料对金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌有明显的抑制作用。将密度为5×105CFU/mL的100μL细菌悬浮液均匀地分散到琼脂板上,然后将搭载聚合物/金杂化膜的水凝胶敷料切成长3mm宽4mm的长方形,并轻轻的放在琼脂板上,在37℃孵育24小时。之后,样品周围产生生长抑制区,对每一组进行拍照,并通过测量板上样品周围产生的抑制区的半径来确定抗菌活性。
以上内容仅仅是对本发明结构所作的举例和说明,所属本技术领域的技术人员对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代,只要不偏离本发明的结构或者超越本权利要求书所定义的范围,均应属于本发明的保护范围。
Claims (6)
1.一种环境敏感型聚合物/金杂化敷料的制备方法,其特征在于:所述敷料由聚合物/金杂化膜与水凝胶载体两部分组成,由聚姜黄素前药开始,脱除保护基团暴露主链上大量的巯基,并通过金-硫键从聚合物链上抓取金纳米粒子,经由界面自组装的方法得到杂化膜,聚乙烯亚胺和六氯三聚磷腈通过一锅法得到水凝胶载体,水凝胶载体与杂化膜共同组成所述环境敏感型聚合物/金杂化敷料,其中,所述聚姜黄素前药由疏水性药物姜黄素、疏水性分子三苯甲基硫代甘油、亲水性辅料短链聚乙二醇以及提供草酸酯键的草酰氯单体组成,并通过三氟乙酸脱去三苯基保护基团使聚合物主链上有大量巯基。
2.根据权利要求1所述的一种环境敏感型聚合物/金杂化敷料的制备方法,其特征在于:所述金纳米粒子通过柠檬酸钠还原法制得,且金纳米粒子直径为21nm,所述金纳米粒子均匀分散在去离子水中,聚合物上亲水性辅料为分子量为300-500的短链聚乙二醇。
3.根据权利要求1所述的一种环境敏感型聚合物/金杂化敷料的制备方法,其特征在于:所述六氯三聚磷腈在酸性环境下分解,使得水凝胶载体在伤口酸性环境下发生解离,释放出药物分子PEI与姜黄素。
4.根据权利要求1所述的一种环境敏感型聚合物/金杂化敷料的制备方法,其特征在于,所述杂化膜的具体制备方法包括以下步骤:
(1)三苯基保护巯基单体合成:将硫代甘油与三苯基氯甲烷用四氢呋喃溶解,加入三乙胺,在室温下搅拌反应过夜,然后过滤、萃取、洗涤、分离并干燥得到产物Ⅰ,产物Ⅰ的结构式为:
(2)姜黄素聚合物合成:产物Ⅰ与姜黄素、聚乙二醇用干燥除水的四氢呋喃溶解,充入氮气置换反应瓶中的空气并且置于冰浴中,用一次性注射器加入干燥除水的三乙胺,搅拌5min,再将溶有草酰氯的四氢呋喃溶液缓慢滴加到反应体系中,在室温下反应8-10h,过滤、浓缩,沉淀,干燥得到聚合物Ⅱ,聚合物Ⅱ的结构式为:
(3)姜黄素聚合物保护基团脱除:将聚合物Ⅱ、三乙基硅烷加入反应瓶中,充入氮气置换空气并置于冰浴中,用一次性注射器加入溶解了三氟乙酸的无水二氯甲烷,完全溶解后于室温下反应0.5小时,反应完成后用冰甲醇沉淀聚合物,过滤、干燥得到聚合物Ⅲ,聚合物Ⅲ的结构式为:
(4)金纳米粒子合成:次氯金酸用去离子水溶解,搅拌并加热,待将要沸腾时快速加入柠檬酸钠水溶液,继续搅拌20min后停止加热,自然冷却至室温并通过离心纯化产物,收集离心后下层黑色固体并重新分散在去离子水中,得到产物Ⅳ金纳米粒子水溶液;
(5)聚合物/金杂化膜合成:聚合物Ⅲ用无水三氯甲烷溶解并加入到螺口瓶中,将产物Ⅳ金纳米粒子水溶液逐滴加入到螺口瓶中,在室温下静置48小时自然成膜。
5.根据权利要求1所述的一种环境敏感型聚合物/金杂化敷料的制备方法,其特征在于,所述水凝胶载体的具体制备方法包括以下步骤:将聚乙烯亚胺、丙三醇用去离子水溶解,姜黄素用N,N-二甲基甲酰胺溶解并一起加入到反应皿中,加入六氯三聚磷腈十秒反应体系失去流动性开始凝胶化,6h后将完全凝胶化的凝胶取出并浸泡在去离子水中去除未反应完的单体与溶剂,冷冻干燥即得所述水凝胶载体,将水凝胶载体保存于室温下。
6.根据权利要求1所述的一种环境敏感型聚合物/金杂化敷料的制备方法,其特征在于:所述杂化膜可用于处于伤口抗菌消炎。
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