New advances strategies for surface functionalization of iron oxide magnetic nano particles (IONPs)

Abstract

Over the past two of decades, iron oxide nanoparticles (IONPs) have attracted significant attention for a wide range of biomedical applications. For the successful use of IONPs in nano-biotechnology, surface coating and specific functionalization is critical. Many types of materials can be used in the surface coating of IONPs for nano-bio applications, including organic compounds and inorganic materials. This review focuses on recent developments and various strategies for surface coating of IONPs. In addition, the different materials used for the functionalization of IONPs are classified and discussed in detail. The design of IONPs with multifunctional coatings for bio-applications is an area of considerable interest. Surface functionalization of IONPs allows them to attach to various biomolecules, making them a promising candidate for bio-applications.

Graphical Abstract

Full text

New advances strategies for surface functionalization
of iron oxide magnetic nano particles (IONPs)
Hamed Nosrati
1
•Marziyeh Salehiabar
2
•Soodabeh Davaran
3
•
Ali Ramazani
4
•Hamidreza Kheiri Manjili
5,7
•
Hossein Danafar
6,7,8
Received: 4 January 2017 / Accepted: 12 July 2017 / Published online: 19 August 2017
Springer Science+Business Media B.V. 2017
Abstract Over the past two of decades, iron oxide nanoparticles (IONPs) have attracted
significant attention for a wide range of biomedical applications. For the successful use
of IONPs in nano-biotechnology, surface coating and specific functionalization is crit-
ical. Many types of materials can be used in the surface coating of IONPs for nano-bio
applications, including organic compounds and inorganic materials. This review focuses
on recent developments and various strategies for surface coating of IONPs. In addition,
the different materials used for the functionalization of IONPs are classified and dis-
cussed in detail. The design of IONPs with multifunctional coatings for bio-applications
&Hamidreza Kheiri Manjili
h.kheiri@zums.ac.ir
&Hossein Danafar
danafar@zums.ac.ir
1
Department of Pharmaceutical Biomaterials, School of Pharmacy, Zanjan University of Medical
Sciences, Zanjan, Iran
2
Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz,
Tabriz 5166614766, Iran
3
Drug Applied Research Center, Tabriz University of Medical Sciences,
Tabriz P.O. Box 51656-65811, Iran
4
Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
5
Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences,
Zanjan, Iran
6
Zanjan Pharmaceutical Nanotechnology Research Center, Zanjan University of Medical
Sciences, Zanjan, Iran
7
Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of
Medical Sciences, Zanjan, Iran
8
Department of Medicinal Chemistry and Pharmaceutical Nanotechnology, School of Pharmacy,
Zanjan University of Medical Sciences, Zanjan, Iran
123
Res Chem Intermed (2017) 43:7423–7442
DOI 10.1007/s11164-017-3084-3

is an area of considerable interest. Surface functionalization of IONPs allows them to
attach to various biomolecules, making them a promising candidate for bio-applications.
Graphical Abstract
Keywords Iron oxide nanoparticles Inorganic materials Functionalization
of IONPs Multifunctional coatings for bio-applications
Introduction
Nanoscale systems have received significant attention due to their biological,
medicinal, and industrial applications. Surface modification of nanoparticles enables
their use in nano-biomedical applications—for instance, as contrast agents for
magnetic resonance imaging (MRI) or targeted drug delivery in tumor therapy
[1–5]. Iron oxide nanoparticles (IONPs) have been of particular interest, especially
for biomedical and pharmaceutical applications, because of their physical proper-
ties, magnetic susceptibility, biocompatibility, low toxicity, stability, and availabil-
ity for surface modification. Further, their ability to be easily controlled by the
application of an external magnetic field allows the release of pharmaceutical agents
at an exact rate and a specific site for diagnosis and therapy, or theranostics [6–10].
The ferrite colloids magnetite (Fe
3
O
4
) and maghemite (c-Fe
2
O
3
) are the primary
forms of IONPs, and have been used for a wide range of biomedical applications,
including as contrast agents for vascular and tumor imaging, drug delivery, gene
therapy, hyperthermia treatment, and magnetic separation of cells or molecules
[3,11–15]. Recent developments in the synthesis, characterization, and—most
importantly—the surface modification of the IONPs has enabled researchers to
answer important questions related to their clinical application [16]. It is well known
7424 H. Nosrati et al.
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that molecules comprising the surface coating of IONPs act as the primary interface
between IONPs and the body’s immune system [11]. Thus, the surface chemistry,
desired application, and method of administration, as well as the pharmacokinetics
and biodistribution behavior of the IONPs, differ according to the method used for
their synthesis [17]. The design and development of a unified multifunctional
biomedical platform for individual nanoparticles that is effective in both the
diagnosis and treatment of disease poses a significant challenge [18]. Efforts toward
the development of magnetic nanocarriers continues, with the goal of (i) reducing
the associated side effects by decreasing the systemic distribution of cytotoxic
drugs, and (ii) reducing the required dose through more efficient, localized drug
targeting.
Synthesis strategies
The main pathways for the synthesis of Fe
3
O
4
NPs are as follows: (i) physical
methods, consisting of gas-phase deposition and electron beam lithography,
although control of particle size down to the nanometer scale is difficult [19–21];
(ii) chemical preparation methods, such as sol–gel, oxidation, chemical co-
precipitation, hydrothermal reactions, flow injection, electrochemical, aerosol/vapor
phase, sonochemical decomposition reactions, supercritical fluid, and syntheses
using nanoreactors [22–31]; (iii) microbial methods, which ensure high yields, good
reproducibility and scalability, low cost and moderate temperatures [32,33].
In Synthesis of Metal-Doped Iron Oxide Nanoparticles, Ferrites are complex
magnetic oxides derived from iron oxides, such as magnetite (Fe
3
O
4
) and
maghemite (c-Fe
2
O
3
), that are chemically combined with one or more metallic
elements. Various methods have been proposed for the synthesis of these spinel
metal ferrites. The ferrites have a common component, MFe
2
O
4
, where M can be
Co
2?
,Mn
2?
,Ni
2?
,Zn
2?
, and so on. [34,35]. Iron oxide nanoparticles are
synthesized using one of two main chemical methods: the well-established
conventional method involving co-precipitation of Fe
2?
(ferrous) and Fe
3?
(ferric)
ions in a basic solution [36], and thermal decomposition of organic complexes of
iron (e.g., iron pentacarbonyl, iron oleate, or FeOOH) in the presence of capping
agents (e.g., oleic acid and oleyl amine) [37].
Surface modification
The stability of IONPs is important for their storage and various applications.
IONPs are reactive toward oxidizing agents and moisture. Unfortunately, bare
IONPs are usually unstable and tend to agglomerate. Therefore, surface coating and
functionalization are necessary to impart colloidal stability and prevent agglom-
eration. Due to the interactions between IONPs and the surrounding media, efficient
surface coating methods are needed.
In addition to preventing aggregation and enhancing colloidal stability, the
functionalization of IONPs gives rise to higher water compatibility and better
New advances strategies for surface functionalization of…7425
123

magnetic controllability, while protecting and stabilizing the surface of IONPs,
rendering them biocompatible by lowering or eliminating their toxicity. In addition,
functionalization installs reactive handles for conjugation of biologically active
substances, an important process for nano-bio applications, and non-immunogenic-
ity, non-antigenicity, and protection from opsonization by plasma proteins [38,39].
Also, coating of IONPs with different materials can affect the magnetic and
physicochemical properties, which can decrease the saturation magnetization (Ms),
size, charge, hydrophobicity, and hydrophilicity of the nanoparticles. The Ms of
bare and functionalized IONPs is an important parameter that describes the
magnetic response of IONPs. Although the Ms is improved by agglomeration of
IONPs, it has been shown to reduce if the IONPs are stabilized. The anchor
chemistry can also affect the Ms via strong interactions with the ions in the surface
layer of the magnetic core [40].
Surface modification strategies for IONPs
This section focuses on surface coating strategies for the stabilization, protection,
and functionalization of IONPs. The coating method is dependent on the nature of
the coating materials and the intended application. Surface modification of IONPs is
generally achieved via ligand addition, ligand exchange, or encapsulation. A diverse
group of materials can be used in these coating processes, including small molecule
organic ligands, polymeric ligands, dense polymer matrix, and inorganic materials.
In situ surface modification
In this one-pot synthesis method, abridged particle size and narrow particle size
distributions can be achieved, enabling both the synthesis and surface functional-
ization of IONPs to be carried out in a single step. During IONP synthesis, the
coating process starts as soon as nucleation occurs, preventing further particle
growth. For direct functionalization, carboxylates, phosphonates, thiol, and
hydroxyl groups have commonly been used (Fig. 1).
Ligand addition This method involves the addition of a ligand to the external
surface of the IONPs. Carboxylates, phosphonates, thiol, and hydroxyl are unique
among functional groups because of their strong binding to IONPs. Citrate has been
used extensively for the colloidal stabilization of IONPs. This acid may be adsorbed
on the surface of the IONPs via coordination through one or more carboxylate
functionalities, depending upon the steric nature and the curvature of the surface
[41]. Amino acids interact with the IONP’s surface through their carboxyl groups
[42,43]. The possible structures involved in the coordination between carboxyl
anions and IONPs is depicted in Fig. 2[44]. Molecules with thiol groups can also be
used for the in situ stabilization of IONPs. For example, a one-step sonochemical
synthesis of amorphous Fe
3
O
4
colloids covered with cysteine molecules was
reported by Cohen et al. [45].
7426 H. Nosrati et al.
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Encapsulation Encapsulation is another method for the functionalization and
stabilization of IONPs. In this protocol, IONP synthesis occurs through consecutive
linking with an encapsulating agent present in solution. In situ encapsulation with
polymeric materials and metals such as gold has been described. Using a
combination of a pre-gel method and co-precipitation in aqueous solution, Liao
and et al. prepared a core–shell nanostructure consisting of Fe
3
O
4
nanoparticles as
the core and organic alginate as the shell, with cell-targeting ligands (i.e.,
D-galactosamine) ornamented on the outer surface (denoted as Fe
3
O
4
@Alg-GA
nanoparticles) [46]. Superparamagnetic Au-Fe
3
O
4
bio-functional nanoparticles were
synthesized using a one-step hot-injection precipitation method, as reported by
Pariti et al. [47]. Basuki et al. [48] synthesized a library of magnetic nanoparticles
through the in situ co-precipitation of ferrous (Fe
2?
) and ferric (Fe
3?
) ions from
aqueous solutions in the presence of functional block copolymers.
Post -synthesis surface modification
In this type of surface modification, the protocol is divided into two parts: the
synthesis of IONPs and their surface modification. One advantage of this method is
that a large number of coupling agents are commercially available. Post-synthesis
Fig. 1 Surface functionalization of IONPs by in situ surface modification
Fig. 2 Suggested linkage of
carboxyl anions to iron oxide
surface
New advances strategies for surface functionalization of…7427
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surface functionalization of magnetic nanoparticles is performed mainly via three
mechanisms [49], which are described below.
Ligand addition Ligand addition involves the addition of a ligand to the external
surface of the synthesized IONPs, without the removal of any pre-existing ligands.
Carboxylate, phosphonate, thiol, and hydroxyl functional groups can bind to the
surface of IONPs. Similar to in situ ligand addition, citrate and other small
molecules have been applied for colloidal stabilization of the IONPs by post-
synthesis surface functionalization strategies [41,50,51] (Fig. 3).
Ligand exchange Among small molecules, dopamine and its derivatives are
unique. The catechol unit of dopamine can effectively coordinate with the IONP
surface by the formation of stable five-membered rings [52]—for example,
carboxylates such as citric acid and 2,3-dimercaptosuccinic acid (DMSA), which
contain two carboxyl groups and two sulfhydryl groups [53–55] (Fig. 4).
Encapsulation The encapsulation of IONPs in a biocompatible polymer or
inorganic compounds is another stabilization and modification strategy. Also,
biocompatible hydrophilic shell encapsulation could be used as a promising method
for IONP modifications. There are several encapsulation methods, which can be
categorized according to the shell materials and encapsulation technique (Fig. 5).
Amphiphilic ligands, water-soluble polymer matrixes, and hydrophilic inorganic
materials are typical shell materials. In this method, a large number of natural and
synthetic biodegradable polymers—e.g., polyaspartate [56], polysaccharides [57],
alginate [58], PEG [58], chitosan [59], co-polymers such as poly(maleic
anhydridealt-1-octadecene)-PEG [60], polystyrene-co-PEG (PS-co-PEG) [61],
Fig. 3 Surface functionalization of IONPs by ligand addition
7428 H. Nosrati et al.
123

poly(lactic acid)-co-PEG (PLA-co-PEG) [62], and inorganic material such as silica
[63] and gold [3]—can be used.
Materials used for the modification of IONPs
Many types of materials can be used to coat the surface of IONPs and thus tailor
their use for nano-bio applications. This section focuses on materials used for the
stabilization, protection, and functionalization of IONPs through surface coating. A
diverse set of materials, including organic compounds and inorganic materials, are
utilized in such processes, which are summarized in Fig. 6and briefly described in
the following sections.
Fig. 4 Surface functionalization of IONPs by ligand exchange
Fig. 5 Surface functionalization of IONPs by encapsulation strategy
New advances strategies for surface functionalization of…7429
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Organic compounds
Organic compounds possess good biocompatibility and biodegradability, and can
provide functional groups such as aldehyde, amino, carboxyl, thiol, and hydroxyl
groups. These groups enable linkage with active bio-substances such as drugs,
antibodies, DNA, enzymes, and proteins for further nano-bio applications. A diverse
group of organic compounds, such as small molecule organic and polymeric
ligands, can be applied in such coating processes.
Small molecules Functionalization of IONPs using small molecules is a simple
process. Since bio-applications require a small hydrodynamic size, the use of small
molecules for functionalization is helpful. Among various small molecules,
compounds with thiol, carboxyl, and hydroxyl functional groups possess higher
binding affinity toward IONPs. Dopamine is the most common high-affinity binding
group used for the stabilization of IONPs in water and physiologic buffers
[52,64,65]. The catechol unit of dopamine can coordinate with the IONP surface.
Amstad et al. [66] identified catechol-derived anchor groups which possess inherent
binding affinity to iron oxide and thus can optimally disperse superparamagnetic
nanoparticles under physiologic conditions. Hashemi et al. [67] recently reported
the synthesis of magnetic molecularly imprinted polymers using polydopamine to
Fig. 6 Classification of organic and inorganic materials used for the functionalization of IONPs
7430 H. Nosrati et al.
123

coat magnetic nanoparticles. 2,3-Dimercaptosuccinic acid (DMSA), which contains
two carboxyl groups and two sulfhydryl groups, is another typical small molecule
ligand [55,68]. Carboxylates, including citric acid, constitute an additional class of
small molecule ligands. Citric acid binds to the surface of Fe atoms by coordinating
one or two carboxylic acid groups. Thus, at least one carboxylic acid group is
exposed to the aqueous solvent, endowing the nanoparticle surface with negative
charge, thereby enhancing its water-solubility [53,69,70]. The short-chain amines
and amino silanes are typically used as stabilizing agents in IONPs [71]. Finally,
various amino acids and peptides have been used as stabilizers for coating and
functionalization of IONPs [42,43,51,72,73].
Table 1provides a list of small organic molecules that are used for the
functionalization of IONPs.
Macromolecules Organic polymers are used extensively as coating ligands due to
their unique features, including multidentate binding capability and steric repulsion
effects. In contrast to most small molecules, organic polymers attach to nanopar-
ticles via multiple functional groups, resulting in a stronger steric repulsive force.
Owing to the excellent colloidal stability of IONPs, polymer-functionalized IONPs
are receiving greater attention. Polymer coating typically requires the use of active
terminal groups. Reactive monomers that have been used to promote the attachment
of polymer coatings to the surface of MNPs include alkoxysilanes, citric acid,
bisphosphonates, and DMSA [66,70,84]. In some cases, two or more polymers
must be employed to achieve efficient surface coatings [85–87]. Polymer
Table 1 Small organic molecules used for functionalization of IONPs
Coating molecule CS HS Applications References
Dopamine 80 Drug delivery [67]
Dopamine 11 Covalent immobilization of enzyme [74]
Dopamine 10–25 Catalyst [75]
DMSA 8 24 MRI application and targeting [76]
DMSA ?PEG 12 49 MRI application [77]
DMSA 6–12 MRI application [68]
Carboxylates 12 Drug delivery [78]
Carboxylates 9.5 Delivery of interferon gamma [79]
Citrate (VSOP-C184) 4 8.6 MRI pre-clinical characterization [80]
Citrate (VSOP-C184) 4 7 MRI application [53]
Bisphosphonate ?PEG 5.5 23 MRI application [81]
Citrate 7 Drug delivery [69]
Arginine and lysine 8–7 Evaluation of anti-listeria monocytogenes effect [42,82]
c(RGDyK) peptide 8.4 Tumor-specific targeting [72]
Vitamin C 5.1 MRI application [83]
CS/HS core size and hydrodynamic size, DMSA meso-2,3-dimercaptosuccinic acid, PEG polyethylene
glycol
New advances strategies for surface functionalization of…7431
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functionalizing materials can be classified into two groups, natural and synthetic
polymers, which are discussed below.
Table 2provides a summary of synthetic and natural polymers used for the
functionalization of IONPs.
Natural polymers
a. Dextran
Dextran, a polysaccharide polymer consisting of R-D glucopyranosyl units, is an
interesting material for coating of IONPs, and has been used in diverse applications
such as MRI and cancer imaging and treatment [115]. IONPs coated with dextran
have been clinically approved for use in MRI of the liver [116]. Most clinical MNPs
have used dextran as a surface stabilizer (Combidex, dextran; Feraheme,
carboxymethyl dextran; Feridex, dextran; and Resovist, carboxy dextran)
[117–120]. One of the main drawbacks to the use of dextran coating is the weak
bonding between dextran and the IONP surface [38]. Several published studies have
investigated dextran coating of IONPs. Creixell and co-workers [121], for example,
used dextran to coat the surface of peptized iron oxide nanoparticles. Jafari et al.
[122] described dextran-coated IONPs that were conjugated with bombesin to
produce a targeting contrast agent for MRI application.
b. Chitosan
Chitosan is a linear polysaccharide composed of randomly distributed b-(1-4)-
linked D-glucosamine (deacetylated) and N-acetyl-D-glucosamine (acetylated)
units. Chitosan is an alkaline, biocompatible, biodegradable, hydrophilic, and safe
polymer [123]. In addition, it has antimicrobial properties and is able to absorb toxic
material. Chitosan-coated IONPs have received considerable attention due to their
easy synthesis and numerous applications [124–127]. Because of the presence of
primary amine groups, chitosan is commonly preferred in pharmaceutical applica-
tions. It is also frequently chosen for drug and gene delivery applications due to its
mucoadhesive property and positive charge. Castello et al. [128] reported the use of
chitosan for the synthesis of IONPs and their functionalization. Arias et al. reported
an Fe
3
O
4
/chitosan nanocomposite for magnetic drug targeting cancer therapy [104].
The application of Fe
3
O
4
–chitosan nanoparticles for hyperthermia treatment was
described by Jingmiao et al. [103].
Synthetic polymers
a. Polyethylene glycol (PEG)
Polyethylene glycol (PEG) is a synthetic, biocompatible, flexible, and hydrophilic
polymer, devoid of antigenicity and immunogenicity, which is frequently used in
the functionalization of nanoparticles for biomedical applications [129]. The PEG-
coated IONPs exhibit excellent solubility and stability in both aqueous solution and
physiological media. The biocompatibility of PEG has been recognized by the US
7432 H. Nosrati et al.
123

Table 2 Macromolecules used for functionalization of IONPs
Coating polymer CS HS Applications References
Dextran (ferumoxide [feridex]) 4.5 160 MRI application [88]
Dextran (AMI25) 4–7 72 MRI application [89]
Dextran (AMI 227) 4–6 20 MRI application [90]
Dextran 4–6 MRI of spinal cord [91]
Dextran (ocean nanotech) 20 42 Brain tumor targeting
and MRI application
[92]
Dextran (ferumoxtran-10 [Sinerem]) 35 MRI of atherosclerotic
plaque
[93]
Cross-linked dextran (20 kDa) 250 MRI, protein adsorption
and blood half-life
analysis
[94]
Carboxy dextran (SHU 555 C [Resovis]) 3–5 60–80 MRI application of
inflammatory bowel
disease
[95]
Carboxy dextran (Ferumoxytol [AMI7228]) 7 30 MRI application [96,97]
Carboxy dextran 3–4 Drug delivery [98]
Carboxy dextran 10 Drug delivery [99]
Dextran ?citrate (ferumoxtran [Sinerem]) 4.5 34 MRI application [100]
Carboxymethyl dextran 80 83 Drug delivery [101]
Carbomethyldextran (ferumoxytol [C7228]) 6.7 35 MRI application [97]
Carboxymethyl-b-cyclodextrin ?chitosan Drug delivery [102]
Chitosan ?PEG 7 30 Cancer targeting and
MRI application
[85]
Chitosan 10.5 Hyperthermia [103]
Chitosan 9 180 Magnetic drug targeting [104]
Chitosan 10 82 Drug delivery [105]
PEG ?starch (NC100150 [Clariscan]) 5–7 20 MRI application [86]
PEG ?lipid 5 10 Kidney targeting/
imaging (g-Fe
2
O
3
core
crystals
[106]
Cystamine tert-acylhydrazine ?PEG 100 183 Drug delivery [84]
PEG-phosphine oxide 2.2 MRI application [37]
PEG 16.5 43.6 Delivery of IONPs
across the blood–brain
barrier
[107]
Nitrodopamine ?PEG 10 68 MRI application [108]
Catechol ?chitosan ?PEI ?PEG 5.3 Gene transfection [109]
PVA 5.78 [110]
PVA 10 Drug delivery [111]
Alginate 5–10 193.8 Pharmacokinetics, tissue
distribution, and
applications for
detecting liver cancers
[112]
Alginate ?chitosan ?carboxymethylcellulose Controlled release of
naproxen
[87]
New advances strategies for surface functionalization of…7433
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Food and Drug Administration (FDA) [130]. The presence of PEG on the surface of
IONPs prevents opsonization and reduces the uptake of the IONPs by macrophages
[131]. This leads to nanoparticles with increased blood circulation time, which may
be very beneficial in drug release applications. The only disadvantage of
functionalizing with PEG is that it is not biodegradable in the human body [132].
Anbarasu et al. reported a facile method for the synthesis of PEG-coated IONPs by
way of chemical co-precipitation, in which polymerized polyethylene glycosylated
bilayers were used to prepare the novel IONPs [133]. Several approaches have been
suggested for attaching PEG to IONPs, including polymerization at the NP surface
[134], modification through the sol–gel approach [135], and silane grafting onto the
oxide surfaces [136,137]. In addition to PEG, the polysaccharide dextran has been
widely used in the design of IONP surface coatings for in vivo imaging applications
[138–140].
b. Polyvinyl alcohol (PVA)
Polyvinyl alcohol (PVA) is a synthetic, biocompatible, hydrophilic polymer with
low toxicity, which prevents agglomeration of nanoparticles in biological media
[141,142]. The multiple hydroxyl group of PVA give rise to its enhanced
crystallinity, which results in high elastic modulus and tensile strength for bio-
related applications [143,144]. A key drawback of PVA-coated IONPs is their
limited tissue distribution and penetration [145]. Pardoe et al. [110] reported the
coating of IONPs with PVA using in situ strategies. Mahmoudi et al., on the other
hand, used a post-synthesis strategy, in which they first synthesized iron oxide
nanoparticles and then coated them by adding the PVA solution [146]. Albornoz
et al. [147] reported the synthesis of an aqueous ferrofluid and the preparation of a
magnetic gel with PVA and glutaraldehyde.
c. Alginate
Alginate, an anionic polysaccharide, is typically extracted from brown algae. This
water-soluble biopolymer consists of two monomeric units: alpha-(1-4)-L-glu-
curonic acid and beta-(1-4)-D mannuronic acid. The carboxyl groups of alginate and
iron ions interact, resulting in electrostatic repulsion. Alginate gels are widely used
in encapsulation and controlled drug release [148–151]. Ma et al. [112] developed a
novel modified two-step co-precipitation method for the synthesis of alginate-coated
Table 2 continued
Coating polymer CS HS Applications References
Alginate ?chitosan 5 Controlled release of
insulin
[113]
HSA 10 195 Drug delivery [114]
CS/HS core size and hydrodynamic size, DMSA meso-2,3-dimercaptosuccinic acid, PEG polyethylene
glycol, PEI polyethylenimine, PVA polyvinyl alcohol, HSA human serum albumin
7434 H. Nosrati et al.
123

IONPs. Additional work by Morales et al. [152] demonstrated that the use of a
polymer limited particle size. Magnetic microcapsules based on alginate and
synthesized through a completely green route have also been described [87].
d. Co-polymers
PEG-phospholipid copolymers are archetypal co-polymer IONP coatings. Lee
et al. synthesized encapsulating magnetite nanoparticles functionalized with
PEG-phospholipid, which demonstrated high colloidal stability and good biocom-
patibility [153]. Many other copolymers can be used as well, including polylac-
tide-PEG [154], poly(maleic anhydridealt-1-octadecene)-PEG [60], and
polystyrene-poly(acrylic acid) (PS-PAA) [155]. The incorporation of IONPs in
a hydrophilic, dense polymeric matrix is an additional method for generating water-
soluble IONPs. Numerous copolymers, such as polystyrene-co-PEG (PS-co PEG)
[61], poly(lactic-co-glycolic acid)-co-PEG (PLGA-co-PEG) [156], polystyrene-co
poly-(acrylic acid) (PS-co-PAA) [157], and poly(lactic acid)-co-PEG (PLA-co-
PEG) [62], have been used as matrixes.
Inorganic compounds
To provide colloidal stability and to prevent agglomeration of IONPs, inorganic
compounds such as silica, metal, nonmetal, metal oxides, and sulfides, as well as
silica (SiO
2
), gold (Au), and silver (Ag) coating materials, have been used. The
functionalization of IONPs with inorganic compounds can significantly increase
their antioxidant properties when compared to bare IONPs [39].
Table 3provides a list of inorganic materials that are used for coating of IONPs.
Silica Silica is one of the most extensively used coating materials due to its
efficiency, hydrophilicity, reduced toxicity of the derived nanoparticles, and its
ability to prevent nanoparticle aggregation. Additional advantages include the high
density of surface functional groups that silica provides, and its readily tuned shell
thickness [63,167,168]. The surface of silica is negatively charged as a result of the
deprotonation of terminal silanol groups. Thus, electrostatic repulsive forces
stabilize IONPs encapsulated in silica. Furthermore, silica-coated IONPs are both
colloidally and photochemically stable, robust, and water-soluble [169]. A common
method for encapsulating IONPs in silica is the sol–gel reaction (also known as the
Sto
¨ber process), in which silica is synthesized via the hydrolysis and condensation
of silicon orthoester (Si(OR)
4
) (e.g., tetraethyl orthosilicate [TEOS] and tetramethyl
orthosilicate [TMOS]) [168,170]. Im et al. [171] used the Sto
¨ber process to prepare
silica colloids loaded with superparamagnetic IONPs. In this process, silica is
formed in situ through the hydrolysis of a sol–gel precursor. The surface silanol
groups can be modified with amine and sulfhydryl functional groups by employing
the respective aminoethoxy silane and mercapto ethoxy silane. Carboxylic acid
functional groups can also be introduced by reaction with an aminoethoxy silane
followed by succinic anhydride [172]. Submicronic silica-coated magnetic sphere
aerosols have been prepared by Tartaj et al. [173].
New advances strategies for surface functionalization of…7435
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Metals Metallic elements, when used for surface coating, act as a protective layer
and are relatively inert. Among the many types of metallic coating materials
reported in the literature, we have focused on coatings with gold, as these inorganic
materials have been most commonly used in previous studies. Gold-coated magnetic
nanoparticles were first reported in 2001 by Lin et al. [174]. Gold (Au) is
biocompatible and has a great capacity for functionalization, making it particularly
attractive for surface modification of IONPs. Disadvantages include the attenuation
of the magnetic properties of IONPs functionalized with gold coatings, and
difficulties in the maintenance of the coating arising from interaction between two
dissimilar surfaces. Nevertheless, gold-coated IONPs have been found to be
stable under neutral and acidic pH [175]. Wang et al. [176] prepared gold-coated
IONPs by reducing the gold precursors on them. Xu et al. [177] reported the
synthesis of core–shell-structured Fe
3
O
4
/Au by reducing HAuCl
4
on the IONP
surface. Kheiri et al. [158] reported the use of iron-gold core–shell magnetic
nanoparticles as contrast agents in radiation therapy for treatment of breast cancer.
In addition, this group designed and investigated a novel PEGylated gold-coated
IONP as a potential drug delivery system [3,15].
Conclusion
The ability to tailor the physicochemical properties of IONPs to applications in the
pharmaceutical and biomedical fields continues to drive the development of new
strategies for the synthesis of IONPs. IONPs have consistently demonstrated their
Table 3 Inorganic materials used for functionalization of IONPs
Coating molecule CS HS Applications References
Au 70 Sensitization of breast cancer
cells to irradiation
[158]
Au ?PEG 31.42 Drug delivery [3]
Au ?PEG 60 Drug delivery [15]
Au 6.25 [159]
Au ?cysteamine 52.11 68.92 Bimodal cancer cell imaging and
photothermal therapy
[160]
Silica ?PEI 10 Notch-1 siRNA Carrier for
Targeted Killing of Breast
Cancer
[161]
Silica ?PEG 70 MRI application [162]
APTES ?PEG 70 Drug delivery [163]
3-Aminopropyltriethoxysilane ?PEG 10–15 Drug delivery [164]
Silica 22 Drug delivery [165]
TEOS ?APTES ?PAMAM ?BSA 400 Separation of racemates [166]
CS/HS core size and hydrodynamic size, APTES 3-Aminopropyl)triethoxysilane, TEOS tetraethyl
orthosilicate, PEG polyethylene glycol, PEI polyethylenimine, PAMAM poly(amidoamine), HSA bovine
serum albumin
7436 H. Nosrati et al.
123

therapeutic and diagnostic potential. Eventually, their unique ability to interface
with organic and inorganic materials may lead to their use in various clinical
therapies. Optimized and scalable IONP synthesis is critical for the development of
pre-clinical and clinical applications. Further research exploring fabrication
techniques for nanomaterials, especially applications of IONPs with diverse
features, will contribute to innovation in a variety of areas [178]. The design of
IONPs with multifunctional coatings for bio-applications has attracted significant
attention. Surface functionalization of IONPs allows the attachment of various
biomolecules, rendering them a promising candidate for bio-applications. Different
chemical materials (synthetic and natural) have been studied and have been found to
be efficient for the functionalization of IONPs. This review summarizes the
preparation of IONPs through various synthetic techniques, and functionalized with
a diverse range of coating molecules.
Acknowledgements This work has been supported financially by the Faculty of Pharmacy, Zanjan
University of Medical Sciences, Zanjan, Iran.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
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