CN109153073A - 制备具有金属核的中空纳米颗粒的方法 - Google Patents

制备具有金属核的中空纳米颗粒的方法 Download PDF

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CN109153073A
CN109153073A CN201780027826.9A CN201780027826A CN109153073A CN 109153073 A CN109153073 A CN 109153073A CN 201780027826 A CN201780027826 A CN 201780027826A CN 109153073 A CN109153073 A CN 109153073A
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瓦莱利奥·瓦利安尼
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Abstract

本发明涉及二氧化硅中空纳米颗粒，其空腔内具有金属核，该金属核由无机纳米结构组成，该无机纳米结构涂覆有保护剂并与聚合物聚集剂聚集，其特别适用于医学中生物成像技术医学和/或放疗或化疗技术；本发明还涉及制备该纳米颗粒的方法。

Description

制备具有金属核的中空纳米颗粒的方法
技术领域
一般而言，本发明涉及纳米材料领域，更确切地说，本发明涉及合成具有金属核的中空纳米颗粒的新方法，以及这种纳米颗粒，其特别是在医药中用作治疗剂或用于生物成像技术。
背景技术
近年来，金属纳米颗粒的意想不到的特性使得有可能创造出创新、高效和个性化的治疗剂和诊断剂。实例是许多纳米结构被提议作为用于活体内组织或器官可视化的造影剂，用于细胞内分子的靶向转运，或者用于基于光热效应或X射线效应增强的治疗。
尽管贵金属纳米颗粒具有吸引人的品质和高度预期，但是目前没有一种贵金属纳米颗粒能够从动物模型中转换为人类的实际用途。事实上，为了使这种用途在人体中成为可能，纳米颗粒在人体内进行诊断或治疗作用后，必须在合理的时间内被完全消除。这一要求在历史上已由美国食品和药物管理局针对每种类型的化学治疗剂确定，并且现在已经标准化。
消除注射到人体的药剂的最有效途径被认为是肾脏排泄的途径，其通过肾小球的过滤来控制，并且已经显示出最大喷射的颗粒尺寸的阈值是8nm。较大的物体可以通过人体排泄的其他途径消除，即分别通过肝脏或脾脏分泌在胆汁和粪便中。通过肝脏的消除途径特别适合于捕获和消除流体动力学直径为10-20nm的生物材料，例如病毒。另一方面，通过脾脏的排泄路径由静脉窦中的内皮内裂隙形成，裂隙的尺寸约为200nm，理论上通过它可以消除大于上述8nm的颗粒。不幸的是，通过这些途径排出注入的金属纳米颗粒被证明是一个极其缓慢和低效的过程，导致在生物体中金属的积累，从而增加了长期毒性的可能性。因此，需要对可注射到人体内的纳米颗粒的尺寸的上述严格要求，公认最大为8nm。
在金属纳米颗粒的生物医学用途中需要考虑的另一个缺点是，如果保留在体内，则它们可能会与医学中常用的诊断技术(如放射技术)相互作用和/或干扰。例如，放射检查可能特别容易受到在患者器官中积累的具有高原子序数的金属的影响，使得金属会由于线性衰减系数的变化而干扰X射线图像。另一个例子是磁共振，其中没有质子的空间由具有高原子序数的金属的积累而产生将引起显着的干扰，或者超声波检查仍然会导致回声增加，或者正电子发射断层检查(Positron Emission Tomographic,PET)会受到光子衰减的影响，例如参见《药理学综述》(Pharmacol.Rev.53:283-318,2001)。因此，为了避免干扰其他常用的诊断技术，注入到人体内的金属纳米颗粒在它们发挥作用之后必须从人体内完全排泄出。
此外，如果使用的金属纳米颗粒的尺寸小于3nm，则它们的化学、物理和生理特性可能被改变，甚至丧失。例如，直径小于2nm的金纳米颗粒失去了其特有的等离子体共振，并且由于高的表面/体积比值，表面活性也可能危及这些纳米颗粒的潜在应用。此外，它们从体内的排泄速度如此之快，以至于使得例如在有肿瘤的情况下不可能在组织中产生所需的积累。因此，在本领域中，不仅需要可用的超小尺寸的金属纳米颗粒，还需要这种纳米颗粒在其可能的应用(特别是生物医学中的应用)中具有良好的化学和物理性能，其中纳米颗粒的生物降解性至关重要。
《化学通讯》(Cassano D.et al.,Chem.Commun.,2015,51,9939-9941)公开了含有金纳米颗粒阵列的中空二氧化硅纳米球。
鉴于上述内容，显然具有适用于制备具有上述特征并特别适用于生物医学用途的金属纳米颗粒的方法是至关重要的。另一方面，据申请人所知，制备金属纳米颗粒的方法迄今尚未开发出来，该方法可再现并且能够控制获得的纳米颗粒的尺寸，以获得具有可通过肾脏途径消除的治疗和/或诊断目的的有用特性的纳米颗粒。如上所述，仍然非常需要这种制备方法。
发明内容
现在申请人已经发现了制备中空二氧化硅纳米颗粒的新方法，在中空二氧化硅纳米颗粒的空腔中具有金属核(metal core)，该金属核包含无机亲水纳米结构，由合适的涂层保护并且由于合适的聚合物聚集剂而彼此聚集。
该方法允许制备具有明确限定的尺寸和特征的纳米颗粒，此外，当它们用于例如生物成像技术中时，能够作为合适尺寸的单一体与细胞和组织相互作用，随后还能够非常快速地生物降解成它们自己的组分，使得它们不会在人体内长时间停留，而是通过肾脏途径快速排出体外。此外，该制备方法允许在中空纳米颗粒内插入超小磁性结构，进一步拓宽了具有金属核的纳米颗粒的可能应用领域，如下文详细描述。
因此，本发明的主题是制备中空二氧化硅纳米颗粒的方法，所述中空二氧化硅纳米颗粒的直径小于100nm，并且空腔内的金属核包含亲水性无机纳米结构，每个亲水性无机纳米结构的直径小于3nm并一起形成聚集体，该方法的基本特征在所附权利要求书中的第一个权利要求中限定。
本发明的另一主题由上述制备方法中的中间体表示，如本文所附的权利要求10中所限定。
直径小于100nm的二氧化硅中空纳米颗粒，可通过上述方法获得，并且在其空腔中具有亲水性无机纳米结构的聚集体，每个亲水性无机纳米结构的尺寸小于3nm，如本文所附权利要求12所限定，以及它们作为诊断剂和/或治疗剂的用途，仍代表了本发明的又一主题。
本发明的制备方法和通过该方法获得的纳米颗粒的其他重要特征在以下详细描述中说明。
附图简要说明
图1显示了用透射电子显微镜(TEM)获得的以下实施例3中描述制备的中空纳米颗粒的显微照片。
图2显示了对以下实施例1-3中获得的产品所记录的紫外-可见吸收光谱，如对于实施例1的金团簇(用-表示)，对于实施例2的60kDa的聚(4-乙烯基吡啶)聚集体(用---表示)，以及对于实施例3的聚集体的二氧化硅中空纳米颗粒(用…表示)。
发明详述
在本发明中，“无机纳米结构”是指尺寸小于3nm的无机纳米颗粒，优选选自超顺磁性氧化铁的纳米颗粒，选自金、银和铂的金属团簇，以及这些团簇的混合物。根据本发明的特别优选的实施方案，包含在本发明纳米颗粒的核中的无机纳米结构是金团簇。
根据本发明的制备二氧化硅中空纳米颗粒的方法包括以下步骤，在其空腔中具有无机纳米结构聚集体。
i)通过用硼氢化钠还原醇溶液中的酸或金属盐，形成具有负电荷涂层的超小亲水无机纳米结构；
ii)通过将所述聚(4-乙烯基吡啶)加入到步骤i)获得的无机纳米结构的醇溶液中，形成具有聚(4-乙烯基吡啶)作为上述亲水性无机纳米结构的聚集剂的聚集体；
iii)在步骤ii)获得的所述聚集体的存在下，通过在乙醇和水的混合物中水解由氨催化的正硅酸乙酯，形成所述二氧化硅中空纳米颗粒，所述二氧化硅中空纳米颗粒在所述空腔中具有金属核，所述金属核包含上述亲水无机纳米结构的聚集体。
在本发明的纳米结构中，负电荷涂层优选由具有羧基的涂层剂产生，更优选由谷胱甘肽产生。
谷胱甘肽或GSH是由甘氨酸、半胱氨酸和谷氨酸形成的三肽，具有众所周知的抗氧化特性。这是一种已少量存在于活生物体中的产物，它主要具有来自自由基的细胞的保护功能。近年来，由于其抗氧化性能，它被提出作为几种产品中的活性成分，如补充剂或具有抗氧化活性的药物；因此，它是完全可接受的产品，用于旨在摄入诊断或治疗目的的产品。聚(4-乙烯基吡啶)也是一种已知安全无毒的产品，并被频繁使用；优选地，在本发明方法中，使用平均分子量为60kDa的聚(4-乙烯基吡啶)。由二氧化硅制成的本发明的纳米颗粒的外部中空结构保护金属核免受外部环境的影响，这也是完全生物相容的和可生物降解的，并且它可以容易地用生物分子涂覆或功能化。更具体地，在本发明的方法中，本发明的中空纳米颗粒的外表面可以容易地被改性和功能化，并且这可以通过标准方案来实现。表面改性可以用各种聚合物或肽或盐化分子实现，优选用(3-氨基丙基)三乙氧基硅烷(APTES)进行表面改性。一旦被修饰，表面可以通过标准方案(例如通过肽化学技术)依次被各种生物分子(例如基于纳米颗粒必须指向的靶标选择的抗体、适体、荧光团、蛋白质等)功能化。
通过本发明的方法，可以合成限定尺寸的纳米颗粒，其由二氧化硅中空纳米结构组成，其中彼此聚集的无机纳米结构通过聚合物聚集剂结合在空腔内。尽管所得到的结构复杂并且由几个组分组成，但是除了直径小于100nm之外，该结构极其稳定，能够到达人体中的目靶组织，以产生期望的诊断和/或治疗作用，然后到降解并通过肾脏途径以单一组分的形式排泄。
换句话说，例如从光学角度来看，本发明纳米颗粒的金属核表现为独特的主体，但是它随后降解为生物体内的单一组分以用于排泄或用于特定功能，例如治疗功能，这可能是它的目的。无机纳米结构上的涂层的存在，特别是当涂层剂是谷胱甘肽时，谷胱甘肽分子的两部分羧酸，可以允许与药物活性成分或前药结合；因此，本发明的中空纳米颗粒可以代表生物体中活性成分的控释系统，通过二氧化硅壳的降解和一旦到达靶组织就从金属核释放。
通过本发明的方法可获得的中空纳米颗粒的最终结构的直径小于100nm，优选在30nm至40nm之间，而这些纳米颗粒的空腔内的金属团簇各自的直径小于3nm，优选在0.6nm至2nm之间。
根据本发明的一个特别优选的实施方案，通过本发明方法制备的纳米颗粒，其直径在30nm至40nm之间，这些尺寸对于改善组织细胞内化和到达靶组织的可能性是最佳的。
在人体内给药后，例如通过肠内或优选肠胃外途径给药，这些纳米颗粒可以在活体内成像技术中用作造影剂、诊断剂和/或治疗剂。在体内，在纳米颗粒被内化到靶组织细胞中的一段时间后，它们通过释放单一组分而降解，其中可以通过肾脏途径毫无困难地消除最大尺寸为3nm的金属团簇。用于本发明纳米颗粒的这种类型的可能应用的例子是在光声学中，或者在放射疗法中。
因此，本发明方法的优点是多方面的：首先，该方法允许获得比制备类似颗粒已知的方法小得多的颗粒。此外，本发明方法允许获得纳米颗粒，一旦它们通过与细胞和组织的相互作用在人体中作为诊断剂和/或治疗剂发挥作用，每个颗粒就会作为独特主体，它们被降解成具有这种性质和尺寸的单一组分，从而通过肾脏途径容易和快速地将其消除。不希望与理论联系在一起，发明人特别注意到，从所进行的试验来看，涂覆金属团簇的谷胱甘肽分子的存在以及它们小于3nm的尺寸，似乎影响了在非常短的时间内完成的本发明纳米颗粒在生物体中的排泄。
如果需要，本发明方法还允许获得纳米颗粒，该纳米颗粒可以通过标准方案在其外表面上用几种分子(例如抗体、适体、荧光团等)功能化。此外，当使用例如超顺磁性氧化铁纳米颗粒(Super Paramagnetic Iron Oxide Nanoparticles,SPIONs)来形成金属核磁性纳米结构时，可以将超小磁性结构结合在本发明的纳米颗粒的空腔内。最终，这是一个极其简单、低成本和可重复的过程。
通过发明本方法获得的纳米颗粒可进行冷冻干燥，并且以冷冻干燥的形式储存很长时间而不丧失其性质。最后，它们可用于上述生物医学应用，它们也具有最佳尺寸，以利用所谓的增加渗透性和保留的效果。
提供以下实施例作为本发明的非限制性说明。
实施例1
金属团簇的合成
按照以下程序已制备了金团簇。将1.0mmol(0.307g)谷胱甘肽加入到50mlHAuCl4·3H2O(0.25mmol，0.1g)甲醇溶液中。然后将混合物在冰浴中搅拌冷却30分钟，直至温度约0℃。然后，在剧烈搅拌下，在该混合物中快速注入12.5ml新制备的0.2M硼氢化钠水溶液(0.1g)。将混合物再反应1小时。然后通过离心收集所得沉淀物，并通过离心沉淀物并用甲醇洗涤3次(每次在13400rpm下洗涤10分钟)，以除去原料。最后，将沉淀物溶解在milliQ水中并冷冻干燥，得到70mg深褐色粉末形式的金团簇。
实施例2
金属团簇的聚集体的合成
将0.5mg以上实施例1中上述制备的金团簇溶解在5ml乙醇中，然后加入10μl聚(4-乙烯基吡啶)的二甲基甲酰胺(60kDa，DMF中20mg/ml)溶液，保持在室温下搅拌30分钟。通过离心(13400rpm持续3分钟)收集如此获得的金聚集体，在400ml乙醇中重悬浮，并进行至多4分钟的超声处理。
实施例3
含金属团簇的聚集体的中空纳米颗粒的合成
在100ml圆底烧瓶中倒入35ml无水乙醇、1.2ml 30％氢氧化铵水溶液和20μl正硅酸乙酯(TEOS,98％)。将如此获得的反应混合物在室温下保持搅拌20分钟，然后向400μl如实施例2中所述制备的金聚集体的乙醇溶液中加入1ml milliQ，并在搅拌下再保持3小时。一旦停止搅拌，将反应混合物在4000rpm下离心30分钟以收集形成的纳米颗粒，然后通过离心用乙醇洗涤两次(每次在13400rpm下洗涤3分钟)以除去未反应的前体，并重悬浮在1ml乙醇中。如此获得的胶体产品最终在13400rpm下离心5分钟，再悬浮在500μl milliQ水中，进行超声处理5分钟，冷冻干燥过夜。由此获得粉红色粉末，如果在10℃的温度下储存在暗处，则其稳定至少一年。
实施例4
实施例1-3中获得的产物的表征
通过扫描电子显微镜(SEM)和透射电子显微镜(TEM)分析在其空腔中具有金属种子(metal seed)聚集体的二氧化硅中空纳米颗粒，并分析中间产物，即金属团簇及其与聚(4-乙烯基吡啶)的聚集体。
在图1中可见如上实施例3中所述制备的纳米颗粒的TEM显微照片。这些分析允许检查在本发明方法中实际形成的产物，并且除其他外，显示聚集体形式的金属种子如何在二氧化硅空心球中完全内化。
在图2中描绘了在PBS 1x缓冲溶液中记录的按照实施例1-3描述制备的金团簇、其聚集体和含有它们的纳米颗粒的紫外-可见吸收光谱。鉴于金团簇尺寸极小，在团簇本身的表面上具有很高比例的金属原子。这意味着其表面上的配体诱导其电子和光学性质上相关的修饰。事实上，图2中的团簇的光谱(用-表示)显示了可能与等离子共振(约560nm)相关的谱带和与金属中心带间跃迁相关的谱带(约740nm)。用聚(4-乙烯基吡啶)(用---表示)聚集后，740nm处的谱带移至700nm。这可能归因于GSH(带负电)和聚合物(带正电)之间的离子相互作用。聚集体(用…表示)周围的纳米胶囊的形成似乎导致了进一步轻微向蓝色谱带移动。在这种情况下，这种效应可能与光谱上较低的散射组分有关。

Claims (15)

1.制备二氧化硅中空纳米颗粒的方法，所述二氧化硅中空纳米颗粒的直径小于100nm并且在空腔内的金属核包含无机纳米结构，每个所述无机纳米结构的直径小于3nm并与聚(4-乙烯基吡啶)一起形成聚集体，所述方法包括以下步骤：
i)通过用硼氢化钠还原醇溶液中的酸或金属盐，形成具有负电荷涂层的超小亲水无机纳米结构；
ii)通过将所述聚(4-乙烯基吡啶)加入到步骤i)获得的无机纳米结构的醇溶液中，形成具有聚(4-乙烯基吡啶)作为所述亲水性无机纳米结构的聚集剂的聚集体；
iii)在步骤ii)获得的所述聚集体的存在下，通过在乙醇和水的混合物中水解由氨催化的正硅酸乙酯，形成所述二氧化硅中空纳米颗粒，所述二氧化硅中空纳米颗粒在所述空腔中具有金属核，所述金属核包含亲水无机纳米结构的所述聚集体。
2.根据权利要求1所述的方法，其中所述无机纳米结构选自超顺磁性氧化铁的纳米颗粒，选自金、银和铂的金属团簇，以及所述团簇的混合物。
3.根据权利要求2所述的方法，其中所述金属是金。
4.根据权利要求1所述的方法，其中所述二氧化硅中空纳米颗粒的直径在30nm至40nm之间，所述无机纳米结构的直径在1nm至2nm之间。
5.根据前述权利要求中任一项所述的方法，其中所述无机纳米结构的所述涂层由具有羧酸基团的涂层剂形成。
6.根据权利要求5所述的方法，其中所述涂层剂是谷胱甘肽。
7.根据前述权利要求中任一项所述的方法，其中来自步骤i)的所述无机纳米结构在随后的步骤ii)中的聚集之前进行涂层的功能化，所述涂层具有一种或多种功能性分子，所述功能性分子具有药理活性。
8.根据前述权利要求中任一项所述的方法，还包括用一种或多种分子修饰和/或功能化所述二氧化硅纳米颗粒的外表面的步骤，所述分子如抗体、适体、荧光团、蛋白质、聚合物或硅烷化肽。
9.根据前述权利要求中任一项所述的方法，还包括步骤iii)获得的二氧化硅纳米颗粒的冻干的步骤。
10.如权利要求1至9所限定的制备纳米颗粒的方法中的中间体，由具有负电荷涂层的无机纳米结构的聚集体组成，每个无机纳米结构的直径小于3nm并与聚(4-乙烯基吡啶)一起形成聚集体。
11.如权利要求8所限定的中间体在制备二氧化硅中空纳米颗粒中的用途，所述二氧化硅中空纳米颗粒在其空腔内具有金属核，所述金属核包括聚集体形式的无机纳米结构。
12.通过制备如权利要求1-9中限定的纳米颗粒的方法获得的中空二氧化硅纳米颗粒，其直径小于100nm，其空腔内的金属核包括具有负电荷涂层的无机纳米结构，每个无机纳米结构的直径小于3nm，并与聚(4-乙烯基吡啶)一起形成聚集体。
13.根据权利要求12所述的纳米颗粒，其直径在30nm至40nm之间，并且在其空腔内的核中包括无机纳米结构，每个所述无机纳米结构的尺寸在1nm至2nm之间。
14.权利要求10所述的中间体或权利要求12所述的纳米颗粒，其中所述无机纳米结构是金团簇。
15.如权利要求12-14中限定的纳米颗粒作为诊断剂和/或治疗剂的用途，所述诊断剂和/或治疗剂适于通过肠内或非肠道途径给药到人体中，用于生物成像技术和/或用于放射治疗或化学治疗技术。
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