CN114939172B - 一种植物多酚修饰的抗生素纳米颗粒的制备方法及其产品和应用 - Google Patents
一种植物多酚修饰的抗生素纳米颗粒的制备方法及其产品和应用 Download PDFInfo
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- CN114939172B CN114939172B CN202210566979.3A CN202210566979A CN114939172B CN 114939172 B CN114939172 B CN 114939172B CN 202210566979 A CN202210566979 A CN 202210566979A CN 114939172 B CN114939172 B CN 114939172B
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- plant polyphenol
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Abstract
本发明公开了一种植物多酚修饰的抗生素纳米颗粒的制备方法及其产品和应用,涉及生物医药材料领域。该制备方法以苯硼酸类化合物为中间桥梁,将植物多酚通过动态共价键的方式修饰在含氨基的抗生素上,制备形成纳米颗粒。本发明采用苯硼酸类化合物为桥梁,将植物多酚与含氨基的抗生素通过动态共价键连接形成具有抗菌、抗炎协同功能的纳米颗粒,同时该纳米颗粒可以有效降低抗生素的毒性,并增强其抑制生物膜形成的能力。
Description
技术领域
本发明涉及生物医药材料领域,特别是涉及一种植物多酚修饰的抗生素纳米颗粒的制备方法及其产品和应用。
背景技术
常用的含氨基的抗生素包括多肽类抗生素和氨基糖苷类抗生素,在临床使用中存在一定的限制。以多粘菌素为例,多粘菌素是一种抗多种耐药病原体的多肽抗生素,在临床上使用主要以静脉注射为主,主要对革兰氏阴性病原菌如大肠杆菌、克雷伯氏菌、肠杆菌、铜绿假单胞菌和不动杆菌有抑制作用。多粘菌素携带强烈的正电荷,因此它们与带负电荷的细菌细胞膜结合,从而破坏细胞膜,导致细菌细胞内容物的泄漏。多粘菌素的正电性也导致了其容易与正常的组织细胞相互作用,在血液中的稳定性较低,需要高剂量的药物来达到治疗阈值。这种做法导致了药物副作用的出现,如神经毒性、肝毒性和肾毒性等,从而限制了其在临床上的应用。降低多粘菌素自身的毒性有望提高其临床治疗效果。此外,抗生素很难渗透进入细菌生物膜,且容易被细菌生物膜内部的酯酶降解,对细菌生物膜的治疗效果较差。细菌生物膜引发的感染占实际细菌感染病例的80%,因此如何提高多肽类和氨基糖苷类的抗生素对细菌生物膜的治疗效果有重大的意义。
炎症的消除是治疗细菌感染应考虑的一个重要因素,炎症的消除可以调控机体免疫微环境,实现抗菌和抗炎的协同对细菌感染的治疗至关重要。植物多酚是一类广泛存在于植物体内的多元酚结构的化合物,具有较强的抗氧化性和清除自由基的能力。可以用来清除炎症部位的自由基,具有抗炎的功效。现有的治疗方式主要采用联合用药的方式,但不同药物具有不同的药代动力学,难以实现在细菌感染部位的共同富集和协同。
发明内容
本发明的目的是提供一种植物多酚修饰的抗生素纳米颗粒的制备方法及其产品和应用,以解决上述现有技术存在的问题,本发明采用苯硼酸类化合物为桥梁,将植物多酚与含氨基的抗生素通过动态共价键连接形成具有抗菌、抗炎协同功能的纳米颗粒,同时该纳米颗粒可以有效降低抗生素的毒性,并增强其抑制生物膜形成的能力。
为实现上述目的,本发明提供了如下方案:
本发明提供一种植物多酚修饰的抗生素纳米颗粒的制备方法,以苯硼酸类化合物为中间桥梁,将植物多酚通过动态共价键的方式修饰在含氨基的抗生素上,制备形成纳米颗粒。
进一步地,所述含氨基的抗生素为多肽类抗生素或氨基糖苷类抗生素。
进一步地,所述苯硼酸类化合物为4-甲酰基苯硼酸、3-甲酰基苯硼酸、2-甲酰基苯硼酸、4-乙酰基苯硼酸、3-乙酰基苯硼酸或2-乙酰基苯硼酸。
进一步地,所述植物多酚为槲皮素、表没食子儿茶素没食子酸酯、鞣花酸或单宁酸。
进一步地,所述制备方法具体包括:
(1)将所述苯硼酸类化合物、植物多酚和含氨基的抗生素,分别用溶剂溶解,得到苯硼酸类化合物溶液、植物多酚溶液和含氨基的抗生素溶液;
(2)在缓冲溶液中加入所述苯硼酸类化合物溶液,然后滴加加入所述含氨基的抗生素溶液,之后滴加加入所述植物多酚溶液,反应得到所述植物多酚修饰的抗生素纳米颗粒。
进一步地,所述缓冲溶液为pH为8.5的Na2CO3/NaHCO3缓冲溶液。
进一步地,步骤(2)的反应体系中还加入了聚乙烯吡咯烷酮。
进一步地,在步骤(2)中,所述反应的条件为:25℃,0.5-1h。
本发明还提供一种根据上述的制备方法制备得到的植物多酚修饰的抗生素纳米颗粒。
本发明还提供上述的植物多酚修饰的抗生素纳米颗粒在制备所述抗生素的药物制剂中的应用。
本发明公开了以下技术效果:
本发明的目的是构筑具有杀灭耐药菌性能、抑制生物膜生长的低毒纳米颗粒的制备平台,制备方法原料易得,制备过程简单快速,制备形成的纳米颗粒均一稳定。在本发明中,以苯硼酸类化合物为中间桥梁,将植物多酚通过动态共价键的方式修饰在含氨基的抗生素上制备形成纳米颗粒,然后利用形成的纳米颗粒对耐药菌进行各种性能的探索。结果显示,多酚修饰含氨基的抗生素可以形成纳米颗粒,具有有效抑制生物膜形成,和降解形成的生物膜的能力,同时可以有效降低多粘菌素的溶血性能。该方法可以减小抗生素自身的毒性并可有效抑制细菌生物膜的形成,还可实现抗菌及抗炎功能的协同,具有较高的临床转化前景。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为实施例1制备的纳米颗粒的粒径(a)、聚合物分散性指数(PDI)(b)和表面电势(c)测试结果;
图2为实施例1中A1B1C1实验组制备得到的纳米颗粒的扫描电镜(SEM)照片;
图3为实施例1中A1、B1、C1和A1B1C1的核磁谱图(NMR)和傅里叶红外吸收(FT-IR)曲线,其中a为核磁谱图,b为傅里叶红外吸收曲线;
图4为涂布法表征不同浓度的多粘菌素或多粘菌素纳米粒子对生物膜形成的抑制效果(a)和解离生物膜的效果(b);
图5为溶血实验表征不同浓度的多粘菌素或多粘菌素纳米粒子溶血性能的测试结果。
具体实施方式
现详细说明本发明的多种示例性实施方式,该详细说明不应认为是对本发明的限制,而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
应理解本发明中所述的术语仅仅是为描述特别的实施方式,并非用于限制本发明。另外,对于本发明中的数值范围,应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值,以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明,否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料,但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入,用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时,以本说明书的内容为准。
在不背离本发明的范围或精神的情况下,可对本发明说明书的具体实施方式做多种改进和变化,这对本领域技术人员而言是显而易见的。由本发明的说明书得到的其他实施方式对技术人员而言是显而易见得的。本发明说明书和实施例仅是示例性的。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等,均为开放性的用语,即意指包含但不限于。
实施例1
一、多酚修饰含氨基的抗生素制备纳米颗粒的方法,具体步骤如下:
(1)将含氨基的抗生素:多粘菌素B(Poly B,在本发明中用A1指代),庆大霉素(Gen,在本发明中用A2指代),阿米卡(Ami,在本发明中用A3指代),妥布霉素(Tob,在本发明中用A4指代),阿泊拉霉素(Apra,在本发明中用A5指代),分别溶于超纯水中配制成质量浓度为10mg/mL的抗生素溶液;
(2)将不同的苯硼酸类化合物:4-甲酰基苯硼酸(4-FPBA,在本发明中用B1指代),3-甲酰基苯硼酸(3-FPBA,在本发明中用B2指代),2-甲酰基苯硼酸(2-FPBA,在本发明中用B3指代),4-乙酰基苯硼酸(4-APBA,在本发明中用B4指代),3-乙酰基苯硼酸(3-APBA,在本发明中用B5指代),2-乙酰基苯硼酸(2-APBA,在本发明中用B6指代),分别溶于二甲基亚砜(DMSO)中,配制成质量浓度为10mg/mL的苯硼酸类化合物溶液;
(3)将不同的多酚:槲皮素(Que,在本发明中用C1指代)溶于二甲基亚砜(DMSO),表没食子儿茶素没食子酸酯(EGCG,在本发明中用C2指代)和鞣花酸(EA,在本发明中用C3指代)分别溶于2-乙烯基吡咯烷酮(NMP),单宁酸(TA,在本发明中用C4指代)溶解在超纯水中,均配制为质量浓度为10mg/mL的多酚溶液;
(4)根据表1所示的制备溶液组合,对各实验组分别进行以下操作:称取6mg的聚乙烯吡咯烷酮(PVP),加入2.21mLpH为8.5的Na2CO3/NaHCO3缓冲溶液将其溶解,取162μL步骤(2)配制的苯硼酸类化合物溶液,在搅拌条件下加入其中,然后向其中逐滴滴加300μL步骤(1)配制的抗生素溶液,最后取327μL步骤(3)配制的多酚溶液,以1滴/10s的速度加入其中,室温(25℃)搅拌1h(0.5-1h可达相同效果),配制为总体积3mL,抗生素浓度为1mg/mL的纳米组装体系。
表1
实施例2性能测试
(1)将上述制备的纳米体系分别用超纯水稀释10倍,过膜处理后进行粒径测试,结果见图1。
图1中显示出均一的粒径分布,不同的多酚、苯硼酸类化合物和抗生素的组合均可以形成直径在100-200纳米左右的纳米颗粒,其粒径均匀分布;具有较低的多分散性,PDI在0.1-0.6之间电势均为负电荷;并且表面电势均为负电势。
(2)将实验组A1B1C1制备的多粘菌素纳米粒子滴加到硅片上,静置24h晾干。进行SEM测试,即可得到图2所示的TEM照片,图2中显示出规则的纳米颗粒结构。
(3)对冷冻干燥后的A1B1C1和原料A1、B1、C1分别进行固体核磁的表征,得到图3a的固体核磁谱图,显示出在形成纳米颗粒A1B1C1后,原料B1中的醛基上的氢的峰消失,原料C1中的活泼氢的峰消失,同时在A1B1C1中出现了亚胺键的峰;同时对A1B1C1、A1、B1和C1分别进行傅里叶红外吸收测试,得到图3b的红外吸收曲线,显示在形成纳米颗粒A1B1C1后,原料B1,C1中的羟基O-H的震动峰消失,同时C=O的伸缩震动峰变为C=N的伸缩震动峰,在A1B1C1中出现了B-N的伸缩震动峰。固体核磁及红外吸收谱图表明纳米颗粒A1B1C1中动态共价键亚胺-硼酯键的形成。
(4)抑制生物膜及解离形成的生物膜的测试
①抑制生物膜解离的实验步骤如下:
将表2所示的实验材料A、B和C分别配制成128μg/mL、64μg/mL和32μg/mL(配置方法如表2所示)的磷酸盐缓冲溶液(PBS),并分别进行以下操作:取100μL上述水溶液加入96孔板,静置15min后取出;取100μL浓度为2×108CFU/mL的E.coli菌液置于上述孔板中,于37℃恒温培养箱中静置培养1h。培养结束后将菌液吸出来,用无菌PBS冲洗1次,重新加入100μL上述水溶液培养12h;将生物膜吹打碎,采用菌落计数法统计细菌菌落生长情况,结果如图4a所示。
表2
②解离形成的生物膜的实验步骤如下:
首先培养12h的E.coli生物膜,随后将步骤①配制9种水溶液,分别加入到生物膜中,培养8h,采用菌落计数法统计细菌菌落生长情况,结果如图4b所示。
从图4可以看出,与A和B材料相比,C材料可以更高效地抑制生物膜的形成,同时对已经形成的生物膜具有较好的解离效果。
(5)溶血性能的测试
①将取自小鼠的2mL血加入10mLPBS中,4000rpm离心15min,分离红细胞;取10mLPBS溶液冲洗红细胞,洗涤4-5次左右,将洗后的红细胞稀释至40mLPBS中;
②将表2所示的三种材料,分别配制质量浓度为1000、500、250、125、62.5、31.25μg/mL(如表3所示)的PBS水溶液;
表3
③将步骤①稀释后的红细胞悬液0.5mL加入到0.5mL步骤②配制的各浓度的水溶液中,每组三个平行样;
④每组样品在37℃培养箱中静置1h;
⑤每组样品4000rpm离心5min,取上清液100μL于96孔板中,测545nm处的吸光度,结果见图4(并测单独材料即形成纳米颗粒后的A1B1C1,在545nm处的吸光度,处理数据时将材料自身吸光度扣除计算)。
从图5可以看出,与A和B材料相比,C材料的溶血率均在2%以下,几乎没有出现溶血现象。
以上所述的实施例仅是对本发明的优选方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案做出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (4)
1.一种植物多酚修饰的抗生素纳米颗粒的制备方法,其特征在于,以苯硼酸类化合物为中间桥梁,将植物多酚通过动态共价键的方式修饰在含氨基的抗生素上,制备形成纳米颗粒;
所述含氨基的抗生素为多粘菌素B;
所述植物多酚为槲皮素;
所述制备方法具体包括:
(1)将所述苯硼酸类化合物、植物多酚和含氨基的抗生素,分别用溶剂溶解,得到苯硼酸类化合物溶液、植物多酚溶液和含氨基的抗生素溶液;
(2)在缓冲溶液中加入所述苯硼酸类化合物溶液,然后滴加加入所述含氨基的抗生素溶液,之后滴加加入所述植物多酚溶液,反应得到所述植物多酚修饰的抗生素纳米颗粒;
所述缓冲溶液为pH为8.5的Na2CO3/NaHCO3缓冲溶液;
步骤(2)的反应体系中还加入了聚乙烯吡咯烷酮;
在步骤(2)中,所述反应的条件为:25 ℃,0.5-1h。
2.根据权利要求1所述的制备方法,其特征在于,所述苯硼酸类化合物为4-甲酰基苯硼酸、3-甲酰基苯硼酸、2-甲酰基苯硼酸、4-乙酰基苯硼酸、3-乙酰基苯硼酸或2-乙酰基苯硼酸。
3.一种根据权利要求1或2所述的制备方法制备得到的植物多酚修饰的抗生素纳米颗粒。
4.一种如权利要求3所述的植物多酚修饰的抗生素纳米颗粒在制备所述抗生素的药物制剂中的应用。
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