Iron Oxide Nanoparticle Based Contrast Agents for Magnetic

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Review

Iron Oxide Nanoparticles-based Contrast Agents for Magnetic Resonance Imaging Zheyu Shen, Aiguo Wu, and Xiaoyuan Chen Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.6b00839 • Publication Date (Web): 24 Oct 2016 Downloaded from http://pubs.acs.org on October 25, 2016

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Molecular Pharmaceutics

Iron Oxide Nanoparticles-based Contrast Agents for Magnetic Resonance Imaging

2 3

Zheyu Shen,†,‡ Aiguo Wu,*,† and Xiaoyuan Chen*,‡

4 5

†

6

Nanodevices, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of

7

Sciences, Ningbo, Zhejiang 315201, P. R. China.

8

‡

9

Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, Maryland

10

Key Laboratory of Magnetic Materials and Devices & Division of Functional Materials and

Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical

20892, United States.

11 12 13 14

Corresponding Authors

15

*E-mail: [email protected].

16


17 18 19 20

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ACS Paragon Plus Environment


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Abstract

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Magnetic iron oxide nanoparticles (MIONs) have attracted enormous attention due to their wide

3

applications, including magnetic separation, magnetic hyperthermia and as contrast agents for

4

magnetic resonance imaging (MRI). This review article introduces the methods of synthesizing

5

MIONs, and their application as MRI contrast agents. Currently, many methods have been reported

6

for the synthesis of MIONs. Herein, we only focus on the liquid-based synthesis methods including

7

aqueous phase methods and organic phase methods. In addition, the MIONs larger than 10 nm can

8

be used as negative contrast agents and the recently emerged extremely small MIONs (ES-MIONs)

9

smaller than 5 nm are potential positive contrast agents. In this review, we focus on the ES-MIONs

10

because ES-MIONs avoid the disadvantages of MION-based T2- and gadolinium chelate-based

11

T1-weighted contrast agents.

12 13

Keywords: Magnetic Iron Oxide Nanoparticles (MIONs), Extremely Small MIONs (ES-MIONs),

14

Synthesis Methods, Magnetic Resonance Imaging (MRI), Contrast Agents.

15 16

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Contents

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1. Introduction................................................................................................................................. 4

3

2. Synthesis Methods of MIONs ..................................................................................................... 5

4

2.1 Co-precipitation Method........................................................................................................ 6

5

2.2 Reduction-precipitation Method ............................................................................................ 7

6

2.3 Hydrothermal Method ......................................................................................................... 8

7

2.4 Solvothermal Method .......................................................................................................... 8

8

2.5 Reverse Micelle Method ...................................................................................................... 8

9

2.6 Thermal Decomposition Method ........................................................................................... 9

10

2.7 Polyol Method ..................................................................................................................... 10

11

3. MION-based Contras Agents for Magnetic Resonance Imaging ................................................ 10

12

3.1 MION-based Negative Contrast Agents ............................................................................... 11

13

3.2 MION-based Positive Contrast Agents ................................................................................ 12

14

3.2.1 ES-MIONs Synthesized by Thermal Decomposition Method ........................................ 13

15

3.2.2 ES-MIONs Synthesized by Polyol Method ................................................................... 14

16

3.2.3 ES-MIONs Synthesized by Co-precipitation Method .................................................... 14

17

3.2.4 ES-MIONs Synthesized by Reduction-precipitation Method ......................................... 15

18

4. Conclusions and Future Prospective .......................................................................................... 17

19

Acknowledgements ....................................................................................................................... 19

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References .................................................................................................................................... 19

21 22

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1. Introduction

2

Magnetic iron oxide nanoparticles (MIONs) have attracted extensive attention due to their wide

3

applications, including magnetic separation, magnetic hyperthermia and contrast agents for

4

magnetic resonance imaging (MRI). The first true MR image was published in Nature in 1973 by

5

Prof. Paul C. Lauterbur, a chemist working at the State University of New York at Stony Brook.1

6

Prof. Peter Mansfield, a physicist working at the University of Nottingham, further refined Prof.

7

Lauterbur’s method into a line-scan technique, producing the first image of a human body part, a

8

finger, in 1977. The MRI was then approved for clinical use by U.S. Food and Drug Administration

9

(FDA) in 1985. Subsequently, Prof. Lauterbur and Prof. Mansfield shared the 2003 Nobel Prize in

10

Physiology or Medicine due to their contributions to MRI (Lauterbur's contribution: projectional

11

NMR tomography; Mansfield's contribution: use of a field gradient for slice selection), which had

12

received wide clinical application around the world for diagnosing or monitoring many diseases,

13

including necrotic tissue, infarcted artery and malignant tumors, and so on.2

14

MRI is an imaging modality for clinical use and depends on measuring the nuclear magnetic

15

resonance (NMR) signals, which are emitted from the protons in human bodies that should be

16

placed in a magnetic field. MRI performance can be significantly improved through affecting the

17

MR signal properties of surrounding tissues by contrast agents, which are administered in 40-50%

18

of all MR examinations. MRI contrast agents can be summarized to two groups, i.e. positive

19

contrast agents (or T1-weighted contrast agents) and negative contrast agents (or T2-weighted

20

contrast agents). The positive contrast agents can shorten the longitudinal relaxation times (T1) of

21

protons, resulting in brighter image in T1-weighted MRI. However, the negative contrast agents can

22

shorten the transverse relaxation times (T2) of protons, leading to darker image in T2-weighted

23

MRI.3

24

Currently, most of the MRI contrast agents on the market are gadolinium chelates based positive

25

contrast agents, including Magnevist® (Gd-DTPA) (the first MRI contrast commercialized in 1988),

26

Gadovist® (Gd-DO3A-Butriol) and Eovist® (Gd-EOB-DTPA) from Schering AG, Germany; 4


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ProHance® (Gd-DO3A-HP) and Multihance® (Gd-BOPTA) from Bracco Imaging, Italy;

2

OptiMARK® (Gd-DTPA-BMEA) from Mallinckrodt Inc., USA; Dotarem® (Gd-DTOA) from

3

Guerbet SA, France; and Omniscan® (Gd-DTPA-BMA) from Amersham-Nycomed, Norway.3

4

However, more recent studies indicate that these gadolinium chelates may raise the possibility of

5

nephrotoxicity by forming strong complexes with biological ligands in vivo.4-6 Thus, the FDA has

6

issued a general warning for all gadolinium-based contrast agents and advise against their use in all

7

patients with acute renal insufficiency.7 Although gadolinium chelates dominate the current market

8

of MRI contrast agents due to the good T1-weighted imaging efficiency, they will likely be obsolete

9

in the near future because of gadolinium-associated nephrogenic systemic fibrosis (NSF) (Scheme

10

1).

11

Compared with the gadolinium-based contrast agents, MION-based contrast agents have superior

12

biocompatibility and safety profiles because iron is an essential element in human body, but

13

gadolinium is not (Scheme 1). Therefore, MION-based contrast agents have received more and

14

more attention for MR imaging.

15

The focus and scope of this review article is to introduce the solvent-based synthesis methods of

16

the MIONs, summarize the pros and cons of these synthesis methods, discuss their application as

17

MRI contrast agents. Especially, the recently emerged extremely small MIONs (ES-MIONs)

18

smaller than 5 nm, which are potential T1-weighted contrast agents due to their suppressed

19

magnetization and very low transversal relaxivity (r2), are discussed in detail. Although several

20

review articles involving MIONs for biological applications have recently been published,8-13 none

21

of them summarized the ES-MIONs as T1-weighted contrast agents.

22 23

2. Synthesis Methods for MIONs

24

There are many reported synthesis methods for MIONs. In this review, we only focus on the

25

liquid-based synthesis methods by which the MIONs can be applied as MRI contrast agents. The

26

liquid-based synthesis methods of MIONs can be summarized into two categories, i.e. aqueous 5



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phase methods and organic phase methods.

2

The aqueous phase methods for the synthesis of MIONs include co-precipitation method,

3

reduction-precipitation method and hydrothermal method, whose reactions of Fe3+ and Fe2+ happen

4

in aqueous solutions.12 The advantage of these aqueous phase methods is that the synthesized

5

MIONs are well water-soluble. Due to this advantage, the commercially available MION-based

6

MRI contrast agents, such as Feridex® produced by Berlex, USA, Endorem® produced by Guerbet,

7

France, and Resovist® produced by Schering AG, Germany, are all synthesized by the aqueous

8

phase methods. These particles can be degraded in lysosome due to their biodegradability at acidic

9

conditions, or eliminated via hepatobiliary excretion due to their uptake by the reticuloendothelial

10

system (RES). However, these aqueous phase methods have several fundamental shortcomings,

11

which include: 1) the mono-dispersity of the synthesized MIONs is somewhat low; 2) the particles

12

do not have regular morphologies; 3) the particle sizes are hard to be uniform. These drawbacks can

13

be ascribed to the high reactivities of Fe3+ and Fe2+ in aqueous solutions.

14

The organic phase methods for the synthesis of MIONs include solvothermal method, reverse

15

micelle method, thermal decomposition method and polyol method. In these methods, organic

16

solvents are used in the reaction systems. Because the reactivities of iron ions in organic solvents

17

and iron-organic compounds pyrolysis are not so high, the organic phase methods can overcome the

18

drawbacks associated with the above-mentioned aqueous phase methods. The mono-dispersity of

19

the synthesized MIONs is often high in the organic solvents, the morphologies are consistent and

20

the particle sizes are rather uniform. However, the water-solubility of the synthesized MIONs is not

21

good, which limits their direct application as in vivo MRI contrast agents. So, further processing is

22

necessary to obtain water-soluble MIONs.13

23

These synthesis methods of MIONs are reviewed below and summarized in Table 1.

24 25 26

2.1 Co-precipitation Method The co-precipitation method is the most popular synthesis method for commercial MION-based 6


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MRI contrast agents due to the following reasons: 1) the synthesis procedure is simple; 2) the

2

synthesis conditions are mild; 3) the synthesis cost is low; 4) easy to scale up; 5) the yield of

3

MIONs is high; 6) the obtained MIONs are water-soluble due to the hydrophilic surface; 7) toxic

4

reagents are not used.14,15

5

It has been over three decades since the co-precipitation method was first reported to synthesize

6

MIONs by Massart et al.16 A base (sodium hydroxide or ammonium hydroxide) was added into the

7

mixed solution of Fe3+ and Fe2+, resulting in the formation of iron oxide precipitate.17 In order to

8

obtain ideal MIONs with good water-solubility (or stability), good mono-dispersity, regular

9

morphologies, uniform sizes and high saturation magnetization, in the last few decades, lots of

10

researchers have optimized most of the synthesis conditions including the feeding molar ratio of

11

Fe3+/Fe2+,18-20 reaction temperature,21,22 reaction time,23 and pH value of the reaction solution.23

12

Although the synthesis conditions of co-precipitation have been widely investigated and

13

optimized, the particle sizes are still not uniform and the morphologies are not regular. Therefore,

14

the MIONs synthesized by co-precipitation method have to be further processed prior to be used as

15

a pharmaceutical drug, such as functional surface modification, filtration or centrifugation.

16 17

2.2 Reduction-Precipitation Method

18

The reduction–precipitation method was first reported by Qu et al., which is an improved

19

synthesis method of MIONs based on the above-mentioned co-precipitation method. By this

20

reduction–precipitation method, spherical MIONs with size of sub-10 nm can be synthesized using

21

ferric chloride (FeCl3) as starting material, which can be partially reduced to ferrous (Fe2+) salts by

22

Na2SO3 before alkalinizing with ammonia. The advantage of this method lies in the formation of a

23

red intermediate during the reduction process, which prevents the reoxidation of ferrous ions by

24

adding precipitation agents at the end of the reduction reaction without protection by nitrogen or

25

argon.24 Subsequently, many other groups repeated the reduction–precipitation method and

26

optimized the synthesis conditions.25-27 7



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2.3 Hydrothermal Method

3

Hydrothermal method is a kind of method for the synthesis of single crystals including MIONs in

4

aqueous solution in a sealed container. The reaction temperature is high up to 100-250 oC, and the

5

vapor pressure is high up to 0.3-4 MPa.28,29 Hydrothermal method has been developed not only for

6

the synthesis of naked MIONs,30-33 but also for the synthesis of surface-functionalized MIONs.34,35

7

The advantages of the hydrothermal method include: 1) the synthesized MIONs are water-soluble

8

because the reaction solvent is water; 2) the crystallinity of the MIONs is better than those

9

synthesized by other methods because the reaction temperature and pressure are higher; 3) it is a more

10

versatile method than other methods because lots of reactants and experimental conditions can be

11

used for the hydrothermal process. However, every coin has two sides. The properties of the obtained

12

MIONs are more difficult to be controlled or predicted, expensive autoclaves are necessary for the

13

hydrothermal method, and observing the crystal during its growth is impossible. In addition, scale-up

14

synthesis is a challenge due to the high reaction pressure.

15 16

2.4 Solvothermal Method

17

Solvothermal method is very similar to the hydrothermal method, and the only difference is that the

18

aqueous solution is replaced with organic solvent. Stojanovic et al. reported a simple solvothermal

19

method for the synthesis of MIONs. The reaction solvent is water-ethanol-oleic acid solvent system,

20

the oleate anion is used as a surface stabilizer, and glucose is used as a reducing agent. The

21

morphology and size of the obtained MIONs are much better than those synthesized by the

22

hydrothermal methods. However, the surface of the MIONs is hydrophobic, resulting in poor

23

water-solubility, the biocompatibility is a concern due to the usage of organic solvents.36

24 25 26

2.5 Reverse Micelle Method Reverse micelle method was first reported in 1999 for the synthesis of metallic iron nanoparticles 8


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using hydrazine as a reducing agent and cetyltrimethyl-ammonium bromide (CTAB) as a surfactant.

2

The reverse micelles are surfactant-stabilized water-in-oil microemulsions, which are used as

3

nanoreactors for the synthesis.37 Hereafter, the reaction conditions of the reverse micelle method

4

have been optimized to obtain MIONs with high quality and yields.38-41

5

The reverse micelle method is also called growth confined co-precipitation method because the

6

reactants in the reverse micelle method are almost the same as those in the co-precipitation method

7

and

8

reduction-precipitation method, the advantages of the reverse micelle method are that the

9

morphology is regular, the size can be very small ranging from 3 to 12 nm and uniform because the

10

nanoreactors can limit the crystal growth and prevent the particle agglomeration. However, the

11

disadvantages include: 1) the yields are low and the water-solubility is bad compared with the

12

co-precipitation method and reduction-precipitation method; 2) the size distributions are not

13

excellent compared with the thermal decomposition method and polyol method; 3) the surfactants

14

used in the synthesis and those adhered to the nanoparticles may result in biosafety concerns; 4) the

15

purification process to remove the surfactants is complex, leading to difficulty of scaling up.

reduction-precipitation

method.

Compared

with

the

co-precipitation

method

and

16 17

2.6 Thermal Decomposition Method

18

MIONs can also be synthesized by decomposition of organometallic complexes at high

19

temperatures in high boiling-point organic solvents. The organometallic complexes, also known as

20

precursors, can be ferric acetylacetonate (Fe(acac)3) or iron pentacarbonyl (Fe(CO)5). The surfactants

21

can be fatty acids, oleic acid and hexadecylamine. The species and feeding amounts of the precursors,

22

surfactants and solvents are the key points to control the morphologies, particle size and size

23

distributions of the synthesized MIONs.42-46

24

The main advantage of the thermal decomposition method is that the high reactivity of Fe3+ and/or

25

Fe2+ is avoided because the reaction happens in organic solvents, not in water. Thus, the obtained

26

MIONs are monodisperse, the morphologies are regular, the particle sizes are uniform and well 9



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controlled, and the values of saturation magnetization are high. However, the obtained MIONs are

2

not water-soluble, the organic solvents and surfactants may remain in the products resulting in

3

toxicity. Although the large-scale synthesis of the MIONs using the thermal decomposition method

4

have been reported,47,48 However, these materials need to be rendered water soluble for use as

5

contrast agents. The complex purification process to remove the organic solvents and surfactants

6

remains an issue.

7 8

2.7 Polyol Method

9

Although the thermal decomposition method has several advantages, the main problem is the

10

poor water-solubility. In order to solve this problem, polyol methods have been recently developed

11

to synthesize water-soluble MIONs. The polyol methods are essentially thermal decomposition of

12

organometallic compounds (i.e. precursors) in polyol solvents, which could also be the surfactants

13

and/or reducing agents.49-51 Hu et al. synthesized MIONs in diethylene glycol through a one-pot

14

reaction. The obtained MIONs are ultra-small (3-6 nm) with a regular morphology, uniform size,

15

narrow size distribution, with modest water-solubility.52

16

Overall, the MIONs synthesized by the polyol methods have no problems as to morphologies,

17

particle sizes, size distributions and water-solubility. However, it remains a significant challenge to

18

remove the organic solvents and surfactants. Similar to the thermal decomposition method, scale up

19

is not easy as the removal of the organic solvents and surfactants is nontrivial.

20 21

3. MION-based Contrast Agents for Magnetic Resonance Imaging

22

MRI contrast agents include positive contrast agents (or T1-weighted contrast agents) and

23

negative contrast agents (or T2-weighted contrast agents). Currently, most of the MRI contrast

24

agents on the market are gadolinium chelates based positive contrast agents.3 Compared with the

25

gadolinium chelates, the MIONs have one important advantage that is the better biocompatibility.

26

The MIONs larger than 10 nm can be used as negative contrast agents and the recently emerged 10


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1

extremely small MIONs (ES-MIONs) smaller than 5 nm are potential positive contrast agents

2

(Scheme 1).

3

The mechanism about the MION-based T1 and/or T2 contrast agents is discussed below. When a

4

strong magnetic field (e.g. MRI scanner) is applied to the body, the spins of hydrogen nuclei can be

5

polarized from a chaotic state to an ordered state in accordance with the direction of the magnetic

6

field. After applying a strong radiofrequency pulse, the magnetization, which is created by the spins

7

of hydrogen nuclei, interacts with the receiver coil and then the spin polarization could be observed

8

by the coil. After removing the radiofrequency pulse, the net magnetization will return to its

9

position of equilibrium in the direction of the applied magnetic field. The recovery of the

10

longitudinal magnetization corresponds to the T1 relaxation, and the decay of the transversal

11

magnetization corresponds to the T2 relaxation. The different amounts of water protons in different

12

organs result in different T1 and/or T2 relaxation times, which is the main source of contrast in MR

13

images. After intravenous or oral administration, the MIONs can shorten the T1 and/or T2 relaxation

14

times of water protons inside various organs, leading to contrast in the MR images.53-57

15 16

3.1 MION-based Negative Contrast Agents

17

On the market, Ferumoxide and Ferucarbotan were ever two popular commercialized

18

formulations of MIONs used as negative contrast agents. Ferumoxide is also known as Feridex® in

19

USA (from Berlex, USA) and Endorem® in Europe (from Guerbet, France). Ferumoxide is a colloid

20

of MIONs with coating of dextran (low Mw), whose overall particle size ranges from 120 to 180 nm.

21

The transversal relaxivity (r2) and longitudinal relaxivity (r1) are ~98 and ~24 mM-1 s-1,

22

respectively.58 Ferucarbotan is also known as Resovist® developed by Schering AG, Germany. The

23

MIONs of Resovist are coated by carboxydextrane, and the overall particle size ranges from 45 to

24

60 nm, which is much smaller than that of the MIONs of Ferumoxide. The r2 and r1 values are ~150

25

and 25 mM-1 S-1, respectively.59

26

The advantages of the MION-based negative contrast agents include: 1) they are all specific and 11



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high-performance contrast agents for MR imaging of liver or spleen because the MIONs can be

2

cleared from the blood to the liver via reticuloendothelial system (RES) after intravenous

3

administration;60-62 2) they are all non-toxic and very safe because the MIONs can be metabolized

4

in lysosomes to a soluble and non-magnetic species of iron ions, including ferritin, hemoglobin, and

5

so on.63-65

6

However, currently, only Resovist® is available in few countries including USA and Japan. Other

7

commercialized MION-based negative contrast agents have been removed from the market.59 The

8

probable reasons are summarized below: 1) the negative contrast agents result in dark images that

9

can be confused with the signals of other pathogenic conditions, including hemorrhage, calcification

10

and metal deposits (such as endogenous iron); 2) the high magnetic moments of the negative

11

contrast agents can cause susceptibility artifact (i.e. distortion of the magnetic field on the

12

surrounding of disease regions, or background distortion), which destroys the background around

13

disease regions and generates unclear images;66,67 3) the relatively large particle sizes of the MIONs

14

used for the T2-weighted contrast agents (60~180 nm) result in a slow clearance (several weeks or

15

months to be degraded and cleared from the body), which may cause long-term side effects;68 4) the

16

process time of T2-weighted MR imaging is much longer than that of the T1-weighted MR imaging

17

(Scheme 1).

18 19

3.2 MION-based Positive Contrast Agents

20

In order to overcome the disadvantages of the MION-based negative contrast agents (i.e.

21

T2-weighted contrast agents), Taupitz et al. first explored ES-MIONs (named as VSOP-C184) as

22

potential positive contrast agents. The ES-MIONs are smaller than 5 nm and have a suppressed

23

magnetization along the longitudinal axis (Mz), which is proportional to r2 relaxivity, resulting in an

24

increased r1 relaxivity ranging from 2 to 50 mM-1 s-1 and a decreased ratio of r2/r1 smaller than

25

5.69,70 Hereafter, lots of scientists have been interested in exploring ES-MION-based T1-weighted

26

MRI contrast agents.71,72 The reported synthesis methods for the ES-MIONs mainly include thermal 12


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decomposition, polyol, co-precipitation or reduction-precipitation. The synthesis methods and

2

properties of the ES-MIONs are summarized in Table 2.

3 4

3.2.1 ES-MIONs Synthesized by Thermal Decomposition Method

5

In 2004, Sun et al. reported a thermal decomposition method using Fe(acac)3, Co(acac)2 or

6

Mn(acac)2 as the precursors to synthesize monodispersed MFe2O4 (M = Fe, Co, Mn) nanoparticles.

7

They focused on the study of nanoparticle compositions and size control. Although MRI studies were

8

not carried out using these nanoparticles, they obtained Fe3O4 nanoparticles that are smaller than 5

9

nm (i.e. ES-MIONs).38

10

Based on this thermal decomposition method, in 2009, Tromsdorf et al. synthesized

11

superparamagnetic PEGylated ES-MIONs and applied as potential T1-weighted MRI contrast agents.

12

The size of the core ES-MIONs, and the density and length of PEG coating were optimized

13

according to the nanoparticles’ cytotoxicity and stability under physiological conditions. The

14

optimized ES-MIONs have a low ratio of r2/r1 (2.4) and reasonably high r1 relaxivity (7.3 mM-1 s-1),

15

which is twice as much as that of the Magnevist® (Gd-DTPA), indicating that it is a potential

16

positive contrast agent.73

17

In 2011, Kim et al. synthesized uniform ES-MIONs through a thermal decomposition method

18

using iron-oleate complex as the precursor in the presence of oleic acid and oleyl alcohol in

19

diphenyl ether. The size of the ES-MIONs is very uniform and can be controlled from 1.5 to 3.7 nm

20

with high crystallinity (Figure 1 a-e). The magnetic property of the ES-MIONs is highly dependent

21

on the size of the particles. They are superparamagnetic when the particle size is larger than 2.2 nm,

22

but paramagnetic when the particle size is 1.5 nm (Figure 1 f). The low magnetization of the

23

ES-MIONs could be ascribed to the spin canting effect. The ES-MIONs are efficient T1-weighted

24

MRI contrast agents with brighter T1-weighted images at higher concentrations (Figure 1 g). For the

25

ES-MIONs with particle size of 12, 3 and 2.2 nm, the r1 relaxivities are 2.37, 4.77 and 4.78 mM-1

26

s-1, respectively (Figure 1 h), and the r2/r1 ratios are 24.8, 6.12 and 3.67. These results indicate that 13



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Page 14 of 39

1

the smaller particles have better positive contrast.48 The in vivo T1 imaging efficiency of ES-MIONs

2

was further studied and compared with DOTAREM® (Gd-DOTA).48 Figure 2 shows ES-MIONs and

3

DOTAREM enhanced kidney T1-weighted MR images with dynamic time-resolved MR sequence.

4

Of note is the much slower kidney clearance of ES-MIONs than that of DOTAREM and thus longer

5

efficient imaging time.

6 7

3.2.2 ES-MIONs Synthesized by Polyol Method

8

The ES-MIONs synthesized by thermal decomposition method are not water-soluble and will

9

need further surface modification using hydrophilic polymers. To synthesize water-soluble

10

ES-MIONs, Park et al. developed a polyol method to make monodispersed PEG-modified

11

ES-MIONs in triethylene glycol. The average particle size is determined to be 1.7 nm by TEM

12

(Figure 3 a, b), and the hydrodynamic diameter is measured to be 5.4 nm by DLS (Figure 3 c). The

13

M-H curves demonstrate that the PEG-modified ES-MIONs are ferromagnetic at temperature of 5

14

K, but are superparamagnetic at 300 K (Figure 3 d). In addition, the PEG-modified ES-MIONs have

15

relatively high r1 (4.46 mM-1 s-1) and low r2/r1 ratio (3.4) (Figure 3 e, f), demonstrating that they can

16

be used as T1-weighted MRI contrast agents.74

17 18

3.2.3 ES-MIONs Synthesized by Co-Precipitation Method

19

Co-precipitation method is also utilized by Li et al. to synthesize water-soluble ES-MIONs. Thiol

20

functionalized poly(methacrylic acid) (PMAA-PTMP) is used as a stabilizer. FeCl3 and FeSO4 are

21

used as the iron precursors to react with ammonia solution. The mean particle size of the obtained

22

ES-MIONs determined by HR-TEM is 3.3 ± 0.5 nm (Figure 4 a, b), and the hydrodynamic diameter

23

determined by DLS is 7.5 nm (Figure 4 c). The M-H curve indicates that the ES-MIONs are

24

superparamagnetic with a magnetization of 16 emu g-1 at room temperature (Figure 4 d). The r1

25

relaxivity is 8.3 mM-1 s-1, which is also much larger than that of the commercial T1-weighted MRI

26

contrast agent Gd-DTPA (r1 = 4.8 mM-1 s-1) (Figure 4 e). In addition, the r2/r1 ratio of the 14


Page 15 of 39

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1

ES-MIONs is 4.2 (Figure 4 e, f), which is also relatively small indicating their potential as

2

T1-weighted MRI contrast agents.75

3

The in vivo imaging efficiency of the 3.3 nm ES-MIONs was also investigated. Figure 5 a, b

4

compared T1- and T2-weighted images of mouse liver and kidneys using 3.3 nm ES-MIONs (Figure

5

5 a) and Magnevist® (Gd-DTPA) (Figure 5 b) as contrast agents. The signal intensities of labeled

6

areas are shown in Figure 5 c-f. It is found that the kidney and liver signal intensities of the

7

ES-MIONs are much stronger, and the time is much longer than that of the Magnevist®. These

8

results demonstrate the potential of ES-MIONs as an alternative to Gd-based T1-positive contrast

9

agents.

10 11

3.2.4 ES-MIONs Synthesized by Reduction-Precipitation Method

12

One more reported method for the synthesis of ES-MIONs is the reduction-precipitation method.

13

In 2013, Peng et al. synthesized ES-MIONs with a particle size of 2-3 nm by redox reaction of

14

K2FeO4 (an iron precursor) and water molecules (i.e. reduction-precipitation). The obtained

15

ES-MIONs are antiferromagnetic showing a very low magnetization (Mz), which is two orders of

16

magnitude smaller than any currently reported ES-MIONs. The extremely low Mz leads to a low

17

r2/r1 ratio (2.03) and r2 relaxivity (7.64 mM-1 s-1), which is proportional to Mz. These results open

18

up a new avenue for designing powerful antiferromagnetic T1-weighted MRI contrast agents.76

19

In order to synthesize ES-MIONs under mild reaction conditions including room temperature and

20

normal atmospheric pressure, Liu et al. developed a one-step and room temperature synthesis of

21

glutathione (GSH)-modified ES-MIONs via an improved reduction-precipitation method. FeCl2 and

22

FeCl3 are used to react with NaOH and tetrakis(hydroxymethyl) phosphonium chloride (THPC),

23

which is used as the reducing agent. GSH is used as a stabilizer. The mean particle size of the

24

obtained GSH-modified ES-MIONs determined by HR-TEM is 3.72 ± 0.12 nm (Figure 6 a, b). The

25

GSH-modified ES-MIONs have a good T1 imaging efficiency (Figure 6 c) due to the low r2/r1 ratio

26

(2.28) and r2 relaxivity (8.28 mM-1 s-1) (Figure 6 d). The low r2 relaxivity that is proportional to Mz 15



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Page 16 of 39

1

can be ascribed to the intrinsic antiferromagnetic property of the GSH-modified ES-MIONs, which

2

exhibit a very low magnetization (Figure 6 f). The GSH-modified ES-MIONs have good

3

biocompatibility because they can be well-secreted by the kidneys (Figure 6 e, g). The

4

GSH-modified ES-MIONs open a new dimension in efforts towards high performance and

5

long-circulating T1-weighted MRI contrast agents.77

6

The above-introduced synthesis methods of ES-MIONs (i.e. thermal decomposition, polyol,

7

co-precipitation or reduction-precipitation) have been widely used for the synthesis of MIONs with

8

larger size. The modifications of these methods that have been used to obtain extremely small size

9

are highlighted below: 1) lower temperature that slowers reaction rate;45,48,73,76 2) shorter reaction

10

time;45,73 3) introducing positively or negatively charged polymers as stabilizers to enhance the

11

electrostatic repulsion between nanoparticles during reaction;45,73,75 4) lower concentration of iron

12

precursors that results in slower reaction rate.48,74,75,77

13

To evaluate the biosafety of the ES-MIONs compared with other T1-weighted contrast agents

14

including gadolinium and manganese-based contrast agents, the biodistribution, histopathological

15

and hematological changes of ESIONs (i.e. ES-MIONs), gadopentetate dimeglumine (GDI) and

16

manganese oxide nanoparticles (MnONPs) are studied for parallel comparison.78 Figure 7 a, b, c

17

show the Gd, Fe, and Mn element analysis in various organs and tissues by inductively coupled

18

plasma-mass spectrometry (ICP-MS) at 24 h after intravenous administration of GDI, ESIONs, and

19

MnONPs.78 It is found that the Gd or Fe concentration in the spleen is higher than that in the liver

20

after intravenous injection of GDI or 3 nm sized ESIONs (Figure 7 a, b). However, The Mn

21

concentration in the liver is higher than that in the spleen (Figure 7 c) due to the larger particle size.

22

Comparatively, the Gd concentrations detected in the kidneys of the GDI group were significantly

23

higher than those in the kidneys of the ESIONs or MnONPs group. The above-mentioned results

24

indicate that the Gd element tends to be accumulated in the kidneys increasing the likelihood of

25

nephrotoxicity. Figure 7 d shows the histopathological images of mouse tissues after intravenous

26

injection (24 h) of GDI, ESIONs, and MnONPs. The obvious pathological changes in cells 16


Page 17 of 39

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1

including swelling/atrophy are shown via red arrows; significantly widened renal capsule is pointed

2

out using yellow arrows. It is obvious that both GDI and MnONP treatments lead to obvious

3

damage to the lungs and kidneys, however, ESION (even at high dose) did not result in any obvious

4

damage to the observed tissues.78

5

Figure 8 shows the hematological changes and inflammation levels after intravenous injection

6

(24 h) of GDI, ESIONs, and MnONPs.78 The total WBC (white blood cell) amount was almost not

7

affected at 24 h after injection of ESIONs, but that of the group of GDI and MnONPs significantly

8

decreased (Figure 8 a). The group of GDI or MnONP-M showed a higher percentage of LYM

9

(lymphocytes) and GRN (granulocytes), indicating that these contrast agents may have different

10

mechanisms of toxicity (Figure 8 b). The group of MnONP-H slowed an obvious increase of RBC

11

(red blood cells) (Figure 8 c). In addition, significantly increased levels of TNF-R and IL-6 were

12

detected in the serum of the GDI group (Figure 8 d, e). These results indicate that the inflammation

13

results from Gd3+ release may be responsible for nephrogenic systemic fibrosis (NSF) of

14

gadolinium-based contrast agents. Furthermore, the ratio of alanine transaminase (ALT) to aspartate

15

transaminase (AST) increased for the group of ESION-H or MnONP-H (Figure 8 f) indicating a

16

decreased liver function.78 This result demonstrates that nanoparticles may have higher toxicity to

17

liver than GDI.

18 19

4. Conclusions and Future Prospective

20

In summary, although aqueous phase methods for the synthesis of MIONs have been applied to

21

make commercial MION-based MRI contrast agents, the future challenges of aqueous phase

22

synthesis include: 1) the mono-dispersity need to be enhanced; 2) the morphology need to be more

23

regular; 3) the particle size need to be more uniform. Potential strategies to overcome these

24

challenges may be to reduce the reaction rate (e.g. decrease the reaction temperature and/or

25

concentration of iron precursors) and prolong the reaction time. In addition, the organic phase

26

methods for synthesis of MIONs can be improved by: 1) introducing hydrophilic stabilizers during 17



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Page 18 of 39

1

the synthesis process, hydrophilic surface modifications after synthesis, and so on to increase

2

water-solubility; 2) removal of the residual organic solvents and/or surfactants in the products via

3

various purification technologies.

4

Currently, the clinicians do not enjoy the commercialized MIONs for clinic use as T2-weighted

5

contrast agents due to the concerns of artifact, large particle size and long process time. The

6

gadolinium-based T1-weighted contrast agents that occupied most of the market are also not ideal

7

contrast agents due to their nephrotoxicity. Because the problems of the MION-based T2-weighted

8

contrast agents and gadolinium-based T1-weighted contrast agents do not exist for the

9

ES-MION-based T1-weighted contrast agents, they might be the future generation of MRI contrast

10

agents. The future challenges and opportunities in the application of ES-MIONs as T1 imaging

11

agents include: 1) although most of the reported r1 values of the ES-MIONs are higher than that of

12

Magnevist® (Gd-DTPA), it may be further enhanced via improving the magnetism, crystallinity,

13

particle size, water dispersity, size uniformity, and/or morphologies; 2) the short retention time in

14

the body due to the extremely small size may be prolonged via enlarging the hydrodynamic size by

15

surface modifications; 3) the tumor specificity of the ES-MIONs modified with hydrophilic

16

polymers may be improved via various targeting strategies including active targeting, Trojan-horse

17

targeting,63 and so on; 4) the ES-MIONs may also be functionalized with other imaging agents or

18

chemotherapeutic drugs as multi-modality imaging agents or theranostic agents.

19 20

AUTHOR INFORMATION

21

Corresponding Authors

22


23


24

Notes

25

The authors declare no competing financial interest

26 18


Page 19 of 39

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1


ACKNOWLEDGMENTS

2

This work is financially supported by National Natural Science Foundation of China (Grant Nos.

3

51411140243, 61571278 and 21305148), Youth Innovation Promotion Association of Chinese

4

Academy of Sciences (2016269), NSFC-Guangdong Province Joint Project on National

5

Supercomputer Centre in Guangzhou (NSCC-GZ) (A. Wu), and the Intramural Research Program

6

(IRP), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of

7

Health.

8 9 10 11

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Table 1. Typical reaction conditions, advantages and disadvantages of MION synthesis methods. Synthesis Method

Co-precipitation 3+

2+

Reductionprecipitation 3+

Hydrothermal

Solvothermal

2+

Reverse Micelle 3+

Thermal Decomposition

Polyol

2+

Reaction Substance

Fe , Fe , NaOH / NH3.H2O


Numerous

Numerous


Organometallic Compounds

Organometallic Compounds

Reaction Temperature (oC)

Iron Oxide Nanoparticle Based Contrast Agents for Magnetic

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