CN112807443B - 一种多重协同的抗菌纳米前药 - Google Patents
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Abstract
本发明公开了一种多重协同的抗菌纳米前药,其主体为聚乙二醇修饰的支化聚乙烯亚胺,主体上修饰有硼酸基团,硼酸基团通过形成五元和/或六元环状硼酸酯键连接有抗菌化合物,所述抗菌化合物具有1,2‑位羟基或1,3‑位羟基结构。本发明一些实例的抗菌纳米前药,通过聚阳离子PEI、抗菌药物大黄素和pH敏感的药物释放等多重协同作用,具有显著增强的抗菌性能,具有意料之外的效果。
Description
技术领域
本发明涉及纳米药物与生物医学技术领域,涉及一种多重协同的抗菌纳米前药及其制备方法和应用。
背景技术
目前细菌感染和抗生素导致的细菌耐药已经成为一个世界性的问题,严重威胁公众生命健康。针对耐药菌需要开发新的抗菌药物或者抗菌材料,在保持高效杀菌的同时对环境友好且避免耐药性的产生极其重要。
由于药物分子本身性质不稳定以及在体内容易分解,再加上近年来所开发出的全新药物相对较少,因此对药物进行化学结构的修饰将其制备成一种性质较稳定的化合物以利于在体内酶、pH、温度等条件下最终生成原来的药物并在人体组织内发挥药效作用。这类经过修饰后并能够在人体内释放出来的药物分子被称为前药。1958年,Albert提出了前药的概念,前药作为一种药物分子的衍生物,特点是生物可逆,其在人体内经过化学或酶的转化后,能够释放出有药效活性以达到治疗效果的代谢物或原物。对药物进行前药设计主要是为了改善药物易降解、半衰期太短、药物透膜能力低等功效。
在前药设计中,常用来修饰药物的活性官能团主要有:羟基、羧基、氨基、磷酸盐、碳酸盐、羰基等,利用以上官能团修饰可产生酯、氨基甲酸酯、酰胺、磷酸酯、肟等化学基团的特点能够利于前药在人体细胞特殊环境下释放药物。近年来,刺激响应型纳米载体由于具有药物的可控性释放的特点而得到了诸多报道。其中,硼酸由于独特的化学性质被广泛应用于构筑刺激响应性药物载体的响应位点,在没有任何外部辅助条件的情况下,硼酸基团能够在水溶液中与二醇基团迅速发生酯化反应,生成硼酸酯键,且该反应在酸性条件下可逆。据此,可利用硼酸酯键将药物连接到载体中形成纳米前药体系,从而实现pH酸敏感释药的目的。
现有的纳米前药体系虽然已经取得了较大的发展,但是还存在细胞毒性较大,稳定性不足等缺陷,有待进一步的改进。
发明内容
本发明的目的在于克服现有技术的至少一个不足,提供一种多重协同的抗菌纳米前药及其制备方法和应用。
本发明所采取的技术方案是:
本发明的第一个方面,提供:
一种多重协同的抗菌纳米前药,其主体为聚乙二醇修饰的支化聚乙烯亚胺,主体上修饰有硼酸基团,硼酸基团通过形成五元和/或六元环状硼酸酯键连接有抗菌化合物,所述抗菌化合物具有1,2-位羟基或1,3-位羟基结构。
在一些实例中,所述抗菌纳米前药的结构通式如式I所示:
式I中,R为含有1,2-或1,3-位羟基结构的抗菌化合物,n为11~228的整数。
在一些实例中,所述抗菌化合物选自大黄素(emodin)、槲皮素(quercetin)、木犀草素(luteolin)、黄芩苷(baicalein)等。
在一些实例中,所述支化聚乙烯亚胺的相对分子量为600~10000,优选为1600~2400。
在一些实例中,所述聚乙二醇为相对分子量500~10000的甲氧基聚乙二醇,相对分子量优选为1600~2400。
在一些实例中,PEI与PEG的摩尔比为1:(1~20),优选为1:1。
在一些实例中,步骤S1)的反应温度为30℃~50℃。
在一些实例中,步骤S2)的反应温度为70~80℃。
在一些实例中,步骤为30℃~50℃。
上述步骤S1)~S3)的反应温度既可以保证反应的顺利进行,又不会破坏分子的结构。
在一些实例中,步骤S2)中mPEG-PEI与4-溴甲基苯硼酸的比例为1:(1~100)。具体的比例可以根据要连接的抗菌化合物的量进行一定的调整。一般而,需要键合的抗菌化合物越多,4-溴甲基苯硼酸的用量就应越大。
在一些实例中,步骤S3)中,mPEG-PEI-PB与含有1,2-或1,3-位羟基结构的抗菌化合物的摩尔比为1:(5~50)。
在一些实例中,mPEG-PEI-PB与抗菌化合物的摩尔比为1:(5~15),PEI的平均分子量为1800,mPEG的平均分子量为2000,抗菌化合物为大黄素。
本发明的第二个方面,提供:
抗菌纳米前药在制备抗菌药物中的应用,所述抗菌纳米前药如本发明第一个方面所述。
本发明的有益效果是:
本发明一些实例的抗菌纳米前药,通过聚阳离子PEI、抗菌药物大黄素和pH敏感的药物释放等多重协同作用,具有显著增强的抗菌性能,具有意料之外的效果。
本发明一些实例的抗菌纳米前药,mPEG与PEI的分子量可根据使用需要进行灵活调整;同理,苯硼酸基团和药物的接枝度可根据使用需要进行灵活调整。
本发明一些实例的抗菌纳米前药,含1,2-或1,3-位羟基药物的选择可以根据使用需要进行灵活调整。
附图说明
图1为mPEG-PEI的核磁谱图;
图2为mPEG-PEI-PB的核磁谱图;
图3为mPEG-PEI-PB-Emodin的核磁谱图;
图4为pH 7.4 时纳米前药的粒径分布和透射电镜图;
图5为mPEG-PEI-PB-Emodin在不同pH条件下的药物释放曲线;
图6为mPEG-PEI-PB-Emodin(PPPE)在不同浓度和pH下对大肠杆菌和金黄色葡萄球菌的抑制能力定量结果,以大黄素作为对照;
图7为平板涂布法研究mPEG-PEI-PB-Emodin(PPPE)在不同pH下对大肠杆菌和金黄色葡萄球菌的抑制能力,以大黄素作为对照。
具体实施方式
为便于技术人员充分理解本发明,下面结合附图根据具体的实施例对本发明进行详细说明。以下实施例均以前面所述技术方案为前提进行操作,给出了详细的实施过程和各项实施参数,但本发明的保护范围不限于下述的实施例,所有没有经过改进或其他创造性劳动改变的其他实施例,一律属于本发明所属保护的范围之内。所述试剂材料,如无特殊注明,均来自商业渠道。
实施例1
本实施例是一种含pH敏感硼酸酯键的纳米前药抗菌体系的制备方法,包括如下步骤:
(1) 制备mPEG-PEI:称取336 mg PEI(聚乙烯亚胺,1800 g/mol)溶于10 ml DMF为混合物1,再称取336 mg mPEG-NHS(甲氧基聚乙二醇活性酯,2000 g/mol)溶于10 ml DMF为混合物2,混合物2往混合物1逐滴加入,并于40℃反应24 h;随后用透析袋(MWCO:3500)装载混合物置于2L蒸馏水透析3天,冻干,得到白色固体。其核磁谱图如图1所示。
(2) 制备mPEG-PEI-PB:称取282.0 mg mPEG-PEI(3800 g/mol)用20 mL甲醇溶解,以1:10的摩尔比称量159.4 mg 4-溴甲基苯硼酸(214.85 g/mol),将混合物置于圆底烧瓶,在76℃油浴反应24 h;冷却,用旋转蒸发仪减压蒸馏除去甲醇,获得乳黄色粘稠样品,将烧瓶中的混合物在蒸馏水中溶解,置于透析袋(MWCO:3500)中透析3天,冻干。其核磁谱图如图2所示。
(3) 制备mPEG-PEI-PB-Emodin:取Emodin(270 g/mol)与mPEG-PEI-PB(5600 g/mol)摩尔比为10:1,在20 mL DMF 中溶解112mg mPEG-PEI-PB,5 mL甲醇中溶解54 mgEmodin,二者混合后于40℃条件下搅拌反应24 h,减压蒸馏除去甲醇,置于透析袋(MWCO:3500)中避光透析3天,过滤后冻干得到最终纳米前药。其核磁谱图如图3所示。
(4) 通过动态光散射(DLS)和透射电子显微镜(TEM)分别考察纳米前药的粒径大小和形貌(图4),DLS结果显示在pH为7.4时纳米前药的粒径大小为102.8±12 nm,PDI为0.264±0.025,TEM下观察到球形纳米颗粒,其尺寸与DLS结果基本一致;在pH为5.0时由于前药结构解体,DLS测不到准确的粒径值,且TEM下也找不到明确结构的纳米颗粒。进一步研究纳米前药在不同pH下的药物释放行为(图5),发现纳米前药在 pH=7.4 时缓慢释放药物,在 216 h 内仅有不到 40%的药物释放出来,而在pH=5.0 时药物释放明显加快,短时间内即有大量药物释放出来,此后逐渐趋于平缓,在整个过程中有超过 80% 的药物释放出来,这也证实了该纳米前药确实具有 pH 敏感的特性。
(5) 通过定性和定量的实验来考察纳米前药在不同pH下的体外抗菌性能。如图6所示,当细菌悬液与纳米前药共培养后,在高药物浓度时几乎所有的细菌生长都受到抑制,在pH为5.0时抑制效果更为明显,这与酸敏感纳米前药的结构设计有关。与此同时,在所有相同条件下纳米前药的抑菌效果均优于自由的大黄素药物。在pH为5.0时,纳米前药和大黄素对金黄色葡萄球菌的抑制率分别为73.7%和34.4%,而对大肠杆菌则分别达到了96.0%和78.0%。由此可见,将小分子药物键合到高分子上形成纳米前药,通过聚阳离子PEI、抗菌药物大黄素和pH敏感的药物释放等多重协同作用,可以极大提升其抗菌效果。平板涂布法所得定性实验结果如图7所示,与上述结果完全一致。
实施例2
本实施例是一种含pH敏感硼酸酯键的纳米前药抗菌体系的制备方法,包括如下步骤:
(1) 制备mPEG-PEI:称取336 mg PEI(聚乙烯亚胺,1800 g/mol)溶于10 ml DMF为混合物1,再称取336 mg mPEG-NHS(甲氧基聚乙二醇活性酯,2000 g/mol)溶于10 ml DMF为混合物2,混合物2往混合物1逐滴加入,并于40℃反应24 h;随后用透析袋(MWCO:3500)装载混合物置于2L蒸馏水透析3天,冻干,得到白色固体。
(2) 制备mPEG-PEI-PB:称取282.0 mg mPEG-PEI(3800 g/mol)用20 mL甲醇溶解,以1:20的摩尔比称量318.8 mg 4-溴甲基苯硼酸(214.85 g/mol),将混合物置于圆底烧瓶,在76℃油浴反应24 h;冷却,用旋转蒸发仪减压蒸馏除去甲醇,获得乳黄色粘稠样品,将烧瓶中的混合物在蒸馏水中溶解,置于透析袋(MWCO:3500)中透析3天,冻干。
步骤(3) (4) (5)同实施例1。
实施例3
本实施例是一种含pH敏感硼酸酯键的纳米前药抗菌体系的制备方法,包括如下步骤:
步骤(1)(2)同实施例1。
(3) 制备mPEG-PEI-PB-Quercetin:槲皮素(302.2 g/mol),mPEG-PEI-PB(5600 g/mol)摩尔比10:1,将槲皮素与mPEG-PEI-PB溶解在20 ml DMF中,于40℃条件下搅拌反应24h,置于透析袋(MWCO:3500)中透析3天,过滤后冻干得到最终前药。
步骤(4) (5)同实施例1。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (8)
2.根据权利要求1所述的抗菌纳米前药,其特征在于:
所述支化聚乙烯亚胺的相对分子量独立为600~10000;
所述聚乙二醇独立为相对分子量500~10000的甲氧基聚乙二醇。
3.一种抗菌纳米前药的制备方法,所述抗菌纳米前药如权利要求1或2所述,包括:
S1)将支化聚乙烯亚胺PEI与活化后的mPEG-NHS反应,得到聚乙二醇修饰的mPEG-PEI;
S2)mPEG-PEI与4-溴甲基苯硼酸反应,得到含有硼酸基团的mPEG-PEI-PB;
S3)mPEG-PEI-PB与含有1,2-位羟基或1,3-位羟基结构的抗菌化合物反应,纯化得到含有五元或六元环状结构硼酸酯键的pH敏感型纳米前药。
4.根据权利要求3所述的制备方法,其特征在于:PEI与PEG的摩尔比为1:(1~20)。
5.根据权利要求3所述的制备方法,其特征在于:步骤S1)和S3)的反应温度独立为30℃~50℃;步骤S2)的反应温度独立为70~80℃。
6.根据权利要求3~5任一项所述的制备方法,其特征在于:
步骤S2)中mPEG-PEI与4-溴甲基苯硼酸的比例为1:(1~100);
步骤S3)中,mPEG-PEI-PB与含有1,2-或1,3-位羟基结构的抗菌化合物的摩尔比为1:(5~50)。
7.根据权利要求6所述的制备方法,其特征在于:mPEG-PEI-PB与抗菌化合物的摩尔比为1:(5~15),PEI的平均分子量为1800,mPEG的平均分子量为2000,抗菌化合物为大黄素。
8.权利要求1或2所述抗菌纳米前药在制备抗菌药物中的应用。
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