CN106535942A - 均匀的纳米复合物、其制备方法及其用途 - Google Patents
均匀的纳米复合物、其制备方法及其用途 Download PDFInfo
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- CN106535942A CN106535942A CN201580036663.1A CN201580036663A CN106535942A CN 106535942 A CN106535942 A CN 106535942A CN 201580036663 A CN201580036663 A CN 201580036663A CN 106535942 A CN106535942 A CN 106535942A
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- 238000000034 method Methods 0.000 title claims abstract description 58
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- 239000000243 solution Substances 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 18
- 229910052751 metal Inorganic materials 0.000 claims description 16
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- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 claims description 15
- 239000002184 metal Substances 0.000 claims description 15
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
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- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 5
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- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 5
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 4
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- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 claims description 4
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- XSOKHXFFCGXDJZ-UHFFFAOYSA-N telluride(2-) Chemical compound [Te-2] XSOKHXFFCGXDJZ-UHFFFAOYSA-N 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 3
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- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
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- 238000003384 imaging method Methods 0.000 claims description 3
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- MBMLMWLHJBBADN-UHFFFAOYSA-N Ferrous sulfide Chemical compound [Fe]=S MBMLMWLHJBBADN-UHFFFAOYSA-N 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- 229910021575 Iron(II) bromide Inorganic materials 0.000 claims description 2
- 239000004793 Polystyrene Substances 0.000 claims description 2
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- 235000001014 amino acid Nutrition 0.000 claims description 2
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- 229960002413 ferric citrate Drugs 0.000 claims description 2
- VEPSWGHMGZQCIN-UHFFFAOYSA-H ferric oxalate Chemical compound [Fe+3].[Fe+3].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O VEPSWGHMGZQCIN-UHFFFAOYSA-H 0.000 claims description 2
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- 239000011790 ferrous sulphate Substances 0.000 claims description 2
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 2
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 2
- 229910000398 iron phosphate Inorganic materials 0.000 claims description 2
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- WBJZTOZJJYAKHQ-UHFFFAOYSA-K iron(3+) phosphate Chemical compound [Fe+3].[O-]P([O-])([O-])=O WBJZTOZJJYAKHQ-UHFFFAOYSA-K 0.000 claims description 2
- HEJPGFRXUXOTGM-UHFFFAOYSA-K iron(3+);triiodide Chemical compound [Fe+3].[I-].[I-].[I-] HEJPGFRXUXOTGM-UHFFFAOYSA-K 0.000 claims description 2
- 229910000155 iron(II) phosphate Inorganic materials 0.000 claims description 2
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 2
- NPFOYSMITVOQOS-UHFFFAOYSA-K iron(III) citrate Chemical compound [Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NPFOYSMITVOQOS-UHFFFAOYSA-K 0.000 claims description 2
- GYCHYNMREWYSKH-UHFFFAOYSA-L iron(ii) bromide Chemical compound [Fe+2].[Br-].[Br-] GYCHYNMREWYSKH-UHFFFAOYSA-L 0.000 claims description 2
- APVZWAOKZPNDNR-UHFFFAOYSA-L iron(ii) citrate Chemical compound [Fe+2].OC(=O)CC(O)(C([O-])=O)CC([O-])=O APVZWAOKZPNDNR-UHFFFAOYSA-L 0.000 claims description 2
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- SDEKDNPYZOERBP-UHFFFAOYSA-H iron(ii) phosphate Chemical compound [Fe+2].[Fe+2].[Fe+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O SDEKDNPYZOERBP-UHFFFAOYSA-H 0.000 claims description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
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- PVFSDGKDKFSOTB-UHFFFAOYSA-K iron(3+);triacetate Chemical compound [Fe+3].CC([O-])=O.CC([O-])=O.CC([O-])=O PVFSDGKDKFSOTB-UHFFFAOYSA-K 0.000 claims 1
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Classifications
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F10/00—Thin magnetic films, e.g. of one-domain structure
- H01F10/08—Thin magnetic films, e.g. of one-domain structure characterised by magnetic layers
- H01F10/10—Thin magnetic films, e.g. of one-domain structure characterised by magnetic layers characterised by the composition
- H01F10/12—Thin magnetic films, e.g. of one-domain structure characterised by magnetic layers characterised by the composition being metals or alloys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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Abstract
本申请提供了一种悬浮在液体介质中的均匀的纳米复合物簇。本申请还提供了制备此类纳米复合物的方法以及此类纳米复合物的用途。该纳米复合物能够用于核酸提取和诊断测定,用于免疫测定,用于细胞分离、鉴定和调节,用于受控功能分子的保护和释放,用于在临床(伴随诊断)或在治疗开发过程(药物靶点验证)中使用的测定,以及用在经导管动脉化学栓塞的系统中,并且其由于均匀的性质或单分散性而表现出优异的性能。
Description
相关申请的交叉引用
本申请要求2014年8月2日提交的美国临时申请序号62/032,567的优先权,其全部内容通过引用并入本申请。
发明领域
本发明一般涉及均匀的纳米复合物簇的合成。
发明背景
来自很多领域,包括磁流体、催化、生物技术、生物医学、磁共振成像、数据存储和环境修复的研究人员对磁性纳米粒子都是非常感兴趣的。特别地,已经证明超顺磁性纳米粒子对于生物技术/生物医学应用是非常有希望的,因为当不存在磁场时它们表现为非磁性材料且保持分散,而在外部磁场控制下它们能够显示出强的磁性相互作用。氧化铁纳米粒子受到了最多的关注,因为它们具有在生理条件下的生物相容性和低毒性。
然而,控制纳米粒子在所需溶剂中的尺寸、形状、稳定性和分散性存在技术挑战。已开发出了几种用于合成具有受控尺寸分布的磁性氧化铁纳米粒子的方法,其通常通过在高温下在有机溶剂中进行有机金属过程完成。对于生物医学应用而言,通常进行另外的表面改性步骤以便将疏水性纳米粒子从有机溶剂中转移至水中。而且,因为这些方法涉及在高温下的有机溶剂反应混合物,所以难以工业化并且生产成本较高。
因此,对于具有高均匀性的磁性纳米粒子以及用于制备这种均匀磁性纳米粒子的有效且环境友好的方法存在持续的需求。
发明概述
本公开提供了一种均匀的纳米复合物簇、制备这种纳米复合物的方法以及这种纳米复合物的用途。这种纳米复合物可以用于经导管动脉化学栓塞的系统中。
在一个方面,本公开涉及一种组合物,所述组合物包含悬浮在液体介质中的均匀的纳米复合物簇。本文所述的纳米复合物具有落入约1nm至约1000nm之间范围内的平均尺寸(优选尺寸为约1-900nm、1-500nm、2-400nm、5-200nm、1nm、2nm、3nm、4nm、5nm、6nm、7nm、8nm、9nm、10nm、11nm、12nm、13nm、14nm、15nm、16nm、17nm、18nm、19nm、20nm、50nm、100nm、200nm、300nm、400nm、500nm、600nm、700nm、800nm、900nm)。在某些实施方式中,簇中的纳米复合物具有基本相同的尺寸。在某些实施方式中,纳米复合物的尺寸分布(标准偏差)小于纳米复合物簇平均尺寸的20%、15%、10%、9%、8%、7%、6%、5%、4%或3%。在某些实施方式中,纳米复合物的70%具有落入纳米复合物簇平均尺寸的20%、15%、10%、9%、8%、7%、6%、5%、4%或3%内的尺寸。在某些实施方式中,纳米复合物簇具有小于0.15的通过动态光散射技术测得的多分散性指数(PDI)。优选地,纳米复合物簇具有小于0.1的PDI。更优选地,纳米复合物簇具有小于0.08、0.07、0.06、0.05或0.04的PDI。
在某些实施方式中,本公开所述的纳米复合物包含核心纳米粒子和涂层。在某些实施方式中,核心纳米粒子是磁性纳米粒子或非磁性纳米粒子。在某些实施方式中,磁性纳米粒子是超顺磁性氧化铁(SPIO)纳米粒子。在某些实施方式中,SPIO纳米粒子掺杂有镁、锌、锰、钴、金、银或其组合。
在某些实施方式中,涂层是硅烷化涂层。在某些实施方式中,涂层是表面活性剂或聚合物。在某些实施方式中,涂层包含官能团。在一些优选的实施方式中,官能团是单羧酸、二羧酸、三羧酸或四羧酸。在某些实施方式中,官能团选自下组:链霉亲和素、蛋白A、蛋白G、抗体、肽、适体、荧光团、酶和药物。在某些实施方式中,涂层是低密度、多孔性3-D结构。
在另一个方面,本公开提供了制备均匀的纳米复合物簇的方法。在一个实施方式中,本发明提供了一种制备均匀的纳米复合物簇的方法,所述方法包括(1)在水/醇溶剂中混合金属盐前体和表面活性剂,以形成反应溶液;(2)向反应溶液中加入沉淀剂;(3)获得纳米复合物簇;其中将反应溶液控制在低于300C的温度下。优选地,将反应溶液控制在低于200C的温度下。更优选地,将反应溶液控制在低于100C的温度下。在另一个优选的实施方式中,反应溶液不含醇以外的有机溶剂。在另一个实施方式中,本公开提供了一种由本文所述方法制备的复合物。
在又一个方面,本公开提供了通过使用均匀的纳米复合物簇向肿瘤组织递送功能性分子的方法。在一个实施方式中,递送是通过经导管动脉化学栓塞。在另一个实施方式中,本公开提供了通过经导管动脉化学栓塞递送均匀的纳米复合物簇的系统。
在另一个方面,本公开涉及用于活化在某一应用中使用的纳米粒子的溶液,所述溶液包含酸、碱或盐。在某些实施方式中,酸选自下组:盐酸、硫酸、亚硫酸、膦酸、亚磷酸、羧酸和氨基酸及其组合。在某些实施方式中,碱选自下组:氢氧化钠、氢氧化铵、氢氧化钾、四甲基氢氧化铵及其组合。在某些实施方式中,盐选自下组:Tris盐酸盐、羧酸钠、羧酸铵、硫酸钠、烷基硫酸钠及其组合。在某些实施方式中,溶液还包含聚乙二醇、吐温、CHAPS、丙二醇、丁二醇、盐、甘油、蔗糖,脱氧核糖核苷酸、小肽或蛋白。
在另一个方面,本公开涉及一种在某一应用中使用纳米复合物的方法,所述方法包括提供悬浮在液体介质中的纳米复合物簇;以及向该簇中加入溶液以活化用于所述应用的纳米复合物。
附图简述
图1:由实施例1中所述工序制备的纳米复合物。
图2:使用本公开所公开的方法制备的掺杂金属的磁性纳米复合物。
图3:单分散纳米复合物是水溶性的,因此其完全分散在水相中。在由己烷组成的顶相中未观察到纳米复合物。
图4:由本公开所公开方法制备的纳米复合物簇的透射电镜图。其显示了由动态光散射法测定的单分散性。
图5:均匀的磁性纳米复合物可以以更清楚的截止分子量用于DNA尺寸片段的选择。
图6:均匀的磁性纳米复合物能够与抗体结合并用于抗体的纯化和免疫测定。纳米复合物的单分散性产生更一致的检测数据。
图7:利用纳米复合物递送化疗药物和收集过量化学药物的装置的示意图。该装置包含两条导管。一条导管插入向器官内的肿瘤输送的动脉中,例如通过肝动脉分支。从导管或与导管连接的容器注射纳米复合物,并将其导向肿瘤。另一条导管插入肝静脉,其具有引入后能够延伸至导管外部的磁性结构。磁性结构能够通过磁性吸引收集携带药物的过量纳米复合物。磁性结构还可以是沉积在过滤材料上的磁性结构,以改善单独使用过滤材料对携带化学药物的过量纳米复合物的收集。
图8A:在显微镜下观察到的含有全氟化碳和均匀的磁性纳米复合物的乳液。
图8B:在显微镜下观察到的纳米泡乳液。由于对乳液进行物理振摇,产生了各种尺寸的气泡。
发明详述
在对本公开更加详细的描述之前,应理解本公开不限于所描述的特定实施方式,并且其当然是可以改变的。还应理解本申请中使用的术语仅用于描述特定实施方式的目的,并不旨在限制,因为本公开的范围仅由所附的权利要求限定。在提供数值范围时,应理解在该范围的上限和下限之间每个居中值和任何其他表述或该表述范围内的居中值,到下限的单位的十分之一,都被包括在本公开的范围内,除非上下文另有明示。这些更小范围的上限和下限可以独立地包括在更小的范围中,并且也被包括在本公开的范围内,服从所述范围中任何特定排除的极限值。在所述的范围包括一个或两个极限值时,排除一个或两个在内的极限值的范围也被包括在本公开的范围内。
除非另有定义,本文使用的所有科技术语具有的含义与本公开所属领域技术人员通常理解的含义相同。Singleton等,Dictionary of Microbiology and MolecularBiology 2nd ed.,J.Wiley&Sons(New York,N.Y.1994)和March,Advanced OrganicChemistry Reactions,Mechanisms and Structure 4th ed.,John Wiley&Sons(NewYork,N.Y.1992)向本领域技术人员提供本申请中使用的多数术语的一般性指导。虽然与本文所述的方法和材料类似或等价的任何方法和材料也可用于本公开的实践或试验,但是以下描述优选的方法和材料。
在本说明书中引用的所有出版物和专利都通过引用并入本申请,相当于每篇出版物或专利都特别地和单独地被指出通过引用并入,并且其通过引用并入本申请以披露和描述与所引用的出版物有关的方法和/或材料。所引用的任何出版物均在本申请提交日之前公开,不应将所述公开中的任何事项看作是承认本申请由于在先公开而没有资格早于这些公开。而且,所提供的公开日可能不同于实际的公开日,其可能需要单独确认。
本领域技术人员在阅读本公开后将理解,本申请中所描述和解释的各个实施方式均具有离散的组成和特性,在不脱离本公开范围或主旨的前提下,可以容易地将其分离或者与任意其他若干实施方式的特性组合。任何所述的方法均可以所叙述的事件顺序或者逻辑上可能的任何顺序进行。
除非另有明示,本公开的实施方式将采用化学、固态化学、无机化学、有机化学、物理化学、分析化学、材料化学、生物化学、生物学、分子生物学、重组DNA技术、药理学、成像等技术,其均在本领域技术的范围内。在文献中对这种技术进行了充分阐述,如"MolecularCloning:A Laboratory Manual",第二版,(Sambrook等,1989);"OligonucleotideSynthesis"(M.J.Gait编著,1984);"Animal Cell Culture"(R.I.Freshney编著,1987);"Methods in Enzymology"丛书(Academic Press,Inc.);"Current Protocols inMolecular Biology"(F.M.Ausubel等编著,1987,并且定期更新);"PCR:The PolymeraseChain Reaction"(Mullis等编著,1994)。可以使用本领域公知的标准技术制备本申请中使用的引物、多核苷酸和多肽。
在对本公开的实施方式进行详细描述前,除非另有明示,应理解本公开不仅限于特定材料、试剂、反应原料、生产工艺等,其是可以改变的。还应理解在本申请中使用的术语仅用于说明特定实施方式的目的,并不旨在限制。可以以逻辑上可能的不同顺序执行本公开中的步骤也是可能的。
给出下述实施方式以便向本领域的普通技术人员完整的披露和描述本申请所公开和主张的方法是如何进行的以及纳米结构是如何使用的。要努力确保数字的准确度(例如量、温度等),但是应考虑一些误差和偏差。
需要指出的是,如用于本说明书和所附权利要求中的,单数形式“一(a)”、“一个(an)”和“该(the)”包括复数对象,除非上下文另有明示。因此,例如“化合物”包括多个化合物。在本说明书和下文中的权利要求中,将给出多个术语以供参考,将对其进行定义以使其具有下述含义,除非具有明显相反的意图。
本公开提供了一种均匀的纳米复合物簇、制备此类纳米复合物的方法和此类纳米复合物的用途。
均匀的纳米复合物簇
在一个方面,本公开涉及一种组合物,所述组合物包含悬浮于液体介质中的均匀的纳米复合物簇。
在本文使用的术语“均匀的纳米复合物”或“均匀的纳米复合物簇”指具有基本上相同的尺寸、形状或质量的多个纳米复合物。
在某些实施方式中,本文所述的纳米复合物簇具有落入约1nm至约1000nm之间范围内的平均尺寸或直径(优选尺寸为约1-900nm、1-500nm、2-400nm、5-200nm、1nm、2nm、3nm、4nm、5nm、6nm、7nm、8nm、9nm、10nm、11nm、12nm、13nm、14nm、15nm、16nm、17nm、18nm、19nm、20nm、50nm、100nm、200nm、300nm、400nm、500nm、600nm、700nm、800nm、900nm)。在本申请中公开了合成具有受控尺寸的均匀的纳米复合物簇的方法。
在某些实施方式中,当簇中的任意两个纳米复合物具有基本上相同的尺寸时,纳米复合物簇是均匀的。在某些实施方式中,当纳米复合物的尺寸分布(即纳米复合物尺寸的标准偏差)小于簇平均尺寸的20%,优选15%、10%,更优选9%、8%、7%、6%、5%、4%或3%时,纳米复合物簇是均匀的。在某些实施方式中,当纳米复合物的70%具有落入纳米复合物簇平均尺寸的20%,优选15%、10%,更优选9%、8%、7%、6%、5%、4%或3%内的尺寸时,纳米复合物簇是均匀的。在某些实施方式中,纳米复合物簇具有小于0.15的通过动态光散射技术测得的多分散性指数(PDI)。优选地,纳米复合物簇具有小于0.1的PDI。更优选地,纳米复合物簇具有小于0.08、0.07、0.06、0.05或0.04的PDI。
如本文使用的,多分散性指数(PDI)是混合物中纳米复合物的尺寸分布的度量。如果纳米复合物具有基本上相同的尺寸、形状或质量,则纳米复合物的集合是均匀的。测定纳米粒子尺寸和尺寸分布的一种常规方法是使用动态光散射(DLS)技术,这是一种确定小颗粒在悬液中的尺寸分布的技术。动态光散射的详细机理和应用可以参见Berne,B.J.和Pecora,R.,Dynamic Light Scattering.Courier Dover Publications(2000),其通过引用并入本申请。在本专利申请中,相关的DLS检测在Brookhaven Nanosizer上进行。
在某些实施方式中,本文所述的纳米复合物包含核心纳米粒子和涂层。
本公开所述的核心纳米粒子可以是磁性纳米粒子或非磁性纳米粒子。在某些优选的实施方式中,磁性纳米粒子是超顺磁性氧化铁(SPIO)纳米粒子。在某些实施方式中,SPIO纳米粒子掺杂有镁、锌、锰、钴、金、银或其组合。
SPIO纳米粒子是氧化铁纳米粒子,磁赤铁矿(γ-Fe2O3)或磁铁矿(Fe3O4),或者由这两相组成的纳米粒子。据称纳米粒子处于超顺磁状态,因为在不存在外部磁场的情况下其磁化强度似乎平均为零,但纳米粒子可以被外部磁场磁化。本申请中公开了合成均匀的SPIO纳米粒子簇的方法。
非SPIO纳米粒子包括例如金属纳米粒子(例如金纳米粒子或银纳米粒子(参见例如Hiroki Hiramatsu,F.E.O.,Chemistry of Materials 16,2509-11(2004)))、半导体纳米粒子(例如具有单个或多个组分的量子点,如CdSe/ZnS(参见例如M.Bruchez等,Science281,2013-16(1998)))、无掺杂的重金属的量子点(参见例如Narayan Pradhan等,J.Am,Chem.Soc 129,3339-47(2007))或其他半导体量子点);聚合物纳米粒子(例如由PLGA(乳酸-羟基乙酸共聚物)(参见例如Minsoung Rhee等,Adv.Mater.23,H79-83(2011))、PCL(聚己内酯)(参见例如Marianne Labet等,Chem.Soc.Rev.38,3484-3504(2009))、PEG(聚乙二醇)或其他聚合物中的一种或组合制备的粒子);含硅纳米粒子,和非SPIO磁性纳米粒子(例如MnFe2O4(参见例如Jae-Hyun Lee等,Nature Medicine 13,95-99(2006))、合成的反铁磁性纳米粒子(SAF)(参见例如A.Fu等,Angew.Chem.Int.Ed.48,1620-24(2009))和其他类型的磁性纳米粒子)。核心纳米粒子的尺寸为约1nm至约900nm(优选1-500nm、2-400nm、5-200nm、1nm、2nm、3nm、4nm、5nm、6nm、7nm、8nm、9nm、10nm、11nm、12nm、13nm、14nm、15nm、16nm、17nm、18nm、19nm、20nm、50nm、75nm、100nm、125nm、150nm、175nm、200nm)。
在某些实施方式中,核心纳米粒子具有球形、棒状、四脚形、金字塔形、多臂、纳米管、纳米线、纳米纤维或纳米板的形状。
在本申请中公开了合成具有非SPIO核心纳米粒子的均匀的纳米复合物簇的方法。
如本文使用的,术语“涂层”指至少一个核心纳米粒子可嵌入其中的任意物质。可以使用本领域公知的任意适宜涂层,例如表面活性剂、聚合物涂层和非聚合物涂层。涂层与核心纳米粒子通过如下相互作用:1)分子间相互作用,如共价键(例如σ键、π键、δ键、双键、三键、四重键、五重键、六重键、3c-2e键、3c-4e键、4c-2e键、抓氢键、弯曲键、偶极键、π反向键、共轭、超共轭、芳香性、哈普托数和反键)、金属键(例如与核心纳米粒子中的金属原子的螯合相互作用)或离子键(阳离子π-键和盐键),和2)分子间相互作用,如氢键(例如二氢键、二氢复合物、低势垒氢键、对称氢键)和非共价键(例如疏水性、亲水性、电荷-电荷或π堆叠相互作用、范德华力、伦敦分散力、机械键、卤素键、亲金作用、嵌入、堆叠、熵力和化学极性)。
在某些实施方式中,涂层是硅烷化涂层。在一个实施方式中,硅烷化涂层是在SPIO纳米粒子表面上的包含硅烷和/或硅烷样分子(或那些分子与表面的反应产物)的涂层。
涂层可以是无定形的。可以对涂层的厚度进行控制以便能够产生用于特定应用的涂覆的纳米粒子。在一个实施方式中,通过将三甲氧基硅烷与适宜的官能团(如巯基基团、氨基基团、巯基/氨基基团、羧基基团、膦酸酯基基团、烷基基团、聚环氧乙烷基团(PEG)及其组合)交联来制备硅烷化涂层。
在某些实施方式中,涂层是表面活性剂。在某些实施方式中,表面活性剂是含有羧酸酯、磺酸酯、硫酸酯、磷酸酯、氢、胺、铵、甜菜碱和磺基甜菜碱基团的化合物。
在某些实施方式中,涂层是含有羧酸酯、磺酸酯、硫酸酯、磷酸酯、氢、胺、铵、甜菜碱和磺基甜菜碱基团的化合物。
在某些实施方式中,涂层是聚合物。聚合物的示例包括但不限于可以任选地用各种侧基官能化的多肽。聚合物涂层可以选自下组:壳聚糖、聚苯乙烯、聚乙二醇、聚丙二醇、聚甲基丙烯酸酯、聚丙烯酸酯、聚丙烯酰胺、聚醛、葡聚糖、蔗糖、多糖、琼脂糖。
在某些实施方式中,涂层含有一个或多个官能团。官能团的示例包括但不限于氨基、巯基、单羧酸、二羧酸、三羧酸或四羧酸、链霉亲和素、亲和素、蛋白A、蛋白G、抗体、肽、适体、荧光团、酶和药物。
可以在涂层形成过程中引入官能团,例如通过在交联过程中加入含有此类官能团的含硅化合物。还可以在涂层形成之后引入官能团,例如通过化学改性将官能团引入涂层表面。在某些实施方式中,官能团是涂层中固有的。
在某些实施方式中,涂层是如在以整体并入本申请的WO2013112643中所公开的低密度、多孔性3-D结构。低密度、多孔性3-D结构指密度比现有介孔材料(例如孔径为2至50nm的介孔材料)低至少10倍的结构。在某些实施方式中,低密度、多孔性3-D结构具有<1.0g/cc(例如0.01mg/cc至1000mg/cc)的密度。
当悬浮于液体介质中时,本文所述的纳米复合物簇保持均匀性和稳定性。在某些实施方式中,纳米复合物可溶于液体介质中,即纳米复合物在液体介质中是稳定的和可分配的。悬浮在液体介质中的纳米复合物不聚集或沉淀。用于悬浮纳米复合物的液体介质包括但不限于水、生物缓冲液(例如PBS、TBS)、醇及其组合。
制备方法
在另一个方面,本公开提供了用于制备均匀的纳米复合物簇的方法。在所需溶剂中控制纳米复合物的尺寸、形状、稳定性和分散性是一项技术挑战。已开发出了几种用于合成具有受控尺寸分布的磁性氧化铁纳米粒子的方法,其通常通过在高温下在有机溶剂中进行有机金属过程完成(参见例如US20080032132)。对于生物医学应用而言,通常进行另外的表面改性步骤以便将疏水性纳米粒子从有机溶剂中转移至水中。然而,因为这些方法涉及有机溶剂在高温下的反应混合物,所以难以工业化并且生产成本较高。本发明令人吃惊的发现之一是一种在温和制备条件下(水/醇溶剂和相对低的温度)制备均匀的纳米复合物簇的方法,所述均匀的纳米复合物簇为可分配的或水溶性的。
在一个实施方式中,制备均匀的纳米复合物簇的方法包括(1)在水/醇溶剂中混合金属盐前体和表面活性剂,以形成反应溶液;(2)向反应溶液中加入沉淀剂;(3)获得纳米复合物簇;其中将反应溶液控制在低于300℃的温度下。优选地,将反应溶液控制在低于200℃的温度下。更优选地,将反应溶液控制在低于100℃的温度下。
金属盐前体包括但不限于氯化物、硫酸盐、硝酸盐、氟化物、溴化物、碘化物、硫化物、硒化物、碲化物、乙酸盐、草酸盐、柠檬酸盐或磷酸盐形式的铁盐、镁盐、锌盐、镉盐、锰盐、镍盐、钴盐、金盐、银盐。
在某些实施方式中,金属盐前体是亚铁盐和铁盐的混合物。亚铁盐包括氯化亚铁、硫酸亚铁、硝酸亚铁、氟化亚铁、溴化亚铁、碘化亚铁、硫化亚铁、硒化亚铁、碲化亚铁、乙酸亚铁、草酸亚铁、柠檬酸亚铁和磷酸亚铁。铁盐包括氯化铁、硫酸铁、硝酸铁、氟化铁、溴化铁、碘化铁、硫化铁、硒化铁、碲化铁、乙酸铁、草酸铁、柠檬酸铁和磷酸铁。
在某些实施方式中,金属盐前体的混合物还包括非铁金属,如相应的盐形式的钴、镍、镁、锰、锌、金和银。在这种情况下,可以将这些非铁金属引入合成中以使得终产物是基于铁的复合氧化物。
用于本公开方法的适宜表面活性剂可以选自广泛的聚合电解质,所述聚合电解质例如但不限于含有羧酸酯基团的那些,包括聚丙烯酸和聚甲基丙烯酸、柠檬酸、酒石酸、乳酸、乙酸、草酸、丙酸、丁酸、油酸、戊酸、己酸、庚酸、鞣酸、辛酸、壬酸、癸酸、十一烷酸、月桂酸,十三烷酸、肉豆蔻酸、棕榈酸、十七烷酸、硬脂酸、花生酸,以及含有磺酸酯、硫酸酯、磷酸酯、胺、铵、甜菜碱或磺基甜菜碱基团的那些。
用于本公开方法的适宜醇可以选自具有1、2、3、4、5、6、7、8、9、10、11、12个或更多个碳原子的醇。在某些实施方式中,醇可以是一元醇或多元醇。一元醇的说明性示例包括甲醇、乙醇、丙醇、丁醇、戊醇、己醇等。多元醇的说明性示例包括丙二醇、甘油、苏糖醇、木糖醇等。
在某些实施方式中,醇可以具有饱和碳链或不饱和碳链。具有饱和碳链的醇可以用化学式CnH(2n+2)O表示。在某些实施方式中,n不小于3,或不小于4,或不小于5(例如n=3、4、5、6、7、8、9、10、11、12或以上)。具有不饱和碳链的醇在两个碳原子之间具有双键或三键。在某些实施方式中,醇可以是环醇,例如环己醇、肌醇或薄荷醇。
在某些实施方式中,醇可以具有直链碳链(例如正丙醇、正丁醇、正戊醇、正己醇等)或支链碳链(例如异丙醇、异丁醇、叔丁醇等)。在某些实施方式中,醇以约30%至约70%的体积分数存在(例如约30%至约70%、约30%至约60%、约30%至约55%、约40%至约70%、约45%至约70%、约40%至约60%)。在某些实施方式中,醇以50%左右的体积分数存在(例如45%左右、46%左右、47%左右、48%左右、49%左右、50%左右、51%左右、52%左右、53%左右、54%左右、55%左右、56%左右、57%左右、58%左右、59%左右或60%左右)。
在另一个优选的实施方式中,反应溶液不含有醇以外的有机溶剂。醇以外的有机溶剂包括但不限于甲苯、氯仿、己烷。
在本公开的方法中,纳米复合物簇的沉淀可以通过加入沉淀剂引发。沉淀剂包括但不限于第1族和第2族金属、铵的氢氧化物、碳酸盐、碳酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐(例如NaOH、KOH、NH4OH、Na2CO3、K2CO3),四甲基氢氧化铵,氨以及负碳离子、酰胺和氢化物的第1族的盐。
方法限定的产品
本公开的另一个方面涉及通过本文提供的任意方法制备的纳米复合物簇。可以任选地使用本文所述的方法和/或本领域公知的常规方法分离、纯化或干燥本文制备的纳米复合物。
使用方法
在又一个方面,本公开提供了本文所述的均匀的纳米复合物簇的用途。均匀的纳米复合物簇的用途包括但不限于制备治疗或诊断组合物,制备用于定性或定量检测的试剂,制备用于分子成像的试剂,和制备用于分离、纯化或富集的试剂。本公开的均匀的纳米复合物簇还可以用于包封或保护功能性分子(如药物),或用作功能性分子的载体。本公开的均匀的纳米复合物簇还可以用于靶向递送或控制释放功能性分子。
在某些实施方式中,均匀的纳米复合物簇用于与核酸相互作用以用于提取、尺寸选择、诊断检测,并且由于纳米复合物的单分散性而获得更好的结果。
在某些实施方式中,均匀的纳米复合物簇用于免疫检测,并且由于纳米复合物的单分散性而获得更好的结果(如一致性)和更好的定量。
在某些实施方式中,均匀的纳米复合物簇用于细胞分离、鉴定和调节实验,并且由于纳米复合物的单分散性而获得更好的结果(如基于细胞表面标记物与均匀的纳米复合物之间的相互作用定量鉴定不同细胞类型),更好的细胞分选和区分(其通过细胞表面上标记的均匀粒子的荧光信号或磁性性质),或者均匀的纳米复合物对细胞行为的更一致的刺激。
在某些实施方式中,由于纳米复合物的均匀性,均匀的纳米复合物簇更好地用于诊断检测或处理临床样品。均匀的纳米复合物簇能够提供更一致和可靠的数据,例如在治疗方法开发的靶点验证方面,或者用于检测最早期癌症或治疗后的预测性评估的伴随诊断方面。
在某些实施方式中,本公开的均匀的纳米复合物簇能够用于功能性分子的系统或局部递送,如化疗。
在一个实施方式中,功能性分子的局部递送是通过经导管动脉化学栓塞(TACE)。在一个示例中,通过TACE向肿瘤组织施用携带化疗剂的均匀的磁性纳米复合物簇。纳米复合物防止化疗剂在栓塞后从肿瘤组织洗去。在一个优选的实施方式中,使用磁性支架收集过量的带有化疗剂的纳米复合物并将其从体内移除以减少毒副作用。
在另一个方面,本公开提供了用于通过TACE递送均匀的纳米复合物簇的装置。在某些实施方式中,该装置包含两条导管:一条导管包含可注射容器,所述可注射容器将纳米复合物-化学药物溶液保持在导管中,用于将纳米复合物-化学药物栓塞注射至靶组织或器官部位;另一条导管保持有磁性结构,所述磁性结构一旦就位就能够伸出导管以收集过量的纳米复合物-化学药物栓塞。磁性结构可以是永久磁性支架、可磁化的磁性网状结构或能够接通或断开以产生所需磁力的电磁体,以便从机体外部位置吸引过量的纳米复合物-化学药物栓塞(对于该设置的图示参见图7)。
提供下述实施例以说明本发明。其并非旨在以任何方式进行限制。
实施例1
下述是均匀的SPIO纳米复合物簇的制备和表征的示例。
将含0.5g FeCl2的5ml diH2O与含1.0g FeCl3的5ml H2O在250ml的具有3个入口的反应瓶中混合。将烧瓶在填充有65至70℃水的超声器中超声并使用N2吹洗约10分钟。通过将80mg月桂酸溶解在异丙醇中,随后加入80mg油酸而制备基质混合物。在将基质混合物加入烧瓶前,将15ml 30%NH4OH加入酸和油酸的混合物中。加入基质混合物后,在加热和N2吹洗下将烧瓶再超声10分钟,随后停止N2吹洗。然后在无N2的条件下将烧瓶超声20分钟。将烧瓶从超声器中取出并冷却5至15分钟。
转移烧瓶中的粗产物并在rotarack上旋转至少2小时。将粗产物洗涤5次,前三次使用约30ml异丙醇洗涤,后两次使用diH2O。在转移至洁净容器前,在显微镜下检查洗涤后的小珠(见图1)。当必要时进行尺寸选择。
通过控制纳米复合物反应中不同成分的量来控制纳米复合物的尺寸,或者可以通过控制涂层材料的量来调节涂层的厚度。
如图2中所示,可以使用类似方法制备掺杂有其他金属元素的纳米复合物。
制备了具有从100纳米至1μm的不同尺寸并且具有不同表面涂层/分子/功能的纳米复合物。
如图3所示,制得的纳米复合物能够分散于水溶液中。
使用BrookHaven NanoSizer测定了纳米复合物的尺寸分布。如表1中所示,纳米复合物的多分散性指数低至<0.05,这在动态散射仪的极限附近。
表1:纳米复合物簇的平均尺寸和尺寸分布
图5是使用透射电子显微镜显示的纳米复合物簇。所形成的这些纳米复合物能够进行硅烷化涂布,并且证实了如表1中使用动态光散色实验显示的单分散性。
实施例2
下述是使用均匀的纳米复合物簇分离DNA的示例。
将1,000ng 100~1,000bp的DNA梯(Fisher Scientific)与20μl纳米复合物在室温下混合30分钟。将纳米复合物在磁性支架上丸粒化,并使用100μl新鲜的70%乙醇洗涤两次。洗脱所捕获的梯并在3%琼脂糖凝胶上分析。如图4中所示,磁性纳米复合物在DNA尺寸片段选择中显示了清楚的截止分子量。与市场上的其他产品比较,使用均匀的磁性纳米复合物一致产生了具有更清晰结果的DNA文库。
实施例3
下述是使用均匀的纳米复合物簇结合抗体的示例。
如图6中所示,将仅由磁性纳米粒子组成或具有磁性和荧光性质的均匀的纳米复合物用于蛋白捕获检测。纳米复合物与蛋白A或蛋白偶联。将偶联的纳米复合物用于从溶液中捕获抗体。如实施例6中所示,使用10μg的与蛋白A偶联的纳米复合物进行两次重复实验,以捕获1μg的在溶液中的抗体。在磁性分离后,均匀的纳米复合物显示出更一致和可重复的结果。这种特征对于临床免疫诊断检测是非常重要的。
实施例4
可以将均匀的纳米复合物簇用于功能性分子(如蛋白、核酸、信号产生分子、药物)的控制和释放。下述示例使用均匀的纳米复合物簇用于DNA的控制和释放。
将经测定含有80ng小珠的两个磁性纳米复合物样品(样品1和样品2)溶液与在pH8缓冲液(tris,PEG 8000,NaCl)中的浓度为50μg/ml的10ul DNA混合30分钟。使用100μl70%的乙醇洗涤2次所得到的物质,然后空气干燥5分钟。向试管中的干燥物质中加入20μl洗脱溶液:含有10mM NaCl的Tris缓冲液。在磁珠吸附后溶液的原始上清液反映了未吸附于磁性纳米复合物上的DNA的量,利用使用Pico绿染料的荧光酶标仪测定5min和10天后所得到的洗脱DNA和标准DNA。使用DNA对照样品的线性拟合曲线计算释放百分率。如表2中所示,吸附30min后均匀的纳米复合物吸附90%以上的DNA。
在20μl溶液中20%、60%和100%的量的标准DNA对照样品的荧光读数为:569、1488和1606。
表2:不同时间点的未吸附DNA的量和释放结果
实施例5
下述是使用本文所述的均匀的纳米复合物制备全氟化碳乳剂的示例。
通过组合下述成分来制备稳定的乳剂:
(A)全氟化碳液体,其具有高的氧溶解度并且可以用于在体内携带氧;
(B)pH 8的含有6种成分的组合的水溶液;
(C)植物油,如葵花油、橄榄油、鳄梨油和菜籽油;
(D)均匀的纳米复合物。
所形成的乳剂是浅棕色均匀的微粘稠液体,其在室温和4℃下稳定。如图8A和图8B所示,磁性粒子很好地分散在乳液中,并且在振摇乳剂后观察到一些气泡。
使用水或0.02%SDS溶液将纳米泡的两个配方分别稀释6倍或20倍。使用动态散射(DLS)技术测定这两个经稀释的含有PFC和磁性纳米复合物的纳米泡配方的尺寸和分布。如表3中所示,该乳剂具有较小的粒子尺寸和粒子尺寸分布。
乳剂将全氟化碳从25%稳定至达40%,并且其作为含有达15mg/ml的纳米复合物的均匀溶液是稳定的。
表3:纳米泡乳剂的尺寸和分布
尽管已参照特定实施方式(其中的一些是优选实施方式)特别地示出和描述了本发明,本领域技术人员应理解在不脱离如本文所公开的本发明的主旨和范围的前提下可以对其形式和细节做出各种改变。
Claims (28)
1.一种组合物,所述组合物包含悬浮在液体介质中的纳米复合物簇,所述纳米复合物簇具有平均尺寸和尺寸分布,其中所述平均尺寸落入约1nm至约1000nm之间的范围内,所述尺寸分布在所述平均尺寸的约20%以内,其中每个所述纳米复合物包含核心纳米粒子和涂层。
2.根据权利要求1所述的组合物,其中所述纳米复合物簇具有小于0.15的通过动态光散射技术测得的多分散性指数(PDI)。
3.根据权利要求1所述的组合物,其中所述核心纳米粒子包含磁性纳米粒子、非磁性纳米粒子或其组合。
4.根据权利要求1所述的组合物,其中所述核心纳米粒子是超顺磁性氧化铁(SPIO)纳米粒子。
5.根据权利要求4所述的组合物,其中所述SPIO纳米粒子掺杂有镁、锌、锰、钴、金、银或其组合。
6.根据权利要求4所述的组合物,其中所述非磁性纳米粒子包含金纳米粒子、银纳米粒子、石墨烯纳米粒子、聚苯乙烯纳米粒子、半导体纳米粒子或其组合。
7.根据权利要求1所述的组合物,其中所述涂层是硅烷化涂层。
8.根据权利要求1所述的组合物,其中所述涂层是表面活性剂或聚合物涂层。
9.根据权利要求1所述的组合物,其中所述涂层包含配体。
10.根据权利要求8所述的组合物,其中所述配体是单,二,三或四硫酸盐、磺酸盐、亚硫酸盐、膦酸盐、羧酸盐、氨基酸或其组合。
11.根据权利要求1所述的组合物,其中所述涂层是低密度、多孔性3-D结构。
12.根据权利要求1所述的组合物,其中所述涂层包含功能性分子。
13.根据权利要求12所述的组合物,其中所述功能性分子选自下组:显色底物、链霉亲和素、蛋白A、蛋白G、抗体、肽、适体、荧光团、酶和药物。
14.根据权利要求1所述的组合物,其中所述液体介质是水、PBS、TRIS缓冲液、醇或水和醇的混合物。
15.根据权利要求1所述的组合物,其还包含全氟化碳液体。
16.一种制备均匀的纳米复合物簇的方法,所述方法包括:
在水/醇溶剂中混合金属盐前体和表面活性剂,以形成反应溶液;
向反应溶液中加入沉淀剂和表面活性剂;
获得所述纳米复合物簇;
其中将所述反应溶液控制在低于300摄氏度的温度下。
17.根据权利要求16所述的方法,其中所述金属盐前体包含亚铁盐前体和铁盐前体。
18.根据权利要求17所述的方法,其中所述亚铁盐前体选自下组:氯化亚铁、硫酸亚铁、硝酸亚铁、氟化亚铁、溴化亚铁、碘化亚铁、硫化亚铁、硒化亚铁、碲化亚铁、乙酸亚铁、草酸亚铁、柠檬酸亚铁和磷酸亚铁,所述铁盐前体选自下组:氯化铁、硫酸铁、硝酸铁、氟化铁、溴化铁、碘化铁、硫化铁、硒化铁、碲化铁、乙酸铁、草酸铁、柠檬酸铁和磷酸铁。
19.根据权利要求17所述的方法,其中所述金属盐前体还包括非铁金属盐前体。
20.根据权利要求19所述的方法,其中所述非铁金属盐前体选自下组:氯化物、硫酸盐、硝酸盐、氟化物、溴化物、碘化物、硫化物、硒化物、碲化物、乙酸盐、草酸盐、柠檬酸盐、磷酸盐或氯金酸形式的镁、锌、锰、镉、钴、金和银。
21.根据权利要求16所述的方法,其中所述表面活性剂是含有羧酸酯、磺酸酯、硫酸酯、磷酸酯、氢、胺、铵、甜菜碱和磺基甜菜碱基团的化合物。
22.根据权利要求16所述的方法,其中所述反应溶液不含有除了醇之外的有机溶剂。
23.根据权利要求16所述的方法,其中所述水溶液不被加热超过300摄氏度。
24.根据权利要求16所述的方法,其中所述水溶液不被加热超过200摄氏度。
25.根据权利要求16所述的方法,其中所述水溶液不被加热超过100摄氏度。
26.一种由权利要求16-25中任意一项所述的方法制备的组合物。
27.权利要求1-15和26中任意一项所述的组合物在制备治疗性或诊断性组合物,或在制备用于定性或定量检测的试剂,或在制备用于分子成像的试剂,或在制备用于分离、纯化或富集的试剂中的用途。
28.根据权利要求1-15和26中任意一项所述的组合物在包封/携带/保护/靶向递送/控制释放功能性分子中的用途。
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