CN116212049A - 一种基于小胶质细胞炎性衰老调节的手性纳米材料在制备治疗阿尔茨海默症的药物中的应用 - Google Patents
一种基于小胶质细胞炎性衰老调节的手性纳米材料在制备治疗阿尔茨海默症的药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种基于小胶质细胞炎性衰老调节的手性纳米材料在制备治疗阿尔茨海默症的药物中的应用，本发明制备了一种超小型手性金纳米颗粒，所述纳米颗粒与靶向炎症小体NLRP3的抗体偶联形成手性纳米组装体。本发明制备的超小手性金纳米粒子具有选择性抑制β淀粉样蛋白聚集的能力。本发明制备的手性纳米组装体利用手性金纳米颗粒与SLC3A2的高效结合，克服了抗体靶向递送中的血脑屏障(BBB)的制约，有效的将抗体递送至脑内小胶质细胞中。抗体靶向NLRP3并以TRIM21依赖性蛋白酶体降解的途径降解小胶质细胞中NLRP3，抑制小胶质细胞的炎性衰老，以及恢复神经元的损伤实现治疗阿尔兹海默症的目的。
Description
技术领域
本发明涉及一种基于小胶质细胞炎性衰老调节的手性纳米材料在制备治疗阿尔茨海默症的药物中的应用，属于纳米药物技术领域。
背景技术
阿尔兹海默症(Alzheimer disease，AD)是神经退行性疾病中最常见的形式。β-淀粉样肽(β-amyloid peptide，Aβ)在AD的发生和发展中起着至关重要的作用。Aβ沉积通过激活NLRP3炎症小体的途径刺激小胶质细胞的持续活化，从而导致大脑神经炎症。最近的研究还表明，小胶质细胞的持续炎症激活促进了其在AD中的衰老，进而加剧AD进展。因此，旨在抑制Aβ沉积和NLRP3激活的策略具有作为AD治疗选择的重要前景。
手性在自然界中广泛存在，并在生物体系中表现出典型的独特偏好和选择性。Aβ原纤维作为一种形式的手性超分子体系对手性环境敏感。因此，当选择性靶向抑制Aβ聚集时，手性偏好可能代表一个关键问题。手性纳米粒子由于其良好的生物相容性和跨越血脑屏障(BBB)的潜在能力，被认为是抑制和重定向Aβ原纤维化的实用纳米药物。与一些小分子抑制剂相比，功能性蛋白质治疗被认为是治疗多种疾病的安全可靠的方法。抗体是蛋白质家族的功能性成员，可与靶蛋白结合并通过泛素-蛋白酶体降解途径引起靶蛋白的快速降解。该策略已被广泛探索用于蛋白质治疗，特别是神经退行性疾病治疗和癌症免疫治疗。然而，手性NP与蛋白质的结合用于AD的靶向治疗尚未得到充分阐明。
发明内容
针对目前已有报道关于AD治疗的纳米颗粒大，无法穿透BBB、生物相容性低、无选择性、易在肝肾聚集等缺点，本发明首先提供一种基于小胶质细胞炎性衰老调节的手性纳米组装体的制备方法，再提供所述基于小胶质细胞炎性衰老调节的手性纳米组装体在制备治疗阿尔茨海默症的药物中的应用。
本发明的第一个目的是提供一种基于小胶质细胞炎性衰老调节的手性纳米组装体的制备方法，包括如下步骤：
S1、将GSH溶液与HAuCl4溶液混合，然后将混合物在80～100℃下加热并搅拌20～40分钟，冷却后离心纯化得到GSH保护的手性金纳米粒子；
S2、将S1步骤制备的手性金纳米粒子冷冻干燥为粉末状，将粉末状手性金纳米粒子溶解后进行酰胺反应，然后与靶向炎症小体NLRP3的抗体的水溶液混合，并在0～8℃反应10～20小时，离心纯化得到所述手性纳米组装体。
进一步地，所述方法还包括在制备前，将反应容器采用王水浸泡处理的步骤。
进一步地，GSH溶液的浓度为4～6mmol/L，HAuCl4溶液的浓度为2～4mmol/L，GSH溶液与HAuCl4溶液的体积比为1.4～1.8:1。
进一步地，所述酰胺反应是通过1-(3-二甲基氨丙基)-3-3乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺进行活化反应。
进一步地，所述1-(3-二甲基氨丙基)-3-3乙基碳二亚胺盐酸盐(EDCI)的浓度为0.5-1mmol/L，所述N-羟基琥珀酰亚胺(NHS)的浓度为0.75-1.5mmol/L。
进一步地，所述手性金纳米粒子溶解后的终浓度为0.4～0.6mg/mL。
进一步地，S2步骤中，所述活化反应的时间为40～80min。
进一步地，S1或S2步骤中，所述离心是在10000～15000rpm离心20～40min。
进一步地，S2步骤中，所述抗体浓度为0.08～0.12mg/mL。
进一步地，所述抗体与手性金纳米粒子的摩尔比为1:5。
本发明的第二个目的是提供所述制备方法制备得到的基于小胶质细胞炎性衰老调节的手性纳米组装体。
本发明的第三个目的是提供所述的基于小胶质细胞炎性衰老调节的手性纳米组装体在制备治疗阿尔兹海默症的药物中的应用。
本发明的有益效果是：
1、本发明制备的超小手性金纳米粒子具有选择性抑制β淀粉样蛋白聚集的能力。
2、本发明制备的手性纳米组装体，利用手性金纳米颗粒与SLC3A2的高效结合，克服了抗体靶向递送中的血脑屏障的制约，有效的将抗体递送至脑内小胶质细胞中。
3、本发明制备的手性纳米组装体以TRIM21依赖性蛋白酶体降解途径降解小胶质细胞中NLRP3，抑制小胶质细胞的炎性衰老，以及恢复神经元的损伤实现治疗阿尔兹海默症的目的。
4、本发明制备的手性纳米组装体的生物相容性良好，稳定性好。
5、本发明提供的手性纳米组装体制备过程简单，产品可直接保存和使用。
6、除阿尔兹海默症治疗外，本发明还可以应用于其他功能性抗体治疗相关的脑部疾病，例如脑胶质瘤、抑郁症、帕金森症等疾病。
附图说明：
图1为本发明的基于小胶质细胞炎性衰老调节的手性纳米复合药物的合成及其作用示意图。
图2为实施例1中L-NP与D-NP的高分辨透射电镜图。
图3为实施例1中L-NP与D-NP的紫外吸收光谱图以及圆二色光谱图。
图4为实施例1中L-NP或D-NP抑制Aβ聚集的透射电镜表征。
图5为实施例2中L-NP或D-NP与抗体结合后的紫外吸收光谱图。
图6为实施例2中L-NP或D-NP表面修饰PEG并与抗体结合后的DLS粒径图与Zeta电位变化统计图。
图7为实施例2脑组织中Cy5.5染料标记的anti-NLRP3,L-NP,D-NP,L-NP-aNLRP3或D-NP-aNLRP3的荧光成像图、流式统计结果以及脑切片免疫荧光成像图。
图8为实施例2细胞内Cy5.5染料标记的anti-NLRP3,L-NP,D-NP,L-NP-aNLRP3或D-NP-aNLRP3的流式分析结果。
图9为实施例2中L-NP或D-NP与受体蛋白SLC3A2的等温量热滴定测试结果。
图10为实施例3细胞中NLRP3，p16ink4a和SA-β-GAL蛋白的表达。
图11为实施例3细胞上清液中炎症因子IL-1β，TNF-α和IL-6含量。
图12为实施例4中水迷宫实验路径图。
图13为实施例5中脑内小胶质细胞中NLRP3，p16ink4a和SA-β-GAL蛋白的表达。
图14为实施例5脑组织中炎症因子IL-1β，TNF-α和IL-6的含量。
图15为实施例6脑组织中Aβ蛋白和磷酸化的Tau蛋白的含量。
具体实施方式
下面结合具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。应理解，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。实施例中所用到的各种常用试剂，均为市售产品。
实施例1：制备具有选择性抑制β淀粉样蛋白聚集能力的超小手性金纳米粒子
(1)反应容器的前处理：将反应瓶用王水浸泡24h，洗净，晾干；
(2)手性超小金纳米粒子的制备：将4.8mmol/L的(左旋或右旋)GSH溶液与3mmol/LHAuCl4混合于超纯水中(GSH与HAuCl4的比例为1.6:1)，然后将混合物在90℃下加热并搅拌30分钟，冷却至室温并以13000rpm的转速离心纯化产物，用超纯水洗涤三次以产生GSH保护的(L型或D型)手性超小金纳米粒子，简称L-NP或D-NP。
图2是实施例1制备得到的L-NP或D-NP的高分辨透射电镜图，由图2可以得出：合成了粒径约为2.5～3nm，形貌为不规则球形的均匀分散的纳米颗粒。
图3是实施例1制备得到的L-NP或D-NP的紫外吸收光谱和圆二色光谱，由图3可以得出：L-NP和D-NP在350nm处展现出镜像对称的圆二色特征吸收信号。
图4是实施例1制备得到的L-NP或D-NP抑制Aβ聚集的透射电镜表征。将β淀粉样蛋白(Aβ42)单体溶解至磷酸盐缓冲液(pH＝7.4，10mM，10mM NaCl)中，并将浓度定至40μM，此溶液为防止聚集必须现配现用。随后将功能性纳米凝胶稀释至200μg/mL，等体积与Aβ42单体溶液充分混合，封口膜密闭，并于37℃条件下孵育48小时，通过透射电子显微镜观察其形态学变化。由图4可以得出：D-NP比L-NP更有效地防止溶液中从天然Aβ42无规则线圈到纤维状的结构转变。
实施例2：
制备手性纳米组装体，利用手性金纳米颗粒与SLC3A2的高效结合，克服了抗体靶向递送中的血脑屏障的制约，有效的将抗体递送至脑内。
手性纳米组装体制备步骤：
(1)反应容器的前处理：将反应瓶用王水浸泡24h，洗净，晾干；
(2)手性纳米组装体的制备：将实施例1中所得手性超小金纳米粒子冷冻干燥为粉末状，取一定质量溶解于超纯水中，终浓度为0.5mg/mL，并通过0.5-1mmol/L的1-(3-二甲基氨丙基)-3-3乙基碳二亚胺盐酸盐和0.75-1.5mmol/L的N-羟基琥珀酰亚胺进行活化反应1小时，将颗粒表面部分羧基转化成活性酯，然后与靶向炎症小体NLRP3的抗体的水溶液混合，4℃反应12小时，最终以13000rpm的转速离心纯化，磷酸盐缓冲液洗涤三次以产生(L型或D型)手性纳米组装体，简称L-NP-aNLRP3或D-NP-aNLRP3。其中，抗体与手性金纳米粒子的比为1:5，所述抗体浓度为0.1mg/mL。
图5是实施例2制备得到的L-NP-aNLRP3或D-NP-aNLRP3的紫外吸收变化。由图5可以得出：抗NLRP3抗体(anti-NLRP3)在约193nm处具有特征紫外吸收峰，L-NP或D-NP表面修饰anti-NLRP3后分别得到L-NP-aNLRP3或D-NP-aNLRP3，并在193nm处测得吸收强度约为0.5吸收峰。将L-NP-aNLRP3或D-NP-aNLRP3分别溶解于磷酸盐缓冲液和培养基中，吸收强度未发生变化，表面L-NP-aNLRP3或D-NP-aNLRP3的具有优良的生物稳定性。
如图6所示，L-NP或D-NP表面修饰抗anti-NLRP3后，DLS粒径从4.2±0.6nm增加到了12±2.4nm，Zeta电位也表现了显著的变化过程，进一步表明抗体成功结合在L-NP或D-NP表面，且结合率相当。
为了评估L-NP-aNLRP3或D-NP-aNLRP3介导的抗体穿过血脑屏障的能力，我们将相同浓度的Cy5.5染料修饰到不同颗粒或抗体(anti-NLRP3,L-NP,D-NP,L-NP-aNLRP3或D-NP-aNLRP3)表面，使用活体动物成像系统(IVIS)监测脑中Cy5.5的荧光强度。在静脉注射后6小时取完整脑组织进行荧光成像分析，结果表明，经D-NP-aNLRP3尾静脉注射的小鼠脑组织中观察到相较于L-NP-aNLRP3更显著的Cy5.5荧光信号(图7A)。
将脑组织研磨匀浆，然后重悬在1毫升的磷酸盐缓冲液中，用流式细胞仪进一步分析大脑内Cy5.5荧光信号，实验结果见图7B。
将脑组织取出做蜡切片，并进行免疫荧光染色，共聚焦荧光成像表征脑切片的Cy5.5荧光信号和anti-NLRP3信号，实验结果见图7C。
为了研究L-NP-aNLRP3或D-NP-aNLRP3穿过血脑屏障的机制，用不同的抗体或siRNA预处理内皮细胞3小时以抑制跨膜蛋白，然后加入Cy5.5标记的L-NP-aNLRP3或D-NP-aNLRP3孵育12小时。流式细胞仪分析结果显示，相比于L-NP-aNLRP3，经D-NP-aNLRP3处理的内皮细胞的平均荧光强度更强，这表明D-NP-aNLRP3被细胞摄取的量更多。当受体蛋白SLC3A2被阻断时，经L-NP-aNLRP3或D-NP-aNLRP3处理的内皮细胞平均荧光强度显著降低,实验结果见图8。
等温量热滴定(ITC)评估L-NP或D-NP与受体蛋白SLC3A2的亲和性；将手性NP(50μM)溶解在磷酸盐缓冲液中，并以每次2μL的剂量注入SLC3A2溶液(50μM)中。测量期间的搅拌速度为300rpm。通过NanoAnalyze软件分析数据和样本模型。结果表明，D-NP与内皮细胞表面SLC3A2受体蛋白的亲和力(Ka)更强，相比之下，L-NP与SLC3A2的亲和力较弱，实验结果见图9。
综上所述，制备了一种手性纳米-抗体组装体，利用手性金纳米颗粒与受体蛋白SLC3A2的高效结合，克服了抗体靶向递送中的血脑屏障的制约，有效的将抗体递送至脑内。
实施例3：
制备的D-NP-aNLRP3可有效的将抗体递送至小胶质细胞内，并以TRIM21依赖性蛋白酶体途径降解内源性NLRP3，减轻Aβ诱导的小胶质细胞的炎症和衰老表型。
将5μM Aβ原纤维分别与PBS，anti-NLRP3,L-NP,D-NP,L-NP-aNLRP3或D-NP-aNLRP3混和，每天刺激BV2小胶质细胞，共刺激三天，并用流式细胞仪对炎症小体NLRP3以及衰老标记物p16ink4a，β-半乳糖苷酶(SA-β-GAL)进行定量分析，实验结果见图10。
由图可知，Aβ组小胶质细胞中NLRP3，p16ink4a和SA-β-GAL的表达均高于正常未处理组。经D-NP-aNLRP3处理后的小胶质细胞，炎症小体及衰老标志物的表达均最大程度的减弱至正常组水平。
利用ELISA试剂盒对上清液中炎症因子IL-1β，TNF-α和IL-6进行定量检测，实验结果见图11。
由图可知，Aβ组上清液中炎症因子IL-1β，TNF-α和IL-6均高于正常未处理组。经D-NP-aNLRP3处理后的上清液，炎症因子最大程度的降低至正常组水平。
实施例4：
制备的D-NP-aNLRP3经尾静脉注射60天后可恢复AD老鼠的行为学能力：
每周给AD老鼠尾静脉注射PBS、anti-NLRP3、L-NP,D-NP,L-NP-aNLRP3或D-NP-aNLRP3(20mg/kg Au,5mg/kg anti-NLRP3)，在尾静脉第八周(第56天)的时候对小鼠进行为期四天的水迷宫行为学训练，并在第60天进行测试。
在具体实施过程中，AD组的小鼠2分钟时仍未找到逃生台，手动停止计时，而WT组小鼠经前期训练后，能够迅速找到台子。经D-NP-aNLRP3尾静脉注射后的AD鼠相比于其他治疗组，能以最快的速度找到台子。说明经D-NP-aNLRP3治疗60天后，AD小鼠行为学改善。实验结果见图12。
实施例5：
制备的D-NP-aNLRP3经尾静脉注射60天后可减轻AD老鼠脑内小胶质细胞的炎症和衰老表型：
当AD小鼠行为学有所改善时，利用流式细胞仪对小鼠脑中小胶质细胞炎症小体NLRP3以及衰老标记物p16ink4a，SA-β-GAL的表达进行定量分析，实验结果见图13。
由图可知，AD组的小胶质细胞NLRP3，p16ink4a和SA-β-GAL的表达均高于WT鼠。经D-NP-aNLRP3治疗后的AD鼠，小胶质细胞NLRP3，p16ink4a和SA-β-GAL的表达均显著下降。
利用ELISA试剂盒对小鼠脑组织中炎症因子IL-1β，TNF-α和IL-6进行定量检测，实验结果见图14。
由图可知，AD组的炎症因子IL-1β，TNF-α和IL-6的水平均高于WT鼠。经D-NP-aNLRP3处理后的AD鼠，炎症因子最大程度的降低至WT组水平。
实施例6：
制备的D-NP-aNLRP3经尾静脉注射60天后可减轻AD老鼠脑内Aβ沉积和Tau蛋白磷酸化，最终实现治疗阿尔兹海默症的目的：
当AD小鼠行为学有所改善时，利用ELISA试剂盒对小鼠脑组织中Aβ蛋白和磷酸化的Tau蛋白进行定量检测，实验结果见图15。
由图可知，AD组的Aβ蛋白和磷酸化的Tau蛋白的含量均高于WT鼠。经D-NP-aNLRP3处理后的AD鼠，Aβ蛋白和磷酸化的Tau蛋白的含量最大程度的降低至WT组水平。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例，本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换，均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。
Claims (10)
1.一种基于小胶质细胞炎性衰老调节的手性纳米组装体的制备方法，其特征在于，包括如下步骤：
S1、将GSH溶液与HAuCl4溶液混合，然后将混合物在80～100℃下加热并搅拌20～40分钟，冷却后离心纯化得到GSH保护的手性金纳米粒子；
S2、将S1步骤制备的手性金纳米粒子冷冻干燥为粉末状，将粉末状手性金纳米粒子溶解后进行酰胺反应，然后与靶向炎症小体NLRP3的抗体的水溶液混合，并在0～8℃反应10～20小时，离心纯化得到所述手性纳米组装体。
2.根据权利要求1所述制备方法，其特征在于，所述方法还包括在制备前，将反应容器采用王水浸泡处理的步骤。
3.根据权利要求1所述制备方法，其特征在于，GSH溶液的浓度为4～6mmol/L，HAuCl4溶液的浓度为2～4mmol/L，GSH溶液与HAuCl4溶液的体积比为1.4～1.8:1。
4.根据权利要求1所述制备方法，其特征在于，所述酰胺反应是通过1-(3-二甲基氨丙基)-3-3乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺进行活化反应。
5.根据权利要求4所述制备方法，其特征在于，所述1-(3-二甲基氨丙基)-3-3乙基碳二亚胺盐酸盐(EDCI)的浓度为0.5-1mmol/L，所述N-羟基琥珀酰亚胺(NHS)的浓度为0.75-1.5mmol/L，所述手性金纳米粒子溶解后的终浓度为0.4～0.6mg/mL。
6.根据权利要求1所述制备方法，其特征在于，S2步骤中，所述酰胺反应的时间为40～80min。
7.根据权利要求1所述制备方法，其特征在于，S2步骤中，所述抗体浓度为0.08～0.12mg/mL。
8.根据权利要求1所述制备方法，其特征在于，所述抗体与手性金纳米粒子的摩尔比为1:5。
9.一种权利要求1～8任一项所述制备方法制备得到的基于小胶质细胞炎性衰老调节的手性纳米组装体。
10.权利要求9所述的基于小胶质细胞炎性衰老调节的手性纳米组装体在制备治疗阿尔兹海默症的药物中的应用。
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