CN113750234B - 一种基于槐糖脂的两亲性光敏剂及其制备方法和应用 - Google Patents
一种基于槐糖脂的两亲性光敏剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种基于槐糖脂的两亲性光敏剂及其制备方法和应用。所述光敏剂是由槐糖脂和含有氨基的光敏剂通过反应形成化学键连接得到的。该两亲性光敏剂合成条件温和,操作简单,利用槐糖脂的可以跨膜的特点,提高光敏剂在病原微生物细胞上的积累,一方面可以提高荧光诊断的检测限,另一方面,在光动力作用下显著提高光动力灭菌性能,是一种新型的荧光检测试剂和高效光动力光敏剂。
Description
技术领域
本发明属于临床医学细菌感染检测与治疗领域,具体地说,涉及一种新型生物安全高效的基于槐糖脂的两亲性光敏剂及其制备方法和应用。
背景技术
自1928年,青霉素被发现后,手术过程中的感染问题得到很好地解决,随后越来越多的抗生素被发现,包括氨基糖苷类、四环素类、氯霉素类、大环内酯类、糖肽类、恶唑烷酮类、安莎霉素类和喹诺酮类,为人们控制细菌感染提供了很好的解决方案。但是随着人们大量使用抗生素,过度依赖抗生素,细菌不断出现耐药性,最终导致超级细菌的出现。有报道称,一些病原体(尤其是铜绿假单胞菌、金黄色葡萄球菌、肺炎克雷伯菌和粪肠球菌)对多种抗生素的耐药性越来越强,因此对于这些病原体的灭活工作也越来越难。抗生素的滥用使得病人在感染了超级细菌后,病情加重、恶化,甚至危及生命而无法得到有效治疗。这些问题给微生物的灭活工作带来了更多的挑战。
目前,细菌耐药性已经上升为公共卫生问题中最重要的问题之一。抗生素耐药细菌引起的感染的发病率也在不断上升,特别是在发展中国家。根据哈佛大学医学院的预测,到2050年每年可能有1000万人死于抗生素耐药性。如今的医疗技术,对于治疗选择的范围有限,抗生素耐药细菌导致的临床感染通常特别难以治疗。另外对于临床上细菌感染的快速及时检测,是制定有效治疗方案的前提条件,但是细菌样本培养以及检测其中的DNA和RNA以确定细菌种类的金标准虽然结果准确,但是耗时长,工作量大。荧光诊断是一种新型的快速检测手段,但是传统的光敏剂在细菌表面积累量过低,达不到检测限。因此,当前迫切地需要寻找能够快速检测以及杀灭多药耐药菌株的抗菌方法。抗菌光动力疗法(antibacterial photodynamic therapy,APDT)作为一种替代传统的抗菌治疗方法,以其无创性、作用时间短和同时荧光成像特性而受到越来越多的关注。APDT不仅在抗菌治疗中效果显著,也可以应用于其他杀菌领域,对于空气消毒、医疗器械(软管缝隙及其他难以清理的角落)消毒的安全性也比化学法消毒要高。APDT对空气无污染,残留光敏剂也可以被光解。但是由于光敏剂本身的物理化学性质,导致了光敏剂在细菌细胞表面积累过少,达不到治疗的有效浓度。因此,研究开发能靶向、高效积累的光敏剂,以及利用其荧光显色和光动力治疗作用,开发APDT对抗耐药细菌方面具有巨大的潜力,有望在未来减少对抗生素的过度依赖。
发明内容
针对现有技术的上述问题,本发明提出了利用槐糖脂(Sophorolipid),尤其是微生物生产的胞外生物表面活性剂槐糖脂可以跨越细胞膜和微生物细胞外复杂生物组分的扩散阻力的本质,将其与光敏剂通过化学键结合的方式,获得一类新型两亲性光敏剂,其与游离光敏剂相比,该两亲性光敏剂可以显著提高其在细菌细胞上的积累浓度和光动力灭菌性能。
为实现上述目的,本发明采用如下的技术方案:
一种基于槐糖脂的两亲性光敏剂,其是由槐糖脂和含有氨基的光敏剂通过反应形成化学键连接得到的。
优选的,所述光敏剂为卟啉类光敏剂、酞菁类光敏剂、二氢卟吩类光敏剂、竹红菌素类光敏剂或吩噻嗪类光敏剂中的一种或多种。
优选的,所述的槐糖脂是从酵母菌株发酵提纯得到的。最优选的,所述酵母为球似假丝酵母。
优选的,所述的卟啉类光光敏剂为血卟啉衍生物或5-氨基酮戊二酸(5-ALA);所述的二氢卟吩类光敏剂为氨基二氢卟吩;所述的酞菁类光敏剂为四氨基酞菁铜或四氨基酞菁锌;所述的竹红菌素类光敏剂为氨基竹红菌素;所述的吩噻嗪类光敏剂为甲苯胺蓝。
本发明第二个目的在于提供上述基于槐糖脂的两亲性光敏剂的制备方法,包括如下步骤:
(1)向槐糖脂的水溶液中先后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl)和N-羟基琥珀酰亚胺(NHS)并调节pH以活化羧基;
(2)在20~40℃条件下,向活化后的槐糖脂的水溶液中加入光敏剂反应即得。
优选的,所述制备方法还包括:
(3)将步骤(2)得到的反应混合物采用有机溶剂萃取后去除有机溶剂的步骤。
优选的,步骤(3)中所述有机溶剂为三氯甲烷和甲醇的混合液。更优选的,三氯甲烷和甲醇的体积比为1:1~20:1。
优选的,步骤(3)所述的去除有机溶剂的方法为旋转蒸发法或真空干燥法。
优选的,步骤(1)中所述的活化在0~5℃下进行。
优选的,步骤(1)调节pH为5~6。
优选的,步骤(2)所述反应的时间为10~24h。
本发明还提供所述基于槐糖脂的两亲性光敏剂的应用。
所述应用为在制备临床医学中的细菌感染荧光检测剂中的应用或在制备光动力灭菌治疗药物中的应用。
本发明所述的基于槐糖脂的两亲性光敏剂的积累浓度与游离光敏剂相比提高4~8倍。
本发明所述的基于槐糖脂的两亲性光敏剂对铜绿假单胞菌和金黄色葡萄球菌的CFU减少量(log10)为4~10。
本发明技术方案有有益效果在于:
1.本发明所制备的两亲性光敏剂为槐糖脂化学结合的光敏剂,通过槐糖脂的羧基官能团和光敏剂以化学键结合,提高了光敏剂在靶向细菌细胞表面的积累浓度。
2.本发明所制备的两亲性光敏剂为槐糖脂化学结合的光敏剂,成功结合了槐糖脂的光敏剂增强了两亲性,提高了光敏剂的渗透性,而且将光敏剂穿过磷脂双分子层带入细菌体内,提高光敏剂的灭菌效率。
因此,本发明所制备的基于槐糖脂的两亲性光敏剂,其两亲特性使得该光敏剂可以提高与细菌表面复杂生物物质相互作用,不仅可以提高其在细菌细胞表面的积累浓度,而且可以穿透细菌细胞膜磷脂双分子层,在光照下产生的光动力效应了其对细菌的抑制率,可应用于临床快速检测细菌感染以及高效光动力治疗细菌感染病症中。
附图说明
图1是实施例1所制备的槐糖脂-甲苯胺蓝(SL-TB)的1H NMR图。
图2是实施例1所制备的槐糖脂-甲苯胺蓝(SL-TB)和游离甲苯胺蓝(TB)的FT-IR图。
图3是实施例1所制备的槐糖脂-甲苯胺蓝(SL-TB)与游离甲苯胺蓝对铜绿假单胞菌和金黄色葡萄球菌荧光显色结果。
图4实施例1所制备的槐糖脂-甲苯胺蓝(SL-TB)与游离甲苯胺蓝对铜绿假单胞菌和金黄色葡萄球菌的光动力灭菌平板。
图5是实施例1游离甲苯胺蓝与槐糖脂-甲苯胺蓝(SL-TB)两亲光敏剂灭菌柱状图。
图6是实施例2所制备的槐糖脂-四氨基酞菁锌两亲光敏剂与游离的四氨基酞菁锌光敏剂细胞摄取定量结果。
图7是实施例2所制备的槐糖脂-四氨基酞菁锌两亲光敏剂与游离的四氨基酞菁锌光敏剂的灭菌柱状图。
图8是实施例3游离四氨基酞菁铜与槐糖脂-四氨基酞菁铜两亲光敏剂灭菌柱状图。
图9是实施例4游离氨基竹红菌素与槐糖脂-氨基竹红菌素两亲光敏剂灭菌柱状图。
图10是实施例5游离氨基二氢卟吩与槐糖脂-氨基二氢卟吩两亲性光敏剂灭菌柱状图。
图11是实施例6游离5-氨基酮戊酸(5-ALA)与槐糖脂-5-氨基酮戊酸(5-ALA)两亲性光敏剂灭菌柱状图。
图12是对比例1游离甲苯胺蓝与油酸-甲苯胺蓝两亲性光敏剂灭菌柱状图。
图13是对比例2中甲苯胺蓝、槐糖脂、甲苯胺蓝与槐糖脂物理混合的光反应与暗反应灭菌柱状图。
具体实施方式
测试方法:
(1)细菌培养方法:
使用铜绿假单胞菌和金黄色葡萄球菌作为研究菌体,培养方法如下。将菌体从-80℃里取出,接种1ml到液体培养基中活化,有氧条件下放入振荡培养箱培养12h,振荡培养箱温度设置为37℃,转速为200rpm。活化两次,用接种环在固体培养基上划线,放入恒温培养箱,37℃培养24h,收取单菌落,放入4℃冰箱保存。灭菌实验时,用接种环将单菌落接种到液体培养基中,放入振荡培养箱,条件同上,培养12h。铜绿假单胞菌生长12h后,每毫升菌液的菌落形成单位(CFU)≈1011,金黄色葡萄球菌生长12小时,每毫升菌液的CFU≈1013。
(2)光敏剂细胞摄取实验方法:
在所有的实验中,细菌浓度固定在每毫升菌液CFU≈1011。分别将菌悬液与光敏剂或两亲光敏剂等体积混合,混合后的体积为10ml,光敏剂与菌液混合后浓度保持在200μmol/L。室温暗箱孵育30min,然后使用离心机8000rpm离心10min收集菌体,获得的细菌用PBS多次洗涤,使上清颜色洗脱,最终制备10ml菌悬液。每个样用超声波细胞粉碎机(工作2s,间隔3s,功率为300W)超声10分钟,将裂解的细菌溶液再次离心,得到上清液。用荧光光谱仪测定不同菌株样品的荧光强度。测定光敏剂及两亲光敏剂荧光光谱的标准曲线,根据标准曲线计算各种样品的浓度。
(3)细菌荧光显色实验方法:
将铜绿假单胞菌和金黄色葡萄球菌接种到培养基黑暗孵育12h和10h备用,使得细菌浓度固定在每毫升菌液CFU≈1011,分别将菌悬液与光敏剂或两亲光敏剂等体积混合,混合后的体积为10ml,光敏剂与菌液混合后浓度保持在200μmol/L。室温暗箱孵育30min,然后使用离心机8000rpm离心10min收集菌体,获得的细菌用PBS多次洗涤,使上清颜色洗脱,最终制备10ml菌悬液。取少量滴加到载玻片上,使用荧光显微镜调至红色光板,观察并拍摄菌落的荧光强度。(4)灭菌平板计数实验方法:
配制不同浓度的光敏剂溶液,在超净台里用0.22μm的滤菌膜过滤上述溶液。分别取100μl光敏剂溶液与100μl不同梯度的菌液于灭过菌的离心管中,标记。将离心管放入金属浴中混合,金属浴设置温度25℃,100rpm,避光混合30min。将光敏剂与菌液充分混匀后,放入660nm(30mW/cm2)光源下光照30min,各取100μl涂平板,标记,放入恒温培养箱培养24h,记录平板剩余菌落数,比较各个浓度的灭菌效果。每个实验均进行三次。
实施例1槐糖脂-甲苯胺蓝两亲光敏剂的制备
称取0.5g槐糖脂(SL)溶于100mL水中,充分搅拌后加入EDC·HCl和NHS,后用酸碱溶液调节溶液的pH值为6。然后在0℃的恒温水浴锅中搅拌30min,活化羧基后调节温度为20℃,慢慢加入0.5g甲苯胺蓝(TB)使甲苯胺蓝充分溶解,反应时间为10h。使用三氯甲烷与甲醇体积比为10:1的混和溶液萃取SL-TB光敏剂。使用旋转蒸发仪除去三氯甲烷和甲醇,旋蒸仪温度设置为40℃,转速30rpm。将少量未完全除去的三氯甲烷和甲醇放入真空干燥箱烘干,温度设置为50℃,所得固体为槐糖脂-甲苯胺蓝两亲光敏剂。其化学结构分析如图1和2所示。
细菌对不同光敏剂摄取差别用细菌的荧光显色方法进行测定。将菌悬液分别与光敏剂及制备得到的SL-TB光敏剂等体积混合,光敏剂与菌液混合后浓度保持在200μmol/L。室温暗箱孵育30min,然后使用离心机离心收集菌体,获得的细菌用PBS多次洗涤,使上清颜色洗脱,最终制备10ml菌悬液。用荧光显微镜对菌体进行观察并成像,结果如图3所示。
灭菌效果测试采用平板计数法进行。游离的光敏剂和制备得到的SL-TB光敏剂灭菌与菌液充分混匀后,放入660nm(30mW/cm2)光源下光照30min,各取100μl涂平板,标记,放入恒温培养箱培养24h,记录平板剩余菌落数。平板菌落结果照片如图4所示。灭菌结果柱状图如图5所示。
实施例2槐糖脂-四氨基酞菁锌两亲光敏剂的制备
称取1g槐糖脂溶于100mL水中,充分搅拌后加入EDC·HCl和NHS,后用酸碱溶液调节溶液的pH值为5。然后在5℃的恒温水浴锅中搅拌120min,活化羧基后调节温度为30℃。慢慢加入0.5g四氨基酞菁锌使之充分溶解,反应时间为12h。使用三氯甲烷与甲醇体积比为5:1的混和溶液萃取两亲性光敏剂。使用旋转蒸发仪除去三氯甲烷和甲醇,旋蒸仪温度设置为40℃,转速30rpm。将少量未完全除去的三氯甲烷和甲醇放入真空干燥箱烘干,温度设置为50℃,所得产物即为槐糖脂-四氨基酞菁锌两亲性光敏剂。光敏剂细胞摄取实验按上述实验方法进行,用荧光光谱仪进行定量测定,结果如附图6所示。灭菌效果测试采用平板计数法进行。游离的光敏剂和制备得到的槐糖脂-四氨基酞菁锌光敏剂与菌液充分混匀后,放入660nm(30mW/cm2)光源下光照30min,各取100μl涂平板,标记,放入恒温培养箱培养24h,记录平板剩余菌落数。灭菌结果如附图7所示。
实施例3槐糖脂-四氨基酞菁铜两亲光敏剂的制备
称取1g槐糖脂溶于100mL水中,充分搅拌后加入EDC·HCl和NHS,后用酸碱溶液调节溶液的pH值为5。然后在0℃的恒温水浴锅中搅拌30min,活化羧基后调节温度为40℃。慢慢加入1.0g四氨基酞菁铜使之充分溶解,反应时间为24h。使用三氯甲烷与甲醇体积比为1:1的混和溶液萃取两亲性光敏剂。使用旋转蒸发仪除去三氯甲烷和甲醇,旋蒸仪温度设置为40℃,转速30rpm。将少量未完全除去的三氯甲烷和甲醇放入真空干燥箱烘干,温度设置为50℃,所得产物即为槐糖脂-四氨基酞菁铜两亲性光敏剂。灭菌效果测试采用平板计数法进行,灭菌结果如附图8所示。
实施例4槐糖脂-氨基竹红菌素两亲光敏剂的制备
称取1g槐糖脂溶于100mL水中,充分搅拌后加入EDC·HCl和NHS,后用酸碱溶液调节溶液的pH值为5。然后在0℃的恒温水浴锅中搅拌60min,活化羧基后调节温度为30℃。慢慢加入0.5g氨基竹红菌素,使之充分溶解,反应时间为24h。使用三氯甲烷与甲醇体积比为10:1的混和溶液萃取两亲性槐糖脂-氨基竹红菌素光敏剂。使用旋转蒸发仪除去三氯甲烷和甲醇,旋蒸仪温度设置为40℃,转速30rpm。将少量未完全除去的三氯甲烷和甲醇放入真空干燥箱烘干,温度设置为50℃,得到槐糖脂-氨基竹红菌素两亲光敏剂。灭菌效果测试采用平板计数法进行,灭菌结果如附图9所示。
实施例5槐糖脂-氨基二氢卟吩两亲性光敏剂的制备
称取0.5g槐糖脂溶于100mL水中,充分搅拌后加入EDC·HCl和NHS,后用酸碱溶液调节溶液的pH值为5。然后在0℃的恒温水浴锅中搅拌30min,活化羧基后调节温度为30℃。慢慢加入3g氨基二氢卟吩使之充分溶解,反应时间为24h。使用三氯甲烷与甲醇体积比为5:1的混和溶液萃取产物。使用旋转蒸发仪除去三氯甲烷和甲醇,旋蒸仪温度设置为40℃,转速30rpm。将少量未完全除去的三氯甲烷和甲醇放入真空干燥箱烘干,温度设置为50℃,所得产物即为槐糖脂-氨基二氢卟吩两亲光敏剂。灭菌效果测试采用平板计数法进行,灭菌结果如附图10所示。
实施例6槐糖脂-5-氨基酮戊酸(5-ALA)两亲性光敏剂的制备
称取1g槐糖脂溶于100mL水中,充分搅拌后加入EDC·HCl和NHS,后用酸碱溶液调节溶液的pH值为5。然后在0℃的恒温水浴锅中搅拌30min,活化羧基后调节温度为30℃。慢慢加入1g 5-氨基酮戊酸使之充分溶解,反应时间为24h。使用三氯甲烷与甲醇体积比为20:1的混和溶液萃取产物。使用旋转蒸发仪除去三氯甲烷和甲醇,旋蒸仪温度设置为40℃,转速30rpm。将少量未完全除去的三氯甲烷和甲醇放入真空干燥箱烘干,温度设置为50℃,所得产物即为槐糖脂-5-氨基酮戊酸(5-ALA)两亲性光敏剂。灭菌效果测试采用平板计数法进行,灭菌结果如附图11所示。
对比例1:油酸-甲苯胺蓝两亲性光敏剂的制备及光动力灭菌
称取1g油酸分散于100mL水中,充分搅拌后加入EDC·HCl和NHS,后用酸碱溶液调节溶液的pH值为5。然后在0℃的恒温水浴锅中搅拌30min,活化羧基后调节温度为30℃。慢慢加入1g甲苯胺蓝使之充分溶解,反应时间为24h。使用三氯甲烷与甲醇体积比为20:1的混和溶液萃取产物。使用旋转蒸发仪除去三氯甲烷和甲醇,旋蒸仪温度设置为40℃,转速30rpm。将少量未完全除去的三氯甲烷和甲醇放入真空干燥箱烘干,温度设置为50℃,所得产物即为油酸-甲苯胺蓝两亲性光敏剂。对比其对铜绿假单胞菌和金黄色葡萄球菌的光动力灭菌率,结果如图12所示。
对比例2:甲苯胺蓝、槐糖脂、甲苯胺蓝与槐糖脂物理混合的光反应与暗反应灭菌性能对照
按照上述方法,对甲苯胺蓝、槐糖脂、甲苯胺蓝与槐糖脂物理混合的光反应与暗反应灭菌性能进行测定,结果如图13所示。
Claims (11)
1.一种基于槐糖脂的两亲性光敏剂,其特征在于,所述两亲性光敏剂是由槐糖脂和含有氨基的光敏剂通过槐糖脂的羧基官能团反应形成化学键连接得到的。
2.根据权利要求1所述的两亲性光敏剂,其特征在于,所述的槐糖脂是从酵母菌株发酵提纯得到的。
3.根据权利要求2所述的两亲性光敏剂,其特征在于,所述酵母为球似假丝酵母。
4.根据权利要求1所述的两亲性光敏剂,其特征在于,所述光敏剂为卟啉类光敏剂、酞菁类光敏剂、二氢卟吩类光敏剂、竹红菌素类光敏剂或吩噻嗪类光敏剂中的一种或多种。
5.根据权利要求4所述的两亲性光敏剂,其特征在于,所述的卟啉类光敏剂为血卟啉衍生物或5-氨基酮戊二酸;所述的二氢卟吩类光敏剂为氨基二氢卟吩;所述的酞菁类光敏剂为四氨基酞菁铜或四氨基酞菁锌;所述的竹红菌素类光敏剂为氨基竹红菌素;所述的吩噻嗪类光敏剂为甲苯胺蓝。
6.权利要求1-5任一所述基于槐糖脂的两亲性光敏剂的制备方法,其特征在于,包括如下步骤:
(1)向槐糖脂的水溶液中先后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺并调节pH以活化羧基;
(2)在20~40℃条件下,向活化后的槐糖脂的水溶液中加入光敏剂反应即得。
7.根据权利要求6所述的制备方法,其特征在于,所述制备方法还包括:
(3)将步骤(2)得到的反应混合物采用有机溶剂萃取后去除有机溶剂的步骤。
8.根据权利要求6所述的制备方法,其特征在于,步骤(1)中所述的活化在0~5℃下进行。
9.根据权利要求6所述的制备方法,其特征在于,步骤(1)调节pH为5~6。
10.根据权利要求6所述的制备方法,其特征在于,步骤(2)所述反应的时间为10~24h。
11.权利要求1-5任一所述基于槐糖脂的两亲性光敏剂在制备临床医学中的细菌感染荧光检测剂中的应用或在制备光动力灭菌治疗药物中的应用。
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