Introduction

Magnetic resonance imaging (MRI) is widely used as an effective medical imaging technique providing both three-dimensional and cross-section images of soft tissues without using radioactive radiations. But the application of this technique is sometimes restricted by poor anatomic description and visualization of changes in soft tissues (Hao et al. 2010; Laurent et al. 2008). Therefore, paramagnetic contrast agents including dysprosium, gadolinium, and manganese complexes are used to raise the sensitivity of imaging (Xiao et al. 2016). Gadolinium is the most commonly used metal atom as an MRI contrast agent due to its most stable ion with unpaired electrons and high magnetic momentum (Caravan 2006). However, the sensitivity of gadolinium-based contrast agents is still relatively low and a high dose of the agents may cause toxicity on some organs (Hermann et al. 2008). Some studies have reported the deposition of gadolinium in the bone and brain of patients with normal renal function, which raises concerns associated with the toxicity of gadolinium-based agents (Ramalho et al. 2016).

Over the past decade, the chemical synthesis methods and the applications of magnetic iron oxide nanoparticles have been widely studied for high-technology medical uses such as contrast agents in MRI, hyperthermia therapy, targeted drug or gene delivery, tissue engineering, and cell separation (Boyer et al. 2010). Magnetic iron oxide nanoparticle contrast agents might be considered as one of the most successful examples of medical applications of inorganic nanoparticles due to their unique properties such as effective contrast features, capability and flexibility of surface functionalization, and biocompatibility (Lee and Hyeon 2012; Santra et al. 2009).

After a while, iron was suggested as a potential contrast agent to overcome the mentioned disadvantages associated with applying gadolinium complexes. Iron is known as a vital element for several biological processes such as synthesis of heme applied in oxygen transport by hemoglobin and cellular respiration via iron-containing redox enzymes. Moreover, iron is a vital element in living organisms and plays a key role in metabolic pathways of the cells of all mammals (Abbate and Hider 2017; Coe et al. 2015). Although in recent years, magnetic nanoparticles have received considerable attention due to their unique potential applications as magnetic resonance contrast agents, naked nanoparticles might be easily oxidized by the air leading to loss of dispersibility and magnetization (Qiao et al. 2009). Therefore, by providing suitable surface coatings, some effective surface protection strategies were developed to increase the stability of magnetic iron oxide nanoparticles (Zheng et al. 2018). These approaches involve surface coating with some molecules such as biological molecules, surfactants, organic and inorganic polymers, and amino acids (Plachtova et al. 2018; Hedayati et al. 2018). Improved surface coating magnetic iron oxide nanoparticles with high relaxivity are developed to produce effective imaging contrast agents for prolonged circulation and specific targeted imaging, which offer unique opportunities for ultrasensitive magnetic resonance imaging and result in accurate diagnosis (Table 1) (Clauson et al. 2018; Wei et al. 2017).

Table 1 Characteristics of FDA-approved iron oxide magnetic nanoparticle MRI contrast agents (Lohrke et al. 2016)
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This review summarizes the chemical synthesis approaches of magnetic iron oxide nanoparticles and their recent advances in biomedical imaging. In addition, it makes a bridge between synthetic and surface chemistry for the advancement of the potential applications of inorganic/organic-coated magnetic nanoparticles in magnetic resonance imaging.

MRI contrast agents

MRI technique

The first examination using the MRI technique on living human beings was performed in 1977, and since then, MRI has evolved into a widespread clinically important imaging tool (Hillman and Schwartz 1985). Magnetic resonance imaging is based on the behavior of hydrogen atoms in a magnetic field and is known as a very useful non-invasive diagnosing approach for internal organ imaging (Saddik et al. 2006).

The nucleus of an atom, with a net positive charge, consists of protons and neutrons. The nuclei of some elements have a specific property known as spin which is dependent on the number of protons or neutrons such as 1H, 13C, 31P, 19F, etc. The nuclei with an odd number of protons and/or neutrons possess quantized spin angular momentum and a magnetic moment (Liu et al. 1993). In the absence of an applied external magnetic field, all the spin states of the nucleus are in an equivalent level of energy with the same population. For example, hydrogen nuclei adopt only +1/2 or −1/2 spin and the nuclear magnetic moments (μ) in these two cases are pointed in opposite directions (Fig. 1).

Fig. 1
figure 1

Schematic representation of proton behavior in the presence of an external magnetic field applied in magnetic resonance imaging

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The nuclear magnetic signal occurs when nuclei aligned with an external field are induced to absorb energy and change their spin orientation (Yang et al. 2004). The differences between the energy levels of these two spin states are dependent on the strength of the external magnetic field and increases with the raising of the field strength. Particular characteristics of hydrogen atoms in water molecules in the presence of magnetic fields provide a contrast between soft tissues according to their binding to water or lipid molecules (Henkelman et al. 2001).

In an applied magnetic field of 3 T, the energy difference of two spin states of a proton is compared with the radio frequency energy.

Magnetic fields in the range of 0.5–1.5 T are usually used in diagnostic MRI scanners, and 3-T systems are regularly used in research. High-field-strength systems possess some advantages including improved quantification, increased signal-to-noise ratio, enhanced temporal resolution, and reduced imaging time (Nielles-Vallespin et al. 2007). When the external magnetic field is applied, the nucleus begins to precess about its own axis of spin with angular Larmor frequency. The energy of radiofrequency waves of the oscillating electric field can be absorbed by other nuclei and changes the spin state (Grover et al. 2015).

The differences in signal intensity and resolution between tissues or anatomic spaces can be increased by the introduction of certain chemical agents for manipulating the relaxation parameters (longitudinal and transverse) of water as the most abundant molecule in human tissues.

T1- and T2-weighted MR imaging

The exited nuclei return to the ground state via longitudinal (spin-lattice) and transverse (spin-spin) relaxations that occur as first-order rate processes and are characterized by relaxation times T1 and T2, respectively (Mansfield et al. 1994). These two relaxation times are the fundamental parameters behind magnetic resonance imaging, and accurate determination of the T1 and T2 values allows quantitative imaging of tissues. Through the longitudinal relaxation process, the energy of the spins is transferred to the surroundings as thermal energy and increases the temperature of the matrix. The relaxation time T1 is also known as the time required for the z component of the magnetic field (M) to return to 63% of its original value and provides a mechanism by which the protons return to their original orientation (Fig. 2) (Plewes and Kucharczyk 2012). However, the inverse of the spin–lattice relaxation time (1/T1) is considered as the rate constant for the decay process.

Fig. 2
figure 2

The relaxation time of a longitudinal magnetization relaxation (T1) as the time required for longitudinal magnetization to recover to 63% of its maximum value and b transverse magnetization relaxation (T2) as the time required for transverse magnetization to fall to 37% of its initial value

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On the other hand, the transverse relaxation process takes place in a plane perpendicular to the direction of the external magnetic field and does not change the energy of the spin system. The relaxation time T2 is the time required for the transverse component of M to decay to 37% of its initial value via irreversible processes (Nan et al. 2020).

A T1-weighted image is a basic pulse sequence in MRI and depicts differences in signal based on the intrinsic T1 relaxation time of various tissues. For example, fat shows high signal intensity on T1-weighted images, while fluid reveals low signal intensity (Thomson et al. 1993). However, T2-weighted images provide the best depiction of disease, because most tissues involved in a pathologic process have higher water content than normal tissues such as cerebrospinal fluid and vitreous humor that appear bright on T2-weighted images (Hajela et al. 2000). The transverse relaxation in gradient-echo sequences (T2*) is a combination of T2 relaxation and relaxation caused by magnetic field inhomogeneities. The relationship between T2 and T2* can be expressed by the equation 1/T2* = 1/T2 + γ ΔBinhom, where γ is the gyromagnetic ratio and ΔBinhom is the magnetic field inhomogeneity (Hajela et al. 2000).

Moreover, the resolution of MRI is increased by shortening the T1 and T2 relaxation times using contrast agents which increase the distinction between normal and affected tissues. Contrast agents are the essential elements of the developmental efforts to advance the medical diagnosis applications of MR technology.

Gadolinium-based contrast agents

Improvement of the signal intensity and the visibility of internal organs are the main purpose of using contrast agents that decrease the T1 relaxation of water molecules (Spandonis et al. 2004). Gadolinium (III)-containing chemical complexes are known as the most important applied contrast agents for raising the resolution of MRI. Gadolinium with seven unpaired electrons is a paramagnetic metal that behaves like protons in the presence of an external magnetic field. Stored energy in the processing electrons of gadolinium plays as a reservoir of magnetization, and this energy can be transferred to adjacent water protons helping them to reaccumulate longitudinal magnetization more quickly after an excitation pulse. This process eventually results in the shortening the T1 of adjacent protons leading to an increase in the signal intensity on T1-weighted images (Bonnet et al. 2010; Winter et al. 2011).

Gadopentetate dimeglumine (Magnevist®) was introduced in 1988 as one of the first developed contrast agents for clinical applications (Fig. 3). During the last decades, several gadolinium-containing agents were also approved worldwide for diagnostic imaging across the body including the heart, brain, breast, and lungs, and the circulatory, central nervous, genitourinary, gastrointestinal, lymphatic, and musculoskeletal systems (Lohrke et al. 2016).

Fig. 3
figure 3

The Food and Drug Administration (FDA)–approved gadolinium-based contrast agents (generic name, trade name, and approval year)

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Generally, gadolinium-based contrast agents are classified into four distinguished categories with different characteristics and important clinical implications, including linear, macrocyclic, ionic, and nonionic agents (Moser et al. 2018). Macrocyclic and ionic agents possess higher stability compared to linear and non-ionic compounds, respectively (Blahut et al. 2017). Gadoterate meglumine (Dotarem®), a thermodynamically stable MRI agent, consists of organic acid tetraxetan and is applied for visualization of the disruption of the blood–brain barrier and abnormal vascularity in the brain and spine (Kielar et al. 2018).

Although gadolinium complexes are the most potent contrast agents due to their unpaired electrons and isotropic electronic ground state, there are a few other metal ions such as Mn(II), Mn(III), Eu(II), and Fe(III) that can serve as effective relaxation agents.

Safety concerns of gadolinium complexes

Gadolinium chelates as extensively applied MRI contrast agents have conventionally been considered safe and well-tolerated when applied at recommended dosing levels (Rogosnitzky and Branch 2016). However, a correlation has been recognized between the administration of gadolinium-containing contrast agents and nephrogenic systemic fibrosis in patients with severe renal impairment (Berger et al. 2018; Fraum et al. 2017). Patients with normal renal function are able to remove the gadolinium complexes, while several reports in animals and humans have showed that Gd3+ is retained in some tissues (Blumfield et al. 2017). In addition, some in vitro studies revealed adverse effects of exposure or administration of gadolinium-containing contrast agents such as induction of apoptosis and necrosis in renal tubular cells (Rah et al. 2018). Moreover, significant growing data demonstrate the accumulation of gadolinium in the kidney, bone, and brain of patients exposed to gadolinium-containing MRI contrast agents (Behzadi et al. 2017; Dekkers et al. 2018; Prince and Weinreb 2018). Although early clinical investigations were primarily focused on gadolinium chelates, today, iron oxide nanocomposites have been identified as potential alternative MR contrast agents with higher T1 relaxivities and lower toxicity than gadolinium-containing agents.

Preparation methods of magnetic iron oxide nanoparticles

Several synthetic approaches are developed to produce magnetic iron oxide nanoparticles for medical imaging applications including co-precipitation (Fakayode et al. 2018; Mogharabi-Manzari et al. 2018a), microemulsions (Kaur et al. 2018), sol–gel syntheses (Sciancalepore et al. 2018), sonochemical reactions (Sodipo and Aziz 2018), and hydrothermal reactions (Lassoued et al. 2018). Generally, the synthesis of magnetic nanoparticles is known as a complicated process due to the colloidal nature of the particles. Adjustment of experimental conditions in the chemical approaches leads to the formation of monodisperse magnetic grains of appropriate size (Park et al. 2005). In addition, applying reproducible and simple procedures might be industrialized without the requirement of a complex, multi-step, and expensive purification process such as magnetic filtration, ultracentrifugation, or size-exclusion chromatography (Teja and Koh 2009). However, some approaches have been developed to produce magnetic nanoparticles with homogeneous composition, narrow size distribution, and high magnetic saturation, such as co-precipitation, hydrothermal, sol–gel, and polyol methods (Fig. 4).

Fig. 4
figure 4

Various methods used for production of iron oxide magnetic nanoparticles, extracted from 1560 papers published from 2000 to 2020

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Co-precipitation

The co-precipitation approach is one of the most important chemical pathways for the synthesis of magnetic nanoparticles in which iron oxides are typically prepared by an aging process of a stoichiometric mixture of various ferric and ferrous salts in an aqueous solution (Kim et al. 2001; Lin et al. 2017). Thermodynamics of the co-precipitation method provide complete precipitation of magnetite at a pH ranging from 8 to 14 in the presence of a 2:1 stoichiometric ratio of Fe3+/Fe2+ in a non-oxidizing environment (Lassoued et al. 2017; Mogharabi-Manzari et al. 2019a). However, one of the main advantages of this technique is the one-step production of large quantities of nanoparticles. In the co-precipitation approach, kinetic parameters control the growth of the crystal and limit the particle size distribution. The co-precipitation process consists of two main steps including nucleation and growth of the nuclei. The nucleation is a fast step and occurs when the concentration of the species reaches critical supersaturation, but growth of the nuclei is a slow process and performed by the diffusion of the solutes to the surface of the crystals (Suryawanshi et al. 2018). In a supersaturated solution, the nuclei form at the same time followed by their growth, resulting in a very narrow particle size distribution (Šutk et al. 2015; Mogharabi-Manzari et al. 2018b).

Extensive varieties of important factors affect the features of magnetic iron oxide nanoparticles such as size, magnetic characteristics, and surface properties (Kandasamy and Maity 2015; Mogharabi-Manzari et al. 2019b). The most important experimental conditions affecting the shape and the size of the nanoparticles are ionic strength and pH of the medium, temperature, type of the iron salts (chlorides, nitrates, perchlorates, or sulfates), and the molar ratio of Fe(II) to Fe(III) (Mahmed et al. 2014; Roth et al. 2015). Moreover, the control of the size can be achieved during the synthesis of magnetite nanoparticles using organic chelators such as acetate, citrate, or gluconate anions containing carboxylate or α-hydroxy carboxylate groups. In addition, some organic polymers are also applied for the coating of the surface of the nanoparticles leading to the control of their size and shape, such as polyvinyl alcohol, starch, dextran, and carboxydextran (Nadeem et al. 2016).

Temperature is a key factor in the synthesis of magnetic nanoparticles via co-precipitation process. At temperatures below 60 °C, the main product is Fe2O3, while Fe3O4 is the expected product when the reaction is carried out at temperatures above 80 °C. The nature of the alkali used in the synthesis procedure is also affected by the properties of the produced iron oxide nanoparticles, and it has been reported that replacing sodium hydroxide with ammonium hydroxide in the co-precipitation reaction improves the magnetization, crystallinity, and particle size (Mallakpour and Madani 2015).

Although the co-precipitation approach suffers from challenging control of shape and size distribution of the particles, this technique is still the preferred method for the synthesis of magnetic nanoparticles due to the convenient reaction conditions such as short reaction time, low temperatures used, and water as an environmentally friendly solvent, compared to hydrothermal and decomposition methods.

Hydrothermal

Hydrothermal reactions are carried out in aqueous media at temperatures and pressures higher than 200 °C and 2000 psi, respectively (Cheng et al. 2016; Gyergyek et al. 2017; Li et al. 2014). In the hydrothermal process, the characteristics of the prepared particles are affected by reaction conditions such as temperature, pressure, solvent system, and reaction time (Cui et al. 2006; Ozel et al. 2015). For example, the size of the precipitated iron oxide nanoparticles increases with the raising of water content of the solvent system as well as raising reaction time (Ge et al. 2009). Nucleation and grain growth are two key factors that mainly control the size of the particles in the hydrothermal process, and it was found that increasing the temperature and prolonging the reaction time might be favorable for crystal nucleation and growth, respectively (Takami et al. 2007). The hydrothermal approach possesses several advantages over the conventional methods, including the possibility of direct precipitation of crystallized nanoparticles from the solution that regulates the nucleation rate, uniformity, and growth rate (Table 2). However, advanced control of the processes of nucleation and growth improves the size and morphology of the produced magnetic nanoparticles and significantly reduces the aggregation of the nanoparticles (El-Boubbou 2018; Maghsodi et al. 2018).

Table 2 Some advantages and disadvantages of the MOF synthesis methods
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The hydrothermal method is a very interesting technique for the production of iron oxide magnetic nanoparticles offering unique advantages such as short time reaction, controlled size and morphological characteristics, and high magnetization saturation.

Sol–gel reactions

Challenging control of the morphology of the nanoparticles in solid-state chemical synthesis reactions led to the development of some effective alternative wet methods (Gash et al. 2001). The sol–gel is an appropriate wet technique based on the hydroxylation and condensation of organic/inorganic molecular precursors for the production of nanostructured magnetic iron oxides in a solution (Lu et al. 2002). This technique consists of condensation and inorganic polymerization processes leading to the formation of a three-dimensional network of metal oxide (Akbar et al. 2015). Generally, the sol formation is performed by hydrolysis and partial condensation of precursors followed by gelation via a polycondensation process to form metal–oxygen–metal covalent bonds. Water acts as an oxygen supplier for the formation of metal oxide, and various metal salts are applied as the precursors of metals, such as acetates, alkaloids, citrates, chlorides, nitrates, or sulfates.

Some key factors are influencing the properties of the produced magnetic nanoparticles via sol–gel technique, including pH, temperature, precursor concentration, and solvent system (López-Ramón et al. 2018). In an aqueous sol–gel process, the control of size and morphology is complicated due to the high reactivity of metal precursors and dual activity of water as both a ligand and a solvent (Hussain et al. 2018). However, non-aqueous sol–gel systems were developed to overcome the disadvantages of aqueous solvents and offer improved crystallinity and uniform morphology. In the non-aqueous methods, the oxygen atom is provided by non-hydrolytic organic solvents such as alcohols, aldehydes, ethers, or ketones (Silva et al. 2017).

Polyol

The polyol technique is known as a useful method for the high yield synthesis of nano- and micro-sized particles with uniform morphology (Hachani et al. 2016). In this method, polyol compounds are employed as solvents, such as polyethylene glycol (PEG), 1,5-pentanediol, and 1,2-propylene glycol. Applying polyol solvents provides interesting properties such as high dielectric constants, ability to dissolve various inorganic compounds, and high boiling points that offer an extensive operating temperature (Yamada et al. 2016). Polyols also act as reducing agents and stabilizers that prevent the aggregation of the nanoparticles and improve their size and morphology (Cheng et al. 2011). Generally, the synthesis of the nanoparticles via a polyol approach has four distinguished steps including metal precursor dissolution, intermediate formation, nucleation, and growth. In this method, metal salts are applied as starting compounds in combination with various anions such as Cl−, SO4−, NO3−, and OH− (Hachani et al. 2016). Increased solubility of precursors in the presence of polyols improves the formation of metal complexes. In the next step, the intermediate is precipitated and the metal clusters are formed via nucleation process. The efficiency of the nucleation step might be improved by adding external nanoparticles to the reaction mixture that facilitates the formation of fine and uniform particles (Yamada et al. 2016).

Although the growth process suffers from aggregation, long-chain alkylamines are used to adjust the shape and size of the nanoparticles as well as to prevent aggregation of the nanoparticles in the growth step (Cheng et al. 2011).

Miscellaneous methods

Flow injection is known as an important method for the continuous production of magnetic nanoparticles with uniform morphology and narrow size distribution (Salazar-Alvarez et al. 2006). However, in the flow injection approach, a particular design of the reactor can serve as an alternative to matrix confinement offering some unique advantages such as high homogeneity, high reproducibility, laminar conditions, and effective control of reaction conditions (Lunvongsa et al. 2006).

Aerosol approaches such as laser and spray pyrolysis have also become attractive based on continuous chemical processes that increase the rate of nanoparticle formation. In the spray pyrolysis method, a solution containing metal salts and reducing agent that is dissolved in an organic solvent are sprayed onto a hot surface to evaporate the solvent (Arimoto et al. 2002). Spray pyrolysis is a cost-effective technique that has some considerable benefits such as easy to perform under ambient conditions and no need for high-quality solvents and reagents. Furthermore, the characteristics of produced nanoparticles can be easily controlled by adjusting the reaction conditions including flow rate, concentrations of precursors, and temperature (Morales et al. 2003).

Laser pyrolysis as an effective approach for gas-phase synthesis of a wide range of nanoparticles performs based on decomposition of liquid or gas reactants using a powerful carbon dioxide laser followed by a quenching process (Bautista et al. 2005). In this process, the gaseous precursor is introduced into a reactor through an inert carrier gas and meets a high-power laser beam leading to molecular decomposition and vaporization to initiate nucleation and growth of nanoparticles with a narrow size distribution ranging from 5 to 60 nm (Rohani et al. 2019).

The sonochemical synthesis approach as one of the most important chemical synthesis techniques is widely applied for the preparation of ferrite nanoparticles with controllable physical characteristics such as morphology, particle size, and saturation magnetization (Yadav et al. 2020). Amorphous Fe3O4 nanoparticles are prepared using the sonolysis of an aqueous iron pentacarbonyl solution in the presence of sodium dodecyl sulfate (SDS) (Pinkas et al. 2008). The sonochemical synthesis of nanoparticles involves advantages such as high yield, reduced reaction time, and reduced costs (Mukh-Qasem and Gedanken 2005).

Coatings of iron oxide nanoparticles

Surface coatings are needed to improve the colloidal stability of the iron oxide magnetic nanoparticles in a physiological environment. Generally, the main purposes of surface modifications are improved dispersion of nanoparticles, adjustment of the surface activity, improvement of the mechanical and physicochemical characteristics, and increasing the biocompatibility of nanoparticles. Furthermore, the tendency of magnetic nanoparticles toward agglomeration can be prevented by coating of the surface with an organic or inorganic shell that enhances their hydrophilicity and biocompatibility (Dadfar et al. 2019).

Various synthetic and natural polymers are used for coating of iron oxide nanoparticles, such as porous and non-porous silica, PEG, poly(vinyl-pyrrolidone) (PVP), poly(vinyl alcohol) (PVA), poly(lactic-co-glycolic acid) (PLGA), gelatin, dextran, and chitosan (Table 3)

Table 3 Physical, chemical, and biological properties of various iron oxide nanoparticles applied as MRI contrast agents
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.

Silica

Magnetic iron oxide nanoparticles encapsulated in a suitable organic or inorganic shell have been successfully applied in an extensive variety of biomedical applications ranging from the separation of biological macromolecule to increasing the contrast of magnetic resonance images. Silica is one of the most commonly prepared and documented materials that is applied for coating the surface of various nanoparticles. Silica not only increases the stability of magnetic nanoparticles in both aqueous and organic solutions but also provides an appropriate support that can be easily functionalized through various functional groups (Fig. 5).

Fig. 5
figure 5

Synthesis of silica-coated magnetic iron oxide nanoparticles

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Nonporous silica coatings

Ultra-small and monodispersed magnetic Fe3O4 nanoparticles with a diameter of 4 nm were coated with silica shell using reverse microemulsion technique (Stepanov et al. 2018).

Iqbal et al. (Iqbal et al. 2015) applied superparamagnetic silica-coated iron oxide nanoparticles with T1 relaxivity of 1.2 mM−1 s−1 and low r2/r1 ratios 6.5 mM−1 s−1 as T1 contrast agents. In this study, T1-weighted magnetic resonance images were recorded using a clinical instrument. Accuracy of tumor diagnosis was improved using fluorescent silica-coated iron oxide nanoparticles (Jang et al. 2016). In addition, the silica-coated nanoparticles were used for in vitro cellular labeling and enhancement of contrast in MRI visualization (Raschzok et al. 2013).

Stepanov et al. (Stepanov et al. 2018) synthesized superparamagnetic iron-oxide nanoparticles via high-temperature decomposition of iron oleate as a precursor. In the next step, nanoparticles were coated with a silica layer to improve their hydrophilicity and prevent them from aggregation. They revealed transverse relaxivity values 134.74, 163.11, and 153.84 mM−1 s−1 for aqueous colloids at 0.47, 1.41, and 14.1 T, respectively. Moreover, the obtained nanoparticles showed r1 and r2 as 53.7 and 375.5 mM−1 s−1 at 15 MHz, respectively.

Synthesis of silica-coated contrast agents with a particle size of 10 nm showed that the coating process can also be applied for the production of the ultra-small contrast agent (Xue et al. 2014; Yan et al. 2004).

Zhang et al. (2007) showed that the T2 relaxivity of silica-coated particles (339.80 s−1 mM−1) was higher than that of its derivatives such as (3-aminopropyl)trimethoxysilane-coated (134.40 s−1 mM−1) and [N-(2-aminoethyl)-3 aminopropyl]trimethoxysilane-coated (84.79 s−1 mM−1) particles. The obtained results revealed that silica-coated nanoparticles are very promising T1 contrast agent candidates with the extraordinary ability to increase the brightness of the images.

Porous silica coatings

Mesoporous silica-coated nanoparticles are recognized as safe and biocompatible materials for MRI cell labeling and tracking. Dispersion of paramagnetic iron species into highly porous silica was carried out successfully as a promising approach for the development of efficient T2-weighted MRI contrast agents applying in vivo cell tracking (Fig. 6) (Ye et al. 2012). The effect of surface coating on the efficiency of contrast agent was also studied, and it was found that the efficiency increased with the thickness of the coated nanoparticles (Ye et al. 2012).

Fig. 6
figure 6

Chemical procedure for the synthesis of mesoporous silica–coated iron oxide

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Colloidal stability and minimal non-specific cell uptake of silica-coated contrast agents caused an enhancement in the MR signal. In addition, functionalized mesoporous silica coatings can improve MR imaging performance and increase the potential clinical applications of contrast agents (Hurley et al. 2016). Porous Fe3O4@SiO2 nanorods with drug release capabilities were applied as magnetic resonance contrast agent (Beg et al. 2017). Patel et al. (2010) developed ion-sensing nanoparticles composed of a superparamagnetic iron oxide core and a porous silica shell with a great potential for use in MR cell tracking. Relaxivity of the prepared silica-coated nanoparticles was found to be 7.6 S−1 mM−1 that was comparable with the relaxivity of commercially available iron oxide contrast agents such as Feridex® (Patel et al. 2010). Chen et al. (2013) reported a monodisperse bifunctional silica system based on manganese-doped iron oxide nanoparticles as an MRI contrast agent. The nanoparticles with different iron to manganese ratios showed different saturation magnetizations and relaxivities. Magnetic resonance images of brain revealed an improvement in T1 values after intravenous injection of nanoparticles in rats (Chen et al. 2013). In addition, T2*-weighted images of liver showed a gradual darkening as time progressed. In the future, bifunctional silica-coated contrast agents might be applied for the clinical study of inactivated and silent areas of the brain.

Dendrimers

Dendrimers are repetitively branched macromolecules with unique molecular architectures and properties that make them attractive for biomedical applications such as detecting agents, affinity ligands, targeting components, imaging agents, and pharmaceutically active compounds (Basly et al. 2010; Qiao and Shi 2015). Generally, dendrimers can be divided into three distinguished domains including core, inner shells, and outer shell (Fig. 7) (Chang et al. 2012b). The core is normally a small molecule with a variable number of functional groups that define the number of branches in the final structure. Inner shells are composed of repeating units and define the generation (G). The outer shell possesses a large number of functional groups depending on the generation and can be manipulated to modulate dendrimer properties and applications (Sato et al. 2001). The dendrimer scaffolds have been used as powerful coatings in the development of different magnetic resonance imaging agents.

Fig. 7
figure 7

Chemical structure of polyamidoamine dendrimer with three generations (G) as one of the most common classes of dendrimers suitable for the surface coating of iron oxide nanoparticles

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Dendrimers are not only used as stabilizers in the synthesis of iron oxide nanoparticles, they are also applied as coating for magnetic contrast agents. For example, Luong et al. (Luong et al. 2017) used a magnetic iron oxide core which was coated with folic acid–polyamidoamine dendrimers for delivery of 3,4-difluorobenzylidene-curcumin as a highly potent hydrophobic anticancer drug. The prepared particles were also studied as contrast agent, and the relaxation studies showed a significant decline in the T2-weighted signal intensity of the magnetic resonance images with increasing iron concentration (Luong et al. 2017).

An approach has been developed by combining a layer-by-layer self-assembly method and dendrimer chemistry to produce dendrimer-coated iron oxide nanoparticles for magnetic resonance imaging (Fig. 8). The fabricated nanoparticles were water-soluble, stable, and biocompatible. Folic acid–modified iron oxide nanoparticles have been efficiently applied as magnetic resonance imaging agents in both in vitro and in vivo studies (Shi et al. 2008b). To prepare these nanoparticles, Shi et al. (2008b) synthesized iron oxide nanoparticles with a diameter of 8.4 nm via controlled co-precipitation process, and the surface was modified with dendrimers composed of folic acid, fluorescein isothiocyanate, and polystyrene sulfonate sodium salt. These decorated nanoparticles were also used in resonance magnetic imaging of human epidermoid carcinoma cells where the T2 values were reduced as a function of iron concentration (Wang et al. 2007). In another study, Lamanna et al. (2011) reported iron oxide nanoparticles coated with small-size dendrons with a hydrodynamic diameter smaller than 100 nm. The prepared nanoparticles were applied in magnetic resonance and fluorescence imaging. Measurements of the relaxation at 1.5 T and 37 °C proved a relationship between iron concentration and the T1 value. Cai et al. (2015) developed a unique method to form folic acid–modified Fe3O4/Au nanocomposite as contrast agent for targeted dual-mode computed tomography and magnetic resonance imaging.

Fig. 8
figure 8

Synthetic procedure for production of polyamidoamine-grafted iron oxide

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Dendrimers as promising coatings of magnetic contrast agents are a flourishing area of research mainly due to their precisely defined structure and composition, and also their high tunable surface chemistry (Basly et al. 2013). Reduction of the costs of dendrimer production is a major challenge for industrial development of dendrimer-based contrast agents.

In addition, the safety concerns of the dendrimer based nanoscale contrast agents is still raised because of the lack of total clearance of large molecules after administration and toxicity associated with some dendrimeric MR contrast agents. The improvement of multifunctional, multi-mode, and smart dendrimer-based contrast agents is an interesting research area and offer great challenges for development of potential clinical applications of dendrimer-based MRI contrast agents.

Polymers

Natural polymers

Alginate and gelatin

Several natural polymers have been investigated for microencapsulation of iron oxide nanoparticles with appropriate biocompatibility and structural stability. Bar-Shir et al. (2014) reported the synthesis and the application of superparamagnetic iron oxide nanoparticles for the noninvasive determination of changes in extracellular calcium ion levels by conventional magnetic resonance imaging. They showed that coated nanoparticles with monodisperse and purified alginate could be successfully applied for the determination of Ca2+ concentrations in the range from 250 μM to 2.5 mM, even in the presence of various competitive ions (Bar-Shir et al. 2014). Ma et al. (2008) synthesized alginate-coated superparamagnetic iron oxide contrast agents via a modified co-precipitation approach. The prepared particles possess T1 and T2 relaxivity values of 7.86 ± 0.20 mM−1 s−1 and 281.2 ± 26.4 mM−1 s−1 in saline at 1.5 T and 20 °C, respectively. In addition, the obtained results showed that alginate-coated superparamagnetic iron oxide nanoparticles might have the ability to improve the detection of liver tumors as an effective MR contrast agent. For example, it was found that incorporation of ferrofluid in alginate led to the successful synthesis of highly stable magnetic alginate nanocomposites (Ma et al. 2008; Shen et al. 2003).

Gelatin as a non-toxic, non-immunogenic, and biodegradable macromolecule is mainly obtained from the insoluble collagen of skin and bones via a hydrolysis process. Gelatins possess active groups such as acid, amine, and hydroxyl which made them attractive for biomedical applications. After injection of multi-functional gelatin-coated iron oxide nanoparticles, a darkening was observed at the tumor site and showed that the prepared particles can be used as T2-weighted MRI contrast agent (Cheng et al. 2014).

Chitosan

Chitosan-based MRI contrast agents have great potentials for the diagnosis of various diseases (Fig. 9). Xiao et al. (2015) reported magnetic MRI contrast agents coated by high molecular weight chitosan derivatives applying as a novel tumor-targeted vehicle. In this study, superparamagnetic iron oxide nanoparticles were encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan micelles (Fig. 10). After intravenous administration of the prepared micelles, the signal intensities of T2-weighted images in HeLa-derived tumors declined. Therefore, it was found that the produced magnetic micelles can potentially serve as effective and safe contrast agents for detecting folate receptor overexpressing tumors (Xiao et al. 2015). Iron oxide nanoparticles coated with chitosan-functionalized graphene oxide sheets have been also developed as MRI contrast agents. Wang et al. (2013) obtained the R2 relaxivity of 140.93 mM–1 S–1 for chitosan-coated iron oxide which proves that the prepared particles have sufficient magnetism to be effective as an MRI contrast agent.

Fig. 9
figure 9

Chitosan-coated magnetic iron oxide nanoparticles used as MRI contrast agent

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Fig. 10
figure 10

Synthesis of folate-conjugated N-palmitoyl chitosan for coating of superparamagnetic iron oxide nanoparticles as MRI contrast agent

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Chitosan-coated superparamagnetic iron oxide nanoparticles were also used as a novel MRI contrast agent to monitor mouse islet grafts (Juang et al. 2010). Iron oxide microspheres coated by chitosan were also applied as contrast agent that improves the T2 value in the MRI process (Kim et al. 2007). The iron oxide nanoparticles directly were co-precipitated inside a porous matrix of chitosan in an aqueous solution at pH 9.5 and 50 °C. the obtained composite was applied as MRI contrast agent for cell tracking, and quantitative parameters obtained for R1, R2, and R2/R1 ratio were found to be as 22.0 mM–1 s–1, 202.6 mM–1 s–1, and 9.2, respectively (Tsai et al. 2010).

Polymer-stabilized iron oxide nanoparticles have been employed as MRI contrast agents due to their unique superparamagnetic properties. Shen et al. (2011) synthesized a quaternized chitosan, i.e., N-[(2-hydroxy-3-trimethylammonium)propyl] chitosan chloride, encapsulating superparamagnetic iron oxide that exhibited low toxicity, the least effect on cell growth, and improved relaxation processes resulting in an enhanced image contrast (Shen et al. 2011).

Several stem cell labeling approaches have been developed for detecting of fast growing and promising field of stem cell imaging by MRI. Many of them use iron oxide nanoparticles for cell labeling which provide improved signal effects on T2-weighted MR images. For example, in vivo tracking of mesenchymal stem cells labeled with a chitosan-coated superparamagnetic iron oxide nanoparticles using MRI was reported by Reddy et al. (Reddy et al. 2010). The ionotropic gelation method for the encapsulation of superparamagnetic iron oxide nanoparticles was reported and encapsulated nanoparticles showed enhanced dispersion ability in aqueous solution with R2/R1 ratios between 6.65–6.81 (Sanjai et al. 2014). In addition, Shi et al. (2008b) developed carboxymethyl chitosan-modified superparamagnetic iron oxide nanoparticles for magnetic resonance imaging of stem cells with R1 and R2 values of 3.86 and 160.5 mM–1 s–1, respectively. A value of R2/R1 ratio was calculated to be about 40 which is greater than those of some commercial agents such as Feridex and Resovist (between 7 and 17). Colloids of iron oxide nanoparticles dispersed in chitosan, in addition to improving the T2 value, also showed low toxicity and high intolerability when tested on New Zealand white rabbits (Lee et al. 2005). The prepared MRI contrast agents could potentially be applied in medical diagnostic methods and would provide noninvasive visualization by the improvement of T2 value.

Dextran

Colloidal suspensions of magnetic iron oxide nanoparticles were synthesized by Bautista et al. (2004) via the laser pyrolysis approach and were coated with dextran in an aqueous solution for rising biocompatibility of the nanoparticles. Studies have been performed on the synthesis of Herceptin-containing MRI contrast agents in which the surfaces of superparamagnetic iron oxide nanoparticles were coated with dextran and Herceptin to improve their physical and chemical properties such as magnetization, dispersion, and targeting of the specific receptors on cells. The prepared Herceptin-containing agents have been administered intravenously to mice bearing breast tumor allograft (Fig. 11). The MRI investigations have shown a high level of accumulation of the contrast agent within the tumor sites and prove the efficient targeting of cancer cells using dextran and Herceptin-containing contrast agent (Morales et al. 2003; Chen et al. 2009).

Fig. 11
figure 11

Synthetic procedure of Herceptin–dextran iron oxide nanoparticles

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Dextran-coated magnetite nanoparticles were prepared by Bulte et al. (1992) for applying as an MRI contrast agent to visualize lesions with a blood–brain barrier disruption. Moreover, Dai et al. (2014a) used dextran-conjugated folic acid-coated iron oxide nanoparticles as MRI contrast agents for diagnosis and treatment response of rheumatoid arthritis. The T2 relaxation coefficient (r2) of the prepared nanoparticles was obtained by measuring the relaxation rate based on iron concentration as 161.3 mM–1 s–1. Dextran-coated iron oxide magnetic nanoparticles were also prepared and applied as a potential contrast agent for MR imaging of lymph, bone marrow, and liver (Hong et al. 2008).

Naha et al. (2014) reported hybrid contrast agents composed of dextran-coated bismuth–iron oxide nanoparticles applied for MR imaging and computed tomography. T2-weighted MRI contrast decreased with increasing bismuth content, and the T2 relaxivity of the bismuth (30%) and iron (50%) formulation was found to be 0.4 mM−1 s−1 (Naha et al. 2014). In addition, Park et al. (2008) found that the geometry and the size of the iron oxide nanoparticles influence their efficiency by increasing the relaxivity in both in vitro and in vivo conditions. Increasing the ability of the nanoparticles to attach to tumor cells was caused by enhanced multivalent interactions between peptide modified particles and target cell receptors. Dextran-stabilized superparamagnetic iron oxide nanoparticles were also applied for in vivo MR imaging of liver fibrosis, and the evaluation of magnetic relaxivity on a 1.5 T showed R2/R1 ratio of 56.28 (Saraswathy et al. 2014).

Synthetic polymers

Polyethylene glycol

Polymer-coated contrast agents are of special interest due to their intrinsic advantages including excellent biocompatibility, low toxicity, long-term stability, and facile conjugation with functional molecules. For example, the most successful strategy to minimize aggregation is to coat the nanoparticles’ surface with hydrophilic polymers such as polyethylene glycol (PEG). Monodisperse iron oxide nanoparticles coated with PEG at various molecular weights were prepared by Chen et al. (2010) via the self-assembly process and as an MRI contrast agent were applied for in vitro cellular uptake studies. The obtained results showed that the saturation magnetization and T2 relaxivity decreased when coating thickness increased (Chen et al. 2010). Dai et al., (2014b) prepare PEG-coated superparamagnetic iron oxide nanoparticles with an average hydrodynamic diameter of 11.7 nm via a facile one-pot approach and examined the synthesized nanoparticle as an MRI contrast agent. The nanoparticles were characterized in terms of their magnetic resonance imaging properties and the dual contrast in both T1- and T2-weighted MR imaging significantly improved with longitudinal and transverse relaxivity of 35.92 mM−1 s−1 and 206.91 mM−1 s−1, respectively.

Several pH-responsive polymeric micelles with a capability of rapid responding to an acidic stimuli environment were prepared by Gao et al. (2011) and applied as intelligent carriers to deliver iron oxide nanoparticles for MRI. In their study, iron oxide nanoparticles were encapsulated in the polymeric micelles and used as MRI contrast agents by introducing amidoamine groups into the pH-sensitive poly(β-amino ester) blocks (Fig. 12). In this structure, methoxy poly(ethylene glycol) and poly(β-amino ester)/(amidoamine) moieties of the micelle act as a hydrophilic shell and pH-sensitive component, respectively (Gao et al. 2011).

Fig. 12
figure 12

PEG-poly(β-amino ester)/(amido amine) composite as coating of magnetic nanoparticles applied as contrast agent

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An efficient and facile approach was developed for the synthesis of ultra-small PEGylated iron oxide nanoparticles acting as dual contrast agents for T1- and T2-weighted MRI with high crystallinity and size uniformity with an average diameter of 5.4 nm (Hu et al. 2011). The investigation of PEGylated iron oxide nanoparticles revealed a remarkable saturation magnetization, R1, and R2/R1 ratio as 94 emu g−1, 19.7 mM−1 s−1, and 2.0, respectively (Hu et al. 2011). Iron oxide nanoparticles coated with poly(ethylene glycol)-poly(aspartic acid) block copolymer were also synthesized as unique MR contrast agents for in vivo imaging of tumors (Kumagai et al. 2007).

Lutz et al. (2006) reported the synthesis of a polymeric composite containing polyethylene glycol and methacrylic acid via the central radical polymerization approach (Fig. 13). The prepared poly(oligo(ethylene glycol) methacrylate-co-methacrylic acid) composite was used as a coating for magnetic iron oxide nanoparticles and tested as an MRI contrast agent. The diameter of the magnetic nanoparticles was adjusted in the range of 10 to 25 nm by changing the initial coating polymers concentration (Lutz et al. 2006).

Fig. 13
figure 13

Synthesis of a polymeric composite containing poly ethylene glycol and methacrylic acid via central radical polymerization approach

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The prepared nanoparticles exhibited high colloidal stability in both aqueous solutions and physiological buffers. However, maximum liver accumulation was observed 6 h after intravenous administration in rats, indicating a prolonged circulation time for the polymer-coated nanoparticles compared to commercial agents such as Resovist®, which accumulate in the liver only 5 min after administration (Lutz et al. 2006; Masoudi et al. 2012). However, the biodistribution kinetics of these promising PEGylated ultrasmall nanoparticles is currently an attractive research area.

Liu et al. (2014) applied PEGylated iron oxide nanoparticles for MRI of post-ischemic blood–brain barrier damages. The R2 value of PEG-coated particles was calculated to be 92.7 mM−1 s−1. However, the intensity of the signal was increased in the presence of the PEGylated super magnetic iron oxide nanoparticles so that the R1 value was 0.84 mM−1 s−1 (Liu et al. 2014).

Ultra-small superparamagnetic iron oxide nanoparticles represent a promising platform for the development of agents for multimodal medical imaging. Sandiford et al. (2013) reported ultra-small superparamagnetic iron oxide nanoparticles coated by PEG polymer conjugate containing a terminal 1,1-bisphosphate group (Fig. 14). They found that the PEGylated nanoparticles were very stable in physiological solutions and possessed a longitudinal relaxivity of 9.5 mM−1 s−1. The MR images and pharmacokinetic profile confirm the majority circulation of PEGylated nanoparticles in the bloodstream the high signal in the heart, blood vessels, and vascular organs. It is expected that contrast agent based on PEG-coated iron oxide particles could provide better detectability and quantification capabilities of vascular targets involved in cardiovascular and oncologic diseases.

Fig. 14
figure 14

Ultra-small superparamagnetic iron oxide nanoparticles coated by PEG polymer–conjugated 1,1-bisphosphate group

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Pöelt et al. (2012b) reported detailed experimental data on contrast optimization of PEGylated iron oxide MR contrast agent with controlled aggregation of nanoparticles into stable and biocompatible clusters with narrow size distributions (Pöselt et al. 2012b). Superparamagnetic iron oxide nanoparticles with a diameter of 11 nm were PEGylated without anchoring groups and investigated as an efficient T2 contrast agent with a spin–spin relaxivity of 123 ± 6 mM−1 s−1 (Thapa et al. 2017).

It is essential to modify the surface of iron oxide nanoparticles with hydrophilic molecules that minimizes aggregation of the particles and prevents nonspecific uptake by mononuclear phagocyte system in physiological conditions. Therefore, PEGylation have been widely employed to modify the surface of the particles to enhance their function in physiological conditions. For example, the stability of PEG-oleic acid-coated magnetic nanoparticles was investigated under physiological conditions with various ionic strength and pH (Fig. 15). The obtained results showed that Fe3O4@PEG–oleic acid nanoparticles were highly stable in saline solution (up to 300 mM NaCl) and in the pH range of 3–10 (Yue-Jian et al. 2010).

Fig. 15
figure 15

Chemical synthetic procedure for the production of PEG-oleic acid as coating of iron oxide magnetic nanoparticles

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Using PEG in the synthesis of nanoparticles and coating of them combine the advantages of precipitation and thermal decomposition with hydrophilic nature for the control of size and geometry. In addition, PEG coating can decorate contrast agents with unique advantages such as nanoparticles with biocompatibility, hydrophilicity, soft surface, and in vivo long circulation.

Poly (lactic-co-glycolic acid)

Organic poly(lactic-co-glycolic acid) (PLGA)–coated nanoparticles have been widely applied in the various biomedical applications such as drug delivery, tissue engineering, and molecular imaging. Combining the advantages of PLGA microcapsules and magnetic Fe3O4 nanoparticles, the hybrid composites provide broader and feasible MRI contrast agents.

Superparamagnetic PLGA-coated iron oxide microspheres have been synthesized and applied as contrast agent in MRI of liver tissue with an improved T2-weighted signal (Zhou et al. 2015). Xu et al. (2015) developed a premix membrane emulsification technique to obtain uniform PEGylated PLGA microcapsules with magnetic iron oxide nanoparticles surrounded by a shell of polymer for magnetic resonance imaging. In vitro and in vivo studies showed that Fe3O4@PEG-PLGA microcapsules with a diameter about 3.7 μm and very narrow size distribution could efficiently act as a dual-modal contrast agent to simultaneously enhance ultrasound and magnetic resonance imaging performances (Xu et al. 2015). Multimodal and multifunctional contrast agents are considered as cutting edge technologies that develop the advantages of nanoparticles.

A cyclic peptide composed of arginine, glycine, and aspartate has been used for surface modification of PLGA-coated iron oxide nanoparticles as an MR contrast agent for the detection of thrombosis (Liu et al. 2017). The obtained results by Liu et al. (2017) demonstrated that the T2 signal reduced at the mural thrombus within 10 min after injection and then gradually increased until 50 min.

Polyvinylpyrrolidone

To improve the stability of Fe3O4 nanoparticles, a polymeric layer is coated on the surface of magnetic nanoparticles such as dendrimers, gelatin, dextran, chitosan, pullulan, PEG, and PLGA. Polyvinylpyrrolidone (PVP) attracted much interest in biomedical and molecular imaging because of biodegradability, non-toxicity, low cost, and antiviral properties.

Iron oxide nanoparticles coated by PVP have been used to investigate the influence of nanoparticle size on in vivo MRI of hepatic lesions. Huang et al. (2010) prepared the polymer-coated biocompatible nanoparticles with different sizes by a simple one-pot pyrolysis process. High T2 relaxivities and good crystallinity were observed in PVP-coated magnetic nanoparticles. In addition, PVP was used as a stabilizer in the preparation of ultra-small Fe3O4 nanoparticles through the co-precipitation method (Zhang et al. 2010). The PVP-coated magnetic nanoparticles with a diameter between 6.5 and 1.9 nm were guided to the target sites using a permanent magnet. The particles were successfully concentrated, and an improved contrast was observed on the target area.

Lee et al. (2008) reported PVP-coated iron oxide nanoparticles as an MRI contrast agent with a core size of about 8–10 nm, the overall hydrodynamic diameter around 20–30 nm, and R2 and R1 relaxivity of 141.2 and 338.1 mM−1 s-1, respectively. Water-soluble iron oxide nanoparticles coated with polyvinylpyrrolidone were also produced by transferring oleic acid-coated iron oxide nanocrystals from hexane to water (Li et al. 2015). The prepared nanoparticles showed excellent monodispersity with a particle size of about 14 nm and were guided to the target site by an external magnet. Therefore, the PVP-coated iron oxide particles encourage potential applications in MRI and magnetic delivery of contrast agents to the target organ.

Polyglycerol

The polyether backbone of polyglycerol is a water-soluble and biocompatible polymer that makes it an attractive polymeric compound for pharmaceutical and biomedical applications. The hyper-branched structure of the polyglycerol provides many reactive hydroxyl groups for modifications intended for various applications. In addition, the polyglycerol can be covalently grafted to the surface of superparamagnetic iron oxide nanoparticles. In this process, the surface of superparamagnetic magnetic iron oxide nanoparticles synthesized by co-precipitation method in aqueous solution is modified to introduce reactive groups. In the next step, polyglycerol is grafted on the surface of the activated nanoparticles by anionic ring-opening polymerization of glycidol in the presence of n-butyllithium as an initiator.

Arsalani et al. (Arsalani et al. 2012) examined the potential of a polyglycerol-coated ferrofluid for applying as a negative MRI contrast agent by studying its physical characteristics such as relaxometry and magnetometry (Fig. 16).

Fig. 16
figure 16

Chemical synthesis approach for production of polyglycerol-coated superparamagnetic iron oxide nanoparticles

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The obtained results showed that the calculated R1 and R2 at various magnetic fields were higher than those of some reported commercially available agents. In addition, in vivo MRI studies showed that the intravenously injected particles produced a modified contrast in the liver and kidneys that remained for 80 min and 110 min, respectively. The reduction of negative MR signals in the kidneys and liver over time suggested that polyglycerol coating optimized the renal excretion of the nanoparticles (Arsalani et al. 2012). Dendritic polyglycerol-modified iron oxide nanoparticles have been also reported as selective MRI contrast agents in which polyglycerol ligands are efficiently functionalized by one to three phosphonate groups acting as linkers (Nordmeyer et al. 2014). Although the high initial R2 value of the iron oxide nanoparticles usually decreases during the ligand exchange reaction, their relaxivities are still comparable to those of commercial nanoparticle-based MRI contrast agents (Nordmeyer et al. 2014).

Cao et al. (2016a) reported a mixed polymeric micellar MRI contrast agent with a hydrodynamic diameter of about 85 nm that exhibited much higher r1 relaxivity (14.01 mM−1 S−1) than commercial Magnevist® (3.95 mM−1 S−1). Although dendrimers with uniform hyper-branched structures are known as one of the best supports for imaging probe and drug delivery, their biological applications are limited due to their complicated and multi-step synthesis methods and poor biocompatibility. Han et al. (2016) reported an efficient method for the synthesis of zwitterionic polyglycerol dendrimers with a β-cyclodextrin core as MRI contrast agent carriers. Cao et al. (2016b) synthesized a linear macromolecular contrast agent with a composition of polyglycerol as a backbone and partial hydroxyl connected with gadolinium labeled poly (L-lysine) dendrons. A ring-opening polymerization reaction has been used for the synthesis of polyglycerol-coated magnetic iron oxide nanoparticles applying hexanoic acid as a linker (Fig. 17). However, Wang et al. (2009) used this method to prepare composite nanoparticles with a diameter of 23.0 ± 0.3 nm that were highly stable in both aqueous and cell culture media. Chemical stability under physiological conditions is known as one of the most important properties of nanoparticles for their use as injectable MRI agents.

Fig. 17
figure 17

Superparamagnetic hyper-branched Fe3O4@polyglycerol nanoparticles applied as a MRI contrast agent

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Miscellaneous polymers

Polymeric liposome–coated superparamagnetic iron oxide nanoparticles with a targeting ligand and the ability of transferring from organic phases to aqueous solutions have been evaluated as a magnetic resonance imaging contrast agent. The obtained results from the investigation of Liao et al. (2011) demonstrated a narrow range of size dispersity with a core size of about 8–10 nm and T2 relaxivities of 164.14 mM−1 s−1.

Zhou et al. (2010) obtained superparamagnetic fulvic acid-coated iron oxide nanoparticles by co-precipitation of iron salts and small molecules of fulvic acid as stabilizers. Transmission electron microscopy observations showed that the prepared nanoparticles had a diameter of about 10 nm. In addition, fulvic acid–coated magnetic nanoparticles showed proper T2 relaxation rates, which make them suitable as contrast agent for MRI of liver because of their increased sensitivity leading to the differentiation between normal and pathologic tissues in the liver.

Polypyrrole coated-magnetic nanoparticles were reported by Tian et al. (2014) with an r2 value of 290.91 mM−1 S−1, which was higher than those of some commercially available MRI contrast agents such as Feridex (152 mM−1 S−1) and Resovist (86 mM−1 S−1). Moreover, a hybrid composite has been reported as a contrast agent for MRI of liver tumors consisting of superparamagnetic iron oxide nanoshells and doxorubicin as an anticancer (Wang et al. 2014).

Conclusion and future prospective

In summary, this review discussed several important aspects of organic/inorganic polymer-coated iron oxide nanoparticles as MRI contrast agents that are progressively studied for the past few years. Iron oxide ultra-small nanoparticles have been efficiently synthesized via some methods such as high-temperature co-precipitation, thermal decomposition, and polyol approaches. Although polyol methods are feasible for large-scale production of magnetic nanoparticles, thermal decomposition and co-precipitation methods are highly efficient by controlling the reaction conditions affecting the relaxation properties of the nanoparticles such as the size and surface capping molecules. The development of iron oxide nanoparticles as MRI contrast agents may lead to the focus of major research on the integration of MRI with other imaging techniques such as positron emission tomography and computed tomography. Numerous studies have shown that iron oxide contrast agents are less toxic than gadolinium-based contrast agents; however, the development of magnetic contrast agents is still in its infancy and studies on in vitro and in vivo biocompatibility, bio-distribution, pharmacokinetics, and toxicity should be considered for their further potential clinical applications. Although iron oxide particles offer many perspectives for in vitro and in vivo researches, it seems that the particles might be developed as the future MRI contrast agents for human clinical applications.