CN101283276A - 具有荧光性的磁性纳米颗粒及其制备方法和应用 - Google Patents
具有荧光性的磁性纳米颗粒及其制备方法和应用 Download PDFInfo
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- CN101283276A CN101283276A CNA2006800330700A CN200680033070A CN101283276A CN 101283276 A CN101283276 A CN 101283276A CN A2006800330700 A CNA2006800330700 A CN A2006800330700A CN 200680033070 A CN200680033070 A CN 200680033070A CN 101283276 A CN101283276 A CN 101283276A
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Abstract
公开了一种具有荧光性的磁性纳米颗粒(MNPs)及其制备方法和应用。本发明的磁性纳米颗粒既具有光学性能也具有磁性能,因此能够广泛地应用于生物领域。通过使用亲水性的材料对磁性纳米颗粒的二氧化硅表面进处理,能够将多种化学官能团引入至纳米尺寸的材料中。另外,通过使用这种被化学修饰的纳米尺寸的材料,能够提高或降低磁性纳米颗粒向细胞中的渗透性能,并且能够提高只作用于预期的特定细胞的选择性。
Description
技术领域
本发明涉及一种具有荧光性的磁性纳米颗粒(MNPs)及其制备方法和应用。
背景技术
磁性材料在包括医学诊断和生物传感器在内的常规的生物学应用中十分重要。因此,目前,大量的调查和研究均集中于使用纳米颗粒的细胞染色(生物成像)、细胞的分离、体内药物的传递、和体内基因送递。特别地,在生物领域利用纳米颗粒的方法受到了极大的关注,开始于使用发光量子点纳米颗粒通过量子点的细胞内的吸收来进行量子点的荧光的外部检测的研究(见授予Barbera-Guillem Emilio的名称为″Lipophilic,FunctionalizedNanocrystals and Their Use for Fluorescence Labeling of Membranes″的US6194213,以及授予Bawendi Moungi G.、Mikulec Frederic V.和Sundar VikramC的名称为″Biological applications of quantum dots″的US 6306610)。
然而,由于大多数包括量子点的纳米颗粒是由重金属如铬(Cd)、锌(Zn)、钴(Co)等组成的,为了增强它在生物领域的适应性,合成的纳米颗粒的表面应该具有生物相容性。因此,积极地展开了对纳米颗粒进行表面处理的各种尝试,例如,通过在合成的纳米颗粒的表面引入已知对活体组织无毒副作用的无机或有机化合物如二氧化硅(SiO2)或聚乙二醇(PEG),从而提高了纳米颗粒的亲水性并延长了该纳米颗粒在体内的循环时间(Shuming Nie et al.,Invivo Cancer Targeting And Imaging With Semiconductor Quantum Dots Nat.Biotechnol.,2004(22),969)。
然而,这种常规的量子点的合成方法涉及复杂且苛刻的合成条件,并且在进行表面处理后,存在总产率较低的问题。
近年来,对癌细胞的识别的研究进行了尝试,通过在量子点表面引入抗体以在其上结合特定的癌细胞,从而对癌细胞进行识别。对量子点的发光进行检测和定位的方法是研究难点之一并且对体外研究来说是十分重要的,但在体内研究中具有局限性。这是由于深层浓厚的生物组织的屏蔽,因此对量子点的发光进行检测存在困难(Mark Stroh et al.,″Zooming In and Out WithQuantum Dots″,Nat.Biotechnol.,2004(22),959)。
作为克服上述问题的另一种途径,进行了关于磁性纳米颗粒的研究。这是由于在体内引入磁性纳米颗粒能够很方便地通过施加外部强磁场如核磁共振成像(MRI)来对磁性材料的磁性能进行检测(见授予Gref Ruxandra等的名称为″Biodegradable Injectable Particles for Imaging″的US 5565215)。
因此,最近为了克服与量子点在生物领域的利用相关的问题,国内外的调查和研究团体和机构已经付出了大量的努力,例如,通过合成具有磁性能的纳米颗粒以及在其上引入二氧化硅外壳,从而使其适合用于生物领域。不幸的是,与纳米颗粒的表面处理相反,这种利用外部强磁场的方法不易适用于体外研究,如细胞研究。
在利用磁性能的另一个传统领域中,使用了将粒径为300nm至几微米的聚合物凝聚物与若干磁性纳米颗粒结合的材料(以搅炼的形式)。在上述经过处理的材料表面引入特定的化合物如万古霉素后,可以通过施加外部磁场对特定的细菌进行识别和分离。然而,有机聚合物在体内具有毒性,并且由于其合成的材料的尺寸过大,因而也不适合用于血管内的循环。
另外,为了得到预期的表面处理水平,具有有机聚合物外壳的这种材料必须经过非常复杂的合成过程,因此它的应用具有很大的局限性。也就是说,该合成材料的尺寸和表面可处理性对确保潜在的应用如体内的药物输送和基因送递而言是十分重要的因素。
发明内容
因此,着眼于上述问题而提出了本发明,本发明的一个目的是为了提供一种具有荧光性的磁性纳米颗粒。
本发明的另一个目的是为了提供一种磁性纳米颗粒以及含有该颗粒的基因送递系统(gene delivery system),其中,具有荧光性的磁性纳米颗粒与带负电荷的基因或核酸分子相结合。
本发明的又一个目的是为了提供一种磁性纳米颗粒以及含有该颗粒的基因送递系统,其中,具有荧光性的磁性纳米颗粒与带负电荷的核酸分子相结合。
本发明的再一个目的是为了提供一种磁性纳米颗粒以及含有该颗粒的细胞染色试剂,其中,具有荧光性的磁性纳米颗粒与抗体相结合。
本发明的另一个目的是为了提供一种上述磁性纳米颗粒的制备方法。
也就是说,由于对能够解决上述问题的并且能够在体内和体外应用的磁性纳米颗粒进行大量广泛而深入的研究和实验,本发明的发明人成功地合成并发表了具有生物相容性的含有被聚乙二醇(PEG)修饰的二氧化硅外壳的磁性纳米颗粒(Tae-Jong Yoon et al.,″Multifunctional Nanoparticles Possessing aMagnetic Motor Effect for Drug or Gene Delivery″,Angew.Chem.In.Ed.2005(44),1068-1071)。然而,由于聚乙二醇不带有电荷,因此很难与带电荷的生物分子如DNA分子相结合。
为了克服该问题,本发明的发明人发明了一种用带电荷的材料对磁性纳米颗粒的表面进行修饰的方法,该颗粒含有有机荧光材料并包覆有二氧化硅外壳。结果,我们合成了一种磁性纳米颗粒,该颗粒包覆有含有有机荧光材料的二氧化硅外壳并被带电荷的材料进行了表面修饰;并且我们还证实了,在细胞中引入该磁性纳米颗粒后,通过施加外部磁场能够对引入的纳米颗粒进行定位和控制,并且还能够通过简单方便的荧光检测在体内或体外研究中有效地使用该颗粒。基于这些发现完成了本发明。
根据本发明的一个方面,本发明的上述和其它目的可以通过提供具有含有磁性材料的核和表面修饰的二氧化硅外壳的磁性纳米颗粒来实现,所述外壳含有有机荧光材料并包覆在所述核上,该纳米颗粒的尺寸小于100nm并且是水溶性的。
根据本发明的另一个方面,提供了一种磁性纳米颗粒以及含有该颗粒的基因送递系统,其中,该磁性纳米颗粒与带负电荷的基因或核酸分子相结合。
根据本发明的又一个方面,提供了一种磁性纳米颗粒以及含有该颗粒的基因送递系统,其中,具有荧光性的磁性纳米颗粒与带负电荷的核酸分子相结合。
根据本发明的再一个方面,提供了一种磁性纳米颗粒以及含有该颗粒的细胞染色试剂,其中,具有荧光性的磁性纳米颗粒与抗体相结合。
根据本发明的另一个方面,提供了一种制备上述磁性纳米颗粒的方法。
本发明的磁性纳米颗粒具有可视性能和磁性能,能够适用于生物领域。通过该纳米颗粒的高度的亲水性能和简单的化学表面处理技术,能够使用多种化合物将化学官能团引入至纳米尺寸的材料中。使用这种化学修饰的纳米尺寸的材料能够提高或降低磁性纳米颗粒向细胞中的渗透性能。此外,使用带有正电荷的纳米尺寸的材料,通过将期望的质粒DNA转移至靶细胞中,该磁性纳米颗粒能够有效地用作基因送递系统;使用合适的表面处理技术,基于能够将纳米颗粒选择性地与特定的细胞相结合,并能够对结合有该颗粒的细胞进行识别的技术,该磁性纳米颗粒还能够有效地用于细胞的染色。另外,通过施加外部强磁场,能够对选择性识别的细胞进行分离和纯化。
附图说明
通过以下详细的描述并结合附图,可以更清楚地理解本发明的上述或其它目的、特征和其它优点,附图为:
图1为含有有机荧光材料并包覆有二氧化硅外壳的磁性纳米颗粒(MNP@ SiO2(RITC或FITC))的制备方法的示意图;
图2A-2C为含有有机荧光材料并包覆有二氧化硅外壳的磁性纳米颗粒(MNP @ SiO2(RITC或FITC))的透射电子显微镜(TEMs)图像;
图3为使用多种硅化合物对本发明的磁性纳米颗粒(MNP@ SiO2(RITC或FITC))的表面进行化学处理的示意图;
图4为对本发明的磁性纳米颗粒进行各种表面处理后,检测到的所有磁性纳米颗粒的表面电荷变化的ζ电位曲线图(黑色:未进行表面处理的MNP@SiO2(RITC),红色:(CH3O)3Si-PEG-表面处理的MNP@SiO2(RITC)-PEG,淡绿色:(CH3O)3Si-PMP-表面处理的MNP@SiO2(RITC)-PMP,和蓝色:(CH3O)3 Si-PTMA-表面处理的MNP@SiO2(RITC)-PTMA);
图5A-5D为显示了MNP@SiO2(RITC)-PEG、MNP@SiO2(RITC)-PTMA、MNP@SiO2(RITC)和MNP@SiO2(RITC)-PMP在乳腺癌细胞中的渗透率的共聚焦激光扫描(confocal laser scanning)的显微照片;
图6A-AH为显示了在相同的条件下以相同的量向乳腺癌细胞中注射了MNP@SiO2(RITC)-PEG和MNP@SiO2(RITC)-PMP之后,纳米颗粒在细胞内的定位的共聚焦激光扫描的显微照片(6A-6D:注射了MNP@SiO2(RITC)-PEG的显微照片,6E-6H:注射了MNP@SiO2(RITC)-PMP的显微照片;6A和6E:红色荧光显微照片,6B和6F:光学显微照片,6C和6G:经过DAPI核染色确认的荧光显微照片,和6D和6F:分别为6A-6C和6E-6G的叠加显微照片);
图7为显示了使用MNP@SiO2(RITC)、MNP@SiO2(RITC)-PEG、MNP@SiO2(RITC)-PMP、和MNP@SiO2(RITC)-PTMA分别对乳腺癌细胞系(MCF-7)、肺癌细胞系(A549)和正常(非恶性)的肺上皮细胞系(NL20)进行细胞毒性试验(MTT分析)的结果的柱状图;
图8为通过将MNP @ SiO2(RITC)-PTMA与质粒DNA相结合,而将其用作基因送递系统的示意图;
图9A-9D为通过使用结合有质粒DNA的MNP@SiO2(RITC)-PTMA进行基因送递而转染的细胞的共聚焦激光扫描的显微照片(9A:蓝色荧光显微照片,9B:光学显微照片,9C:红色荧光显微照片,和9D:9A、9B和9C的叠加显微照片);
图10为使用(CH3O)3Si-PEG和3-氨基丙基三乙氧基硅烷(APS)对MNP@SiO2(FITC)的表面进行共处理、在MNP@SiO2(FITC)表面的胺基中引入马来酰亚胺基、和引入用于对特定细胞进行识别的抗体的过程的示意图;
图11A-11D为在细胞染色中使用了结合有抗体的MNP@SiO2(FITC)-PEG/APS-MaI的共聚焦激光扫描的显微照片;(11A:蓝色荧光显微照片,11B:光学显微照片,11C:红色荧光显微照片,和11D:11A、11B和11C的叠加显微照片);其中,渗入细胞的材料为发射红色荧光的MNP@SiO2(RITC),结合于细胞膜的材料为发射蓝色荧光的MNP@SiO2(FITC)-PEG/APS-MaI-Her2Ab(下文称作MNP@SiO2(FITC)-Her2Ab);
图12A-12F为显示了被引入到蓝色纳米颗粒中以后,具有CD10抗体的、能够选择性地结合于白血病细胞(SP2/O)的细胞膜上的MNP@SiO2(FITC)-CD10Ab的选择性的显微照片,其中,MNP@SiO2(FITC)-CD10Ab选择性地结合于白血病细胞(SP2/O)的细胞壁上(12A-12C),但没有与肺癌细胞(A549)相结合(12D-12F);
图13A和13B为光学显微照片,该照片显示了MNP@SiO2(FITC)-CD10Ab被白血病细胞的细胞壁选择性地识别,然后被外部磁场所捕获(A:不施加外部磁场,和B:对红色虚线区域施加外部磁场,然后引起细胞向特定区域移动);和
图14显示了在对小鼠腹膜内注射了MNP@SiO2(RITC)以后,以预定的时间间隔进行核磁共振成像分析的结果,其中,对照为未注射磁性纳米颗粒的小鼠的显微照片,其余的为使用合成的磁性纳米颗粒对小鼠进行注射15分钟、30分钟、1小时、1天、和3天后的显微照片。
具体实施方式
在下文中将对本发明进行更加详细的描述。
本发明的磁性纳米颗粒含有位于颗粒内部的磁性材料,并且该颗粒的核的外部包覆有非磁性二氧化硅外壳,该外壳含有有机荧光材料并被带电材料进行了表面修饰。因此,本发明的磁性纳米颗粒既具有光学性能也具有磁性能,能够广泛的应用于生物领域。
本发明的磁性纳米颗粒可以通过包括以下步骤的方法制备得到:
1)使用聚乙烯吡咯烷酮(PVP)聚合物对水溶性磁性纳米颗粒的表面进行处理,将该纳米颗粒转变成可分散于乙醇中的颗粒,随后进行离心分离;
2)将步骤1中分离得到的聚合物稳定的磁性纳米颗粒分散于用于二氧化硅包覆的乙醇中;
3)将由3-氨基丙基三乙氧基硅烷(ASP)处理的有机荧光材料的溶液和四乙氧基硅烷(TEOS)的溶液加入到步骤2中得到的溶液中,并在该混合溶液中加入NH4OH以诱导在含有有机荧光材料的磁性纳米颗粒的表面形成二氧化硅;和
4)使用硅化合物对步骤3中得到的磁性纳米颗粒的二氧化硅外壳的表面进行处理。
根据相应的步骤,下文中将对本发明的磁性纳米颗粒的制备方法进行更加详细的描述。
在步骤1中,所述水溶性磁性纳米颗粒可以通过本领域中已知的常规方法制备得到,例如,湿法、干法或真空法。这些方法的例子包括但不限于,对大尺寸材料进行研磨、从溶液中沉淀、共沉淀法、微乳化作用、多聚法(polyol process)、有机前驱体的高温降解、溶液技术、气溶胶/气泡法(aerosol/bubble method)、喷雾热解法、等离子喷雾法、和激光热解法。优选情况下,本发明的水溶性磁性纳米颗粒可以通过共沉淀法制备得到。
所述水溶性磁性纳米颗粒包括钴(Co)和铁(Fe)的氧化物,并且可以包括过渡金属如锰(Mn)、锌(Zn)、镍(Ni)、铜(Cu)等的氧化物。
在步骤3中,所述有机荧光材料优选为异硫氰酸罗丹明B(RITC)或异硫氰酸荧光素(FITC),但不限制于这些,还可以包括现有的有机荧光材料的化学变体。例如,它们可以由亚历克莎(Alexa Fluor)、罗丹明红X(RhodamineRed-X)、德克萨斯红(Texas Red)、四甲基罗丹明、瀑布蓝(Cascade Blue)、DAPI(4′,6-二脒基-2-苯基吲哚)、香豆酮、荧光黄(Lucifer Yellow)、和丹酰基胺(Dansylaminde)制成。
本发明的二氧化硅的原料TEOS的量的增加将导致磁性纳米颗粒的二氧化硅外壳的厚度的增加。因此,通过控制TEOS的量能够控制所述磁性纳米颗粒的大小。
在步骤4中,用于对所述二氧化硅外壳进行表面修饰的硅化合物优选为带电荷的材料,即,具有离子官能团的有机硅化合物。例如,该有机硅化合物可以包括引入有(CH3O)3Si-官能团的特定的功能化合物如离子化合物、水溶性化合物和药物。特别地,能够用于本发明的硅化合物可以包括但不限于选自由(CH3O)3Si-PEG[(CH3O3)SiCH2CH2CH2O(CH2CH2O)6-9CH3]、(CH3O)3Si-PMP[(CH3O)3SiCH2CH2CH2PO2(OCH3)Na]、(CH3O)3Si-PTMA[(CH3O)3SiCH2 CH2CH2N+(CH3)3Cl-]、和3-氨基丙基三乙氧基硅烷(APS)所组成的组中的一种化合物。
本发明的磁性纳米颗粒对包括乳腺癌细胞系(MCF-7)、肺癌细胞系(A549)和正常(非恶性的)肺上皮细胞系(NL20)在内的所有种类的细胞均未显示出毒性。
将本发明的磁性纳米颗粒摄入到细胞内之后,将该细胞暴露于外部磁场,磁性纳米颗粒的量未达到引起细胞毒性的量,但已经足够使细胞显示出能够诱导移动的磁性。上述细胞可以包括真核细胞、人细胞、动物细胞、和植物细胞。所述磁性颗粒的平均粒径为约小于100nm,优选为约30-80nm。
通过施加磁通密度为0.3特斯拉的外部磁场(ca.0.3 tesla,T),渗入有磁性纳米颗粒的细胞以0.5-1毫米/秒的速率移动。所述外部磁场的强度和移动的速率并不限于上述范围。
另外,通过将表面修饰的二氧化硅外壳的表面与多种材料如带负电荷的基因、或核酸分子和抗体相结合,本发明的包覆有含有有机荧光材料的二氧化硅外壳并且表面被带电荷的材料修饰的磁性纳米颗粒可以用于多种领域。
例如,在本发明的磁性纳米颗粒的表面修饰的二氧化硅外壳的表面上,带正电荷的MNP@SiO2(RITC)-PTMA与带负电荷的基因相结合。
结合有带负电荷的基因的磁性纳米颗粒可以通过包括以下步骤的方法制备得到:
1)在HEPES[N-(2-羟乙基)-哌嗪-N′-(2-乙磺酸)]缓冲溶液中,加入带负电荷的基因和带正电荷的MNP@SiO2(RITC)-PTMA并进行孵育;
2)将CaCl2加入到步骤1中孵育后的溶液中,并进一步孵育该溶液2小时,和;
3)将杜氏改良培养基(Dulbecco’s Modified Eagle Medium,DMEM)加入到步骤2中孵育后的溶液中,并调节Ca2+离子浓度至4.5mM,然后进一步孵育该溶液4小时,之后用磷酸盐缓冲液(PBS)对该溶液进行洗涤。
当与带负电荷的基因结合的磁性纳米颗粒{质粒DNA-[MNP@SiO2(RITC)-PTMA]}进入靶细胞时,它们穿过细胞膜并将带负电荷基因送递到细胞中,然后该颗粒与基因分离而作为残留在细胞质中的磁性纳米颗粒(红色荧光)。此外,可以确认,在细胞质中合成了由送递的DNA编码的蓝色蛋白质(见图8)。
优选情况下,所述带负电荷的基因包括但不限制于质粒DNA,特别是pcDNA3.1/CT-GFP。因此,根据本发明的磁性纳米颗粒可以与多种基因相结合。
除了能够与带负电荷的基因结合外,根据本发明的磁性纳米颗粒还可以与带负电荷的核酸分子结合。
因此,通过将该颗粒附着于带负电荷的基因或核酸分子,本发明的磁性纳米颗粒可以有效地用于基因送递系统。
此外,通过将抗体引入到本发明的磁性纳米颗粒的表面修饰的二氧化硅外壳的表面,该磁性纳米颗粒可以选择性地与特定的细胞相结合。引入到细胞中的磁性纳米颗粒可以通过施加外部磁场诱导它们移动而被分离出。
结合有抗体的磁性纳米颗粒可以通过包括以下步骤的方法制备得到:
1)使用Si-PEG/3-氨基丙基三乙氧基硅烷(APS)对含有有机荧光材料的磁性纳米颗粒的表面进行共处理;
2)将步骤1中得到的磁性纳米颗粒与马来酰亚胺丁酸反应,从而在位于磁性纳米颗粒的二氧化硅外壳的表面上的氨基中引入马来酰亚胺基(MaI);
3)使抗体与2-巯基乙胺反应以生成具有巯基的抗体;和
4)将使步骤3中得到的抗体与位于步骤2中得到的磁性纳米颗粒的二氧化硅外壳的表面上的马来酰亚胺基(MaI)进行结合。
步骤4中可用的抗体的例子包括抗白血病细胞的CD-10抗体和抗乳腺癌细胞的Her2抗体。然而,能用于本发明的抗体并不限于此,可以包括多种细胞的抗体如干细胞的抗体。
因此,通过将纳米颗粒与感兴趣的抗体结合,本发明的磁性纳米颗粒可以有效地用作细胞染色剂。
另外,在使用该纳米颗粒对小鼠进行腹膜内给药以后,在小鼠的肝脏内可以观察到显示为黑色磁性信号的本发明的磁性纳米颗粒。
因此,本发明的磁性纳米颗粒可以有效地用于细胞染色(生物成像)、细胞分离、体内的药物输送、和体内的基因送递。
此外,本发明的磁性纳米颗粒还可以用作能够同时进行荧光分析和核磁共振成像分析的分析试剂。
实施例
下面通过参考以下实施例对本发明进行更加详细的说明。提供这些实施例仅仅是为了对本发明进行说明而不应该理解为对本发明的范围和宗旨的限制。
实施例1:本发明的磁性纳米颗粒的制备
1、含有有机荧光材料并被二氧化硅外壳包覆的磁性纳米颗粒的制备
在34.7ml的铁酸钴磁性纳米颗粒的水溶液中加入0.65ml的聚乙烯吡咯烷酮(PVP)水溶液(浓度为25.6g/L),并在室温下搅拌1天。将水和丙酮的比例为1∶10的溶液加入到由聚乙烯吡咯烷酮稳定的磁性纳米颗粒溶液中,将得到的混合溶液在4000rpm的条件下离心10分钟。倒掉上清液,将沉淀的纳米颗粒重新分散于10ml的乙醇中。在得到的分散体中加入有机荧光材料溶液,如用3-氨基丙基三乙氧基硅烷(ASP)处理的RITC(异硫氰酸罗丹明B)或FITC(异硫氰酸荧光素),和四乙氧基硅烷(TEOS)的乙醇溶液(摩尔比为0.04∶03)。将0.86ml的含30重量%NH3的NH4OH加入到该混合溶液中,从而诱导在磁性纳米颗粒的表面形成二氧化硅。使用高速离心机将包覆有含有有机荧光材料的二氧化硅外壳的磁性纳米颗粒在18,000rpm的条件下离心30分钟,然后用水和乙醇对沉淀物进行洗涤。得到的材料可以迅速地分散于水或醇中。
图1显示了包覆有含有有机荧光材料的二氧化硅外壳的磁性纳米颗粒(MNP@SiO2(RITC或FITC))的制备方法,和图2显示了包覆有含有有机荧光材料的二氧化硅外壳的磁性纳米颗粒(MNP@SiO2(RITC或FITC))的透射电子显微镜(TEMs)图像。
如图2所示,作为二氧化硅的原料的TEOS的量的增加将导致磁性纳米颗粒的尺寸增加。因此,通过控制TEOS的量能够将所述磁性纳米颗粒的外壳厚度调节至预期的范围内。
2、包覆有含有有机荧光材料的二氧化硅外壳并且表面被带电荷的材料修饰的磁性纳米颗粒的制备
将45mg在部分1中制得的磁性纳米颗粒(MNP@SiO2(RITC))分散在10mL的乙醇中,在该分散液中各自加入0.02mmol的硅化合物[125mg的(CH3O)3Si-PEG,(CH3O)3SiCH2CH2CH2O(CH2CH2O)6-9CH3;238mg的(CH3O)3Si-PMP,(CH3O)3SiCH2CH2CH2PO2(OCH3)Na;和257mg的(CH3O)3Si-PTMA,(CH3O)3SiCH2CH2CH2N+(CH3)3Cl-],然后用NH4OH将溶液的酸度调至pH值为12。在60℃下剧烈振荡该溶液3小时。然后使用高速离心机在转速为18,000rpm的条件下对该溶液离心30分钟,从而使表面处理的纳米颗粒沉淀。过量的硅化合物残留在滤液中。使用水和乙醇洗涤沉淀的纳米颗粒3次,并进行纯化和分离。这样制得的纳米颗粒在水中显示出很高的稳定性。
图3显示了使用多种硅化合物对本发明的磁性纳米颗粒的表面进行化学处理过程,图4显示了对本发明的磁性纳米颗粒进行各种表面处理后,检测到的全部磁性纳米颗粒的表面电荷变化的ζ电位曲线。
从图3和4中可以看出,未进行表面处理的MNP@SiO2(RITC)(黑线)的电荷值为-16.8mV;(CH3O)3Si-PEG-表面处理的MNP@SiO2(RITC)-PEG(红线)的电荷值为2.4mV;(CH3O)3Si-PMP-表面处理的MNP@SiO2(RITC)-PMP(淡绿线)的电荷值为-50mV;(CH3O)3Si-PTMA-表面处理的MNP@SiO2(RITC)-PTMA(蓝色线)的电荷值为+35.7mV。
实验实施例1:本发明的磁性纳米颗粒的细胞渗透性
为了检测本发明的磁性纳米颗粒的细胞渗透性,特进行以下实验。
从ATTC(American Type Culture Collection)购得乳腺癌细胞系(MCF-7)。将该乳腺癌细胞系置于DMEM培养基中进行培养,该培养基含有40μl的10%的牛胎血清(FBS)、2mg/mL的实施例1中制得的未进行表面处理的磁性纳米颗粒[MNP@SiO(RITC)]、和2mg/mL的实施例1中制得的硅表面处理的磁性纳米颗粒[MNP@SiO2(RITC)-PEG,MNP@SiO2(RITC)-PMP,或MNP@SiO2(RITC)-PTMA]。将所有细胞置于Lab-Tek腔室玻片(glasschamber slide)上培养并通过共聚焦激光扫描(CLSM)进行观察。
在相同的条件下,向乳腺癌细胞中注射相同量的未进行表面处理的磁性纳米颗粒[MNP@ SiO2(RITC)]和硅表面处理的磁性纳米颗粒[MNP@SiO2(RITC)-PEG,MNP@SiO2(RITC)-PMP或MNP@SiO2(RITC)-PTMA],所述纳米颗粒在细胞中的渗透性如图5所示。另外,在相同的条件下,向乳腺癌细胞中注射相同量的MNP@SiO2(RITC)-PEG和MNP@SiO2(RITC)-PMP,所述纳米颗粒在细胞中的渗透性如图6所示。
如图5所示,在相同的条件下,向乳腺癌细胞中注射相同量的硅表面处理的磁性纳米颗粒,检测到的这些纳米颗粒在细胞中的渗透性的强度依次为:MNP@SiO2(RITC)-PEG>MNP@SiO2(RITC)-PTMA=MNP@SiO2(RITC)>MNP@SiO2(RITC)-PMP。
此外,如图6所示,6A-6D为注射了MNP@SiO2(RITC)-PEG的显微照片,6E-6H为注射了MNP@SiO2(RITC)-PMP的显微照片;6A和6E为红色荧光显微照片,6B和6F为光学显微照片,6C和6G为经过DAPI核染色确认的荧光显微照片,和6D和6F分别为6A-6C和6E-6G的叠加显微照片。使用(CH3O)3Si-PEG进行表面处理的磁性纳米颗粒具有中性电性能并且其在渗透入细胞内后在细胞质中呈现不规则的分布,而(CH3O)3Si-PMP表面处理的磁性纳米颗粒具有负电型电性能并分散于核膜的周围。
也就是说,根据修饰部分的种类,本发明的包覆有含有有机荧光材料的二氧化硅外壳并且表面被带电荷的材料修饰的磁性纳米颗粒在细胞上具有不同的定位,因此通过使用本发明的磁性纳米颗粒的表面电荷能够诱导该纳米颗粒在细胞内的定位发生变化。
实验实施例2:细胞毒性试验(MTT分析)
为了检测本发明的磁性纳米颗粒的细胞毒性,进行了以下实验。
从ATTC(American TypeCulture Collection)购得乳腺癌细胞系(MCF-7)、肺癌细胞系(A549)和正常(非恶性)肺上皮细胞系(NL20)。将MCF-7细胞系置于DMEM培养基中进行培养,该培养基含有40μl的10%的牛胎血清(FBS)和2mg/mL的本发明的纳米颗粒。在相同的培养条件下,将A549细胞系和NL20细胞系在RPMI培养基(含有10%的FBS、2mM的L谷氨酰胺、1mM的丙酮酸钠、1×非必需氨基酸、和5mM的2-巯基乙醇)中进行培养。将所有细胞置于Lab-Tek腔室玻片上培养以便于通过共聚焦激光扫描(CLSM)进行观察。
将每个细胞系各自置于96孔培养板上进行培养,孵育结束后向各孔中加入50μl的MTT[3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑盐溴化物],然后加入磷酸盐缓冲液(PBS,0.2mg/mL,pH 7.2)使最终的细胞毒性(MTT)浓度为0.4mg/mL。将细胞在5%的CO2环境下在37℃下进一步孵育4小时。用移液器小心地移除培养基,将通过负责存活细胞的细胞呼吸的线粒体脱氢酶的作用而形成的甲月替晶体(formazan crystals)溶解于150μl二甲基亚砜(DMSO)中。使用振荡器将得到的溶液振荡10分钟,并分别检测其在490nm和620nm处的光密度值(OD)。
结果如图7所示。
如图7所示,根据本发明的磁性纳米颗粒对所有种类的细胞均未显示出毒性[乳腺癌细胞系(MCF-7)、肺癌细胞系(A549)、和正常(非恶性)的肺上皮细胞系(NL20)]。
实施例2:结合有质粒DNA的MNP@SiO2(RITC)-PTMA的制备
使用pcDNA3.1/CT-GEP作为质粒DNA基因。
将质粒DNA和MNP@SiO2(RITC)-PTMA置于30μl的HEPES[N-(2-羟乙基)-哌嗪-N′-(2-乙磺酸)]缓冲液中,将得到的杂交产物在4℃下孵育2小时,随后加入30μl的100mM的CaCl2。将得到的溶液进一步孵育2小时,然后转移至24孔培养板中。随后,在培养板中加入0.6ml的DMEM,并将Ca2+离子浓度调节为4.5mM。在37℃下进一步孵育4小时后,使用PBS溶液对结合有DNA的纳米颗粒进行洗涤。将结合有DNA的纳米颗粒加入到细胞中,并观察基因送递的信号。
图8显示了通过将用(CH3O)3Si-PTMA对本发明磁性纳米颗粒进行表面处理得到的MNP@SiO2(RITC)-PTMA与质粒DNA进行结合来作为基因送递系统的过程。图9为通过使用结合有质粒DNA的MNP@SiO2(RITC)-PTMA进行基因送递而转染的细胞的共聚焦激光扫描的显微照片。
如图8所示,一旦进入细胞,与作为质粒DNA基因的pcDNA3.1/CT-GFP结合的带正电荷的纳米颗粒(MNP@SiO2(RITC)-PTMA)穿过细胞膜,然后该颗粒从质粒DNA上分离下来,从而将磁性纳米颗粒留在细胞质中(红色荧光)并将质粒DNA转移至细胞。该转移的DNA在细胞质中合成了蓝色的蛋白。
如图9所示,9A为蓝色荧光显微照片,9B为光学显微照片,9C为红色荧光显微照片,和9D为9A、9B和9C的叠加显微照片。红色斑点与MNP@SiO2(RITC)-PTMA相对应,蓝颜色表示通过DNA转染在细胞质中显示的GFP荧光。
因此,通过与质粒DNA基因结合,本发明的磁性纳米颗粒能够有效地用作基因送递系统。
实施例3:MNP@SiO2(FITC)-PEG/APS-MaI材料的制备
根据与实施例1相同的方法制备MNP@SiO2(FITC)-PEG/APS,不同在于在用实施例1部分1中的(C3HO)3Si-PEG化合物对磁性纳米颗粒(MNP@SiO2(FITC))进行处理时,使用3-氨基丙基三乙氧基硅烷(APS)进行共处理。
将MNP@SiO2(FITC)-PEG/APS的无水二甲基甲酰胺溶液[36.5mL;Si-PEG/APS=5/1(摩尔比),22.9mg/mL,胺浓度为6.5mmol/g],加入到马来酰亚胺丁酸(0.96g,1.4mmol)、PyBOP(六氟磷酸苯并三唑-1-基-氧-三吡咯烷基鏻)(0.43g,0.826mmol)、和HOBt(N-羟基苯并三唑)(0.19g,1.4mmol)在无水二甲基甲酰胺中的溶液中。接下来,将纯化的二异丙基乙胺(0.2ml)加入到混合物中,然后在室温下振荡20小时。将反应材料转移至Eppendorf管中,并用二甲基甲酰胺(DMF)洗涤数次。将纳米颗粒重分散于0.8ml的DMF中,在避光状态下室温保存。
图10显示了使用(CH3O)3Si-PEG和3-氨基丙基三乙氧基硅烷(APS)对MNP@SiO2(FITC)的表面进行共处理、在MNP@SiO2(FITC)表面的胺基中引入马来酰亚胺基、和引入用于对特定细胞进行识别的抗体的过程。
实施例4:在本发明的纳米颗粒中引入抗体生物分子以及细胞染色
用10μl的0.5M的EDTA对抗体(CD-10或Her2Ab)在PBS中的溶液(200μg/ml)进行预处理。将2-巯基乙胺(5μl,0.779mmol)在500μl的PBS中的溶液加入到抗体溶液中,然后在37℃下孵育90分钟。通过此步骤,抗体被分为使用置于实施例3中得到的MNP@SiO2(FITC)-PEG/APS-MaI(0.8ml,22.9mg/mL PBS)中的Sephadex G-25进行纯化的部分和在37℃孵育20小时的部分。在转速13,000rpm的条件下,对结合有抗体的纳米颗粒进行离心沉淀20分钟,随后进行过滤。将1ml的PBS加入到过滤物中使结合有抗体的纳米颗粒重新分散,并在4℃下保存。
图11显示了在细胞染色中使用了结合有抗体的磁性纳米颗粒的共聚焦激光扫描的显微照片。
图12显示了在用于白血病细胞和肺癌细胞的细胞染色中,使用了结合有抗体的磁性纳米颗粒的共聚焦激光扫描的显微照片。
如图11所示,渗入细胞的材料为发射红色荧光的MNP@SiO2(RITC),结合于细胞膜的材料为发射蓝色荧光的MNP@SiO2(FITC)-PEG/APS-MaI-Her2Ab;11A:蓝色荧光显微照片,11B:光学显微照片,11C:红色荧光显微照片,和11D:11A、11B和11C的叠加显微照片。
如图12所示,CD10抗体选择性地结合于白血病细胞(SP2/O)的细胞壁上(12A-12C),但没有与肺癌细胞相结合(12D-12F)。
实施例5:用本发明的磁性纳米颗粒对小鼠进行腹腔内给药(体内试验)
为了检测根据本发明的磁性纳米颗粒的体内作用,进行了以下实验。
作为本次实验的实验室动物,将无特定病原的、4周鼠龄的雄性ICR小鼠(n=12)在条件维持在温度为22±3℃的、湿度为55±10%的、和光暗循环为12:12小时的实验室的选育室中进行饲养。在进行实验前,将小鼠在实验室的选育室的新环境中驯化1周。使用实验室动物饲料(用于鼠,来自Cheiljedang Corporation,Seoul,Korea)和灭菌后的双蒸水对动物进行饲养。
使用本发明的MNP@SiO2(RITC)通过腹膜内注射对小鼠进行给药,每隔15分钟通过核磁共振成像进行观察。对照组没有使用本发明的纳米颗粒进行给药。
结果如表14所示。
如图14所示,在使用该纳米颗粒对小鼠进行给药以后,在小鼠的肝脏内可以观察到黑色磁性信号。
工业适用性
本发明的磁性纳米颗粒既具有光学性能也具有磁性能,可以广泛地应用于生物领域。由于该纳米颗粒的高度的亲水性能和简单的化学表面处理技术,能够通过使用多种化合物将化学官能团引入至纳米尺寸的材料中。
虽然以说明的目的在此公开了本发明的优选实施方式,但本领域技术人员在不背离所附权利要求所公开的本发明的范围和宗旨的情况下,能够容易地进行各种可能的修改、补充和替换。
Claims (24)
1、一种磁性纳米颗粒,该纳米颗粒包括核和包覆在该核上的表面修饰的二氧化硅外壳,该核含有磁性材料,该外壳含有有机荧光材料,其中,该纳米颗粒的尺寸小于100nm,并且是水溶性的。
2、根据权利要求1所述的纳米颗粒,其中,该磁性纳米颗粒包括选自由钴的氧化物、铁的氧化物、锰的氧化物、锌的氧化物、镍的氧化物、和铜的氧化物所组成的组中的一种金属氧化物。
3、根据权利要求1所述的纳米颗粒,其中,所述有机荧光材料为异硫氰酸罗丹明B或异硫氰酸荧光素。
4、根据权利要求1所述的纳米颗粒,其中,所述二氧化硅外壳的表面被带电荷的材料所修饰。
5、根据权利要求4所述的纳米颗粒,其中,所述带电荷的材料为具有离子官能团的有机硅化合物。
6、根据权利要求5所述的纳米颗粒,其中,所述具有离子官能团的有机硅化合物为选自由(CH3O)3SiCH2CH2CH2O(CH2CH2O)6-9CH3、(CH3O)3SiCH2CH2CH2PO2(OCH3)Na、(CH3O)3SiCH2CH2CH2N+(CH3)3Cl-、和3-氨基丙基三乙氧基硅烷所组成的组中的一种化合物。
7、根据权利要求1所述的纳米颗粒,其中,所述磁性纳米颗粒渗入细胞,并且通过施加磁通密度为0.3特斯拉的外部磁场,所述磁性纳米颗粒以0.5-1毫米/秒的速率移动。
8、根据权利要求7所述的纳米颗粒,其中,所述细胞为真核细胞、人细胞、动物细胞或植物细胞。
9、一种结合有基因的磁性纳米颗粒,其中,带负电荷的基因结合于如权利要求1-8中的任意一项所述的磁性纳米颗粒的表面修饰的二氧化硅外壳的表面。
10、根据权利要求9所述的纳米颗粒,其中,所述带负电荷的基因为质粒DNA。
11、根据权利要求10所述的纳米颗粒,其中,所述质粒DNA为pcDNA3.1/CT-GFP。
12、一种基因送递系统,该系统包括如权利要求9所述的结合有基因的磁性纳米颗粒。
13、一种结合有核酸的磁性纳米颗粒,其中,带负电荷的核酸分子结合于如权利要求1-8中的任意一项所述的磁性纳米颗粒的表面修饰的二氧化硅外壳的表面。
14、一种基因送递系统,该系统包括如权利要求13所述的结合有核酸的磁性纳米颗粒。
15、一种结合有抗体的磁性纳米颗粒,其中,抗体结合于如权利要求1-8中的任意一项所述的磁性纳米颗粒的表面修饰的二氧化硅外壳的表面。
16、根据权利要求15所述的纳米颗粒,其中,所述表面修饰的二氧化硅外壳的表面被3-氨基丙基三乙氧基硅烷所修饰。
17、根据权利要求16所述的纳米颗粒,其中,所述3-氨基丙基三乙氧基硅烷的氨基被马来酰亚胺丁酸处理,从而在氨基中引入马来酰亚胺基。
18、根据权利要求17所述的纳米颗粒,其中,所述抗体具有通过与2-巯基乙胺反应而形成的巯基。
19、根据权利要求18所述的纳米颗粒,其中,所述抗体为抗白血病细胞的CD-10抗体、或抗乳腺癌细胞的Her2抗体。
20、一种细胞染色剂,该染色剂包括如权利要求15所述的结合有抗体的磁性纳米颗粒。
21、一种磁性纳米颗粒的制备方法,该方法包括:
1)使用聚乙烯吡咯烷酮聚合物对水溶性磁性纳米颗粒的表面进行处理,将该纳米颗粒转变成可分散于乙醇的颗粒,随后进行离心分离;
2)将步骤1中分离的聚合物稳定的磁性纳米颗粒分散于用于二氧化硅包覆的乙醇中;
3)将由3-氨基丙基三乙氧基硅烷处理的有机荧光材料的溶液和四乙氧基硅烷溶液加入到步骤2中得到的溶液中,并在该混合溶液中加入NH4OH,以诱导在含有有机荧光材料的磁性纳米颗粒的表面上形成二氧化硅;和
4)使用硅化合物对步骤3中得到的磁性纳米颗粒的二氧化硅外壳的表面进行处理。
22、一种结合有带负电荷的基因的磁性纳米颗粒的制备方法,该方法包括:
1)在N-(2-羟乙基)-哌嗪-N′-(2-乙磺酸)缓冲溶液中,加入带负电荷的基因和带正电荷的MNP@SiO2(RITC)-PTMA,并进行孵育;
2)将CaCl2加入到步骤1中孵育后的溶液中,并进一步孵育该溶液2小时;和
3)将杜氏改良培养基加入到步骤2中孵育后的溶液中,并调节Ca2+离子浓度至4.5mM,然后进一步孵育该溶液4小时,之后用磷酸盐缓冲液对该溶液进行洗涤。
23、一种结合有抗体的磁性纳米颗粒的制备方法,该方法包括:
1)使用Si-PEG/3-氨基丙基三乙氧基硅烷对含有有机荧光材料的磁性纳米颗粒的表面进行共处理;
2)将步骤1中得到的磁性纳米颗粒与马来酰亚胺丁酸反应,从而在位于磁性纳米颗粒的二氧化硅外壳的表面上的氨基中引入马来酰亚胺基;
3)使抗体与2-巯基乙胺反应,以形成具有巯基的抗体;和
4)将步骤3中得到的抗体与步骤2中得到的磁性纳米颗粒的二氧化硅外壳的表面上的马来酰亚胺基进行结合。
24、一种分析试剂,该试剂通过使用如权利要求1-8中的任意一项所述的磁性纳米颗粒而能够同时进行荧光分析和核磁共振成像分析。
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