CN101014531A - 用多官能团配体稳定的水溶性纳米颗粒及其制备方法 - Google Patents

用多官能团配体稳定的水溶性纳米颗粒及其制备方法 Download PDF

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CN101014531A
CN101014531A CNA2004800438769A CN200480043876A CN101014531A CN 101014531 A CN101014531 A CN 101014531A CN A2004800438769 A CNA2004800438769 A CN A2004800438769A CN 200480043876 A CN200480043876 A CN 200480043876A CN 101014531 A CN101014531 A CN 101014531A
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soluble nanoparticles
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千珍宇
全永旭
崔真实
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Yonsei University
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Abstract

本发明公开了水溶性纳米颗粒，所述水溶性纳米颗粒由多官能团配体包围，该多官能团配体包括粘合区、交联区和反应区。在水溶性纳米颗粒中，多官能团配体的交联区与邻近的多官能团配体的另一交联区交联。此外，本发明提供一种制造水溶性纳米颗粒的方法，该方法包括(1)在有机溶剂中合成非水溶性纳米颗粒，(2)在第一溶剂中溶解非水溶性纳米颗粒，并在第二溶剂中溶解水溶性多官能团配体，(3)将步骤(2)中的两种溶液混合，使多官能团配体取代非水溶性纳米颗粒的表面，并将混合物溶解在水溶液中以进行分离过程，(4)使取代的多官能团配体相互交联。

Description

用多官能团配体稳定的水溶性纳米颗粒及其制备方法
技术领域
本发明总体而言涉及水溶性纳米颗粒，更具体而言，涉及由多官能团配体(LI-LII-LIII)包围的水溶性纳米颗粒，该多官能团配体(LI-LII-LIII)包括粘合区(LI)、交联区(LII)和反应区(LIII)，其中多官能团配体的交联区与邻近的多官能团配体的另一交联区交联。
此外，本发明涉及一种制造水溶性纳米颗粒的方法，该方法包括(1)在有机溶剂中合成非水溶性纳米颗粒，(2)在第一溶剂中溶解非水溶性纳米颗粒，并在第二溶剂中溶解水溶性多官能团配体，(3)将步骤(2)中的两种溶液混合，使多官能团配体取代非水溶性纳米颗粒的表面，并将混合物溶解在水溶液中以进行分离过程，(4)使取代的多官能团配体相互交联。
背景技术
惯常用于使物质调节或控制在原子或分子水平的纳米技术，适用于创造新的物质和材料，并应用在各种领域，例如电子、材料、通信、机械、医药、农业、能源和环境领域。
近来，各种纳米技术都在发展当中，而纳米技术通常分成下列三种。第一种涉及利用纳米材料合成超微细的新物质和物体的技术。第二种涉及一种生产器件的技术，该器件通过联合或设置纳米级材料实现其预定的功能。第三种涉及一种使纳米技术应用在生物工程学中的技术，称为纳米生物(nano-bio)。
特别地，在纳米生物领域中，纳米颗粒专门地用于杀死癌细胞、促进免疫反应、使细胞融合、传递基因或药物、进行诊断等。为了将纳米颗粒应用到上述领域，纳米颗粒必须具有活性组分能够粘合的部分，而且其必须在体内稳定地传递和分散，也就是，在水溶性环境中稳定地传递和分散。最近已经开发了很多满足这些条件的技术。
美国专利6,274,121公开了顺磁纳米颗粒，其包括诸如铁氧化物等的金属，其与具有结合部位的无机材料粘合，该结合部位能够与组织特异性结合物质和诊断学或药学活性物质结合。
美国专利6,638,494涉及顺磁纳米颗粒，其包括诸如铁氧化物等的金属，并且公开了一种防止纳米颗粒在重力场或磁场中进行粘合和沉淀的方法，其中特定的羧酸与纳米颗粒表面粘合。上述羧酸的例子包括例如马来酸、酒石酸和葡萄糖二酸的脂肪族二羧酸，或例如柠檬酸、环己烷和三羧酸的脂肪族多羧酸。
美国专利6,649,138公开了一种改善纳米颗粒的水溶性特性的方法，其中在具有半导体或金属材料的疏水纳米颗粒的表面上形成一个多重两性分散剂层。该多重两性分散剂以(1)具有亲水支链的疏水骨架，(2)具有疏水支链的亲水骨架，或(3)同时具有亲水和疏水支链的疏水或亲水骨架作为例子。
美国专利申请2004/0033345公开了一种包覆纳米颗粒的方法，其中在金属或半导体周围形成疏水性配体层，利用胶囊将纳米颗粒溶于水溶液中。此时，胶囊由亲水壳和疏水核组成。
美国专利申请2004/0058457提出了被单层包围的功能纳米颗粒，其中双官能肽与单层粘合，并且包括DNA和RNA的各种生物聚合物结合在肽上。
然而，根据上述方法制造的水溶性纳米颗粒具有以下缺点。在美国专利6,274,121和6,638,494，以及美国专利申请2004/0058457中，纳米颗粒是在水溶液中合成。在这种情况下，难以控制纳米颗粒的尺寸，而且合成的纳米颗粒尺寸分布不均匀。此外，由于它们是在低温下合成，纳米颗粒的结晶度低而且易于生成非化学计量化合物。另外，纳米颗粒的表面以单分子表面稳定剂涂覆，但稳定剂和纳米颗粒之间的结合强度不高，因此纳米颗粒在水溶液中稳定性较低。美国专利6,649,138和美国专利申请2004/0033345中的水溶性纳米颗粒由两性聚合物包围，因此与无机纳米颗粒相比，具有显著增大的直径。进而，这些纳米颗粒的成功应用实例被限制为半导体纳米颗粒。
发明内容
因此，本发明的目的在于提供水溶性纳米颗粒，其在水溶液中高度稳定，且对活体的毒性低，因此应用在各种领域，例如生物诊断和治疗，以及电子材料中，本发明的目的还在于提供此水溶性纳米颗粒的制备方法。
为了达到上述目的，本发明人将多官能配体加入到从有机溶剂中得到的纳米颗粒中，由此制造在水溶液中稳定且能够与各种活性组分结合的纳米颗粒。所述各多官能配体包括(a)与纳米颗粒结合的粘合区，(b)在水溶液中稳定纳米颗粒的交联区，和(c)能够与活性组分结合的反应区。
本发明提供了水溶性纳米颗粒，其由多官能团配体包围，该多官能团配体包括粘合区、交联区和反应区，其中多官能团配体的交联区与邻近的多官能团配体的另一个交联区交联。
此外，本发明提供一种制造水溶性纳米颗粒的方法，其包括(1)在有机溶液中合成非水溶性纳米颗粒，(2)在第一溶剂中溶解非水溶性纳米颗粒，并在第二溶剂中溶解水溶性多官能团配体，(3)将步骤(2)中的两种溶液混合，使多官能团配体取代非水溶性纳米颗粒的表面，并将混合物溶解在水溶液中以进行分离处理，(4)使取代的多官能团配体相互交联。
附图说明
通过与附图结合的以下详细说明，将更清楚地了解本发明的上述和其它目的、特征和其它优点，其中：
图1图示了根据本发明从非水溶性纳米颗粒到水溶性纳米颗粒的制造；
图2示意了本发明的水溶性纳米颗粒；
图3图示了根据本发明由二巯基丁二酸包围的水溶性铁氧化物纳米颗粒的制造工艺；
图4图示了在有机溶剂中由有机表面稳定剂包围的铁氧化物纳米颗粒的溶解性，以及在水溶液中由水溶性多官能团配体包围的铁氧化物的溶解性；
图5图示了本发明的水溶性铁氧化物纳米颗粒的电泳结果；
图6A至图6D是本发明的水溶性铁氧化物纳米颗粒(4，6，9和12nm)的透射电子显微镜(TEM)图；
图7图示了本发明的水溶性核-壳(FePt@Fe3O4)纳米颗粒的电泳结果；
图8是本发明的水溶性核-壳(FePt@Fe3O4)纳米颗粒的透射电子显微镜(TEM)图；以及
图9图示了本发明的水溶性铁氧化物纳米颗粒的电泳结果，其显示水溶性铁氧化物纳米颗粒能够与活性组分结合。
具体实施方式
在本发明的说明书中，“纳米颗粒”意指包括金属材料、金属硫族化合物、磁性材料、磁性合金、半导体材料、或多组分混合结构的颗粒，且其直径为1-1000nm，优选2-100nm。
在本发明的说明书中，“非水溶性纳米颗粒”意指由疏水表面稳定剂包围的纳米颗粒，其可通过纳米颗粒前体在有机溶剂中发生化学反应而制成，其包含常用的表面稳定剂，从而具有优异的结晶性和理想的尺寸、形状和组成。“表面稳定剂”意指能够稳定纳米颗粒的状态和尺寸的有机官能分子，代表性例子包括表面活性剂。
关于本发明的“水溶性纳米颗粒”，是在非水溶性纳米颗粒表面形成水溶性多官能团配体层而不是疏水表面稳定剂。多官能团配体相互交联，因此，水溶性纳米颗粒能够在水溶液中稳定地溶解和分散。具体而言，水溶性纳米颗粒由包括粘合区、交联区和反应区的多官能团配体包围。多官能团配体的交联区与邻近的多官能团配体的其它交联区交联。
本发明的纳米颗粒可以根据金属、金属硫族化合物、磁性材料、磁性合金、半导体材料或多组分混合结构、以及多官能团配体的类型以各种形式提供。
金属的例子包括Pt、Pd、Ag、Cu、Au、Ru、Rh、和Os，且金属硫族化合物的实例为MxEy(M＝Ti、V、Cr、Mn、Fe、Co、Ni、Cu、Zr、Mo、Ru、Rh、Ag、W、Re、Ta、Zn；E＝O、S、Se，0＜x≤3，0＜y≤5)、BaSrxTi1-xO3、PbZrxTi1-xO3(O≤x≤1)、和SiO2。磁性材料的例子包括Co、Mn、Fe、Ni、Gd、MM’2O4、和MxOy(M或M’＝Co、Fe、Ni、Mn、Zn、Gd、Cr、0＜x≤3，0＜y≤5)，磁性合金的例子包括CoCu、CoPt、FePt、CoSm、NiFe、CoAu、CoAg、CoPtAu、CoPtAg和NiFeCo。
此外，半导体材料可包括由选自第II族(Zn、Cd、Hg)和第VI族(O、S、Se)的元素组成的半导体材料、由选自第III族(B、Al、Ga、In)和第V族(P、As、Sb)的元素组成的半导体材料、由选自第IV族(Si、Ge、Pb、Sn)的元素组成的半导体材料、由选自第IV族(Si、Ge)和第VI族(O、S、Se)的元素组成的半导体材料、或由选自第V族(P、As、Sb、Bi)和第VI族(O、S、Se)的元素组成的半导体材料。
“多组分混合结构”是包括两种或更多种选自由金属、金属硫族化合物、磁性材料、磁性合金和半导体材料组成的组群中的组分的颗粒，且核-壳或条码为形状上的代表例子。
在本发明的说明书中，“多官能团配体(LI-LII-LIII)”意指包括(a)粘合区(LI)、(b)交联区(LII)、和(c)反应区(LIII)的材料。在下文中，将会提供多官能团配体的详细说明。
“粘合区(LI)”意指多官能团配体的一部分，其包含能够与纳米颗粒粘合的官能团，优选为配体的一端。因此，优选粘合区包括对组成纳米颗粒的材料具有高亲合性的官能团，且粘合区的官能团可根据组成纳米颗粒的材料类型而选择。粘合区可包括-COOH、-NH2、-SH、-CONH2、-PO3H、-PO4H、-SO3H、-SO4H、或-OH作为官能团。
“交联区(LII)”意指多官能团配体的另一部分，其包括能够与邻近的多官能团配体交联的官能团，且优选为配体的中心部分。“交联”意指邻近的多官能团配体间的分子间相互作用。分子间相互作用的说明性而非限定性的例子包括疏水性相互作用、氢键、共价键(例如二硫键)、范德华键、以及离子键。由于分子间相互作用不限制于上述例子，待交联的官能团可以根据所需的分子间相互作用的类型而选择。交联区可包括-SH、-NH2、-COOH、-OH、-环氧基、-乙烯基、或-乙炔基作为官能团。
“反应区(LIII)”意指多官能团配体的另一部分，其包括能够与活性组分粘合的官能团，且优选与反应区相对的另一端。反应区的官能团根据活性组分的化学式和类型而选择(见表1)。反应区的官能团的说明性，但非限定性的例子包括-SH、-COOH、-NH2、-OH、-NR4 +X-、磺酸基(-sulfonate)、硝酸基(-nitrate)或膦酸基(-phosphonate)作为官能团。
表1：多官能团配体中所包括的反应区的官能团例子
    I     II     III
    R-NH2     R4-COOH     R-NHCO-R1
    R-SH     R4-SH     R-SS-R
R-OH R4-(环氧基) R-OCH2C(OH)CHrR1
    RH-NH2     R4(环氧基)     R-NHCH2C(OH)CH2-R6
    R-SH     R4-(环氧基)     R-SCH2C(OH)CH2-R4
    R-NH2     R4-COH     R-N＝CH-R4
    R-NH2     R4-NCO     R-NHCONH-R4
    R-NH2     R4-NCS     R-NHCSNH-R1
    R-SH     R4-COCH2     R1-COCH2S-R
    R-SH     R4-O(C＝O)X     R-OCH2(C＝O)O-R1
    R-(氮丙啶基团)     R4-SH     R-CH2CH(NH2)CH2S-R4
    R-CH＝CH2     R4-SH     R-CH2CHS-R4
    R-OH     R4-NCO     R4-NHCOO-R
    R-SH     R4-COCH2X     R-SCH2CO-R1
    R-NH2     R1-CON3     R-NHCO-R1
    R-COOH     R1-COOH     R-(C＝O)O(C＝O)-R1+H2O
    R-SH     R1-X     R-S-R1
    R-NH2     R1CH2C(NH2+)OCH3     R-NHC(NH2+)CH2-R1
    R-OP(O2-)OH     R1-NH2     R-OP(O2-)-NH-R1
    R-CONHNH2     R4-COH     R-CONHN＝CH-R1
    R-NH2     R4-SH     R-NHCO(CH2)2SS-R1
(I：多官能团配体的反应区的官能团，II：活性组分，III：通过I与II的反应形成的键的例子)
在本发明中，原本包含上述官能团的化合物可用作水溶性多官能团配体。或者，通过在本领域中熟知的化学反应而修饰或制造从而包括上述官能团的化合物，可用作多官能团配体。
在本发明的水溶性纳米颗粒中，优选的多官能团配体的例子是二巯基丁二酸。这是由于二巯基丁二酸原本具有粘合区、交联区和反应区。换句话说，位于二巯基丁二酸一端的-COOH与纳米颗粒结合，位于二巯基丁二酸中间的-SH与邻近的二巯基丁二酸通过二硫键结合，位于二巯基丁二酸另一端的-COOH和-SH与活性组分结合。除了二巯基丁二酸以外，包括作为粘合区(LI)的官能团的-COOH、作为交联区(LII)的官能团的-SH、以及作为反应区(LIII)的官能团的-COOH或-SH的化合物可作为优选的多官能团配体。化合物的说明性，但非限定性的例子包括二巯基马来酸和二巯基戊二酸(dimercaptopentadionic acid)。
在本发明的水溶性纳米颗粒中，优选的多官能团配体的另一例子是肽。肽是由若干氨基酸组成的低聚物/聚合物。氨基酸在其两端具有-COOH和-NH2官能团，因此肽自然地包括粘合区和反应区。此外，由于某些氨基酸具有-SH或-OH的支链，由此制造的肽使得所述氨基酸包含在交联区中，该肽可用作本发明中的多官能团配体。
在本发明中，多官能团配体可与生物可降解聚合物联合形成。生物可降解聚合物的例子包括聚磷腈、聚乳酸、聚交酯-共-乙交酯、聚己酸内酯、聚酸酐、聚马来酸及其衍生物、聚烷基氰基丙烯酸酯、聚羟基丁酸酯、聚碳酸酯、聚原酸酯、聚乙二醇、聚-L-甜菜碱、聚乙交酯、聚甲基丙烯酸甲酯、和聚乙烯比咯烷酮。
同时，根据本发明，与多官能团配体的反应区结合的“活性组分”可根据本发明的水溶性纳米颗粒的应用而选择。活性组分的例子可包括生物活性组分、聚合物、或无机载体。
生物活性组分的说明性，但非限定性的例子包括组织特异性结合物质，例如抗原、抗体、RNA、DNA、半抗原、抗生物素蛋白、抗生物素蛋白链菌素、蛋白A、蛋白G、凝集素、选择蛋白；以及药学上的活性组分，例如抗癌药物、抗生素、激素、激素拮抗剂、白细胞介素、干扰素、生长因子、肿瘤坏死因子、内毒素、淋巴毒素、尿激酶、链激酶、组织纤溶酶原激活剂、蛋白酶抑制剂、烷基磷酸胆碱、表面活性剂、心血管药物、肠胃药物、和神经药物。
聚合物的例子包括聚磷腈、聚乳酸、聚交酯-共-乙交酯、聚己酸内酯、聚酸酐、聚马来酸及其衍生物、聚烷基氰基丙烯酸酯、聚羟基丁酸酯、聚碳酸酯、聚原酸酯、聚乙二醇、聚-L-甜菜碱、聚乙交酯、聚甲基丙烯酸甲酯、和聚乙烯比咯烷酮。
无机载体的说明性，但非限定性的例子包括石英(SiO2)、氧化钛(TiO2)、氧化铟锡(ITO)、碳材料(纳米管、石墨、富勒烯等)、半导体衬底(Si、GaAs、AlAs等)、和金属衬底(Au、Pt、Ag、Cu等)。
本发明制造水溶性纳米颗粒的方法包括(1)在有机溶剂中合成非水溶性纳米颗粒，(2)在第一溶剂中溶解非水溶性纳米颗粒，并在第二溶剂中溶解水溶性多官能团配体，(3)将步骤(2)中的两溶液混合，使多官能团配体取代非水溶性纳米颗粒的表面，并将混合物溶解在水溶液中，以进行分离过程，(4)使取代的多官能团配体相互交联。
本方法的步骤(1)涉及一种制造非水溶性纳米颗粒的工艺。本发明的制造非水溶性纳米颗粒的工艺包括在10-600℃下，将纳米颗粒前体加入含有表面稳定剂的有机溶剂中，将所得溶液处于适合于制成所需的非水溶性纳米颗粒的温度和时间条件下，使纳米颗粒前体发生化学反应，并因此长出纳米颗粒，然后分离和纯化非水溶性纳米颗粒。
有机溶剂的说明性，但非限定性的例子包括苯类溶剂(例如苯、甲苯、卤代苯等)、烃类溶剂(例如辛烷、壬烷、癸烷等)、醚类溶剂(例如苯甲醚、苯醚、烃醚等)、以及聚合物溶剂。
在本方法的步骤(2)中，将在前面步骤制造的纳米颗粒溶解在第一溶剂中，并在第二溶剂中溶解多官能团配体。第一溶剂的例子包括苯类溶剂(例如苯、甲苯、卤代苯等)、烃类溶剂(例如辛烷、壬烷、癸烷等)、醚类溶剂(例如苯甲醚、苯醚、烃醚等)、卤代烃(例如二氯甲烷、溴甲烷等)、醇(例如甲醇、乙醇等)、亚砜类溶剂(例如二甲亚砜等)、以及酰胺类溶剂(例如二甲基甲酰胺等)。除了能够用作第一溶剂的溶剂以外，还可用水作为第二溶剂。
在本方法的步骤(3)中，两种溶液相互混合。在此步骤中，非水溶性纳米颗粒的有机表面稳定剂被水溶性多官能团配体取代(见图1)。如上所述的被水溶性多官能团配体取代的纳米颗粒可以通过本领域已知的一般方法进行分离。通常，由于水溶性纳米颗粒以沉淀物形式生成，优选用离心或过滤的方法进行分离。在分离步骤后，优选通过滴定将pH控制在5-10以得到稳定分散的水溶性纳米颗粒。
在本方法的步骤(4)中，多官能团配体通过某些化学反应相互交联，从而稳定水溶性纳米颗粒。用于交联的化学反应的说明性，但非限定性的例子包括氧化反应(例如二硫键)和还原反应、使用了分子连接体的交联反应、以及氢键。通过交联稳定的纳米颗粒在pH5-10、盐浓度约1M或更小的条件下分散良好并没有出现聚集。
通过下列示例性说明，但非限定性的实施例，可以对本发明进行更好的理解。
实施例1
各种尺寸的铁氧化物纳米颗粒的制造
通过在260℃下，于含有0.3M月桂酸和0.3M月桂胺的苯醚溶剂中，对三乙酰丙酮化铁(Aldrich)进行1小时热分解，合成4nm铁氧化物纳米颗粒。除了使用苯甲醚作为溶剂，以及290℃为反应温度外，以合成4nm铁氧化物纳米颗粒的相同过程合成6nm铁氧化物纳米颗粒。为了合成9nm铁氧化物纳米颗粒，将含有0.1M月桂酸、0.1M月桂胺、8mg/ml 6nm铁氧化物纳米颗粒和三乙酰丙酮化铁的苯甲醚溶液在290℃下加热1小时。除了是将浓度为8mg/ml的9nm铁氧化物纳米颗粒放入溶液外，以合成9nm铁氧化物纳米颗粒的相同过程合成12nm铁氧化物纳米颗粒。
实施例2
水溶性铁氧化物纳米颗粒的制造
将5mg实施例1所制得的铁氧化物纳米颗粒溶解在1ml甲苯中。然后将其中溶解了20mg 2，3-巯基丁二酸的0.5ml甲醇加入上述甲苯溶液中(见图3)。24小时后，形成深棕色沉淀物。在室温下将沉淀物以2000rpm进行离心5分钟，然后分散在1ml去离子水中。液面下鼓入空气5分钟以形成2，3-巯基丁二酸的二硫键。
实施例3
水溶液中水溶性铁氧化物纳米颗粒的稳定性评估
a.水溶性铁氧化物纳米颗粒的溶解度分析
将实施例1制造的水不溶性铁氧化物纳米颗粒溶解在氯甲烷中，随后加入水，同时将实施例2制造的水溶性铁氧化物纳米颗粒溶解在水中，随后加入氯甲烷。然后分析由纳米颗粒的表面取代所引起的溶解度的变化。
从图4可以确认有机表面稳定剂被多官能团配体(2，3-巯基丁二酸)取代，从而将非水溶性纳米颗粒转化为水溶性纳米颗粒。因此，凭肉眼观察可以确认沉淀或团聚并没有发生，由此可见，水溶性铁氧化物纳米颗粒在水溶液中分散良好。
b.通过电泳的分析
将含有水溶性铁氧化物纳米颗粒，其浓度约1mg/ml的10μl溶液于1％琼脂糖凝胶中上样，且在1X TBE(tris-borate-EDTA)缓冲溶液中经受电泳，并同时对所得溶液施加5V/cm的电压30分钟。
如图5所示，由于水溶性铁氧化物纳米颗粒小于琼脂糖凝胶中形成的空腔，因此可以在琼脂糖凝胶中移动。此外，在凝胶上形成窄带，由此可见水溶性铁氧化物纳米颗粒的尺寸一致，并没有聚集。同时，迁移率随着纳米颗粒尺寸增大而减小，也说明水溶性铁氧化物纳米颗粒尺寸一致没有聚集。通过上述结果，可见水溶性铁氧化物纳米颗粒分散于水溶液中，且其尺寸一致，并且没有聚集。
c.使用透射电子显微镜(TEM)的分析
将包含水溶性铁氧化物纳米颗粒的20μl溶液滴到涂有碳膜的TEM网格(Ted Pella Inc.)上，干燥约30分钟，用电子显微镜(EF-TEM，Zeiss，加速电压100kV)观察。
如图6所示，形成了尺寸一致的水溶性铁氧化物纳米颗粒。
实施例4
核-壳(FePt@Fe3O4)纳米颗粒的制造
将0.5mmol乙酰丙酮化铂溶解在10ml苯甲醚中，加热至100℃。将4mmol油酸、1.5mmol Fe(CO)5、以及4mmol油胺加至所得苯甲醚溶液中，加热至240℃，在该温度下保持1小时以进行反应。此时，Fe(CO)5分解。随后，将所得溶液加热至300℃并在该温度下保持1小时。反应完成后，注入空气5分钟以制造核-壳(FePt@Fe3O4)纳米颗粒。
实施例5
水溶性核-壳纳米颗粒的制造
除了使用实施例4所制造的核-壳纳米颗粒外，采用与实施例2相同的程序制造水溶性核-壳纳米颗粒。
实施例6
水溶液中水溶性核-壳纳米颗粒的稳定性评估
采用实施例3相同的程序，对实施例5制造的水溶性核-壳纳米颗粒在水溶液中的稳定性进行评估(见图7和图8)。
实施例7
用肽作为多官能团配体制造水溶性铁氧化物纳米颗粒
除了使用下列肽取代二巯基丁二酸外，通过与实施例2相同的步骤制造水溶性铁氧化物纳米颗粒。
(1)GSE SGG SG(Cha)CC(Cha)CDD-序列号：1
(2)GRR SHG(Cha)CC(Cha)CDD-序列号：2
(3)GKK HGH Y(Cha)CC(Cha)DCD-序列号：3
*Cha＝环己基丙胺酸
用肽取代纳米颗粒表面以制造在水溶液中稳定的纳米颗粒。在肽中，含有-COOH的CDD或DCD部分作为粘合区，含有-SH的CC部分作为交联区，其余部分作为反应区。
实施例8
与作为活性组分的tie2受体抗体结合的水溶性铁氧化物纳米颗粒的制造
将0.2mg tie2受体抗体溶解在100μl的10mM PBS(磷酸盐缓冲盐水，pH7.2)中，与20μg的sulfo-SMCC(购自Pierce Inc.)反应30分钟。随后，通过凝胶过滤(Sephadex G-25)将与sulfo-SMCC结合的抗体分离。分离的抗体与0.2mg由实施例2制造的水溶性铁氧化物纳米颗粒反应12小时，用凝胶过滤柱将与tie2受体抗体结合的水溶性铁氧化物纳米颗粒分离(Sephacryl S200，S400)。
实施例9
确认水溶性铁氧化物纳米颗粒与tie2受体抗体的结合
采用与实施例3相同的程序，将实施例8的产物进行电泳，结果示于图9中。
图9显示了生物活性组分(tie2受体抗体)能够与水溶性纳米颗粒的反应区结合。从电泳结果可以看出，与抗体结合的铁氧化物纳米颗粒在电泳中低速移动，这与蛋白染色的结果相似。因此，可以看出铁氧化物纳米颗粒与抗体结合了。
工业实用性
本发明的水溶性纳米颗粒尺寸一致，尤其在水溶液中很稳定。因此，利用各种活性组分的纳米颗粒能够应用在复合材料、电子材料、生物诊断和治疗中。

Claims (27)

1.水溶性纳米颗粒，其各自由多官能团配体(LI-LII-LIII)包围，所述多官能团配体(LI-LII-LIII)包括粘合区(LI)、交联区(LII)和反应区(LIII)，其中多官能团配体的交联区与邻近的多官能团配体的另一交联区交联。
2.如权利要求1所述的水溶性纳米颗粒，其中各纳米颗粒包括金属、金属硫族化合物、磁性材料、磁性合金、半导体材料或多组分混合结构，且各纳米颗粒的直径为1-1000nm。
3.如权利要求2所述的水溶性纳米颗粒，其中所述金属选自由Pt、Pd、Ag、Cu、Ru、Rh、Os和Au组成的组。
4.如权利要求2所述的水溶性纳米颗粒，其中所述金属硫族化合物选自由MxEy(M＝Ti、V、Cr、Mn、Fe、Co、Ni、Cu、Zr、Mo、Ru、Rh、Ag、W、Re、Ta、Zn；E＝O、S、Se，0＜x≤3，0＜y≤5)、BaSrxTi1-xO3、PbZrxTi1-xO3(O≤x≤1)和SiO2组成的组。
5.如权利要求2所述的水溶性纳米颗粒，其中所述磁性材料选自由Co、Mn、Fe、Ni、Gd、MM’2O4和MxOy(M或M’＝Co、Fe、Ni、Mn、Zn、Gd、Cr，0＜x≤3，0＜y≤5)组成的组。
6.如权利要求2所述的水溶性纳米颗粒，其中所述磁性合金选自由CoCu、CoPt、FePt、CoSm、CoAu、CoAg、CoPtAu、CoPtAg、NiFe和NiFeCo组成的组。
7.如权利要求2所述的水溶性纳米颗粒，其中所述半导体材料是由选自第II族和第VI族的元素组成的第一半导体材料、由选自第III族和第V族的元素组成的第二半导体材料、由第IV族元素组成的第三半导体材料、由选自第IV族和第VI族的元素组成的第四半导体材料、或由选自第V族和第VI族的元素组成的第五半导体材料。
8.如权利要求2所述的水溶性纳米颗粒，其中所述多组分混合结构包括两种或更多种选自由权利要求3至7中任一项的金属、金属硫族化合物、磁性材料、磁性合金、和半导体材料组成的组中的组分，且所述多组分混合结构具有核-壳或条码的形状。
9.如权利要求1所述的水溶性纳米颗粒，其中所述粘合区(LI)包括选自由-COOH、-NH2、-SH、-CONH2、-PO3H、-PO4H、-SO3H、-SO4H、和-OH组成的组中的官能团。
10.如权利要求1所述的水溶性纳米颗粒，其中所述交联区(LII)包括选自由-SH、-NH2、-COOH、-OH、环氧基、乙烯基和乙炔基组成的组中的官能团。
11.如权利要求1所述的水溶性纳米颗粒，其中所述反应区(LIII)包括选自由-SH、-COOH、-NH2、-OH、-NR4 +X-、磺酸基、硝酸基和膦酸基组成的组中的官能团。
12.如权利要求1所述的水溶性纳米颗粒，其中所述活性组分选自由生物活性组分、聚合物和无机载体组成的组。
13.如权利要求12所述的水溶性纳米颗粒，其中所述生物活性组分选自由抗原、抗体、RNA、DNA、半抗原、抗生物素蛋白、抗生物素蛋白链菌素、蛋白A、蛋白G、凝集素、选择蛋白、抗癌药物、抗生素、激素、激素拮抗剂、白细胞介素、干扰素、生长因子、肿瘤坏死因子、内毒素、淋巴毒素、尿激酶、链激酶、组织纤溶酶原激活剂、蛋白酶抑制剂、烷基磷酸胆碱、由放射性同位素标记的组分、表面活性剂、心血管药物、肠胃药物和神经药物组成的组。
14.如权利要求12所述的水溶性纳米颗粒，其中所述聚合物选自由聚磷腈、聚乳酸、聚交酯-共-乙交酯、聚己酸内酯、聚酸酐、聚马来酸及其衍生物、聚烷基氰基丙烯酸酯、聚羟基丁酸酯、聚碳酸酯、聚原酸酯、聚乙二醇、聚-L-甜菜碱、聚乙交酯、聚甲基丙烯酸甲酯和聚乙烯比咯烷酮组成的组。
15.如权利要求12所述的水溶性纳米颗粒，其中所述无机载体选自石英(SiO2)、氧化钛(TiO2)、氧化铟锡(ITO)、碳材料、半导体衬底、和金属衬底组成的组。
16.如权利要求1所述的水溶性纳米颗粒，其中所述多官能团配体是包含具有-SH、-COOH、-NH2或-OH为支链的至少一个氨基酸的肽。
17.如权利要求16所述的水溶性纳米颗粒，其中所述肽包含任一在序列号1-3中所述的氨基酸序列。
18.如权利要求1所述的水溶性纳米颗粒，其中所述多官能团配体为包括作为粘合区(LI)的官能团的-COOH、作为交联区(LII)的官能团的-SH、以及作为反应区(LIII)的官能团的-COOH或-SH的化合物。
19.如权利要求18所述的水溶性纳米颗粒，其中所述化合物选自由二巯基丁二酸、二巯基马来酸和二巯基戊二酸组成的组。
20.如权利要求1所述的水溶性纳米颗粒，其中所述多官能团配体与生物可降解聚合物结合。
21.如权利要求20所述的水溶性纳米颗粒，其中所述生物可降解聚合物选自由聚磷腈、聚乳酸、聚交酯-共-乙交酯、聚己酸内酯、聚酸酐、聚马来酸及其衍生物、聚烷基氰基丙烯酸酯、聚羟基丁酸酯、聚碳酸酯、聚原酸酯、聚乙二醇、聚-L-甜菜碱、聚乙交酯、聚甲基丙烯酸甲酯和聚乙烯比咯烷酮组成的组。
22.一种制造水溶性纳米颗粒的方法，包括：
(1)在有机溶剂中合成非水溶性纳米颗粒；
(2)在第一溶剂中溶解非水溶性纳米颗粒，并在第二溶剂中溶解水溶性多官能团配体；
(3)将步骤(2)中的两种溶液混合，使多官能团配体取代非水溶性纳米颗粒的表面，并将混合物溶解在水溶液中以进行分离过程；
(4)使取代的多官能团配体相互交联。
23.如权利要求22所述的方法，其中步骤(1)的非水溶性纳米颗粒是通过纳米颗粒前体在含有表面稳定剂的有机溶剂中进行化学反应而制得。
24.如权利要求23所述的方法，其中根据一种工艺制造所述非水溶性纳米颗粒，所述工艺包括在10-600℃下，将纳米颗粒前体加入含有表面稳定剂的有机溶剂中，使所得溶液处于适合于制成所需的非水溶性纳米颗粒的温度和时间条件下，使纳米颗粒前体进行化学反应，并因此长出纳米颗粒，然后分离和纯化纳米颗粒。
25.如权利要求22-24任一项所述的方法，其中所述有机溶剂选自由苯类溶剂、烃类溶剂、醚类溶剂和聚合物溶剂组成的组。
26.如权利要求22所述的方法，其中步骤(2)中的第一溶剂选自由苯类溶剂、烃类溶剂、醚类溶剂、卤代烃、醇、亚砜类溶剂和酰胺类溶剂组成的组。
27.如权利要求22所述的方法，其中步骤(2)中的第二溶剂选自由苯类溶剂、烃类溶剂、醚类溶剂、卤代烃、醇、亚砜类溶剂、酰胺类溶剂和水组成的组。
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