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We report a one-pot hydrothermal synthesis of manganese ferrite clusters (MFCs) that offers independent control over material dimension and composition. Magnetic separation allows rapid purification while surface functionalization using sulfonated polymers ensures the materials are non-aggregating in biologically relevant medium. The resulting products are well positioned for biomedical applications.
Manganese ferrite clusters (MFCs) are spherical assemblies of tens to hundreds of primary nanocrystals whose magnetic properties are valuable in diverse applications. Here we describe how to form these materials in a hydrothermal process that permits the independent control of product cluster size (from 30 to 120 nm) and manganese content of the resulting material. Parameters such as the total amount of water added to the alcoholic reaction media and the ratio of manganese to iron precursor are important factors in achieving multiple types of MFC nanoscale products. A fast purification method uses magnetic separation to recover the materials making production of grams of magnetic nanomaterials quite efficient. We overcome the challenge of magnetic nanomaterial aggregation by applying highly charged sulfonate polymers to the surface of these nanomaterials yielding colloidally stable MFCs that remain non-aggregating even in highly saline environments. These non-aggregating, uniform, and tunable materials are excellent prospective materials for biomedical and environmental applications.
The inclusion of manganese as a dopant in an iron oxide lattice can, under the appropriate conditions, increase the material's magnetization at high applied fields as compared to pure iron oxides. As a result, manganese ferrite (MnxFe3-xO4) nanoparticles are highly desirable magnetic nanomaterials due to their high saturation magnetization, strong response to external fields, and low cytotoxicity1,2,3,4,5. Both single domain nanocrystals as well as clusters of these nanocrystals, termed multidomain particles, have been investigated in diverse biomedical applications, including drug delivery, magnetic hyperthermia for cancer treatment, and magnetic resonance imaging (MRI)6,7,8. For example, the Hyeon group in 2017 used single domain manganese ferrite nanoparticles as a Fenton catalyst to induce cancer hypoxia and exploited the material's T2contrast for MRI tracking9. It is surprising in light of these and other positive studies of ferrite materials that there are few in vivo demonstrations as compared to pure iron oxide (Fe3O4) nanomaterials, and no reported applications in humans9,10.
One immense challenge faced in translating the features of ferrite nanomaterials into the clinic is the generation of uniform, non-aggregating, nanoscale clusters11,12,13,14. While conventional synthetic approaches to monodomain nanocrystals are well developed, multidomain clusters of the type of interest in this work are not easily produced in a uniform and controlled fashion15,16. Additionally, ferrite composition is usually non-stoichiometric and not simply related to the starting concentration of the precursors and this can further obscure systematic structure-function characterization of these materials9,12,13,17. Here, we address these issues by demonstrating a synthetic approach that yields independent control over both the cluster dimension and composition of manganese ferrite nanomaterials.
This work also provides a means to overcome the poor colloidal stability of ferrite nanomaterials18,19,20. Magnetic nanoparticles are generally prone to aggregation due to strong particle-particle attraction; ferrites suffer more from this problem as their larger net magnetization amplifies particle aggregation. In relevant biological media, these materials yield large enough aggregates that the materials rapidly collect, thereby limiting their routes of exposure to animals or people20,21,22. Hilt et al. found another consequence of particle-particle aggregation in their study of magnetothermal heating and dye degradation23. At slightly higher particle concentrations, or increased time of exposure to the field, the effectiveness of the materials was reduced as materials aggregated over time and the active particle surface areas decreased. These and other applications would benefit from cluster surfaces designed to provide steric barriers that precluded particle-particle interactions24,25.
Here we report a synthetic approach to synthesize manganese ferrite clusters (MFCs) with controllable dimensions and composition. These multidomain particles consist of an assembly of primary manganese ferrite nanocrystals that are hard aggregated; the close association of the primary nanocrystals enhances their magnetic properties and provides for an overall cluster size, 50-300 nm, well matched to the optimum dimensions for a nanomedicine. By changing the amount of water and manganese chloride precursor, we can independently control the overall diameter and composition. The method utilizes simple and efficient one-pot hydrothermal reactions that allow for frequent experimentation and material optimization. These MFCs can be easily purified into a concentrated product solution, which is further modified by sulfonated polymers that impart colloidal stability. Their tunability, uniformity, and solution phase stability are all features of great value in applications of nanomaterials in biomedical and environmental engineering.
1. Synthesis of MFCs with control over MFCs' overall diameter and ferrite composition
2. Magnetic separation and purification of MFCs
3. Surface functionalization of MFCs toward ultra-high colloidal stability
NOTE: The synthesis of nitro-dopamine and Poly(AA-co-AMPS-co-PEG) can be found in our previous work16. The copolymer is made through free radical polymerization. Add 0.20 g of 2,2′-Azobis(2-methylpropionitrile) (AIBN), 0.25 g of acrylic acid (AA), 0.75 g of 2-Acrylamido-2-methylpropane sulfonic acid (AMPS), and 1.00 g of Poly(ethylene glycol) methyl ether acrylate (PEG) in 10 mL of N,N-Dimethylformamide (DMF). Heat the mixture in a 70 °C water bath for 1 h and transfer it to a dialysis bag (Cellulose Membrane, 3 kDa) in water. The weight ratio of AA, AMPS, and PEG is 1:3:4. Polymerization for these monomers has a 100% conversion rate as confirmed by freeze drying and weighing.
After hydrothermal treatment, the reaction mixture turns into a viscous black dispersion as can be seen in Figure 1. What results after purification is a highly concentrated MFC solution that behaves like a ferrofluid. The fluid in the vial responds within seconds when placed near a handheld magnet (<0.5 T), forming a macroscopic black mass that can be moved around as the magnet is placed at different locations.
This synthesis yields products whose dimension a...
This work demonstrates a modified polyol synthesis of manganese ferrite nanocrystals clustered together into uniform nanoscale aggregates29. In this synthesis, iron(III) chloride and manganese(II) chloride undergo a forced hydrolysis reaction and reduction, forming molecular MnxFe3-xO4. These ferrite molecules form primary nanocrystals under the high temperature and high pressure in the reactors, ultimately assembling into spherical aggregates termed her...
The authors have nothing to disclose.
This work was generously supported by Brown University and the Advanced Energy Consortium. We gratefully thank Dr. Qingbo Zhang for his established synthetic method of iron oxide MFCs.
Name | Company | Catalog Number | Comments |
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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