Review Novel SERS labels: Rational design, functional integration and biomedical applications Beibei Shan, Yuhan Pu, Yingfan Chen, Mengling Liao, Ming Li ⇑ School of Materials Science and Engineering, State Key Laboratory for Power Metallurgy, Central South University, Changsha, Hunan 410083, China article info Article history: Received 10 February 2018 Accepted 7 May 2018 Keywords: Optical labels Surface-enhanced Raman scattering Surface plasmon resonance Biosensors Disease diagnostics abstract Driven by the growing demand for healthcare and point-of-care test applications, next-generation diag- nostic tools of diseases require sensing platforms that enable rapid, quantitative readout of analytes with excellent specificity and sensitivity. Although label-free detection permits simplicity, flexibility and high specificity, it has usually poor throughput, limited sensitivity and requires professional instrumentation. Label-based detection using optical labels overcomes many of these drawbacks and has been demon- strated to be an effective alternative for improved sensing performances. The current research focus has been directed towards innovating high-performance optical labels for ultrasensitive biosensing and disease diagnostics in place of conventional optical labels. Surface-enhanced Raman scattering (SERS) labels have proven to be excellent labels for biosensing because of their merits in many aspects, such as flexibility, less interference from biological matrices, high photostability, easy multiplex encoding, etc. These fantastic features make SERS labels particularly suitable for ultrasensitive detection of disease biomarkers in body fluids and targeted imaging of diseased cells and tissues, respectively. In this Review, we introduce the design and deployment of SERS labels for ultrasensitive detection, and summarize recent research progress in the development of SERS label-based sensing platforms and their applications in disease biomarker detection, targeted cellular imaging and spectroscopic detection of tumor lesions. First, we will discuss the design principles and comprehensive considerations of SERS labels, and the on-demand integration of functionalities. Next, we introduce the design of SERS sensing platforms on basis of SERS labels for ultrasensitive and selective detection of diverse pathology-related biomarkers, including proteins, nucleic acids, small molecules and inorganic ions. In addition, through the rational incorporation of targeting ligands on SERS labels, novel SERS probes are created for targeting near-infrared (NIR) imaging and spectroscopic detection of tumor, taking advantages of large NIR light penetration depth, high brightness, stability, etc. Our and other research efforts have demonstrated the promising potential of SERS label-based sensing platforms for detection of diverse circulating biomarkers for non-invasive disease diagnostics and deep-tissue spectroscopic detection of tumor. It is believed that this review will motivate further exploration of clinical applications of SERS labels in near future. Ó 2018 Elsevier B.V. All rights reserved. Contents 1. Introduction .......................................................................................................... 12 2. Surface-enhanced Raman scattering ....................................................................................... 13 3. Design and fabrication of SERS labels ...................................................................................... 14 3.1. Plasmonic materials .............................................................................................. 14 3.2. Structure of SERS labels ........................................................................................... 14 3.3. Fabrication of SERS labels .......................................................................................... 16 3.3.1. Native SERS labels ........................................................................................ 16 3.3.2. Sandwich SERS labels ...................................................................................... 19 https://doi.org/10.1016/j.ccr.2018.05.007 0010-8545/Ó 2018 Elsevier B.V. All rights reserved. ⇑ Corresponding author. E-mail address: [email protected](M. Li). URL: http://www.ming-group.com (M. Li). Coordination Chemistry Reviews 371 (2018) 11–37 Contents lists available at ScienceDirect Coordination Chemistry Reviews journal homepage: www.elsevier.com/locate/ccr
Beibei Shan, Yuhan Pu, Yingfan Chen, Mengling Liao, Ming Li ⇑School of Materials Science and Engineering, State Key Laboratory for Power Metallurgy, Central South University, Changsha, Hunan 410083, China
a r t i c l e i n f o
Article history:Received 10 February 2018Accepted 7 May 2018
Driven by the growing demand for healthcare and point-of-care test applications, next-generation diag-nostic tools of diseases require sensing platforms that enable rapid, quantitative readout of analytes withexcellent specificity and sensitivity. Although label-free detection permits simplicity, flexibility and highspecificity, it has usually poor throughput, limited sensitivity and requires professional instrumentation.Label-based detection using optical labels overcomes many of these drawbacks and has been demon-strated to be an effective alternative for improved sensing performances. The current research focushas been directed towards innovating high-performance optical labels for ultrasensitive biosensing anddisease diagnostics in place of conventional optical labels. Surface-enhanced Raman scattering (SERS)labels have proven to be excellent labels for biosensing because of their merits in many aspects, suchas flexibility, less interference from biological matrices, high photostability, easy multiplex encoding,etc. These fantastic features make SERS labels particularly suitable for ultrasensitive detection of diseasebiomarkers in body fluids and targeted imaging of diseased cells and tissues, respectively.In this Review, we introduce the design and deployment of SERS labels for ultrasensitive detection, and
summarize recent research progress in the development of SERS label-based sensing platforms and theirapplications in disease biomarker detection, targeted cellular imaging and spectroscopic detection oftumor lesions. First, we will discuss the design principles and comprehensive considerations of SERSlabels, and the on-demand integration of functionalities. Next, we introduce the design of SERS sensingplatforms on basis of SERS labels for ultrasensitive and selective detection of diverse pathology-relatedbiomarkers, including proteins, nucleic acids, small molecules and inorganic ions. In addition, throughthe rational incorporation of targeting ligands on SERS labels, novel SERS probes are created for targetingnear-infrared (NIR) imaging and spectroscopic detection of tumor, taking advantages of large NIR lightpenetration depth, high brightness, stability, etc. Our and other research efforts have demonstrated thepromising potential of SERS label-based sensing platforms for detection of diverse circulating biomarkersfor non-invasive disease diagnostics and deep-tissue spectroscopic detection of tumor. It is believed thatthis review will motivate further exploration of clinical applications of SERS labels in near future.
A biosensor is an analytical device that converts biologicalinteractions into measurable (i.e., optical, electrochemical) signalsfor detecting the presence or quantifying the concentrations ofspecific analytes. Biosensors have been extensively applied inmultiple areas, such as healthcare and environmental monitoring[1–4]. Among these applications, disease diagnostics and therapeu-tic efficacy evaluation are the most promising application domainsof biosensors through detection of disease-specific biomarkers.Glucose biosensors and pregnancy test strips are two typical exam-ples of biosensors widely used in the present biosensor market,which count for at least 90% of the global biosensor market[5–8]. Biosensors can be broadly classified into two categories:label-free and label-based biosensors. Label-free detection utilizesintrinsic molecular signatures or molecular biophysical properties,such as molecular weight, refractive index and charge, to deter-mine presence or amounts of analytes. In the label-free detection,molecular interactions are directly transduced as diverse (mechan-ical, electrical or optical) signals, and are thus detectable withoutany label. Therefore, label-free detection permits merits of simplic-ity, flexibility, high specificity, real-time tracking, etc. However,label-free detection suffers from poor throughput, limited sensitiv-ity and requires expensive instrumentation [9,10]. Label-baseddetection uses extrinsic signal labels for analyte measurements.Commonly used labels include electrochemical active molecules,isotopic elements, organic dyes and nanoparticles [11–15]. Label-based detection methods have been demonstrated to be quitepromising for a broad range of biosensing applications, overcomingmany of drawbacks mentioned above in the label-free detection.Mass spectrometry has been used routinely for detection of variousbiomarkers (i.e., proteins, metabolites) with high sensitivity andspecificity [16–18]. However, the complicated signal assignmentand expensive equipment limit its practical applications. Consider-ing the widespread use and growing demand of optical biosensors,intensive efforts have been currently devoted to the developmentof novel optical labels for diagnostic applications in place of con-ventional optical labels, such as fluorescent dyes and quantumdots.
Surface-enhanced Raman scattering (SERS) labels represent anintriguing class of optical labels for biosensing and bioimagingapplications, mainly attributed to multiple merits from SERS[19–24]. In principle, SERS exploits the confined electromagneticfield resulting from the excitation of the localized surface plasmonresonance (LSPR) and thus has become a potent analytical toolwith near single-molecule detection sensitivity and fingerprintingcapability [3,25–29]. Plasmonic materials play critical roles in SERSenhancement, that determines the detection performance of SERSsensing platforms. In general, plasmonic properties stronglydepend on geometry (i.e., size, shape), chemical composition, localdielectric environment of plasmonic materials and the interparticleinteractions [30–40]. Tremendous efforts have been made to con-
struct superior SERS biosensors through innovating plasmonicnanostructures. SERS biosensors can fall into two categories oflabel-free and label-based ones as well. Despite the direct informa-tion acquisition by the label-free SERS detection, focuses have beenon the development of SERS label-based biosensors as a competi-tive alternative due to weak intrinsic Raman signals and poor con-trollability in the label-free detection. Use of SERS labels in sensingand bioimaging facilitates the direct assignment of SERS peaksfrom SERS labels, excluding the possibility of misassignment ofcomplicated SERS spectra of large bio-molecules [41]. SERS labelsare quite robust because of the ultrafast energy transfer from theexcited Raman molecules to plasmonic metal materials so thatthe photoinduced breaching is considerably suppressed in SERSlabels [42,43]. Thus, development of SERS labels is one of the maintasks to move SERS biosensors forward for practical applications.Typical plasmonic nanostructures for SERS applications includecolloidal nanoparticles, two-dimensional (2D) materials andassembled three-dimensional (3D) hierarchical structures [44–49].The highly developed synthetic methodology of plasmonicnanostructures and the broadly tailorable nature of their LSPRbands make it quite feasible to optimize plasmonic substrates toachieve maximal sensing and imaging sensitivity [50–52].Colloidal suspensions of nanoparticles with various sizes andshapes are more suitable for biomedical applications because itcan be simply administrated in live cell and animals. However,for in vitro and in vivo biomedical applications, these nanostruc-tures often suffer from poor biocompatibility and matrix interfer-ence due to the direct surface exposure to complex biologicalenvironments. Recent studies have made great contributions tothe development of SERS labels for ultrasensitive detection andtargeted spectroscopic imaging of cancer cells and tumors.Applications of SERS labels have been exemplified for assessinglevels of disease biomarkers for in vitro disease diagnostics andin vivo applications [19,20,53–60].
SERS labels have attracted much attention from scientific andclinical communities because multiple unique merits of SERS makeSERS labels promising for diverse biomedical applications. Thisreview is to first provide valuable guideline for rational design ofSERS labels and its applications in biosensing and bioimaging. Thenwe will focus on the recent progress on the development of SERSlabel-based biosensors, serving as the promising diagnostic ‘‘liquidbiopsy” tools or imaging agents of high ‘‘brightness”. Optimizationof plasmonic structures, biocompatibility improvement and com-prehensive considerations of SERS labels used in biosensors willbe addressed, and implementation of quantitative detection of dis-ease biomarkers using SERS labels in clinic samples and targetedimaging of tumor cells or tissues will be elucidated. We will dis-cuss about important implications of these scientific findings andtechnological advances, and thereby provide scientific insights intodesign strategies. We expect that this review will stimulate newideas and inspire further endeavors for development of SERSlabel-based sensing platforms for biomedical applications.
Fig. 1. (A) Schematic illustration of localized surface plasmon resonance (LSPR)effects under the incident light. The incident field induces coherent motion of freeelectron gas in the nanostructure and the motion continues as damped oscillationsafter the incident field is turned off. The electromagnetic field distribution of a goldnanoparticle with 520 nm incident light excitation is shown as well. (B) Schematicrepresentation of the SERS enhancement mechanisms, mainly including electro-magnetic enhancement and chemical enhancement [73]. The plasmonic excitationproduces a significant localized electromagnetic field enhancement, contributing tothe enhanced scattering field as well. The chemical enhancement is associated withthe charge transfer (② + ③) between the SERS substrate and the Raman molecule,leading to the increase in polarizability of metal-molecule complexes underincident light. When the laser energy is consistent with the electronic transitionof the formed complex, the resonant Raman scattering occurs (①).
B. Shan et al. / Coordination Chemistry Reviews 371 (2018) 11–37 13
2. Surface-enhanced Raman scattering
Although the Raman scattering phenomenon was observed in1928 by C.V. Raman [61], the Raman scattering technique failedto be recognized as a practical biosensing tool until SERS was dis-covered. The main reason is the low probability of Raman scatter-ing, only about 1 in 107 photons [62,63]. In 1974, Fleischmann andco-workers discovered accidently the SERS phenomenon that apyridine monolayer adsorbed on a rough Ag electrode showedincreased Raman scattering intensity [64]. Following this, VanDuyne and Creighton independently revealed that the SERSenhancement could not be explained solely by the large surfacearea of the rough electrode surface, and further concluded thatthe increased Raman scattering cross-section might be responsiblefor the large SERS enhancement factor [65]. The underlying physicsof SERS lies in the light-matter interactions between the incidentelectromagnetic wave and plasmonic materials. The SERS enhance-ment mechanism is still under debate, but two commonly recog-nized mechanisms are electromagnetic enhancement andchemical enhancement [66–71]. The SERS electromagneticenhancement involves the LSPR excitation, inducingre-distribution of the electromagnetic field around plasmonicnanostructures, while chemical enhancement refers to thedynamic charge transfer between plasmonic materials andRaman molecules [72–74]. Further, when the incident light is inresonance with the optical excitation of Raman molecules,the Raman scattering experiences resonance enhancement,producing surface-enhanced resonance Raman scattering (SERRS)enhancement with relative high SERS enhancement factors(EFs). SERRS has been widely used in biosensing and bioimaging.Usually, the electromagnetic and chemical enhancements coexistand work together in concert to yield the overall SERSenhancement effect. Total SERS EFEM can be treated as the productof electromagnetic and chemical EFs. The electromagneticenhancement typically is the largest contributor to SERS with anEF of �1010–1011, significantly higher than that of chemicalenhancement (typically EF of 103) so that most of SERS-basedbiosensors have been developed by utilizing the plasmonicproperties of nanostructures [75–80]. Thus, this review willnarrowly focus on SERS biosensors based on plasmonic propertiesof nanomaterials. It is worth noting that this review is focusedon design and applications of SERS labels, and we only brieflydescribe the SERS enhancement mechanism for betterunderstanding of SERS label-related applications. For more detailsof SERS enhancement mechanism, we refer the readers to severalcomprehensive reviews [28,40,73,81].
According to the Maxwell’s equation, LSPR excitation of plas-monic nanostructures under an incident light generates an ampli-fied electromagnetic field outside of the structure. This outsideelectromagnetic field (Eout) is responsible for the SERS enhance-ment (Fig. 1A) [66,82]. The Drude model suggests that the LSPRabsorption is not only determined by the dielectric function (ei)of the plasmonic materials but also that (e0) of medium (Eq. (1)),described as: [83,84]
eðxÞ ¼ 1� x2p
xðxþ icÞ ; ð1Þ
where xp is the plasma frequency originating from natural oscilla-tion of free-electron plasma charge density, and c is the collisionrate reflecting the free electron damping.
When a Raman-active molecule is in close proximity to theplasmonic structures, the enhanced electromagnetic field increasesthe cross-section of Raman scattering significantly (Fig. 1B). TheSERS intensity (I(xs)) on a SERS substrate can be generallyexpressed as: [85]
IðxsÞ ¼ NAXdrðxsÞdX
PLðxLÞðeðxLÞÞ�1QðxsÞTmT0EF ð2Þ
where I(xs) is the SERS intensity at Raman shift xs, N for the mole-cule surface density, A for the excitation area, X for the solid angleof photon collection, dr(xs)/dX for the Raman scattering cross-section, PL(xL) for the radiant flux at excitation frequency xL, e(xL) for the energy of the incident photon, Q(xs) for the quantumefficiency of the detector, Tm for the transmission efficiency of thespectrometer, T0 for the transmission efficiency of the collectionoptics, and EF for the total enhancement factor. From the electro-magnetic enhancement point of view, the overall SERS enhance-ment (EFEM) involves two separate processes of incident fieldenhancement (E(x)) and scattered field enhancement (E(x0)), sothe SERS EF can be written as: [73,85]
EFEM ¼ jEðxLÞjjE0j2
2jEðxsÞjjE0j2
2
; ð3Þ
where E(xL) and E(xs) are the respective local electric fields at theincident frequencyxL and the Stokes shifted frequencyxs, and E0 isthe incident field. In most cases, the Raman shift is small so thatxL �xs. This leads to the famous expression of the SERSenhancement, referred to as the |E|4-approximation [73,85].
EFEM � jEðxÞjjE0j4
4
; ð4Þ
The nature of plasmon resonance absorption largely dependson the material’s composition, dimension and geometry. It isfound that the local electromagnetic field intensity induced by
14 B. Shan et al. / Coordination Chemistry Reviews 371 (2018) 11–37
the plasmon excitation is the largest in regions with high localcurvature or in the gap between dimers of nanostructures, theso-called ‘hot spots’ [33,86,87]. In the past decades, intensiveefforts have been devoted to innovating high-performance SERSsubstrates with high EFs. Fabrication of SERS substrates andtheir plasmonic properties are out of scope of this review, butinterested readers are referred to excellent reviews on this topicin literature [27,40,88–93].
3. Design and fabrication of SERS labels
3.1. Plasmonic materials
Plasmonics studies the interactions between incident electro-magnetic fields and free conduction electrons in nanostructures.It has been widely utilized to enhance near-field optics and opticalspectroscopies (i.e., SERS, plasmon-enhanced fluorescence)[3,27,40,88–97]. A plasmonic nanoparticle can be described as aconduction electron gas confined to a lattice of positive ions(Fig. 1A) [88,98]. Under the external incident field, the conductionelectron gas deforms with respect to its uniform equilibrium distri-bution. The displacement of the conduction electrons exposes thepositive background on one side of the nanoparticle and negativecharges on the other side. Thus, the Coulomb interactions createa restoring force that brings the electron gas back to its initial sta-tus, and the surface plasmon undergoes a continuous sinusoidal-type motion until damping forces bring the system to rest. In thecase of a sinusoidal applied external field, there exists at leastone frequency of maximum amplitude associated with electronoscillation. This frequency is called plasmon frequency.
Since colloidal nanoparticles are the commonly used plasmonicmaterials in SERS labels for biosensing and bioimaging, plasmonicnanoparticles with sharp edges or vertices have been intensivelyexplored. The main reason is that nanostructures of sharp edgesor vertices confine the electromagnetic field and thus dramaticallyboost the amplification of Raman signals through the well-known‘‘lightning rod effect” [33,99,100]. Typically, noble metals such asgold and silver are the most commonly used plasmonic materialsin SERS-based applications. Silver nanoparticles afford strong SERSsignals, but their toxicity remains a concern for in vivo applications.Gold is preferable for medical applications due to their low cyto-toxicity, water solubility, long-term stability, excellent biocompat-ibility and easy functionalization for bioconjugation [101]. Inaddition, gold nanostructures have features of LSPRs at longerwavelengths, making them more suitable for NIR use. Therefore,most in vivo biomedical applications involve use of gold as SERSsubstrates. SERS enhancements originating from the lighteningrod effect of particles with sharp features can reach an EF as highas 1011, while spherical nanoparticles can only give rise to an EFon the order of �103. It is revealed that as particles become larger,higher order modes of electron oscillations become more pro-nounced with a red-shift of the plasmon absorption band [102].These higher order modes decrease the collective motion of elec-trons, leading to wider plasmon band widths and lower SERSenhancements. It is recognized that the increasing particle sizered-shifts the LSPR wavelength and increases the particle surfacearea and extinction cross-sections. It is found that the highestenhancements for silver and gold nanoparticles with sphericalshapes are achieved in the size range of 40–60 nm in diameter[102–108]. Size-dependence of LSPR absorption of sphericalnanoparticles is well described by Mie theory, the analytical solu-tion of Maxwell’s equation [27,40]. However, the tunable range ofLSPR bands of spherical nanoparticles is quite narrow. Anisotropicnanoparticles with sharp edges or vertices offer a broader degree offreedom in tuning the LSPR absorption bands, with a range fromthe visible to NIR regions, and usually permit much higher SERS
EFs with respect to its spherical counterpart [31,83,101–111]. Typ-ical anisotropic structures include nanorods [109–111], nanocubes[112–114], nanostars [115], nanorice [116,117], nanotriangleplates [118], nanoflower [119], etc. (Fig. 2). Anisotropic nanostruc-tures with ‘‘built-in” hot spots are quite attractive for SERS labelcreation because of their high SERS enhancement capability with-out the need for complicated manipulation of nanostructures thatis usually used to achieve hot spots. 1D gold nanorods (GNRs) areelongated nanoparticles with distinctive optical properties depen-dent on their aspect ratios. GNRs exhibit two principal plasmonabsorption bands, which are the transverse plasmon band corre-sponding to the vibrational mode along the short axis and the lon-gitudinal plasmon band corresponding to the vibrational modealong the long axis. The transversal mode is usually located at�520 nm, with a slight blue-shift as the aspect ratio increases,and the longitudinal model can be tuned to the NIR region above1000 nm from the visible with the increasing aspect ratio. Theplasmon absorption of hollow gold nanospheres (HGN) is tunablein the entire visible-NIR region through controlling the size andthickness [120–123]. Thin metal nanoshells coated on a dielectriccore feature a plasmon band tunable from UV to NIR regions byaltering the core size and shell thickness. Halas pioneered a classof core-shell plasmonic nanoparticles that comprise a spherical sil-ica core and a gold shell [124–126]. The SPR band can be tunedfrom 800 nm to �1064 nm by carefully adjusting the size of silicacore and the thickness of a gold shell. Gold nanostars (GNSs) exhi-bit superior plasmonic properties due to multiple sharp tips on theGNS surface. We also demonstrated the broad tunability of theplasmon band of GNSs from 630 nm to 830 nm upon changingthe size and sharp tips [115]. Yin et al. conducted the systematicinvestigation of the plasmonic properties of silver nanotriangleplates, showing that the plasmon absorption band is tunable inthe range of 500 nm–2500 nm by changing the edge dimensions[51,118]. Current synthetic methodologies and lithography tech-niques have allowed the flexible tailoring of various shapes ofnanostructures with desirable plasmon absorption properties andoptimal SERS enhancement. The underlying physics of plasmonproperties of these novel nanostructures have been in-depth inves-tigated and well-understood, as introduced in previous literature[27,83,88,90,92,126–131].
3.2. Structure of SERS labels
A SERS label could be simply considered the SERS equivalent toa fluorescent label in fluorescent sensing and imaging. SERS labelsare created to intrinsically carry SERS signals and are able to selec-tively identify target molecules or sites by incorporating specificrecognition elements [3,20,33,58,136–142]. Typically, the maincomponents of a SERS label include one plasmonic nanoparticlecore, Raman reporter molecules and sometimes an outer protectiveshell (Fig. 3) [3,33,137]. The plasmonic field acts as the signalamplifier of Raman scattering, producing SERS signals characteris-tic of molecular signatures of Raman molecules. Plasmonic nanos-tructures of high density of built-in ‘‘hot spots” are preferableplasmonic cores used in SERS labels, such as nanocubes, hollowstructures, nanostars and nanoflowers (Fig. 2) [109–117,132–135]. Raman molecules used in SERS labels are required to bearhigh affinity toward metallic surfaces and possess large Ramanscattering cross sections and long-term stability against the robustexternal environment and strong laser irradiation, as well as char-acteristic Raman peaks non-overlapping with those of other mole-cules [143]. Raman molecules for SERS labels often possesspolarizable p-conjugation molecular structures with functionalgroups such as thiols, isothiocyanates or amines. It should be notedthat Raman reporter molecules of high water solubility cancompromise the stability and reproducibility of SERS signals in
Fig. 2. Representative colloidal plasmonic nanostructures and their tunable LSPR absorption bands. TEM images and tunable extinction spectra of (A) gold nanospheres, (B)gold nanorods, (C) silver nanocubes, (D) gold nanostars, (E) silver triangle nanoplate and (F) gold nanocages [33,114,118,132–135].
B. Shan et al. / Coordination Chemistry Reviews 371 (2018) 11–37 15
SERS labels because the robust biological environments couldcause desorption of Ramanmolecules from the plasmonic core sur-face. We suggest the utility of Raman active molecules of slight lowwater solubility, such as malachite green isothiocyanate (MGITC),4-nitrothiophenol (4-NTP) and others when SERS labels are appliedin robust biological environments [3,33,137]. Recently, alkyne-containing compounds have attracted wide interests for SERSlabels because its characteristic Raman signatures appears at�2100 cm�1, the cell-silent region where no other peaks fromendogenous molecules exist, achieving exquisite detectionspecificity [144–149]. Table 1 lists representative Raman-activemolecules commonly used in current literature [60,150–167].
Both electrostatic interaction and covalent binding are widelyused to attach Raman-active molecules onto the surface of
plasmonic nanostructures for creation of SERS labels. It is logicallyrealized that the SERS substrates and Raman active molecules areparamount in obtaining high performance SERS labels [3]. Carefuldesign of plasmonic cores and Raman-active molecules enablesimprovement of detection sensitivity of SERS biosensors, which isone of the most important factors when designing for diagnostictests, especially early diagnostics of diseases. Most of the com-monly used Raman molecules have an absorption band in theUV–visible region (Table 1). It is well recognized that NIR lasersare preferable for in vivo biomedical applications because of itslarge penetration depth and negligible autofluorescence/absorp-tion interference, but SERS signals are quite low when a NIR laseris used. It is also well-known that the Raman scattering intensityis inversely proportional to the forth power of the laser wavelength
Fig. 3. (A) SERS labels without (i) and with (ii) protective outer layers, i.e., silica,polymers, PEG and antibodies. Raman active molecules can be adsorbed onto themetallic surface through covalent binding or physical interactions. (B) SERS labelsfunctionalized by functional biomolecules.
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[168]. To improve NIR SERS sensitivity, NIR active Raman mole-cules have been explored for SERRS. 3,30-diethylthiatricarbocyanine (DTTC) is usually considered as the standard in NIR SERS.However, DTTC shows only a moderate Raman intensity, whichlimits the NIR SERS applications in vivo. Chang’s group performeda systematic investigation of an 80-member tricarbocyaninelibrary with varying amine structures for 785 nm NIR laser excita-tion [169]. It is revealed that the SERS intensities of CyNAMLAcompounds varied significantly dependent on the amine structure.CyNAMLA derivatives containing mostly aromatic amines exhib-ited much higher SERS intensities with respect to that of DTTC. Fur-thermore, CyNAMLA-381 showed �12-fold increase of sensitivityrelative to the standard DTTC. Due to the availability of few NIRRaman active molecules, further exploration of NIR Raman activemolecules is essential to push SERS forward for clinicalapplications.
Direct adsorption of Raman-active molecules on the surface ofplasmonic materials comprises one prime type of SERS labels(Fig. 3A). It mainly utilizes electrostatic interactions or the highaffinity of functional groups (i.e., thiols, isothiocyanates, amines)toward metallic surfaces. However, this type of SERS labels, callednative SERS labels here, exposes Ramanmolecules to the surround-ing environment, leading to their potential desorption in practicalapplications, especially when used in clinical settings (Fig. 3A)[172–175]. To obtain stable SERS labels more suitable for in vitroand in vivo applications, a protective layer is suggested to encapsu-late the plasmonic core incorporated with Raman molecules. Aprotective shell could prevent coalescence and fouling, and moreimportantly, provide stable SERS signals and introduce flexibilityof the on-demand surface functionality integration for biomedicalapplications. A variety of biocompatible materials including anti-bodies, polyethylene glycol (PEG), polymers, silica and biologicalderivative materials are good choice of protective shell materialsto improve the stability and biocompatibility of SERS labels
(Fig. 3B) [3,33,58,137,148,176,177]. These biomaterials as protec-tive layer materials for SERS labels have attracted great interestbecause of their low toxicity, low cost and well-established surfacechemistry for surface modification [178,179]. A diversity of SERSlabels encoded with visible–NIR responsive Raman molecules andexcellent bioapplicability are being pursued by the scientific com-munity for both in vitro and in vivo applications [180–185]. In addi-tion, it has been recently demonstrated that graphene and itsgraphene oxide derivatives can act as an effective protective shellfor SERS labels of high-quality as well [186–188]. This type of SERSlabels combined the huge electromagnetic enhancement of noblemetals with unique properties of graphene, including (i) strongpre-concentration capability through the p-p interaction, (ii)charge transfer-induced chemical enhancement, and (iii)superquenching capability toward the fluorescence, eliminatingthe effect of fluorescence on the Raman signal. Thus, SERS labelswith graphene or graphene oxide protective shells are promisingfor biosensing and bioimaging. Carbon nanotubes have been alsoinvestigated for SERS labels because of their strong G and D bands[189,190].
In the one hand, encapsulated SERS labels with protective layersoffer additional extraordinary merits for biomedical applications[3,33,137,191–196], including (i) strong SERS signals due to a largenumber of encapsulated Raman-active molecules in a single SERSlabel, (ii) excellent stability with negligible leaching out of Ramanmolecules, (iii) high water solubility due to high hydrophilicity ofthe shell materials, (iv) excellent biocompatibility and flexibilityfor biomolecule conjugation, (v) less water interference and lesstoxicity, (vi) easy multiplexing due to the narrow spectral signa-tures excitable with a single laser wavelength, and (vii) less aut-ofluorescence from tissues and blood. SERS labels with protectivelayers have been demonstrated to be promising for developmentof SERS biosensors for biomolecular sensing and targeted imagingwith high sensitivity. In the other hand, when it comes to practicalapplications, instead of chasing the ultimate limit of sensitivity, thereproducibility issue has become the major concern of SERS label-based detection to develop reliable and reproducible measure-ments. In particular, reproducibility becomes very important fordetecting low levels of biomarkers for early stage assessment ofcancer. Another limitation of SERS labels is the large size comparedwith that of dye molecules or quantum dots, which may affect thecellular uptake and thus lead to low sensing or imaging efficiency.
cores and Raman-active molecules (Fig. 4). Two early deploymentsof native SERS labels for biosensing were performed in 1999 by thePorter group and in 2002 by the Mirkin group, respectively[197,198]. In the Porter’s work, they covalently adsorbed Raman-active molecules (such as thiophenol, 2-naphthalenethiol, 4-mercaptobenzoic acid or their mixture) onto gold colloids, fol-lowed by functionalization of antibodies to incorporate the target-ing ability [197]. The thiol group of Raman-active molecules canchemically bind onto the surface of metal nanoparticles. A SERSlabel-based ELISA-like immunoassay was demonstrated with thetarget antigen, and further the multiplex detection capability basedon these native SERS labels was exemplified as well in this work.Later, the Mirkin group developed a SERS label with Raman-active dyes and oligonucleotides whose SERS intensity can be fur-ther enhanced by a silver coating [198]. This design has beenemployed for the successful multiplexed detection oligonucleotidetargets with high sensitivity and excellent selectivity. In nativeSERS labels, the physical adsorption is rarely used for constructionof SERS labels because of the poor stability caused by the surrounding
Table 1Representative Raman active molecules used for preparation of SERS labels [60,150–171]
Fig. 4. Schematic representation of fabrication of native SERS labels (left) and sandwich SERS labels. Native SERS labels represent a type of SERS labels that are prepared bydirectly adsorbing Raman-active molecules onto a plasmonic core without a protective layer, and sandwich SERS labels are a combination of a plasmonic core with Raman-active molecules encapsulated within a protective layer.
B. Shan et al. / Coordination Chemistry Reviews 371 (2018) 11–37 19
robust environment. This type of SERS labels has been used forSERS-based biosensing and bioimaging with high sensitivity andmultiplexing capability. However, due to the direct exposure ofRaman-active molecules, native SERS labels suffer from poor sta-bility and reproducibility. In addition, Raman-active moleculesare competitively adsorbed on the plasmonic core with functionalbiomolecules, which may compromise the stability of SERS signals.In early studies, small molecules and organic dyes have been usedas Raman-active molecules in SERS labels by covalent binding or
Fig. 5. SERS labels in various forms. (A) Native SERS labels which are encoded with dprotection layer. Sandwich SERS labels are first encoded with Raman-active molecules, a[182,208,209] or (D) graphene [187].
electrostatic interactions. These SERS labels exhibit their strongactivity in UV-visible regions. Few studies have recently con-tributed to the development NIR-responsive SERS labels to achieveoptimal SERS performance under the NIR incident excitation [180–185].
labels may desorb from the plasmonic cores due to the external
ifferent Raman dyes and oligonucleotides [198]. The native SERS labels have nond (B) then coated successively with glass and silica [178], (C) coated with proteins
Fig. 6. Schematic representation of functionalization of SERS labels and their use for biosensing and cellular imaging. (A) Functionalization of SERS labels [223]. SERS labelscan be modified with a variety of functional molecules to improve their biocompatibility and incorporate the targeting capability. (B) Representative SERS assays and cellularimaging based on SERS labels. SERS labels can be used as the signal probe in the ELISA assay and analyte detection for DNA based biosensors. SERS labels can be used fortargeting cellular SERS imaging with modification of targeting moieties.
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robust environment. To improve the stability and applicability ofSERS labels in biomedical applications, a protective layer outsideplasmonic cores coated with Raman-active molecule (also nativeSERS labels above) is often introduced, which effectively avoidsloss of Raman-active molecules (Fig. 4) [3,33,137,191–196]. Thatis, sandwich SERS labels are core-shell structured nanoparticleswhere a nanometer-scale plasmonic core is functionalized withRaman-active molecules and then encapsulated within a protectiveshell. Sandwich SERS labels provide with multiple merits forbiomedical applications mentioned above, such as chemical andmechanical stability, ultrahigh sensitivity, molecular specificity,multiplex capacity and flexible function integration.
Glass has been widely used as a class of protective matrix of flu-orescent quantum dots, and demonstrated with its excellent bio-compatibility and robustness against external environments[15,199,200]. Taking with these unique properties, Natan and co-workers developed the first sandwich SERS label in 2003 by utiliz-ing glass as the protective materials [178]. They demonstrated therobustness of the glass-coated sandwich SERS labels by exposureto aqua regia. In their work, a thick layer of silica was furthercoated onto the glass-coated SERS labels, leading to the large sizeof the final SERS labels unsuitable for in vivo applications. To over-come drawbacks of sandwich SERS labels for in vitro and in vivobiomedical applications, Nie and co-workers found that use oforganic dyes with an isothiocyanate (AN@C@S) group or multiplesulfur atoms as Raman-active molecules could improve the stabil-ity of sandwich SERS labels with only the thin glass protective layer[150]. This sandwich SERS labels exhibited excellent chemical andmechanical stability in both aqueous electrolytes and organic
solvents, with SERS EFs on the order of 1013–1014, large enoughfor single-particle or even single-molecule spectroscopy. Silicahas been demonstrated for preparation of sandwich SERS labelswith excellent biocompatibility, chemical stability and flexiblefunctionalization. However, when SERS labels are used in biosens-ing and bioimaging, proteins and nucleic acids from biologicalmatrices are often adsorbed onto the surface of SERS labels to formso-called ‘‘corona” [201,202]. The ‘‘corona” formation around SERSlabels will affect the performance of SERS applications. Nie et al.devoted further efforts to improving performance of SERS labelsin in vitro and in vivo biomedical applications using polyethyleneglycol (PEG) to encapsulate gold nanoparticles encoded withsmall-molecule Raman-active molecules [177]. It was observedthat the PEGylation of organic dye-encoded gold nanoparticlesdid not displace the chemical binding of Raman-active moleculeson the gold surface. In addition to the excellent biocompatibilityand flexible functionalization, PEG coating of SERS labels couldeffectively inhibit cell adhesion and the adsorption of bovin serumalbumin, laminin, fibronectin, erythrocytes and macrophages[203–207]. Due to high sensitivity of SERS label based biosensors,Nie et al. conjugated PEGylated SERS labels to tumor-targetingligands and achieved considerably bright in vivo SERS imaging inthe near-infrared window, 200 times higher than quantum dots[150].
In some metallic nanoparticles, the synthetic methodologyrequires use of surfactants so that the surface of nanoparticles con-tain organic layers positively or negatively charged [108–118].Polyelectrolytes have been assembled by way of layer-by-layeronto metallic nanoparticles to form sandwich SERS labels
Table 2Comparison of performance of selective SERS label-based sensing platforms with conventional approaches for detection of biomarkers [241–251].
Biomarker Sensing principle Sample LOD Linear range Refs #
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[210–212]. Compared to silica and PEG coating, polyelectrolytecoating not only simplifies the preparation process but also effec-tively avoids competitive adsorption with Raman-active mole-cules. However, one of drawbacks is that interference of Ramanpeaks from polyelectrolytes may occur. In addition, a variety ofderived biomaterials such as proteins [208,212], peptides, lipids[213] and carbohydrates [214,215], are widely used as protectivelayers in sandwich SERS labels as well. These biomaterials havebenefits of high biocompatibility, low cellular toxicity, suitablebiodegradability and easy clearance from the body.
Fig. 7. Schematic representation of (A) sandwich SERS immunoassay and (B)competitive SERS immunoassay for detection of protein biomarkers in body fluids.
3.3.3. Carbon coated SERS labelsCarbon materials exhibit a variety of chemical, optical and
mechanical properties depending on their structures and surfacechemistry. Carbon materials have been also used as protectivematerials for SERS labels (Fig. 5D) [186–188]. Both graphitic andamorphous carbon materials as the protective layer can benefitthe sensitivity, specificity and multiplexing of SERS label basedbiosensors. Graphite carbon, especially graphene and its derivativegraphene oxide, can coat onto the Raman-active molecule encodedgold/silver nanoparticles. Graphene has strong adsorption capabil-ity toward aromatic compounds due to the p-p interaction so thatgraphene coated SERS labels possess pre-concentration capability,leading to high detection sensitivity; graphene can quench fluores-cence, eliminating the effect of fluorescence on the Raman signal.One intriguing feature from graphene coated SERS labels is thatgraphene provides excellent Raman intensity called G and D bands,which can be used for SERS labels without the need for otherRaman-active molecules. Amorphous carbon acting as the protec-tive shell materials includes various glucose, cellulose and polysac-charide [216–219]. Li et al. prepared graphene oxide coated slivernanoparticles (Ag@GO), and demonstrated the enhancement abil-ity of Ag@GO toward various aromatic dyes, such as Rhodamine6G, Rhodamine B and crystal violet, with high sensitivity and
signal-to-noise ratio [216]. The combination of plasmonic metalliccores with graphene endows SERS labels with excellent attributesfor both in vitro and in vivo biomedical applications. Currently,reproducible preparation methods for carbon coated SERS labelsand their applications in biosensing and bioimaging are beingintensively pursued.
3.4. Surface modification of SERS labels
Specific demands for sensitive detection or imaging of targetsrequire diverse functionality integration into SERS labels. Oncethe target is identified, a targeting ligand with optimal bindingaffinity, specific size and functional groups must be rationally
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designed. The targeting ligands that are introduced onto the SERSlabels selectively bind to the corresponding analytes or recognizesurface receptors on the targeted sites (i.e., cells, tissues) (Fig. 6)[220]. SERS labels without a protective shell are usually functional-ized with thiol-containing molecules such as HS-DNA, HS-PEG andproteins by the strong AuA or AgAS bond (Fig. 4). When the pro-tective outer shell exists, the biocompatible shell materials allowus to easily introduce various functional groups (i.e., ACOOH,ANH2, ASH), which can meet various needs for conjugation of bio-molecules or other functional moieties. A wide range of targetingligands have been used, which are categorized into antibodies,aptamers, small protein scaffolds, peptides and low-molecular-weight non-peptidic ligands (Fig. 6) [221,222]. As for quantitativedetection of disease biomarkers or other analytes of interest, highbinding affinity is important to achieve high detection specificity;for targeted imaging, the molecular size as well as binding affinityof targeting ligands should be carefully taken into account. If theligand size can be controlled without a substantial loss of speci-ficity and binding affinity, low-molecular-weight targeting ligandswill be generally preferred on account of several merits such as fastdiffusion, accumulation and clearance, and high formulation stabil-ity as well as synthesis purity, efficiency and economy, as opposed
Fig. 8. SERS label based immunoassays for detection of protein biomarkers. (A) SERS imformation for sandwich structures [241]. SERS labels are functionalized with MCU4-animmunoassay occurs between functionalized SERS labels, MCU4 antigen and capture antidetection of VEGF. The silver triangle nanoarray is coupled to the SERS label based nanoprlabel nanoprobes. Both the triangle nanoarray and SERS labels are functionalized withbased immunoassay process for the simultaneous detection of f-PSA and c-PSA [223]. (i)of SERS labels to form sandwich immunocomplexes. (iii) Separation of magnetic immuno(D) Schematic illustration of SERS immunoassay for multiplex detection of protein biomaand SERS labels are functionalized with their respective antibodies against their analytes.of the SERS response is correlated to the levels of corresponding biomarkers.
to antibodies or aptamers [191]. High binding affinity, prolongedcontact time to targeted sites and fast diffusion are conducive totargeted imaging and drug delivery for disease management.
4. Detection of biomarkers for disease diagnosis
An abundance of biomarkers are produced by tumor tissuesthemselves or by other tissues and eventually shed to the circula-tion system via tumor cell necrosis, apoptosis and active release ofcellular metabolites. These tissue- or disease-specific biomarkerscan be proteins, cell-free nucleic acids (i.e., DNA, RNA, microRNA,methylated DNA), circulating tumor cells, metabolites, small mole-cules and ions in various body fluids as well as from various phys-iological processes. These biomarkers have important implicationsin disease detection, management, and monitoring of therapeuticefficacy by the so-called ‘liquid biopsy’ for molecular diagnostics[224–230]. These biomarkers, individual or combined as a panel,can serve as effective indicators of a specific biological state, thepresence or the stage of disease, and even work for early diseasedetection. Detection and profiling of biomarkers for diagnosticsof diseases and monitoring of subsequent therapeutic treatmentshave been well reported. Extensive efforts have been devoted to
munoassay for detection of pancreatic cancer specific MCU4 biomarker through thetibody, and the capture antibody is immobilized on the substrate. The sandwichbody. (B) Schematic illustration of the operation principle of SERS immunosensor forobes to form a 3D plasmonic field, significantly enhancing the SERS signal from SERSthe target-specific antibody as the recognition element [193]. (C) Sequential SERS-Mixing of f-PSA, c-PSA, and t-PSA antibody-conjugated magnetic beads. (ii) Additioncomplexes using a magnetic bar. Simultaneous detection of (iv) f-PSA and (v) c-PSA.rkers [195]. The SERS chip is defined for specific analytes, and both defined regionsImaging is performed over a wide field of wells in the SERS panel and spatial average
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the development of novel diagnostic methods that detect andquantify biomarkers with high sensitivity and reliability, con-tributing to better disease diagnostics and prognostics. SERS labelsact as an excellent alternative to fluorescent labels in manybiomedical applications [231–240]. Besides traits similar to thosein fluorescent labels, SERS labels offer unique features benefitingbiosensing and bioimaging for disease diagnostics with muchhigher sensitivity and accuracy. Taking with great advantages ofSERS, we will introduce applications of SERS labels for quantitativedetection of protein biomarkers, genetic biomarkers, small mole-cules and inorganic ions for disease diagnosis and managementwith SERS label-based platforms, followed by in vivo diagnosticor theranostic applications [3,33,137,191–196]. Table 2 lists theperformance of SERS label-based sensing platforms in comparisonwith conventional approaches [241–251].
4.1. Protein biomarker detection
Protein biomarkers offer tremendous potential for early detec-tion, prognosis and therapeutic response monitoring of cancer.Early diagnostics and management of cancer heavily rely on pro-tein biomarker detection in body fluids such as blood and urine[252,253]. Typical techniques for detection and profiling of proteinbiomarkers include mass spectrometry, western blot, gel elec-trophoresis and enzyme-linked immunosorbent assay (ELISA).These techniques are complicated, laboratory-based, time-consuming and require experienced personnel to conduct theassay analysis. One of the well-established methods for proteinmeasurement is immunoassay, which exploits the specificity ofantigen-antibody interactions. The immunoassays commonly usesandwich or competitive immunoassay formats. The concentrationof protein biomarkers associated with early stage cancers andinfectious diseases generally ranges from 10�16 to 10�12 M, andcommercially available immunoassays, like ELISA, are typicallycapable of measuring proteins with a limit of detection (LOD) atthe picomolar level, which cannot optimally meet the critical needfor protein biomarker detection [193,254]. Taking with tremen-dous advantages of SERS labels for SERS detection in terms of ultra-sensitivity, excellent specificity, easy multiplexity and lessbackground interference, SERS label-based sensing platforms havebeen intensively studied and investigated. Similarly, SERSimmunoassay used for biomarker detection can be classified intosandwich and competitive SERS immunoassays as well (Fig. 7).The combination of high sensitivity in SERS with the excellentspecificity of the antibody-antigen interactions makes the SERS-based immunoassays particularly suitable for detection of low con-centration protein biomarkers in early cancer diagnostics.
SERS label based immunoassays have great advantages overother conventional methods and demonstrated its success fordetection of circulating protein biomarkers. Merits of SERSimmunoassays include [3,33,137,191–196] (i) high sensitivitydue to both a huge plasmonic amplification capability and a largenumber of encapsulated Raman-active molecules in a single SERSlabel, (ii) excellent chemical, mechanical stability and negligiblephotobleaching, (iii) excellent biocompatibility and flexibility forbiomolecule conjugation, (iv) easy multiplexing due to the narrowspectral signatures excitable with a single laser wavelength, and(vi) less interference and less autofluorescence from biologicalmatrices, tissues and blood. Porter and co-workers first exploitedSERS labels as the signal readout to develop a SERS basedimmunoassay [197]. The SERS immunoassay first requires captureantibody immobilization onto the substrate, and then analytes arecaptured followed by addition of SERS probes. SERS immunoassayshave been broadly applied for detection of a wide range of disease-specific protein biomarkers. Pancreatic cancer (PC) is the fourthleading cause of cancer-related deaths in the United States, with
a 5-year survival rate of only 6%. Studies showed that the mucinprotein MUC4 is aberrantly expressed in pancreatic adenocarci-noma cell lines and tissues but is undetectable in normal pancreasand chronic pancreatitis. Thus, the level of MUC4 in patient serahas the potential to function as a diagnostic and prognostic marker.Lipert et al. developed a SERS based immunoassay for the first everdetection of MUC4 in cancer patient serum samples (Fig. 8A) [241].This work confirmed the significantly higher SERS response forMUC4 from sera of patients with pancreatic cancer PC comparedto sera from healthy individuals and from patients with benign dis-eases. Further, we developed an ultrasensitive SERS immunosensorfor selective detection of the vascular endothelial growth factor(VEGF) in human blood plasma of patients. VEGF is a protein bio-marker for tumor-associated angiogenesis and upregulated in sev-eral forms of human cancers (Fig. 8B) [193]. Albeit GNS based SERSlabels provide extremely strong SERS signals and enable high sen-sitivity for protein biomarker detection, we further improved thedetection sensitivity through coupling sandwich SERS labels to aperiodic gold triangle nanoarray. When protein biomarkers arepresent, the SERS label-based nanoprobes are captured over thegold triangle nanoarray and consequently form a confined 3D plas-monic field, leading to the enhanced electromagnetic field in inten-sity and 3D space. This SERS immunosensor exhibits a widedynamic detection range (0.1 pg/mL to 10 ng/mL) and a LOD aslow as 7 fg/mL. In addition to high sensitivity and specific molecu-lar signatures, SERS suffers from less interference from the com-plex biological matrices compared with plasmonic, fluorescentand electrochemical modalities.
Nevertheless, single protein biomarkers may be inadequate indescribing complex pathological transformations, and cause accu-racy issues for disease diagnostics. Ratiometric method is an effec-tive way for quantifying the dual biomarker level ratio for accurateanalysis of specific biomarkers. Choo et al. reported a SERS basedimmunoassay for determination of free to total prostate specificantigen (f-PSA/t-PSA) ratio (Fig. 8C) [223]. The level of f-PSA thatdoes not combine with other proteins decreases in men who haveprostate cancer relative to those with a benign condition. Thus, thef-PSA/t-PSA ratio can be additionally used in clinically diagnosticsto discriminate between prostate cancer and benign prostatichyperplasia. Higher t-PSA level and lower percentage of f-PSA areassociated with a higher risk of prostate cancer. This is particularlyuseful for patients with t-PSA level that falls in the ‘‘diagnostic grayzone” between 4.0 and 10.0 ng/mL. In their work, two differentSERS labels encoded with different Raman signatures, one for f-PSA and the other for complexed PSA (c-PSA), were created, whichformed magnetic sandwich immunocomplexes for both PSA mark-ers. This work presents simultaneous detection of dual PSA mark-ers in blood serum using SERS label based assays under singlewavelength excitation, offering advantages over conventionalmethods such as reduced sample consumption, rapid detectiontime, high detection throughput and low cost per assay. They fur-ther demonstrated the feasibility of the proposed method as a clin-ical tool in prostate cancer diagnostics through comparing assayresults for 30 clinical samples with those measured by electro-chemiluminescence assay.
Parallel measurements of multiple biomarkers are required toachieve the desired clinical sensitivity and accuracy of diseasediagnosis while conserving patient specimen and reducing turn-around time [195,255–257]. Several strategies have been adoptedto detect multiple biomarkers from clinical complex samples. Forexample, multiple biomarkers are individually readout using theirrespective immunoassays of single protein biomarkers describedabove; microarray methods that integrate immunoassays of differ-ent biomarkers into one single chip have been well-established.Inspired from previous work, we developed a SERS imaging basedmethod for multiplex detection of a panel of biomarkers consisting
Fig. 9. SERS detection of genetic and epigenetic biomarkers. (A) DNA hybridization monitoring using SERS label based probes [3]. The complementary ssDNA is used as thecapture probe and first immobilized onto the substrate, and the SERS probe is made by conjugating detection probe onto the SERS label. The incubation of both probes causesthe hybridization, leading to the detectable SERS signal. (B) The operation principle for sandwich SERS detection of HBV DNA using SERS probes [194]. The silver nanorice isused as the plasmonic core for the SERS labels, which is conjugated with DNA detection probes. The gold triangle nanoarray is modified with the complementary DNA captureprobe. The presence of nucleic acid targets results in the sandwich assay with the capture and detection probes. The coupling of plasmonic silver nanorice with the goldtriangle nanoarray contributes to the significantly amplified plasmonic field and high detection sensitivity. (C) Multiplex SERS detection of DNA and microRNA using SERSlabel based biosensors [267]. Three types of SERS probes with different Raman signatures are functionalized with their respective capture DNA/RNA followed by hybridizationwith their corresponding SERS probes, leading to the formation of concomitant multiple sandwich complexes. (D) Multiplex SERS assay for triple-target microRNA biomarkers[263]. Three type SERS probes encoded with different Raman signatures are functionalized by their respective probe DNAs. Target microRNA is captured by capture DNAimmobilized on silver microsphere, followed by hybridization with its own SERS probe.
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of breast cancer markers cancer antigen (CA) 15-3, CA 27-29 andcancer embryonic antigen (CEA) using SERS label based nanop-robes (Fig. 8D) [195]. The SERS chip was well defined with therespective antibodies for recognition of different analytes and theSERS labels were modified with their corresponding antibodies.As a consequence, the SERS imaging across the chip using thewide-field compact Raman scanning setup enables simultaneousquantification evaluation of multiple biomarkers. The LODs werecomputed to be 0.99 U/mL, 0.13 U/mL and 0.05 ng/mL for CA15-3, CA27-29 and CEA, respectively, which are significantly smallerthan the corresponding LOD values reported from the conventionalmethods. Using this assay format, we also achieved four orders ofdynamic range in the LODs for three of protein biomarkersinvestigated.
4.2. Nucleic acid biomarker detection
Genetic and epigenetic biomarkers are the most promisingbiomarkers in cancer and other disease research, and are thereforeinvaluable tools for early detection, diagnostics, treatment, prog-nostics and recurrence monitoring of a variety of diseases [258–261]. These genetic and epigenetic biomarkers include nucleic acidmutants, microRNA, methylated DNA, siRNA and so forth. Micro-RNAs play roles in almost all aspects of cancer biology, such as pro-liferation, apoptosis, invasion/metastasis and angiogenesis. Thepattern of microRNA expression can be correlated with cancertype, stage, and other clinical variables. DNA methylation is a hall-mark of various diseases, in particular of cancer, usually responsi-ble for tumor formation and progression. Diagnosis based on DNA
Fig. 10. (A) Operation principle of the SERS sensor for ATP detection [192]. Themolecular structures of ATP and its analogs and DNA sequences are shown. (B) SERSdetection of Hg2+ and Ag+ using sandwich SERS labels functionalized with DNA[280].
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methylation alteration is advantageous and applicable for clinicalpurposes because of its high stability and low methylation levelin normal tissues. Thus, their detection has brought a great dealof attention to the development of ultrasensitive sensors. However,the low concentration of these genetic and epigenetic biomarkersin blood requires sensitive detection methods [262]. Several tech-niques have been developed for genetic and epigenetic biomarkerprofiling such as polymerase chain reaction (PCR), quantitativereal-time PCR, microarray, in situ hybridization and serial analysisof gene expression (SAGE), MethyLight technique and bisulfiterestriction analysis. Main drawbacks of these methods includecomplicated operation, professional training required, long timeand high cost. Use of SERS labels for detection of genetic or epige-netic biomarkers benefits high sensitivity [263–266]. Reliable andquantitative measurement methods for ultrasensitive detectionof circulating genetic and epigenetic biomarkers in a small amountof methylated DNA have been extremely desired. We have recentlyemployed SERS label based nanoprobes to monitor the DNAhybridization and detect the presence of DNA targets (Fig. 9) [3–194]. Hepatitis B is a prevalent and potential life-threatening dis-ease caused by hepatitis B virus (HBV). Chronic carriers of ‘inactive’HBV often have no symptoms but can still transmit the virus toothers. Hepatitis B can lead to chronic liver disease, cirrhosis ofthe liver, and even liver cancer. Our group developed a SERSnanoprobe using a single stranded DNA (ssDNA) capture probe thatcan specifically bind to the HBV DNA target (Fig. 9) [194]. The silvernanorice antennae are coupled with the gold triangle nanoarraychip to create spatially broadened plasmonic ‘hot spots’ for SERSenhancement. The sensitivity of SERS detection is governed by sev-eral factors, including (i) the signal amplification capability of thelocal plasmonic field, (ii) the affinity of the DNA target with thecapture probe, (iii) the noise level of instrumentation, and other
factors. This work presents a LOD of 50 aM toward HBV DNA withthe capability of discriminating a single-based mutant of DNA.
4.3. Small molecule and ion detection
In addition to those ‘big’ biomarkers such as proteins, nucleicacids and circulating cells, small (low-weight) molecules and ionsrepresent another important class of disease biomarkers indicatingdisease progression and therapeutic efficacy [268–273]. Thesesmall biomarkers include, but not limited to, blood glucose, serumcreatinine, dopamine, amino acids, adenosine triphosphate (ATP),toxic substances, metabolites, drugs and various ions [192,274–276]. Several typical examples of detecting small molecules for dis-ease diagnostics can be found in the commercial market. For exam-ple, blood tests of glucose are widely used to diagnose diabetes andprediabetes despite that there exists no symptom at the earlystages of some types of diabetes. A wide range of optical and elec-trochemical approaches have been developed for invasive or non-invasive detection of glucose in blood. Wu et al. have developeda SERS sensor for detection of glucose through monitoring the SERSsignal of H2O2 [277]. This design made use of the production ofH2O2 through the oxidation of glucose by glucose oxidase enzyme(GOx) that is pre-grafted onto the silica coated GNS nanoparticles.Thus, we are able to indirectly determine the concentration of glu-cose by quantifying the H2O2 concentration. This SERS method isable to reach a LOD of 16 lM with a dynamic detection range ofthree orders of magnitude (25 lM to 25 mM).
ATP is a universe energy carrier in biological systems and playsa crucial role in the regulation of cellular metabolism and biochem-ical pathways in cell physiology. We developed a SERS sensor usingsandwich SERS labels for detection of ATP using an aptamer as therecognition moiety that can selectively bind to the ATP target(Fig. 10) [192]. Aptamer is a short oligonucleotide that can fold intoa unique tertiary structure for recognition of a specific target rang-ing from small molecules, proteins to cells. The SERS label basednanoprobes specific for ATP were made by conjugation of the apta-mer onto the sandwich SERS label, and then pre-immobilized ontoa gold film modified with the complementary ssDNA to form arigid duplex DNA. In the presence of ATP, the interaction betweenATP and the aptamer results in the dissociation of the duplex DNAstructure and thereby removal of the SERS probe from the goldfilm, reducing the Raman signal. The aptamer-based SERS probeexhibits high sensitivity with a LOD of 12.4 pM and specificity overits analogs. This excellent performance is ascribed to the high SERSintensity in SERS probe and high specificity of aptamer as therecognition element toward ATP. Aptamer has much higher stabil-ity than proteins in biological fluids and lower production costs, soit has advantages for applications in SERS biosensors as recognitionelements.
A large number of positive and negative inorganic ions can befound in our body and body fluids, which plays important rolesin various physiological activities [268–273,278]. Their presenceand concentrations are good indicators for human health and havebeen long-term employed for disease diagnosis. These ions may beabsorbed into human body and eventually into body fluids fromthe food chain or drugs. Developing SERS sensors for ultrasensitivedetection of ions of interest in body fluids are highly desirable.Gold nanohole array has been previously reported with uniqueoptical properties such as extraordinary optical transmission andtunable visible-NIR LSPR bands [47,48,279]. We developed anultrasensitive SERS sensor using sandwich SERS labels for detectionof silver(I) and mercuric(II) ions in saliva in which gold nanoholearray is coupled to the GNS of SERS probes to promote the SERSdetection sensitivity [280]. LSPR peaks of both gold nanohole arrayand GNS were tuned to 785 nm, resonant with the incident 785 nmlaser excitation wavelength, providing optimal SERS enhancement.
Fig. 11. SERS LFAs for detection of biomarkers. (A) Schematic illustration of a conventional LFA strip and the SERS-based LFA strip [292]. Only one red band is observed in thecontrol zone in the absence of the target antigen (negative), while two red bands appear in the presence of the target antigen (positive). With the SERS-based LFA strip, highlysensitive quantification of target analytes is possible by monitoring the SERS peak intensity. (B) SERS based LFA for detection of neuron-specific enolase in blood plasma.Sandwich SERS labels are used as the signal readout [251]. (C) SERS based LFA biosensor for the simultaneous detection of two nucleic acids [293]. The strip is composed oftwo test lines and one control line. Target DNAs, associated with Kaposi’s sarcoma-associated herpesvirus (KSHV) and bacillary angiomatosis (BA), were tested to validate thedetection capability of the SERS-based LFA strip. KSHV DNA-gold nanoparticle complexes were captured by the probe KSHV DNAs on the first test line; BA DNA-goldnanoparticle complexes were captured by the probe BA DNAs on the second test line, and excess KSHV and BA detection DNAs attached to gold nanoparticles were capturedby control DNAs through T20–A20 hybridization on the third control line. Corresponding DNA hybridizations for two test lines and one control line are listed as well. Digitalphotographic images and corresponding Raman spectra of two test lines for different concentrations of KSHV and BA DNAs are shown (right).
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Using the DNA strands with deliberately designed C-C or T-T mis-matches as the recognition elements, the DNA hybridization occursdue to the specific C-Ag(I)-C or T-Hg(II)-T interactions in the pres-ence of silver(I) or Hg(II) ions [281–286]. This sensor enablesdetection of both ions in human saliva, which could be suitableto monitor the release of metal ions from dental amalgam fillings.
5. Paper or chip-based SERS detection
Current challenges of biosensing for disease diagnosticsdemand early and sensitive detection of various fatal diseases by
developing new biosensors, and further require integrated plat-forms which can handle complex samples in a high throughputfashion involving minimal cost and professional training. Paper/chip based biosensors integrate multiple functions or tests into asingle unit, which is expected to be low cost, compact, cheap tofabricate, fast, and sensitive [287–289]. More importantly, it is por-table, requires small sample volumes, and provides a high degreeof process control. The merger of paper or chip and biosensorshas generated miniaturized devices for sample processing and sen-sitive detection with quantitation. Paper/chip based biosensorsprovide promising platforms for robust and cost-effective point-of-care diagnostics and therapeutic efficacy monitoring. SERS
Fig. 12. SERS based microfluidic systems. (A) metal ion separation/detection system using SERS labels as the signal readout [304]. The interior of the capillary isfunctionalized with (3-aminopropyl)triethoxy silane to immobilize gold nanoparticles. The capillary’s interior is then covered with a dense layer of gold nanoparticles ontowhich Raman-active molecules are adsorbed. 4-Mercaptobenzoic acid acts simultaneously as a metal-ion chelating agent and SERS label. The capillary system is used toseparate Hg2+ and Pb2+ ions, and SERS is used to monitor their relative concentrations along the length of the capillary. (B) Multiplex microfluidic SERS system for detection ofpathogen antigens [305]. NYscFv fragments are used as probe for pathogen antigen detection. (C) SERS based microdroplet biosensors for wash-free magnetic immunoassay[307]. The biosensor is composed of five compartments with droplet generation and reagent mixing, formation of magnetic immunocomplexes, magnetic bar mediatedisolation of immunocomplexes, generation of larger droplets containing the supernatant for SERS detection and generation of smaller droplets containing magneticimmunocomplexes.
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labels can act as the signal readout in these biosensors with highsensitivity, specificity and great multiplex detection capability.Two popular applications of SERS labels in biomedical fields areSERS based lateral flow assays (LFAs) and SERS based microfluidicassays (Fig. 11). LFAs is a paper-based platform for the detection ofand quantification of analytes in complex matrices [290,291]. LFAshave numerous advantages in terms of low cost, simpleness, rapid-ness and portability. A typical lateral flow test strip consists ofoverlapping membranes that are mounted on a backing card forbetter stability and handling. Samples for test migrate throughthe conjugate release pad, which contains antibodies that arespecific to the target analyte and are conjugated to colored or flu-
orescent particles–most commonly colloidal gold and latex micro-spheres. Their role is to react with the analyte bound to theconjugated antibody. Recognition of the sample analyte results inan appropriate response on the test line, while a response on thecontrol line indicates the proper liquid flow through the strip.The most typical example of LFA applications is the pregnancy teststrip which measures the hCG in a sandwich based assay, asdescribed above. Maneeprakorn et al. developed a SERS basedLFA for sensitive influenza detection where SERS labels were con-jugated with the antibody specific to influenza A nucleoprotein[249]. With the combination of LFA and SERS techniques, thedetection system achieved simultaneous separation and detection
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of influenza A nucleoprotein with a LOD as low as 6.7 ng/mL, sig-nificantly lower than that (67 ng/mL) from visual detection. Thedetection sensitivity by SERS LFA was improved approximately37 and 300-fold, compared with fluorescence or colorimetric LFAs,respectively. Choo and co-workers reported a SERS based LFAbiosensor for detection of staphylococcal enterotoxin B [292].Raman molecule encoded hollow gold nanospheres were used asSERS probes in replacement of conventional gold nanoparticles.Similar to the conventional LFA, the presence of staphylococcalenterotoxin B generates a visual color change in the test zone. Inaddition, the highly sensitive quantitative evaluation can be per-formed by the SERS readout from the test zone with a LOD aslow as 0.001 ng/mL, three orders of magnitude more sensitive thanthat achieved with the corresponding ELISA method (Fig. 11).Recently, Wu et al. reported an inexpensive and disposable paperbased SERS LFA [251]. They used the high SERS active gold nanostaras the plasmonic core to create the sandwich SERS labels with silicaas the shell materials. This SERS LFA was implemented for detec-tion of neuron-specific enolase (NSE), a traumatic brain injury pro-tein biomarker, in diluted blood plasma samples with a LOD of0.86 ng/mL. The SERS LFA exhibited superior sensitivity in a bloodplasma-containing sample matrix, compared with the colorimetricLFA.
In addition to SERS lateral flow immunoassays, SERS LFAs alsoare used for detection of nucleic acids including DNAs, microRNAsand methylated DNA [290]. Choo et al. recently reported a SERSLFA biosensor for multiplex detection of dual DNA biomarkers[293]. Similar to the conventional LFA, this SERS LFA strip is com-posed of two test lines and one control line, and SERS labels arefunctionalized with DNA detection probes. Target DNAs, associatedwith Kaposi’s sarcoma-associated herpesvirus (KSHV) and bacillaryangiomatosis (BA), were tested to validate the detection capabilityof this SERS-based LFA strip. The LODs for KSHV and BA weredetermined to be 0.043 pM and 0.074 pM, respectively, approxi-mately 10000 times higher sensitivity than previously reportedvalues using conventional colorimetric method. SERS LFAs providean effective platform for point-of-care diagnostics of diseases, andeven enable to perform take-at-home test with low cost and easyto use. LFAs are widely accepted by end-users and regulatoryauthorities, further exploration of SERS LFAs for detection of vari-ous biomarkers for disease diagnostics is the task in the incomingfuture.
Microfluidics is becoming increasingly attractive in bioanalysisbecause microfluidic devices require only small amounts of sam-ple, but offer highly precise controlled manipulation of biologicalsamples within microscale channels [294–298]. The small size ofthese devices provides the potential of creating portable lab-on-a-chip devices that facilitate the low LODs required in biologicaltarget identification. Microfluidic platforms that integrate electro-chemical, fluorescence, absorption and scattering techniques havebeen extensively reported. The functionality of microfluidics is sig-nificantly expanded in these integrated microfluidic systems. How-ever, they face some challenges such as sensitivity, specificity andmultiplexing. Use of SERS labels in microfluidic systems overcomesdrawbacks in these microfluidic systems [298–303]. SERS labelbased microfluidic detection offers significant advantages, includ-ing (i) miniaturization of devices, (ii) enabling detection with asmall sample/reagent volume, (iii) on-chip preparing sample andpreconcentrating analytes, (iv) allowing multiplex detection in asingle chip, and (v) shortening the assay time. Intensive effortshave been devoted to the development of SERS microfluidic detec-tion systems for detection of various analytes. Here we narrowdown our discussion to the SERS label based microfluidic detectionsystems. It is well-known that metal ion carboxylate complexespossess ion-specific Raman bands. Moskovits et al. developed aSERS method for monitoring chromatographic separation of ions
in a miniaturized volume using SERS labels consisting of 4-mercaptobenzoic acid and gold nanoparticles (Fig. 12A) [304]. Trauand co-workers combined glass-coated SERS labels with amicrofluidic device to develop a SERS microfluidic method fordetection of duplex microfluidic SERS detection of pathogen anti-gens (Fig. 12B) [305,306]. In their work, nanoyeast single-chainvariable fragments (NYscFv) were used to substitute monoclonalantibodies, which reduces cost, improves stability in solution andtarget-specificity. The SERS microfluidic detection achieved a LODof 1 pg/mL for individual Entamoeba histolytica antigenEHI_115350 and 10 pg/mL for EHI_182030. Droplet basedmicrofluidics has recently emerged as an attractive alternativebecause it has significantly high throughput and low assay vol-umes. Incorporation of SERS detection into droplet based microflu-idics enables in situ detection and dynamic measurements ofmolecular events. A droplet based microfluidic device for detectionof prostate specific antigen (PSA) has been developed using SERSlabels by Choo et al. (Fig. 12C) [307]. In this work, the magneticbar embedded in a droplet based microfluidic system segregatesthe free and bound SERS labels by splitting the droplets into twosmall parts. The presence of PSA leads to the formation of immuno-complex in one droplet so that fewer SERS labels remain in anothersupernatant solution droplet. This approach enables a rapid andsensitive assay that is applicable for PSA cancer markers in serumwithout any washing. The LOD by this SERS based microdropletbiosensor is estimated to be below 0.1 ng/mL, significantly belowthe clinical cut-off value for the diagnosis of prostate cancer. Rapidanalysis is possible since the entire process is automatic and min-imal value of samples is needed.
6. Cellular imaging and in vivo tumor detection with SERS
A variety of extracellular biomarkers (i.e., protein receptors,nucleic acids, low-weight receptors) on cell surfaces have beenwidely identified to be differentially overexpressed among variouscancerous and normal cells. Rapid and effective differentiationbetween cancerous cells and normal cells on the basis of theseextracellular biomarkers is desirable for cancer detection, diagno-sis and prognosis. Numerous efforts have been made to developvarious strategies for detection and visualization of cancer cellsthrough specific recognition of cell surface biomarkers [308–311]. It has been demonstrated that SERS labels can achieve muchbrighter cellular imaging at a low concentration of SERS labels dueto their much higher cross-section in comparison with fluorescentdye molecules or quantum dots [177,237]. There are some require-ments that need to be considered when SERS labels are applied forin vitro cellular imaging and in vivo cancer diagnostics. These fac-tors considered include (i) nontoxicity, (ii) colloidal stability, (iii)non-fouling against adsorption of plasma proteins, (iv) controlledsurface charge, (v) nonaggregation tendency, and (vi) controlledhydrodynamic dimension and stability. These must be equilibriumbetween these properties because very low nanoparticle dimen-sion can determine their uncontrolled distribution, permeation,and accumulation inside many cells. Safety and efficacy are themajor criteria for biomedical applications of SERS labels. The idealway to maximize safety and efficacy is to modify with a targetingligand that exhibits little affinity for normal cells but high affinityfor pathologic cells. Although it has been reported that the increas-ing accumulation of nanomaterials occurs in malignant tissues dueto the enhanced permeability and retention (EPR) effect, the EPReffect is less pronounced in human than in animal models. Moreimportantly, a recent survey showed that only 0.7% of an adminis-tered nanoparticles dose is commonly delivered to solid tumors[312]. The targeted imaging and accurate diagnostics of tumorrequire incorporation of the targeted ligands into the detection
Fig. 13. Targeted cellular imaging using SERS labels. (A) Live cell Raman imaging using SERS labels encoded with methylene blue (MB), 4,40-azobis (pyridine) (AB) and 4,40-dipyridyl (44DP) [313]. MB-encoded SERS label was modified with mPEG thiol and RGD peptide (RGDRGDRGDRGDPGC) targeting the cytoplasm; 44DP-encoded SERS labelmodified with mPEG thiol, RGD peptide, and MLS peptide (MLALLGWWWFFSRKKC) targeting the mitochondria; and AB-encoded SERS label modified with mPEG thiol, RGDpeptide, and NLS peptide (CGGGPKKKRKVGG). SERS imaging demonstrated the visualization of cytoplasm, mitochondria and nucleus. (B) SERS labels for multiplexquantitative detection and cancer cell imaging [314]. The SERS label is prepared by sandwiching Raman active molecules between the gold nanoparticle core and thesilver/gold shell. Surface modification of SERS labels with antibody or aptamer enables the targeted SERS imaging. (C) Schematics of a SERS imaging agent which arecomposed of a sandwich SERS label and a urea-based small molecule (Glu-urea-Lys-linker-NHS), and its use for targeted SERS imaging of single prostate cancer cells withoverexpressing PSMA [191]. Dose-dependent SERS images of PSMA+ PC3 PIP cells following incubation in various concentrations (10, 20, 30 and 50 pM) of SERS agents.
B. Shan et al. / Coordination Chemistry Reviews 371 (2018) 11–37 29
systems with superior biocompatibility, high sensitivity andspecificity.
Through incorporating different targeting ligands onto therespective SERS labels encoded with different Raman active mole-cules, Lim et al. reported the multiplex SERS imaging for subcellu-lar structure visualization by targeting various organelles(Fig. 13A) [313]. The three different Raman active molecules placedin the narrow intra-nanogap showed a strong and uniform Ramanintensity even under transient exposure time and low input powerof incident laser. The high-resolution Raman image shows the dis-tribution of gold nanoparticles for their targeted sites such as cyto-plasm, mitochondria or nucleus, and enables us to monitor rapidlychanges in cell morphologies without inducing significant damageson cells. Further, Yang et al. reported a label free SERS imagingmethod for cell imaging (Fig. 13B) [314]. The SERS label was madeby covalently binding Raman dyes and mPEG-SH onto goldnanoparticles, followed by deposition of silver and its etching withHAuCl4. The developed SERS labels demonstrated the capability ofmultiplex quantitative detection and targeted cancer cell imagingas a new approach for early diagnostics of cancer. The advantagesof SERS label based applications in this work include (i) high,
uniform and reproducible SERS signals, (ii) low cost, simple andrapid synthesis, and (iii) easy functionalization for multiplextargeted cell imaging.
It has been reported that prostate-specific membrane antigen(PSMA), a type II integral membrane protein, is significantly over-expressed on the cell surface of most prostate cancers but particu-larly in castration-resistant, advanced and metastatic disease. Inlight of this, we developed a SERS imaging agent for targetedlive-cell imaging through specific recognition of PSMA for prostatecancer cells (Fig. 13C) [191]. The SERS imaging agent was createdby conjugation of PSMA-specific urea-based small-molecule inhi-bitors onto the SERS labels, and exhibits ultrahigh affinity towardPSMA+ PC3 PIP cells with low cytotoxicity. The developed SERSagent enables precise visualization of single live prostate cancercells with high sensitivity, specificity and excellent photostabilityat ultralow concentrations. In addition, as more SERS agents homein on the cell surface at higher concentrations, the SERS agents canenter the cell through the internalization process, increasing theimaging sensitivity and improving the imaging brightness.
In addition, SERS labels have been widely employed for in vivodetection of tumor. In in vivo applications, sandwich SERS labels
Fig. 14. In vivo SERS detection of tumor lesions. (A) in vivo SERS imaging using SERS labels through the passive EPR effect [319]. The sandwich SERS labels are first preparedwith silica as the coating layer followed by PEGylation. Contrast-enhanced Raman imaging of prostate neoplasia (bottom). Raman images and photos of in situ prostateneoplasia detection using contrast-enhanced Raman imaging in a Hi-Myc mouse that was i.v. injected with PEGylated SERS labels (30 fmol/g). A Raman-guided resection wasperformed of lesion 1 (along the dotted line in left-hand image). After resection 1, Raman imaging was performed and a second Raman-guided resection was performed (alongthe dotted line in center image). To screen for residual disease, Raman imaging was performed after resection 2. A residual lesion (4) was found and biopsied (dotted line inright-hand image). Histopathological examination of H&E-stained sections of the excised tissues 1–4 identified lesion 1 as high-grade prostate intraepithelial neoplasia (PIN;a precursor lesion to prostate cancer) and lesions 2–4 as advanced prostate cancer. (B) Deep-tissue multiplex SERS imaging of living mice using SERS labels encoded withdifferent Raman active molecules [321]. 10 SERS labels respectively encoded with 10 different Raman active molecules show clear separate SERS peaks. Five SERS labels aresimultaneously injected into a live mouse, and after 24 h the deep-tissue multiplex imaging using SERS is performed. S420 (red), S421 (green), S440 (blue), S466 (yellow) andS470 (orange) are associated with five unique Raman peaks from their corresponding SERS labels with little spectral overlap. Raman images (bottom) of liver overlaid ondigital photo of mouse show accumulation of all five SERS labels accumulating in the liver after 24 h post i.v. injection.
30 B. Shan et al. / Coordination Chemistry Reviews 371 (2018) 11–37
B. Shan et al. / Coordination Chemistry Reviews 371 (2018) 11–37 31
are preferable because the coating layer (i.e., silica, PEG) can pre-vent displacement of Raman active molecules caused by compli-cated biological matrices [3,201–203]. In general, SERS labelsshould be endowed with antifouling surface coatings, typicallymodified with PEG. SERS labels without such coatings are doomedto foul with a ‘‘protein corona” due to the adsorption of proteins,which are rapidly removed by the resident macrophages and thereticuloendothelial system (RES). A SERS label typically has a muchlarger size compared with the dye molecules or quantum dots,which may limit the accessibility of SERS labels to the target sitesin body. However, the large size may prolong the stay of SERSlabels in vivo. Nie et al. first developed a biocompatible and non-toxic SERS label for in vivo tumor targeting and spectroscopicdetection [177]. The SERS label was encoded with Raman activemolecules on gold nanoparticles followed by PEG coating and con-jugation with single-chain variable fragment (ScFv) antibodies.They found that Raman active molecules coated onto SERS labelswere not displaced but were stabilized by thiol-modified PEGs.ScFv modified SERS labels were able to target tumor biomarkerssuch as epidermal growth factor receptors on human cancer cellsand in xenograft tumor models. Kircker et al. have been intensivelyworking in this area and greatly advanced applications of SERSlabels for targeted tumor imaging. They have developed NIR activeSERS labels where NIR active Raman molecules (pHPMA) are sand-wiched between biocompatible polymers and gold nanoparticles.The synthesized SERS labels have small size benefiting excretionand circulation, and demonstrated its application for multiplexedlymph-node imaging in all-in-one SERS labels. Further, Kirckerand co-workers realized the precise visualization of tumor mar-gins, microscopic tumor invasion, and multifocal locoregionaltumor spread using SERS labels (Fig. 14A) [182,315–318]. The SERSlabels feature a gold nanostar core, Raman active molecules reso-nant in the near-infrared spectrum, and a silica shell. The workingprinciple is that SERS labels accumulate in tumor by the EPR effect,which is a passive targeting mechanism [319]. To improve the tar-geting capability, they further incorporated targeting ligands suchas aptamer and folate receptor targeting antibody (aFR-Ab) ontothe surface of SERS labels to create SERS label targeting probes[315,320]. The developed SERS probes enable the detection oftumor lesions in animal models, holding promise for intraoperativedetection of microscopic residual tumors. One of the most attrac-tive features in SERS is the multiplex capability [321–323]. Gamb-hir et al. demonstrated the ability of SERS labels encoded with 10different Raman signatures for in vivo detection (Fig. 14B) [321].Five most intense and spectrally unique SERS labels are i.v. injectedinto a living mouse, and then their accumulation in the liver wasimaged. All five types of SERS labels were successfully identifiedand spectrally separated. These results show great potential formultiplexed imaging in living subjects in cases in which severaltargeted SERS probes could offer better detection of multiplebiomarkers associated with a specific disease. Although this workdemonstrated the intriguing capability of SERS labels for in vivodetection of deep tissues, they did not move further forward fordetection of diseases. More efforts are needed to implement thetargeted imaging with disease specific targeting ligands. Optimiza-tion of surface chemistry with various sizes and PEG/targetingligand ratios is necessary to alleviate the non-specific accumula-tion in normal tissues and RES, and reduce adsorption of biologicalproteins in circulation systems. Current studies of SERS have beendirected towards the ‘smart diagnostics’ that utilize the specificenvironments to trigger SERS signal ‘‘on/off” such as pH changeand enzyme specific to disease sites.
Moreover, theranostics is an emerging area in nanomedicinewhich combines therapy and diagnostics into a single construct[183,324,325]. Such a combination can increase the specificity,diagnostic accuracy and therapeutic efficacy, resulting in improved
outcomes and reduced side effects. Multi-modality theranosticswith incorporation of SERS as one of the diagnostic modality offerseasy multiplexing and high sensitivity, and does not suffer fromphotobleaching usually occurring in fluorescence based methods.Multifunctional nanoprobes with integration of SERS, fluorescence,photoacoustics, magnetic resonance imaging (MRI), computedtomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT), photothermaltherapy, photodynamic therapy and drug therapy have been therecent focus [324,326]. SERS modality that works as the diagnostictool in multifunctional probes offers great advantages due to highsensitivity, specificity, anti-interference from biological matrices,easy operation and low cost. Therefore, multifunctional nanop-robes provide a promising platform for future biomedical applica-tions [327].
7. Conclusions and outlook
In this Review, we have summarized design and development ofSERS labels, and then introduced recent advances of SERS labelbased nanoprobes for disease biomarker detection, live-cell imag-ing and in vivo spectroscopic detection. SERS labels present greatmerits for developing detection and bioimaging platforms, whichinclude high sensitivity, long-term physicochemical stability andphotostability, multiplexing, less external interference and easyintegration of multiple functionalities. SERS nanoprobes candirectly readout the levels of a vast array of biomarkers in complexmatrices (e.g., blood, urine and saliva) of real world samples. Devel-oping multimodal probes by integrating multiple functionalities(e.g., diagnosis, therapy) into a single SERS label for biomedicalapplications is highly desirable. Further efforts still should bedevoted to seeking for high-performance plasmonic nanostruc-tures, which include tuning of their optical properties and opti-mization of materials composition, and surface ligands of SERSlabels as well. Integration of SERS nanoprobes with paper ormicrofluidic based point-of-care devices is promising and enablesthe real-time detection of drug release and the monitoring ofmetabolite generation and distribution of cells for pathologicalstudies of diseases. Extended biomedical applications will be defi-nitely brought about along with new observations of opticalfeatures.
Although promising for targeted cell imaging with high sensi-tivity, few studies have demonstrated that the SERS imaging oftumor tissues using SERS labels can be realized through passiveaccumulation of enhanced permeability and retention (EPR) effect.Effective strategies should be further explored to develop activetargeting imaging of tumor tissues using controllable targetingligands to reduce the diagnostic errors. The fast attenuation of SERSsignal as the propagation distance causes challenges in the non-invasive detection of invisible tumor and metastatic sites, the com-bination of SERS nanoprobes with surface enhanced spatially offsetRaman spectroscopy (SESORS) imaging technique is an emergingresearch topic to achieve deep-tissue SERS detection of invisiblecancer sites, especially for the imaging-guided surgery of cancer[328]. Current studies are mainly focused on visible and NIRresponsive SERS applications concomitantly with NIR relatedapplications such as fluorescence and photothermal therapy. Inmost previous studies, the NIR incident excitation falls within thefirst biological window ranging from 650 to 950 nm. The SERS exci-tation and photothermal therapy typically use 785 nm or 808 nmlaser, respectively. Recently, it is recognized that the second opticalwindow between 1000 nm and 1350 nm offers more efficient tis-sue penetration relative to the first biological optical windowwhenconsidering absorption and scattering effects in tissue. Thus, futurestudies should be directed towards exploration of plasmonic
32 B. Shan et al. / Coordination Chemistry Reviews 371 (2018) 11–37
materials responsive in the second biological optical windows, andinvestigation of their SERS performances and photothermal ther-apy. We believe that interdisciplinary collaboration with scientistsand clinicians of different expertise will no doubt transform newideas for the development of SERS platforms for biomedical appli-cations and thereby lead to their new applications in the clinic.
Acknowledgements
M. L. acknowledges financial support by the National ThousandYoung Talents Program of China and Innovation-Driven Project ofCentral South University (No. 2018CX002).
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