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Optical Imaging of Individual Plasmonic Nanoparticles in Biological Samples Lehui Xiao1 and Edward S. Yeung2 1

Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education, Key Laboratory of Phytochemical Research and Development of Hunan Province, College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha, Hunan 410081, China; email: [email protected]

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Department of Chemistry, Iowa State University, Ames, Iowa 50011; email: [email protected]

Annu. Rev. Anal. Chem. 2014. 7:8.1–8.23

Keywords

The Annual Review of Analytical Chemistry is online at anchem.annualreviews.org

optical microscopy, darkfield, scattering imaging, interference detection, plasmonic nanoparticles

This article’s doi: 10.1146/annurev-anchem-071213-020125 c 2014 by Annual Reviews. Copyright  All rights reserved

Abstract Imaging of plasmonic nanoparticles (PNP) with optical microscopy has aroused considerable attention in recent years. The unique localized surface plasmon resonance (SPR) from metal nanoparticles facilitates the transduction of chemical or physical stimulus into optical signals in a highly efficient way. It is therefore possible to perform chemical or biological assays at the single object level with the help of standard optical microscopes. Because the source of background noise from different samples is different, distinct imaging modalities have been developed to discern the signals of interest in complex surroundings. With these convenient yet powerful techniques, great improvements in chemical and biological assays have been demonstrated, and many interesting phenomena and dynamic processes have also been elucidated. Further development and application of optical imaging methods for plasmonic probes should lead to many exciting results in chemistry and biology in the future.

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1. INTRODUCTION

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Recent advances in optical imaging techniques have revolutionized our ability to explore interested objects inside microenvironments with high temporal and spatial resolution (1–6). Those ambiguous kinetic or intermediate processes can thus be tracked and analyzed in real time without perturbing their native state to reveal features that are especially important in cell biology and physics for the understanding of underlying mechanisms (7–10). The target objects are normally stained by a fluorescent moiety to provide contrast. An attractive advantage of fluorescence-based imaging is that the target signal can be effectively differentiated from the background noise by the excitation or the emission wavelength. With a charge-coupled device (CCD) camera, the red-shifted emission signal can then be promptly read out in a high-throughput manner. Several important biological and physical processes have been extensively explored with this method (4, 5, 7, 9, 10). One of the major limitations of the fluorescence-based detection scheme is that the commonly used fluorescent contrast agents are very sensitive to photobleaching. Consequently, extended observation becomes a challenge (11). In addition, some fundamental meta-stable states might be hidden during the limited window of observation. Another important issue is that the absorption cross sections of these fluorescent molecules are normally small, on the order of 10−16 cm2 (11–13). The collected photons captured by the detector will be very limited with a short-pulse excitation, which greatly reduces the temporal resolution. To enhance the fluorescence signal from individual objects, chemists have provided alternative solutions to the above issues. The 1–10-nm semiconducting quantum dots exhibit size-dependent fluorescent effect (14, 15). More importantly, these nanomaterials provide an increase of one to two orders of magnitude in the optical absorption cross section (11). Greatly improved signalto-noise ratios (S/N) can thus be achieved by using these labels under the same imaging setup when compared to that of fluorescent dyes. In addition, these nanomaterials are not sensitive to photobleaching to facilitate extended observation. However, due to the nature of the chemical composition of quantum dots, toxic metal ions might leak out into biological fluids, which will affect the function of DNAs or proteins inside living cells (16–19). Progress in the fabrication and bioconjugation of nanometer-sized gold or silver colloids has produced a new class of biological labels (20–24). These particles typically have diameters in the range of 10 to 120 nm and exhibit fascinating spectral properties. Surface plasmons give rise to characteristic resonances in light absorption or scattering that do not occur in thin metallic films. In contrast to fluorophores, the scattered signal is comparable to those of thousands of fluorescein molecules (12, 23, 25). Therefore, with simple optical imaging setups, single-particle sensitivity can be readily achieved. In the past few years, many elegant works have demonstrated successful applications of plasmonic nanoparticles (PNP) in biological sensing and imaging to reveal detailed dynamic information related to important biological processes (26–30). In this review, we summarize the significance of PNP and corresponding optical imaging methods for ultrasensitive single-particle imaging and sensing in biological samples. We introduce the basic optical properties of PNP that give rise to advantages in ultrasensitive assay. We focus on recent progress about the development of optical imaging methods and their applications in cellular imaging and sensing.

2. BASIC OPTICAL PROPERTIES OF PLASMONIC NANOPARTICLES The remarkable absorption or scattering of nanostructured noble metals such as gold and silver arises from the conduction-band electrons known as surface plasmons (31–37). In the presence 8.2

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Figure 1 (a) Schematic representation of localized surface plasmon. (b) Color image of gold nanospheres in water with different diameters and a representative TEM image of 40-nm gold nanospheres. (c) UV-vis absorption spectra of gold nanospheres of different sizes. (d ) SEM image of gold nanorods with diameters of 25 nm and 60 nm in length. (inset) Darkfield image of gold nanorods. (e) UV-vis absorption spectrum of a gold nanorod. (inset) Polar plot of polarization modulation results from the longitudinal oscillation mode of a single gold nanorod. Abbreviations: SEM, scanning electron microscope; TEM, transmission electron microscopy.

of an electromagnetic field, the conduction-band electrons of these nanoparticles undergo collective coherent oscillation. When the wavelength of incident light matches well with the resonance condition (surface plasmon resonance, SPR), a strong absorption band appears in the UV-vis spectrum, which is the origin of observed color from the colloidal solution (Figure 1b). Subsequently, the oscillating electrons emit electromagnetic radiation with the same frequency as the oscillations. This elastic reradiation of light is typically called plasmon scatter. The strength of the scattered photons at the resonance frequency is far beyond their physical cross sections. For wavelengths away from the resonance frequency, the emitted light is mainly controlled by the physical constraints of its cross section. In the case of much larger size metal nanoparticles, the spectroscopic response is modified due to the excitation of multipoles and a plasmon damping effect. The absorption and scattering properties are dependent on factors that can contribute to the charge distribution on the particle surface, such as size, morphology, chemical composition, and dielectric function of the surroundings (31, 32). For example, the UV-vis absorption spectrum of www.annualreviews.org • Optical Imaging of Plasmonic Nanoparticles

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40-nm spherical gold nanoparticles in solution is typically located at around 520 nm (Figure 1c). This resonance frequency will be red-shifted for anisotropic nanoparticles with the same volume, such as triangular prisms and nanorods. As early as 1908, Mie had quantitatively elucidated the optical responses of a simple spherical nanoparticle with arbitrary material in a homogeneous surrounding based on the rigorous analytical solutions of Maxwell’s equations (32, 33, 34, 35). By applying approximate boundary conditions in spherical coordinates using multiple expansions of incoming electric and magnetic fields, the extinction cross section of a spherical nanoparticle (with d  λ) can be quantified according to the particle size and the optical functions of the particle materials and of the surrounding medium: ω ε2 (ω) σe xt = σs c a + σabs = 9 εm3/2 V 0 , c [ε1 (ω) + 2εm ]2 + ε2 (ω)2

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where σe xt is the extinction cross section of the nanoparticle, σs c a and σabs are the scattering and absorption cross sections, V 0 = (4π/3)R3 denotes the particle volume, εm is the dielectric function of the embedding medium, and ε1 (ω) and ε2 (ω) are the real and imaginary parts of the dielectric function of the particle material. This expression considers only the dipole contribution. This is because in this size region, higher multipolar contributions, such as quadrupole and octupole modes, are suppressed. For a spherical nanoparticle with ε1 (ω)  ε2 (ω), a maximum of the extinction cross section σe xt may be realized when ε1 (ω) ≈ −2εm . Most alkali metals fulfill this resonance condition because the imaginary part of the dielectric constant is small and does not change much in the vicinity of the resonance frequency. In the case of gold or silver nanoparticles, ε2 (ω) further varies as a function of size. Therefore, the optical responses of these noble metal nanoparticles are not solely dependent on the size or the environmental dielectric function. Several pathways concurrently contribute to the plasmon damping effect (i.e., radiative and nonradiative) (36). Figure 1c shows the extinction spectrum of gold nanospheres as a function of particle size. We can see that the resonance frequency red-shifts continuously, and the full width at half-maximum suffers substantial broadening in a nonlinear way due to plasmon damping. When the size of the noble metal nanoparticle increases, the conduction electrons on the nanoparticle surface do not oscillate exactly in phase in comparison with those of small nanoparticles, leading to a remarkably reduced depolarization field around the nanoparticle. Another factor that affects the extinction cross section is the radiation damping process due to the increased particle size. This is demonstrated in the following expressions of σs c a and σabs :   2 8π 2 3 m −1 R Im 2. σabs = − λ m2 + 2 and

 2 128π 5 6  m2 − 1  σsca = − R  2 , 3. 3λ4 m + 2 where m is the ratio of refractive indices of the particle and the medium (34, 35). For small particles, in the range of 20–40 nm, the shape of the extinction spectra is similar to the absorption spectra. With increasing size, the scattering causes drastic shifts and broadening, and increases the amplitude of the extinction cross section due to the increasing cluster volume. Another important consideration of Equation 1 is that the cross section is environmentally dependent. With an increase in the dielectric constant of surrounding, the polarization charges on the dielectric side of the interface will increase. This also attenuates the restoring force, leading to a red shift of the extinction spectrum. On the basis of this unique feature, many ultrasensitive biosensors have been designed (37, 38). Briefly, biomolecules typically have distinct dielectric constants compared to that of the surrounding solution; as such, binding of additional molecules

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onto the surface will affect the charge distribution. On the basis of this feature, PNP have been widely applied to analyze protein-protein and DNA-protein interactions (37, 39, 40). These sensors exhibit much better sensitivity over traditional detection strategies (37, 38, 41). It is important to note that Mie theory is based on the assumption that the nanoparticle is well separated from the neighboring ones. The coupling effect (near field or far field) between other particles or the solid substrate is not considered. Another important constraint of Mie theory is that the shape effect is not well explained. The rapid development in controllable fabrication of nanoparticles has resulted in significantly different shapes of functional nanostructures. Because of the anisotropic morphological nature of these nanostructures (e.g., gold nanorods), the surface plasmon is not evenly distributed around the nanoparticle, manifesting in shape dependence of the extinction cross section. The spatially focused electromagnetic field at a particular direction significantly enhances the electromagnetic field (42–44). This is one of the major causes of metal-enhanced effects such as metal-enhanced fluorescence and surface-enhanced Raman scattering. Another interesting consideration of the orientation-dependent optical property of anisotropic nanoparticles is the capability for angularresolved imaging (45). Most biological events inside living cells involve rotational motions (46– 50). Understanding the spatial orientation of target objects can provide additional knowledge for addressing interesting reaction mechanisms. To describe the optical property of anisotropic nanostructures, several numerical methods have been developed to solve Maxwell’s equations, for example, discrete dipole approximation, finite-difference time-domain, and finite-element methods (51, 52). Even though these methods can provide satisfactory simulation results, the calculation is normally very complex and time consuming. However, for a simple anisotropic nanostructure, for example an ellipsoid, the optical property can still be determined according to a simple dipole approximation (Figure 1d ). Gans and coworkers provided a quantitative description of the optical cross sections of elliptical particles excited by polarized light parallel to the principle axes: i = σabs

2π 3/2 ε2 (ω)/ni2 εm V 0 3λ [ε1 (ω) + ((1 − ni )/ni )εm ]2 + ε2 (ω)2

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and 8π 3 2 2 (ε1 (ω) − εm )2 + ε2 (ω)2 /ni2 εm V 0 , 4 9λ [ε1 (ω) + ((1 − ni )/ni )εm ]2 + ε2 (ω)2 where ni is the depolarization factor, defined by   √ 2 R + R2 − 1 R ln −1 na = 2 √ √ R − 1 2 R2 − 1 R − R2 − 1 i σsca =

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where a, b, and c are the three axes of the elliptical particle with a > b = c, and R is the aspect ratio, R = a/b (35, 53). Equations 4 and 5 show that the absorption or scattering cross section is orientation dependent. By illuminating the nanorod with polarized white light along the long or short axis, noticeably different resonance frequencies will be observed in the absorption and scattering spectra (Figure 1e) (54). The stronger resonance in the red region represents the oscillation along the long axis; this is referred to as longitudinal oscillation. The blue-shifted peak corresponds to transverse oscillation. In colloidal solution where nanorods rotate freely, both of these oscillation modes can be seen simultaneously in the absorption spectrum as distinct peaks. For gold nanorods, the transverse oscillation mode is not very sensitive to size and is usually located close to 530 nm. Alternatively, the longitudinal mode is highly sensitive to the change in www.annualreviews.org • Optical Imaging of Plasmonic Nanoparticles

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aspect ratio and variations of the surrounding dielectric constant. The ultrasensitive response to the local environment has been extensively applied in biomolecule sensing. The binding kinetics of biomolecules on the surfaces of individual gold nanorods can be readily monitored with a conventional darkfield microscope, thus alleviating the need for expensive detectors (55). In aqueous solution, the longitudinal resonance (λmax , nm) essentially increases linearly as a function of the aspect ratio of the nanorod due to weakening of the charge coupling as the charges are separated over longer distances (12). This can be described by the following empirical formula (12): λmax = 90.6R + 445.4.

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3. IMAGING OF PLASMONIC NANOPARTICLES WITH FAR-FIELD OPTICAL METHODS So far, several optical microscopic methods have been developed to image individual PNP in different surroundings. Generally, they can be classified into three groups based on the detection principles, i.e., scattering-, absorption-, and photoluminescence-based detections. Among these schemes, the first one is the most straightforward way to realize high S/N in complex surroundings for single PNP and the setup is also convenient to be modulated for specific biological imaging applications. Herein, we mainly focus on recent advances of scattering-based optical detections.

3.1. Direct Scattering Detection On the basis of theoretical calculations, the scattering cross section of an 80-nm gold nanoparticle is found to be millions of times larger than that of single-dye molecules (12, 40, 56). It is thus practical and cost-effective to carry out single-molecule labeling and signal quantification with individual PNP by using a simple optical detection system. For example, a common CCD or complementary metal–oxide–semiconductor camera should be sensitive enough to acquire adequate dynamic information with greatly improved temporal resolution in contrast to the expensive single-dye imaging systems (26). This forms the basis of intense ongoing interest in the development of scattering-based imaging strategies for biological samples. The scattered light from PNP can be detected in the forward, backward, and lateral (with respect to the incoming beam) configurations. Collecting the signals sideways relative to the excitation light can effectively circumvent the direct exposure of the detector to the incident light, leading to a dark background in the absence of a scattering source (Figure 2a). The first observation of light scattered by individual nanoparticles using an optical microscope is based on darkfield illumination (40). In the conventional darkfield illumination mode, a darkfield ring assembled inside the condenser blocks the inner part of the focused light, and thus the condenser guides the incident beam to the sample plane within a hollow cone. Collecting the scattered signals with a low numerical aperture (NA) objective can avoid the detection of the incident light, and only photons transmitted through the inner part of the cone will be captured. The image contrast is amenable to be further improved by using water or other index-matching solution that reduces the background scattering from the biological sample. It is worth noting that the transmitted darkfield illumination scheme imposes several restrictions on biological sample observation. For example, it limits the sample thickness, requires transparent samples, and restricts access to manipulate the sample during the observation process and therefore hinders the concomitant combination with other analytical tools. In addition, the high magnification objectives are typically not compatible with living cells in culture due to the requirement of index-matching oils. Curry et al. (57) demonstrated an interesting objective-type 8.6

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illumination scheme that utilizes the microscope’s objective for both illumination and imaging of the sample (Figure 2b). By using a refractive axicon, the collimated light from the light source is converted into a ring of light at a specified angle of 1.3. This engineered ring light is then introduced into the back focal plane of the objective through a beam splitter. The light emerges at the sample side of the objective as a collimated ring of light converging at a high angle. The back-reflected light by the glass slide is then blocked with a field stop. A portion of scattered light delivered from the PNP passes through the center of the field stop to be captured with a CCD camera. This imaging configuration enables extended observation of living cells in a cell culture dish and provides a versatile approach for the simultaneous manipulation of the sample. Analogous objective-type illumination was introduced by Nan et al. (58; see also 59) to track the dynamics of individual PNP on microtubules. They applied asymmetric darkfield illumination by projecting a single round, focused beam onto the back aperture of the objective. A small mirror mounted on clear glass is used to reflect the incident beam into the objective. A stop iris is again used to block the back-reflected excitation light, and only the scattered signal transmitted through the center of the iris is delivered to the detector. In contrast to the axicon scheme, this design is shown to be more convenient and allows efficient reflection of the incident beam as well as efficient collection of the scattered signal. At moderate power density (30–50 μW/μm2 ), the detected signal from www.annualreviews.org • Optical Imaging of Plasmonic Nanoparticles

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100-nm gold nanoparticles was found to be approximately 200–1,000 times higher than that of quantum-dot aggregates. Although the width of the point spread function from PNP is substantially larger than the actual dimension (due to diffraction), the spatial coordinates of the PNP can still be precisely determined at the nanometer scale. For example, the authors showed that motor protein–labeled gold nanoparticles can be tracked with exceptional spatial precision (1–2 nm) as well as unprecedented time resolution (25 μs). Even though the above-mentioned methods can offer good spatial information in a twodimensional manner, the resolution in the z direction is typically very poor owing to the reduced NA value of the objective. Louit et al. (60) introduced a confocal Rayleigh light-scattering imaging system with a femtosecond supercontinuum laser as the light source. By taking advantage of the z scan capability from confocal detection, the diffusion dynamics of gold nanoparticles on living cell membrane was mapped in a detailed manner. An alternative illumination mode that potentially provides improved z direction information is the sheet light excitation scheme (4, 61, 62). The fundamental limit of degenerated z scan capability from the transmitted and reflected illumination modes is mainly attributed to the reduced NA value of the objective where the incident light is effectively blocked. However, without sacrificing the NA value, it is still possible to form a high contrast darkfield image. This can be achieved by illuminating the focal plane with a sheet of light delivered orthogonally to the detection axis. The illumination sheet light is generated by focusing the output of an optical fiber and then passing it through a cylindrical lens (Figure 2c). In this way, the horizontal incident light will not travel into the vertical direction even when using a larger NA objective. In contrast to conventional darkfield illumination, the interfering signals from cellular organelles or other PNP out of the illumination plane is blocked, resulting in improved contrast for single-particle imaging (62). Evanescent wave illumination provides another attractive approach with similar capability to suppress the interfering signals out of the focal plane (Figure 2d ). Analogous to total internal reflection fluorescence imaging, total internal reflection scattering can be implemented as either prism type or objective type (63–65). Because of the strictly confined evanescent wave in the orthogonal direction (with a depth of approximately 200 nm), only those PNP located close to the total internal reflection interface could generate signals, leading to remarkably enhanced S/N. With a prism-type imaging modality, Wei et al. (65) could detect PNP with sizes down to several nanometers on a clean glass slide surface. This result is significant for biological labeling applications because ultrasmall size probes might exhibit much better labeling efficiency in subcellular imaging and possess improved biocompatibility for conjugated functional molecules. Additionally, it is also possible for them to enter certain cells that are not accessible to large probes.

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3.2. Indirect Scattering Detection The signals generated according to the above documented approaches are based on direct detection of scattering amplitude from PNP. Discrimination of PNP from the background noise is commonly achieved by separating the incident light from scattered signals at the cost of reduced light collection efficiency. Because the scattering cross section drops as the sixth power of particle diameter, in the case of small particles, it is normally not trivial to directly detect the scattered signals. Interference detection provides a versatile alternative to overcome this limitation and enables the direct observation of individual small nanoparticles in aqueous environments (66). If a dielectric nanoparticle is positioned at the center of a focused coherent monochromatic beam, the outgoing beam obtained in the far-field region is the superposition (or interference) of the transmitted or reflected focused beam and the scattered radiation from the particle. The scattered 8.8

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field Es in the far-field region can be expressed as Es = Eo |s | exp(iϕ) = Eo

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where Eo is the incident plane wave in the focal plane, k = 2π n/λ, α is the polarizability, λ is the vacuum wavelength, n is the square root of the dielectric constant of the surrounding medium, and R is the radial distance. In a reflected confocal detection configuration, when a nanoparticle is put on a glass slide surface, the total measured interference intensity from the reflected and scattered field at the detector equals

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Idet = |Er + Es |2 = |Eo |2 (r 2 + |s |2 − 2r|s |sin(ϕ)),

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where Er = r Eo exp(−iπ/2) is the reflected field at the detector, and r is the parameter that takes into account an effective field reflectivity for the incident focused beam (Figure 3a) (67, 68). The first term in this equation depicts the noise background that is reflected from the sample’s upper surface. The second term is the direct contribution of the scattered signal. This term is typically very small for small PNP due to the sixth power scaling law. For larger particles, this term contributes significantly, and it is possible to directly image the nanoparticle. In the case of small PNP, the third term plays a central role in the generation of measurable interference signals

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over the background noise because it is multiplied by the reflectivity. Therefore, a negative signal in the image will be observed. The significance of this scheme is that it allows practical measurements near the theoretical limits of speed and sensitivity (i.e., the shot-noise limit). It is also possible to distinguish the sign of the scattered field as well, providing a convenient pathway to differentiate PNP from bubbles or other scatterers. An analogous reflection interferometry introduced by Ignatovich & Novotny (69) is demonstrated to be capable of recognizing nanoparticles with different refractive index or size in free solution (Figure 3b). The scheme relies on detecting the scattered electric field amplitude as opposed to the scattered power. Different from the backscattered interference scheme, the reference beam is not generated from the glass/air interface. A 50/50 beam splitter is put in front of the objective. One beam is the scattering signal from the dielectric particles. The other beam serves as a reference beam that is reflected back to recombine with the scattered beam collimated by the objective. A major improvement in this strategy is that the power of the reference beam could be attenuated arbitrarily. With regard to the signal S(t)  sensed by the detector [S(t) ∝ Re(α) P f /Pr , where Pf and Pr are the powers of the focused laser beam and the reference beam, respectively], the two variables Pf and Pr are independent from each other. Therefore, an intense incident laser beam can be applied to illuminate the sample and the reference beam can be attenuated simultaneously by a wave plate or neutral density filter, leading to a convenient way to enhance the signal intensity. It is thus possible to realize the detection of small PNP (as small as 5 nm within a 1-ms time window) and the discrimination of different PNP with distinct polarizabilities (such as size and shape). In addition to the reflected mode, transmitted detection also provides an efficient route to image small PNP on the basis of interferometry. Batchelder & Taubenblatt (66) initiated a proof of concept experiment based on Normarski optics for the visualization of single-polystyrene spheres as small as 38 nm in diameter (Figure 3c). In this mode, the core idea is the utilization of a pair of head-to-head Normarski objectives. This design splits a circularly polarized laser beam into two spots of orthogonal linear polarization at the focus (one serves as a reference beam and the other is used as a probe beam) and then recombines them by another Normarski prism. The interference signal of these two beams is analyzed through a Wollaston prism analyzer at 45◦ to the Normarski splitting. This common path interferometry method is more stable than the separate path inference modality in suppressing noise sources such as vibration, turbulence, as well as the instability of the laser. As a result of this pioneering experiment, analogous commercially available common path interferometry, i.e., the differential interference contrast (DIC) microscope, has also been applied to the determination of individual PNP in complex surroundings (70–72).

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4. BIOLOGICAL APPLICATIONS OF SINGLE-NANOPARTICLE IMAGING Because of the fascinating optical properties and flexibility in the various modes of signal detection, there is growing interest to explore the applications of PNP in ultrasensitive detection and imaging in biological systems. Until now, many elegant and novel strategies have been introduced and implemented to sense small molecules with simple spectroscopic detection systems, such as aggregation-based assay using gold nanoparticles for DNA hybridization, nanoparticle-promoted reduction of silver for target detection on DNA arrays, and surface-enhanced Raman (or fluorescence) spectroscopy for biochemical detection; many comprehensive and expert reviews have already documented these topics extensively (38, 73–80). In the following section, we focus mainly on the recent applications of PNP in ultrasensitive assays with optical microscopy, particularly encompassing single-molecule detection, enzyme catalysis observation, dynamic single-particle positional and orientational tracking, etc. 8.10

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4.1. Single-Nanoparticle Imaging and Sensing Schultz et al. (56) demonstrated the labeling of single-molecule target sites with individual PNP. With a conventional darkfield microscope, individual silver nanoparticles with sizes of approximately 40–100 nm were readily discerned in various biological samples based on direct scattering, such as Drosophila polytene chromosomes, chicken skeletal muscle, etc. Those results indicate that PNP could be a promising alternative to conventional labels in broad applications, such as in DNA hybridization assay, immunohistochemistry in mounted tissue samples, and quantification of target molecules in a counting-based assay in the equivalent of a “sandwich” enzyme-linked immunosorbent assay. Currently, detection and quantification of gene expression has played a central role in basic pharmaceutical and clinical research (81–83). Single-particle counting renders a general platform to extend the detection limit of biomolecule detection and quantification. A typical example was demonstrated by Oldenburg et al. (84). They utilized single-particle counting to discriminate base pair mismatch with high sensitivity. Rather than measuring the scattered intensity, they counted the number of PNP hybridized on a DNA array in a high-throughput manner by using a CCD camera on a standard darkfield microscope (Figure 4a). The detection sensitivity is approximately 60 times higher than that achieved by using fluorescent labels. Although, in principle, it is possible to integrate this detection scheme into low-cost and quantitative detection systems for single-nucleotide polymorphism analysis, its performance is seriously affected by the nonspecific adsorption and interfering scattering on the surface. An analogous single-particle quantification approach is also demonstrated in the photothermal domain by Blab et al. (85). Detection of DNA hybridization events relying on laser-induced scattering around a nanoabsorber (photothermal heterodyne detection) overcomes the restriction on particle size in darkfield configuration. Much smaller probes can thus be used, leading to increased specificity and reactivity. More importantly, this imaging modality can effectively remove the false-positive readout from noisy scatters. The detection limit of this scheme is thus only constrained by the degree of nonspecific DNA hybridization and by the quality of surface treatment. In contrast to the previously reported scanometric DNA array detection, bypassing the signal amplification procedure could significantly reduce the time and effort needed and lower the chance of errors. However, similar to the scattering-based approach based on surface modification, it is still very difficult to completely suppress nonspecific adsorption at the single-molecule/particle level. To circumvent the above limitations and realize the ultimate goal of chemical detection at the single-molecule level, Xiao et al. (86) proposed a convenient approach to detect short-stranded DNA in a one-pot manner (Figure 4b). The design was based on sandwich hybridization where two different nucleic acid probes complementary to a 30-base target DNA molecule were attached onto the PNP surface. In the presence of target DNA molecules, the two probes could be brought into proximity in a tail-to-tail mode, resulting in a significant plasmon resonance coupling effect between the two particles. A distinct spectral shift over the native plasmon resonance frequency can then be detected. Provided the monomer is homogeneous in shape and size, it is very easy to differentiate hybridization-induced aggregates from free probes without any cross-talk. According to calculations, 40 nm is the suitable diameter for a gold nanoparticle to generate readily detectable color shift with a simple color CCD on a conventional darkfield microscope without sedimentation or nonspecific aggregation. By counting the color-coded PNP, single molecule–level detection sensitivity was achieved. The merit of this detection scheme is that the two probes guarantee specific counting of positive hybridization events. That is, this robust assay greatly reduces the risk of sample contamination, avoids complicated experimental operations, ensures good reproducibility, and is amenable to automation for routine analysis. Furthermore, it is also possible to perform

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parallel assays in a complex surrounding by using a set of PNP with different combinations of probes. It is of interest to utilize PNP as a miniaturized universal sensing platform for ultrasensitive monitoring of stochastic single-molecule adsorption events in a label-free manner, expression levels of trace molecules within living cells, as well as enzyme dynamics in real time (27, 37, 41, 87, 88). These studies are possible based on the sensitive response of the localized SPR peak to the variation of local refractive index that is altered by the binding of biomolecular targets to the receptor-functionalized nanostructures. A microspectrometer is therefore required to be 8.12

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incorporated into the scattering-based detection scheme for the analysis of the optical signal transduced by the binding events. This detection modality provides several key improvements that will enable new nanoscale sensing experiments while retaining all the capabilities of existing nanoparticle array and thin-film SPR techniques. First, the absolute detection limit can be dramatically reduced to the single-molecule level for biomolecules, and the sample volume can be greatly reduced as well. Second, in traditional ensemble spectroscopic assay, the heterogeneous distributions in particle dimension, morphology, as well as surface functionality induce irregular broadening of the LSPR spectrum, thus leading to significantly decreased sensitivity. Inhomogeneity is, however, suppressed through detection in a single-particle manner. Finally, time-dependent kinetic observation can be followed without the need for synchronization. An early example to detect biomolecules with single PNP was reported by Raschke et al. (87). With streptavidin as a model molecule, they first anchored biotinylated bovine serum albumin on the surface of a gold nanoparticle with a diameter of 40 nm. The specific recognition between streptavidin and biotin ensures an efficient linkage of an additional protein layer onto the nanoparticle surface. The minor refractive index change on the nanoparticle surface is then transduced into an optical signal output (i.e., a noticeable red shift in the LSPR spectrum). This report showed the capability of sensing biomolecular binding events at the single-particle level while the concentration detection limit was only 1 μM, in contrast to the nanomolar streptavidin detection limit reported by ensemble mode sensors. The poorer detection limit might be primarily controlled by mass transport limitations as well as the limited refractive index sensitivity of gold nanospheres (70 nm/RIU). In a later report, Nusz et al. (89) replaced the nanosphere by a more sensitive structure, namely, a gold nanorod (262 nm/RIU). An improved sensitivity (at a concentration of 1 nM) was readily realized. This scheme, however, still fails to detect individual binding events owing to the limited refractive index change caused by single biomolecules. Particle-particle coupling allows the development of ultrasensitive sensors for the monitoring of single-biomolecule binding events. When an analyte is labeled with a plasmonic particle and the corresponding receptor molecules are anchored on a probe surface, the specific biorecognition brings these two particles into close proximity. The plasmon coupling between these two PNP thus causes a noticeable resonance peak shift of the probe particle. Sannomiya et al. (90) successfully applied this concept to monitor individual DNA hybridization processes on a 100-nm gold nanoparticle surface with 20-nm gold nanoparticles comprising a signal amplifier. In addition to biomolecule binding observations, it is also interesting to implement the particleparticle coupling effect in the observation of enzymatic dynamics, distance measurement, etc. (Figure 4d ) (27, 88). It is known that the spectral shift of particle-particle coupling is determined by several parameters in terms of the shape and size of PNP, the distance in the gap, and the orientation of the pair. Among these factors, the distance-dependent spectral response has aroused significant attention because it is possible to implement the coupling effect as a sensitive nanometer distance ruler with much broader dynamic range compared to the method based on Forster ¨ resonance energy transfer (FRET). Specifically, PNP coupling is suitable for measuring longer distances that are not accessible by FRET. For example, in the case of gold nanoparticle dimers, the spectral shift as a function of the gap distance and the diameter of the gold nanoparticle can  s ≈ 0.18 × exp − 0.23D , where λ is the magnitude of the spectral peak shift be expressed as λ λo due to plasmonic coupling, λo is the peak position of an individual gold nanoparticle, s is the interparticle distance, and D is the diameter of the nanoparticle (86). Sonnichsen et al. (91) first ¨ implemented this concept to monitor the distance change during DNA hybridization between two PNP on a standard darkfield microscope. It was pointed out that with 40-nm particles and a 0.1-nm spectral resolution for determining the plasmon resonance position, particle separation of up to 70 nm could be accessible with better than 1-nm resolution. In comparison with FRET, the plasmon ruler neither blinks nor bleaches and more importantly, for spherical PNP, does www.annualreviews.org • Optical Imaging of Plasmonic Nanoparticles

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not depend on the relative probe orientation. Therefore, it has the potential of becoming an alternative to FRET for single-molecule experiments in diverse areas, especially for extended observation times and long distance measurements. Indeed, the merits of plasmon rulers have been extensively demonstrated not only in in vitro studies but also within living cells (27).

4.2. Positional and Orientational Tracking at the Single-Nanoparticle Level

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As early as several decades ago, gold nanoparticles with diameters as large as 40 nm were conjugated with phospholipids or proteins and applied to study the compartment effect on plasma membranes (92). Because the dimension of lipid domains is usually below the optical diffraction limit, the timescale that individual lipid molecules or proteins are trapped inside each corral is very short. Therefore, to access detailed information on the membrane compartment effect, a single-particle tracking approach with high spatial and temporal resolution is necessary. With a bright field microscope, Fujiwara et al. (28) imaged and tracked individual gold nanoparticles on relatively clean plasma membranes with a spatial precision of 17 nm and a temporal resolution of 25 μs. Obvious hop diffusion trajectory was found from these phospholipid-labeled gold nanoprobes. The lipid molecule on the cell membrane was found to be confined within 230-nm diameter compartments for 11 ms on average before hopping to adjacent compartments. Although this spatial and temporal resolution is adequate to reveal the dynamics of gold nanoparticle-labeled lipids or proteins within lipid domains, there are several major constraints in this imaging modality for broad applications. First, the S/N of the bright field imaging mode is very limited owing to the strong background noise from transmitted light, leading to relatively large localization errors in image analysis. Second, cellular organelles also generate perplexing signals analogous to that from gold probes. It is therefore a great challenge to differentiate positive signals from the complex cellular environment. Third, 40 nm is relatively large for a single-molecule labeling probe, which might sterically hinder the interaction between labeled molecules or alter their movements in confined environments. Although detection of interference scattering signal through a confocal microscope can push the size dimension down to 5 nm, this modality is more suitable for studying dynamic events at a glass/water interface. This is mainly due to the complicated scattering and reflection phenomenon in living cell systems. Darkfield illumination provides a more sensitive and efficient approach to detect PNP in biological samples (Figure 5a), because the background from incident light is largely removed. Nan and coworkers (58) used an objective-type darkfield microscope to track the translocation process of motor-protein-loaded gold nanoparticles (with diameters of approximately 100 nm) on microtubules within living HeLa cells. Xu’s group (93–99) also demonstrated several interesting examples on the utilization of darkfield microscopy to image individual functionalized silver nanoparticles on cell membranes. Because the scattering cross section of silver nanoparticles is noticeably larger than gold nanoparticles with a comparable dimension, the size of the probe can be reduced greatly while still keeping adequate S/N. For example, they utilized 10-nm silver nanoparticles conjugated with IgG to detect individual receptor molecules and map the distribution of receptors on living cell membranes over hours (95). Moreover, they demonstrated for the first time that these small silver probes could be further applied in in vivo optical imaging, e.g., measuring the viscosities and flow patterns of multiple proximal nanoenvironments in the segmentation stage of zebra fish embryos in real time (96). Despite these attractive demonstrations and great improvements on the size of plasmonic probes, progress on their implementation in living cell systems is still fairly slow. One of the major challenges is the interfering noise from crowding cellular organelles. Under the scattering mode, the majority of cellular organelles are strong Raleigh scatterers owing to the large refractive index mismatch with cytosol. Fortunately, 8.14

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the scattering response of cellular organelles is fairly constant over a broad wavelength range. Therefore, the background noise from native cellar structures can be considered a constant value between two adjacent wavelengths at a short timescale. On the basis of the unique resonance effect from PNP, it is possible to realize background-free imaging by eliminating the background noise with dual-wavelength difference imaging. Xiao et al. (100) demonstrated a proof-of-concept experiment on a conventional darkfield microscope and successfully tracked the dynamics of individual gold nanoparticles, not only on the living cell membrane but also inside living cells with high S/N (Figure 5b). Similar to the protein- or lipid-functionalized nanoprobes, more than 80% of the nucleic acid–functionalized GNPs also exhibited analogous restricted diffusion on the cell membrane. The two-wavelength difference imaging modality did not require any changes to the optical light path except for the addition of a dual-view module in front of the detection window. As a consequence, this method is suitable for biologists and chemists who are lacking in sophisticated optical expertise. Positional tracking of individual objects provides a host of mechanistic information essentially in two domains (92, 101). First, from the static perspective, the detailed trajectory diagram provides concrete spatial information such as where the object starts, the final destination of the object, and the intermediate pathways that the object passes through. However, the dynamic 2- or 3D diffusion velocity as a function of spatial position and time unveils the properties of the heterogeneous local www.annualreviews.org • Optical Imaging of Plasmonic Nanoparticles

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environment in the cellular system, such as the viscosity of the surrounding, the binding affinity with adjacent molecules, the density of receptor molecules, etc. Nonetheless, it would be a great challenge to elucidate additional important features that are correlated with conformational or orientational fluctuations, for example, the catalytic process of ATPase, the dynamin-coupled endocytosis process, motor protein–mediated nanocargo translocation on microtubules, dynamic protein-receptor interaction on living cell membranes, etc. (26, 46–48, 59, 102). The development of anisotropic PNP (in particular nanorods) renders an efficient platform to address the interesting questions listed above (Figure 6). Because of the anisotropic structure, the optical responses in absorption and scattering domains are also anisotropic in directions along the principle axes. A first example to demonstrate the capability of orientational imaging with gold nanorods was reported by Sonnichsen & Alivisatos (45). By introducing a birefringent calcite ¨ crystal into the detection light path, the scattered light excited by a standard darkfield microscope was split into two orthogonal polarization directions for each gold nanorod to form two spots on the detector. Because the scattering intensity of each gold nanorod in one particular polarization direction is proportional to the square of the cosine of the angle between the rod and that crystal axis of birefringent crystal, the orientation angle of each gold nanorod at any time point can be deduced according to the normalized measured intensity from one of the two spots. With this method they explored the rotational dynamics of gold nanorods on a glass slide surface. 8.16

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This polarization measurement method is suitable for the monitoring of fast rotational processes because the angular information can be directly deduced from the intensity fluctuation track. Spetzler et al. (26) applied a similar polarization measurement approach to explore F1 -ATPase rotation (after coupling to a gold nanorod) with a very high temporal resolution of 400,000 fps. This frequency is fast enough to precisely resolve the catalysis rate at which the γ-subunit travels from one dwell state to another. They found that the transition time of Escherichia coli F1 -ATPase γ-subunit rotation was approximately 7.6 rad/ms, and the rate-limiting dwell time between rotation events at saturating substrate concentration was 8 ms. These results are comparable to the previous observation from Mg2+ -ATPase. One of the major limitations of these polarization detection schemes is that the results only reflect the orientation information projected on the x-y plane within the first quadrant. Therefore, it is a challenge to discern the concrete angular information from the mirror positions in the Cartesian coordinate system. Furthermore, in the majority of cases, because the nanorod will not continuously stay within the x-y plane, elucidating the out-of-plane (tilting) angle would also provide plenty of additional information. On the basis of these concerns, Failla et al. (103) successfully implemented confocal microscopy in combination with high-order laser modes to discern the actual orientation of individual gold nanorods in the x-y plane. Xiao et al. (104) introduced another convenient approach with a conventional darkfield microscope to resolve the orientation of gold nanorods in 3D. This is realized on the basis that the 3D orientation of individual gold nanorods is uniquely coded by a particular defocused scattering image. By matching the measured image pattern with the simulation results, the in-plane and tilt angle of individual gold nanorods can be readily resolved in 3D. With this method, they tracked the translational and rotational dynamics of drug delivery cargo (with gold nanorods as a model system) on living cell membranes (Figure 6) (105). According to the rotational and translational results, dynamic protein-receptor association and dissociation during the surveying process on living cell membranes were revealed. Later this concept is further implemented in the two-photon fluorescence mode (106). In addition to the cell membrane, the rotational dynamics of individual nanocargo walking on microtubules in a living cell was also followed in a 3D manner with a planar illumination scheme (62). It was found that during the translocation process, the nanorod did not rotate continuously on the microtubule. The transition state crossing different microtubules was also tracked. Finally, DIC microscopy is also suitable for studying rotational dynamics. According to the black and white signal information from the interference image, this method was used to resolve the rotational process of microtubules labeled with gold nanorods on a motor protein array (71). Later, this technique was further improved for 3D measurement on living cell membranes in combination with the image pattern recognition approach (72). Besides scattering-based detection, the absorption process from the nanorod structure is also polarized. It is therefore interesting to adopt photothermal imaging for angularly resolved single-particle tracking (107). Perhaps because of the complexity of the photothermal imaging setup, there have not been reports about the application of this technique in biological samples.

5. THE FUTURE OF OPTICAL IMAGING OF SINGLE-PLASMONIC NANOPARTICLES Over the past few years, the distinct optical properties of PNP have aroused a new wave of interest in the development of ultrasensitive detection platforms. Owing to the highly efficient signal transduction capability, it is possible to perform optical analysis at the single-particle level. This feature greatly reduces the sample volume assayed and avoids the heterogeneity from other probes in contrast to ensemble measurements. Therefore, with optical microscopy, many vital www.annualreviews.org • Optical Imaging of Plasmonic Nanoparticles

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biological events and trace chemicals inside living cells could be followed and explored in real time. As documented here, progress in these areas have already resulted in several elegant studies. Despite these great achievements, a critical point that should be carefully considered is the native activity of labeled biomolecules on the nanoparticle surface. Prior to the single-particle imaging or sensing applications, the biological activity of those functional molecules should be characterized in advance. Besides sensing trace chemicals or biomolecules within living cells, it is also possible to utilize this detection platform in multiplexed chemical or reaction condition screening. The high spatial and temporal resolution of optical microscopy enables ultrasensitive detection of minor signal responses from each nanoparticle, analogous to having individual laboratories on each nanoparticle. By taking advantage of the high-throughput of microarray or droplet-based microfluidics, it should be highly efficient to perform multiplexed screening with plasmonic probes. Another interesting topic is disease-related cell or tissue diagnosis. Development of efficient clinical diagnosis methods for early detection of various major diseases has attracted much attention recently. Owing to the strong optical response (in either scattering or absorption domain) of plasmonic probes, it should be possible to target and discriminate disease-related cells in a simple way. Indeed, gold nanospheres and nanorods have been applied to cancer cell targeting with darkfield microscopy (108, 109). For tissue samples, the scattering-based method will need further development due to the strong background noise in tissue samples. Other optical imaging modalities (for example, photothermal imaging) may be good candidates for this kind of diagnosis.

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DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS L.X. is supported by NSFC 21205037, Hunan Natural Science Funds for Distinguished Young Scholar (14JJ1017), the Aid Program for the Science and Technology Innovation Research Team in Higher Education Institutions of Hunan Province and the Program for New Century Excellent Talents in University (NCET-13-0789), China. LITERATURE CITED 1. Stephens DJ. 2003. Light microscopy techniques for live cell imaging. Science 300(5616):82–86 2. Weijer CJ. 2003. Visualizing signals moving in cells. Science 300(5616):96–100 3. Moerner WE. 2007. New directions in single-molecule imaging and analysis. Proc. Natl. Acad. Sci. USA 104(31):12596–602 4. Wilt BA, Burns LD, Wei Ho ET, Ghosh KK, Mukamel EA, Schnitzer MJ. 2009. Advances in light microscopy for neuroscience. Annu. Rev. Neurosci. 32(1):435–506 5. Toomre D, Bewersdorf J. 2010. A new wave of cellular imaging. Annu. Rev. Cell Dev. Biol. 26(1):285–314 6. Tønnesen J, N¨agerl UV. 2013. Superresolution imaging for neuroscience. Exp. Neurol. 242:33–40 7. Ha T, Ting AY, Liang J, Caldwell WB, Deniz AA, et al. 1999. Single-molecule fluorescence spectroscopy of enzyme conformational dynamics and cleavage mechanism. Proc. Natl. Acad. Sci. USA 96(3):893–98 8. Moerner WE. 2002. A dozen years of single-molecule spectroscopy in physics, chemistry, and biophysics. J. Phys. Chem. B 106(5):910–27 9. Schuler B, Lipman EA, Eaton WA. 2002. Probing the free-energy surface for protein folding with single-molecule fluorescence spectroscopy. Nature 419(6908):743–47 8.18

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Optical imaging of individual plasmonic nanoparticles in biological samples.

Imaging of plasmonic nanoparticles (PNP) with optical microscopy has aroused considerable attention in recent years. The unique localized surface plas...
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