Review
pubs.acs.org/ac
Magnetoplasmonic Nanomaterials for Biosensing/Imaging and in
Vitro/in Vivo Biousability
Van Tan Tran, Jeonghyo Kim, Lemma Teshome Tufa, Sangjin Oh, Junyoung Kwon, and Jaebeom Lee*
■
Department of Cogno-Mechatronics Engineering, Pusan National University, Busan, 609-735 Republic of Korea
CONTENTS
Magneto-Optical Biosensors
Magneto-Optical Surface Plasmon Resonance
Magneto-Optical Antennas
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
Magneto-Electrochemical Sensors
Magnetic Field in Electrochemistry
Downloaded via ROBERT GORDON UNIV on January 29, 2023 at 19:12:24 (UTC).
Magnetoplasmonic-Based Electrochemical Bio-
sensors
Colorimetric Sensors
Enzyme-Based Biosensors
Non-Enzyme-Based Sensors
In Vitro/in Vivo Biousability and Bioimaging
Applications
Magnetoplasmonic Therapeutics
Multimodal Imaging
Conclusions and Perspectives
Author Information
Corresponding Author
ORCID
Notes
Biographies
Acknowledgments
References
M ost commonly, magnetoplasmonic nanoparticles (Mag-
Plas NPs) are unique composites combining magnetic
and plasmonic materials within a confined nanoscale area that
simultaneously show magnetic and plasmonic characteristics.
They generally use Fe, Co, or Ni-based magnetic materials and
noble-metal (e.g., Au, Ag, Cu, or Pt) plasmonic components,
comprising a precious metal layer along a magnetic core or the
inverse structure. MagPlas NPs are emerging multifunctional
materials in the fields of nanoscale optoelectronics, anisotropic
optics, electronics, optical sensing, and imaging. Their potential
for sensing, targeting, and multimodal imaging is highly
attractive for nanomedicine and nanobiotechnology. Because
they possess suitable biocompatibility,1 MagPlas NPs have also
been used in biosensor systems, hyperthermia,2 and magnetic
resonance imaging (MRI)3 applications. In addition, many
researchers study MagPlas nanomaterials because no other
technology can precisely control the locations of nanoscale
materials at designated positions, except for magnetic NPs
using external magnetic fields. In order to easily produce
metamaterial films and novel self-assembled structures, acute
control via dynamic external magnetic forces has recently
emerged with the assistance of substrate−particle interactions
and van der Waals forces.4
Various MagPlas nanomaterials, i.e., core@shell, dimer,
cluster, alloy, have been developed using different synthesis
© 2017 American Chemical Society
and fabrication techniques including coprecipitation, thermal
decomposition, hydro/solvothermal, microemulsion, lithogra-
226
phy, and so on.5,6 Strategies of improving both sensitivity and
226
selectivity for biosensors using these multifunctional MagPlas
228
nanomaterials are attractive and have received considerable
228
attention. The magneto-optical (MO) activity of MagPlas
228
nanostructures has been shown to be greatly enhanced by
plasmon resonance effect.7 Chau et al. demonstrated that
230
231
modulation of particle transparency is largely dependent on
231 magnetic field in Co/Au core/shell microparticles due to spin-
231 dependent interface effects.8 The 3d transition ferromagnetic
metals, such as Co, Fe and Ni, and ferrimagnetic metals and
233 their alloys can also develop MO activity.9,10 Novel magneto-
233 optical surface plasmon resonance (MOSPR) sensors using a
234 new type of transducer was demonstrated to yield improved
236 sensitivity to refractive index changes of up to 2 orders of
236 magnitude, compared to classical SPR assays.11 Furthermore,
236 localized surface plasmon resonance (LSPR)-based technolo-
236 gies for label-free single-molecular detection are particularly
236 attractive for biomedical applications.12−14 Recently, magneto-
236 plasmonic effects in nanostructures that support LSPR have
237 attracted intensive study.15,16
237 Regarding to electrochemical biosensing, the MagPlas NPs
serving as active elements for the self-assembly, concentration,
separation, and capture of analytes have been developed for
enhancing the analytical detection. New concepts of electro-
chemical biosensors using MagPlas NPs have been reported
during past few years, including integrated magneto-electro-
chemical sensor and electro-chemiluminescence (ECL) bio-
sensor.17,18
MagPlas NPs-integrated colorimetric biosensors also have
enormous potentials for the simple and cost-effective in vitro
diagnostic test platform. Magnetic and intrinsic enzyme-like
activity of Fe-based NPs is highly attractive properties, which
can be utilized for simple and robust biosensing strategies with
the naked-eye detection or quantified by and inexpensive
devices. Employing the novelty of MagPlas nanomaterials, our
group has recently demonstrated novel magnetophoretic-based
sensing strategies for rapid, ultrasensitive and early detection of
Mycobacterium tuberculosis (TB) using gold NPs (as reporter)
and magnetic particles (as separator).19,20
Many studies using MagPlas nanomaterials and assembled
structures thereof have focused on biomedical applica-
tions.21−26 Tomitaka et al. presented the contribution of
magnetic core/Au shell MagPlas NPs to concentration-
Special Issue: Fundamental and Applied Reviews in Analytical
Chemistry 2018
Published: October 31, 2017
225 DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry Review

Figure 1. (a, left) Schematic of the employed MagPlas multilayer transducer in transversal configuration, (a, right) schematic of MOSPR system. (b)
Specific MOSPR (black, Au−Co alloy) and SPR (for Au chip, red) responses for several injections of Anti-HIgG. The difference between washing
levels for each concentration in the two cases (MOSPR and SPR) are marked with dotted lines. Reprinted from Biosens. Bioelectron., Vol. 63, David,
S.; Polonschii, C.; Luculescu, C.; Gheorghiu, M.; Gáspár, S.; Gheorghiu, E. Magneto-plasmonic biosensor with enhanced analytical response and
stability, pp. 525−532 (ref 37). Copyright 2015, with permission from Elsevier. (c) Schematic of the detection of CFP-10 on the SPR chip surface
based on MagPlas particle signal enhancement. (d) SPR signals amplification with three kinds of MagPlas NPs, spherical (black line), short spiky
(red line), long spiky (blue line) at CFP-10 concentration of 100 ng mL−1 and (e) SPR angle shifts using spherical MagPlas NPs with variable
concentration of CFP-10. Reprinted from Sens. Actuators B Chem., Vol. 250, Zou, F.; Wang, X.; Qi, F.; Koh, K.; Lee, J.; Zhou, H.; Chen, H. Magneto-
plamonic nanoparticles enhanced surface plasmon resonance TB sensor based on recombinant gold binding antibody, pp. 356−363 (ref 46).
Copyright 2017, with permission from Elsevier.

dependent contrast in MRI and X-ray computed tomography

(CT).27 Chen et al. synthesized γ-Fe2O3/Au core/shell NPs
and subsequently used them in a high-Tc superconducting
quantum interference device (SQUID) system. They found
that both the proton spin−lattice relaxation time (T1) and
proton spin−spin relaxation time (T2) were influenced by the
presence of the γ-Fe2O3/Au core/shell NPs.28 Seo et al. utilized
MagPlas NPs for targeting proteins with high spatiotemporal
resolution, investigating their utility in the cell-surface activation
of the Notch and E-cadherin mechanoreceptors.29 A trans-
migration study of MagPlas NPs using an in vitro blood−brain
barrier model demonstrated enhanced transmigration efficiency
without disruption of the integrity of the blood−brain barrier,
showing potential applicability to brain diseases and neuro-
logical disorders.27 The magnetic activity of MagPlas NPs can
improve the delivery of therapeutic agents to specific locations.
Furthermore, magnetic NPs can induce heat for hyperthermia
based on hysteresis loss and relaxation losses under applied
alternating magnetic fields. The increase in temperature of the
magnetic NPs can be controlled by changing the strength and
frequency of the alternating magnetic field.
Previously, we reviewed the developments of different
approaches to integrate magnetic and plasmonic properties in
a single NP with different morphological traits.30 This review
focuses on research published in the past few years,
encompassing MagPlas-based magneto-optical biosensors,
electrochemical sensors, and colorimetric sensors as well as
therapeutic and multimodal bioimaging applications of MagPlas
nanomaterials. Because of the explosion of scholarly articles in
this active field, we have certainly missed many important
contributions during the last 3 years, and we sincerely apologize
to the authors for their important work that is unintentionally
left out.
226
■ MAGNETO-OPTICAL BIOSENSORS
Magneto-Optical Surface Plasmon Resonance. Among
typical magnetic sensors such as fluxgate sensors, magneto-
resistors, Hall-effect sensors, resonance magnetometers,
SQUID, and spin valve-based sensors, magneto-optical (MO)
sensors based on the Faraday and Kerr effects have recently
attracted increasing interest. The Faraday and Kerr effects
describe the rotation of the polarization plane of linearly
polarized light when passed through or reflected from a
magnetized medium, respectively. MO sensors provide the
opportunity to combine the advantages of optical methods (i.e.,
contact-free analysis, wide dynamic range, and no electrical
connections) with those of magnetic methods, thus easing
restrictions on the overall sensor setup. Recently, the use of
optical resonances of noble metal nanostructures has been
explored for enhancing MO phenomena.15,31,32
When metals with plasmonic properties are merged with MO
sensors, unique physical properties can arise from plasmonic
enhancement and electromagnetic correspondence with a
magnetic field. Multilayered ferromagnetic/noble-metal struc-
tures called MagPlas modulations have been observed to exhibit
Kerr rotation enhancement due to the thin-film surface
plasmon resonance (SPR) of the noble metal.33−39 This
modulation arises from the simultaneous excitation of MO
effects and SPR in structures with both plasmonic and MO
activity. In the MOSPR approach, the modulation of the
reflectivity (i.e., SPR) curve is accomplished by applying an
alternating transverse magnetic field, perpendicular to the
propagation plane of a p-polarized beam of light incident via a
prism coupler, onto a sensor chip exhibiting both magnetic and
plasmonic properties (Figure 1a). When SPR is achieved in
MOSPR transducers, large enhancements of transverse MO
Kerr effects are produced. These effects depend strongly on the
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry Review

Figure 2. (a) Scanning electron microscopy image of the Ni ruler with 30 nm gap size and (b) spectra of the Kerr polarization rotation angle for the
MagPlas rulers with different gap sizes. Inset: the magnified view. (c, left axis) Mean Kerr rotation angle per 10 nm for the ruler configuration in
panel a and (c, right axis) the corresponding figure-of-merit. Reproduced from Zubritskaya, I.; Lodewijks, K.; Maccaferri, N. Ç .; Mekonnen, A.;
Dumas, R. K.; Åkerman, J.; Vavassori, P.; Dmitriev, A. Nano Lett., 2015, 15, 3204−3211 (ref 47). Copyright 2015 American Chemical Society. (d)
Simultaneous excitation of LPR and MO-LPR induces an elliptical polarization ε of the transmitted and reflected field Et, (e) plot of the inverse of
transmitted and reflected light ellipticity λε as a function of molecular layer deposition cycles. The horizontal and vertical error bars indicate the
standard deviation of the average thicknesses and the experimental error in the magneto-optical measurements, respectively. The insets show the
corresponding 1/|Δε| spectra for reflection measurement, top-left inset, and transmission measurement, bottom-right inset. Reprinted by permission
from Macmillan Publishers Ltd.: NATURE, Maccaferri, N.; Gregorczyk, K.; De Maccaferri, T. V.; Kataja, M.; Van Dijken, S.; Pirzadeh, Z.; Dmitriev,
A.; Åkerman, J.; Knez, M.; Vavassori, P. Nat. Commun. 2015, 6, 6150 (ref 16). Copyright 2015.

excitation conditions of the surface plasmon polariton (SPP)
mode and, hence, on the refractive index of the dielectric
material in contact with the metal layer. This is the basis of the
sensing principle for novel MOSPR devices.40−42 The MOSPR
response measured at a single angle of incidence provides
sensitivity improved by up to 2 orders of magnitude to changes
in the refractive index, compared to that of classical SPR assays,
as substantiated by both theoretical and experimental studies.11
In a typical multilayered MOSPR system, the thin
ferromagnetic layers embedded in metallic matrix to form the
magneto-plasmonic composite can both enable high MO
activity and support the propagation of surface plasmon
modes. Manera et al. compared the sensing performances of
traditional SPR and MOSPR transducing techniques and found
that modifications in the structure and roughness of the chip to
deepen the SPR dip and reduce its width could further improve
the precision and sensitivity of MOSPR assays. MOSPR
evolved from the traditional SPR platform intended to
modulate surface plasmon waves by applying external magnetic
fields in the transverse configuration. When the plasmon
resonance is excited in these structures, the external magnetic
field induces a modification of the coupling of the incident light
with the SPP. In addition, these structures can show enhanced
MO activity when the SPP is excited. This phenomenon has
been exploited to demonstrate the possibility of using enhanced
MO signals as proper transducer signals for investigating liquid-
phase biomolecular interactions.43
In a further development, David et al. used the optimized
MOSPR structure in an angle-resolved MOSPR bioassay and
experimentally confirmed both increased sensitivity compared
to those of current SPR/MOSPR approaches and higher
227
stability, similar to that achieved with classic Au-only SPR chips,
in liquid saline samples.37 The MOSPR chip show good
stability in buffer and regeneration solutions after antihuman
immunoglobulin G (Anti-HIgG) with concentrations ranging
from 5 to 80 nM is injected consecutively onto the sensor’s
surface. The improvement of the signal-to-noise (SNR) for the
Au−Co alloy-based MOSPR assay as compared to the Au-
based classic SPR assays (Figure 1b) is evaluated by comparing
the limit of detection (calculated as three times the standard
deviation of blank) which is approximately 0.60 and 0.96 nM
for the MOSPR and SPR assays, respectively, representing a
160% improvement in the sensitivity of MOSPR over that of
SPR assays. In another study, Manera et al. investigated
different aspects of Au/Co/Au multilayers related to the
optimization of MOSPR transducers.33 The optimized
sensitivity depended on the total thickness of the full multilayer,
the Co layer thickness, the Co position within the film, and the
discrepancy between the optical constants of very thin layers
and bulk materials. They found that surface sensitivity could be
maximized with respect to variations in the bulk properties of
the measuring fluid, thereby ensuring improved performance
relative to those of traditional SPR biosensors.
In addition to ferromagnetic multilayer-enhanced SPR,
MagPlas NPs have been employed to enhance signals in SPR
spectroscopy to examine the interactions of MagPlas NPs with
Au film SPR. Wang et al. prepared Fe3O4−Au nanocomposites
by coating magnetic Fe3O4 NPs with Au shells and investigated
their effects on SPR sensitivity.44 The Fe3O4−Au nano-
composites had diameters ranging from 8 to 30 nm and were
functionalized with goat antihuman immunoglobulin M (IgM)
for SPR sensing of human IgM molecules. A wide detected
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry
concentration range of 0.30−20 mg mL−1 was achieved for the
target human IgM molecules using this SPR biosensor based on
20 nm Fe3O4−Au nanocomposites. However, a narrower
concentration range of 1.25−20 mg mL−1 was obtained in the
absence of the nanocomposites.45 Recently, Zou et al. studied
the effects of MagPlas NPs with three different morphologies
(spheres, short spikes, and long spikes) comprising Fe3O4@Au
on the sensitivity enhancement of an SPR immunosensor. A
sandwich SPR immunosensor was constructed by immobilizing
Au-binding anti-CFP-10 (Ab1) onto an Au chip surface via
Au−S bond. Au-binding anti-CFP-10 (Ab2) captured on
MagPlas NPs surface was utilized to amplify the SPR signals
(Figure 1c). Compared to the spiky MagPlas NPs, the spherical
MagPlas NPs, which concentrated the electric charge density
and thereby immobilized more Abs on its surface, significantly
enhanced the electronic coupling effect (Figure 1d). The
increase in SPR angle was proportional to CFP-10 concen-
tration in the range of 0.1−100 ng mL−1 with the detection
limit is 0.1 ng mL−1 (Figure 1e). The implementation of
MagPlas NPs caused a 30-fold enlargement of the SPR signal at
the limit of detection. To this end, an immunoassay was
performed to couple the specificity of antibody−antigen
interactions with the high sensitivity of spherical MagPlas NP
signal-enhanced SPR.46
Magneto-Optical Antennas. Magnetoplasmonic effects in
nanostructures that support localized surface plasmons have
recently attracted attention. These nanostructures are com-
posed of bare-metallic and hybrid-metallic magnetic materials
distributed on planar substrates. Such structures exhibit novel
properties arising from the modulation of the optical response
to an external low-intensity magnetic field.15,47−52 The unique
properties of these nanostructures can be used to control and
manipulate light at the nanoscale. In addition, the planar
distributions of the MagPlas nanoantennas make them an
effective choice for chip-based sensors.
Zubritskaya et al. reported a magnetic field-activated
plasmonic ruler via Kerr polarization rotation. (Figure 2a−
c).47 A plasmonic ruler consisting of Ni disc MagPlas
nanoantennas is shown in Figure 2a. The Kerr rotation angle
spectrum of the most sensitive ruler configuration is shown in
Figure 2b for gap distances from 10 to 40 nm. The capability of
this ruler to resolve the gap size is better seen in the inset in
Figure 2b, which shows the magnified 625−635 nm spectral
range available in the most common single-wavelength MO
Kerr-effect (MOKE) setups. The advantage of the MagPlas
ruler over its nonmagnetic counterpart is summarized in Figure
2c, the left axis of which demonstrates the comparison of the
most sensitive ruler configuration to the mean Kerr rotation
angle per 10 nm of nanogap distance. High absolute rotation
per distance and minimized error in the mean rotation variation
are achievable in the 10−30 nm and 10−40 nm nanogap
ranges. This implies that the MagPlas ruler can measure both
small and large distances with the same precision, which is
difficult to achieve with nonmagnetic plasmon rulers. More-
over, the figure-of-merit (FOM), which is defined as the ratio
between sensitivity and the width of the resonance peak, of the
MagPlas ruler is ∼50 times larger than that of the nonmagnetic
plasmon rulers (∼0.62, marked with the horizontal dotted line).
By analogy with SPR-based sensors, substituting non-
magnetic nanoantennas with MagPlas ones could further
improve the sensitivity. This concept was demonstrated by
using MagPlas nanoantennas consisting of Ni discs fabricated
on a glass substrate (Figure 2d,e).16 In contrast to conventional
228
Review
nanoantenna-based sensors, the Ni nanoantennas were
designed to produce exact phase compensation in the electric
field component of otherwise elliptically polarized transmitted
light at a specific wavelength λϵ. Importantly, changes in light
polarization can be measured with high precision. Thus, the
determination of λϵ provides a phase-sensitive detection of the
plasmon resonance of the MagPlas nanoantenna. Molecular-
level detection experiments were demonstrated by polarization
ellipticity measurements of polyamide 6.6 deposition on Ni
nanonatenna-based sensors. Detection of λε with ∼0.5 nm
precision was reported without the application of any fitting
procedure (Figure 2e). They found the minimum detectable
range reduces to 0.1 ML in reflection geometry, which is
corresponding to ∼3 300 and 2 200 polyamide 6.6 molecules
per disk. A raw limit of detection of a few zeptograms per
nanoantenna can be achieved when considering advanced
polarimeters with submicro-radiant resolution. Through this
research, they emphasize that the ultrasensitive sensing
capabilities of their MagPlas nanoantennas could be highly
promising for label-free biosensing applications such as cancer
serum detection. In another study, Feng et al. demonstrated a
strategy to maximize the electromagnetic field in specific
regions by placing a MO-active component composed of
ferromagnetic metals; significant enhancement of MO activity
was reported.53 Various complex structures of split ring
resonator with Co inclusions inserted under the gap were
fabricated and studied. Enhanced MO activity by a factor of 3 of
the MagPlas ring was achieved with respect to the equivalent
ring by optimizing the split ring gap opening.
The novel idea of active enhancement and tunability of MO
activity using an external magnetic field was described based on
the excitation of Fano lattice surface modes in photonic crystals
of MagPlas nanoantennas.54,55 Their study exhibited that the
excitation of Fano lattice surface modes in elliptical Ni
nanoantennas array is governed by the individual antenna
polarizability, the relative position between LSPRs in the
individual antennas and diffraction edges caused by the
periodicity of the crystal lattice. The excitation of the magnetic
field-induced Fano lattice surface modes provided strong
enhancement and tunability of MO activity with respect to
those from continuous films or aperiodic noninteracting
MagPlas nanoantennas. The unique features of the MagPlas
nanoantenna crystal such as spectral selectivity and tunability as
well as MO enhancement has direct practical implications
including further improvement of the detection limits in label-
free phase-sensitive biosensing systems.
■
MAGNETO-ELECTROCHEMICAL SENSORS
Magnetic Field in Electrochemistry. Magneto-electro-
chemistry, or study of magnetic effects in electrochemistry, has
rapidly developed in the recent years. In particular, the
characterization of NPs using electrochemistry is emerging as
a necessary nanotechnology. For example, no technique was
available previously that could differentiate among intact,
broken, or cracked shells on MagPlas core−shell NPs. A
simple comparison of the charge measured during the stripping
of the core material before and after the removal of the shell
enables a determination of the quality of the shells and an
estimate of their thicknesses.56 Ngamchuea et al. reported the
effects of the magnetic field on mass transport by running
chronoamperometric measurements for 10 s in the presence
and absence of an external NdFeB permanent magnet (Figure
3a).57 For electrodes modified with Fe3O4 NPs, the mass
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry Review

Figure 3. (a) Chronoamperograms of (i) 9.5 mM [Fe(CN)6]4− (aq) solution, (ii) 9.5 mM [Fe(CN)6]3− (aq) solution in the presence of a magnet
(red) and in the absence of a magnet (black). Reproduced from Ngamchuea, K.; Tschulik, K.; Compton, R. G. Nano Res., 2015, 8, 3293−3306 (ref
57). Copyright 2015 Tsinghua University Press and Springer-Verlag Berlin Heidelberg. (b) (i) Electrochemical cell illustration. The cell was built in
a NMR tube of 5 mm diameter (ii) NMR spectra acquired under the following ex situ (black line, B = 0 T) and in situ (red line, B = 14 T)
conditions: 30° pulse, 64 scans, relaxation delay (d1) of 2 s and 25 °C. Spectra were recorded after chronoamperometric measurements (30 min, 600
mV (vs Ag/AgCl pseudo-RE)), (a) ex situ and (b) in situ. Reproduced from Gomes, B. F.; da Silva, P. F.; Lobo, C. M. S.; da Silva Santos, M.;
Colnago, L. A. Anal. Chim. Acta, 2017, 983, 91−95 (ref 58). Copyright 2017 Elsevier B.V. (c) (i) Sensor schematic. The sensor can simultaneously
measure signals from eight electrodes. Small cylindrical magnets are located below the electrodes to concentrate immunomagnetically captured
exosomes. (ii) Circuit diagram. The sensor system has eight potentiostats, an 8-to-1 multiplexer, an analog-to-digital converter (ADC), a digital-to-
analog converter (DAC), and a microcontroller unit (MCU). Each potentiostat has three electrodes: reference (R), counter (C), and working (W).
(iii) Packaged device. The device has a small form factor (9 × 6 × 2 cm3). (iv) Schematic of iMEX assay. Exosomes are captured on magnetic beads
directly in plasma and labeled with HRP. Reproduced from Jeong, S.; Park, J.; Pathania, D.; Castro, C. M.; Weissleder, R.; Lee, H. ACS Nano, 2016,
10, 1802−1809 (ref 60). Copyright 2016 American Chemical Society.

transport-controlled currents and total charges measured via
chronoamperometry for the [Fe(CN)6]3−/4− redox couple were
larger than those for bare electrodes or electrodes modified
with diamagnetic NPs. For bare glassy carbon electrodes and
glassy carbon electrodes modified with Ag NPs and Au NPs,
the current and charge enhancement were no greater than
approximately 2% for both the oxidation of [Fe(CN)6]4− and
the reduction of [Fe(CN)6]3−, whereas an enhancement of
approximately 8% was observed for the Fe3O4-modified glassy
229
carbon electrode. This arose from Lorentz forces and large
magnetic gradient forces formed by the high magnetic gradients
created at magnetic Fe3O4 NPs by the external NdFeB magnet.
Gomes et al. demonstrated the effect of the magnetic field
strength of a nuclear magnetic resonance (NMR) spectrometer
on electrochemical reactions.58 The reduction process of a
diamagnetic material was monitored in situ in a 600-MHz (14-
T) NMR spectrometer. The magnetic force of the NMR
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry Review

Figure 4. (a) (i) Schematic of DNA immobilization processes on aligned MagPlas nanochains, (a) (ii) optical microscopy image of the nanochains
on the electrode, and (a) (iii) sensing responses of electrode toward DNA functionalization and hybridization. Reprinted from Sens. Actuator B-
Chem., Vol. 203, Tran, V. T.; Zhou, H.; Kim, S.; Lee, J.; Kim, J.; Zou, F.; Kim, J.; Park, J. Y.; Lee, J. Self-assembled Magplas nanochain for DNA
sensing, pp. 817−823 (ref 64). Copyright 2014, with permission from Elsevier. (b) Schematic of the preparation process of BGNs/Fe3O4@luminol-
AuNPs nanocomposites and the fabrication of the ECL sensor. Reproduced from Gu, W.; Deng, X.; Gu, X.; Jia, X.; Lou, B.; Zhang, X.; Li, J.; Wang,
E. Anal. Chem., 2015, 87, 1876−1881 (ref 18). Copyright 2015 American Chemical Society.

spectrometer increased electrochemical reduction rate of
benzoquinone by a factor of 5 (Figure 3b).
In addition to magnetohydrodynamic effects in enhancing
analyte mass transport to the electrode surface, the magnetic
gradient force can be used to manipulate the attraction of
magnetic NPs conjugated biomolecules to the surface of
electrodes. In magnetobiosensors, the magnetic beads are
attached onto the surface of the working electrode for
electrochemical measurement by using an external magnetic
field. Magnetobiosensors offer great advantages in preconcen-
tration of target analyte on the surface of magnetic beads while
the external magnet allows separation of the magnet bead−
analyte complex from the matrix of the sample, benefits in
selectivity of the assay.59 An integrated magneto-electro-
chemical sensor was developed for exosome analysis,60 in
which the sensor combined the two orthogonal modalities of
magnetic selection and electrochemical detection, as shown in
Figure 3c. The magnetic beads are used for exosome capture
and labeling; the captured exosomes are the detected by
electrochemical methods. This bead-based magnetic enrich-
ment assisted in enhancing the detection sensitivity, with
reliable and simplified conjugation chemistry and recovery of
the bead-bound vesicles.
Magnetoplasmonic-Based Electrochemical Biosen-
sors. In recent decades, extensive research has been performed
to develop electrochemical biosensors for diagnosis of disease
with better sensitivity, selectivity, reliability, ease of fabrication
and use, and cost. The performance of biosensors is known to
depend greatly on their ability to immobilize biomolecules. The
ability of MagPlas NPs to provide stable immobilization of
biomolecules while retaining bioactivity is highly advantageous
for biosensor preparation.61 Furthermore, MagPlas NPs permit
direct electron transfer between redox proteins and bulk
electrode materials, thus allowing electrochemical sensing to be
performed without electron transfer mediators.62 Other
characteristics of MagPlas NPs, such as high surface-to-volume
ratio, high surface energies, ability to decrease protein−metal
particle distance, and the ability to function as electron-
conducting pathways between prosthetic groups and the
electrode surface have served to facilitate electron transfer
between redox proteins and electrode surfaces.
230
Among a variety of MagPlas NPs, Fe3O4@Au NPs are widely
used in immunoassay, combine the excellent properties of
Fe3O4 and Au NPs. The higher surface surface-to-volume ratio
and high surface energy of magnetic NPs along with the growth
of Au NPs around a magnetic core allows easy immobilization
of biological molecules through several binding strategies,
enabling the achievement of optimum loading to enhance
sensitivity of the electrochemical bioassay.17,63 As an example,
Tran et al. reported an electrical biosensor based on MagPlas
nanochains of Fe3O4@Au NPs for rapid and label-free
detection of DNA (Figure 4a).64 Superparamagnetic Fe3O4@
Au NPs were synthesized in an aqueous solution by a simple
one-step reaction. Subsequently, MagPlas nanochains, of
magnetic controlable dimensions were formed on a micro-
electrode through the magnetic field-induced alignment of
Fe3O4@Au NPs. The electrical properties of the as-prepared
MagPlas nanochains were poor because of quantum effect and
cavities inside the MagPlas nanochains. Accordingly, annealing
was performed to improve the electrical properties of the
MagPlas nanochains. The annealed MagPlas NCs prepared on
the microelectrodes were used as transducers for electrical
DNA detection. Probe DNA was immobilized onto the
MagPlas nanochains followed by the hybridization of
complementary target DNA. A significant increase in resistance
was detected by hybridization at a reasonably low concentration
of the target DNA. The results showed the potential of these
sensors for the detection of pathogens and human genetic
disorders as well as for environmental monitoring.
Gu et al. presented an ultrasensitive electrochemilumines-
cence (ECL) biosensor platform for label-free determination of
HeLa (human cervical carcinoma cell) cells using a multifunc-
tional nanocomposite, by combining the branched poly-
(ethylenimine) functionalized grapheme/iron oxide hybrids
(BGNs/Fe3O 4) and highly luminescent luminol-AuNPs
(Figure 4b).18 Branched poly-(ethylenimine) functionalized
grapheme/Fe3O4 hybrids acts as a nanocarrier to load highly
luminescent luminol-AuNPs efficiently, while the magnetic
Fe3O4 NPs controlled via an external magnetic field to fabricate
the solid-state ECL sensor easily. This magnetically controlled
ECL biosensor platform was able to detect the concentration of
HeLa cell as low as 8 cells/mL with a linear range from 20 to 1
× 104 cells/mL.
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry Review

Figure 5. (a) Nanozyme-based LFA strips for Ebola detection that employing Fe3O4 NPs as peroxidase mimic. Reprinted from Biosens. Bioelectron.,
Vol. 74, Duan, D.; Fan, K.; Zhang, D.; Tan, S.; Liang, M.; Liu, Y.; Zhang, J.; Zhang, P.; Liu, W.; Qiu, X. Nanozyme-strip for rapid local diagnosis of
Ebola, pp. 134−141. (ref 67). Copyright 2015, with permission from Elsevier. (b) Magnetophoretic chromatography for the detection of Salmonella
bacteria and the light absorption intensities depending on bacteria concentration. Reproduced from Kwon, D.; Joo, J.; Lee, J.; Park, K. H.; Jeon, S.
Anal. Chem. 2013, 85, 7594−7598 (ref 73). Copyright 2013 American Chemical Society. (c) Quantitative detection of hCG using Fe3O4−Pt core−
shell nanozyme-based LFIA strips. Reproduced from Kim, M. S., Kweon, S. H., Cho, S., An, S. S. A., Kim, M. I., Doh, J., Lee, J. ACS Appl. Mater.
Interfaces 2017, 9, 35133−35140 (ref 75). Copyright 2017 American Chemical Society.

■ COLORIMETRIC SENSORS
Enzyme-Based Biosensors. Artificial enzymes are a
fascinating aspect of biomimetic chemistry. Many inorganic
nanomaterial-based artificial enzymes, or nanozymes, have been
reported recently. Inorganic nanomaterials offer significant
potential as alternatives to natural enzymes because they are
highly stable and robust, with large surface areas and sizes. After
the reports by Yan’s and Wang’s groups, nanozymes have been
widely used for detecting targets including immune proteins,
nucleic acids, metal ions, aptamers, cancer cells, and even
bacteria.65,66
In particular, Fe-based magnetic NPs have exhibited the dual
functionality of magnetism and enzyme-like activities; they can
directly replace peroxidase/catalase in enzyme-linked immuno-
sorbent assay (ELISA) and other colorimetric bioassays, while
providing a method for the rapid separation and enrichment of
target molecules, which improve the sensitivity and efficiency of
the bioassays. Recently, a nanozyme-based lateral flow assay
(LFA) strip was developed by Duan et al.; it showed sensitivity
100 times higher than that of conventional Au NP strips used
to detect the Ebola virus. (Figure 5a).67 Bacteria and cancer
cells have also been detected using magnetic nanozyme-based
assays; Wen et al. reported the sensitive detection of Shewanella
oneidensis (a facultative anaerobic bacterium) in river water68
and Zhang et al. demonstrated the detection of Listeria
monocytogenes (L. monocytogenes) in food.69
Although these works have demonstrated that Fe 3O4
nanozyme-based immunoassay showing improved sensitivity
and specificity by integrating with magnetic enrichment, the
catalytic activity of iron oxide NPs are relatively lower than
other peroxidase mimics. The catalytic activity could be further
enhanced by coassembly with other nanomaterials, particularly
plasmonic materials like Au, Ag, and Pt, which are promising
doping elements because they have superior catalytic activity.
The noble metal-Fe3O4 heterogeneous NPs showed increased
catalytic activity compared to bare metal or Fe3O4 NPs,
231
explained by the polarization effect and synergistic effects
between the two materials.70 To enhance peroxidase-like
activity for use in glucose detection, a novel method for
synthesizing tailor-made folic acid (FA)−cysteine (Cys)-
conjugated Au-coated magnetite NPs (Fe3O4@Au−Cys−FA)
was reported.71 The proposed Fe3O4@Au−Cys−FA possessed
a high affinity toward both H2O2 and 2,20-azino-bis(3-
ethylbenzothiazoline)-6-sulfonic acid (ABTS), which is attrib-
uted to the surface modification of Fe3O4 with FA and Cys. The
designed colorimetric method provided a linear dynamic range
for glucose detection from 10 μM to 1 mM (r2 = 0.998) and a
detection limit of 3.8 μM (3 SDblank/slope) with good
reproducibility and reusablility for six or more cycles.72 Kwon
et al. developed a facile and sensitive analytical method using
Au/Pt-coated magnetic NP clusters and magnetophoretic
chromatography with a precision pipet; it enables the detection
of pathogenic bacteria with the naked eye (Figure 5b).73,74
Antibody-conjugated magnetic clusters can be used to capture
Salmonella bacteria in milk and then separated from the milk
under an external magnetic field. More recently, Lee group
developed a point-of-care (POC) LFA strip for hCG
monitoring, Fe3O4−Pt core−shell NPs incorporated into the
conventional LFA strips as highly active and magnetically
separable probe (Figure 5c).75 They showed limit of detection
(LOD) of magnetic-Pt nanozyme-based LFA were approx-
imately 100-fold and 10-fold lower than that of conventional Au
NPs-based LFA and their previously developed Pt-based LFA.
Non-Enzyme-Based Sensors. Hybridization of MagPlas
nanostructures offers many possibilities for the colorimetric
detection of biomolecules. These include optical monitoring of
the particles while controlling their motions magnetophoreti-
cally through the application of an external field gradient. In
these systems, plasmonic NPs served as optical transducers and
magnetic NPs served as magnetic separators. In the presence of
target marker, two NPs hybridized as a sandwich-structured
nanocomposite can be rapidly separated by external magnetic
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry Review

Figure 6. (a) Schematic illustrations of the plastic chip based magnetophoretic assay for detection of TB biomarkers. Reproduced from Kim, J.; Jang,
M.; Lee, K. G.; Lee, K. S.; Lee, S. J.; Ro, K. W.; Kang, I. S.; Jeong, B. D.; Park, T. J.; Kim, H. J; Lee, J. ACS Appl. Mater. Interfaces 2016, 8, 23489−
23497 (ref 19). Copyright 2016 American Chemical Society. (b) Reflection spectra and digital photographs (inset) of the as-obtained free-standing
thermochromic photonic crystal film at different temperatures. Reproduced from Ma, H.; Zhu, M.; Luo, W.; Li, W.; Fang, K.; Mou, F.; Guan, J. J.
Mater. Chem. C 2015, 3, 2848−2855 (ref 82), with permission of The Royal Society of Chemistry. (c) Reflection spectra of polyacrylate capped
Fe3O4 magnetic photonic crystals in the absence and presence of NaCl at various ionic strength. The lines from right to left were corresponding to
the ionic strength (NaCl) from 0 to 0.40 mmol L−1 with step concentration of 0.05 mmol L−1. (d) The relationship between Δλ and ionic strength
of NaCl solution. Reproduced from Li, Y. R.; Sun, Y.; Wang, H. F. Analyst 2015, 140, 3368−3374 (ref 83), with permission of The Royal Society of
Chemistry.

force, resulting in the solution turbidity changes. In recent
studies, magnetophoretic assay strategies have been demon-
strated to detect diverse target molecules for quantitative
analysis.19,20,76−78
We reported a novel sensing system using magnetic and Au
NPs to monitor tuberculosis (TB) antigens, where TB was
monitored by a sandwich assay-like mechanism using two
different probe antibodies. After coupling between probes and
analytes, color changes could be easily monitored.79 However,
the major drawback of the system was the minimum sensing
volume of 1.5−3 mL because of the limitations of the cuvette
and absorbance spectrophotometer used; the volume of the
sample holder directly corresponds with the consumption of
immunomoieties and nanomaterials. Notably, a low volume
negatively affects the LOD because colorimetry corresponds
with the beam path (l) of a sample solution according to the
Beer−Lambert law (A = εcl). Therefore, to utilize a minimal
amount of sensing components and a combination of
immunoassay and colorimetry sensing systems, we developed
a novel plastic-chip-based magnetophoretic immunoassay
(pcMPI) analysis for detecting the CFP-10 antigen (Figure
6a).19 By combining a plastic chip and automated spectropho-
tometer setup, the pcMPI allowed simple and convenient
immunoassay with an ultrasensitive LOD level of 1.8 pg mL−1
and high specificity. Importantly, this approach of detecting a
secretory antigen could differentiate between Mycobacterium
tuberculosis and nontuberculosis mycobacteria (NTM) infec-
232
tions, helping clinicians determine appropriate treatment
decisions where standard liquid culture diagnostic tools fail.
Recently, a rapid MPI-based method for monitoring the
CFP-10 antigen was developed for the early detection of the
growth of Mycobacterium tuberculosis.20 The MPI was designed
to capture CFP-10 antigens effectively using two different types
of NPs and two specific monoclonal antibodies against CFP-10
antigen, with Au NPs for signaling and magnetic particles for
separation. The sensing linearity of MPI was demonstrated in
the range of pico- to micromoles and the detection limit was
0.3 pM. The MPI using clinical samples showed robust and
reliable sensing while monitoring Mycobacterium tuberculosis
growth with the monitoring time of 3−10 days, comparable to
that of the mycobacteria growth indicator tube test.
The newly developed magnetic field-induced assembly
techniques facilitate more cheaply, quickly, and at larger scale
fabrication process of photonic crystals, which make them
highly promising for practical applications. Compared to
conventional colloidal assembly methods, magnetic assembly
technique is rapid, effective, reversible, and contactless
manipulation because of the unique feature of long-range
magnetic dipolar interactions. Xuan et al. and Hu et al.
developed novel responsive photonic crystal-based colorimetric
humidity sensors by combining magnetic assembly and rapid
polymerization.80,81 The sensor was fabricated through the fast
magnetically induced self-assembly of magnetic colloidal
clusters, followed by an instant radical polymerization to fix
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry Review

Figure 7. (a) Schematic of Magplas nanoassembly mediated photothermal therapy, causing tumor regression in mice (left) and photographs of mice
before and after therapy (right). Reproduced in part from Li, L.; Fu, S.; Chen, C.; Wang, X.; Fu, C.; Wang, S.; Guo, W.; Yu, X.; Zhang, X.; Liu, Z.
ACS Nano 2016, 10, 7094−7105 (ref 22). Copyright 2017 American Chemical Society. (b) Fe3O4−PEI@AuNSs−EGCG/PEG and their functions
for near-infrated photothermal therapy, magnetic tumor-targeted therapy, and MR/X-ray dual-mode imaging, MR images of control and NP treated
mice (bottom left), and relative tumor volume to investigate the in vivo antitumor efficiency (bottom right). Reproduced in part from Yin, Y.; Cui,
L.; Yan, F.; Zhang, Z.; Li, W.; Wang, L. J. Mater. Chem. B 2017, 5, 454−463 (ref 91), with permission of The Royal Cociety of Chemistry. (c)
Illustration of magnetite silver hybrid NPs (left), tumor growth behavior (middle), and histological analysis of mouse organs and tumors after NP
treatments (right) to magnetic hyperthermia performance of magnetite silver hybrid NPs for tumor suppression. Reprinted from Biomaterials, 124,
Ding, Q.; Liu, D.; Guo, D.; Yang, F.; Pang, X.; Che, R.; Zhou, N.; Xie, J.; Sun, J.; Huang, Z. Shape-controlled fabrication of magnetite silver hybrid
NPs with high performance magnetic hyperthermia, 35−46 (ref 24), Copyright 2017, with permission from Elsevier.

the photonic colloidal crystals inside humidity-responsive
polymer gel matrix. The obtained sensor shows good
sensitivity, reversibility, and durability for a humidity range of
97% ∼ 11%.
Guan’s group fabricated a free-standing, flexible colorimetric
temperature sensor by polymerization of colloidal-crystal
nonaqueous suspension consisting of thermoresponsive mono-
mer under a magnetic field.82 Since the poly(N-isopropylacry-
lamide) (PNIPAM) gel has a much lower refractive index than
the low IS range (Figure 6c). The reduced sensitivity of Δλ
against INaCl in the high INaCl range was probably attributed to
the adsorption of Na+ onto the surface of PA−Fe3O4 NPs
(Figure 6d). It is likely that each Na+ ion has a higher chance to
attach to the negatively charged surface of PA−Fe3O4 NPs at
lower INaCl, leading to a more effective reduction of the negative
charges on the surface of PA−Fe3O4 NPs and thereby to a
stronger reduction in the interparticle distances and finally
eventually to a superior sensitivity of Δλ against INaCl.83

that of the polyvinylpyrrolidone-coated Fe3O4 colloidal cluster
and experiences remarkable changes in volume with temper-
ature, the as-prepared thermochromic one-dimensional pho-
tonic crystal films displays bright, iridescent colors with obvious
temperature sensitivity, good reversibility, and durability, even
at low volume fractions of colloidal clusters of 0.1 vol % (Figure
6b). These materials have the significant advantages of simple,
quick one-step strategy and mechanical durability as well as
tunable responsive range, which are essential for the practical
applications.
Li et al. presented a novel colorimetric sensor for rapid and
sensitive monitoring of ionic strength (IS) based on the
electrolyte-induced wavelength shifts of polyacrylate capped
Fe3O4 (PA-Fe3O4) colloidal crystals. The PA−Fe3O4 colloidal
crystals exhibited wavelength blueshifts identical to the total IS
of the aqueous solutions, regardless of the kind of electrolytes
in the solutions such as HCl, MgSO4, NaCl, KCl, MgCl2,
CaCl2, Na2SO4, and their mixtures. The magnetic colloidal
crystal sensor was more sensitive to the IS of NaCl (INaCl) in
233
■
IN VITRO/IN VIVO BIOUSABILITY AND
BIOIMAGING APPLICATIONS
Magnetoplasmonic Therapeutics. Nanotechnology
shows immense potential for creating nanoplatforms for
biomedical applications, including early cancer detection,
diagnosis, and therapy. Although body temperatures above 37
°C are commonly defined as fevers and associated with
illnesses, temperature increases in specific targeted tissues have
multiple therapeutic benefits in patients with cancer.84
Hyperthermia, or the controlled increase of tissue temperature
between to 41−48 °C in localized areas, is a clinically relevant
thermal treatments that causes minimal side effects in healthy
organs compared to radiotherapy and chemotherapy.85 Among
novel tools and techniques for this therapy, photothermal
therapy has attracted particular focus, because it offers high
selectivity and minimal invasiveness. This therapy is based on
NPs with photoabsorbing capabilities that generate heat under
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry
near-infrared irradiation, thus causing thermal ablation of
cancer cells.
Au NPs of different sizes and shapes with optical properties
tunable in the near-infrared region are very useful for cancer
imaging because they have high transmission rate through
biological tissues.86 In recent years, the superparamagnetic iron-
oxide NPs (SPIONs) have been explored for various
applications in the biomedical sector including MRI, targeted
drug delivery, radionuclide therapy, hyperthermia, and cell
sorting/separation.87 For most of these applications, the critical
factors are biocompatibility and associated toxicity; SPIONs at
any efficiency level would be biomedically inapplicable if they
showed toxic behaviors. Au NPs offer biocompatibility,
nontoxicity, and the ability to generate high temperatures at
desired sites; however, the greatest potential of plasmonic Au
nanotechnology medicine is in its use in the early detection and
therapeutic treatment of cancer.88,89 Therefore, the integration
of magnetic and plasmonic functions into a single platform such
as a magnetic core with plasmonic shell could be highly
beneficial for cancer nanomedicine. MRI agents like Gd-based
composites have been integrated with Au NPs to design hybrid
nanomaterials for MRI and photothermal ablation therapy.
Such composites would be useful in cancer therapy.
Gedda et al. developed a nanocomposite for MRI agent and
photothermal therapy by using Au/Gd-doped carbon quantum
dots (Au/GdC). The Au/GdC nanocomposite showed para-
magnetism, SPR in the NIR region, and admirable photo-
stability as well as high longitudinal relaxivity (r1 = 13.95 mM−1
s−1), indicating potential utility as a T1 contrast agent in MRI.
In vitro and in vivo studies have demonstrated the low toxicity
and excellent biocompatibility of the Au/GdC nanocomposite.
The Au/GdC nanocomposite showed successful destruction of
the cancer cells using photothermal ablation, thus indicating a
simple and powerful strategy to fabricate a MOSPR nanoma-
terial for MRI and photothermal ablation of cancer cells.90
Li et al. developed another variety of bioeliminable MagPlas
nanoassembly photothermal cancer therapy guided by trimodal
CT imaging, ablation therapy, and MRI (Figure 7a).22 A single
dose of photothermal therapy under near-infrared light induced
a complete tumor regression in mice. Importantly, the MagPlas
nanoassemblies could respond to local microenvironments with
acidic pH and enzymes where they accumulated including
tumors, liver, and the spleen; in such environments, they
collapsed into small molecules and discrete NPs for elimination
from the body. With this ability, a high dose of 400 mg kg−1
MagPlas nanoassemblies showed good biocompatibility. The
MagPlas nanoassemblies for cancer theranostics demonstrate
the potential for biodegradable bionanomaterials in biomedical
applications.22 Yin et al. reported a highly integrated nanoplat-
form, showing remarkable biostability, rapid cellular uptake, and
excellent in vitro and in vivo antitumor activity (Figure 7b).
Polyethylenimine (PEI)-modified Fe3O4 nanocores and Au
shells were used with epigallocatechin gallate (EGCG) as the
reducing agent to obtain Fe3O4@Au-EGCG core−shell NPs.
After PEG modification, the Fe3O4@Au-EGCG/PEG nano-
platform was completed. This nanoplatform could be used as a
dual-mode MR/X-ray imaging agent.91
Ding et al. presented a simple and effective in situ reduction
strategy to prepare magnetite -Ag hybrid NPs. Pre-existing
carboxyl-rich Fe3O4 NPs were desgned to carry inorganic Ag
bonding junctions in order to overcome the high interfacial
energy barrier. On the basis of this design strategy, the shapes
of the magnetite-Ag hybrid NPs were easily tunable by
234
Review
adjusting the concentration of the intermediate product
Fe3O4−COOAg NPs to produce core−shell Fe3O4@Ag or
heteromer Fe3O4−Ag structures after in situ reduction. The
cytotoxicity of the magnetite-Ag hybrid NPs was much lower
than that of individual Ag NPs. Compared to the individual
Fe3O4 NPs, both Fe3O4@Ag NPs and Fe3O4−Ag heteromers
exhibited greatly enhanced hyperthermia effects in vitro and in
vivo (Figure 7c).24 Hu et al. designed Fe3O4@Au NPs as both
photothermal conversion materials and radiosensitizers.
Fe3O4@Au NPs with uniform morphology showed strong
magnetic properties and superior photothermal effect.92
Azhdarzadeh et al. fabricated Mucin-1 aptamer-targeted Au@
SPIONs for MRI and photothermal therapy of colon cancer.
Finally, cells treated with aptamer-Au@SPIONs exhibited
higher death rates compared to control cells upon exposure
to near-infrared light.93 Ohulchanskyy et al. present a MagPlas
nanoplatform combining Au nanorods and iron-oxide NPs
within phospholipid-based polymeric nanomicelles. The Au
nanorods exhibited plasmon resonance absorbance at near-
infrared wavelengths, enabling photoacoustic imaging and
photothermal therapy, while the Fe3O4 NPs enabled magneto-
phoretic control of the nanoformulation. The application of an
external magnetic field also increased the uptake of the MagPlas
formulation by cancer cells in vitro. Under laser irradiation at
the wavelength of the Au nanorod absorption peak, the
nanomicelle formulation efficiently generated plasmonic nano-
bubbles within the cancer cells, as visualized by confocal
microscopy, causing cell destruction.94
Multimodal Imaging. Noninvasive bioimaging techniques
with various modalities have improved rapidly with the
development of nanomaterials as contrast agents and molecular
probes to examine the anatomical structures, metabolisms, and
biochemistries of tumors, which are crucial for the early
detection of cancers and early and accurate localization.95,96
Current clinical imaging modalities include MRI, CT, positron
emission tomography, optical fluorescence, and ultrasound
imaging. Each possesses functional merits and demerits, but
none can provide complete structural and functional
information separately from all other methods. Therefore,
integrating the advantages of individual modalities may permit
the acquisition of comprehensive information, improving the
spatial resolution and sensitivity to detect tumors or other
metabolism. Meanwhile, diagnosis with multimodalities re-
quires injection of several contrast agents, which can make
patients feel inconvenient and time-consuming. Furthermore,
different contrast agents may interfere signals with each other.
Recently, various types of hybrid NPs that are capable of
generating contrast in different way by using several different
elements is emerging to solve these problems.97−99 Hybrid NPs
integrate several components into single nanostructure systems,
possessing the merits of individual components. They are
usually prepared by assembling various NPs or by modifying
the single component NPs with other materials, producing an
ideal multimodal contrast agent.
To take several example for this, two or more imaging agents
can be encapsulated by a Si nanoshells, lipids, or some other
organic compound.100 Fluorescent dye molecules which can be
used for fluorescence imaging are able to be modified on the
surface of NPs.101 Various NPs can be connected through
covalent or noncovalent couplings.102 However, the multimodal
contrast agents encapsulated with different NPs together have
relatively short circulation times in the blood because they have
large particle size. Moreover, hybrid NPs composed by
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry Review

Figure 8. (a) Scheme showing the synthesis of yolk−shell Fe3O4@Au NPs using SiO2 as the sacrificial template. (b) Simulations of the induced
magnetic field distribution of Fe3O4 (left), core−shell Fe3O4@Au (middle), and yolk−shell Fe3O4@Au (right) NPs. The purple areas represent the
porous Au shell. (c) Representative whole-body coronal PET images of mice bearing U87MG tumors at 2, 8, 24, and 48 h after intravenous injection
of 150 μCi of 64Cu-labeled yolk−shell Fe3O4@Au NPs. The white arrow points to the tumor. (d) T2-weighted MR images and (e) photoacoustic
images of tumor at 0, 4, and 24 h postinjection of yolk−shell Fe3O4@Au NPs. The white circles indicate the tumor sites. Reproduced from Yolk−
Shell Nanostructure: An Ideal Architecture to Achieve Harmonious Integration of Magnetic-Plasmonic Hybrid Theranostic Platform, Lin, L. S.;
Yang, X.; Zhou, Z.; Yang, Z.; Jacobson, O.; Liu, Y.; Yang, A.; Niu, G.; Song, J.; Yang, H. H.; Chen, X. Adv. Mater. Vol. 29, Issue 21 (ref 103).
Copyright 2017 Wiley.

noncovalent bonding are insufficiently stable. However, the
multifunctional MagPlas NPs (FexOy−Au NPs) which are
hybrid NPs with the Au shell directly deposited onto the iron
oxide core have controllable particle size and stable structures
compared to the other type of multimodal contrast agents.23 In
addition, the Au surface in core−shell MagPlas NPs makes it
much easier to functionalize various bioligands thanks to their
rich history in surface chemistry. Therefore, MagPlas NPs
(FexOy−Au NPs) have been extensively studied as a multi-
modal imaging agents. Monaco et al. developed a novel
lipophilic core−shell Fe3O4@SiO2@Au@polymeric micelle-
folic acid-based probe for the targeting and multimodal imaging
of cancer cells.25 The potential use of the prepared Fe3O4@Au
NPs as a multimodal contrast probe for MRI and photoacoustic
imaging was then evaluated. The biomolecule-modified
Fe3O4@SiO2@Au@polymeric micelles incorporating multiple
functionalities into a single nanostructured system, showed
utility for the effective targeting and simultaneous multimodal
imaging of cancer cells. However, the relaxivity of the magnetic
component was typically reduced by the plasmonic component
in conventional core−shell structured MagPlas NPs because of
the water-impenetrable coatings of the particles, which severely
restricted the proximity of protons to the magnetic portion.
Lin et al. introduced a hybrid theranostic platform by using
MagPlas yolk−shell nanostructures comprising a Fe3O4 core
within a hollow cavity encircled by a porous Au outer shell
design (Figure 8a).103 Calculations based on the Landau−
235
Lifshitz−Gilbert equation show that the intensity of the
magnetic field is dramatically decreased with increasing distance
from the surface of Fe3O4 NPs (Figure 8b), suggesting that
moving the water-impermeable component away from the
magnetic component would effectively prevent the decrease of
the r2 value. The experimental results of T2 and r2 also provide
strong support for improvements in the T2 relaxivity of the
yolk−shell Fe3O4@Au NPs relative to that of the core−shell
ones. Positron emission tomography images (Figure 8c)
indicate the gradual accumulation of the yolk−shell Fe3O4@
Au NPs in the tumor at 2, 8, 24, and 48 h after intravenous
injection. T2-weighted MR images and photoacoustic images of
the tumor at 0, 4, and 24 h postinjection of the yolk−shell
Fe3O4@Au NPs show an obvious contrast at the tumor site
(Figure 8d,e). Therefore, the yolk−shell structure could
minimize the weakening of MRI contrast performance by the
integration of magnetic NPs with plasmonic nanomaterials. The
yolk−shell particles were successfully applied for MR/photo-
acoustic/positron emission tomography multimodal imaging
and near-infrared laser-triggered chemothermal synergistic
therapy. Meanwhile, Reguera et al. reported Janus MagPlas
NPs comprising iron-oxide nanospheres and with branched
gold nanostars as contrast agents for multimodal imaging.21
The Janus characteristics of these NPs offer easy and selective
functionalization of each side of the inorganic core. They allow
easy access of water to the iron oxide surface, unlike core−shell
NPs, and show high r2 relaxivity values and Prussian-blue
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry
staining ability. Furthermore, when compared with conven-
tional Janus dumbbell-like NPs, the nanostar morphology of
gold enables their use in photoacoustic and surface-enhanced
Raman scattering (SERS) imaging in the NIR biological
window. Judging from previous reports regarding multimodal
imaging with MagPlas NPs, MagPlas NPs have a great potential
to be used as a practical multimodal contrast agent for MRI,
CT, microwave induced thermoacoustic or photoacoustic
imaging, and magnetomotive photoacoustic imaging.
■ CONCLUSIONS AND PERSPECTIVES
There have been thousands of research papers published during
the last 3 years relating to MagPlas nanomaterials and their
biosensing and biomedical applications. We have summarized
recent remarkable advances in the design, fabrication, and
applications of novel MagPlas NPs and nanostructures, with a
specific focus on biosensing strategies, therapeutic, and
multimodal imaging applications.
MO sensing not only with SPP configurations (MOSPR) but
also with LSP (MOLSPR) is foreseen, with expected enhanced
sensitivities. In multilayer MOSPR systems, enhanced sensi-
tivity is achieved by optimizing the multilayered sensor chip
structure (i.e., the multilayer total thickness, the magnetic layer
thickness, and its position within the film). Although SPP-based
sensors have distinct advantages for label-free detection
techniques, they are not applicable to single-molecule level
detection due to their insufficiently high local sensitivity to the
refractive index. Therefore, much effort focused on improving
the performances of LSPR-based sensors have been done.
MagPlas nanostructures were proved to be promising for
alternative methodologies toward improved LSPR-based
sensing, which utilize complementary properties of light rather
than intensity, such as optical phase, directionality, or
ellipsometric parameters. The measured change in the light
polarization upon transmission and/or reflection from the
system is used as observable to track environmental changes
due to refractive index variation or molecular adsorption.
From the perspective of electrochemical biosensing, the
ability to use the MagPlas NPs as active elements allows the
self-assembly, concentration, separation, and capture of analytes
result in enhancing the analytical detection. By using MagPlas
NPs incorporated in electrochemical sensors, it is possible to
detect a number of analytes of biological interest. Over the past
few years, besides using MagPlas NPs in conventional
configurations, new concepts of electrochemical biosensors
using MagPlas NPs have been reported, including integrated a
magneto-electrochemical sensor and ECL biosensor. The ECL
biosensor concept has shown excellent performance with
extremely low detection limits toward different analytes, such
as human cervical carcinoma cell. Still some crucial aspects are
requiring further study focus on simple design and cost-
effective with improved sensitivity, selectivity, and response
time.
The recent development of MagPlas NPs-integrated
colorimetric biosensors also has enormous potentials for the
simple and cost-effective in vitro diagnostic (IVD) test platform.
Intrinsic enzyme-like activity of Fe-based NPs is highly
attractive property and by combining with plasmonic materials,
their catalytic property could be highly enhanced. Their unique
two properties as a magnetic separator and catalysis have been
actively applied to the current IVD colorimetric tests, which is
promising for future biomedical diagnosis and environmental
monitoring. Colorimetric detection methods based on
236
Review
magnetophoretic assay are also simple and robust biosensing
strategy. Magnetic NPs capture the optical transducers, which
have a color signal due to SPR absorption or Mie scattering,
and then by separating from the solution, rapid visual detection
was possible. Furthermore, magnetically induced assembly
techniques provide efficacy and robustness to the fabrication of
photonic crystal structures, and these films possess diverse
unique plasmo-magnetic optical properties, which makes them
highly attractive for physical, biological sensing platform.
MagPlas NPs allowing rational sensing strategy that leads
improved sensitivity and efficiency with fast colorimetric signal
responses, which can be readily read with the naked eye or
quantified by inexpensive devices. Therefore, these properties
present opportunities for MagPlas NPs-based colorimetric
sensors as a tool for point-of-care (POC) tests that are urgently
needed in resource-limited areas.
The nanotechnology have a great benefit from nano-
technology for biomedical field today such as diagnosis and
therapy of diseases. Through rational design and engineering,
sophisticated multifunctional NPs can meet all important
requirements for nanobased theranostics. There have been
many reports on the development and application of MagPlas
NPs and assemblies for in vitro and in vivo usability and
bioimaging application. Composite plasmonic-magnetic NPs
may pave ways for promoting the tumor targeting multimode
theranostic nanoplatform of cancer therapy. When such NPs
are used as in vivo therapeutic agents for cancer, additional
functions, such as the magnetic NPs, can provide not only
therapeutic potential by hyperthermia but can also use as the
bionanoprobe biodistribution and guidance to the tumor site.
The MagPlas NPs are also a versatile tool for the development
of efficient multimodal bioimaging agents, for both in vitro and
in vivo applications. It is expected that MagPlas contrast agents
with improved detection will be developed based on the
accumulated knowledge and technology in order to improve
clinical results and finally can provide great contributions to
human health. However, several challenges remain, before such
bionanoprobes can be safely applied in therapeutic applications.
Intergrated collaborations of materials scientists with biologists
and clinicians to be interdisciplinary teams should be
established to systematic and evaluate specific properties of
the hybrid NPs, especially in vivo with animal models to identify
the long-term toxicity, pharmacokinetics, biodistribution,
disinfection byproduct effects, and efficiency of such nanobased
therapeutic probes. After biological studies have taken place,
human clinical trials may then start. In the future, the
unexpected properties of these materials effective to human
cancer cells are conducted by medical doctors, the multifunc-
tional MagPlas nanomaterials will provide powerful tools for
simultaneous diagnosis and therapy of various diseases.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: jaebeom@pusan.ac.kr.
ORCID
Jaebeom Lee: 0000-0002-4563-2883
Notes
The authors declare no competing financial interest.
Biographies
Van Tan Tran received his B.S. degree in Engineering Physics from
College of Technology, Vietnam National University (Hanoi,
Vietnam) in 2010. He earned his Ph.D. degree under the supervision
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry
of Prof. Jaebeom Lee at Pusan National University in February 2017.
Currently, he is a postdoctoral researcher in the Department of
Cogno-Mechatronics Engineering at Pusan National University. His
research interests are mainly focused on synthesis, characterization,
and self-assembly of multifunctional and multidimensional nanostruc-
tures of magnetoplasmonic materials and their applications in
biosensors and biomedicine.
Jeonghyo Kim received his B.S. degree and M.S. degree under the
direction of Prof. Jaebeom Lee at Pusan National University.
Currently, he is a Ph.D student at the Department of Cogno-
Mechatronics Engineering at Pusan National University. His current
research interest is focused on self-assembled magneto-plasmonic/
fluorescent nanostructures and their biomedical applications.
Lemma Teshome Tufa received his B.S. degree in Chemistry and M.S.
degree in Physical Chemistry from Jimma University, Ethiopia.
Currently, he is a Ph.D. candidate under guidance of Prof. Jaebeom
Lee at College of Nano Science and Nano Technology, Pusan
National University, Korea. His research interests are in electro-
chemical detection of biomolecule, electrocatalytic process, and
electrochemical investigation of single nanoparticle behavior.
Sangjin Oh received her B.S. degree in 2013 and M.S. degree in 2016
from the College of Nanoscience and Nanotechnology at Pusan
National University in Busan, Korea. Currently, Ms. Oh is a Ph.D.
student at the Department of Cogno-Mechatronics Engineering at
Pusan National University. She is interested in developing nano-
biosensors and electrode platforms using nanomaterials and nano-
composites, such as inorganic nanomaterials, semiconductor materials,
and magnetoplasmonic materials.
Junyoung Kwon received her B.S. in 2014 and her M.S. in 2016 at
Pusan National University under the guidance of Professor Jaebeom
Lee. She is currently a Ph.D. student at the Department of Cogno-
Mechatronics Engineering at Pusan National University. Her current
research interest focuses on synthesis and characterization of chiral
nanostructures, biocompatible Fe-based quantum dots, and magneto-
plasmonic nanoparticles.
Jaebeom Lee is currently a professor in the Departments of Optics and
Mechatronics Engineering, and Cogno-Mechatronics Engineering at
Pusan National University. He received his B.S. degree in chemistry
from Chungnam National University in 1998 and his Ph.D. degree in
chemistry from Robert Gordon University in the United Kingdom in
2003. He worked as a research fellow at the University of Michigan,
Ann Arbor, until 2007. Dr. Lee is currently interested in the fabrication
and characterization of engineered assemblies of magnetoplasmonic
materials. Dr. Lee is also interested in surface modification of
nanocomposites for biocompatibility and biodegradability for bio-
medical applications.
■
ACKNOWLEDGMENTS
This work was supported by the National Research Foundation
of Korea (NRF) Grant funded by the Korean Government
(MSIP) (Grant 2016R1A2B4012072), National Research
Foundation (NRF) of Korea under the auspices of the Ministry
of Science and ICT, Republic of Korea (Grant
2017R1A4A1015627). This study was supported by grants
from the Korea Healthcare Technology R&D Project (Grant
HI17C1260) of the Ministry for Health, Welfare & Family
Affairs and the 2017 Post-Doc. Development Program of Pusan
National University. The TOC graphic is composed from the
following ACS references. Magneto-optical biosensors: (1) ACS
Photonics, 2017, 4 (6), 1403−1412 (ref 39). Copyright 2017
American Chemical Society. (2) Nano Lett., 2011, 11 (12),
237
Review
5333−5338 (ref 49). Copyright 2011 American Chemical
Society. Colorimetric biosensor: ACS Appl. Mater. Interfaces,
2016, 8, 23489−23497 (ref 19). Copyright 2016 American
Chemical Society. Electrochemical biosensors: ACS Nano,
2016, 10, 1802−1809 (ref 60). Copyright 2016 American
Chemical Society. Therapeutics: ACS Nano, 2017, 11 (1),
277−290. Copyright 2017 American Chemical Society. Multi-
modal imaging: (1) Bioconjugate Chem., 2017, 28 (5), 1382−
1390 (ref 25). Copyright 2017 American Chemical Society. (2)
ACS Nano, 2011, 5 (2), 1056−1066. Copyright 2011 American
Chemical Society.
■ REFERENCES
(1) Ling, D.; Hyeon, T. Small 2013, 9, 1450−1466.
(2) Elsherbini, A. A.; Saber, M.; Aggag, M.; El-Shahawy, A.; Shokier,
H. A. Int. J. Nanomed. 2011, 6, 2155.
(3) Hoskins, C.; Min, Y.; Gueorguieva, M.; McDougall, C.; Volovick,
A.; Prentice, P.; Wang, Z.; Melzer, A.; Cuschieri, A.; Wang, L. J.
Nanobiotechnol. 2012, 10, 27.
(4) Tran, V. T.; Zhou, H.; Lee, S.; Hong, S. C.; Kim, J.; Jeong, S. Y.;
Lee, J. ACS Appl. Mater. Interfaces 2015, 7, 8650−8658.
(5) Salihov, S. V.; Ivanenkov, Y. A.; Krechetov, S. P.; Veselov, M. S.;
Sviridenkova, N. V.; Savchenko, A. G.; Klyachko, N. L.; Golovin, Y. I.;
Chufarova, N. V.; Beloglazkina, E. K. J. Magn. Magn. Mater. 2015, 394,
173−178.
(6) Galvez, F.; del Valle, J.; Gomez, A.; Osorio, M. R.; Granados, D.;
de Lara, D. P.; García, M. A.; Vicent, J. L. Opt. Mater. Express 2016, 6,
3086−3096.
(7) Jain, P. K.; Xiao, Y.; Walsworth, R.; Cohen, A. E. Nano Lett. 2009,
9, 1644−1650.
(8) Chau, K. J.; Johnson, M.; Elezzabi, A. Y. Phys. Rev. Lett. 2007, 98,
133901.
(9) Martin, D. H.; Doniach, S.; Neal, K. J. Phys. Lett. 1964, 9, 224−
226.
(10) Chen, L.; Gao, J.; Xia, W.; Zhang, S.; Tang, S.; Zhang, W.; Li,
D.; Wu, X.; Du, Y. Phys. Rev. B: Condens. Matter Mater. Phys. 2016, 93,
214411.
(11) Armelles, G.; Cebollada, A.; García-Martín, A.; González, M. U.
Adv. Opt. Mater. 2013, 1, 10−35.
(12) Shen, Y.; Zhou, J.; Liu, T.; Tao, Y.; Jiang, R.; Liu, M.; Xiao, G.;
Zhu, J.; Zhou, Z. K.; Wang, X. Nat. Commun. 2013, 4, 2381.
(13) Acimovic, S. S.; Ortega, M. A.; Sanz, V.; Berthelot, J.; Garcia-
Cordero, J. L.; Renger, J.; Maerkl, S. J.; Kreuzer, M. P.; Quidant, R.
Nano Lett. 2014, 14, 2636−2641.
(14) Kabashin, A. V.; Evans, P.; Pastkovsky, S.; Hendren, W.; Wurtz,
G. A.; Atkinson, R.; Pollard, R.; Podolskiy, V. A.; Zayats, A. V. Nat.
Mater. 2009, 8, 867.
(15) Maksymov, I. S. Rev. Phys. 2016, 1, 36−51.
(16) Maccaferri, N.; Gregorczyk, K.; De Oliveira, T. V.; Kataja, M.;
Van Dijken, S.; Pirzadeh, Z.; Dmitriev, A.; Åkerman, J.; Knez, M.;
Vavassori, P. Nat. Commun. 2015, 6, 6150.
(17) Shang, F.; Liu, Y.; Wang, S.; Hu, Y.; Guo, Z. Electroanalysis
2017, 29, 2098−2105.
(18) Gu, W.; Deng, X.; Gu, X.; Jia, X.; Lou, B.; Zhang, X.; Li, J.;
Wang, E. Anal. Chem. 2015, 87, 1876−1881.
(19) Kim, J.; Jang, M.; Lee, K. G.; Lee, K. S.; Lee, S. J.; Ro, K. W.;
Kang, I. S.; Jeong, B. D.; Park, T. J.; Kim, H. J.; Lee, J. ACS Appl.
Mater. Interfaces 2016, 8, 23489−23497.
(20) Kim, J.; Lee, K. S.; Kim, E. B.; Paik, S.; Chang, C. L.; Park, T. J.;
Kim, H. J.; Lee, J. Biosens. Bioelectron. 2017, 96, 68−76.
(21) Reguera, J.; de Aberasturi, D. J.; Henriksen-Lacey, M.; Langer,
J.; Espinosa, A.; Szczupak, B.; Wilhelm, C.; Liz-Marzán, L. M.
Nanoscale 2017, 9, 9467−9480.
(22) Li, L.; Fu, S.; Chen, C.; Wang, X.; Fu, C.; Wang, S.; Guo, W.;
Yu, X.; Zhang, X.; Liu, Z. ACS Nano 2016, 10, 7094−7105.
(23) Zhou, H.; Zou, F.; Koh, K.; Lee, J. J. Biomed. Nanotechnol. 2014,
10, 2921−2949.
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry
(24) Ding, Q.; Liu, D.; Guo, D.; Yang, F.; Pang, X.; Che, R.; Zhou,
N.; Xie, J.; Sun, J.; Huang, Z. Biomaterials 2017, 124, 35−46.
(25) Monaco, I.; Arena, F.; Biffi, S.; Locatelli, E.; Bortot, B.; La Cava,
F.; Marini, G. M.; Severini, G. M.; Terreno, E.; Comes Franchini, M.
Bioconjugate Chem. 2017, 28, 1382−1390.
(26) Malekigorji, M.; Alfahad, M.; Lin, P. K. T.; Jones, S.; Curtis, A.;
Hoskins, C. Nanoscale 2017, 9, 12735−12745.
(27) Tomitaka, A.; Arami, H.; Raymond, A.; Yndart, A.; Kaushik, A.;
Jayant, R. D.; Takemura, Y.; Cai, Y.; Toborek, M.; Nair, M. Nanoscale
2017, 9, 764−773.
(28) Chen, K. L.; Yeh, Y. W.; Chen, J. M.; Hong, Y. J.; Huang, T. L.;
Deng, Z. Y.; Wu, C. H.; Liao, S. H.; Wang, L. M. Sci. Rep. 2016, 6,
35477 DOI: 10.1038/srep35477.
(29) Seo, D.; Southard, K. M.; Kim, J. w.; Lee, H. J.; Farlow, J.; Lee, J.
u.; Litt, D. B.; Haas, T.; Alivisatos, A. P.; Cheon, J. Cell 2016, 165,
1507−1518.
(30) Kwon, J.; Mao, X.; Lee, J. Curr. Appl. Phys. 2017, 17, 1066−
1078.
(31) Maksymov, I. S. Nanomaterials 2015, 5, 577−613.
(32) Maccaferri, N.; Inchausti, X.; García-Martín, A.; Cuevas, J. C.;
Tripathy, D.; Adeyeye, A. O.; Vavassori, P. ACS Photonics 2015, 2,
1769−1779.
(33) Manera, M. G.; Pellegrini, G.; Lupo, P.; Bello, V.; de Julián
Fernández, C.; Casoli, F.; Rella, S.; Malitesta, C.; Albertini, F.; Mattei,
G. Sens. Actuators, B 2017, 239, 100−112.
(34) Sepúlveda, B.; Calle, A.; Lechuga, L. M.; Armelles, G. Opt. Lett.
2006, 31, 1085−1087.
(35) Caballero, B.; García-Martín, A.; Cuevas, J. C. ACS Photonics
2016, 3, 203−208.
(36) Ignatyeva, D. O.; Knyazev, G. A.; Kapralov, P. O.; Dietler, G.;
Sekatskii, S. K.; Belotelov, V. I. Sci. Rep. 2016, 6, 28077.
(37) David, S.; Polonschii, C.; Luculescu, C.; Gheorghiu, M.; Gáspár,
S.; Gheorghiu, E. Biosens. Bioelectron. 2015, 63, 525−532.
(38) Regatos, D.; Sepúlveda, B.; Farina, D.; Carrascosa, L. G.;
Lechuga, L. M. Opt. Express 2011, 19, 8336−8346.
(39) Qin, J.; Zhang, Y.; Liang, X.; Liu, C.; Wang, C.; Kang, T.; Lu, H.;
Zhang, L.; Zhou, P.; Wang, X. ACS Photonics 2017, 4, 1403−1412.
(40) Kaihara, T.; Ando, T.; Shimizu, H.; Zayets, V.; Saito, H.; Ando,
K.; Yuasa, S. Opt. Express 2015, 23, 11537−11555.
(41) Manera, M. G.; Montagna, G.; Ferreiro-Vila, E.; González-
García, L.; Sánchez-Valencia, J. R.; González-Elipe, A. R.; Cebollada,
A.; Garcia-Martin, J. M.; Garcia-Martin, A.; Armelles, G. J. Mater.
Chem. 2011, 21, 16049−16056.
(42) Herreno-Fierro, C. A.; Patino, E. J. Phys. Status Solidi B 2015,
252, 316−322.
(43) Manera, M. G.; Ferreiro-Vila, E.; Garcia-Martin, J. M.; Garcia-
Martin, A.; Rella, R. Biosens. Bioelectron. 2014, 58, 114−120.
(44) Wang, J.; Sun, Y.; Wang, L.; Zhu, X.; Zhang, H.; Song, D.
Colloids Surf., B 2010, 81, 600−606.
(45) Zeng, S.; Baillargeat, D.; Ho, H. P.; Yong, K. T. Chem. Soc. Rev.
2014, 43, 3426−3452.
(46) Zou, F.; Wang, X.; Qi, F.; Koh, K.; Lee, J.; Zhou, H.; Chen, H.
Sens. Actuators, B 2017, 250, 356−363.
(47) Zubritskaya, I.; Lodewijks, K.; Maccaferri, N.; Mekonnen, A.;
Dumas, R. K.; Åkerman, J.; Vavassori, P.; Dmitriev, A. Nano Lett. 2015,
15, 3204−3211.
(48) Eslami, S.; Gibbs, J. G.; Rechkemmer, Y.; van Slageren, J.;
Alarcón-Correa, M.; Lee, T. C.; Mark, A. G.; Rikken, G. L.; Fischer, P.
ACS Photonics 2014, 1, 1231−1236.
(49) Bonanni, V.; Bonetti, S.; Pakizeh, T.; Pirzadeh, Z.; Chen, J.;
Nogués, J.; Vavassori, P.; Hillenbrand, R.; Åkerman, J.; Dmitriev, A.
Nano Lett. 2011, 11, 5333−5338.
(50) Yamane, H.; Takeda, K.; Kobayashi, M. Appl. Phys. Lett. 2015,
106, 052409.
(51) Lodewijks, K.; Maccaferri, N.; Pakizeh, T.; Dumas, R. K.;
Zubritskaya, I.; Åkerman, J.; Vavassori, P.; Dmitriev, A. Nano Lett.
2014, 14, 7207−7214.
(52) Toal, B.; McMillen, M.; Murphy, A.; Hendren, W.; Arredondo,
M.; Pollard, R. Nanoscale 2014, 6, 12905−12911.
238
Review
(53) Feng, H. Y.; Luo, F.; Arenal, R.; Henrard, L.; García, F.;
Armelles, G.; Cebollada, A. Nanoscale 2017, 9, 37−44.
(54) Kataja, M.; Hakala, T. K.; Julku, A.; Huttunen, M. J.; Van
Dijken, S.; Törmä, P. Nat. Commun. 2015, 6, 7072.
(55) Maccaferri, N.; Bergamini, L.; Pancaldi, M.; Schmidt, M. K.;
Kataja, M.; Dijken, S. v.; Zabala, N.; Aizpurua, J.; Vavassori, P. Nano
Lett. 2016, 16, 2533−2542.
(56) Tschulik, K.; Ngamchuea, K.; Ziegler, C.; Beier, M. G.; Damm,
C.; Eychmueller, A.; Compton, R. G. Adv. Funct. Mater. 2015, 25,
5149−5158.
(57) Ngamchuea, K.; Tschulik, K.; Compton, R. G. Nano Res. 2015,
8, 3293−3306.
(58) Gomes, B. F.; da Silva, P. F.; Lobo, C. M. S.; da Silva Santos, M.;
Colnago, L. A. Anal. Chim. Acta 2017, 983, 91−95.
(59) Kokkinos, C.; Economou, A.; Prodromidis, M. I. TrAC, Trends
Anal. Chem. 2016, 79, 88−105.
(60) Jeong, S.; Park, J.; Pathania, D.; Castro, C. M.; Weissleder, R.;
Lee, H. ACS Nano 2016, 10, 1802−1809.
(61) Liébana, S.; Drago, G. A. Essays Biochem. 2016, 60, 59−68.
(62) Pingarrón, J. M.; Yánez-Sedeno, P.; González-Cortés, A.
Electrochim. Acta 2008, 53, 5848−5866.
(63) Freitas, M.; Sá Couto, M.; Barroso, M. F.; Pereira, C.; de-los-
Santos-Á lvarez, N.; Miranda-Ordieres, A. J.; Lobo-Castanón, M. J.;
Delerue-Matos, C. Acs Sensors 2016, 1, 1044−1053.
(64) Tran, V. T.; Zhou, H.; Kim, S.; Lee, J.; Kim, J.; Zou, F.; Kim, J.;
Park, J. Y.; Lee, J. Sens. Actuators, B 2014, 203, 817−823.
(65) Wang, X.; Hu, Y.; Wei, H. Inorg. Chem. Front. 2016, 3, 41−60.
(66) Gao, L.; Zhuang, J.; Nie, L.; Zhang, J.; Zhang, Y.; Gu, N.; Wang,
T.; Feng, J.; Yang, D.; Perrett, S. Nat. Nanotechnol. 2007, 2, 577−583.
(67) Duan, D.; Fan, K.; Zhang, D.; Tan, S.; Liang, M.; Liu, Y.; Zhang,
J.; Zhang, P.; Liu, W.; Qiu, X. Biosens. Bioelectron. 2015, 74, 134−141.
(68) Wen, J.; Zhou, S.; Chen, J. Sci. Rep. 2015, 4, 5191
DOI: 10.1038/srep05191.
(69) Zhang, L.; Huang, R.; Liu, W.; Liu, H.; Zhou, X.; Xing, D.
Biosens. Bioelectron. 2016, 86, 1−7.
(70) Gao, L.; Fan, K.; Yan, X. Theranostics 2017, 7, 3207.
(71) Ponlakhet, K.; Amatatongchai, M.; Sroysee, W.; Jarujamrus, P.;
Chairam, S. Anal. Methods 2016, 8, 8288−8298.
(72) Sroysee, W.; Ponlakhet, K.; Chairam, S.; Jarujamrus, P.;
Amatatongchai, M. Talanta 2016, 156, 154−162.
(73) Kwon, D.; Joo, J.; Lee, J.; Park, K. H.; Jeon, S. Anal. Chem. 2013,
85, 7594−7598.
(74) Kwon, D.; Lee, S.; Ahn, M. M.; Kang, I. S.; Park, K. H.; Jeon, S.
Anal. Chim. Acta 2015, 883, 61−66.
(75) Kim, M. S.; Kweon, S. H.; Cho, S.; An, S. S.; Kim, M. I.; Doh, J.;
Lee, J. ACS Appl. Mater. Interfaces 2017, 9, 35133−35140.
(76) Chen, S.; Chu, L. T.; Yeung, P. P.; Zhao, Z.; Bao, Y.; Chan, M.
S.; Lo, P. K.; Chen, T. H. ACS Appl. Mater. Interfaces 2015, 7, 22821−
22830.
(77) Han, Y. D.; Park, Y. M.; Chun, H. J.; Yoon, H. C. Sens. Actuators,
B 2015, 220, 233−242.
(78) Zhao, Z.; Bao, Y.; Chu, L. T.; Ho, J. K. L.; Chieng, C. C.; Chen,
T. H. Lab Chip 2017, 17, 3240−3245.
(79) Zhou, H.; Kim, J.; Zou, F.; Koh, K.; Park, J. Y.; Lee, J. Sens.
Actuators, B 2014, 198, 77−81.
(80) Xuan, R.; Wu, Q.; Yin, Y.; Ge, J. J. Mater. Chem. 2011, 21,
3672−3676.
(81) Hu, H.; Chen, Q. W.; Cheng, K.; Tang, J. J. Mater. Chem. 2012,
22, 1021−1027.
(82) Ma, H.; Zhu, M.; Luo, W.; Li, W.; Fang, K.; Mou, F.; Guan, J. J.
Mater. Chem. C 2015, 3, 2848−2855.
(83) Li, Y. R.; Sun, Y.; Wang, H. F. Analyst 2015, 140, 3368−3374.
(84) Axelrod, Y. K.; Diringer, M. N. Neurol. Clin. 2008, 26, 585−603.
(85) Fauci, A. S. Harrison’s Principles of Internal Medicine; McGraw-
Hill, Medical Publishing Division: New York, 2008.
(86) Zhang, X. Cell Biochem. Biophys. 2015, 72, 771−775.
(87) Li, X.; Wei, J.; Aifantis, K. E.; Fan, Y.; Feng, Q.; Cui, F.; Watari,
F. J. Biomed. Mater. Res., Part A 2016, 104, 1285−1296.
DOI: 10.1021/acs.analchem.7b04255
Anal. Chem. 2018, 90, 225−239
Analytical Chemistry Review

(88) Croissant, J.; Maynadier, M.; Mongin, O.; Hugues, V.;

Blanchard-Desce, M.; Chaix, A.; Cattoën, X.; Wong Chi Man, M.;
Gallud, A.; Gary-Bobo, M. Small 2015, 11, 295−299.
(89) Guo, T.; Lin, Y.; Li, Z.; Chen, S.; Huang, G.; Lin, H.; Wang, J.;
Liu, G.; Yang, H. H. Nanoscale 2017, 9, 56−61.
(90) Gedda, G.; Yao, Y. Y.; Chen, S. H.; Ghule, A. V.; Ling, Y. C.;
Chang, J. Y. J. Mater. Chem. B 2017, 5, 6282−6291.
(91) Yin, Y.; Cui, L.; Yan, F.; Zhang, Z.; Li, W.; Wang, L. J. Mater.
Chem. B 2017, 5, 454−463.
(92) Hu, R.; Zheng, M.; Wu, J.; Li, C.; Shen, D.; Yang, D.; Li, L.; Ge,
M.; Chang, Z.; Dong, W. Nanomaterials 2017, 7, 111.
(93) Azhdarzadeh, M.; Atyabi, F.; Saei, A. A.; Varnamkhasti, B. S.;
Omidi, Y.; Fateh, M.; Ghavami, M.; Shanehsazzadeh, S.; Dinarvand, R.
Colloids Surf., B 2016, 143, 224−232.
(94) Ohulchanskyy, T. Y.; Kopwitthaya, A.; Jeon, M.; Guo, M.; Law,
W. C.; Furlani, E. P.; Kim, C.; Prasad, P. N. Nanomedicine 2013, 9,
1192−1202.
(95) Kim, M. M.; Parolia, A.; Dunphy, M.; Venneti, S. Nat. Rev. Clin.
Oncol. 2016, 13, 725.
(96) Mi, P.; Kokuryo, D.; Cabral, H.; Wu, H.; Terada, Y.; Saga, T.;
Aoki, I.; Nishiyama, N.; Kataoka, K. Nat. Nanotechnol. 2016, 11, 724−
730.
(97) Liu, W.; Naydenov, B.; Chakrabortty, S.; Wuensch, B.; Hübner,
K.; Ritz, S.; Cölfen, H.; Barth, H.; Koynov, K.; Qi, H. Nano Lett. 2016,
16, 6236−6244.
(98) Vecchione, D.; Grimaldi, A. M.; Forte, E.; Bevilacqua, P.; Netti,
P. A.; Torino, E. Sci. Rep. 2017, 7, 45121.
(99) Zhu, H.; Wang, Y.; Chen, C.; Ma, M.; Zeng, J.; Li, S.; Xia, Y.;
Gao, M. ACS Nano 2017, 11, 8273−8281.
(100) Liu, Z.; Rong, P.; Yu, L.; Zhang, X.; Yang, C.; Guo, F.; Zhao,
Y.; Zhou, K.; Wang, W.; Zeng, W. Mol. Pharmaceutics 2015, 12, 3119−
3128.
(101) Zhou, H.; Hou, X.; Liu, Y.; Zhao, T.; Shang, Q.; Tang, J.; Liu,
J.; Wang, Y.; Wu, Q.; Luo, Z. ACS Appl. Mater. Interfaces 2016, 8,
4424−4433.
(102) Sun, M.; Xu, L.; Ma, W.; Wu, X.; Kuang, H.; Wang, L.; Xu, C.
Adv. Mater. 2016, 28, 898−904.
(103) Lin, L. S.; Yang, X.; Zhou, Z.; Yang, Z.; Jacobson, O.; Liu, Y.;
Yang, A.; Niu, G.; Song, J.; Yang, H. H.; Chen, X. Adv. Mater. 2017,
29, 1606681.

239 DOI: 10.1021/acs.analchem.7b04255

Anal. Chem. 2018, 90, 225−239