具有可调纳米尺度尺寸和成分的锰铁氧体簇的稳定水悬浮液
Summary
我们报告了锰铁氧体簇（MFC）的一锅水热合成，可对材料尺寸和成分进行独立控制。磁分离允许快速纯化，而使用磺化聚合物的表面功能化可确保材料在生物相关介质中不聚集。由此产生的产品非常适合生物医学应用。
Abstract
锰铁氧体簇（MFC）是数十至数百个初级纳米晶体的球形组件，其磁性在各种应用中都很有价值。在这里，我们描述了如何在水热工艺中形成这些材料，该过程允许独立控制产品簇尺寸（从30到120nm）和所得材料的锰含量。酒精反应介质中加入的水总量和锰与铁前驱体的比例等参数是实现多种类型的MFC纳米级产品的重要因素。快速纯化方法使用磁分离来回收材料，使磁性纳米材料的克数生产非常有效。我们克服了磁性纳米材料聚集的挑战，将高电荷的磺酸盐聚合物应用于这些纳米材料的表面，产生胶体稳定的MFC，即使在高盐度环境中也保持非聚集性。这些非聚集、均匀和可调的材料是生物医学和环境应用的优秀前瞻性材料。
Introduction
与纯氧化铁相比，在适当的条件下，在氧化铁晶格中加入锰作为掺杂剂可以增加材料在高外加磁场下的磁化。因此，锰铁氧体（MnxFe3-xO4）纳米颗粒由于其高饱和磁化，对外部磁场的强烈响应和低细胞毒性而成为非常理想的磁性纳米材料1，2，3，4，5。单域纳米晶体以及这些纳米晶体的簇（称为多域粒子）已在各种生物医学应用中进行了研究，包括药物递送，用于癌症治疗的磁热疗和磁共振成像（MRI）6，7，8。例如，Hyeon小组在2017年使用单结构域锰铁氧体纳米颗粒作为Fenton催化剂来诱导癌症缺氧，并利用该材料的T2contrast进行MRI跟踪9。令人惊讶的是，鉴于这些和其他对铁氧体材料的积极研究，与纯氧化铁（Fe3O4）纳米材料相比，几乎没有体内演示，也没有报道在人类中的应用9，10。
将铁氧体纳米材料的特征转化为临床时面临的一个巨大挑战是产生均匀的、非聚集的纳米级簇11、12、13、14。虽然传统的单域纳米晶体合成方法已经发展良好，但这项工作中感兴趣的多域簇不容易以统一和受控的方式生产15，16。此外，铁氧体组成通常是非化学计量的，并且不仅仅与前驱体的起始浓度相关，这可能进一步模糊这些材料的系统结构功能表征9，12，13，17。在这里，我们通过展示一种合成方法来解决这些问题，该方法可以对锰铁氧体纳米材料的簇尺寸和组成进行独立控制。
这项工作也为克服铁氧体纳米材料的胶体稳定性差提供了一种手段18，19，20。磁性纳米颗粒通常由于强烈的颗粒 – 颗粒吸引力而容易聚集;铁氧体受这个问题的影响更大，因为它们较大的净磁化放大了粒子聚集。在相关的生物介质中，这些材料产生足够大的聚集体，使材料迅速收集，从而限制了它们与动物或人的接触途径20，21，22。Hilt等人在研究磁热加热和染料降解时发现了颗粒- 颗粒聚集的另一个后果23。在颗粒浓度略高或暴露于场中的时间增加时，随着材料随着时间的推移而聚集并且活性颗粒表面积减小，材料的有效性降低。这些应用和其他应用将受益于簇表面，这些表面旨在提供空间位阻，排除粒子 – 粒子相互作用24，25。
在这里，我们报告了一种合成方法，用于合成具有可控尺寸和成分的锰铁氧体簇（MFC）。这些多域颗粒由硬聚集的初级锰铁氧体纳米晶体的组装组成;初级纳米晶体的紧密结合增强了它们的磁性，并提供了50-300 nm的整体簇尺寸，与纳米医学的最佳尺寸很好地匹配。通过改变水和氯化锰前体的量，我们可以独立控制整体直径和成分。该方法利用简单有效的一锅水热反应，允许频繁的实验和材料优化。这些MFC可以很容易地纯化成浓缩的产品溶液，通过赋予胶体稳定性的磺化聚合物进一步修饰。它们的可调性、均匀性和溶液相稳定性都是纳米材料在生物医学和环境工程中的应用具有重要价值的特点。
Protocol
1. 控制中间商联总直径和铁氧体组成的中间商联苯合成 清洗并彻底干燥所有用于合成的玻璃器皿。合成中的水量会影响MFC的尺寸，因此确保玻璃器皿中没有残留水至关重要16，26。 要清洗玻璃器皿，请用水和洗涤剂冲洗，并用烧瓶刷擦洗以清除碎屑。彻底冲洗以除去所有洗涤剂，然后用去离子水冲洗完毕。 要干燥玻璃…
Representative Results
水热处理后，反应混合物变成粘稠的黑色分散体，如图 1所示。纯化后的结果是高度浓缩的MFC溶液，其行为类似于铁磁流体。当放置在手持式磁铁（<0.5 T）附近时，小瓶中的液体在几秒钟内就会做出反应，形成宏观的黑色团块，当磁铁放置在不同的位置时，可以四处移动。 该合成产生的产物的尺寸和铁氧体组成取决于反应混合物中加入的水量和锰与铁前…
Discussion
这项工作证明了锰铁氧体纳米晶体的改性多元醇合成，这些纳米晶体聚集在一起形成均匀的纳米级聚集体29。在该合成中，氯化铁（III）和氯化锰（II）进行强制水解反应和还原，形成分子MnxFe3-xO4。这些铁氧体分子在反应器中的高温和高压下形成初级纳米晶体，最终组装成球形聚集体，这里称为磁铁矿铁氧体簇（MFC）。没有足够的反应时间或足够…
Divulgations
The authors have nothing to disclose.
Acknowledgements
这项工作得到了布朗大学和先进能源联盟的慷慨支持。我们非常感谢张青波博士建立的氧化铁MFC合成方法。
Materials
| 0.1 Micron Vaccum Filtration Filter | Thermo Fisher Scientific | NC9902431 | for filtration of aggregated clusters after synthesis and surface coating to achieve a uniform solution |
| 2-Acrylamido-2-methylpropane sulfonic acid (AMPS, 99%) | Sigma-Aldrich | 282731-250G | reagent used in copolymer to surface coat nanoclusters and functionalize them for biological media |
| 2,2′-Azobis(2-methylpropionitrile) (AIBN) | Sigma-Aldrich | 441090-100G | reagent used in copolymer making as the free ridical generator |
| 4-Morpholineethanesulfonic acid, 2-(N-Morpholino)ethanesulfonic acid (MES) | Sigma-Aldrich | M3671-250G | acidic buffer used to stabilize nanocluster surface coating process |
| Acrylic acid | Sigma-Aldrich | 147230-100G | reagent used in copolymer to surface coat nanoclusters and functionalize them for biological media; anhydrous, contains 200 ppm MEHQ as inhibitor, 99% |
| Analytical Balance | Avantor | VWR-205AC | used to weigh out solid chemical reagents for use in synthesis and dilution |
| Digital Sonifier and Probe | Branson | B450 | used to sonicate nanocluster solution during surface coating to break up aggregates |
| Dopamine hydrochloride | Sigma-Aldrich | H8502-25G | used in surface coating for ligand exchange reaction |
| Ethylene glycol (anhydrous, 99.8%) | Sigma-Aldrich | 324558-2L | reagent used as solvent in hydrothermal synthesis of nanoclusters |
| Glass Vials (20mL) | Premium Vials | B1015 | container for nanocluster solution during washing and surface coating as well as polymer solutions |
| Graduated Beaker (100mL) | Corning | 1000-100 | container for mixing of solid and liquid reagents during hydrothermal synthesis (to be transferred into autoclave reactor before oven) |
| Handheld Magnet | MSC Industrial Supply, Inc. | 92673904 | 1/2" Long x 1/2" Wide x 1/8" High, 5 Poles, Rectangular Neodymium Magnet low strength magnet used to precipitate nanoclusters from solution (field strength is increased with steel wool when needed) |
| Hydrochloric acid (ACS grade, 37%) | Fisher Scientific | 7647-01-0 | for removing leftover nanocluster debris and cleaning autoclave reactors for next use |
| Hydrothermal Autoclave Reactor | Toption | TOPT-HP500 | container for finished reagent mixture to withstand high temperature and pressure created by the oven in hydrothermal synthesis |
| Iron(III) Chloride Hexahydrate (FeCl3·6H2O, ACS reagent, 97%) | ACS | 236489-500G | reagent used in synthesis of nanoclusters as source of iron (III) that becomes iron (II) in finished nanocluster product (keep dry and weigh out quickly to avoid water contamination) |
| Labware Washer Brushes | Fisher Scientific | 13-641-708 | used to wash and clean glassware before synthesis |
| Magnetic Stir Plate | Thermo Fisher Scientific | 50093538 | for mixing of solid and liquid reagents during hydrothermal synthesis |
| Manganese chloride tetrahydrate (MnCl2·4H2O, 99.0%, crystals, ACS) | Sigma-Aldrich | 1375127-2G | reagent used in synthesis of nanoclusters as source of manganese |
| Micropipette (100-1000μL) | Thermo Fisher Scientific | FF-1000 | for transferring liquid reagents such as water and manganese chloride |
| N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) | Sigma-Aldrich | 25952-53-8 | used in surface coating to assist in ligand exchange of copolymer (keep bulk chemical in freezer and diluted solution in refrigerator) |
| N,N-Dimethylformamide (DMF) | Sigma-Aldrich | 227056-2L | reagent used in copolymer making as the solvent |
| Polyacrylic acid sodium salt (PAA, Mw~6,000) | PolyScience Inc. | 06567-250 | reagent used in hydrothermal synthesis to initially coat the nanoclusters (eventually replaced in surface coating step) |
| Poly(ethylene glycol) methyl ether acrylate | Sigma-Aldrich | 454990-250ML | reagent used in copolymer to surface coat nanoclusters and functionalize them for biological media; average Mn 480, contains 100 ppm BHT as inhibitor, 100 ppm MEHQ as inhibitor |
| Reagents Acetone, 4L, ACS Reagent | Cole-Parmer | UX-78920-66 | used as solvent to precipitate nanoclusters during washing |
| Single Channel Pipette, Adjustable 1-10 mL | Eppendorf | 3123000080 | for transferring ethylene glycol and other liquids |
| Steel Wool | Lowe's | 788470 | used to increase the magnetic field strength in the vial to aid in precipitation of nanoclusters for washing and surface coating |
| Stirring Bar | Thomas Scientific | 8608S92 | for mixing of solid and liquid reagents during hydrothermal synthesis |
| Table Clamp | Grainger | 29YW53 | for tight sealing of autoclave reactor to withstand high pressure of oven during hyrothermal synthesis |
| Urea (ACS reagent, 99.0%) | Sigma-Aldrich | U5128-500G | reagent used in hydrothermal synthesis to create a basic solution |
| Vaccum Filtration Bottle Tops | Thermo Fisher Scientific | 596-3320 | for filtration of aggregated clusters after synthesis and surface coating to achieve a uniform solution |
| Vacuum Controller V-850 | Buchi | BU-V850 | for filtration of aggregated clusters after synthesis and surface coating to achieve a uniform solution |
| Vacuum Oven | Fisher Scientific | 13-262-51 | used to create high temperature and pressure needed for nanocluster formation in hydrothermal synthesis |
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Citer Cet Article
Effman, S., Avidan, S., Xiao, Z., Colvin, V. Stable Aqueous Suspensions of Manganese Ferrite Clusters with Tunable Nanoscale Dimension and Composition. J. Vis. Exp. (180), e63140, doi:10.3791/63140 (2022).