CN116549418B - 一种抗胃癌术后感染与复发的纳米粒及其制备方法与应用 - Google Patents
一种抗胃癌术后感染与复发的纳米粒及其制备方法与应用 Download PDFInfo
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Abstract
本发明提供了一种抗胃癌术后感染与复发的纳米粒及其制备方法与应用,该纳米粒包括双硫仑和锌离子,锌离子在人血清蛋白调控下与碳酸根离子经生物矿化反应得到碳酸锌纳米粒,双硫仑吸附于所述碳酸锌纳米粒表面,双硫仑作为所述锌离子载体促进锌离子突破细菌细胞壁进入细胞内以进行有效抑菌。该纳米粒通过响应弱酸性微环境,纳米粒可以快速被降解,释放出双硫仑和Zn2+。其中双硫仑不仅具有化疗功效,可以有效杀死肿瘤细胞,清除残余灶从而预防胃癌术后复发;更为重要的是双硫仑可以作为离子载体与锌离子鳌合,促进Zn2+突破细胞壁进入细菌内,以达到良好的胃癌术后抗菌效果;同时,该纳米粒结构稳定,制备简单,具有较高的生物安全性。
Description
技术领域
本发明涉及纳米材料和纳米生物医药领域,具体涉及一种抗胃癌术后感染与复发的纳米粒及其制备方法与应用。
背景技术
细菌感染是指由于细菌侵入人体,在人体内寄生、繁殖所引起的疾病。临床以寒战、高热、皮疹、关节痛及肝脾肿大为特征,部分可有感染性休克和迁徙性病灶。病原微生物自伤口或体内感染病灶侵入血液引起的急性全身性感染,可出现烦躁、四肢厥冷及紫绀、脉细速、呼吸增快、血压下降等。尤其是老人、儿童、有慢性病或免疫功能低下者,可发展为败血症或者脓毒血症。癌症患者是细菌感染的高危人群。由于肿瘤的消耗会导致患者免疫力低下,放疗、化疗以及手术治疗也会进一步降低病人的抵抗力,因此,肿瘤患者存在更高的感染风险,且更容易对抗生素产生耐药性。
胃癌是起源于胃黏膜上皮的恶性肿瘤。手术是胃癌患者获得根治的唯一可能方法,早期患者术后可获得根治。但是,由于手术切除创面较大,术后伤口极易发生感染,从而导致伤口愈合慢甚至出现全身感染的情况。目前临床上治疗细菌感染首选抗生素。然而,由于抗生素的滥用,细菌对抗生素的耐药性已成为一个棘手的临床问题,因此,越来越多的非抗生素抗菌药物或策略已经逐渐取代使用频繁的合成抗生素。金属离子抗菌剂不会像抗生素一样使细菌产生耐药性,且抗菌谱广、抗菌活性高,已用于细菌感染治疗。其中,锌离子(Zn2+)对革兰氏阴性菌和革兰氏阳性菌都显示出了优异的抗菌性能。Zn2+能作为活性催化中心催化氧产生羟自由基及活性氧离子,从而产生氧化应激反应,破坏细菌的繁殖能力,致使细菌死亡。但是细菌由于细胞壁的阻隔保护作用,一般药物或者离子难以在细菌体内富集来产生抗菌作用,尤其是革兰氏阳性菌,其细胞壁主要由肽聚糖和包括磷壁酸的酸性多糖构成,细胞壁较厚,约20~80nm,能够有效阻挡外界溶菌酶、抗生素或者锌离子等的进入,这也是目前金属离子抗菌效果不佳的主要原因之一。
近年来,传统戒酒药双硫仑(DSF)在乳腺癌、前列腺癌、成胶质细胞瘤、肺癌、宫颈癌、肝癌、骨髓瘤、黑色素瘤、神经母细胞瘤等多种癌症模型中被证明具有一定的抗癌活性,并对肿瘤组织具有天然的靶向性。但是对于胃癌患者来说,术后的抗感染与残余病灶清除、防止肿瘤复发是提高胃癌患者治疗效果的关键,因此,开发出一种可以同时清除胃癌术后残余灶并可高效抗菌的纳米药物具有很好的临床应用价值。
发明内容
为解决上述技术问题,本发明提出了一种抗胃癌术后感染与复发的纳米粒及其制备方法与应用,其目的是为了构建一种共递送Zn2+和双硫仑(DSF)的纳米载体,该纳米粒具有酸敏性,可在病理弱酸性微环境下完全降解,快速释放出Zn2+和DSF,DSF可以作为离子载体,提高细菌细胞壁对于Zn2+的通透性,介导Zn2+进入细菌以增加细菌内Zn2+的浓度进而增强抑菌效果;同时,DSF具有抗肿瘤功效,DSF作为离子载体螯合Zn2+后可进一步提高其抗肿瘤效果,可有效清除术后残余病灶以预防胃癌术后复发。
为了实现上述目的,本发明首先提供了一种抗胃癌术后感染与复发的纳米粒,包括双硫仑和锌离子,所述锌离子在人血清蛋白(HSA)调控下与碳酸根离子经生物矿化反应得到碳酸锌纳米粒,所述双硫仑吸附于所述碳酸锌纳米粒表面,所述双硫仑作为所述锌离子载体促进锌离子突破细菌细胞壁进入细胞内以进行有效抑菌。
生物矿化是指由生物体通过生物大分子的调控生成无机矿物的过程,该过程参与了人体骨骼、牙齿的形成。
作为优选,所述锌离子、碳酸根离子和双硫仑的摩尔比为5:5:1~2。
作为优选,所述锌离子为氯化锌,所述碳酸根离子为碳酸钠。
基于一个总的发明构思,本发明还提供了一种抗胃癌术后感染与复发的纳米粒的制备方法,包括以下步骤:
S1、将锌离子溶液、人血清蛋白在超纯水涡旋混匀,静置得到混合液;
S2、向步骤S1中得到的混合液中加入碳酸根离子,水浴超声,离心收集得碳酸锌纳米粒;
S3、将步骤S2得到的碳酸锌纳米粒加入双硫仑甲醇溶液中,室温搅拌,离心收集得双硫仑-碳酸锌纳米粒,即为抗胃癌术后感染与复发的纳米粒。
作为优选,所述锌离子溶液浓度为10mM,所述人血清蛋白浓度为1mg/mL,所述双硫仑甲醇溶液浓度为10mM。
作为优选,所述步骤S2中水浴超声时间为10~30min,所述步骤S3中搅拌时间为30~60min。
基于一个总的发明构思,本发明还提供了一种抗胃癌术后感染与复发的纳米粒在制备胃癌术后兼具抗细菌感染与防复发药物中的应用。
与现有技术相比,本发明具有以下有益效果:
1、本发明提供的抗胃癌术后感染与复发的双硫仑-碳酸锌纳米粒,通过响应弱酸性微环境,纳米粒可以快速被降解,完全释放出DSF和Zn2+。其中,DSF结构中含有二硫键可以鳌合Zn2+离子,因此DSF在释放后可以作为离子载体与锌离子鳌合,提高细菌细胞壁对于Zn2 +的通透性,从而介导Zn2+突破细菌细胞壁阻隔保护顺利进入细胞内,使得Zn2+在细菌胞内富集,并催化氧产生羟自由基及活性氧离子,破坏细菌的繁殖能力,致使细菌死亡,显著提升Zn2+的抑菌作用,可以起到良好的胃癌术后抗菌效果,并促进伤口愈合;与此同时,DSF本身具有化疗功效,在其与锌离子鳌合后可提高入胞效率以有效杀死肿瘤细胞,增强抗肿瘤效果,,清除胃癌术后的残余灶从而预防胃癌术后复发。本发明纳米粒实现胃癌术后的强效抗菌与残余灶清除的有机结合,协同提高胃癌术后的恢复效果。
2、该双硫仑-碳酸锌纳米粒可在靶向胃肿瘤后响应弱酸性微环境中快速完全降解,可避免材料在体内蓄积引起的毒性,纳米粒释放出DSF和Zn2+作为有效成分发挥药效,同时释放出的HSA和碳酸根离子是人体血液或组织液的成分。该纳米粒在血液循环或正常组织中能保持结构稳定,在病灶部位可降解发挥药效。因此,该纳米粒不论是系统性给药或是局部给药,都可避免损伤正常组织或器官,具有高度的生物相容性,安全性高。
3、本发明通过将锌离子在HSA中生物矿化,然后DSF吸附于纳米粒表面,制备过程简易温和,反应过程简单可控且绿色环保,无需额外添加中间载体,也无需添加和使用有机溶剂,不会引入其他杂质;采用人血清蛋白调控离子的生物矿化过程,形成的双硫仑-碳酸锌纳米粒粒径均一,呈类球形,平均粒径150nm,其中水合粒径243nm左右,粒径均一,分散性好。
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为本发明实验例1检测获得的ZnCO3@DSF纳米粒的透射电镜图;
图2为本发明实验例2检测获得的ZnCO3@DSF纳米粒的粒径图;
图3为本发明实验例3检测获得的ZnCO3@DSF纳米粒在不同pH环境下的实物降解图;
图4为本发明实验例4检测获得的ZnCO3、ZnCO3@DSF纳米粒和游离DSF的体外抑菌结果图,图4A和4B分别为ZnCO3@DSF纳米粒、ZnCO3纳米粒和游离DSF与SA或HP孵育12h后测定的细菌存活率结果;
图5为本发明实验例5检测获得的ZnCO3、ZnCO3@DSF纳米粒和游离DSF处理细菌后细菌中Zn2+含量结果图;
图6为本发明实验例6检测获得的ZnCO3、ZnCO3@DSF纳米粒和游离DSF的体外抗肿瘤结果图;
图7为本发明实验例7检测获得的ZnCO3、ZnCO3@DSF纳米粒和游离DSF的体内促进伤口愈合结果图;
图8为本发明实验例8检测获得的ZnCO3@DSF纳米粒的实验例7伤口细菌密度统计结果图;
图9为本发明实验例9检测获得的ZnCO3@DSF纳米粒的体内抗肿瘤结果图。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚,下面将结合附图及具体实施例进行详细描述。
以下实施例用于说明本发明,但不用来限制本发明的范围。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。
若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段;若未特别指明,实施例中所用试剂均为市售。
实施例1
制备双硫仑-碳酸锌纳米粒(ZnCO3@DSF)
分别配制10mM ZnCl2水溶液,10mM Na2CO3水溶液,1mg/mL HSA水溶液,10mM DSF甲醇溶液。
将100μL ZnCl2水溶液、200μL HSA水溶液和600μL超纯水涡旋混匀,静置30min,随后与200μL Na2CO3水溶液混匀,水浴超声10mim,离心收集得碳酸锌纳米粒,等体积复溶,将20μL DSF甲醇溶液与1mL碳酸锌纳米粒溶液混合,室温搅拌1h,离心收集得双硫仑-碳酸锌纳米粒ZnCO3@DSF。
根据实施例1获得的纳米材料,检测ZnCO3@DSF纳米粒物理化学性质和药学特性,具体包括微观形态、粒径、体外细胞毒性、体外抑菌能力、体内抗肿瘤效果及抗感染能力,其中以实施例1得到的相关材料做具体阐述。
实验例1
形态:观察ZnCO3@DSF纳米粒的形态,形态的检测方法:样品滴加在覆盖碳膜的400目锌网上,置于干燥箱中,待其自然干燥后置于透射电镜Titan G2-F20下观察,其结果如图1所示,粒子均呈类球形,粒子直径约150nm。
实验例2
粒径检测:分别检测ZnCO3纳米粒和ZnCO3@DSF纳米粒的粒径,测量方法为:取样品溶液置于Marlven Nano ZS仪器,采用动态光散射法检测粒径,测定池温度设定为25℃,每个样品平行操作3份,其结果如图2所示。从图2的结果可知:ZnCO3纳米粒的平均水合粒径约200nm左右,而ZnCO3@DSF纳米粒的水合粒径约243nm,粒径相比ZnCO3纳米粒增加,这也证明了DSF吸附于ZnCO3纳米粒表面,且ZnCO3@DSF纳米粒粒径均一,分散性好。
实验例3
考察ZnCO3@DSF在弱酸性环境下的降解情况
离心ZnCO3@DSF纳米粒,拍照,弃上清分别加入10mM pH 7.4和pH 5.5PBS在37℃孵育2h,随后离心,观察沉淀量并拍照,其结果如图3所示。从图3的结果可知:ZnCO3@DSF纳米粒在正常生理环境下(pH 7.4)可保持结构稳定,而在弱酸性条件下(pH 5.5)会完全降解,孵育30min后弱酸性环境下的ZnCO3@DSF纳米粒即已经基本降解,样品溶液变澄清。
实验例4
考察ZnCO3@DSF纳米粒的体外抑菌效果,实验步骤如下:
取金黄色葡萄球菌(SA)或幽门螺杆菌(HP)稀释至OD600=0.01,将ZnCO3@DSF分别在pH 7.4或pH 5.5的缓冲液中预处理0.5h,然后分别与SA或HP混合(梯度浓度:0.3、0.6、1.5、3、6、15μM,以Zn2+浓度计),加至96孔板(细菌终浓度以OD600=0.01计),37℃、180rpm孵育12h,酶标仪测定各孔OD600。
其检测结果如图4所示,图4A和4B分别为ZnCO3@DSF纳米粒、ZnCO3纳米粒和游离DSF与SA或HP孵育12h后测定的细菌存活率结果。从图4结果可以看出,ZnCO3@DSF在弱酸性环境中可有效抑制细菌生长的活性。
实验例5
考察ZnCO3@DSF纳米粒等处理细菌后细菌中Zn2+含量,实验步骤如下:
取金黄色葡萄球菌(SA)或幽门螺杆菌(HP)稀释至一定浓度,将2μM ZnCO3@DSF纳米粒、ZnCO3纳米粒分别在pH 7.4或pH 5.5的缓冲液中预处理0.5h,随后与SA混合,加至6孔板(细菌终浓度以OD600=0.05计),37℃、180rpm孵育12h,收集各组细菌并裂解,检测各组Zn2+浓度。
其检测结果如图5所示,图5为ZnCO3@DSF纳米粒、ZnCO3纳米粒和游离DSF与SA孵育12h后测定的Zn2+浓度。从图5结果可以看出,游离DSF与对照组基本一致,pH 7.4环境下预处理的ZnCO3@DSF和ZnCO3组的Zn2+浓度略高于对照组,pH 5.5预处理的ZnCO3@DSF和ZnCO3组的Zn2+浓度均高于pH 7.4组,而pH 5.5预处理的ZnCO3@DSF的Zn2+含量最高。这是由于ZnCO3@DSF纳米粒响应弱酸性环境降解后会同时产生Zn2+和DSF,DSF的双硫键可以有效螯合Zn2+,提高细菌细胞壁对于Zn2+的通透性,从而介导Zn2+突破细菌细胞壁阻隔保护顺利进入细胞内,使得Zn2+在细菌胞内富集。这也进一步验证了实验例4中ZnCO3@DSF的体外抑菌效果要明显优于ZnCO3纳米粒的原因。
实验例6
考察ZnCO3@DSF纳米粒的体外抗肿瘤效果,实验步骤如下:
取胰酶消化对数生长的MFC细胞,用含10% FBS的1640培养基稀释成密度为5×104个/mL的细胞悬液,以每孔100μL接种于96孔培养板中。在二氧化碳培养箱内(37℃、5%CO2、饱和湿度)培养12h后移弃培养液。
每孔加入100μL用培养基稀释至不同浓度的ZnCO3@DSF纳米粒、ZnCO3纳米粒和游离DSF(纳米粒浓度为:7、14、35、70、140、350μg/mL,DSF对应浓度分别为18、45、90、180、450ng/mL),同一浓度做6个复孔,孵育24h后吸弃培养液,PBS润洗3次。
每孔加入100μL MTT溶液(0.5mg/mL),孵育4h后吸弃上清。
每孔加入100μL DMSO,置摇床上低速振摇10min使结晶溶解完全,用酶标仪测定各孔在490nm波长处的吸光值(OD)。
其检测结果如图6所示,图6为ZnCO3@DSF纳米粒、ZnCO3纳米粒和游离DSF与细胞孵育48h后,用MTT法测定的细胞存活率结果。从图6结果可以看出,ZnCO3在该浓度范围内对肿瘤细胞无明显毒性,游离DSF和ZnCO3@DSF纳米粒对MFC细胞有浓度依赖性的细胞毒性,由于ZnCO3@DSF入胞效率高于游离DSF,因此ZnCO3@DSF的肿瘤抑制效果明显优于游离DSF。
实验例7
考察ZnCO3@DSF纳米粒的体内促进伤口愈合能力,实验步骤如下:
以雌性C57BL/6小鼠为动物模型,建立圆形全层创面,创面直径约为8mm。然后在皮肤全层创面接种金黄色葡萄球菌悬液(200μL,1010CFU/mL)以建立伤口感染模型。
将感染创面小鼠随机分为4组(n=6):PBS空白组、ZnCO3@DSF纳米粒、ZnCO3纳米粒和游离DSF组。每三天进行尾静脉注射药物,共给药四次,给药剂量以DSF计为1mg/kg。拍摄第0、3、7、10、14天创面图像,测量并计算创面大小。相对创面面积=Sx/S0(S0,原始创面面积;Sx,特定一天的创面面积)。
其结果如图7所示,图7表明,ZnCO3@DSF治疗后创面面积最小,促进伤口愈合效果最佳。
实验例8
考察ZnCO3@DSF纳米粒的体内抑菌活性,实验步骤如下:
取实验例5治疗结束后创面周围皮肤组织匀浆,用PBS稀释后铺于LB板,培养24h后,统计各组菌落数目。
其结果如图8所示,图8表明,ZnCO3@DSF组菌落数量最少,体内抑制细菌活性最强。
实验例9
考察ZnCO3@DSF纳米粒的体内抗肿瘤效果,实验步骤如下:
收集对数生长的MFC细胞制备成细胞悬液,以3×106个/100μL/只的密度种于雌性C57BL/6小鼠皮下,观察小鼠肿瘤生长情况,待肿瘤生长至200mm3左右时(肿瘤体积=长×宽2/2),切除95%的肿瘤组织,将小鼠平均分为4组,每组6只。具体分组为:对照组、ZnCO3@DSF纳米粒、ZnCO3纳米粒和游离DSF组。每三天进行尾静脉注射药物,共给药四次,给药剂量以DSF计为1mg/kg。每两天记录小鼠肿瘤体积,给药第16天后处死小鼠,取出肿瘤称重,绘制肿瘤生长曲线图。
其结果如图9所示,图9为复发肿瘤生长曲线。与对照组相比,其他3组均有一定的肿瘤抑制效果,其中ZnCO3@DSF纳米粒治疗后复发肿瘤体积最小,抑制肿瘤复发效果最佳。
以上所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明所述原理的前提下,还可以作出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (4)
1.一种抗胃癌术后感染与复发的纳米粒,其特征在于,包括双硫仑和锌离子,所述锌离子在人血清蛋白调控下与碳酸根离子经生物矿化反应得到碳酸锌纳米粒,所述双硫仑吸附于所述碳酸锌纳米粒表面,所述双硫仑作为所述锌离子载体促进锌离子突破细菌细胞壁进入细胞内以进行有效抑菌;
所述锌离子、碳酸根离子和双硫仑的摩尔比为5:5:1~2;
所述抗胃癌术后感染与复发的纳米粒的制备方法包括以下步骤:
S1、将锌离子溶液、人血清蛋白在超纯水涡旋混匀,静置得到混合液;
S2、向步骤S1中得到的混合液中加入碳酸根离子,水浴超声,离心收集得碳酸锌纳米粒;
S3、将步骤S2得到的碳酸锌纳米粒加入双硫仑甲醇溶液中,室温搅拌,离心收集得双硫仑-碳酸锌纳米粒,即为抗胃癌术后感染与复发的纳米粒;
所述锌离子为氯化锌,所述碳酸根离子为碳酸钠。
2.根据权利要求1所述的抗胃癌术后感染与复发的纳米粒,其特征在于,所述锌离子溶液浓度为10 mM ,所述人血清蛋白浓度为1 mg/mL,所述双硫仑甲醇溶液浓度为10 mM。
3.根据权利要求1所述的抗胃癌术后感染与复发的纳米粒,其特征在于,所述步骤S2中水浴超声时间为10~30min,所述步骤S3中搅拌时间为30~60min。
4.一种如权利要求1~3任一项所述纳米粒在制备胃癌术后兼具抗细菌感染与防复发药物中的应用。
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