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Magnetic-Plasmonic Heterodimer Nanoparticles: Designing Contemporarily Features for Emerging Biomedical Diagnosis and Treatments

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Magnetic-plasmonic heterodimer nanostructures synergistically present excellent magnetic and plasmonic characteristics in a unique platform as a multipurpose medium for recently invented biomedical applications, such as magnetic hyperthermia, photothermal therapy, drug delivery, bioimaging, and biosensing. In this review, we briefly outline the less-known aspects of heterodimers, including electronic composition, interfacial morphology, critical properties, and present concrete examples of recent progress in synthesis and applications. With a focus on emerging features and performance of heterodimers in biomedical applications, this review provides a comprehensive perspective of novel achievements and suggests a fruitful framework for future research.
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nanomaterials
Review
Magnetic-Plasmonic Heterodimer Nanoparticles:
Designing Contemporarily Features for Emerging
Biomedical Diagnosis and Treatments
S. Fatemeh Shams 1, * , Mohammad Reza Ghazanfari 2and Carolin Schmitz-Antoniak 1
1Peter-Grünberg-Institut (PGI-6), Forschungszentrum Jülich, 52425 Jülich, Germany;
c.schmitz-antoniak@fz-juelich.de
2
Department of Materials Science and Engineering, Ferdowsi University of Mashhad, Mashhad 9177948974,
Iran; ghazanfari.mr@gmail.com
*Correspondence: f.shams@fz-juelich.de; Tel.: +49-30-8062-14779
Received: 12 December 2018; Accepted: 8 January 2019; Published: 13 January 2019


Abstract:
Magnetic-plasmonic heterodimer nanostructures synergistically present excellent magnetic
and plasmonic characteristics in a unique platform as a multipurpose medium for recently invented
biomedical applications, such as magnetic hyperthermia, photothermal therapy, drug delivery,
bioimaging, and biosensing. In this review, we briefly outline the less-known aspects of heterodimers,
including electronic composition, interfacial morphology, critical properties, and present concrete
examples of recent progress in synthesis and applications. With a focus on emerging features and
performance of heterodimers in biomedical applications, this review provides a comprehensive
perspective of novel achievements and suggests a fruitful framework for future research.
Keywords:
hybrid nanostructures; interfacial morphology; electronic structure; biocompatibility;
noble metals; magnetic ferrites; hyperthermia; photothermal therapy; bioimaging; drug delivery
1. Introduction
Aqueous colloids of heterodimer nanoparticles are a fascinating class of multimodal hybrid
structures, which have appeared in the last decade and increasingly attracted many attentions. In
general, heterodimer structures are composed by targeted and controlled junction of two main parts as
a guest/host template with simultaneous retention of the key properties of components as well as the
influence on the conjugated part through interfacial interactions.
In most cases, magnetic nanoparticles have been firstly pre-synthesized via common methods
and employed as host seeds for the chemical deposition of the plasmonic component [
1
,
2
], so that
the crystallized magnetic-plasmonic heterodimers consist of magnetic hosts and plasmonic guests.
Although heterodimer nanostructures have been commonly synthesized based on the same protocols
of seed-mediated process [
1
3
], utilization of various techniques, such as coprecipitation [
4
9
],
thermal decomposition [
10
14
], solvothermal [
15
,
16
], flame aerosol [
17
,
18
], and Brust method are
reported [1921].
The elaborate design of heterodimer nanoparticles does not only result in a combination of
the critical characteristics of both components in a single structure, but also leads to emerging
new excellent features [
22
25
]. The resulting heterodimer can be greater than the sum of its parts
because of mutual influences of the constituents leading to new characteristics e.g., by structural
modifications, electronic hybridization, or exchange coupling phenomena at the interface. Particularly,
the combination of metallic/nonmetallic nano-ingredients with different magnetic, electronic, optical,
and chemical properties lead to impressive developments in a wide range of research fields,
Nanomaterials 2019,9, 97; doi:10.3390/nano9010097 www.mdpi.com/journal/nanomaterials
Nanomaterials 2019,9, 97 2 of 39
ranging from basic research perspectives to catalytic [
26
34
], magnetic [
35
,
36
], electronic [
37
], and
biomedical [3843] applications.
The latter was pioneered in 2005 by Yu et al. who designed novel Fe
3
O
4
-Au
nano-heterodimers
[44,45]
. Subsequently, the positive roles of different magnetic-plasmonic
heterodimers for various biomedical diagnostic and therapeutic treatments have been reported,
including magnetic resonance imaging (MRI) [
46
48
], cellular uptake [
49
51
], plasmon imaging [
52
,
53
],
X-ray computed tomography (CT) [
54
], positron emission tomography (PET) [
55
], photothermal
therapy (PTT) [
56
58
], magnetic fluid hyperthermia (MFH) [
59
,
60
], and drug/gene delivery [
1
,
61
]
(Scheme 1). More general, the magnetic component provides potential features, like magnetic targeting
of structure and heat-generation, while the plasmonic constituent is responsible for photothermal
phenomena, plasmonic imaging, cell tracking, and improvement of biocompatibility.
Nanomaterials 2019, 9, x FOR PEER REVIEW 2 of 38
electronic, optical, and chemical properties lead to impressive developments in a wide range of
research fields, ranging from basic research perspectives to catalytic [26–34], magnetic [35,36],
electronic [37], and biomedical [38–43] applications.
The latter was pioneered in 2005 by Yu et al. who designed novel Fe3O4-Au nano-heterodimers
[44,45]. Subsequently, the positive roles of different magnetic-plasmonic heterodimers for various
biomedical diagnostic and therapeutic treatments have been reported, including magnetic resonance
imaging (MRI) [46–48], cellular uptake [49–51], plasmon imaging [52,53], X-ray computed
tomography (CT) [54], positron emission tomography (PET) [55], photothermal therapy (PTT) [56–
58], magnetic fluid hyperthermia (MFH) [59,60], and drug/gene delivery [1,61] (Scheme 1). More
general, the magnetic component provides potential features, like magnetic targeting of structure and
heat-generation, while the plasmonic constituent is responsible for photothermal phenomena,
plasmonic imaging, cell tracking, and improvement of biocompatibility.
In order to reveal hitherto unconsidered aspects of hybrid nanomaterials, our review article is
focused on recently reported works about the design of magnetic-plasmonic heterodimer
nanostructures for biomedical applications. To this end, we firstly identify the important desired
magnetic and plasmonic properties for different applications in Section 2. In Section 3, different
structural designs are presented for the creation of novel magnetic-plasmonic heterodimers and are
categorized according to their electronic nature (metallic vs. nonmetallic) and interfacial
morphologies. In Section 4, selected examples of successfully tailored magnetic, plasmonic,
electronic, and biocompatibility properties of heterodimers are summarized before briefly addressing
improved performances in associated applications in theranostics in Section 5. Finally, in Section 6,
an outlook on possible future developments in the mentioned fields is presented.
Scheme 1. Potential biomedical applications of magnetic-plasmonic heterodimers.
2. Hot Properties for Biomedical Applications
Before turning to the discussion of recent developments in tailoring heterodimers for biomedical
applications, a brief summary of magnetic and plasmonic characteristics shall be given here, which
are desired in addition to biocompatibility. Exemplarily, hyperthermia cancer treatment, MRI, and
magnetically targeted drug delivery have been chosen for the magnetic part, and photothermal
therapy and bioimaging were chosen for the plasmonic part.
Scheme 1. Potential biomedical applications of magnetic-plasmonic heterodimers.
In order to reveal hitherto unconsidered aspects of hybrid nanomaterials, our review article
is focused on recently reported works about the design of magnetic-plasmonic heterodimer
nanostructures for biomedical applications. To this end, we firstly identify the important desired
magnetic and plasmonic properties for different applications in Section 2. In Section 3, different
structural designs are presented for the creation of novel magnetic-plasmonic heterodimers and
are categorized according to their electronic nature (metallic vs. nonmetallic) and interfacial
morphologies. In Section 4, selected examples of successfully tailored magnetic, plasmonic, electronic,
and biocompatibility properties of heterodimers are summarized before briefly addressing improved
performances in associated applications in theranostics in Section 5. Finally, in Section 6, an outlook on
possible future developments in the mentioned fields is presented.
Nanomaterials 2019,9, 97 3 of 39
2. Hot Properties for Biomedical Applications
Before turning to the discussion of recent developments in tailoring heterodimers for biomedical
applications, a brief summary of magnetic and plasmonic characteristics shall be given here, which
are desired in addition to biocompatibility. Exemplarily, hyperthermia cancer treatment, MRI, and
magnetically targeted drug delivery have been chosen for the magnetic part, and photothermal therapy
and bioimaging were chosen for the plasmonic part.
2.1. Magnetic Characteristics
The first requirement for magnetic particles in any biomedical application is superparamagnetism,
i.e., a vanishing remanent magnetization that is caused by thermal fluctuations of the magnetization
direction. Otherwise, the particles will form large magnetic agglomerates, yielding unwanted side
effects, like thrombosis.
Magnetic hyperthermia is one the novel methods for cancer therapy that results in destroying
cancerous cells during localized temperature rising up to around 43
C upon applying AC magnetic
field with minimal side effects on the normal cells [
62
]. In fact, the biological integrity of tumor
cells membrane and their cytoskeleton are damaged during hyperthermia [
63
], which is firstly
introduced using Fe
2
O
3
nanoparticles in 1957 [
64
]. In this method, heating efficiency is closely
related to the external AC magnetic field amplitude and frequency, as well as magnetic nanoparticles
characteristics, such as anisotropy, magnetization, inter-/intra-particles interactions, particles size, and
size distribution [
62
66
]. The conversion of magnetic work to internal energy has been described by
Rosensweig [65] and the dissipated power can be formally written as:
P=1
2µ0χH2ωωτ
1+(ωτ)2(1)
where
µ0
is the magnetic constant, Hand
ω
are the amplitude of the external magnetic field and its
frequency, respectively,
χ
is the magnetic susceptibility of the superparamagnetic particles, and
τ
is the relaxation time of their magnetization. Since Hand
ω
are limited by unwanted side effects,
like arrhythmia, stimulation of muscles, and non-specific heating by eddy currents in the tissue,
the magnetic properties of the particles, particularly
χ
and
τ
, have to be tailored to maximize the
dissipated power. A large susceptibility in reasonable external magnetic fields can be achieved by
choosing superparamagnetic particles with large net magnetic moments. To this end, the particles
should also be magnetic single-domain. The relaxation time should fit the inverse frequency of
the external magnetic field,
τ
=
ω1
, to obtain maximum available heating. Since it was found
experimentally [
66
] that the particles are quite immobile in tumor tissue, the relaxation time mainly
depends on the magnetic anisotropy connecting the favored magnetization directions to the crystal
lattice. A review on the use of iron oxide nanoparticles in hyperthermia is given e.g., by Laurent et
al. [67].
MRI is based on the nuclear magnetic resonance of protons (hydrogen nuclei) in the tissue. The
contrast is given by different relaxation times of the nuclear magnetic moments, depending on the
nearest environment usually measured in a sequence of magnetic field pulses. The magnetic stray
field of superparamagnetic particles alters the (T
2
or T
2
*) relaxation time of the protons in the close
environment significantly and it can consequently be used as contrast agents. Since a large stray
field is caused by particles with a high magnetic moment, again, single-domain superparamagnetic
particles are desired. By definition, the large magnetic moment that shall be achieved in reasonably
small external magnetic fields is connected to a large susceptibility. In addition, it is also affiliated to
other intrinsic and extrinsic parameters, such as magnetic exchange, magnetic order, molecular field,
and external applied field [68].
For magnetically targeted drug delivery, a magnetic driving force controls drug distribution and
release, which leads to significantly enhanced rates of drug movement and delivery when compared
Nanomaterials 2019,9, 97 4 of 39
to common approaches, like enhanced permeability and retention (EPR). Because of the biological
limitations, like medication’s half-life in the body, a fast and targeted delivery is desired. In addition,
side effects can be decreased, since the drugs are only locally concentrated. Magnetically targeted drug
delivery is based on an external magnetic gradient field focused on a specific target (e.g., cancerous
tissue) to guide magnetic (and improve therapeutic efficiency on tumors.) Again, large magnetic
moments/magnetization is desired as the most effective factor for this application, because the
magnetic force is proportional to the product of the magnetic field gradient (technically limited) and
the magnetic moment of the nanocarrier.
2.2. Plasmonic Features
Plasmonic characteristics are associated to the response of nanoparticles to electromagnetic
radiation in the specific wavelength ranges of ultra-violet (UV), visible, and near infra-red (NIR) light,
which are used for different biomedical applications, including photothermal therapy and imaging
approaches [6971].
Photothermal therapy is an active photodynamic therapeutic approach that is based on simulating
superficial atoms of plasmonic nanoparticles and localized heating up to a desired temperature.
Nanoparticles convert the energy of irradiated light to heat by surface plasmon absorption (SPA). As a
result, higher absorption intensity leads to enhanced localized heating and treatment efficiency. When
considering the deeper penetration depth of safe NIR as compared to UV and visible light into the
body tissues, nanoparticles with surface plasmon absorption at longer wavelengths are desired.
Different bioimaging techniques are powerful non-invasive approaches for accurate early
diagnosis of various diseases, like cancerous tumors [
72
]. For these applications, again, the
maximum absorption intensity of nanoparticles leads to higher efficiency. Furthermore, nanoparticles
with absorbability in variable ranges of wavelengths shall be simultaneously used in different
imaging methods.
Summary 1. For biomedical applications usually the following magnetic and plasmonic properties are desired
superparamagnetism
large susceptibility/high saturation magnetization (MS)
suitable relaxation time
Maximum surface plasmon absorption (SPA) intensity
Plasmon resonance absorption peak (PRA) in the near infra-red (NIR) regime
Both superparamagnetism and relaxation time in tumor tissue can be tailored by the magnetic
anisotropy. The relaxation time in media with low viscosity mainly depends on the size (which
influences the occurrence of superparamagnetism as well) and surface design. Both SPA intensity
and peak position directly depend on the chemical composition, crystal structure, surface properties,
morphology, and size of nanoparticles.
3. Structure Design
Magnetic-plasmonic heterodimer nanoparticles were designed in various structures, depending
on their desired use. The appropriate structure of particles was identified by obtaining maximum
functionality in intended applications. Different factors including particles size and shape, components
phases, chemical composition, crystal structure, etc. were considered and variated as effective
parameters of heterodimers structure design. Among them, composition nature (metallic vs.
nonmetallic) and morphology of components, as well as their junction interfaces, are the most critical
factors. Accordingly, the following discussion of structural design of recently reported heterodimer
structures is systematically reviewed in two parts: electronic nature of components and interfacial
morphology, respectively.
Nanomaterials 2019,9, 97 5 of 39
3.1. Electronic Nature of Components
Both magnetic and plasmonic components could be comprised of metallic or nonmetallic natures.
Therefore, we classify the heterodimer structures according to the three possible combinations of
different electronic natures, which are presented below: metallic-metallic, metallic-nonmetallic,
and nonmetallic-nonmetallic.
3.1.1. Metallic—Metallic
Noble metals nanoparticles consisting of Au, Ag, Pt, Pd, Cu, and Ti were frequently used as
plasmonic nanomaterials in the synthesis of heterodimer structures [
73
,
74
]. Although most of them,
particularly Au and Ag nanoparticles, demonstrate insignificant magnetic features, they also led
to a functionality enhancement of heterodimers in biomedical applications when combined with
a ferromagnetic material. Metallic nanoparticles of the ferromagnetic elements Fe, Co, and Ni
nanoparticles had been introduced as efficient candidates for the magnetic part of heterodimers
because of their supreme magnetic characteristics, like reasonable saturation magnetization (M
S
)
and anisotropy [
75
]. However, the utilization of metallic magnetic components was commonly
limited by their insufficient chemical stability, so that there was a need for well-designed synthesis
processes and the use of stabilizing surfactants, such as oleic acid, polyethylene glycol (PEG), and
poly(N-vinylpyrolidone) (PVP) [
76
,
77
]. Furthermore, the biocompatibility of these particles, especially
Co and Ni, for biomedical applications was inadequate and additional improving treatments, like
surface coating with silica, biomolecules, and polymers are necessary [78,79].
The reported work in 2007 by Wetz et al. on the synthesis of Co-Au heterodimer nanorods based
on the controlled nucleation and growth of Au nanoparticles at the surfaces of Co nanorods was an
important step forward to introduce a new generation of hybrid materials [
80
]. Recently, Jiang et
al. synthesized Fe-Au heterodimers through ultrasmall Fe (bcc) and Au seeds with the possibility
of controllable transformation to a biocompatible Fe
3
O
4
-Au structure [
81
]. The size and chemical
stability of these nanoparticles were adjusted using oleic acid as chelating agent, so that the diameters
of Au and Fe particles were in the range of 4–10 and 11–15 nm, respectively (Figure 1). Moreover,
multifaceted Fe-Pd heterodimers are simply assembled based on a sequential reduction process of
Fe and Pd metallic nanoparticles [
82
]. In this work, the diameter of the Fe particles was in the range
of 7–15 nm and the mean diameter of Pd nanoparticles was around 1 nm. In addition to biomedical
applications, metallic-metallic heterodimers, such as Ni-Au nanostructures, could be utilized in bio-
and photo-catalysis as well, owing to their multifunctional properties [83].
Nanomaterials 2019, 9, x FOR PEER REVIEW 6 of 38
Figure 1. Transmission electron microscopy (TEM) images of Fe-Au heterodimers with different
particles sizes. 15–4 nm Fe-Au heterodimers (a), 7–13 nm Fe-Au heterodimers (b), and 11–10 nm Fe-
Au heterodimers (c), scale bars: 50 nm. Reproduced with permission from [81], copyright (2016) Royal
Society of Chemistry.
3.1.2. Metallic—Nonmetallic
Metallic–nonmetallic structures form the main category of magnetic-plasmonic heterodimers
because of their optimum characteristics, in particular magnetic properties and chemical/biological
stability. Nonmetallic components were often considered as a host component due to their higher
hydrophilicity when compared to metallic particles, leading to a higher stability of the combined
structure.
According to the literature, most of the metallic-nonmetallic heterodimers had been designed
based on various well-defined nonmetallic magnetic transition metal oxides, particularly ferrites.
Several works on using magnetic ferrites, such as Fe3O4, CoFe2O4, MnFe2O4, and NiFe2O4 combined
with nanoparticles of noble metals, like Au, Ag, Pt, and Pd had been reported [93,94]. Nowadays,
magnetite (Fe3O4) nanoparticles play a key role in biomedical applications as they are approved by
the United States (US) Food and Drug Administration (FDA) for distinct medical treatments and
currently investigated in clinical trials [95]. In the European Union, functionalized magnetite
nanoparticles are approved for the hyperthermia treatment of brain tumors. Following this route,
different heterodimer structures on the basis of magnetite particles, such as Fe3O4-Au, Fe3O4-Ag,
Fe3O4-Pt, and Fe3O4-Pd with various particles sizes and morphologies were designed for
bioapplications [96–103]. Among them, Fe3O4-Au heterodimers attracted the most attention for
catalytic, analytical, and biomedical applications [104].
For instance, Fantechi et al. synthesized Fe3O4-Au heterodimers through Au seed mediated
thermal decomposition and precisely controlled the size, morphology, Fe/Au ratio, and crystallinity
by deliberately changing of iron initial resources (Figure 2a) [105]. In other works, a considerable
alteration of magnetic and plasmonic features of Au-iron oxide heterodimers was reported as a
consequence of size and shape controlling of Au nanoparticles [106,107]. In spherical Fe3O4-Au
heterodimer structures that was designed by Landgraf et al. not only an improvement in
biocompatibility and a reduction of side effects of magnetic nanoparticles were observed, but also
their performance in MRI applications was optimized from the path of interactions with proteins in
biologic fluids [108]. Additionally, based on the magnetic properties of Fe3O4 and the plasmonic
features of Au nanoparticles, Fe3O4-Au heterodimers could act as ideal contrast agents for
multimodal bioimaging techniques, including CT, MRI, photoacoustic (PA), optical microscopy
(OM), transmission electron microscopy (TEM), and surface-enhanced Raman spectroscopy (SERS)
[109]. Read et al. smartly used Fe3O4-Au heterodimers as host seed platform to assemble the stable
structure of Fe3O4-Au-Ge heterodimers, while a Fe3O4-Ge structure showed insignificant
physicochemical stability (Figure 2a) [110].
Recently, Ding et al. synthesized Fe3O4-Ag heterodimers for magnetic hyperthermia applications
with remarkably enhanced efficiency of magnetic heating when compared to individual Fe3O4
nanoparticles, which could be attributed to the much larger heat transfer efficiency of metallic Ag
attachments as compared to nonmetallic magnetic nanoparticles (Figure 2b) [111]. In addition, the
Figure 1.
Transmission electron microscopy (TEM) images of Fe-Au heterodimers with different
particles sizes. 15–4 nm Fe-Au heterodimers (
a
), 7–13 nm Fe-Au heterodimers (
b
), and 11–10 nm Fe-Au
heterodimers (
c
), scale bars: 50 nm. Reproduced with permission from [
81
], copyright (2016) Royal
Society of Chemistry.
Nanomaterials 2019,9, 97 6 of 39
In comparison with single-element magnetic particles, magnetic bimetallic compounds offered
the possibility to tailor the magnetic characteristics, such as M
S
, anisotropy, coercivity (H
C
), power
square, and remanence-to-saturation ratio (M
r
/M
S
). In addition, they exhibited enhanced chemical
stability [
84
], making bimetallic magnetic nanoparticles the more appropriate candidates for magnetic
components of heterodimers. Bimetallic magnetic structures with compositions of M
x
P
y
(M = Fe,
Co, Ni, and P = Pt, Pd) have been growingly utilized in bioapplications, such as MRI contrast
agents [
85
], cancer therapy treatment killing Hela cells [
86
], and the prevention of the growth and
spread of tumors [
87
,
88
]. As a same trend, heterodimer structures composed of magnetic bimetallic
and noble metals components presented excellent and even occasionally unforeseen features. For
instance, despite the presence of diamagnetic Au nanoparticles in CoPt
3
-Au heterodimers leading to
a decrease of the net magnetic properties, CoPt-Au heterodimer nanostructures showed enhanced
magnetization [
86
]. Moreover, simultaneously strengthened magnetic and plasmonic features of
FePt-Au and FePt-Ag heterodimers were reported [
89
91
]. Recently, Lopez-Ortega et al. developed
metallic Ag@FeCo hybrid nanostructures by combining hot injection and polyol approaches in high
boiling point solvents [
92
] in chemical synthesis. They presented promising results in enhanced
plasmonic and magneto-optical properties, which were comparable to the best reported results for
nanohybrids that were fabricated using physical methods, like lithography. The magnetic control
of light polarization was significantly increased, which is very useful for optical communication,
sensing, and imaging applications. Furthermore, the reported achievements confirmed the capability
of chemical synthesis methods to control size, shape, and compositions of nanohybrids [92].
3.1.2. Metallic—Nonmetallic
Metallic–nonmetallic structures form the main category of magnetic-plasmonic heterodimers
because of their optimum characteristics, in particular magnetic properties and chemical/biological
stability. Nonmetallic components were often considered as a host component due to their
higher hydrophilicity when compared to metallic particles, leading to a higher stability of the
combined structure.
According to the literature, most of the metallic-nonmetallic heterodimers had been designed
based on various well-defined nonmetallic magnetic transition metal oxides, particularly ferrites.
Several works on using magnetic ferrites, such as Fe
3
O
4
, CoFe
2
O
4
, MnFe
2
O
4
, and NiFe
2
O
4
combined
with nanoparticles of noble metals, like Au, Ag, Pt, and Pd had been reported [
93
,
94
]. Nowadays,
magnetite (Fe
3
O
4
) nanoparticles play a key role in biomedical applications as they are approved by the
United States (US) Food and Drug Administration (FDA) for distinct medical treatments and currently
investigated in clinical trials [95]. In the European Union, functionalized magnetite nanoparticles are
approved for the hyperthermia treatment of brain tumors. Following this route, different heterodimer
structures on the basis of magnetite particles, such as Fe
3
O
4
-Au, Fe
3
O
4
-Ag, Fe
3
O
4
-Pt, and Fe
3
O
4
-Pd
with various particles sizes and morphologies were designed for bioapplications [
96
103
]. Among
them, Fe
3
O
4
-Au heterodimers attracted the most attention for catalytic, analytical, and biomedical
applications [104].
For instance, Fantechi et al. synthesized Fe
3
O
4
-Au heterodimers through Au seed mediated
thermal decomposition and precisely controlled the size, morphology, Fe/Au ratio, and crystallinity by
deliberately changing of iron initial resources (Figure 2a) [
105
]. In other works, a considerable alteration
of magnetic and plasmonic features of Au-iron oxide heterodimers was reported as a consequence of
size and shape controlling of Au nanoparticles [
106
,
107
]. In spherical Fe
3
O
4
-Au heterodimer structures
that was designed by Landgraf et al. not only an improvement in biocompatibility and a reduction of
side effects of magnetic nanoparticles were observed, but also their performance in MRI applications
was optimized from the path of interactions with proteins in biologic fluids [
108
]. Additionally,
based on the magnetic properties of Fe
3
O
4
and the plasmonic features of Au nanoparticles, Fe
3
O
4
-Au
heterodimers could act as ideal contrast agents for multimodal bioimaging techniques, including CT,
MRI, photoacoustic (PA), optical microscopy (OM), transmission electron microscopy (TEM), and
Nanomaterials 2019,9, 97 7 of 39
surface-enhanced Raman spectroscopy (SERS) [
109
]. Read et al. smartly used Fe
3
O
4
-Au heterodimers
as host seed platform to assemble the stable structure of Fe
3
O
4
-Au-Ge heterodimers, while a Fe
3
O
4
-Ge
structure showed insignificant physicochemical stability (Figure 2a) [110].
Recently, Ding et al. synthesized Fe
3
O
4
-Ag heterodimers for magnetic hyperthermia applications
with remarkably enhanced efficiency of magnetic heating when compared to individual Fe
3
O
4
nanoparticles, which could be attributed to the much larger heat transfer efficiency of metallic Ag
attachments as compared to nonmetallic magnetic nanoparticles (Figure 2b) [
111
]. In addition, the
performance of hybrid nanostructures in photothermal therapy was improved in comparison with
both individual Fe3O4and Ag nanoparticles and they exhibited better biocompatibility.
In recent years, several heterodimer nanostructures that were composed of Fe
3
O
4
and metallic Pt
and Pd nanoparticles were synthesized (Figure 2c,d) [
112
,
113
]. Although paramagnetic nanoparticles
of Pt and Pd were nominated as plasmonic agents, owing to their more proper biocompatibility and
stability, rather than diamagnetic Au and Ag particles, they were only limitedly utilized because
of the rather complicated synthesis and attaching process. Furthermore, Fe
3
O
4
-Cu heterodimers in
submicron size range exhibited pseudo-superparamagnetic behavior [114].
Other ferrite structures could be actively selected as a magnetic component. For instance,
MnFe
2
O
4
-Ag heterodimers were seed-mediated fabricated via elaborate control of synthesis
parameters, such as reaction temperature, pH, and time [
94
]. Moreover, CoFe
2
O
4
-Au, CoFe
2
O
4
-Ag,
and CoFe
2
O
4
-Pd heterodimers had been synthesized for antibacterial and photocatalysis applications
(Figure 2e) [
115
117
]. The latter system shall be presented here in some more detail. CoFe
2
O
4
-Pd
heterodimer nanostructures were successfully synthesized with different particles sizes (from 7 to
40 nm) using pre-synthesized magnetic nanoparticles of cobalt ferrite (CoFe
2
O
4
) [
118
,
119
] as the
host seeds to reduce ultra-small Pd particles. CoFe
2
O
4
nanoparticles were randomly decorated
with metallic Pd components with a mean diameter of 2 nm [
120
]. Size and weight percent of Pd
nanoparticles of heterodimers were controlled through adjusting synthesis parameters, such as pH,
reaction temperature, and initial concentration of palladium resources. We found that both magnetic
and plasmonic characteristics of CoFe
2
O
4
-Pd heterodimers (Pd amount was varied in the range of
1.5–3%wt) were significantly improved when compared to individual CoFe
2
O
4
nanoparticles, which
are presented in next sections.
There were only a few reports on applying other metal-oxide structures for a magnetic building
block. Biocompatible SiO
2
-covered MnO-Au heterodimers were synthesized by Schick et al. for
use in bioapplications (Figure 2f) [
121
]. Although superparamagnetic MnO nanoparticles indicated
non-highlighted magnetization, they brought considerable benefit to contrast the enhancement in MRI
and particularly fluorescence and confocal laser scanning imaging [
121
,
122
]. On the other hand, the
combination of metallic magnetic and nonmetallic plasmonic parts was occasionally reported. For
example, FePt-CdS hybrid structures were assembled by using magnetic FePt bimetallic nanoparticles
and plasmonic CdS quantum dots (Figure 2g) [
123
,
124
]. Moreover, the synthesis of FePt-CdO
heterodimers was introduced for plasmonic applications (Figure 2h) [73].
Nanomaterials 2019,9, 97 8 of 39
Figure 2.
Microscopic images of different metallic-nonmetallic heterodimers. TEM image of Fe
3
O
4
-Au
heterodimers, scale bar: 40 nm, reproduced with permission from [
110
], copyright (2015) American
Chemical Society (
a
), TEM image of Fe
3
O
4
-Ag heterodimers, scale bar: 40 nm, with permission
from [
111
], copyright (2017) Elsevier (
b
), TEM image of Fe
3
O
4
-Pt heterodimers, scale bar: 30 nm,
with permission from [
112
], copyright (2013) American Chemical Society (
c
), TEM image of Fe
3
O
4
-Pd
heterodimers, scale bar: 30 nm, with permission from [
113
], copyright (2011) Royal Society of Chemistry
(
d
), SEM image of CoFe
2
O
4
-Pd heterodimers, scale bar: 300 nm, with permission from [
117
], copyright
(2016) Royal Society of Chemistry (
e
), TEM image of MnO-Au heterodimers, scale bar: 40 nm, with
permission from [
121
], copyright (2014) American Chemical Society (
f
), TEM image of FePt-CdS
heterodimers, scale bar: 40 nm, with permission from [
123
], copyright (2009) American Chemical
Society (
g
), and TEM image of CdO-FePt heterodimers, scale bar: 100 nm, with permission from [
73
],
copyright (2014) American Chemical Society (h).
3.1.3. Nonmetallic—Nonmetallic
In order to synthesize heterodimer structures, nonmetallic magnetic particles were frequently
utilized, but so far only a few plasmonic components with nonmetallic nature were employed.
The main class of nonmetallic plasmonic nanomaterials is quantum dots (QDs) with numerous
functionalities for biomedical applications, such as drug delivery, especially for small molecules,
like 5-FU [
125
,
126
], biosensing [
127
130
], and multimodal imaging [
131
,
132
]. Since quantum dots
normally show insufficient biocompatibility and colloidal stability, their combination with nonmetallic
magnetic nanoparticles could be helpful to overcome drawbacks. Lee et al. synthesized Fe
3
O
4
-QD
heterodimers that are based on a one pot self-assembly method with simultaneous improvements in
Hela cells uptake and labeling for in-vitro/in-vivo imaging [133].
Investigation of Fe
2
O
3
-CdS heterodimers confirmed the synergistic emergence of magnetic
and photoluminescence properties in a unique structure (Figure 3a) [
134
]. In addition to common
quantum dots, some other nonmetallic structures, such as Ti oxides and Zn oxides, consequently
showed plasmonic features and were used as a plasmonic component of heterodimers [
135
]. Despite
the successful synthesis of Fe
3
O
4
-ZnO [
136
] and CoFe
2
O
4
-ZnO heterodimers (Figure 3b) [
137
], an
investigation of their biological features is missing as of yet. Recently, some new generations of
plasmonic materials, like graphene QD, were employed in the Fe
3
O
4
-graphene QD heterodimers for
bioapplications [84,138].
Nanomaterials 2019,9, 97 9 of 39
Nanomaterials 2019, 9, x FOR PEER REVIEW 8 of 38
bar: 40 nm, with permission from [121], copyright (2014) American Chemical Society (f), TEM image
of FePt-CdS heterodimers, scale bar: 40 nm, with permission from [123], copyright (2009) American
Chemical Society (g), and TEM image of CdO-FePt heterodimers, scale bar: 100 nm, with permission
from [73], copyright (2014) American Chemical Society (h).
3.1.3. Nonmetallic—Nonmetallic
In order to synthesize heterodimer structures, nonmetallic magnetic particles were frequently
utilized, but so far only a few plasmonic components with nonmetallic nature were employed. The
main class of nonmetallic plasmonic nanomaterials is quantum dots (QDs) with numerous
functionalities for biomedical applications, such as drug delivery, especially for small molecules, like
5-FU [125,126], biosensing [127–130], and multimodal imaging [131,132]. Since quantum dots
normally show insufficient biocompatibility and colloidal stability, their combination with
nonmetallic magnetic nanoparticles could be helpful to overcome drawbacks. Lee et al. synthesized
Fe3O4-QD heterodimers that are based on a one pot self-assembly method with simultaneous
improvements in Hela cells uptake and labeling for in-vitro/in-vivo imaging [133].
Investigation of Fe2O3-CdS heterodimers confirmed the synergistic emergence of magnetic and
photoluminescence properties in a unique structure (Figure 3a) [134]. In addition to common
quantum dots, some other nonmetallic structures, such as Ti oxides and Zn oxides, consequently
showed plasmonic features and were used as a plasmonic component of heterodimers [135]. Despite
the successful synthesis of Fe3O4-ZnO [136] and CoFe2O4-ZnO heterodimers (Figure 3b) [137], an
investigation of their biological features is missing as of yet. Recently, some new generations of
plasmonic materials, like graphene QD, were employed in the Fe3O4-graphene QD heterodimers for
bioapplications [84,138].
Although the most efficient magnetic-plasmonic nanoparticles are composed of two or more
phases as a combination of magnetic and plasmonic phases, recently some interesting works were
presented based on single-phase magnetic-plasmonic nanomaterials. Nickel-based phases, like
metallic Ni nanoparticles and NiO nanostructures, were the main candidates for single-phase
multifunctional nanoparticles for biomedical applications, because they indicate significant
ferromagnetic and plasmonic features [139,140]. Furthermore, there were some reports on employing
alloyed structures as single-phase magnetic-plasmonic nanoparticles. For instance, Messina et al.
tuned the composition of NixAuy alloy nanoparticles to perform mixing of both magnetic and
plasmonic properties [141]. However, the magnetization of this single-phase (for example Ni67Au33)
was remarkably decreased when compared to pure Ni nanoparticles. Amendola et al. fabricated iron-
doped silver nanotruffles with simultaneous magnetic and plasmonic characteristics [142].
Investigation of their electronic structure confirmed the single-phase formation of FeAg with
significant magnetic and plasmonic properties for photothermal heating applications. The future
developments of single-phase magnetic-plasmonic structures can provide promising advances for
biomedical applications.
Figure 3.
TEM images of different nonmetallic-nonmetallic heterodimers. Fe
2
O
3
-CdS heterodimers,
scale bar: 300 nm, reproduced with permission from [
134
], copyright (2009) American Chemical Society
(
a
), and CoFe
2
O
4
-ZnO heterodimers, scale bar: 50 nm, with permission from [
137
], copyright (2013),
Elsevier (b).
Although the most efficient magnetic-plasmonic nanoparticles are composed of two or more
phases as a combination of magnetic and plasmonic phases, recently some interesting works were
presented based on single-phase magnetic-plasmonic nanomaterials. Nickel-based phases, like metallic
Ni nanoparticles and NiO nanostructures, were the main candidates for single-phase multifunctional
nanoparticles for biomedical applications, because they indicate significant ferromagnetic and
plasmonic features [139,140]. Furthermore, there were some reports on employing alloyed structures
as single-phase magnetic-plasmonic nanoparticles. For instance, Messina et al. tuned the composition
of Ni
x
Au
y
alloy nanoparticles to perform mixing of both magnetic and plasmonic properties [
141
].
However, the magnetization of this single-phase (for example Ni
67
Au
33
) was remarkably decreased
when compared to pure Ni nanoparticles. Amendola et al. fabricated iron-doped silver nanotruffles
with simultaneous magnetic and plasmonic characteristics [
142
]. Investigation of their electronic
structure confirmed the single-phase formation of FeAg with significant magnetic and plasmonic
properties for photothermal heating applications. The future developments of single-phase
magnetic-plasmonic structures can provide promising advances for biomedical applications.
Summary 2.
Metallic-metallic heterodimers can exhibit improved magnetic and plasmonic characteristics
outperforming nonmetallic nanoparticles, while practical restrictions in their chemical and biological
stability limit their use in biomedical applications. Various structures of metallic-nonmetallic heterodimers
were increasingly employed in and developed for bioapplications owing to a variety of tailored features
from magnetization to physiochemical and biological stability. Despite attractive characteristics of
nonmetallic-nonmetallic heterodimers, so far only a few research groups focused on them. In fact, a bright future
in bioapplications could be expected after more studies on this novel kind of magnetic-plasmonic heterodimers.
3.2. Interfacial Morphology
Junction mode and interfacial morphology of heterodimer structures are the most effective
factors for their design, characteristics, and final performance. Interfacial morphology depends
on the composition, individual shape, and surface properties of components. Hitherto, several
magnetic-plasmonic heterodimers with different interfacial morphologies were synthesized. The
most desired morphologies included random-decorated, dumbbell-like shape, mosaic, rod-shape,
and Janus beads (Figure 4) [
143
145
]. Per definition, core-shell structures could be categorized as
heterodimers as well, but due to their great diversity they were classically treated as an individual
group and they are not part of this review. Furthermore, there are some reports on the heterodimers
Nanomaterials 2019,9, 97 10 of 39
with specific interfacial morphologies, such as flower and star-shape. In the following, recent works
on each mentioned category are briefly reviewed.
Nanomaterials 2019, 9, x FOR PEER REVIEW 10 of 38
Figure 4. TEM images of heterodimers with different interfacial morphologies. Random-decorated
Fe2O3-Pd heterodimers, scale bar: 30 nm, reproduced with permission from [32], copyright (2015),
Royal Society of Chemistry (a), Janus Fe3O4-antibody dye heterodimers, scale bar: 100 nm, with
permission from [143], copyright (2018) Elsevier (b), Flower-shaped MnO-Au heterodimers, scale bar:
50 nm, with permission from [121], copyright (2014) American Chemical Society (c), Star-shaped
FeOx-Au heterodimers, scale bar: 100 nm [107], published by The Royal Society of Chemistry (d), Rod-
shaped Fe2O3-TiO2 heterodimers, scale bar: 200 nm, with permission from [144], copyright (2009)
Royal Society of Chemistry (e), Dumbbell-shaped FePt-Au heterodimers, scale bar: 30 nm, with
permission from [90], copyright (2011) Spiringer Nature (f), Mosaic Fe3O4-Au(thiol)@SiO2
heterodimers, scale bar: 50 nm, with permission from [108], copyright (2015) Elsevier (g), and Core-
shell Fe3O4@Au heterodimers, scale bar: 50 nm, with permission from [145], copyright (2005)
American Chemical Society (h).
3.2.2. Dumbbell-Like Shape
Fe3O4-Au heterodimers that were synthesized by Yu et al. in 2005 were introduced as a first
example of dumbbell-like structures [151]. In most dumbbell-like heterodimers, magnetic uniaxial
nanorods acted as host for spherical metallic nanoparticles as plasmonic guests that are
symmetrically attached to the host surfaces [97,100,152]. Dumbbell-like heterodimers demonstrated
desirable performances in photo- and bio-catalysis applications due to their higher symmetry and
larger free surface areas when compared to randomly decorated structures [106]. Hou’s research
group synthesized FePt-Au heterodimers with random decoration and dumbbell-like morphologies
for biomedical and catalysis applications [89,90] based on seed mediated technique of non-spherical
magnetic particles [153]. In both cases, the plasmonic properties were affected by the interfacial
morphology and their UV-Vis absorption peaks were slightly red-shifted in comparison with Au
nanoparticles [154,155]. In fact, UV-Vis spectroscopy of individual Au nanoparticles shows a well-
pronounced peak at 520 nm, while for randomly decorated and dumbbell-like heterodimers, it is
shifted to 525 and 528 nm, respectively, owing to electron transfer from the Au surface to the FePt
component [90].
3.2.3. Mosaic
Mosaic structures are normally utilized when heterodimers need to be covered by a shell or put
in a matrix. The main reasons for these designs are improvement of biocompatibility,
physicochemical stability, and advanced functionality. In several reported mosaic heterodimers,
silica is considered as matrix structure, such as FePt-Au@SiO
2 and FePt/Fe3O4-CdSe@SiO2
nanohybrids [14,156]. Sotiriou et al. fabricated Fe2O3-Ag heterodimers on SiO2 mosaic shell to use in
magnetic hyperthermia (Figure 5a) [17]. The SAR was appreciably increased for the silica coated
structures for all Ag concentrations (Figure 5b). In addition, an unwanted ferromagnetically blocked
Figure 4.
TEM images of heterodimers with different interfacial morphologies. Random-decorated
Fe
2
O
3
-Pd heterodimers, scale bar: 30 nm, reproduced with permission from [
32
], copyright (2015),
Royal Society of Chemistry (
a
), Janus Fe
3
O
4
-antibody dye heterodimers, scale bar: 100 nm, with
permission from [
143
], copyright (2018) Elsevier (
b
), Flower-shaped MnO-Au heterodimers, scale
bar: 50 nm, with permission from [
121
], copyright (2014) American Chemical Society (
c
), Star-shaped
FeO
x
-Au heterodimers, scale bar: 100 nm [
107
], published by The Royal Society of Chemistry (
d
),
Rod-shaped Fe
2
O
3
-TiO
2
heterodimers, scale bar: 200 nm, with permission from [
144
], copyright
(2009) Royal Society of Chemistry (
e
), Dumbbell-shaped FePt-Au heterodimers, scale bar: 30 nm,
with permission from [
90
], copyright (2011) Spiringer Nature (
f
), Mosaic Fe
3
O
4
-Au(thiol)@SiO
2
heterodimers, scale bar: 50 nm, with permission from [
108
], copyright (2015) Elsevier (
g
), and Core-shell
Fe
3
O
4
@Au heterodimers, scale bar: 50 nm, with permission from [
145
], copyright (2005) American
Chemical Society (h).
3.2.1. Randomly Decorated
Seed mediated synthesis methods of heterodimers mostly results in the random joining of
components so that the larger building block is typically considered as a host of arbitrary deposition of
guest particles. In such junction morphology, components could be used with different particles shape,
such as spherical [
111
], cubic [
89
], and irregular non-geometric [
146
148
]. Ding et al. shape-controlled
fabricated Fe
3
O
4
-Ag heterodimers in two formats: randomly decorated Fe
3
O
4
with spherical Ag
nanoparticles and core-shell structures through deliberate changing the concentration of the Ag
precursor [
111
]. Hodges et al. reported the synthesis of Fe
3
O
4
-Ag heterodimers of randomly decorated
and core-shell morphologies. Fe
3
O
4
and Ag particles size and shapes were entirely controlled in
linearly variations at the ranges of 7–24 nm and 3–11 nm, respectively [149].
It was found that different morphologies led to differences in magnetic and biocompatibility
properties with the randomly decorated structures demonstrating enhanced magnetization,
biocompatibility, and specific absorption rate (SAR) in hyperthermia applications [
111
]. Additionally,
different plasmonic features arise from the morphologies changes, so that the localized surface plasmon
resonance (LSPR) peak of random decorated heterodimers shows a blue shift to shorter wavelengths,
while the LSPR peak of core-shell structures is in agreement with that of individual metallic Ag
nanoparticles [150].
Nanomaterials 2019,9, 97 11 of 39
3.2.2. Dumbbell-Like Shape
Fe
3
O
4
-Au heterodimers that were synthesized by Yu et al. in 2005 were introduced as a first
example of dumbbell-like structures [
151
]. In most dumbbell-like heterodimers, magnetic uniaxial
nanorods acted as host for spherical metallic nanoparticles as plasmonic guests that are symmetrically
attached to the host surfaces [
97
,
100
,
152
]. Dumbbell-like heterodimers demonstrated desirable
performances in photo- and bio-catalysis applications due to their higher symmetry and larger
free surface areas when compared to randomly decorated structures [
106
]. Hou’s research group
synthesized FePt-Au heterodimers with random decoration and dumbbell-like morphologies for
biomedical and catalysis applications [
89
,
90
] based on seed mediated technique of non-spherical
magnetic particles [
153
]. In both cases, the plasmonic properties were affected by the interfacial
morphology and their UV-Vis absorption peaks were slightly red-shifted in comparison with Au
nanoparticles [
154
,
155
]. In fact, UV-Vis spectroscopy of individual Au nanoparticles shows a
well-pronounced peak at 520 nm, while for randomly decorated and dumbbell-like heterodimers, it
is shifted to 525 and 528 nm, respectively, owing to electron transfer from the Au surface to the FePt
component [90].
3.2.3. Mosaic
Mosaic structures are normally utilized when heterodimers need to be covered by a shell or put
in a matrix. The main reasons for these designs are improvement of biocompatibility, physicochemical
stability, and advanced functionality. In several reported mosaic heterodimers, silica is considered as
matrix structure, such as FePt-Au@SiO
2
and FePt/Fe
3
O
4
-CdSe@SiO
2
nanohybrids [
14
,
156
]. Sotiriou
et al. fabricated Fe
2
O
3
-Ag heterodimers on SiO
2
mosaic shell to use in magnetic hyperthermia
(Figure 5a) [
17
]. The SAR was appreciably increased for the silica coated structures for all Ag
concentrations (Figure 5b). In addition, an unwanted ferromagnetically blocked fraction was
decreased by the silica shell due to the reduced interactions between the magnetic parts. In
Au(thiol)-Fe
3
O
4
@SiO
2
/PEG heterodimers that were synthesized by Landgraf et al., silica/PEG
possessed not only enhanced biocompatibility and chemical stability, but also improved their efficiency
as MRI contrast agents [
108
]. Moreover, the SiO
2
matrix of designed MnO-Au@SiO
2
heterodimers
for bioimaging led to advances in MRI contrast and fluorescence microscopic cells tracking [
121
].
Recently, Fe
3
O
4
-graphene QD heterodimers with silica mosaic cover were developed with outstanding
magnetic, plasmonic, and biocompatibility properties to utilize in drug delivery, hyperthermia, and
photothermal therapy applications [138].
Further mosaic coatings were employed to support heterodimers. For instance, Giang et al.
synthesized Fe-Au hybrids in a porous Fe
3
O
4
mosaic coating with tunable magnetization and
surface plasmon absorption [
81
]. Additionally, a wide range of biomolecules and polymers could
be performed as a matrix of magnetic-plasmonic structures, which were frequently investigated in
reviews of polymeric coatings [
157
,
158
]. These structures are commonly used as nanocarriers for drug
delivery [95,159].
Nanomaterials 2019,9, 97 12 of 39
Nanomaterials 2019, 9, x FOR PEER REVIEW 11 of 38
fraction was decreased by the silica shell due to the reduced interactions between the magnetic parts.
In Au(thiol)-Fe3O4@SiO2/PEG heterodimers that were synthesized by Landgraf et al., silica/PEG
possessed not only enhanced biocompatibility and chemical stability, but also improved their
efficiency as MRI contrast agents [108]. Moreover, the SiO2 matrix of designed MnO-Au@SiO2
heterodimers for bioimaging led to advances in MRI contrast and fluorescence microscopic cells
tracking [121]. Recently, Fe3O4-graphene QD heterodimers with silica mosaic cover were developed
with outstanding magnetic, plasmonic, and biocompatibility properties to utilize in drug delivery,
hyperthermia, and photothermal therapy applications [138].
Further mosaic coatings were employed to support heterodimers. For instance, Giang et al.
synthesized Fe-Au hybrids in a porous Fe3O4 mosaic coating with tunable magnetization and surface
plasmon absorption [81]. Additionally, a wide range of biomolecules and polymers could be
performed as a matrix of magnetic-plasmonic structures, which were frequently investigated in
reviews of polymeric coatings [157,158]. These structures are commonly used as nanocarriers for drug
delivery [95,159].
Figure 5. SiO2 coated Fe2O3-Ag heterodimers. HRTEM image of heterodimer structure, with 10 wt%
Ag (a) and specific absorption rate (SAR) values of uncoated and SiO2 coated heterodimers with
different Ag concentrations (b). Reproduced with permission from [17], copyright (2013) American
Chemical Society.
3.2.4. Rod-Shape
Specific characteristics of rod-shape structures are a possible reason to outperform spherical
particles. For instance, the shape anisotropy remarkably affected hyperthermia efficiency [160–162].
In 2007, Wetz et al. pioneered rod-shape heterodimers by synthesizing Co-Au structures via
nucleation control of Au upon Co seeds [80]. Yang et al. used the electrospinning-presynthesized
CoFe2O4 nanotubes as host seeds to fabricate rod-shape CoFe2O4-Pd heterodimers for H2O2 detection
[117].
The synthesis of rod-shape Fe3O4-Au heterodimers for bioapplications was reported in several
works [101,163–166]. Fe3O4-Pt heterodimers of rod-shape as well as core-shell morphologies were
fabricated using Pt seeds and they exhibited significantly enhanced plasmonic properties for
photothermal therapy when compared to their single components [167]. In the same direction, the
variation of magnetic and particularly plasmonic features as a function of morphologies was reported
for rod-shape NiPt-CdS structures [168]. However, although the rod-shape heterodimers brought
enormous advantages, they were faced with limitations for in vivo applications, like drug delivery,
because of their problematic targeting and transfer in vessels [95].
3.2.5. Janus Beads
Figure 5.
SiO
2
coated Fe
2
O
3
-Ag heterodimers. HRTEM image of heterodimer structure, with 10 wt%
Ag (
a
) and specific absorption rate (SAR) values of uncoated and SiO
2
coated heterodimers with
different Ag concentrations (
b
). Reproduced with permission from [
17
], copyright (2013) American
Chemical Society.
3.2.4. Rod-Shape
Specific characteristics of rod-shape structures are a possible reason to outperform spherical
particles. For instance, the shape anisotropy remarkably affected hyperthermia efficiency [
160
162
]. In
2007, Wetz et al. pioneered rod-shape heterodimers by synthesizing Co-Au structures via nucleation
control of Au upon Co seeds [
80
]. Yang et al. used the electrospinning-presynthesized CoFe
2
O
4
nanotubes as host seeds to fabricate rod-shape CoFe2O4-Pd heterodimers for H2O2detection [117].
The synthesis of rod-shape Fe
3
O
4
-Au heterodimers for bioapplications was reported in several
works [
101
,
163
166
]. Fe
3
O
4
-Pt heterodimers of rod-shape as well as core-shell morphologies
were fabricated using Pt seeds and they exhibited significantly enhanced plasmonic properties for
photothermal therapy when compared to their single components [
167
]. In the same direction, the
variation of magnetic and particularly plasmonic features as a function of morphologies was reported
for rod-shape NiPt-CdS structures [
168
]. However, although the rod-shape heterodimers brought
enormous advantages, they were faced with limitations for
in vivo
applications, like drug delivery,
because of their problematic targeting and transfer in vessels [95].
3.2.5. Janus Beads
Janus beads are particles consisting of two or more different natures in a unique structure.
Although this definition could be associated to any heterodimers, Janus bead usually refers to
combined particles with different surface characteristics and very similar dimensions and shape.
Nanoparticles with different surface coatings [
169
], adsorption [
170
], electrochemical activity [
171
],
and electrical charge [
172
], as well as amphiphilic surfaces [
173
] were introduced as the most common
categories of Janus beads. Various organic (biomolecules and polymers) and inorganic (oxides and
ceramics) materials could be utilized to form Janus beads [
174
,
175
]. Self-assembly of Fe
3
O
4
-Au Janus
beads improved magnetic, plasmonic, and biocompatibility properties and presented two different
approaches of active and passive drug delivery [
108
,
176
]. Jishkariani et al. reported the fabrication of
Janus hybrids with two opposite surface properties, hydrophobic and hydrophilic, by attaching Au and
Pt nanoparticles on Fe
3
O
4
surfaces using intermediary interactions of polar-/nonpolar-dendrons [
176
].
These beads could be used to carry many types of bioagents, like drugs and antibodies.
Reguera et al. synthesized Fe
3
O
4
-Au Janus heterodimers of star-like morphology [
109
]. The
Fe
3
O
4
nanoparticles were jointed to star-shaped Au seeds without morphology change, so that the
plasmonic properties of Janus beads were noticeably enhanced when compared to randomly decorated
Nanomaterials 2019,9, 97 13 of 39
structures. Recently, Chang et al. designed Janus beads with magnetic-fluorescence sensitivity, while
sensitivity is increased via antibody attaching to the carboxyl-functionalized Fe
3
O
4
-dye heterodimers
for rapid identification of foodborne bacteria [143].
3.2.6. Further Specific Shapes
Although morphology is one of the most important parameters to determine the final features
and performance of heterodimers, most reported works were carried out on common shapes, in
particular, spherical. In recent years, there were a few works on the identification of optimum synthesis
conditions for designing heterodimers with specific morphologies, including star- and flower-like
shapes [
107
]. Zhou et al. synthesized star-like Fe
3
O
4
-Au heterodimers by the use of Fe
3
O
4
seeds
and deposited star-shaped Au nanoparticles through the hydroquinone approach (Figure 6a) [
177
].
Magnetic-plasmonic investigations revealed their improved plasmonic characteristics in comparison
with spherical particles as a significant red-shift in UV-Vis absorption. However, magnetization
of star-shaped heterodimers dramatically dropped (Figure 6b). Moreover, in the case of Fe
3
O
4
-Ag
heterodimers, flower-shaped structures showed the largest magnetic anisotropy and highest blocking
temperature (T
B
) among various morphologies [
178
]. Fantechi et al. elaborately designed flower-like
Fe
3
O
4
-Au heterodimers, which led to substantial changes of magnetic and plasmonic behaviors [
105
].
These structures were assembled using Au seeds and by controlling the [Fe]/[Au] molar ratio, heating
rate, reaction time, and surfactant kinds. In addition, the successful synthesis of flower-shaped
MnO-Au nanohybrids was recently reported [
121
]. In addition, the synthesis of designed heterodimers
with other specific shapes, like nanosandwich, nanodisk, and nanodome were reported. Gonzales-Diaz
et al. synthesized magnetic-plasmonic Au/Co/Au nanosandwiches consisting of sputtered trilayer
films using the colloidal lithography (CL) method [
179
]. The heterodimers simultaneously exhibited
strongly localized surface plasmon resonance, magnetic, and magneto-optical properties. In this case,
the plasmonic nanostructures could be directly controlled by an external magnetic field. Moreover,
Au/Co/Au, Au/SiO
2
/Co/Au, and Au/Co/SiO
2
/Au hybrid structures with nanodisk morphology
were fabricated by Banthi et al. using CL and evaporation methods [
180
]. Electromagnetic field
of magneto-optical components (Co) and non-magneto-optical parts (Au) has been controlled by
adjusting the position of the SiO
2
dielectric layer in the hybrid structures, which lead to providing a
system with enhanced magneto-optical activity and moderate absorption.
Nanomaterials 2019, 9, x FOR PEER REVIEW 13 of 38
oxide contrast agents), and active fluorescent and X-ray contrast for magnetically guided and
amplified photothermal therapies [181]. In addition, this research group presented interesting
thermometry nanotechnology based on Fe (or Co)-Au nanodomes [182]. The temperature variations
during magnetic and optical hyperthermia treatments were detected by viscosity variations around
the nanodomes based on the identification of phase lag between the optical signal and driving
magnetic field. The resolution of temperature detection was around 0.05 °C similar to state-of-the art
luminescent nanothermometers, which were highlighted as a low cost temperature detection system
for biomedical applications [182].
Summary 3. Various morphologies and interface structures in heterodimers can be designed today.
For randomly decorated heterodimers, the synthesis process is usually simpler than that of other
morphologies and their magnetic and plasmonic properties can be more appropriate. Therefore,
randomly decorated heterodimers could be the most enthralling selection for biomedical
applications, particularly in vivo treatments, owing to their significant functionality and
biocompatibility.
Heterodimer structures with non-geometric specific shapes may further improve their performance.
However, this research is still in the beginning, so most of the reported work focused on identification
of fundamental factors in morphology control, which is essential to start with practical studies in the
future.
Figure 6. Fe3O4-Au heterodimers. TEM image of spiky-shaped structure, scale bar: 100 nm (a) and
Variation charts of magnetization and UV-Vis absorption peak position as a function of morphology
(b). Adapted from reference [177].
4. Tailored Properties of Selected Heterodimers
Nowadays, the main motivation of design and synthesis magnetic-plasmonic heterodimer
nanostructures is the improvement in their efficiency for various applications. Nanoparticles features
could be defined as an interface point between the design and final performance of structures. In the
following, the most effective features and how they can be tailored in magnetic-plasmonic
heterodimers are concisely reviewed.
4.1. Magnetic Features
Many applications of magnetic-plasmonic heterodimers are attributed to their magnetic
properties. As stated in Section 2, magnetic applications depend on some key parameters, such as
high susceptibility or saturation magnetization (MS), superparamagnetism connected to vanishing
coercive field (HC) and remanent magnetization (Mr), and suitable anisotropy. Since most of the
plasmonic materials exhibit small magnetic moments due to their paramagnetic or diamagnetic
nature, the net magnetization of heterodimers mostly decreased when compared to the individual
magnetic components. Furthermore, magnetic dipole interactions between magnetic nanoparticles
Figure 6.
Fe
3
O
4
-Au heterodimers. TEM image of spiky-shaped structure, scale bar: 100 nm (
a
) and
Variation charts of magnetization and UV-Vis absorption peak position as a function of morphology
(b). Adapted from reference [177].
Recently, new types of magnetic-plasmonic heterodimer nanostructures, namely Co/Au and
Co/Fe nanodomes, were proposed by Nogues’s research group [
181
]. Fe (or Co)-Au nanodomes
Nanomaterials 2019,9, 97 14 of 39
demonstrated larger photothermal conversion efficiency when compared to pure Au nanodomes
and other reported shapes, like Au nanorods and nanoshells as a result of strong optical absorption,
minimized scattering, and low optical anisotropy. The Fe and Au semishells, respectively, provided a
very intense T
2
contrast in nuclear magnetic resonance (up to 15-fold larger than commercial iron oxide
contrast agents), and active fluorescent and X-ray contrast for magnetically guided and amplified
photothermal therapies [
181
]. In addition, this research group presented interesting thermometry
nanotechnology based on Fe (or Co)-Au nanodomes [
182
]. The temperature variations during
magnetic and optical hyperthermia treatments were detected by viscosity variations around the
nanodomes based on the identification of phase lag between the optical signal and driving magnetic
field. The resolution of temperature detection was around 0.05
C similar to state-of-the art luminescent
nanothermometers, which were highlighted as a low cost temperature detection system for biomedical
applications [182].
Summary 3.
Various morphologies and interface structures in heterodimers can be designed today. For
randomly decorated heterodimers, the synthesis process is usually simpler than that of other morphologies and
their magnetic and plasmonic properties can be more appropriate. Therefore, randomly decorated heterodimers
could be the most enthralling selection for biomedical applications, particularly
in vivo
treatments, owing to
their significant functionality and biocompatibility.
Heterodimer structures with non-geometric specific shapes may further improve their
performance. However, this research is still in the beginning, so most of the reported work focused on
identification of fundamental factors in morphology control, which is essential to start with practical
studies in the future.
4. Tailored Properties of Selected Heterodimers
Nowadays, the main motivation of design and synthesis magnetic-plasmonic heterodimer
nanostructures is the improvement in their efficiency for various applications. Nanoparticles features
could be defined as an interface point between the design and final performance of structures. In the
following, the most effective features and how they can be tailored in magnetic-plasmonic heterodimers
are concisely reviewed.
4.1. Magnetic Features
Many applications of magnetic-plasmonic heterodimers are attributed to their magnetic properties.
As stated in Section 2, magnetic applications depend on some key parameters, such as high
susceptibility or saturation magnetization (M
S
), superparamagnetism connected to vanishing coercive
field (H
C
) and remanent magnetization (M
r
), and suitable anisotropy. Since most of the plasmonic
materials exhibit small magnetic moments due to their paramagnetic or diamagnetic nature, the
net magnetization of heterodimers mostly decreased when compared to the individual magnetic
components. Furthermore, magnetic dipole interactions between magnetic nanoparticles are
attenuated in heterodimers, leading to changes of H
C
, M
r
, and M
S
. In addition, surface effects,
including both structural changes and electronic hybridization effects, can significantly modify the
magnetic moments of the magnetic component and the anisotropy [
183
]. For instance, comparing
FePt-Au heterodimers with FePt particles reveals that blocking temperature of heterodimers (25 K) is
reduced from 40 K to 25 K as a result of anisotropy decrease and surface texture changing [
90
,
184
].
However, it has been shown that, while depending on the surface termination, an increasing anisotropy
of this system is possible [183].
The particles size of plasmonic component could affect the magnetization of structures as well.
Jiang et al. reported that the saturation magnetization of Fe-Au heterodimers increased up to 6 and 12%
as a function of size variations of Au nanoparticles from 4 to 7 and 10 nm, respectively because of the
different surface structures [
81
,
185
]. In addition, the shape of magnetic field dependent magnetization
curves was shown to depend on Au particles, so that the saturation field (H
S
) value of decorated
Nanomaterials 2019,9, 97 15 of 39
structures was extremely enhanced due to surface spin canting. In the case of Fe-Pd heterodimers,
a decrease of M
S
was reported when compared to individual Fe particles [
82
]. Heterodimers that
were composed of nonmetallic plasmonic components, like QDs, revealed more devastating impacts
on magnetic properties. For instance, in FePt-CdS [
123
] and CoFe
2
O
4
-ZnO [
137
] structures, the
magnetization is severely diminished when compared to the one of the bare magnetic constituents.
Ding et al. showed a negligibly reduced magnetization of Fe
3
O
4
-Ag hybrids as compared
to Fe
3
O
4
nanoparticles [
111
]. Furthermore, Jiang et al. reported that the coercivity of Fe
3
O
4
-Ag
heterodimers was identical to that of individual Fe
3
O
4
particles, while hybrids magnetization was
slightly decreased [
186
]. On the other hand, the presence of Ag nanoparticles in MnFe
2
O
4
-Ag structures
led to a strong reduction of magnetization [
94
]. Moreover, the magnetization lowering of Fe
3
O
4
-Au
heterodimers was reported in many works [105,109,143].
In order to investigate the changes in the magnetic properties in more detail, in addition
to common averaging magnetometry methods using vibrating sample magnetometer (VSM) or
superconducting quantum interference device (SQUID), the element-specific magnetization was
studied through advanced techniques, like X-ray magnetic circular dichroism (XMCD). For example,
according to calculated parameters based on magneto-optic sum rules [
187
189
], such as spin, orbital,
and total magnetic moments (m
s
, m
l
, and m
tot
), Fe
3
O
4
-Ag heterodimers have lower values than Fe
3
O
4
nanoparticles, owing to spin injection from Fe
3
O
4
to Au particles and associated spin contribution [
190
].
Frequently, diamagnetic plasmonic compounds, like metallic Au, Ag, and Cu particles and QDs,
showed a weakening of the magnetization of the ferromagnetic/ferrimagnetic parts. However, some
paramagnetic noble metals, like Pd and Pt particles, could prevent the decrease of magnetic properties
and/or even improve them occasionally. Synthesized Fe
3
O
4
-Pd heterodimers by Hyon’s research group
presented significant magnetization that was identical to bare Fe
3
O
4
nanoparticles [
113
]. Moreover,
based on VSM and XMCD results of randomly decorated CoFe
2
O
4
-Pd heterodimers, it was found that
their magnetization was considerably increased in comparison with individual CoFe
2
O
4
nanoparticles
(Figure 7) [
120
]. By element-specific analyses of the magnetic response of XMCD it could be deduced
that the Co
2+
ions in CoFe
2
O
4
play a crucial role in the magnetization enhancement (Figure 8).
Interaction of paramagnetic Pd atoms and magnetic cations of Fe and Co at the interface of CoFe
2
O
4
/Pd
nanoparticles could be introduced as a reason of this increase, which led to improved heterodimers’
efficiency in related applications. In addition, calculated magnetic anisotropy of CoFe
2
O
4
nanoparticles
with different sizes was enhanced up to three times as a result of Pd decoration. This achievement
can be considered as an important step-forward to design the new generations of heterodimers for
magnetic applications.
4.2. Plasmonic Properties
The main aim of heterodimers synthesis is the combination of both plasmonic and magnetic
properties in a single structure. Although noble metals, like Au and Ag, are known as ideal candidates
for plasmonic applications, in the bulk state they show negative effects on magnetization while their
nanometric particles have a higher magnetic susceptibility [
191
,
192
] and more suitable conditions
to combine with magnetic components. Au and Ag have superior plasmonic properties than other
metals, like Pt and Pd. Moreover, magnetic metals, such as Fe, Co, and especially Ni, can also exhibit
some plasmonic properties although are quite dampened when compared to noble metals. Individual
nanoparticles of noble metals, such as Au, Ag, Pt, Pd, and Cu demonstrated appropriate plasmon
absorption intensity with PRA peaks at wavelengths between 300 to 520 nm [
69
]. On the other
hand, the plasmonic properties of most magnetic components, in particular nonmetallic particles, are
insignificant, but heterodimers showed enhanced plasmonic features when compared to individual
noble metals particles: Plasmon absorption intensity of FePt-Au and Fe
3
O
4
-Au heterodimers increased
up to three times in comparison with Au nanoparticles [81,89,90,109,158].
Nanomaterials 2019,9, 97 16 of 39
Nanomaterials 2019, 9, x FOR PEER REVIEW 15 of 38
Figure 7. M-H curves of superparamagnetic CoFe2O4 nanoparticles (CFO, mean hydrodynamic size:
24 nm) and CoFe2O4-Pd (CFO-Pd, mean particles size of Pd: 2 nm) heterodimers measured by
vibrating sample magnetometer (VSM) magnetometry at 300 K.
Figure 8. X-ray absorption near-edge structure (XANES) and magnetic circular dichroism (XMCD) of
bare CoFe2O4 nanoparticles (CFO, black lines) and after Pd decoration (CFO-Pd, red lines).
Measurements were performed at 5 K in a magnetic field of 6 T at the Fe L3,2 absorption edges (a) and
Co L3,2 absorption edges (b).
4.2. Plasmonic Properties
The main aim of heterodimers synthesis is the combination of both plasmonic and magnetic
properties in a single structure. Although noble metals, like Au and Ag, are known as ideal
candidates for plasmonic applications, in the bulk state they show negative effects on magnetization
while their nanometric particles have a higher magnetic susceptibility [191,192] and more suitable
conditions to combine with magnetic components. Au and Ag have superior plasmonic properties
than other metals, like Pt and Pd. Moreover, magnetic metals, such as Fe, Co, and especially Ni, can
also exhibit some plasmonic properties although are quite dampened when compared to noble
metals. Individual nanoparticles of noble metals, such as Au, Ag, Pt, Pd, and Cu demonstrated
appropriate plasmon absorption intensity with PRA peaks at wavelengths between 300 to 520 nm
[69]. On the other hand, the plasmonic properties of most magnetic components, in particular
Figure 7.
M-H curves of superparamagnetic CoFe
2
O
4
nanoparticles (CFO, mean hydrodynamic size:
24 nm) and CoFe
2
O
4
-Pd (CFO-Pd, mean particles size of Pd: 2 nm) heterodimers measured by vibrating
sample magnetometer (VSM) magnetometry at 300 K.
Nanomaterials 2019, 9, x FOR PEER REVIEW 15 of 38
Figure 7. M-H curves of superparamagnetic CoFe2O4 nanoparticles (CFO, mean hydrodynamic size:
24 nm) and CoFe2O4-Pd (CFO-Pd, mean particles size of Pd: 2 nm) heterodimers measured by
vibrating sample magnetometer (VSM) magnetometry at 300 K.
Figure 8. X-ray absorption near-edge structure (XANES) and magnetic circular dichroism (XMCD) of
bare CoFe2O4 nanoparticles (CFO, black lines) and after Pd decoration (CFO-Pd, red lines).
Measurements were performed at 5 K in a magnetic field of 6 T at the Fe L3,2 absorption edges (a) and
Co L3,2 absorption edges (b).
4.2. Plasmonic Properties
The main aim of heterodimers synthesis is the combination of both plasmonic and magnetic
properties in a single structure. Although noble metals, like Au and Ag, are known as ideal
candidates for plasmonic applications, in the bulk state they show negative effects on magnetization
while their nanometric particles have a higher magnetic susceptibility [191,192] and more suitable
conditions to combine with magnetic components. Au and Ag have superior plasmonic properties
than other metals, like Pt and Pd. Moreover, magnetic metals, such as Fe, Co, and especially Ni, can
also exhibit some plasmonic properties although are quite dampened when compared to noble
metals. Individual nanoparticles of noble metals, such as Au, Ag, Pt, Pd, and Cu demonstrated
appropriate plasmon absorption intensity with PRA peaks at wavelengths between 300 to 520 nm
[69]. On the other hand, the plasmonic properties of most magnetic components, in particular
Figure 8.
X-ray absorption near-edge structure (XANES) and magnetic circular dichroism (XMCD)
of bare CoFe
2
O
4
nanoparticles (CFO, black lines) and after Pd decoration (CFO-Pd, red lines).
Measurements were performed at 5 K in a magnetic field of 6 T at the Fe L
3,2
absorption edges
(a) and Co L3,2 absorption edges (b).
The plasmon absorption intensity is considered as one criterion for particles efficiency in related
applications. For instance, in imaging and photothermal therapy applications, higher absorption
intensity results in more efficient contrast and heat generation, respectively. Moreover, in all cases, PRA
peaks were faced to a red-shift so that e.g., the peak of Au nanoparticles was shifted to 524–
600 nm
in heterodimers, while it is usually positioned at a wavelength of 520 nm. In fact, PRA peaks of
uncombined plasmonic particles are commonly positioned at the range of UV and visible light, which
show a minor performance for
in vitro
applications, since the penetration coefficient in this range of
light into tissue is very low and is mostly absorbed in the skin layers (approximate penetration depth
of UV: 30–100
µ
m, visible light: 40–250
µ
m). The red-shift moves PRA to NIR range with enhanced
efficiency due to less absorbance [193195].
Improved plasmonic properties of other noble metals were frequently reported in different
heterodimers, such as Fe-Pt [
85
], Fe
3
O
4
-Ag [
111
,
186
], and Ni-Au [
95
] hybrids. The change of LSPR
intensity and position of heterodimers was referred to electron transport across the interface of magnetic
Nanomaterials 2019,9, 97 17 of 39
and plasmonic particles [
90
,
196
]. Then again, in most reported heterodimers, the LSPR sharpness was
lower than that of single plasmonic components and the associated peaks were broadened and/or
sporadically vanished [
105
,
111
]. A handful works reported the reduction of PRA intensity as well
as blue-shifted positions for heterodimers [
81
,
105
,
186
]. Position (red/blue shift) and amplitude of
localized plasmonic resonance closely depend on surface electronic properties of components, such as
electron density, charge state, and electron exchange across the interface of nanoparticles. Increased
free surface of plasmonic particles and their interface with other phases led to a change of energy
levels, enhanced path range of surface plasmon resonance, and stronger electron exchange and larger
red-shift [
89
]. Accordingly, magnetic-plasmonic heterodimers demonstrated significant red-shift with
respect to pure plasmonic particles. Since the magnetic nanoparticles were the electron deficient
components as compared to plasmonic particles, the combined heterodimers indicated lower surface
plasmon resonance energy and decreased associated amplitude [
89
]. Furthermore, the joined magnetic
nanoparticles could act as scattering centers that changed electronic band-band transition states of
plasmonic structures and reduced resonance energy.
In the UV-Vis spectra of synthesized CoFe
2
O
4
-Pd heterodimers with randomly decorated form,
absorption at all desired wavelengths of UV, visible, and especially NIR light was significantly
enhanced when compared to individual CoFe
2
O
4
nanoparticles, which improved their efficiency
in associated biomedical applications, in particular, photothermal therapy [
120
]. In addition, in
compliance with reported results in literature, there is no highlighted LSPR peak for Pd components in
measured spectra at the NIR wavelengths.
QDs and oxide phases, like ZnO particles, are the other class of plasmonic materials that
are reported. Heterodimers with QDs and oxidic plasmonic materials, like FePt-CdS [
124
],
FePt/Fe
3
O
4
-CdSe [
138
], and CoFe
2
O
4
-ZnO [
137
] structures, typically presented lower PRA intensities
as compared to bare plasmonic particles, although the final properties were sufficient for effective uses.
4.3. Electronic Structure
Magnetic and plasmonic properties of heterodimers can be attributed to the electronic structure
of components. In general, the electronic structure depends on crystalline order, cations distribution,
and oxidation states. These characteristics are commonly analyzed using techniques based on the
X-ray sources such as X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and X-ray
absorption spectroscopy (XAS). In many works, XRD analyses were carried out to identify the phase
and crystal structures of heterodimers components [
197
,
198
]. However, since in most heterodimers
the quantity of guest part is very low (<5%), XRD results are inadequate. There are several reports on
the investigation of structural parameters, like cations oxidation state and crystallite size, by using
Rietveld structure refinement of XRD results [
199
]. For instance, Tremel’s research group analyzed XRD
results of super-lattices of Fe
2
O
3
-Pd heterodimers via Rietveld refinement and found that iron cations
appeared in both states of Fe
2+
and Fe
3+
and their ratio depended on the conditions of palladium
nanoparticles [200].
For an accurate evaluation of chemical composition and electronic states at the surface of
heterodimers, the XPS technique is commonly employed. By the identification of binding energies in
XPS spectra, it was possible e.g., to prove the metallic states of Au in CoFe
2
O
4
-Au nanohybrids [
201
]
or metallic Pd states in Fe3O4-Pd heterodimers [202].
A possibility to probe both electronic structure and crystallographic structure is offered by XAS.
While the X-ray absorption near edge structure (XANES) contains information e.g., about oxidation
state of the absorbing element and hybridization effects, the extended X-ray absorption fine structure
(EXAFS) can be used to analyze distance, number, and type of neighboring atoms, as well as the
coordination symmetry [
203
]. In contrast to diffraction methods, EXAFS analysis can be performed for
both crystalline and amorphous materials.
For instance, Muraca and Siervo confirmed the formation of Ag-Fe
3
O
4
(Ag: host) heterodimers
using XANES measurements at the Fe-K edge [
190
]. Based on XANES and XMCD (Fe-L
3,2
edges), they
Nanomaterials 2019,9, 97 18 of 39
concluded that the Fe
3
O
4
structure was composed of magnetite (Fe
3
O
4
) and maghemite (
γ
-Fe
2
O
3
)
phases. The deviation from ideal Fe
3
O
4
stoichiometry could be reduced by enhancing the Ag
concentration. Furthermore, these analyses could be carried out to study the oxidation catalyst
activity of structures. Najafishirtari et al. investigated the oxidation states of Fe (K edge), Cu (K
edge), and Au (L
3,2
edges) in Fe
3
O
4
-Au/Cu heterodimers and identified the dominant phase types
and electronic structure modes before and after the oxidation process at different temperatures [
204
].
The utilization of XANES measurements to evaluate trends in variation of the oxidation states of
heterodimers as a function of temperature was reported in some other works as well [
205
]. In the
case of FePt-Fe
3
O
4
heterodimers, a change of the Fe oxidation state was confirmed by an energy shift
of XANES at the Fe-K edge towards lower energies with increasing temperature [
206
]. Pinader et
al. evaluated the electrical structure of Fe
3
O
4
-Au heterodimers by the use of XANES and XMCD
(Fe K and Au L
3,2
edges) measurements and realized that the presence of Au nanoparticles led to a
shift of Fe (K edge) spectra towards higher energies as a result of Fe oxidation state variation [
207
].
Moreover, the calculated results based on XANES and XMCD measurements revealed paramagnetic
interactions of Au and magnetic particles, which originated from the diffusion of iron cations into the
Au seeds structure, and the local creation of Au
x
Fe
y
alloys [
207
]. Fe
3
O
4
-Ag heterodimers showed a
similar trend of Fe K edge shifting that was related to different oxidation states because of surface
effects [
178
]. Furthermore, based on the electronic structure investigation of CoFe
2
O
4
-Pd heterodimers
using XANES measurements, we found that Pd decoration remarkably changed electronic structures,
like cations, disordering in crystal structure of CoFe
2
O
4
nanoparticles, which is closely connected
to altered magnetic characteristics [
120
]. Even without further analysis, it can be seen in the spectra
(Figure 8) that there is a small energy shift and changes in the characteristic fine structure, particularly
for the Co ions. To connect the spectral features to changes in the electronic structure, a comparison
to calculated spectra is envisaged. Moreover, electron energy loss spectroscopy (EELS) is a very
useful technique for the elementary identification of electronic structure, composition, and oxidation
state of nanoparticles at atomic scale. For instance, Fantechi et al. investigated the elemental
composition and homogeneity of the two magnetic and plasmonic phases [
105
]. The results confirmed
the homogeneous composition of iron oxide counterpart with no changes in the oxidation state.
Additionally, fine structure analysis of EELS spectra proved the formation of magnetite phase,
Fe
3
O
4
, [
105
]. Torruella et al. reported the three-dimensional (3D) visualization of oxidation state
in several spinel structure core-shell heterodimers, such as FeO, Fe
3
O
4
, and Mn
3
O
4
structures using
EELS measurements [
208
,
209
]. The direct mapping of Mn
2+
, Mn
3+
, Fe
2+
, and Fe
3+
cations distribution
in the core and shell crystalline lattice of nanoparticles was reconstructed in three dimensions with
atomic resolution, which provided significant improvement towards a precise understanding the
correlation of the electronic and functional properties of heterodimers [208,209].
In summary, the combination of components to heterodimers considerably changes various
parameters of the electronic structures, which directly affect other features. Thus, a detailed
investigation of electronic structures can be very helpful. Some characteristics, like cations disordering
and crystallinity, need further, more focused studies.
4.4. Biocompatibility and Physiochemical Stability
In order to successfully utilize various nanomaterials in biomedical applications, physiochemical
stability, in particular, biocompatibility, are essential factors. Biocompatibility of heterodimers should
be in the certain level with minimum side effects and appropriate performance for both
in vitro
and
in vivo
mediums. In hybrid structures, the biocompatibility of both magnetic and plasmonic
components should be considered.
The biocompatibility of nanoparticles was evaluated by using
in vitro
analyses, animal model
testing, and finally clinical trials before the utilization in biomedical applications. Most studies were
carried out through
in vitro
analyses such as cell viability, toxicity, and MTT assays. Noble metals as
an ideal choice for plasmonic part indicated excellent biocompatibility that improved the features of
Nanomaterials 2019,9, 97 19 of 39
combined structures. Particularly, Au and Ag nanoparticles for advanced biocompatibility, anticancer,
and antibacterial properties of magnetic-plasmonic heterodimers were frequently used [
108
,
109
,
111
,
210
212
]. This affirmative role is extra-decisive in the case of more toxic magnetic components, like
CoFe2O4particles. For instance, Kooti et al. found antibacterial as well as enhanced biocompatibility
in CoFe
2
O
4
-Ag hybrids [
115
]. Recently, Chen et al. reported using polymeric coating on Fe
3
O
4
-Au
hybrids to improve the biological stability and loading efficiency of doxorubicin anticancer drug [
109
].
Applying a biocompatible layer on the heterodimers surface is useful to decrease toxicity, although
in most structures, the magnetic and plasmonic properties are dramatically weakened. Schick et al.
controlled the biocompatibility of MnO-Au heterodimers through partially silica coating [121].
Nonmetallic plasmonic materials showed two opposite approaches: While oxide structures like
ZnO nanoparticles had suitable biocompatibility and antibacterial behavior, most QDs, like CdS and
CdSe, were toxic and faced practical limitations [
213
]. Regardless of electronic nature (metal/nonmetal),
magnetic ingredients commonly demonstrated acceptable biocompatibility and some of them, like
Fe3O4nanoparticles, were already approved for biomedical applications [95].
Physicochemical stability is one of the most important characteristics of heterodimers. The
improvement of this factor is more highlighted in metallic-metallic hybrids, since the metallic
magnetic and especially plasmonic particles have a strong tendency to agglomeration because of
some specific physical-chemical properties, like surface to volume ratio [
214
]. Combined structures of
host-guest pattern could increase chemical stability and monodispersity. Physicochemical stability
of nanoparticles does not only prevent phase transformations, but it also assists in the easier control
of magnetic and particularly plasmonic features. Chemically stable noble metals could be used to
protect magnetic particles from oxidation and changes of their electronic states, which instantly affect
practical properties [
85
]. Table 1indicates the effectiveness trends of different heterodimers on the
biocompatibility and magnetic-plasmonic characteristics.
Table 1.
Efficacies of different heterodimers on magnetic-plasmonic characteristics like saturation
magnetization M
S
, remanent magnetization M
r
, magnetic coercivity field H
C
, effective anisotropy
constant K, blocking temperature T
B
, electro-magnetic absorption amplitude as well as shift of localized
surface plasmon resonance (LSPR) peak and biocompatibility.
Composition Magnetic Characteristics Plasmonic Characteristics Biocompatib. Ref.
MSMrHCK TBAbs. ampl. LSPR Shift
FePt-Au n/a n/a n/a n/a n/a + Red n/a [89]
FePt-Au - - = - - + Red n/a [90]
FePt-CdS - n/a n/a n/a n/a - Red n/a [123]
Fe-Au - = - = = n/a n/a - Red n/a [81]
Fe-Pd - n/a n/a n/a n/a + Red n/a [82]
Ni-Au n/a n/a n/a n/a n/a + n/a n/a [83]
Fe3O4-Au n/a n/a n/a n/a n/a + Red n/a [81]
Fe3O4-Au - - - n/a n/a - Red n/a [105]
Fe3O4-Au - n/a n/a n/a n/a + n/a + [158]
Fe3O4-Au - n/a n/a n/a + + Red + [109]
Fe3O4-Ag - = n/a n/a n/a n/a + Red + [111]
Fe3O4-Ag - = - = = n/a n/a + Blue + [186]
Fe2O3-Ag n/a n/a n/a n/a n/a + Red + [190]
MnFe2O4-Ag - - - n/a n/a n/a n/a n/a [94]
CoFe2O4-Ag - - - n/a n/a n/a n/a + [115]
CoFe2O4-ZnO - - - n/a n/a - Red n/a [137]
Fe3O4-Pd = = = n/a n/a n/a n/a n/a [113]
Fe3O4-antibody dye = n/a n/a n/a n/a + Red + [143]
Fe3O4-GQDs@SiO2- n/a n/a n/a n/a + n/a + [138]
FePt/Fe
3
O
4
-CdSe/SiO
2- - n/a n/a n/a - Red n/a [156]
MnO-Au - - - n/a n/a n/a n/a n/a [121]
Abbreviations: (+): increase (-): decrease (- =): slight decrease (=): no change, and (n/a): not available.
Summary 4.
The combination of magnetic and plasmonic nanoparticles to heterodimer structures significantly
affects magnetic and plasmonic properties as well as biocompatibility and physicochemical stability and can be
used to tailor the characteristics for various applications. The electronic structure has turned out to play a key
role in understanding the physics behind.
Nanomaterials 2019,9, 97 20 of 39
5. Improved Performances
The combination of magnetic and plasmonic components does not only present various properties
in a single structure, but also causes to emerge new applications. The performances of heterodimers
in above-mentioned applications depend on structure nature, surface modifications, and particles
size and morphology, so that some ideal choices could be introduced for each application. Selected
examples of heterodimers used in specific applications are reviewed in the following.
5.1. Magnetic Hyperthermia
Although the utilization of magnetic-plasmonic heterodimers in hyperthermia is relatively new, it
has been reported in several works [
215
218
]. Fe
3
O
4
and other biocompatible ferrites nanoparticles
turned out to be perfect candidates for hyperthermia applications [
219
,
220
]. However, their insufficient
heat transferring coefficients decreased the efficiency of the treatment. Accordingly, the positive role
of noble metals in hybrid structures was reported to enhance cancerous cells thermosensitivity and
death under
in vitro
and
in vivo
hyperthermia treatments [
221
,
222
]. As mentioned in Section 4.1, most
para-/diamagnetic noble metals reduced the saturation magnetization and magnetic susceptibility,
but their significant effects on the heat transferring could ameliorate the hyperthermia efficiency
in total. Gu’s research group recently studied the magnetic hyperthermia behavior of Fe
3
O
4
-Ag
heterodimers for
in vitro
and
in vivo
models [
111
]. Hyperthermia treatments prevented the rapid
growth of SMMC-7721 tumor volume in mice samples and the prevention efficiency of heterodimers
was much higher than that of pure Fe
3
O
4
nanoparticles. In fact, hyperthermia treatments by using
heterodimers led to a full stop of the tumor growth over a seven-day period (Figure 9a). In addition,
the histopathology results of samples proofed the excellent efficiency of heterodimers hyperthermia,
which revealed massive necrosis and fibrosis symptoms of cancerous tissues (Figure 9b). TUNEL assay
results demonstrated well the apoptosis of cancerous cells (brown cells) in the heterodimers sample.
In another work, the hyperthermia performance of Fe
3
O
4
-graphene QDs heterodimers was studied
by Yao et al. [
138
]. Those heterodimers generated sufficient magnetic heating under the applied AC
magnetic field to increase
in vitro
death of 4T1 cancerous cells when compared to control samples
(Figure 9c).
Moreover, we observed that synthesized CoFe
2
O
4
-Pd heterodimers with different fluid
concentrations and particles sizes generated more heat than individual CoFe
2
O
4
nanoparticles
in an applied AC magnetic field, which led to enhanced efficiency in magnetic hyperthermia
applications [
120
]. In addition, calculated SAR values for ferrofluids with the same volume and
concentration increased from 38 W/g
tot
for CoFe
2
O
4
nanoparticles (with mean hydrodynamic diameter
of 24 nm) to 50 W/g
tot
for CoFe
2
O
4
-Pd heterodimers as a result of magnetic anisotropy enhancement
of heterodimer structures.
In addition to common intra-tumor magnetic hyperthermia, intra-cellular treatments have
attracted much attention in recent years. Intra-cellular hyperthermia demonstrated an effective
therapeutic process through selective penetration into the cancerous cells and lethal heat generation
from inside the cell [
223
,
224
]. Fortin et al. investigated the performance of different iron oxide
phases, like maghemite (
γ
-Fe
2
O
3
) and cobalt ferrite (CoFe
2
O
4
), as nanoheaters for intra-cellular
hyperthermia in human prostatic adenocarcinoma cells (PC3) [
225
]. They found that the magnetic
heating efficiency at an intra-cellular scale is lower than in solution for samples with the same magnetic
elements concentrations, because the dominant heating mechanism of intra-cellular hyperthermia
was Neél relaxation, while the Brownian relaxation mechanism was suppressed in intra-cellular
models due to the immobilization of nanoparticles [
66
]. Moreover, Di Corato et al. employed different
types of magnetic nanomaterials, such as maghemite (nanospheres, nanocubes, and nanoflowers),
liposomal encapsulated maghemite, cobalt ferrite, and
γ
-Fe
2
O
3
-Au heterodimers to investigate
magnetic hyperthermia efficiency in the cellular environment [
226
]. The achieved results confirmed the
complete inhibition of the Brownian loss mechanism in cellular conditions [226]. Ota et al. evaluated
the performance of Fe
3
O
4
nanoparticles in intra-cellular hyperthermia by employing three formats of
Nanomaterials 2019,9, 97 21 of 39
aqueous solution, epoxy mounted, and cellular samples under AC magnetic field using a theoretical
model of measured AC hysteresis loops [
227
]. They reported that, in the cellular conditions, the
dipole-dipole and particle-cell interactions inhibited the magnetic moments and particles rotations,
respectively, yielding lower heat dissipation in the cellular environment as compared to solution and
mounted samples [227].
Nanomaterials 2019, 9, x FOR PEER REVIEW 21 of 38
Figure 9. Therapeutic effects of heterodimers during magnetic hyperthermia in vivo antitumor effect
of subcutaneous SMMC-7721 tumor in mice after seven-day treatment period by Fe3O4-Ag
heterodimers (a). Data taken from reference [111]. Histological analysis of mouse organs and tumor
on the seven-day after treatments for (I): Fe3O4 nanoparticles without ACMF (II): Fe3O4-Ag
heterodimers without ACMF (III): Fe3O4 nanoparticles with ACMF, and (IV): Fe3O4-Ag heterodimers
with ACMF (b). Reproduced with permission from [111], copyright (2017) Elsevier. Cell viability of
the 4T1 cells after treatments by Fe3O4-GQD heterodimers (c). Data taken from reference [142].
5.2. Photothermal Therapy
As an advanced mode of active photodynamic treatment, photothermal therapy was applied to
obliterate tumor cells through locally generated heat by plasmonic nanoparticles upon irradiation
with photons of certain wavelength and energy [69,228]. Noble metals are the main class of plasmonic
materials, which locally generate heat that is based on SPR phenomenon activated by UV, visible,
and NIR waves. Heterodimers composed of Au nanoparticles were most frequently used to rise
temperature up to around 43 °C and destroy cancerous cells under NIR radiation [229,230]. In
addition to common Au and Ag nanoparticles, the use of Pt, Pd, and Cu metallic particles in PTT
applications was reported [231–233]. For example, Ding et al. realized the enhanced heating efficiency
of Fe3O4-Pt heterodimers during simultaneous PTT and radiation therapy processes [167].
As mentioned in Section 4.2, some of the premier advantages of heterodimers when compared
to individual plasmonic components are the red-shift of LSPR peaks as well as increased photon
energy absorption and localized heating. When considering the safety and suitable penetration ability
Figure 9.
Therapeutic effects of heterodimers during magnetic hyperthermia
in vivo
antitumor effect of
subcutaneous SMMC-7721 tumor in mice after seven-day treatment period by Fe
3
O
4
-Ag heterodimers
(
a
). Data taken from reference [
111
]. Histological analysis of mouse organs and tumor on the seven-day
after treatments for (I): Fe
3
O
4
nanoparticles without ACMF (II): Fe
3
O
4
-Ag heterodimers without ACMF
(III): Fe
3
O
4
nanoparticles with ACMF, and (IV): Fe
3
O
4
-Ag heterodimers with ACMF (
b
). Reproduced
with permission from [
111
], copyright (2017) Elsevier. Cell viability of the 4T1 cells after treatments by
Fe3O4-GQD heterodimers (c). Data taken from reference [142].
5.2. Photothermal Therapy
As an advanced mode of active photodynamic treatment, photothermal therapy was applied to
obliterate tumor cells through locally generated heat by plasmonic nanoparticles upon irradiation
with photons of certain wavelength and energy [
69
,
228
]. Noble metals are the main class of plasmonic
materials, which locally generate heat that is based on SPR phenomenon activated by UV, visible,
and NIR waves. Heterodimers composed of Au nanoparticles were most frequently used to rise
Nanomaterials 2019,9, 97 22 of 39
temperature up to around 43
C and destroy cancerous cells under NIR radiation [
229
,
230
]. In addition
to common Au and Ag nanoparticles, the use of Pt, Pd, and Cu metallic particles in PTT applications
was reported [
231
233
]. For example, Ding et al. realized the enhanced heating efficiency of Fe
3
O
4
-Pt
heterodimers during simultaneous PTT and radiation therapy processes [167].
As mentioned in Section 4.2, some of the premier advantages of heterodimers when compared to
individual plasmonic components are the red-shift of LSPR peaks as well as increased photon energy
absorption and localized heating. When considering the safety and suitable penetration ability of NIR
beam, the most practical uses of plasmonic nanoparticles for photothermal therapy were carried out at
NIR range. The first and second absorption windows of NIR laser were determined at wavelengths of
800–820 nm and 1450–1470 nm, respectively, which considerably activated photothermal heating [
143
].
In photothermal therapy, NIR biological windows refer to two regions of wavelengths with maximum
penetration depth in tissue, which are located between 650–950 nm (first window), with the optimal
value at about 808 nm and 1000–1350 nm (second window), and with an optimal value at about 1064
nm [
234
,
235
]. The limits for these NIR biological windows are mainly determined by the absorption
coefficients of blood and water. In detail, NIR photons are absorbed by two hemoglobin types of blood
at short wavelengths (410–600 nm), i.e., before the first window, as well as by the water components of
human tissue at long wavelengths. The NIR transparency at wavelengths in the biological windows
originates from both low absorption and low scattering [
234
]. The latter is the main interaction between
light and tissue in the biological windows.
Although some noble metals, like Pd particles, present no LSPR peaks in these ranges, they were
efficiently utilized for photothermal therapy under NIR radiation with a wavelength of 808 nm, owing
to the absorption enhancement of heterodimers [
236
]. The temperature of nanoparticles increased
from an ambient level (25
C) to the therapeutic temperature of cancerous cells (43
C) in an acceptable
time period (300 s). A desirable rate of temperature rising under NIR radiation with a wavelength of
808 nm was reported for Fe
3
O
4
-Au and Fe
3
O
4
-graphene QDs heterodimers (Figure 10a,b) [
142
,
158
].
Furthermore,
in vitro
analyses illustrated the destruction of 4T1 cancerous cells up to 70% under NIR
irradiation for three minutes, which confirmed the promising performance of magnetic-plasmonic
heterodimers in photothermal therapy applications (Figure 10c) [142].
Nanomaterials 2019, 9, x FOR PEER REVIEW 22 of 38
of NIR beam, the most practical uses of plasmonic nanoparticles for photothermal therapy were
carried out at NIR range. The first and second absorption windows of NIR laser were determined at
wavelengths of 800–820 nm and 1450–1470 nm, respectively, which considerably activated
photothermal heating [143]. In photothermal therapy, NIR biological windows refer to two regions
of wavelengths with maximum penetration depth in tissue, which are located between 650–950 nm
(first window), with the optimal value at about 808 nm and 1000–1350 nm (second window), and
with an optimal value at about 1064 nm [234,235]. The limits for these NIR biological windows are
mainly determined by the absorption coefficients of blood and water. In detail, NIR photons are
absorbed by two hemoglobin types of blood at short wavelengths (410–600 nm), i.e., before the first
window, as well as by the water components of human tissue at long wavelengths. The NIR
transparency at wavelengths in the biological windows originates from both low absorption and low
scattering [234]. The latter is the main interaction between light and tissue in the biological windows.
Although some noble metals, like Pd particles, present no LSPR peaks in these ranges, they were
efficiently utilized for photothermal therapy under NIR radiation with a wavelength of 808 nm,
owing to the absorption enhancement of heterodimers [236]. The temperature of nanoparticles
increased from an ambient level (25 °C) to the therapeutic temperature of cancerous cells (43 °C) in
an acceptable time period (300 s). A desirable rate of temperature rising under NIR radiation with a
wavelength of 808 nm was reported for Fe3O4-Au and Fe3O4-graphene QDs heterodimers (Figure
10a,b) [142,158]. Furthermore, in vitro analyses illustrated the destruction of 4T1 cancerous cells up
to 70% under NIR irradiation for three minutes, which confirmed the promising performance of
magnetic-plasmonic heterodimers in photothermal therapy applications (Figure 10c) [142].
Most of the studies carried out on the field of magnetic-plasmonic heterodimers focused on the
separate investigation of magnetic and optical hyperthermia treatments, but recently some works
introduced the amplification effects of heating efficiency under simultaneously applied AC magnetic
fields and NIR lasers. For instance, Espinosa et al. reported that iron oxide nanocubes exposure to
both AC magnetic field and NIR laser irradiation (808 nm) demonstrated a 2- to 5-fold enhancement
in heating efficiency when compared to individual magnetic stimulation [237]. In addition, they
found that in solid tumors in vivo, separate single treatments (magnetic hyperthermia or laser
irradiation) reduced tumor growth while simultaneous processes led to complete tumor regression
[237]. In another work, Das et al. synthesized Fe3O4-Ag heterodimer nanoflowers with boosted SAR
value more than one order of magnitude under a simultaneously applied AC magnetic field and NIR
laser irradiation for synergistic magnetic and photothermal therapies [238]. Recently, Ovejero et al.
presented considerable enhancement in the treatment effectiveness of iron oxide-Au nanorods
excited by infrared beam and alternating magnetic field [239].
Figure 10. Therapeutic photothermal effects of heterodimers. Photothermal heating of Fe3O4-Au
heterodimers with different Au concentrations under 808 nm near infra-red (NIR) radiation for 300 s
(a). Data taken from reference [158]. Photothermal heating of Fe3O4-GQD heterodimers under 808 nm
NIR radiation for 300 s (b). Data taken from reference [142]. Cell viability of the 4T1 cells with
treatment by Fe3O4-GQD heterodimers under NIR radiation for 3 min (c). Data taken from reference
[142].
Figure 10.
Therapeutic photothermal effects of heterodimers. Photothermal heating of Fe
3
O
4
-Au
heterodimers with different Au concentrations under 808 nm near infra-red (NIR) radiation for 300 s (
a
).
Data taken from reference [
158
]. Photothermal heating of Fe
3
O
4
-GQD heterodimers under 808 nm NIR
radiation for 300 s (
b
). Data taken from reference [
142
]. Cell viability of the 4T1 cells with treatment by
Fe3O4-GQD heterodimers under NIR radiation for 3 min (c). Data taken from reference [142].
Most of the studies carried out on the field of magnetic-plasmonic heterodimers focused on the
separate investigation of magnetic and optical hyperthermia treatments, but recently some works
introduced the amplification effects of heating efficiency under simultaneously applied AC magnetic
fields and NIR lasers. For instance, Espinosa et al. reported that iron oxide nanocubes exposure to
both AC magnetic field and NIR laser irradiation (808 nm) demonstrated a 2- to 5-fold enhancement in
heating efficiency when compared to individual magnetic stimulation [
237
]. In addition, they found
Nanomaterials 2019,9, 97 23 of 39
that in solid tumors
in vivo
, separate single treatments (magnetic hyperthermia or laser irradiation)
reduced tumor growth while simultaneous processes led to complete tumor regression [
237
]. In
another work, Das et al. synthesized Fe
3
O
4
-Ag heterodimer nanoflowers with boosted SAR value
more than one order of magnitude under a simultaneously applied AC magnetic field and NIR
laser irradiation for synergistic magnetic and photothermal therapies [
238
]. Recently, Ovejero et al.
presented considerable enhancement in the treatment effectiveness of iron oxide-Au nanorods excited
by infrared beam and alternating magnetic field [239].
5.3. Bioimaging
Nowadays, bioimaging and biosensing play critical roles in diagnosis, so that without these tools,
diagnostic and therapeutic processes of many diseases are completely disturbed. These techniques
could be applied for both
in vitro
and
in vivo
applications. While biosensing was mostly used
in vitro
,
bioimaging methods were very helpful for
in vivo
cases. Biosensing focused on monitoring of biologic
agents, toxic compounds, drugs, and therapeutic substances [
240
]. Since biosensing that is typically
based on measurements of colorimetry, plasmon resonance, UV-Vis absorption, fluorescence emission,
and solution phase dielectric constant, the noble metals were introduced as the ideal choices for
this aim and Au-containing compounds were the most common biosensing structures [
241
243
].
Moreover, Fe
3
O
4
-Ag [
186
], FePt/Fe
3
O
4
-CdSe [
156
], and Fe
3
O
4
-ZnS [
244
] heterodimers were employed
for biosensing uses. Demeritte et al. successfully designed Fe
3
O
4
-Au/graphene nanohybrids as a
platform of Alzheimer diagnosis biomarkers [212].
The efficiency of most imaging techniques, such as MRI, CT, PET, ultrasonic (US), and NIR
optical imaging (OI), is affected by magnetic and/or plasmonic properties of nanomaterials as contrast
agents [
245
]. Landgraf et al. investigated the performance of Fe
3
O
4
-Au heterodimers as contrast agents
in animal models MRI applications and confirmed their excellent effectiveness (Figure 11a) [
108
]. In
addition, Reguera et al. realized the simultaneous improvement of MRI, CT, and PA techniques by
using Fe3O4-Au contrast agents (Figure 11b) [109].
One of the most promising imaging modalities is the magnetic particle imaging (MPI), which can
be used for diagnosis and therapeutic applications, such as cardiac imaging, solid tumors screening
imaging, and cell tracking. More details about this technique can be found in the work of Gleich and
Weizenecker [
246
], who introduced the first concept of MPI for obtaining high-resolution images by
tracing the signal from magnetic nanoparticles in oscillating magnetic fields applied. While in MRI,
the influence of magnetic contrast agents on the relaxation of surrounding tissue is analyzed; MPI
directly maps the 3D distribution of the magnetic component. MPI can be as widely employed as MRI,
even with less side effects. Main advantages of MPI are high resolution (around 0.5 mm), high contrast,
no radiation, no iodination, and fast imaging process [
247
]. Goodwill et al. presented safe medical
MPI for chronic kidney disease (CKD) patients using superparamagnetic iron oxide nanoparticles
(SPIONs) tracers [
247
]. The used nanoparticles revealed significantly enhanced contrast, sensitivity,
and resolution of imaging (up to 250
µ
m), in comparison with X-ray and CT iodinated angiography,
particularly for CKD patients. Arami et al. conjugated two different types of poly-ethylene-glycol to
monodisperse carboxylated iron oxide nanoparticles labeled with near infrared fluorescent molecule
for
in vitro
and
in vivo
MPI applications [
248
]. They confirmed the tracers’ biodistribution in liver
and spleen by MPI signals and found that the signals intensity of MPI tracers in the blood strongly
depended on their plasmatic clearance pharmacokinetics [
248
]. In another work, Ota et al. comprised
the performance of magnetic nanoparticles as a blood-pooling agent and commercial tracer agent
for MPI applications and found that particles size, structure, and distribution were the most efficient
parameters on the harmonic intensity of MPI signals [
249
]. Recently, Song et al. presented interesting
results about the tailoring of Janus nanoparticles that are composed of iron oxide and semiconducting
polymer phases for MPI and fluorescence imaging [
250
]. The utilized heterodimers introduced the
MPI signal intensity up to three times of commercial MPI contrast (Vivotrax) and seven times of MRI
contrast (Feraheme) for the same iron concentration [250].
Nanomaterials 2019,9, 97 24 of 39
As a result, MPI techniques were presented as a new promising imaging modality for a wide
range of future biomedical.
Nanomaterials 2019, 9, x FOR PEER REVIEW 24 of 38
[72]. For instance, Fe3O4-graphene QDs heterodimers as the nanocarriers of anti-cancer doxorubicin
molecules led to an enhanced drug release of up to 30% in comparison with EPR mechanism [142].
Moreover, noble metals, especially Au nanoparticles, were considered as stable nanocarriers due
to their significant surface functionability [251]. In addition, these particles could activate thermal-
and photo-releasing mechanisms through exposure to electromagnetic radiations for therapeutic
applications, like cancer and HIV treatments [252,253]. In fact, these structures acted as NIR-sensitive
platforms, while the surface bonding was loosed under irradiation and causes drug release with
acceptable rate [254,255].
Summary 5. Tailored magnetic-plasmonic heterodimers can be employed e.g., for hyperthermia with
enhanced efficiency, as consummate contrast agents for multimodal imaging and show considerable
performance in drug delivery uses.
Figure 11. Performance of heterodimers in bioimaging applications. MRI images of the mouse tissues
24 h after injection of Fe3O4 and Fe3O4-Au contrast agents from two sections, (I) first section scan of
ling (yellow), muscle (blue), and heart (red), (II) sectional plane (white stripe in (I)) of liver (purple)
and spleen (green). Reproduced with permission from [108], copyright (2015) Elsevier (a), Multimodal
imaging with contrast agents of Fe3O4-Au heterodimers with different concentrations for (I): MRI, (II):
CT, and (III): PA techniques (b). Reproduced with permission from [109], copyright (2017) Royal
Society of Chemistry.
6. Conclusions and Future Perspective
Figure 11.
Performance of heterodimers in bioimaging applications. MRI images of the mouse tissues
24 h after injection of Fe
3
O
4
and Fe
3
O
4
-Au contrast agents from two sections, (
I
) first section scan of
ling (yellow), muscle (blue), and heart (red), (
II
) sectional plane (white stripe in (
I
)) of liver (purple)
and spleen (green). Reproduced with permission from [
108
], copyright (2015) Elsevier (
a
), Multimodal
imaging with contrast agents of Fe
3
O
4
-Au heterodimers with different concentrations for (I): MRI,
(II): CT, and (III): PA techniques (
b
). Reproduced with permission from [
109
], copyright (2017) Royal
Society of Chemistry.
5.4. Drug Delivery
As a one of new pharmaceutical approaches, drug delivery increases drug effectiveness on its
targeted organ with minimal side effects. Currently, EPR is the most common delivery mechanism. It
is confronted with some disadvantages, such as insufficient rate of drug delivery and release [
159
].
Heterodimer structures could be potentially used to overcome these inadequacies. Magnetic targeting
and thermal-releasing of therapeutic agents were activated through magnetic components [
72
]. For
instance, Fe
3
O
4
-graphene QDs heterodimers as the nanocarriers of anti-cancer doxorubicin molecules
led to an enhanced drug release of up to 30% in comparison with EPR mechanism [142].
Nanomaterials 2019,9, 97 25 of 39
Moreover, noble metals, especially Au nanoparticles, were considered as stable nanocarriers due
to their significant surface functionability [
251
]. In addition, these particles could activate thermal-
and photo-releasing mechanisms through exposure to electromagnetic radiations for therapeutic
applications, like cancer and HIV treatments [
252
,
253
]. In fact, these structures acted as NIR-sensitive
platforms, while the surface bonding was loosed under irradiation and causes drug release with
acceptable rate [254,255].
Summary 5.
Tailored magnetic-plasmonic heterodimers can be employed e.g., for hyperthermia with enhanced
efficiency, as consummate contrast agents for multimodal imaging and show considerable performance in drug
delivery uses.
6. Conclusions and Future Perspective
This review aimed to briefly present fascinating recent achievements in the area of
magnetic-plasmonic heterodimer nanostructures for biomedical diagnosis and treatments focusing on
the less-known characteristics of these nanoparticles, including type and interfacial morphology of
designed structures, specific features, and emerging applications. Various heterodimers composed
of plasmonic components of noble metals and quantum dots and magnetic ingredients, like metallic
superparamagnetic nanoparticles and ferrite compounds, have been increasingly employed for many
biomedical applications, such as magnetic hyperthermia, photothermal therapy, bioimaging, and drug
delivery. The main benefit of heterodimers is the synergistic gain of magnetic and plasmonic properties
in unique structures with mostly enhanced performance when compared to individual components.
Despite many reported works on the magnetic and plasmonic features of heterodimers, a lack of
certain fundamental investigations of their mutual correlations has been identified. In order to design
new heterostructures with optimum performance, the electronic structure should be investigated in
more detail, since it is probably the most important property defining the mutual influence of the two
constituents by electronic hybridization effects and exchange interactions. For experimental works,
element-specific methods, like x-ray absorption spectroscopy, seem to be a powerful method to monitor
even subtle changes.
To identify novel promising candidates and understand the mutual correlations in more detail,
theoretical support is crucial. Substantial improvements in supercomputer architecture and code
development over the last decade point towards a feasible treatment of nanoscale metal/oxide
interfaces and surfaces. For the known biocompatible heterodimers also exhibiting significantly
enhanced physiochemical stability, further
in vivo
studies are needed to make use of the synergistic
features of heterodimers in biomedical theranostics in the future.
In conclusion, the first steps in the development of heterodimers, as a new generation of
multipurpose nanomaterials, have already been made. For a successful continuation of this promising
research field and establishing this class of materials in applications, interdisciplinary cooperation
is vital including e.g., chemistry, material sciences, theoretical and experimental physics, biology,
and medicine.
Author Contributions:
Conceptualization & Design, S.F.S.; Methodology, S.F.S.; Writing—Original Draft
Preparation, S.F.S., M.R.G.; Writing—Review & Editing, S.F.S., M.R.G., and C.S.-A.; Supervision, C.S.-A.; Project
Administration, S.F.S. and C.S.-A.; All authors read, discussed, commented, and approved the final manuscript.
Funding: Parts of this research were funded by the Helmholtz Association, grant number VH-NG-1031.
Acknowledgments:
For fruitful collaboration, we thank Detlef Schmitz (Helmholtz-Zentrum Berlin (HZB))
and Alevtina Smekhova (FZ Jülich). Konrad Siemensmeyer (HZB) is gratefully acknowledged for help in
magnetometry experiments and Eugen Weschke, Enrico Schierle, Florin Radu, Hanjo Ryll, and Chen Luo (HZB) for
kind support during beamtimes. For further experimental support that helped us to synthesize the nanoparticles,
structurally characterize the CoFe
2
O
4
and CoFe
2
O
4
-Pd samples in more detail, measure SAR performance and
UV-Vis spectroscopy, we thank Katherine Ann Mazzio (EM-ISPEK, HZB), Amir Hossein Tavabi and Rafal E.
Dunin-Borkowski (Ernst Ruska-Centre and FZ Jülich), Gil Westmeyer and Susanne Pettinger (Helmholtz Zentrum
München), Beatrix-Kamelia Seidlhofer and Anna-Marie Runge (HZB). Also we thank Mehrdad Kashefi (Ferdowsi
University of Mashhad) for initiating work on heterodimer structures and continuous support. We thank HZB
Nanomaterials 2019,9, 97 26 of 39
and the Max Plank Society for the allocation of access to the Energy Materials In-Situ Laboratory (EMIL) facilities.
We thank HZB for the allocation of synchrotron radiation beamtime.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
CKD Chronic kidney disease
CL Colloidal lithography
CT Computed tomography
EELS Electron energy loss spectroscopy
EPR Enhanced permeability and retention
EXAFS Extended X-ray absorption fine structure
FDA US food and drug administration
HCMagnetic coercivity
HIV Human immunodeficiency virus/AIDS
HRTEM High resolution transmission electron microscopy
K Magnetic anisotropy
LSPR Localized surface plasmon resonance
MrRemanent magnetization
MSSaturation magnetization
MFH Magnetic fluid hyperthermia
MRI Magnetic resonance imaging
MPI Magnetic particle imaging
NIR Near infrared
NPs Nanoparticles
OI Near infrared optical imaging
OM Optical microscopy
PA Photoacoustic imaging
PEG Polyethylene glycol
PET Positron emission tomography
PTT Photothermal therapy
PVP Polyvinylpyrolidone
QDs Quantum dots
SAR Specific absorption rate
SPA Surface plasmon absorption
SPIONs Superparamagnetic iron oxide nanoparticles
SQUID Superconducting quantum interference device
TBBlocking temperature
TEM Transmission electron microscopy
TUNEL Terminal deoxynucleotidyl transferase dUTP nick end labeling
US Ultrasonic
UV Ultraviolet
UV-Vis Ultraviolet-visible
VSM Vibrating sample magnetometer
XANES X-ray absorption near edge structure
XAS X-ray absorption spectroscopy
XMCD X-ray magnetic circular dichroism
XPS X-ray photoelectron spectroscopy
XRD X-ray diffraction
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