CN114470226B - 纳米颗粒包裹的抗生素及其制备方法和应用 - Google Patents
纳米颗粒包裹的抗生素及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种口服纳米颗粒包裹的抗生素及其制备方法和应用,所述纳米颗粒包裹的抗生素包括抗生素和包裹所述抗生素的可降解的生物相容性聚合物,所述生物相容性聚合物包括单糖修饰的聚乙二醇‑聚(乳酸‑羟基乙酸)共聚物(PEG‑PLGA)。本发明可显著改善口服抗生素对肠道菌群的损伤,避免微生物群的破坏,从而防止与肠道微生物失调有关的慢性疾病,具有良好的生物相容性和长期安全性。
Description
技术领域
本发明属于生物医学技术领域,具体涉及到用于包裹抗生素的纳米颗粒材料及其制备方法,所述口服纳米颗粒包裹的抗生素在治疗微生物感染时,具有保护肠道微生物维持肠道微生物稳态的作用。
背景技术
口服抗生素是治疗人体多器官细菌感染最常见有效的药物。然而,在治疗过程中,口服抗生素后没有被肠道吸收的部分会在肠道残留,对人体微生物产生极大的扰动。人体内的共生微生物与许多生理过程相互作用,参与免疫和代谢稳态的调节。因此,肠道中抗生素的暴露可改变这种稳态,促进急性感染和慢性疾病,如病原微生物的入侵和肥胖。此外,过度使用抗生素会促使细菌耐药性的发展,导致控制细菌感染越来越困难。
科学家现在开发了一些策略来保护肠道微生物,使其在抗生素治疗期间免受生态失调的有害后果。比如,2003年Usha stiefei指出口服内酰胺酶可以防止肠道残留的内酰胺类抗生素对肠道微生物的影响,维持肠道处于定植抵抗状态。但是这种做法仅局限于内酰胺类的抗生素。2014年,Jean de Gunzburg研究将活性炭等非特异性吸附剂送到回肠或结肠,用来降低环丙沙星或阿莫西林等口服抗生素的粪便浓度,且不影响血浆药代动力学,但这种方法会增加服药次数。2013年,Wanghua等人提出其他给药途径如静脉注射抗生素会降低肠道抗生素残留带来的肠道菌群抗性水平升高。虽然有利于肠道菌群,但是不方便家庭使用。因此,迫切需要开发更方便的替代方法来解决口服抗生素引起的肠道菌群失衡。
发明内容
本发明的目的在于提供一种纳米颗粒材料包裹的抗生素及其应用,从而增加口服抗生素在治疗细菌感染时小肠前端的吸收,延长抗生素的血液循环,减少抗生素在菌群丰富的肠道中残留,从而保护肠道微生物生态平衡。
为了达到上述目的,一方面,本发明提出了一种纳米颗粒包裹的抗生素,包括抗生素和包裹所述抗生素的可降解的生物相容性聚合物,所述生物相容性聚合物包括单糖修饰的聚乙二醇-聚(乳酸-羟基乙酸)共聚物(PEG-PLGA)。
在一些实施例中,所述单糖修饰的聚乙二醇-聚(乳酸-羟基乙酸)共聚物(PEG-PLGA)选自Glucose-PEG-PLGA、Fructose-PEG-PLGA、Fucose-PEG-PLGA、Galactose-PEG-PLGA、Mannose-PEG-PLGA中的一种或多种。
在一些实施例中,所述抗生素与所述可降解的生物相容性聚合物的重量比为1:0.5-5(例如1:1、1:2、1:3或1:4)。
在一些实施例中,所述纳米颗粒包裹的抗生素中还包括阳离子脂质。
在一些实施例中,所述阳离子脂质选自(2,3-二油酰基-丙基)-三甲铵(DOTAP)、氯化三甲基-2,3-二油烯氧基丙基铵(DOTMA)、(3β-[N-(N’,N’-二甲基胺乙基)胺基甲酰基]胆固醇(DC-Chol)中的一种或多种。
在一些实施例中,所述抗生素与所述阳离子脂质的重量比为1:0.1-1(例如1:0.2、1:0.3、1:0.5或1:0.8)。
在一些实施例中,所述抗生素选自喹诺酮类抗生素、β-内酰胺类抗生素、大环内酯类抗生素、氨基糖苷类抗生素、酰氨醇类抗生素、硝基咪唑类抗生素、四环素类抗生素和糖肽类抗生素中的一种或多种。例如,所述抗生素选自克拉霉素、阿莫西林、甲硝锉、四环素、新霉素、万古霉素等抗菌药物。
另一方面,本发明还提出一种所述纳米颗粒包裹的抗生素的制备方法,包括通过双乳化法、单乳化法、透析法、纳米沉淀法、薄膜水化法或微流体混合法,利用可降解的生物相容性聚合物包裹抗生素,优选地,在制备过程中还加入阳离子脂质。
在一些实施例中,亲水性抗生素采用双乳化法或薄膜水化法进行包裹,疏水性抗生素采用透析法、纳米沉淀法、微流体混合法或单乳化进行包裹。
例如,亲水性抗生素采用双乳化法进行包裹的步骤可包括:
(1)将抗生素的水溶液和可降解的生物相容性聚合物加到挥发性有机溶剂中,超声乳化得到油包水乳状液;
(2)将所述油包水乳状液加入大量的水,再次超声乳化得到水包油包水乳状液;
(3)蒸发除去所述挥发性有机溶剂,水洗去除游离抗生素后获得纳米颗粒包裹的口服抗生素。
其中,所述挥发性有机溶剂选自二氯甲烷、三氯甲烷、乙酸乙酯中的一种或多种,乳化时间为0.5-2分钟。
疏水性抗生素采用透析法进行包裹的步骤可包括:
将抗生素和可降解的生物相容性聚合物溶解在有机溶剂中,加水搅拌得到包载抗生素的纳米颗粒,透析并去除游离的抗生素后获得纳米颗粒包裹的口服抗生素。
疏水性抗生素采用单乳化法进行包裹的步骤可包括:
(1)将抗生素的水溶液和可降解的生物相容性聚合物加到挥发性有机溶剂中,超声乳化得到水包油乳状液;
(2)蒸发除去所述挥发性有机溶剂,水洗去除游离抗生素后获得纳米颗粒包裹的口服抗生素。
其中,所述挥发性有机溶剂选自二氯甲烷、三氯甲烷、乙酸乙酯中的一种或多种,乳化时间为0.5-2分钟。
又一方面,本发明还提出一种所述纳米颗粒包裹的抗生素在制备治疗细菌感染疾病的药物中的用途。例如,细菌感染疾病可以为肺炎链球菌感染或其他微生物感染。
与现有技术相比,本发明提出的纳米颗粒包裹的抗生素的优点在于:
1.本发明所述利用单糖如葡萄糖修饰的阳离子纳米颗粒(PGNPs)包裹抗生素实现了口服抗生素后能够在近端小肠快速吸收,肠道残留少;
2.本发明利用PGNPs包裹抗生素实现了口服抗生素后快速吸收进入血流;
3.本发明所述纳米颗粒包裹的抗生素不改变抗生素的治疗效果,允许使用PGNPs包裹疏水性和亲水性抗生素进行治疗,从而减轻疾病症状;
4.本发明所述纳米颗粒包裹的抗生素可显著改善抗生素对肠道菌群的损伤;
5.本发明所述纳米颗粒包裹的抗生素可避免对微生物群的破坏,从而防止与生态失调有关的慢性疾病;
6.本发明所述纳米颗粒包裹的抗生素具有生物相容性和长期安全性。
附图说明
为了更清楚地说明本申请实施例或者现有技术中的技术方案,下面将对实施例中所需要的附图作简单地介绍。
图1:制备不同的纳米颗粒(PGNPs,PNPs,GNPs,NPs),对不同的纳米颗粒进行尺寸(A图)和电荷(B图)比较。可以看到纳米颗粒的粒径主要集中在80-100纳米左右,有的颗粒带正电荷有的带负电荷;
NPs,纳米颗粒;GNPs,葡萄糖修饰的纳米颗粒;PNPs,阳离子纳米颗粒;PGNPs,葡萄糖修饰的阳离子纳米颗粒;
图2:荧光染料DiD全称为1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindodicarbocyanine,4-Chlorobenzenesulfonate Sal,标记不同的纳米颗粒,给小鼠灌胃后在不同时间点,通过测定荧光强度分析纳米颗粒在肠道的吸收和粪便残留以及血液中的分布。A图为灌胃1小时后,带荧光标记的不同纳米颗粒在肠道不同段吸收。B图为灌胃后,带荧光标记的不同纳米颗粒在肠道粪便中的残留。C图为灌胃后,带荧光标记的纳米颗粒在血液中的荧光强度分析结果。*:P<0.05;**:P<0.01;***:P<0.001;****:P<0.0001;
Free,游离的荧光染料DiD;NPs,纳米颗粒;GNPs,葡萄糖修饰的纳米颗粒;PNPs,阳离子纳米颗粒;PGNPs,葡萄糖修饰的阳离子纳米颗粒。n.s.,没有显著性差异;
图3:筛选得到PGNPs,采用该颗粒包裹抗生素。测定双乳化法,单乳化法,透析法对亲水性和疏水性抗生素的包载率。可以看到双乳化法可以很好的包载亲水性抗生素;
图4:PGNPs包裹的氨苄西林治疗肺炎链球菌引起的肺炎。图A中比较了采用游离氨苄西林(Free-Amp)和PGNPs包裹的氨苄西林(PGNPs-Amp)治疗小鼠肺炎,以及不采用氨苄西林治疗(Water,PGNPs)的小鼠,肺部链球菌的数目。图B是比较各组中小鼠肺部中性粒细胞浸润的比例。*:P<0.05;**:P<0.01;***:P<0.001;****:P<0.0001;
Normal,健康对照;Water,对照组口服水;PGNPs,对照组口服空颗粒;Free Amp,实验组口服游离的氨苄青霉素;PGNPs-Amp,实验组口服葡萄糖修饰的阳离子纳米颗粒包裹氨苄青霉素。N.D,没有检测到。n.s.,没有显著性差异;
图5:比较对照组以及口服游离抗生素(Free-Abx)和PGNPs包裹的抗生素(PGNPs-Abx)对肠道微生物的破坏。图中,A是比较各组中α多样性,B是比较对照组和2种不同的抗生素处理组β多样性。*:P<0.05;**:P<0.01;***:P<0.001;****:P<0.0001;
Water,对照组口服水;PGNPs,对照组口服空颗粒;Free Abx,实验组口服游离的抗生素;PGNPs-Abx,实验组口服葡萄糖修饰的阳离子纳米颗粒包裹的抗生素;
图6:比较对照组以及口服游离抗生素(Free-Abx)和PGNPs包裹的抗生素(PGNPs-Abx),对代谢疾病肥胖的影响。A图是抗生素处理组和对照组小鼠体重图。B图是各组小脂肪重量图。*:P<0.05;**:P<0.01;***:P<0.001;****:P<0.0001;
Water,对照组口服水;PGNPs,对照组口服空颗粒;Free Abx,实验组口服游离的抗生素;PGNPs-Abx,实验组口服葡萄糖修饰的阳离子纳米颗粒包裹的抗生素。n.s.,没有显著性差异;
图7:比较对照组以及口服游离抗生素(Free-Abx)和PGNPs包裹的抗生素(PGNPs-Abx),对小鼠抵抗柠檬酸杆菌(Citrobacter rodentium)感染能力的影响。图中是检测粪便,盲肠和结肠细菌菌落数。*:P<0.05;**:P<0.01;***:P<0.001;****:P<0.0001;
Water,对照组口服水;PGNPs,对照组口服空颗粒;Free Abx,实验组口服游离的抗生素;PGNPs-Abx,实验组口服葡萄糖修饰的阳离子纳米颗粒包裹的抗生素。n.s.,没有显著性差异;
图8:比较对照组以及口服游离抗生素(Free-Abx)和PGNPs包裹的抗生素(PGNPs-Abx),对肠道抗性基因β-内酰胺酶ampC的影响。*:P<0.05;**:P<0.01;***:P<0.001;****:P<0.0001;
Water,对照组口服水;PGNPs,对照组口服空颗粒;Free Abx,实验组口服游离的抗生素;PGNPs-Abx,实验组口服葡萄糖修饰的阳离子纳米颗粒包裹的抗生素。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白,以下结合具体实施例,并参照附图,对本发明作进一步的详细说明。
在本发明的说明书中,提及“一个实施例”时均意指在该实施例中描述的具体特征、结构或者参数、步骤等至少包含在根据本发明的一个实施例中。因而,在本发明的说明书中,若采用了诸如“根据本发明的一个实施例”、“在一个实施例中”等用语并不用于特指在同一个实施例中,若采用了诸如“在另外的实施例中”、“根据本发明的不同实施例”、“根据本发明另外的实施例”等用语,也并不用于特指提及的特征只能包含在特定的不同的实施例中。本领域的技术人员应该理解,在本发明说明书的一个或者多个实施例中公开的各具体特征、结构或者参数、步骤等可以以任何合适的方式组合。
针对上述现有应用方法的不足,本应用提供一种纳米颗粒用于包裹抗生素,口服之后能够在小肠快速吸收进入血液循环,在发挥抗菌作用的同时,解决了口服抗生素肠道残留对菌群的破坏。根据本发明的技术方案,设计合成了荧光染料DiD标记的不同的纳米颗粒,用于筛选在肠道吸收最好的纳米颗粒,用于后续的抗生素包裹。由此制备的纳米颗粒包裹的抗生素可以促进近端小肠吸收。纳米颗粒由在体内可降解、并具有生物相容性的聚合物来制备,所述的生物相容性聚合物包括单糖修饰的聚乙二醇-聚(乳酸-羟基乙酸)共聚物(PEG-PLGA)。
在一个实施例中,采用双乳液-溶剂蒸发法制备了DiD染料标记的不同的纳米颗粒(PGNPs,PNPs,GNPs,NPs)。同时,实验发现,在制备纳米颗粒的过程中掺入一定比例的阳离子脂质,例如(2,3-二油酰基-丙基)-三甲铵(DOTAP),可以使纳米颗粒带有正电荷,而小肠上皮细胞膜带有负电荷,通过正负电荷之间的作用,可以拉近纳米颗粒与小肠上皮细胞之间的距离。加入阳离子脂质的同时,对纳米颗粒进行葡萄糖修饰,能够促进纳米颗粒和小肠前端葡萄糖转运蛋白SGLT1的相互作用,加速纳米颗粒进入血液循环。
在该实施例中,将DiD染料加到0.5mL二氯甲烷中,其中含有0.5mg DOTAP和5mgGlucose-PEG-PLGA(葡萄糖-聚乙二醇-聚(乳酸-羟基乙酸)共聚物)(Avanti PolarLipids)在冰浴上用超声波(Vibra-cellTM,Sonics&Materials,Newtown,CT,USA)在80W下乳化1分钟。然后油包水乳状液在5mL的Mili-Q水中进行超声乳化(80W,乳化1分钟),在冰浴上形成水包油包水乳状液。随后,二氯甲烷被旋转蒸发器除去。所得PGNPs-DiD用超滤管(分子量cutoff=100,000Da,Millipore)超滤三次,去除游离染料。DiD标记的PNPs的制备方法与DiD标记的PGNPs相似,除了用PEG-PLGA代替了聚合物Glucose-PEG-PLGA。DiD标记的GNPs的制备方法与DiD标记的PGNPs相似,除了不在二氯甲烷溶液中添加0.5mg DOTAP。DiD标记的NPs的方法与DiD标记的PGNPs相似,除了不在二氯甲烷溶液中添加0.5mg DOTAP,并用PEG-PLGA代替聚合物Glucose-PEG-PLGA。图1中的A和B分别显示了不同纳米颗粒的尺寸和电荷。
在一个实施例中,对上述不同的纳米颗粒进行筛选,选择在小肠吸收好,肠道残留少的纳米颗粒用于包裹抗生素。通过给小鼠灌胃DiD荧光标记的不同的纳米颗粒,在不同的时间点取小鼠的消化道和粪便,用小动物成像仪测定肠道细胞吸收和粪便中的荧光值,得到不同的纳米颗粒在肠道中的荧光吸收值和粪便残留值。同时采用共聚焦显微镜观察不同纳米颗粒在小鼠血管中的分布。结果如图2所示。可以发现PGNPs-DiD在小肠中的吸收最多,肠道残留最少。并且在血液中的荧光值最高,持续时间比较久。故后续采用PGNPs包裹抗生素研究对疾病的改善以及肠道菌群的影响,菌群破坏后带来的相关疾病的影响。
在一个实施例中,我们采用了双乳化法对亲水性抗生素(比如氨苄西林和万古霉素等)进行包载并测得包载率为50%-60%。采用透析法对疏水性抗生素(比如甲硝唑等)进行包载并测得包载率为25%。采用单乳化法对疏水性抗生素(比如甲硝锉等)进行包载并测得包载率为20%-40%。使用单乳化法、双乳化法、透析等方法可实现多种性质抗生素的纳米颗粒包载。结果如图3所示,双乳化法对亲水性抗生素的包载率最高。
在一个实施例中,利用筛选的PGNPs包裹抗生素。将氨苄西林或万古霉素的水溶液(100mg mL-1)30μL加到0.5mL二氯甲烷中,其中含有0.5mg DOTAP和5mg Glucose-PEG-PLGA在冰浴上用超声波(Vibra-cellTM,Sonics&Materials,Newtown,CT,USA)在80W下乳化1分钟。油包水乳状液在5mL的Mili-Q水中进行超声乳化(80W,乳化1分钟),在冰浴上形成水包油包水乳状液。随后,二氯甲烷被旋转蒸发器除去。然后用超滤管(分子量cutoff=100,000Da,Millipore)超滤三次,去除游离抗生素,获得PGNPs包裹的氨苄西林(PGNPs-Amp)和万古霉素(PGNPs-Van)。
在一个实施例中,验证了PGNPs包裹的氨苄西林口服治疗小鼠肺炎的效果。首先,我们给小鼠滴鼻链球菌诱导小鼠肺炎,在肺炎诱导后2小时和8小时给小鼠服用PGNPs包裹的氨苄西林和游离的氨苄西林,在感染的24小时分析小鼠肺部链球菌的数目以及肺部中性粒细胞浸润的比例,如图4所示,可以看到用PGNPs包裹的氨苄西林和游离的氨苄西林都表现出较好的治疗效果,甚至包裹的氨苄西林治疗效果更好。
在一个实施例中,验证了小鼠口服PGNPs包裹的氨苄西林和万古霉素对肠道菌群的影响。我们给小鼠口服两种形式的抗生素,即PGNPs包裹的抗生素和游离的抗生素,每天一次连续口服5天。对照组不用抗生素处理。在抗生素处理期间和处理后特定的时间点,收集小鼠的粪便存放于-80℃,直到做后面的16S rRNA测序分析。如图5所示,通过测序分析发现,PGNPs包裹的抗生素处理组小鼠和对照组小鼠,肠道菌群的组成都无明显变化,而用游离的抗生素处理组小鼠,肠道菌群的组成发生显著变化,菌群丰度下降。表明,PGNPs包裹的抗生素对小鼠肠道菌群有保护作用。
在一个实施例中,验证了小鼠口服PGNPs包裹的抗生素不会引起小鼠代谢疾病肥胖的发生。我们给5周大的小鼠灌胃PGNPs包裹的氨苄西林和万古霉素以及游离的氨苄西林和万古霉素,对照组不给与抗生素处理。小鼠连续口服5天,每天一次。之后在小鼠9周大时,饲喂高脂食物,在特定的时间点称取小鼠体重,最后分析小鼠脂肪重量。如图6所示,分析发现,口服PGNPs包裹的抗生素组和对照组小鼠,在体重上趋势一致,脂肪重量也一致。而口服游离抗生素组小鼠,体重和脂肪重量相对较高,表明PGNPs包裹的抗生素能够保护肠道菌群不受破坏,从而不会出现由于菌群失调带来的代谢疾病肥胖的发生。
在一个实施例中,验证了小鼠口服PGNPs包裹的抗生素不会增加小鼠对机会致病菌的易感性。我们给6-8周大的小鼠灌胃PGNPs包裹的氨苄西林和万古霉素以及游离的氨苄西林和万古霉素,对照组不给与抗生素处理。小鼠连续口服5天,每天一次。在口服结束的第二天,给小鼠灌胃感染柠檬酸杆菌(Citrobacter rodentium),感染后的第8天分析小鼠粪便,盲肠和结肠柠檬酸杆菌的数目。如图7所示,口服PGNPs包裹的抗生素组和对照组小鼠,柠檬酸杆菌数目上趋势一致。而口服游离抗生素组小鼠,细菌数目相对较高,表明PGNPs包裹的抗生素能够保护肠道菌群,抵抗机会致病菌的感染。
在一个实施例中,验证了小鼠口服PGNPs包裹的氨苄青霉素不会增加肠道菌抗性基因的拷贝数。我们给6-8周大的小鼠灌胃PGNPs包裹的氨苄西林以及游离的氨苄西林,对照组不给与氨苄西林处理。小鼠连续口服5天,每天一次。在抗生素处理期间和处理后特定的时间点,收集小鼠的粪便抽提DNA,测定DNA浓度,稀释成10ng/μl,通过实时荧光定量PCR分析氨苄抗性基因ampC拷贝数。如图8所示,PGNPs包裹的氨青霉素处理组小鼠和对照组小鼠,肠道菌群抗性基因ampC的拷贝数都无明显变化,而用游离的氨苄青霉素处理组小鼠,肠道菌群的ampC的拷贝数急剧增加积累。表明,PGNPs包裹的氨苄青霉素对小鼠肠道菌群有保护作用,不会引起抗性基因的积累。
以下结合具体实施例来进一步说明本发明的应用。
实施例1测定双乳化法,单乳化法和透析法包载不同抗生素的包载率
对于亲水抗生素,比如氨苄西林和万古霉素,使用双乳化法包载,将氨苄西林或万古霉素的水溶液(100mg mL-1)30μL加到0.5mL二氯甲烷中,其中含有0.5mg DOTAP和5mgGlucose-PEG-PLGA。在冰浴上用超声波(Vibra-cellTM,Sonics&Materials,Newtown,CT,USA)在80W下乳化1分钟。油包水乳状液在5mL的Mili-Q水中进行超声乳化(80W,乳化1分钟),在冰浴上形成水包油包水乳状液。随后,二氯甲烷被旋转蒸发器除去。然后用超滤管(分子量cutoff=100,000Da,Millipore)超滤三次,去除游离抗生素。得到包载抗生素的纳米颗粒后,使用离心机15000g高速离心2小时,去除上清,将沉淀重悬,得到纯的纳米颗粒包载的抗生素,使用紫外分光光度计或者HPLC测量纳米颗粒包载抗生素的浓度,被包载抗生素的质量除去总的投入抗生素质量即为包载率,亲水性抗生素的包载率在50%-60%。
对于疏水抗生素,比如甲硝唑等使用透析法,将抗生素融在有机溶剂中(如DMSO)。在一个干净的圆底烧瓶中放入干净的磁子,加入1mL有机溶剂(如DMSO)溶解的Gluc-PEG-PLGA(10mg mL-1)高分子材料和100ul阳离子脂质(10mg mL-1),然后加入100ul抗生素(浓度根据最大溶解度),将圆底烧瓶放在磁力搅拌器上缓慢搅拌混匀,然后加大转速,加入5mLMilliQ水,继续搅拌2min。得到的混合液用超滤管(分子量cutoff=100,000Da,Millipore)超滤三次,去除游离抗生素和其他杂质。截留得到的包载抗生素的纳米颗粒放入1.5m EP管中,放入离心机中3000rpm离心5分钟,取上清,进一步去除游离的抗生素,使用紫外分光光度计或者HPLC测量纳米颗粒包载抗生素的浓度,包载抗生素的质量除去总的投入抗生素质量即为包载率,包载率在20%-25%。
对于疏水抗生素,比如甲硝锉,还可以使用单乳化法包载,将抗生素溶解在挥发性有机溶剂中(如乙酸乙酯),取100μL加到1mL二氯甲烷中,其中含有1mg DOTAP和10mgGlucose-PEG-PLGA。在冰浴上用超声波(Vibra-cellTM,Sonics&Materials,Newtown,CT,USA)在80W下乳化1分钟。随后,二氯甲烷被旋转蒸发器除去。然后用超滤管(分子量cutoff=100,000Da,Millipore)超滤三次,去除游离抗生素和其他杂质。得到包载抗生素的纳米颗粒后,使用离心机3000rpm离心5分钟,取上清,得到纯的纳米颗粒包载的抗生素,使用紫外分光光度计或者HPLC测量纳米颗粒包载抗生素的浓度,被包载抗生素的质量除去总的投入抗生素质量即为包载率,亲水性抗生素的包载率在20%-40%。
实施例2口服PGNPs包裹的抗生素可以有效治疗肺炎链球菌引起的小鼠肺炎
实验方法:
小鼠分成四组,两组对照组不给予氨苄西林治疗,两组治疗组,感染后给与氨苄西林治疗,每组小鼠大于等于3只。通过给小鼠滴鼻3×108CFUs肺炎链球菌,诱导小鼠肺炎的产生。然后,在小鼠感染后的2小时和8小时,口服游离氨苄西林和上述实施例制备的PGNPs包裹的氨苄西林(40mg kg-1)治疗小鼠肺炎。感染24小时后,检测氨苄西林治疗后肺部链球菌的数目。取得小鼠肺组织放入无菌PBS,打碎获得小鼠肺部匀浆,用PBS10倍梯度稀释涂板,计数。检测小鼠肺部中性粒细胞浸润的比例,取得小鼠肺组织,在等体积的PBS中磨碎,离心获得细胞,用流式抗体标记细胞,采用流式细胞仪检测中心粒细胞阳性比例。
实验结果:
采用氨苄西林治疗小鼠肺炎的效果如图4所示,从细菌数目和中性粒细胞的比例上可以看出,氨苄西林治疗组相比于无治疗组的小鼠,肺部链球菌的数目和中性粒细胞的比例明显减少。同时可以看到,纳米颗粒包裹的氨苄西林,能够很好的减少肺部链球菌的数目和中性粒细胞的比例。实验结果说明纳米颗粒包裹的氨苄西林能够发挥氨苄西林的抗菌作用。
实施例3口服PGNPs包裹的抗生素小鼠肠道菌群多样性和组成变化分析
实验方法:
小鼠分成四组,每组小鼠大于等于4只。对照组不给予抗生素处理,实验组给与游离抗生素或者上述实施例制备的PGNPs包裹的抗生素。成年小鼠口服氨苄西林和万古霉素(20mg kg-1)以及PGNPs包裹的氨苄西林和万古霉素,每天一次,连续口服5天。收集小鼠粪便,对粪便样品中总DNA进行抽取,测定浓度以及16S rRNA V4区域进行扩增和测序分析,判断两种不同方式的抗生素处理对肠道菌群多样性和组成的影响。
正向引物(515FB,SEQ ID NO:1-97):
AATGATACGGCGACCACCGAGATCTACACGCTXXXXXXXXXXX XTATGGTAATTGTGTGYCAGCMGCCGCGGTAA
其中XXXXXXXXXXXXXXX代表引物的条形码,用于特异性标记不同的样品;
反向引物(806RB,SEQ ID NO:98):
CAAGCAGAAGACGGCATACGAGATAGTCAGCCAGCCGGACTACNVGGGTWTCTAAT。
扩增所用试剂如下:
试剂 | 体积 |
PCR级用水 | 13.0μL |
PCR酶(2x) | 10.0μL |
正向引物(10μM) | 0.5μL |
反向引物(10μM) | 0.5μL |
模板DNA | 1.0μL |
总体积 | 25.0μL |
扩增条件如下:
温度 | 时间 | 循环数 |
94℃ | 3min | |
94℃ | 45s | X30 |
50℃ | 60s | X30 |
72℃ | 90s | X30 |
72℃ | 10min | |
4℃ | hold |
实验结果:
小鼠肠道菌群α多样性和β多样性变化如图5所示,从图4中可以看出,口服纳米颗粒包裹的氨苄西林和万古霉素(PGNPs-Abx),能够保护肠道菌群多样性,几乎不会影响肠道菌群的结构,有利于肠道菌群的恢复。
实施例4:口服PGNPs包裹的抗生素能够保护由肠道菌群失调带来的临床并发症
肠道菌群对宿主代谢发挥重要的调节作用,尤其是对宿主能量稳态的影响,一些代谢紊乱,如肥胖与肠道菌群失衡密切相关。因此,本实施例利用肥胖模型,机会致病菌感染模型和检测小鼠粪便中内酰胺酶抗性基因ampC的拷贝数去证实纳米颗粒包裹的抗生素对肠道菌群的保护作用。
实验方法:(肥胖模型)
小鼠分成四组,两组对照不给予口服抗生素,两组实验组口服抗生素处理。成年小鼠5周时口服游离的氨苄西林和万古霉素以及上述实施例制备的PGNPs包裹的氨苄西林和万古霉素(20mg kg-1),每天一次,连续口服5天。对照小鼠口服水和不包裹抗生素的PGNPs。小鼠9周大时,饲喂高脂食物,进行体重和脂肪的测定,验证两种种不同的抗生素处理之后,对小鼠肥胖的影响。
实验结果:
小鼠体重和脂肪重量统计图如图6所示,可以看到口服PGNPs包裹的抗生素的小鼠,在饲喂高脂食物后和对照小鼠体重以及脂肪重量趋势一致。而用游离抗生素处理小鼠后,喂食高脂食物,小鼠的体重和脂肪重量会显著增加。实验结果说明,口服游离抗生素会破坏肠道菌群,从而引起代谢疾病肥胖的发生,PGNPs包裹的抗生素则不会破坏小鼠肠道菌群。
实验方法:(机会致病菌模型)
小鼠分成四组,两组对照不给予口服抗生素,两组实验组口服氨苄西林和万古霉素以及上述实施例制备的PGNPs包裹的氨苄西林和万古霉素(20mg kg-1),每天一次,连续口服5天。对照小鼠口服水和不包裹抗生素的PGNPs。在口服结束的第二天,小鼠灌胃感染柠檬酸杆菌(Citrobacter rodentium),在感染后的第8天分析小鼠粪便,盲肠和结肠柠檬酸杆菌细菌菌落数。
实验结果:
小鼠粪便,盲肠和结肠中细菌菌落数统计图如图7所示,可以看到口服PGNPs包裹的抗生素的小鼠,在感染柠檬酸杆菌后和对照小鼠细菌数目趋势一致。而用游离抗生素处理小鼠后,细菌数目会显著增加。实验结果说明,口服游离抗生素会破坏肠道菌群,从而增加对机会致病菌感染的易感性,PGNPs包裹的抗生素则不会破坏小鼠肠道菌群。
实验方法:(抗性基因测定)
小鼠分成四组,每组6只小鼠。对照组不给予抗生素处理,实验组给与游离抗生素或者上述实施例制备的PGNPs包裹的抗生素。实验组小鼠口服氨苄西林(20mg kg-1)以及PGNPs包裹的氨苄西林,每天一次,连续口服5天。在特定的时间点收集小鼠粪便,对粪便样品中总DNA进行抽取,测定浓度,采用实时荧光定量PCR对粪便DNA中氨苄抗性基因ampC和总细菌16S rRNA进行扩增,计算2种基因的拷贝数,判断2种不同方式的抗生素处理对肠道抗性菌丰度的影响。
实验结果:
小鼠肠道抗性基因拷贝数变化如图8所示,可以看出,口服纳米颗粒包裹的氨苄西林(PGNPs-Amp)和对照组趋势一致能够保护肠道菌群,几乎不会影响肠道菌群ampC抗性基因的拷贝数。而用游离抗生素处理小鼠后,破坏了肠道原有的平衡导致抗性基因ampC会急剧增加积累。两种不同的抗生素处理并没有对总的细菌拷贝数产生很大影响。
以上实施例利用葡萄糖修饰的PEG-PLGA研究了纳米颗粒包裹的抗生素的特性,研究表明,利用其它单糖(例如果糖、海藻糖、半乳糖、甘露糖等)修饰的PEG-PLGA具有与葡萄糖修饰的PEG-PLGA相似的性质,同样可以用于制备纳米颗粒包裹的抗生素并取得相似的效果。
以上所述的具体实施例,对本发明的目的、技术方案和有益效果进行了进一步详细说明,应理解的是,以上所述仅为本发明的具体实施例而已,并不用于限制本发明,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (11)
1.一种纳米颗粒包裹的抗生素,包括抗生素和包裹所述抗生素的可降解的生物相容性聚合物,所述生物相容性聚合物包括单糖修饰的聚乙二醇-聚(乳酸-羟基乙酸)共聚物(PEG-PLGA),其中所述单糖修饰的聚乙二醇-聚(乳酸-羟基乙酸)共聚物选自Glucose-PEG-PLGA、Fructose-PEG-PLGA、Fucose-PEG-PLGA、Galactose-PEG-PLGA、Mannose-PEG-PLGA中的一种或多种,所述纳米颗粒包裹的抗生素中还包括阳离子脂质。
2.根据权利要求1所述的纳米颗粒包裹的抗生素,其中,所述抗生素与所述可降解的生物相容性聚合物的重量比为1:0.5-5。
3.根据权利要求2所述的纳米颗粒包裹的抗生素,其中所述抗生素与所述可降解的生物相容性聚合物的重量比为1:1、1:2、1:3或1:4。
4.根据权利要求1所述的纳米颗粒包裹的抗生素,其中,所述阳离子脂质选自(2,3-二油酰基-丙基)-三甲铵、氯化三甲基-2,3-二油烯氧基丙基铵、3β-[N-(N’,N’-二甲基胺乙基)胺基甲酰基]胆固醇中的一种或多种。
5.根据权利要求1所述的纳米颗粒包裹的抗生素,其中,所述抗生素与所述阳离子脂质的重量比为1:0.1-1。
6.根据权利要求5所述的纳米颗粒包裹的抗生素,其中,所述抗生素与所述阳离子脂质的重量比为1:0.2、1:0.3、1:0.5或1:0.8。
7.根据权利要求1所述的纳米颗粒包裹的抗生素,其中,所述抗生素选自喹诺酮类抗生素、β-内酰胺类抗生素、大环内酯类抗生素、氨基糖苷类抗生素、酰氨醇类抗生素、硝基咪唑类抗生素、四环素类抗生素和糖肽类抗生素中的一种或多种。
8.权利要求1-7任一项所述纳米颗粒包裹的抗生素的制备方法,包括通过双乳化法、单乳化法、透析法、纳米沉淀法、薄膜水化法或微流体混合法,利用可降解的生物相容性聚合物包裹抗生素。
9.权利要求8所述纳米颗粒包裹的抗生素的制备方法,其中在制备过程中还加入阳离子脂质。
10.根据权利要求8所述的制备方法,其中,亲水性抗生素采用双乳化法或薄膜水化法进行包裹,疏水性抗生素采用透析法、纳米沉淀法、微流体混合法或单乳化法进行包裹。
11.权利要求1-7任一项所述纳米颗粒包裹的抗生素在制备治疗细菌感染药物中的用途。
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