CN113663082A - 用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇及其制备方法与应用 - Google Patents
用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇及其制备方法与应用,所述乙酰半胱氨酸稳定的金纳米簇(Au NCs‑NAC)包括:金纳米簇,结合于所述金纳米簇表面的乙酰半胱氨酸。本发明Au NCs‑NAC包括表面配体乙酰半胱氨酸以及由所述表面配体保护的金纳米簇。本发明设计的Au NCs‑NAC具有超小的尺寸,能够有效的富集于小鼠肾脏,能通过清除肾小管内大量的活性氧或活性氮以缓解和治疗甘油诱导的急性肾损伤,并且具有优异的抗炎能力,同时具有比乙酰半胱氨酸更好的治疗效果。另外,这种Au NCs‑NAC具有优异的生物相容性和生物安全性。
Description
技术领域
本发明涉及生物医学材料技术领域,尤其涉及一种用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇(记为Au NCs-NAC)及其制备方法与应用。
背景技术
急性肾损伤是人类重要的健康问题。由于其高发病率和死亡率,据估计全球每年有170万人死亡。目前,辅助治疗和肾移植是最常见的治疗方法。最近的研究表明,急性肾损伤的发病机理与细胞内过量的活性氧和活性氮物种相关。此前,一些小分子药物,例如,氨磷汀和乙酰半胱氨酸,已经被证明可以作为抗氧化剂,消除活性氧,以此来缓解急性肾损伤。然而,小分子药物具有较低的利用率,较大的毒副作用以及有限的疗效。这些都阻碍了他们的临床应用。但是,抗氧化剂的成功发展为急性肾损伤未来的治疗提供了充分的基础。
发明内容
发明人研究发现,相较于传统蛋白酶,金属纳米材料具有成本低、催化性质可调、可大规模制备等明显优势。同时,金属纳米材料中,尤其是金纳米簇具有广谱的活性氧和活性氮的清除能力,此外,还具有优异的抗炎能力。更重要的是,超小的金属纳米颗粒可以通过肾脏进行代谢,这就为急性肾损伤的治疗提供了可能。
基于此,本发明开发了利用乙酰半胱氨酸稳定的金纳米簇(Au NCs-NAC)用于急性肾损伤的治疗。
具体地,本发明提供一种用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇(AuNCs-NAC)及其制备方法与应用,旨在解决现有的小分子药物利用率低、副作用大,难以用于急性肾损伤治疗的技术问题。
本发明第一方面,提供一种用于急性肾损伤的Au NCs-NAC,其中,包括:金纳米簇,结合于所述金纳米簇表面的乙酰半胱氨酸。
本发明中,所述金纳米簇与所述乙酰半胱氨酸之间通过金-硫配位键结合。
本发明乙酰半胱氨酸(属于表面配体)能够有效的稳定金纳米簇,控制金纳米簇形成超小的尺寸。并且它们都具有良好的水溶性和生物安全性,不易与血清内蛋白发生作用,有利于Au NCs-NAC在血液中的循环。
需说明的是,本发明不限于乙酰半胱氨酸,半胱氨酸也可作为表面配体稳定在金纳米簇表面。
可选地,所述金纳米簇和所述乙酰半胱氨酸的质量比为1:(1-10)。
可选地,所述Au NCs-NAC为直径小于等于3nm的球形簇状颗粒。
本发明第二方面,提供一种如上所述的用于急性肾损伤的Au NCs-NAC的制备方法,其中,包括步骤:将氯金酸、氢氧化钠和乙酰半胱氨酸混合于水中,搅拌并加热,得到混合溶液;将所述混合溶液进行透析,得到所述Au NCs-NAC。
可选地,所述氯金酸与乙酰半胱氨酸的质量比为1:(1-10),如1:6.528。
可选地,所述搅拌并加热的时间为1-4小时。
可选地,所述搅拌并加热的温度为25-50摄氏度。
本发明第三方面,提供一种如上所述的Au NCs-NAC在制备治疗急性肾损伤制剂中的应用;
或者,提供一种如上所述的方法制得的Au NCs-NAC在制备治疗急性肾损伤制剂中的应用。
本发明Au NCs-NAC包括表面配体乙酰半胱氨酸以及由所述表面配体保护的金纳米簇,所述表面配体能够有效的稳定金纳米簇,控制金纳米簇形成超小的尺寸。由于本发明的Au NCs-NAC具有超小的尺寸,低于肾脏的过滤阈值5.5nm,因此能够有效的富集于小鼠肾脏,并通过清除肾小管内大量的活性氧或活性氮以缓解和治疗甘油诱导的急性肾损伤,并且具有抗炎的能力,同时具有比乙酰半胱氨酸更好的治疗效果。另外,Au NCs-NAC具有优异的生物相容性和生物安全性。
附图说明
图1为本发明具体的实施例中Au NCs-NAC的合成路线图;
图2为本发明具体的实施例中Au NCs-NAC的TEM图;
图3为本发明具体的实施例中Au NCs-NAC的XPS图;
图4为本发明具体的实施例中Au NCs-NAC和NAC对比羟基自由基清除率图;
图5为本发明具体的实施例中Au NCs-NAC和NAC对比超氧阴离子清除率图;
图6为本发明具体的实施例中Au NCs-NAC和NAC对比自由基清除率图;
图7为本发明具体的实施例中Au NCs-NAC处理肾小管细胞(293T)存活率图;
图8为本发明具体的实施例中Au NCs-NAC和NAC对比在肾小管细胞(293T)中活性氧染色图;
图9为本发明具体的实施例中Au NCs-NAC和NAC对比在肾小管细胞(293T)中TNF-α相对水平图;
图10为本发明具体的实施例中Au NCs-NAC和NAC对比在肾小管细胞(293T)中IL-6相对水平图;
图11为本发明具体的实施例中Au NCs-NAC不同治疗组小鼠血清中血尿素氮含量图;
图12为本发明具体的实施例中Au NCs-NAC不同治疗组小鼠血清中血肌酐含量图;
图13为本发明具体的实施例中注射Au NCs-NAC和磷酸缓冲液(对照)的急性肾衰竭老鼠的存活变化图。
具体实施方式
本发明提供一种用于急性肾损伤的Au NCs-NAC及其制备方法与应用,为使本发明的目的、技术方案及效果更加清楚、明确,以下对本发明进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
本发明实施例提供一种用于急性肾损伤的Au NCs-NAC,其中,包括:金纳米簇,结合在所述金纳米簇表面的乙酰半胱氨酸。
本发明实施例Au NCs-NAC包括表面配体乙酰半胱氨酸以及由所述表面配体乙酰半胱氨酸保护的金纳米簇,所述金纳米簇与所述乙酰半胱氨酸之间通过金-硫配位键结合,具体是所述金纳米簇表面的金元素与所述乙酰半胱氨酸中的硫元素形成配位键,使所述乙酰半胱氨酸结合在所述金纳米簇表面。所述乙酰半胱氨酸能够有效的稳定金纳米簇,控制金纳米簇形成超小的尺寸,使得最终获得的Au NCs-NAC有超小的尺寸。并且它们都具有良好的水溶性和生物安全性,不易与血清内蛋白发生作用,有利于Au NCs-NAC在血液中的循环。本发明实施例该Au NCs-NAC具有超小的尺寸,利于有效到达小鼠肾脏,通过清除肾小管内大量的活性氧或活性氮以缓解和治疗急性肾损伤,并且具有优异的抗炎能力,同时其治疗效果远高于同等剂量的单独乙酰半胱氨酸。
需说明的是,本发明实施例不限于所述金纳米簇。
在一种实施方式中,所述金纳米簇和所述乙酰半胱氨酸的质量比为1:(1-10),如1:6.528。该比例范围内得到的Au NCs-NAC具有良好的分散性和稳定性,并且具有很小的尺寸。
在一种实施方式中,所述Au NCs-NAC为直径小于等于3nm的球形颗粒。超小的纳米颗粒有利于到达小鼠肾脏,且超小的纳米颗粒有利于通过肾脏进行代谢。进一步地,所述AuNCs-NAC为直径1-3nm的球形颗粒。
本发明实施例提供一种如上所述的用于急性肾损伤的Au NCs-NAC的制备方法,其中,包括步骤:将氯金酸、氢氧化钠和乙酰半胱氨酸混合于水中,搅拌并加热,得到混合溶液;将所述混合溶液进行透析,得到所述Au NCs-NAC。
在一种实施方式中,将所述混合溶液装入透析袋透析一天,即得到所述Au NCs-NAC。
在一种实施方式中,所述氯金酸与乙酰半胱氨酸的质量比为1:(1-10),如1:6.528。
在一种实施方式中,以质量比计,氯金酸:氢氧化钠:乙酰半胱氨酸=1:1.5:6.528。乙酰半胱氨酸能够还原氯金酸并控制金纳米簇的生长,形成超小的金纳米簇,溶剂的水的使用可以保证材料良好的分散性。
在一种实施方式中,所述搅拌并加热的时间为1-4小时(如2.5小时)。
在一种实施方式中,所述搅拌并加热的温度为25-50摄氏度。
在一种实施方式中,所述氯金酸为氯金酸三水合物或氯金酸四水合物,但不限于此。
一种本发明实施例所述的Au NCs-NAC在制备治疗急性肾损伤制剂中的应用。
一种本发明实施例所述的方法制得的Au NCs-NAC在制备治疗急性肾损伤制剂中的应用。
下面通过具体的实施例对本发明的技术方案作进一步地说明。
实施例1:合成Au NCs-NAC
Au NCs-NAC合成:将氯金酸(2毫升,浓度为20毫克/毫升)和NaOH水溶液(3毫升,浓度为0.5摩尔/毫升)添加到NAC水溶液(20毫升,浓度为80毫摩尔/毫升)中,并在37℃搅拌2.5小时。然后,将反应后水溶液透析两天,每4h换一次水。最后,将所得溶液在4℃冰箱中保存备用。
图1为合成Au NCs-NAC的路线图,其中HAuCl4代表氯金酸,NAC代表乙酰半胱氨酸。所述Au NCs-NAC中的表面配体乙酰半胱氨酸能够很好地稳定金纳米簇。
图2是合成的Au NCs-NAC的TEM图;图3是合成的Au NCs-NAC的XPS图;图2和图3表明Au NCs-NAC的成功合成并具有超小的尺寸,并且XPS中的S元素表明了乙酰半胱氨酸的成功修饰。
实施例2:Au NCs-NAC清除各种活性氧能力及Au NCs-NAC清除羟基自由基的能力
不同浓度Au NCs-NAC(25-100μg/mL)清除羟基自由基的效率是通过羟基自由基抗氧化能力(HORAC)试剂盒(Cell Biolabs,Inc.,USA)测定的。测试是按照制造商提供的方案进行的。
如图4所示,Au NCs-NAC能够有效的清除羟基自由基,并且具有浓度依赖的特性。并且,Au NCs-NAC清除效率明显优于单独的乙酰半胱氨酸。100μg/mL浓度条件下,Au NCs-NAC能够清除77.7%的羟基自由基而乙酰半胱氨酸只能清除47.2%。
不同浓度Au NCs-NAC(25-100μg/mL)清除超氧阴离子的效率是通过SOD检测试剂盒(Sigma-Aldrich,USA)测定的。测试是按照制造商提供的方案进行的。
如图5所示,Au NCs-NAC能够有效的清除超氧阴离子,并且具有浓度依赖的特性。并且,Au NCs-NAC清除效率明显优于单独的乙酰半胱氨酸。100μg/mL浓度条件下,Au NCs-NAC能够清除30.4%的超氧阴离子而乙酰半胱氨酸只能清除6%。
Au NCs-NAC清除ABTS(2,2'-联氮双(3-乙基苯并噻唑啉-6-磺酸)二铵盐)自由基的测试
用ABTS自由基阳离子脱色法测定了Au NCs-NAC的自由基清除能力。将ABTS(7mM)溶于水,加入2.45mM过硫酸钾反应12小时,可产生ABTS自由基阳离子(·ABTS+)。然后在734nm处测定纯·ABTS+溶液(AB)和不同浓度(12.5-100μg/mL)Au NCs-NAC与·ABTS+混合溶液的吸光度值。ABTS清除效率的计算公式为[(AB-AP)/AB]*100。所有的测量都是一式三次。
如图6所示,Au NCs-NAC能够有效的清除自由基,并且具有浓度依赖的特性。并且,Au NCs-NAC清除效率明显优于单独的乙酰半胱氨酸。100μg/mL浓度条件下,Au NCs-NAC能够清除80.6%的·ABTS+而乙酰半胱氨酸只能清除68.9%。
实施例3:Au NCs-NAC细胞毒性和通过清除各种活性氧/活性氮保护肾细胞,并采用标准的MTT法,评价Au NCs-NAC对293T肾胚胎细胞存活率的影响。并进一步使用TNF-α和IL-6的ELISA(酶联免疫吸附剂测定)试剂盒评价细胞中炎症因子水平。
293T细胞以每孔1×104密度接种到96孔板中,并置于37℃、5%CO2条件下培育12h。接着,吸出96孔板中的旧培养基,分别加入含有不同浓度Au NCs-NAC的培养基溶液。继续培养20h后,吸出96孔板中的旧培养基,在每个孔中加入100μL MTT的培养基溶液(0.8mg/mL,继续培养4h。吸出96孔板中的残余培养基,在每个孔中加入150μL DMSO溶液,轻轻摇晃后,在Synergy H1型酶标仪上检测每孔的OD值(检测波长为570nm),用如下公式计算细胞存活率。细胞存活率(cell viability)(%)=(样品的OD570值/空白OD570值)×100%。
对于体外抗炎情况研究,巨噬细胞和293T肾胚胎细胞都被接种到96孔板中。然后,用400ng/mL脂多糖(LPS)处理293T肾胚胎细胞1小时。然后,将293T肾胚胎细胞培养上清液转入96孔板中培养RAW264.7巨噬细胞过夜。最后,用TNF-α/IL-6ELISA试剂盒检测RAW264.7巨噬细胞上清中TNF-α和IL-6的浓度。
如图7所示,合成的Au NCs-NAC对293T肾胚胎细胞的细胞存活率,在达到最大使用浓度200μg/mL时,细胞依然保持80%以上的存活率。表明本实施例的Au NCs-NAC具有低的细胞毒性。
以Au NCs-NAC为例,293T细胞提前4小时处理Au NCs-NAC(100μg/mL)后,加入含2mM过氧化氢的培养基。再分别使用活性氧探针DCFH-DA(图8),洗涤之后使用激光共聚焦显微镜进行成像。如图8所示,与过氧化氢刺激后的细胞相比,经过Au NCs-NAC处理的细胞中的活性氧荧光明显减弱,接近于对照组细胞。这说明Au NCs-NAC能够有效清除细胞中活性氧/活性氮,进而保护细胞。此外,如图9-10所示,Au NCs-NAC能够有效降低巨噬细胞由于LPS刺激产生的炎症因子(TNF-α和IL-6)产生,并接近于正常细胞水平。然而,同等剂量单独的乙酰半胱氨酸则无法实现。
实施例4:Au NCs-NAC治疗急性肾损伤和生物安全性评价
所有的实验操作均按照临床中心动物保健和使用委员会通过的动物使用和保健制度。雌性无胸腺小白鼠(六周,20-25g),在小白鼠后腿肌肉注射8mL/kg 50%的甘油溶液建立老鼠急性肾衰竭模型。2小时后,注射小分子药物乙酰半胱氨酸或者Au NCs-NAC。
小鼠随机分为5组:(1)健康鼠注射磷酸缓冲液;(2)健康鼠注射Au NCs-NAC;(3)甘油诱导的急性肾衰竭鼠注射磷酸缓冲液;(4)甘油诱导的急性肾衰竭鼠注射Au NCs-NAC;(5)甘油诱导的急性肾衰竭鼠注射Au NCs-NAC等量的乙酰半胱氨酸。健康鼠和甘油诱导的急性肾衰竭鼠24小时后安乐死小鼠,取小鼠血液离心获得血清,测量肌酐和血尿素氮含量。注射使用磷酸缓冲液为100μL,Au NCs-NAC注射剂量为4mg/kg,乙酰半胱氨酸注射剂量为4mg/kg。
如图11-12所示,健康鼠注射Au NCs-NAC的肌酐和血尿素氮含量没有明显变化。而注射Au NCs-NAC的急性肾衰竭小鼠肌酐和血尿素氮含量明显低于只注射磷酸缓冲液的小鼠,并接近健康鼠的水平。另一方面,同等剂量的乙酰半胱氨酸并不能有效的降低两个指标。这说明Au NCs-NAC能够有效的缓解和治疗急性肾衰竭,并比单独使用小分子药物乙酰半胱氨酸更好的治疗效果。
此外,使用急性肾衰竭鼠注射磷酸缓冲液和Au NCs-NAC,记录小鼠十五天内的存活情况。如图13所示,与对照组相比,注射Au NCs-NAC的小鼠存活率明显提高。
综上所述,本发明通过简单的合成方法,可大量制备出超小纳米颗粒Au NCs-NAC,该Au NCs-NAC能够有效的清除各类活性氧/活性氮物种,具有广谱的活性氧/活性氮清除能力,明显优于单独的乙酰半胱氨酸。并且其对293T肾细胞的毒副作用较低,与细胞共培养24小时后细胞存活率均达到80%以上;同时它们可以通过清除细胞内多余的活性氧/活性氮来保护细胞免受过氧化氢刺激。此外,能够有效降低炎症因子的产生,而同等剂量条件下单独的乙酰半胱氨酸则无法达到。而且,Au NCs-NAC在甘油诱导的急性肾衰竭小鼠上显示出良好的治疗效果,且明显优于同等剂量的单独的乙酰半胱氨酸。更重要的是,Au NCs-NAC具有良好的生物相容性和生物安全性。
应当理解的是,本发明的应用不限于上述的举例,对本领域普通技术人员来说,可以根据上述说明加以改进或变换,所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (9)
1.一种用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇,其特征在于,所述乙酰半胱氨酸稳定的金纳米簇包括:金纳米簇,结合于所述金纳米簇表面的乙酰半胱氨酸。
2.根据权利要求1所述的用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇,其特征在于,所述金纳米簇与所述乙酰半胱氨酸之间通过金-硫配位键结合。
3.根据权利要求1所述的用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇,其特征在于,所述金纳米簇和所述乙酰半胱氨酸的质量比为1:(1-10)。
4.根据权利要求1所述的用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇,其特征在于,所述乙酰半胱氨酸稳定的金纳米簇为直径小于等于3nm的球形簇状颗粒。
5.一种如权利要求1-4任一所述的用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇的制备方法,其特征在于,包括步骤:将氯金酸、氢氧化钠和乙酰半胱氨酸混合于水中,搅拌并加热,得到混合溶液;将所述混合溶液进行透析,得到所述乙酰半胱氨酸稳定的金纳米簇。
6.根据权利要求5所述的用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇的制备方法,其特征在于,所述氯金酸与乙酰半胱氨酸的质量比为1:(1-10)。
7.根据权利要求5所述的用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇的制备方法,其特征在于,所述搅拌并加热的时间为1-4小时。
8.根据权利要求5所述的用于急性肾损伤的乙酰半胱氨酸稳定的金纳米簇的制备方法,其特征在于,所述搅拌并加热的温度为25-50℃。
9.一种如权利要求1-4任一所述的乙酰半胱氨酸稳定的金纳米簇在制备治疗急性肾损伤制剂中的应用;
或者,一种如权利要求5-8任一所述的方法制得的乙酰半胱氨酸稳定的金纳米簇在制备治疗急性肾损伤制剂中的应用。
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