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Magnetoplasmonic Nanomaterials for Biosensing/ Imaging and In-vitro/In-vivo Bio-usability Van Tan Tran, Jeonghyo Kim, Lemma Teshome Tufa, Sangjin Oh, Junyoung Kwon, and Jaebeom Lee Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b04255 • Publication Date (Web): 31 Oct 2017 Downloaded from http://pubs.acs.org on November 4, 2017

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Analytical Chemistry

Magnetoplasmonic Nanomaterials for Biosensing/Imaging and In-vitro/In-vivo Bio-usability Van Tan Tran, Jeonghyo Kim, Lemma Teshome Tufa, Sangjin Oh, Junyoung Kwon, Jaebeom Lee

Department of Cogno-Mechatronics Engineering, Pusan National University, Busan, 609-735 Republic of Korea Corresponding author: J. Lee, [email protected]

Most commonly magnetoplasmonic nanoparticles (MagPlas 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 multi-functional 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 1

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Various MagPlas nanomaterials, i.e. core@shell, dimer, cluster, alloy, have been developed using different synthesis and fabrication techniques including co-precipitation, thermal decomposition, hydro/solvothermal, microemulsion, lithography and so on.5,6 Strategies of improving both sensitivity and selectivity for biosensors using these multifunctional MagPlas nanomaterials are attractive and have received considerable attention. The magneto-optical (MO) activity of MagPlas nanostructures has been shown to be greatly enhanced by plasmon resonance effect.7 Chau et al. demonstrated that modulation of particle transparency is largely dependent on magnetic field in Co/Au core/shell microparticles due to spin-dependent interface effects.8 The 3-d transition ferromagnetic metals such as Co, Fe and Ni and ferrimagnetic metals and their alloys can also develop MO activity.9,10 Novel magneto-optical surface plasmon resonance (MOSPR) sensors using a new type of transducer was demonstrated to yield improved sensitivity to refractive index changes of up to two orders of magnitude, compared to classical SPR assays.11 Furthermore, localized surface plasmon resonance (LSPR)-based technologies for label-free single-molecular detection are particularly attractive for biomedical applications.12-14 Recently, magnetoplasmonic effects in nanostructures that support LSPR have attracted intensive study.15,16 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 electrochemical biosensors using MagPlas NPs have been reported during last few years, including integrated magnetoelectrochemical sensor and electro-chemiluminescence (ECL) biosensor.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 2


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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 applications.21-26 Tomitaka et al. presented the contribution of magnetic core/Au shell MagPlas NPs to concentration-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 transmigration 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 neurological 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 3



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focuses on research published in the last few years, encompassing MagPlas-based magnetooptical biosensors, electrochemical sensors and colorimetric sensors as well as therapeutic and multi-modal 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 three years, and we sincerely apologize to the authors for their important work that is unintentionally left out.

■ MAGNETO-OPTICAL BIOSENSORS Magneto-Optical Surface Plasmon Resonance. Among typical magnetic sensors such as fluxgate sensors, magnetoresistors, 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 set-up. 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 magnetic

field.

Multilayered

ferromagnetic/noble-metal

structures

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 4


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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 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 two 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

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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 angleresolved MOSPR bioassay and experimentally confirmed both increased sensitivity compared to those of current SPR/MOSPR approaches and higher 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 anti-human 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 6


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nanocomposites had diameters ranging from 8 to 30 nm and were functionalized with goat anti-human immunoglobulin M (IgM) for SPR sensing of human IgM molecules. A wide detected 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 AuS 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 concentration 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

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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. Magnetoplamonic nanoparticles enhanced surface plasmon resonance TB sensor based on recombinant gold binding antibody, pp. 356-363 (ref 46). Copyright 2017, with permission from Elsevier.

Magneto-optical Antennas. Magnetoplasmonic effects in nanostructures that support localized surface plasmons have recently attracted attention. These nanostructures are composed 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

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planar distributions of the MagPlas nanoantennas make them an effective choice for chipbased 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 nm 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) set-ups. The advantage of the MagPlas ruler over its non-magnetic 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 nano-gap ranges. This implies that the MagPlas ruler can measure both small and large distances with the same precision, which is difficult to achieve with non-magnetic plasmon rulers. Moreover, 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 non-magnetic 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 (Fig. 2d–e).16 In contrast to conventional 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 9



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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 10


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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 phasesensitive biosensing systems.

Figure 2. (a) Scanning electron microscopy image of the Ni ruler with 30 nm gap size, (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/|∆ε| 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.

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■ MAGNETO-ELECTROCHEMICAL SENSORS Magnetic Field in Electrochemistry. Magneto-electrochemistry, or study of magnetic effects in electrochemistry, has a 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 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 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 spectrometer increased electrochemical reduction rate of benzoquinone by a factor of five (Figure 3b). 12


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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 magnetobiosensor, the magnetic beads are attached onto surface of working electrode for electrochemical measurement by using external magnetic field. Magnetobiosensors offer great advantages in preconcentration 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-electrochemical 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 enrichment assisted in enhancing the detection sensitivity, while reliable and simplified conjugation chemistry and recovery of the bead-bound vesicles.

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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 magnet (red) and in the absence of 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, 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 14


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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.

Magnetoplasmonic-Based Electrochemical Biosensors. 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. 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 15



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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 microelectrode 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 electrochemiluminescence (ECL) biosensor platform for label-free determination of HeLa (human cervical carcinoma cell) cells using a multifunctional nanocomposite, by combining

the

branched

poly-

(ethylenimine)

functionalized grapheme/iron oxide hybrids(BGNs/ Fe3O4) and highly luminescent luminolAuNPs (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.

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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. 817823 (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.

■ 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 17



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immunosorbent 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 Fe3O4 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 co-assembly 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, 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 tailormade 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 attributed 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 S.D.blank/slope) with good reproducibility and 18


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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-or-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 approximately 100-fold and 10-fold lower than that of conventional Au NPs-based LFA and their previously developed Pt-based LFA.

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 Fe3O4Pt 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, 3513335140 (ref 75). Copyright 2017 American Chemical Society. 19



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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 magnetophoretically 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 that can be rapidly separated by external magnetic force, resulting in the solution turbidity changes. In recent studies, magnetophoretic assay strategies have been demonstrated 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 spectrophotometer setup, the pcMPI allowed simple and convenient immunoassay with an

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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) infections, 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 picoto 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 the photonic colloidal crystals inside humidityresponsive polymer gel matrix. The obtained sensor shows good sensitivity, reversibility and durability for humidity range of 97% ~ 11%. 21



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Guan’s group fabricated free-standing, flexible colorimetric temperature sensor by polymerization of colloidal-crystal non-aqueous suspension consisting of thermoresponsive monomer under a magnetic field.82 Since the poly(N-isopropylacrylamide) (PNIPAM) gel has a much lower refractive index than that of the polyvinyl pyrrolidone-coated Fe3O4 colloidal cluster, and experiences remarkable changes in volume with temperature, the as-prepared thermochromic one-dimensional photonic 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 the low IS range (Figure 6c). The reduced sensitivity of ∆λ 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’s likely that each Na+ ion has a higher chance to attach to the negatively charged surface of PA–Fe3O4 NPs at lower INaCl, and 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 ∆λ against INaCl.83

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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 ∆λ 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.

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■ IN-VITRO/IN-VIVO BIO-USABILITY AND BIO-IMAGING 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 photo-absorbing capabilities that generate heat under nearinfrared 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 fat 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 24


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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 Gdbased 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 paramagnetism, SPR in the NIR region, and admirable photostability 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 nanomaterial for MRI and photothermal ablation of cancer cells.90 Li et al. developed another variety of bioeliminable MagPlas nanoassembly photohtermal 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 bio-nanomaterials in biomedical applications.22 Yin et al., reported a highly integrated nanoplatform, showing remarkable biostability, rapid cellular uptake, and excellent in vitro and in vivo anti-tumor activity 25



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(Figure 7b). Polyethyleneimine (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 nanoplatform 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. Based on this design strategy, the shapes of the magnetite-Ag hybrid NPs were easily tunable by 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 magnetophoretic 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 26


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the Au nanorod absorption peak, the nanomicelle formulation efficiently generateed plasmonic nanobubbles within the cancer cells, as visualized by confocal microscopy, causing cell destruction.94

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 anti-tumor 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 society 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, 3546 (ref 24), Copyright 2017, with permission from Elsevier.

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Multi-modal Imaging. Non-invasive 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 requires injection of several contrast agents, which can make patients feel inconvenient and timeconsuming. 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 28


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composed by 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 bio-ligands thanks to their rich history in surface chemistry. Therefore, MagPlas NPs (FexOy–Au NPs) have been extensively studied as a multimodal 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 designed (Fig. 8a).103 Calculations based on the Landau–Lifshitz–Gilbert equation show that the intensity of the magnetic field is dramatically decreased with increasing distance from the surface of Fe3O4 NPs (Fig. 8b), suggesting that moving the waterimpermeable 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 29



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core–shell ones. Positron emission tomography images (Fig. 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 post-injection of the yolk–shell Fe3O4@Au NPs show an obvious contrast at the tumor site (Fig. 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/photoacoustic/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 coreshell NPs, and show high r2 relaxivity values and Prussian-blue staining ability. Furthermore, when compared with conventional 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.

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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 64Culabeled 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 YolkShell Nanostructure: An Ideal Architecture to Achieve Harmonious Integration of MagneticPlasmonic 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.

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■ CONCLUSIONS AND PERSPECTIVES There have been thousands of research papers published during the last three 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 multi-modal 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 sensitivity 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 SPPbased 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 towards 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. 32


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Over the last few years, besides using MagPlas NPs in conventional configurations, new concepts of electrochemical biosensors using MagPlas NPs have been reported, including integrated magneto-electrochemical sensor and ECL biosensor. The ECL biosensor concept has shown excellent performance with extremely low detection limits towards 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 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 out with the naked eyes or quantified by and inexpensive devices. Therefore, these properties present opportunities for MagPlas NPsbased colorimetric sensors as a tool for point-of-care (POC) tests that are urgently needed in 33



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resource-limited areas. The nanotechnology have a great benefit from nanotechnology 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 nano-based theranostics. There have been many reports on the development and application of MagPlas NPs and assemblies for in-vitro and in-vivo usability and bio-imaging application. Composite plasmonic-magnetic NPs may pave ways for promoting the tumor targeting multi-mode 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 nano-based 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 multifunctional MagPlas nanomaterials will provide powerful tools for simultaneous diagnosis and therapy of various diseases. 34


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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 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 nanostructures 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 focus 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 electrochemical detection of biomolecule, electrocatalytic process and electrochemical investigation of single nanoparticle behavior.

Sangjin Oh received her BS degree in 2013 and MS 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 35



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National University. She is interested in developing nanobiosensors and electrode platform using nanomaterials and nanocomposites, 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 BS degree in chemistry from Chungnam National University in 1998, and his PhD 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 biomedical applications.

Acknowledgements This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (2016R1A2B4012072), National Research Foundation (NRF) of Korea under the auspices of the Ministry of Science and ICT, Republic of Korea (2017R1A4A1015627). This study was supported by grants from the Korea 36


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Healthcare Technology R&D Project (HI17C1260) of the Ministry for Health, Welfare & Family Affairs and the 2017 Post-Doc. Development Program of Pusan National University.

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