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In This Article

  • Summary
  • Abstract
  • Introduction
  • Protocol
  • Results
  • Discussion
  • Disclosures
  • Acknowledgements
  • Materials
  • References
  • Reprints and Permissions

Summary

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.

Abstract

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.

Introduction

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.

Protocol

1. Synthesis of MFCs with control over MFCs' overall diameter and ferrite composition

  1. Wash and thoroughly dry all glassware to be used in the synthesis. The amount of water in the synthesis impacts the dimensions of the MFCs, so it is crucial to ensure the glassware has no residual water in it16,26.
    1. To wash the glassware, rinse with water and detergent and scrub with a flask brush to remove debris. Thoroughly rinse to remove all detergent and finish with a rinse of deionized water.
    2. To dry the glassware, shake water droplets off the surface of the glassware and place into an oven at 60°C until completely dry.
    3. Rinse the polyphenylene-lined (PPL) reactors with 37% hydrochloric acid to remove any debris from previous use. To do this, place the reactors and their caps in a large beaker and fill with hydrochloric acid until the reactors are completely submerged. Let this sit for 30 min before pouring out the hydrochloric acid. Continuously rinse the beaker containing the reactors with water for 1-2 min, and then place the reactors in the oven to dry.
  2. Use an automatic pipette to transfer 20 mL of ethylene glycol into a 50 mL beaker with a magnetic stir bar.
  3. Weigh out the required amount of iron(III) chloride (FeCl3·6H2O, solid) to achieve a final concentration of 1.3 mM and add it to the beaker. Put the beaker on a stir plate and turn it on at 480 rpm to begin continuous stirring of the beaker.
    NOTE: As this is a hydrate, it must be measured and added quickly to avoid unwanted absorption of water from the ambient air.
  4. Weigh 250 mg of polyacrylic acid (PAA, Mw ~6,000, powder) and add it to the beaker. After the addition of PAA, the solution becomes opaque and slightly lighter in color.
  5. Weigh 1.2 g of urea (CO(NH2)2, powder) and add it to the beaker.
  6. Using a pipette, add 0.7 mM manganese(II) chloride (MnCl2·6H2O aq, 3.5 M, 0.2 mL) to the beaker.
  7. Finally, using a pipette add the required amount (0.5 mL) of ultra-pure water to the beaker.
  8. Let the solution stir for 30 min and notice the color change. It will present as a translucent, dark orange color.
  9. Transfer the reaction mixture into the polyphenylene lined (PPL) reactor. Note that after the solution has stirred some solids may have accumulated on the sides of the beaker.
    1. Use a magnet (cubic permanent rare earth magnet, 40 x 40 x 20 mm, hereafter referred to as a "magnet" for all separation and magnetic collection procedures) to drag the stir bar around the walls of the beaker to ensure any solids that have accumulated on the sides are dispersed into the reaction solution.
    2. Once the solution is mixed and ready, transfer it into the 50 mL PPL lined reactor.
    3. Use a clamp and lever to seal the reactor in the stainless-steel autoclave as tightly as possible. Clamp the reactor vessel to a stable surface, and using a rod inserted into the cap as a lever, push the reactor to seal. Note that the sealed reactor should not be able to be opened by hand. This is crucial as the high-pressure environment of the oven requires a tight seal on the reactor.
  10. Place the reactor into an oven for 20 h at 215 °C.
  11. After the hydrothermal reaction is done, remove the reactor from the oven and allow it to cool down to room temperature. The pressure of the oven will enable the reactor to be opened by hand. Note that at this point, the reactor will contain the MFC product dispersed in ethylene glycol with other impurities, such as unreacted polymer, and will be an opaque black solution. The product will be isolated in the following steps.

2. Magnetic separation and purification of MFCs

  1. Place 200 mg of steel wool into a glass vial. Fill the glass vial halfway with the reaction mixture from the reactor. Fill the rest of the vial with acetone and shake well. Note that the steel wool increases the magnetic field strength in the vial and will help magnetic separation of the nanoclusters from the solution.
  2. Place the vial on a magnet for magnetic collection to occur. The result will be a translucent solution with precipitate at the bottom.
    1. Pour off the supernatant solution while the MFCs are magnetically trapped by the steel wool by holding the magnet to the bottom of the vial while pouring. Ethylene glycol will be mostly removed in this step.
    2. Start washing with the low ratio of acetone to water and increase the ratio in subsequent washes until pure. Do this 3-4 times.
  3. Remove the vial from the magnet and fill it with water. Shake well to dissolve the MFCs. Now the product will be fully dispersed in water.
  4. Repeat the previous two steps several times until the aqueous solution of the MFCs produces no bubbles when shaken. The result will be a dark, opaque ferrofluid that will respond strongly to magnets.
    NOTE: In a typical synthesis with 20 mL of ethylene glycol, approximately 80 mg of MFC product will be obtained.

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.

  1. Combine 10 mL of purified nanoparticles (around 100 mg) in a 20 mL vial with 10 mL of saturated N-[2-(3,4-dihydroxyphenyl)ethyl]nitramide (nitro-dopamine) solution (~1 mg/mL). Wait for 5 min.
  2. Wash the nitro-dopamine coated MFCs using magnetic separation. Pour out the pale-yellow supernatant. Add water and shake vigorously. Then, pour out water using the magnet to retain the product. Repeat this washing several times leaving the dark brown collection in the vial.
    NOTE: Prepare a aqueous solution with a concentration of 20 mg/mL, a buffer solution with a concentration of 100 mg/mL, and a poly(AA-co-AMPS-co-PEG) polymer solution with a concentration of 20 mg/mL.
  3. Mix 1 mL of EDC solution, 1 mL of MES buffer, and 3 mL of the polymer solution. Lightly stir by swirling the mixture, and let it sit for approximately 5 min. It should be a clear and colorless solution when fully combined.
  4. Add this mixture to the MFC collection and place the vial in an ice bath. Lower the probe sonicator into the solution, and then turn it on (250 watts of power at 20 kHz).
    1. After a 5 min sonication treatment, add roughly 5 mL of ultra-pure water to the vial while the sonicator is still running. Continue monitoring the vessel to ensure that no product spills. Maintain the ice in the ice-water mixture as some of the initial ice will melt due to the intensity and heat of the sonication.
    2. Allow the mixture to sonicate for an additional 25 min, for a total of 30 min.
  5. Place the vial on top of a magnet to separate the MFCs and pour out the supernatant solution.
  6. Wash the modified MFCs with deionized water several times.
  7. Fill the vial containing the MFCs with ultra-pure water. Pipette this fluid into a vacuum filtration system with a 0.1 µm polyethersulfone membrane filter to remove any irreversibly aggregated MFCs. Make sure to flush the walls of the funnel to minimize any loss of product.
  8. Vacuum filter the solution. Repeat this process 2-3 times. The result will be a purified aqueous solution of monodispersed MFCs.
    NOTE: Roughly 10% of the product will be irreversibly aggregated and this material will remain on the filter and should be discarded.

Results

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...

Discussion

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...

Disclosures

The authors have nothing to disclose.

Acknowledgements

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.

Materials

NameCompanyCatalog NumberComments
0.1 Micron Vaccum Filtration FilterThermo Fisher ScientificNC9902431for filtration of aggregated clusters after synthesis and surface coating to achieve a uniform solution
2-Acrylamido-2-methylpropane sulfonic acid (AMPS, 99%)Sigma-Aldrich282731-250Greagent used in copolymer to surface coat nanoclusters and functionalize them for biological media
2,2′-Azobis(2-methylpropionitrile) (AIBN)Sigma-Aldrich441090-100Greagent used in copolymer making as the free ridical generator
4-Morpholineethanesulfonic acid, 2-(N-Morpholino)ethanesulfonic acid (MES)Sigma-AldrichM3671-250Gacidic buffer used to stabilize nanocluster surface coating process
Acrylic acidSigma-Aldrich147230-100Greagent used in copolymer to surface coat nanoclusters and functionalize them for biological media; anhydrous, contains 200 ppm MEHQ as inhibitor, 99%
Analytical BalanceAvantorVWR-205ACused to weigh out solid chemical reagents for use in synthesis and dilution
Digital Sonifier and ProbeBransonB450used to sonicate nanocluster solution during surface coating to break up aggregates
Dopamine hydrochlorideSigma-AldrichH8502-25Gused in surface coating for ligand exchange reaction
Ethylene glycol (anhydrous, 99.8%)Sigma-Aldrich324558-2Lreagent used as solvent in hydrothermal synthesis of nanoclusters
Glass Vials (20mL)Premium VialsB1015container for nanocluster solution during washing and surface coating as well as polymer solutions
Graduated Beaker (100mL)Corning1000-100container for mixing of solid and liquid reagents during hydrothermal synthesis (to be transferred into autoclave reactor before oven)
Handheld MagnetMSC Industrial Supply, Inc.926739041/2" 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 Scientific7647-01-0for removing leftover nanocluster debris and cleaning autoclave reactors for next use
Hydrothermal Autoclave ReactorToptionTOPT-HP500container 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%)ACS236489-500Greagent 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 BrushesFisher Scientific13-641-708used to wash and clean glassware before synthesis
Magnetic Stir PlateThermo Fisher Scientific50093538for mixing of solid and liquid reagents during hydrothermal synthesis
Manganese chloride tetrahydrate (MnCl2·4H2O, 99.0%, crystals, ACS)Sigma-Aldrich1375127-2Greagent used in synthesis of nanoclusters as source of manganese
Micropipette (100-1000μL)Thermo Fisher ScientificFF-1000for transferring liquid reagents such as water and manganese chloride
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)Sigma-Aldrich25952-53-8used 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-Aldrich227056-2Lreagent used in copolymer making as the solvent
Polyacrylic acid sodium salt (PAA, Mw~6,000)PolyScience Inc.06567-250reagent used in hydrothermal synthesis to initially coat the nanoclusters (eventually replaced in surface coating step)
Poly(ethylene glycol) methyl ether acrylateSigma-Aldrich454990-250MLreagent 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 ReagentCole-ParmerUX-78920-66used as solvent to precipitate nanoclusters during washing
Single Channel Pipette, Adjustable 1-10 mLEppendorf3123000080for transferring ethylene glycol and other liquids
Steel WoolLowe's788470used to increase the magnetic field strength in the vial to aid in precipitation of nanoclusters for washing and surface coating
Stirring BarThomas Scientific8608S92for mixing of solid and liquid reagents during hydrothermal synthesis
Table ClampGrainger29YW53for tight sealing of autoclave reactor to withstand high pressure of oven during hyrothermal synthesis
Urea (ACS reagent, 99.0%)Sigma-AldrichU5128-500Greagent used in hydrothermal synthesis to create a basic solution
Vaccum Filtration Bottle TopsThermo Fisher Scientific596-3320for filtration of aggregated clusters after synthesis and surface coating to achieve a uniform solution
Vacuum Controller V-850BuchiBU-V850for filtration of aggregated clusters after synthesis and surface coating to achieve a uniform solution
Vacuum OvenFisher Scientific13-262-51used to create high temperature and pressure needed for nanocluster formation in hydrothermal synthesis

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