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Recent Advances in Optical Imaging with Anisotropic Plasmonic Nanoparticles Yinhe Peng, Bin Xiong, Lan Peng, Hui Li, Yan He, and Edward S. Yeung Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/ac504061p • Publication Date (Web): 06 Nov 2014 Downloaded from http://pubs.acs.org on November 14, 2014

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Recent Advances in Optical Imaging with Anisotropic Plasmonic Nanoparticles Yinhe Peng†, Bin Xiong†, Lan Peng, Hui Li, Yan He*, and Edward S. Yeung*

State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan University

Hunan University, Changsha, 410082, P. R. China.

† Contributed equally to this work

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Plasmonic nanoparticles show remarkable optical properties relating to localized surface plasmon resonance (LSPR). That is nothing new of course. Without knowing any physics, medieval artists produced stained glass windows that we still admire today after being exposed for centuries in sunlight. More recently, LSPR has been extensively studied for applications in biochemistry and life science.1-10 Due to the rapid development of nanofabrication, anisotropic plasmonic nanoparticles with various morphologies and structures have been prepared and their physicochemical properties have been thoroughly investigated. These are interesting because anisotropic nanoparticles display shape-dependent optical features that go beyond those of isotropic nanoparticles. Based on these unique properties and the emergence of various novel optical imaging techniques, anisotropic nanoparticles have gained increasing attention and are widely exploited as probes for sensing, imaging, diagnostics and therapy.11-16 Optical imaging has emerged as a powerful technique for visualizing and determining biological structures or events at the cell or tissue level. Due to its high sensitivity and low interference, fluorescence imaging is the dominant optical imaging technique, and various organic dyes, quantum dots and fluorescent polymer dots have been demonstrated as probes for fluorescence imaging.17-23 However, several notable drawbacks of fluorescent probes have limited their biological applications. For example, fluorescent dyes usually show poor photostability and low quantum yield in aqueous environments while quantum dots and polymer dots suffer from high cytotoxicity and difficult surface modification. In contrast, metallic nanoparticles

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superior photostability, large optical cross-sections and good biocompatibility, and are ideal optical probes for long-duration cell studies. By using plasmonic nanoparticles optical probes, versatile non-fluorescent imaging techniques have experienced an increasing growth for biochemical and biological investigations in recent years. The significant progress in applications to optical imaging in vitro and in vivo has been reviewed from different perspectives in several excellent articles.24-27

For example,

Long et al. summarized the use of plasmonic probes for biological imaging at the single-particle level.24 Xiao et al. reviewed various optical imaging methods for ultrasensitive single-particle imaging and sensing in biological samples.26 In this critical review, we provide a comprehensive overview of optical imaging with anisotropic plasmonic nanoparticles, including their basic optical properties, coupling with special techniques for optical imaging, and their representative applications to LSPR sensing and optical imaging. Firstly, the unique optical of anisotropic plasmonic nanoparticles compared with spherical nanoparticles are introduced in detail. By taking gold nanorods (AuNRs) as the example, the optical cross sections of AuNRs are analytically deduced according to Gans theory. It can be shown that for the same particle volume, the LSPR of nanorods occur at longer wavelengths than nanospheres. This allows the use of NIR wavelengths for penetrating biological tissues and to reduce background autofluorescence. The LSPR spectral shift due to changes in the dielectric of the surrounding medium is also magnified as the aspect ratio of the nanorod increases due to field enhancement. This translates to increased signal for biosensing and for surface-enhanced Raman

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spectroscopy. Furthermore, by concentrating the dipole moment in one axis, much stronger optical interactions can be observed. Second, to take advantage of these unique properties of anisotropic nanoparticles, we present representative optical techniques for imaging. For background reduction in imaging, implementation of cross-polarization detection selects the anisotropic probes, increasing spatial resolution and suppressing the isotropic cell background. The same selectivity can be achieved by two-color imaging with excitation by linearly polarized light, since the two axes of the nanorod give rise to two distinct spectral peaks. Anisotropy is also the basis for new microscopies such as two-photon imaging. Third, based on the ultrasensitive optical response of anisotropic nanoparticles to changes in the surrounding environment, major advances in LSPR sensing down to the single-particle level are discussed, with a focus on biochemical sensing and real-time monitoring. Finally, we highlight the emerging developments of anisotropic plasmonic nanoparticles for biological and medical applications. The unique application of anisotropic nanoparticles as orientational probes to interrogate cellular and subcellular dynamics is obvious. As strong light absorbers, particularly in the near-infrared region, applications to photothermal therapy for cancer treatment are promising. The larger surface-to-volume ratio of nanorods also allows more material to be transported inside biological cells in drug delivery applications. Furthermore, rods can attach via multiple points to the cell surface to increase the probability of endocytosis.

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Basic Optical Properties of Anisotropic Plasmonic Nanoparticles Theoretical investigation of the optical properties of plasmonic nanoparticles has been of interest in physical chemistry since the middle 1800s. One of the great triumphs in the theoretical understanding of nanoparticle optical properties was made by Mie in 1908 by presenting a rigorous analytical solution of Maxwell’s equations that describe the absorption and scattering spectra of spherical nanoparticles in a homogeneous surrounding. For anisotropic nanoparticles, the shape-dependent LSPR cannot be well explained with Mie’s theory. Therefore, several numerical methods have been proposed for describing the optical properties of anisotropic nanoparticles, including discrete dipole approximation, finite difference time domain method, finite element method and multiple multipole method.28-33 Using these numerical methods, the optical responses of nanoparticles with arbitrary shape that do not allow analytically solving Maxwell’s equations can be quantitatively elucidated with good accuracy. However, it is generally very complex and time-consuming to simulate the optical responses of anisotropic nanoparticles with the above numerical methods. Also, even for a simple anisotropic nanostructure such as an ellipsoid-like nanorod, it is not straightforward to reveal the dependence of optical prosperities on its shape. Nevertheless, the optical properties of a nanorod can be figured out using the quasistatic approximation that assumes the incident electromagnetic field is uniform over the nanorod. This approach was proposed by Gans in 1912.34,35 The absorption and scattering cross-sections of nanorods based on Gans theory are given by the following expressions:

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C sca =

k4 4 α 6π

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(1)

Cabs = k Im(α )

(2)

Cext = Csca + Cabs

(3)

α = 4π abc∑ i

ε (λ ) - εm εm + Li (ε (λ ) - εm )

(4)

where k is the wave vector, α is the polarizability of the nanoparticle, εm and

ε(λ) are the dielectric functions of the surrounding medium and of the metal, V is the volume of the nanoparticle, and a, b and c are the three major axes of the nanorod with a>b=c. The shape-dependent depolarization factors, Li is calculated according to:

L1 =

1 − e2 1 1 + e ( ln( ) − 1) e 2 2e 1 − e

L2 = L3 =

1 − L1 2

e = (1 −1/ φ 2 )

(5)

(6)

(7)

In the above equations, φ is the aspect ratio of the nanorod, defined as φ=a/b. Hence, the absorption and scattering spectra of a nanorod can be obtained and then the LSPR peaks (λmax) can be extracted from the corresponding spectra. These expressions for calculating the optical cross-sections of nanorods are simple and robust. The dependence of LSPR spectra on the aspect ratio of AuNR is obvious. Anisotropic AuNRs have two principal LSPR peaks: longitudinal and transverse surface plasmon modes polarized parallel to the long and short axes of the AuNRs, respectively, as shown in Figure 1a. The longitudinal surface plasmon resonance is usually much stronger than transverse component, and the enhanced localized electric field for longitudinal resonance at the ends of the long axis is also much stronger than that at

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the ends of the short axis. By gradually increasing the aspect ratio of the nanorod with a fixed diameter, the extinction cross-section at the longitudinal λmax remarkably increases, accompanied with a dramatically red-shifted longitudinal λmax from the visible to the near-infrared region, as shown in Figure 1b. The color of the AuNRs solutions thus gradually changed from blue to red when increasing the aspect ratio of the AuNRs, confirming the aspect ratio dependent longitudinal λmax for AuNRs. Based on the analysis of resonance conditions, it can be found that in addition to the aspect ratio, the λmax of AuNRs is also dependent on the dielectric constant of the surrounding medium. Since the dielectric constant equals the square of the refractive index (RI), the variance of refractive index (∆n) of the surrounding medium induced by physical or chemical interactions will give rise to the shift of the longitudinal λmax (∆λmax) of AuNRs, which is the foundation of plasmonic detection using AuNRs as nanosensors. As shown in Figure 1c, AuNRs with large aspect ratios and thus longitudinal λmax at long wavelengths exhibit larger optical responses towards refractive index changes than AuNRs with small aspect ratios and longitudinal λmax at short wavelengths,36,37 thereby favoring the use of AuNRs with large aspect ratios and longitudinal λmax as sensitive nanoprobes for LSPR sensing. According to the above equations, it is clear that the scattering and absorption cross-sections of plasmonic nanorods are orientation dependent (Figure 1d), i.e., by illuminating the nanorods with polarized light along the long or short axis, the resonance frequencies in the absorption and scattering spectra will be different.38 By taking advantage of this unique property, anisotropic AuNRs have been recently exploited for orientation

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sensing and rotation dynamics imaging during various biological processes.39-42 Other types of anisotropic nanoparticles like nanocages, nanocubes and nanoprisms also exhibit shape-related optical properties and have structure-dependent

λmax from visible to near-infrared (NIR) region (Figure 2),43,44 which can only be modeled with complex numerical methods. The LSPR at NIR region of these nanoparticles is also highly sensitive to the variations of refractive index of the surrounding medium. Hence, anisotropic triangle prisms and nanocages are also commonly used nanoprobes for sensing.45-49 Furthermore, like AuNRs, other anisotropic metallic nanoparticles also display anisotropic distribution of enhanced localized electric field near their surface. More detailed features of the optical properties of these anisotropic nanoparticles are described in several recent reviews.50-54 Therefore, compared to non-anisotropic nanoparticles, the unique features of anisotropic nanoparticles can be summarized as follows. Firstly, the absorption and scattering cross-sections are enlarged when tuning the λmax of anisotropic nanoparticles from visible to NIR region so that anisotropic nanoparticles having strong absorption and scattering of NIR light are very promising for the applications of imaging-based diagnosis, photothermal therapy of cancer and controllable delivery of drugs or genes. Secondly, larger spectral shifts in nanoparticle spectra in response to refractive index changes of the surrounding medium can be detected compared to that of nanospheres, suggesting a higher sensitivity of anisotropic nanoparticles as plasmonic sensors. Thirdly, anisotropic nanoparticles show orientation-dependent

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optical responses, which benefit the determination of orientation and rotation behaviors of biomolecules associated with various biological functions. Finally, anisotropic nanoparticles display anisotropic distribution of enhanced electric field confined to their surface. The greatly enhanced anisotropic electric field has been successfully applied to surface enhanced Raman scattering (SERS) and metal enhanced fluorescence (MEF) based techniques. Applications based on the first three features of anisotropic nanoparticles are the focus of this review. Readers interested in plasmonic nanoparticles for SERS and MEF applications are referred to several other recent reviews.55-61

Optical Methods for Anisotropic Nanoparticle Imaging With the ever-improving understanding in the optical properties of anisotropic plasmonic nanoparticles, numerous optical microscopic methods have been proposed for imaging them. Generally, there are four types of techniques for imaging plasmonic nanoparticles: scattering-, absorption-, interference- and photoluminescence-based techniques. These have been thoroughly introduced in several previous reviews.25,62-64 Therefore, we will focus on the most commonly accessible optical techniques for imaging in this section. These are all based on standard commercial instrumentation that is found in chemical and biological laboratories with minimal modification. Dark-field microscopy Dark-field microscopy is one of the most popular optical tools for imaging non-fluorescent samples. In the light path of a dark-field microscope, as shown in

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Figure 3a, oblique illumination is adopted by using a dark-field condenser with large numerical aperture such that only scattered light (or luminescence) from the sample can be collected by an objective. To further prevent any illuminating light from reaching the detector, objectives with small numerical aperture (usually smaller than that of the dark-field condenser) are utilized for dark-field imaging. Therefore, the specimen will appear as a bright image superimposed on a dark background. Dark-field microscopy is commonly used for imaging plasmonic nanoparticles because of their large scattering cross sections. For single plasmonic nanoparticle, the scattering cross section at λmax is usually 5 orders of magnitude or more larger than the light emission of commercially available fluorophores,65 making their LSPR spectral changes readily observable with dark-field microscopy. For example, using a dark-field microscope combined with a spectrophotometer, also known as dark-field spectral microscopy, the in-situ growth of single Ag@Hg alloyed nanoparticles and the corresponding LSPR scattering spectral shifts were monitored at the single-particle level (Figure 3b).66 By inserting a transmission grating before the CCD camera, the incoming scattered light eventually formed a zero-order image and a first-order image. With this method, Cheng et al. monitored the oxidation-induced shortening of hundreds of AuNRs simultaneously.67 The orientation-dependent optical responses of anisotropic nanoparticles can also been observed with polarized dark-field microscopy.

39,41,42

By inserting a birefringent prism in the light path, the

scattered light will be split into two orthogonally polarized beams, and the three dimensional (3D) orientation of single anisotropic nanoparticles can be calculated

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according to the intensities in the two detection channels. Based on this method, Xu et al.41 successfully monitored the orientation dynamics of protein-coated single AuNRs on C18-modified silica surfaces and revealed four different rotational states through a complete desorption process according to the different interactions between nanoparticles and surfaces. Also, dark-field microscopy was widely used for investigating the optical properties of other types of anisotropic nanoparticles such as Au-Ag core-shell nanorods, silver triangular nanoprisms, silver nanocubes, and so on.68-72 Total internal reflection scattering microscopy Derived from total internal reflection fluorescence (TIRF) microscopy, total internal reflection scattering (TIRS) microscopy (Figure 3c) has been developed to inspect non-fluorescent nanoparticles. As in TIRF microscopy, the samples are excited by the evanescent wave in TIRS microscopy, resulting in greatly restricted scattering background and enhanced signal-to-noise ratio for imaging. One of the major applications of TIRS microscopy for imaging anisotropic nanoparticles took advantage of interaction between the spatially confined electric field and AuNRs for determining their 3D orientation and thus the rotation dynamics at biological interfaces.73 Ha et al. recently developed a TIRS-based focused orientation and position imaging (FOPI) technique for studying the 3D orientation of AuNRs on a 50-nm thick gold film (Figure 3d).74 Due to surface plasmon coupling between AuNRs and the 50-nm thick gold substrate, the doughnut-shaped scattering pattern will appear in the image plane when illuminated with p-polarized laser light and the

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3D spatial orientation of AuNRs can be resolved according to the specific scattering patterns without suffering from the angular degeneracy or deterioration in image quality. Since the application of FOPI is limited by the confined plasmon coupling effect, they introduced a dual-color TIRS microscopy imaging system with two orthogonally polarized lasers as light sources. As the scattering intensity of the AuNRs fluctuates according to their 3D orientation, the dynamic in-plane and out-of-plane motions of the probes bound on the surface of lipid membranes can be analyzed.75 Furthermore, based on the orientation-dependent patterns in defocused TIRS microscopy, they developed a technique for studying the rotational dynamics of AuNRs attached to microtubules.76 TIRS microscopy has also been applied for investigating the rotation dynamics in complex environments.77,78 The unique properties of TIRS microscopy such as high precision and high signal-to-noise ratio compared with conventional dark-field microscopy make it ideal for revealing the interactions at complex biological interfaces. Differential Interference Contrast Microscopy (DIC) Differential interference contrast (DIC) microscopy, also known as Normarski Interference Contrast (NIC) or Normarski microscopy, is an optical microscopy that works on the principle of interference to detect optical path (or phase) gradients of the specimen. Most current DIC microscopes consist of a condenser, an objective with large numerical aperture, two birefringent Normarski prisms, a polarizer and an analyzer, as shown in Figure 4a. The incident white light becomes polarized via the polarizer, and then the polarized light is split into two orthogonally polarized light

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rays at the first Normarski prism. Because of the difference in refractive index and the thickness between two adjacent points, the optical path lengths of the two beams after passing through the samples are different, leading to a phase shift between two matching light waves. After collection by the objective, the two polarized beams are recombined by the second Normarski prism, and pass through the analyzer to generate interference in the final DIC image. Because the phase difference originates from the different refractive indexes of the sample and its surrounding environment, constructive (bright) and destructive (dark) interferences are formed with polarized illumination. In recent years, DIC microscopy has been successfully applied to studying single anisotropic plasmonic nanoparticles and the interactions between nanoparticles and cells. Taking AuNRs as example, the wavelength-dependent anisotropic refractive index due to the transverse and longitudinal surface plasmons leads to different bright and dark intensities depending on the orientation of the nanorods relative to the two polarization directions. This property has been exploited for studying the spatial orientation and rotation dynamics of AuNRs in various biological processes.79-82 However, these methods are commonly limited by the inability to decipher the full 3D orientation of a focused AuNR in the four quadrants of the Cartesian plane. To overcome this limitation, Xiao et al.83 proposed a method for extracting full 3D orientation information of single AuNRs (Figure 4b), by combining DIC image pattern recognition with DIC polarization anisotropy measurement that does not sacrifice the spatial and temporal resolution.

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Two-photon luminescence imaging (TPL) microscopy Two-photon luminescence (TPL) is a serial process involving sequential absorption of two photons and emission from the recombination of electrons in the sp-band and holes in the d-band. The process is unique to anisotropic dipoles. As shown in Figure 4c of a TPL microscope that is equipped with a femtosecond laser as the excitation source, a tunable wavelength output in the range of visible to near infrared for dispersion, and a photomultiplier tube (PMT) with a laser filter as the detector. TPL imaging, which permits noninvasive imaging of subcellular features potentially hundreds of micrometers deep into tissue with high resolution and low photo-damage, has considerable potential in biomedical imaging and diagnostics. Anisotropic plasmonic nanoparticles are particularly appealing as TPL imaging agents because they possess much higher two-photon absorption cross-sections than those of spherical plasmonic nanoparticles and organic fluorophores,84,85 and because of the higher photostability and better biocompatibility compared to quantum dots. The TPL properties of anisotropic nanoparticles have been thoroughly studied and widely used for bioimaging.84-91 For example, Gao et al. compared the TPL properties of five different shapes of gold nanoparticles (nanospheres, nanocubes, nanotriangles, nanorods, and nanobranches), and found that the nanobranches had the largest TPL intensity.86 Figure 4d shows the merged two-photon luminescence image and transmission image of HepG2 cells after incubation with gold nanobranches. Wang et al. reported that the TPL signal from a single nanorod is essentially depolarized yet has a cos4 dependence on the excitation polarization and is nearly 60 times brighter

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than the two-photon fluorescence (TPF) from a single rhodamine molecule.87 Motamedi et al. used AuNRs as the contrast agents to reveal the abnormal vessel structure in dysplasia for the first time under TPL microscopy.90 Li et al. revealed orientation-dependent features of single AuNR via defocused TPL microscopy.91 Other anisotropic nanoparticles such as gold nanocages, gold nanostars, and gold nanoprisms have also been used as effective contrast agents for TPL imaging with satisfactory TPL efficiency.92-94 Implementation of TPL does require the use of a two-photon microscope, but commercial instruments require little expertise from the operator. The bonus is that z-sectioning with improved resolution over confocal microscopy can be obtained at the same time. Other methods Absorption-based techniques including photothermal heterodyne imaging and transient absorption microscopy can be used for the imaging of anisotropic nanoparticles due to their strong absorption of NIR light. With these methods, selective imaging with high contrast has been demonstrated by several groups.95,96 Photoacoustic imaging has also emerged as a novel method for observing anisotropic nanoparticles within intracellular microenvironments.97-102

LSPR Sensing As one of the most commonly used label-free detection techniques, LSPR sensing has experienced an explosive development in the past two decades. Several recent reviews have highlighted the applications of plasmonic nanoparticles in sensing.

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For example, Stevens et al.103 discussed the use of plasmonic nanomaterials in the development of diagnostic tools for the detection of a large variety of biomolecular analytes. Yong et al.104 discussed the latest trends and challenges in engineering and applications of nanomaterial-enhanced surface plasmon resonance sensors. Long et al.24 summarized the use of plasmonic probes as single-particle biological nanosensors in vitro and in vivo. Based on the higher sensitivity of anisotropic nanoparticles described in the first section, we will discuss the applications of plasmonic sensing in this section, focusing on single-particle sensing, real-time monitoring and dynamic detection. Anisotropic nanoparticles for label-free detection As the plasmonic resonance of metal nanoparticles is sensitive to the dielectric constant (refractive index, RI) of the surrounding medium, the LSPR spectra of nanoparticles will shift in response to a change in the local surface environment.13 Numerous efforts are ongoing to identify ideal plasmonic sensors, which show a large spectral shift towards a small change in the RI of the surrounding microenvironments. Generally, the RI sensitivity of a plasmonic nanosensor is calculated based on the slope of a linear fit to a plot of LSPR λmax shift versus RI of the surrounding microenvironment. The LSPR spectral shift induced by the change of RI can be approximately described with the following expression:13

∆λmax = m(na − nm ) [1 − exp(−2d / ld )]

(8)

Here m is the bulk refractive-index response of the nanoparticle(s); na is the refractive index of the adsorbate, nm is the refractive index of the surrounding medium,

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d is the effective adsorbate layer thickness, and ld is the characteristic electromagnetic field decay length (approximated as an exponential decay). The selectivity of this technique is achieved by functionalizing the plasmonic probes by using biomolecules with high specificity to targets. For example, biotin, antibodies and nuclear acids are usually used as recognition molecules to modify the nanoparticles for the detection of streptavidin, antigens, DNA and drugs, where the bonding with targets can induce a change of refractive index surrounding the nanoprobes. In particular, anisotropic plasmonic nanoparticles with plasmon bands in the NIR region are more popular in LSPR sensing due to the higher sensitivity to the refractive index change in surrounding environments.105,106 Recently, ultrasensitive and multiplexed sensing have been successfully demonstrated by many research groups using various anisotropic nanoparticles such as gold nanodisks, silver nanocubes, gold nanotstars, gold nanoprisms and gold nanorods.45,107-112 For example, using dark-field spectral microscopy to determine the LSPR spectral shifts, Sim et al. reported the sensitive detection of prostate specific antigens

with α1-antichymotrypsin

functionalized AuNRs as plasmonic probes.113 Due to the sensitive response of AuNRs to the antigen-antibody bonding induced refractive index change, they achieved a limit of detection as low as 111 aM. For further improving the sensitivity of plasmonic nanosensors, Orrit and his coworkers114 developed a novel method based on photothermal assay assisted LSPR sensing, where the bonding of single streptavidin-R-phycoerythrin molecules with biotin modified AuNRs was detected with high signal-to-noise ratio. By utilizing the advantages of TIRS imaging and

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miniaturization at the micrometer scale, Carsten et al.115 proposed a novel tool (Figure 5a) for label-free single-molecule detection. By recording the LSPR wavelength shift of AuNRs fixed in a microscaled capillary, the adsorption of individual fibronectins to the probes can be detected with extremely high temporal resolution. With dark-field spectroscopy, they also demonstrated multiplexed sensing of several types of proteins using different aptamers-functionalized AuNRs as probes.116 The effect of plasmonic coupling with enhanced wavelength shifts has also been applied for promoting the sensitivity of plasmonic sensing with anisotropic nanoparticles. As a demonstration, Hall and coworkers117 modified silver nanoprisms and gold nanoparticles with biotin and antibiotin respectively, and then detected the binding-induced LSPR shifts. They achieved LSPR enhancement for the detection of analytes with up to 400% amplification of the shift upon antibody binding to analyte. It is likely that even more plasmonic sensing techniques with promoted sensitivity and throughput will be developed in near future. The LSPR spectral shift induced by the binding of proteins with plasmonic nanoprobes has also been applied for studying molecular interactions. Based on their earlier work in LSPR sensing,68,117-123 Van Duyne’s group proposed a broadly applicable method to measure molecular affinity constants47,119,120,124 that has attracted increasing attention for studying protein-protein interactions in recent years. As the binding reaction between targeted analytes with capture molecules on the nanoprobes will come to equilibrium due to the balance of adsorption and desorption processes, the adsorption ratio (θ) can be described with the Langmuir equation,

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θ=

K a,surf ⋅ C A ∆R = ∆Rmax 1+ K a,surf ⋅ C A

(9)

where ∆R is the LSPR spectral shift (∆λmax,) at a given analyte concentration (CA), ∆Rmax is the maximum of LSPR spectral shift for a full monolayer coverage, and Ka,surf is the surface-confined thermodynamic affinity constant. By fitting the plot of ∆R/∆Rmax versus CA curve with the Langmuir equation, the affinity constant can be obtained. After monitoring the LSPR shifts of silver nanoprisms induced by the binding of amyloid-βderived diffusible ligands (ADDLs) and second anti-ADDL antibodies, Van Duyne et al.124 revealed that the two ADDL epitopes have binding constants to the first and second antibodies of 7.3 × 1012 M-1 and 9.5 × 108 M-1, respectively. With the same method, they studied the dynamic conformational changes of calmodulin in the calcium binding and release processes,47 as shown in Figure 5b. In their study, the measured dissociation constant for the calcium-calmodulin interaction was 52 µM. More recently, Carsten et al.125 reported the simultaneous characterization of binding affinities between multiple macromolecular partners using individual protein-functionalized AuNRs as probes. As shown in Figure 5c, AuNRs were first modified with three different bacterial division proteins and then fixed on the substrates sequentially for position-encoding. After binding with a batch of target proteins, the LSPR spectral shifts of three kinds of nanoprobes were recorded under dark-field spectral microscopy. Using the Langmuir equation to fit the optical response-concentration curves, the binding affinities for all proteins and targets can be extracted. These studies suggested that this method is very promising for the investigation of protein-protein interactions and dynamic behaviors of proteins during

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various biological functions with high throughput. Anisotropic nanoparticles for dynamic monitoring As the LSPR wavelength of anisotropic nanoparticles is highly sensitive to the dielectric constants of the surrounding medium, monitoring the LSPR spectral shift induced by chemical reaction or physical adsorption on the surface of plasmonic nanoprobes has become a new strategy for studying the reaction kinetics. For example, with dark-field spectral microscopy, Cheng et al. monitored the spectral shifts and intensity changes of individual AuNRs during the H2O2-initiated oxidation process.67 In their study, the heterogeneous reaction activity of individual plasmonic AuNRs was discovered and a self-catalysis mechanism for the chemical reaction between AuNRs and H2O2 was revealed according to the reaction rate measurements. Based on the principle of reactant-concentration dependent reaction rates, dynamic determination of the concentration of reactants can be realized by extracting the reaction rates in real time. By utilizing the fast reaction between H2S and silver in the presence of oxygen, Xiong et al. proposed a novel method for the dynamic detection of H2S in living cells via single-particle plasmonic imaging with Au-Ag core-shell nanorods as nanoprobes.126 Drawing on the high sensitivity of single-particle detection technique and the high specificity of this reaction, they achieved an ultrahigh sensitivity and selectivity towards H2S with a LOD of 0.01 nM. With this method, they demonstrated the rapid determination of concentration as well as its variations of intracellular endogenous H2S with nM sensitivity via kinetic measurement of Ag2S-formation induced spectral shifts of the nanoprobes (Figure 6a), which should be capable of

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tracking H2S fluctuations during cell signaling processes. The heterogeneity of reaction kinetics and dynamic analysis of reactions that take place on the surface of anisotropic plasmonic nanoparticles can be readily revealed by continuously monitoring the LSPR spectral shift of the nanoprobes, which opens up the possibility for investigating reaction kinetics and achieving dynamic determination in complex environments in the future. According to the inherent property of LSPR, the wavelength maximum of plasmonic nanoparticles is also sensitive to perturbations of surface free electrons: 127,128

∆λmax = −

∆N 1− L ⋅ λp ε + ( )ε m 2N L

(10)

where N is the electron density of the metal, L the shape factor of the nanocrystal, ε is the dielectric constant of the metal, and εm is the dielectric constant of the surrounding medium. Thus, the ∆λmax of plasmonic nanoparticles can be used as a measure for electronic perturbations induced by electron transfer or electron charging under different processes. For example, Mulvaney and coworkers observed a blue shift of the LSPR scattering spectra of gold decahedral nanoparticles after adding ascorbic acid as electron injection under dark-field spectral microscopy.127 By monitoring the kinetics of catalytic redox reaction on the surface of single gold nanoparticles, they demonstrated the first direct measurement of the rates of redox catalysis on single nanocrystals. More recently, Long’s group developed a spectroelectrochemistry technique that combines dark-field spectral measurements and electrochemical analysis measurements to study the electrocatalytic oxidation of hydrogen peroxide on

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the surface of single gold nanorods (Figure 6b).129 By simultaneously recording the dark-field scattering spectra of single AuNR during the cyclic voltammograms scanning, which was performed at a scan rate of 10 mVs−1, they found that bare AuNR could catalyze the oxidation of H2O2. Also, from the single-particle spectra, it was obviously that the heterogeneity in size and shape of individual AuNRs caused their differing ability to electrochemically catalyze the oxidation of H2O2. These results indicate that by integrating dark-field spectral microscopy and other techniques, better understanding of the mechanism of various catalytic or electrochemical reactions can be expected through high-throughput screening and dynamic monitoring at the single-particle level.

Biological and Medical Applications Optical imaging, particularly in combination with novel methods, has become a powerful and robust approach for biological and biomedical investigations. As a result, various kinds of imaging contrast agents such as plasmonic nanoparticles, silicon nanomaterials, fluorescent dyes, upconversion nanoparticles and quantum dots have been developed for visualization of morphological details of tissues with subcellular resolution, diseases diagnosis, as well as therapy.51,130-142 Among them, anisotropic plasmonic nanoparticles that have absorption and scattering with tunable LSPR wavelengths from visible to NIR regions display distinct advantages in versatile applications including multiplexed labeling, photothermal therapy, controllable delivery of drugs or genes, polarization and rotational imaging. In this section, the

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applications of such imaging schemes with anisotropic nanoparticles will be discussed in detail. Anisotropic nanoparticles for photothermal therapy of cancer cell Since anisotropic nanoparticles with LSPR wavelengths at NIR region can absorb NIR light and produce heat efficiently, these nanoparticles show promise for photothermal therapy (PTT), a method for cancer therapy built on the photothermal conversion induced cell necrosis. The efficiency of PTT is usually determined by the temperature elevation, which is related to the concentration of anisotropic nanoparticles inside of tumor cells due to the enhanced permeability and retention (EPR) effect of tumors.143-146 Thus, to obtain a desirable PTT performance with these nanoparticles, it is normally necessary to promote the nanoparticle uptake efficiency. Previous studies indicated that surface functionalization of nanoparticles is a useful strategy to enhance their cellular uptake.147,148 A wide variety of surface modification methods

have

been

nanoparticles.149-155

developed

for

tailoring

the

uptake

efficiency

of

For example, by replacing the cytotoxic CTAB surfactant with

alkyl cationic thiols through a ligand exchange strategy, these functionalized AuNRs are favorably internalized by cells and show good biocompatibility according to cytotoxicity tests.152,153 More recently, El-Sayed and coworkers155 reported that RF (Rifampicin)-conjugated AuNRs can greatly enhance the uptake rate as well as the final concentration of nanoparticles inside of cancer cells, as observed as bright scattering signals under dark-field microscopy (Figure 7a). One representative example of biological application is the use of AuNRs with

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precisely controllable LSPR wavelength in NIR window and excellent photothermal efficiency for photothermal therapy of cancer cells.156-163 The first demonstration of AuNRs for photothermal therapy was reported by El-Sayed and co-workers.164 In their study, the AuNRs were first functionalized with anti-epidermal growth factor receptors and then incubated with both malignant and nonmalignant human epithelial cells. After exposure to focused 800-nm red laser light for 1 min, malignant cells were killed while nonmalignant cells were still alive, indicating a targeted photothermal therapy of cancer cells. They also achieved selectively targeted photothermal therapy towards breast cancer cells using less-costly small molecules functionalized AuNRs.165 To improve the therapeutic efficacy, combined treatment of photothermal therapy and other methods such as chemotherapy, magnetic therapy and photodynamic therapy is usually implemented.166-172 For example, Sailor et al. presented a complex nanosystem, AuNRs integrated with magnetic nanoworms (NW) or doxorubicin-loaded liposomes, for synergistic therapy of cancer cells with greatly enhanced efficacy.173 The AuNRs act as photothermal antennas via remote near-infrared laser irradiation, and NW and doxorubicin play the roles as magnetic therapy and chemotherapy, respectively. Since the ultimate goal of photothermal therapy is clinical applications, the investigation of in vivo photothermal therapy with various nanoparticles has attracted extensive research interest. After intravenously injecting the PEGlated AuNRs into tumor-transplanted mice, El-Sayed et al. showed that the growth of squamous cell carcinoma in mice can be effectively suppressed after irradiation with NIR laser.174 Xia’s group also demonstrated the photothermal

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destruction of breast cancer cells both in vitro and in vivo with monoclonal antibodies modified gold nanocages.175,176 As shown in Figure 7b, tumor-bearing mice were injected intravenously with PEGylated gold nanocages with saline as the control and a clear variation in tumor size can be observed by exposing the mice to laser 72 h after injection.176 The change in metabolic activities of the mice before and after photothermal therapy was noninvasively evaluated using

18

F-fluorodeoxyglucose

positron emission tomography. It was found that the metabolic activity of mice injected with gold nanocages remarkably decreased prior to and after the laser irradiation, while there was no significant difference for mice without injection of gold nanocages, suggesting gold nanocages can serve as effective transducers for photothermal treatment of cancer in vivo. Although anisotropic nanoparticles have been demonstrated as promising photothermal transducers in vivo, there are several factors restricting the efficiency of photothermal therapy such as the renal clearance of nanoparticles circulating in blood and the poor selectivity of functionalized nanoparticles targeting tumor in vivo. We believe that addressing these challenges will advance anisotropic nanoparticles based photothermal therapy to the next level in cancer treatment in the near future. Anisotropic nanoparticles for biological imaging Polarization imaging Because the surface plasmons in anisotropic nanoparticles are directional, the measured LSPR spectra are dependent on the orientation of the particles in the exciting field. Thus, orientation specific LSPR scattering spectra can be obtained

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under dark-field microscopy for determining the angles between the major axis of the particle and the polarization directions of the incident light. As the LSPR spectral shifts are normally accompanied by color changes,177-179 orientation dependent colors can also be observed under dark-filed microscopy. This property of anisotropic nanoparticles has been used for polarization imaging. For example, Kim et al.180 reported the polarization dependent LSPR spectra and colors of single AuNRs fixed on glass slides under dark-field microscopy by adjusting the polarization angles between polarizer and analyzer. Based on the orientation dependent optical responses of AuNRs, Cheng et al.181 developed a cross-polarization microscopy for the selective imaging of single and patterned AuNRs with sub-diffraction-limit spatial resolution. This unique interplay between light polarization and anisotropy has also drawn much attention due to potential applications in orientation sensing, optical recording and polarization encryption. Using the combination of LSPR wavelength and polarization for multiplexing, Gu et al. demonstrated multiple optical recording by polarized two-photon luminescent imaging of patterned AuNRs with different LSPR wavelengths.182 In their study, each encoded pattern was fabricated with one type of AuNRs with specific LSPR wavelength. Then, multiple layers were formed by stacking the patterns layer by layer. By utilizing wavelength and polarization mediated recording and readout mechanisms, five-dimensional optical recording (Figure 8a) was achieved under polarized two-photon luminescence microscopy for the first time. With AuNRs encoded patterns, they also showed a 3D orientation-unlimited polarization encryption by configuring the vectoral exciting

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beams in two-photon luminescence imaging (Figure 8b).183 These representative investigations indicated that polarized light imaging with anisotropic nanoparticles as probes provides a breakthrough for various applications such as multiplexing optical recording and encryption, and high-density data storage. Single-particle orientation and rotation dynamics imaging Revealing the dynamics of biological functions and processes is crucial for fundamental understanding in biology and life science. Besides fluorescent imaging techniques, non-fluorescent imaging techniques with plasmonic nanoparticles have gained growing scientific interest in recent years. Previous investigations demonstrated that single-particle imaging has successfully revealed the translational dynamics in various cellular functions, but failed to obtain orientational and rotational information with isotropic probes.184-187 Recently, this limitation has been overcome by advanced optical imaging techniques with anisotropic nanoparticles. In this section we will discuss the recent successes in elucidating the 3D orientational and rotational dynamics of anisotropic nanorods during different biophysical events. The first demonstration of AuNR for orientational imaging was carried out by Alivisatos’ group with polarized dark-field microscopy, where the scattered light of the AuNR was split into two orthogonally polarized beams by a birefringent calcite crystal. Since the scattering intensity of each AuNR in any polarization direction is proportional to the square of its electric dipole in that direction, the orientation angle of single nanorod at any instance could be deduced according to the normalized intensity.39 However, that demonstration was restricted to in-plane angle

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determination only. By using planar illumination method in polarized dark-field microscopy (Figure 9a), He and coworkers proposed a novel method to obtain the 3D orientation of single nanorods according to the relative intensities in two detection channels.40 With this method, they tracked the translational and 3D rotational movements of single AuNRs transported by kinesin motor protein on microtubules in living cells with high spatial and temporal resolution. Recently, they also established dual-channel polarization dark-field microscopy to image 3D rotational dynamics of AuNRs during the transmembrane process.42 By focusing the imaging plane at the sidewall of the cell, the scattering interference from intracellular components was greatly reduced compared to imaging at the top of the cell (Figure 9b). The success in real-time monitoring whole membrane-crossing process of single AuNRs indicates that this simple method is promising for obtaining valuable insights on endocytosis mechanisms of biological cells. As the asymmetric dipole emission patterns are highly dependent on the orientations of the fluorescence molecules, generally referred to as 3D point-spread functions (PSFs),188,189 defocused dark-field microscopy has also been developed for orientational imaging of AuNRs. By matching the measured image patterns with the simulation results, the in-plane and tilt angle of individual AuNRs can be readily resolved.190 However, the drawback of this method is a loss of spatial resolution as a result of the degenerated point-spread-function. Recently, with dual-wavelength dark-field microscopy, Xiao et al. studied the interaction between transferrin-modified

AuNRs

(25×70nm) and

living

cell membrane

before

internalization.191 The well-focused transverse mode from the AuNRs was used for

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translational localization, while the orientational information was simultaneously deciphered through the defocused longitudinal mode. By revealing the dynamic interaction between protein and receptor, they found that more than 90% of transferrin-modified AuNRs experience confined lateral diffusion on the cell membrane and the rotational motion of AuNRs on the living cell membranes is not coordinated with their lateral diffusion. Differential interference contrast (DIC) microscopy is also suitable for studying the 3D orientation of anisotropic nanoparticles, and recent efforts by Fang’s group have made DIC microscopy into a promising tool for tracking AuNRs in biological samples. For example, the rotational motions of AuNRs transported by motor proteins, such as kinesin and dynein, were monitored inside and outside living cells by DIC microscopy.81,192 Recently, they directly visualized the rotational dynamics of transferrin-modified AuNRs in both active directional transport and pausing stages of axonal transport, and revealed how kinesin and dynein motors take the cargo through the alternating stages of active directional transport and pause.79 The kinetic interaction between functionalized nanorods and live cells was also studied under DIC microscopy.80,82,193 By coating AuNRs with cell penetrating peptide (cationic) and transferrin (anionic) respectively, DIC microscopy was applied to investigate the rotational modes during their interaction with live cell membranes. Two basic modes, in-plane rotation and out-of-plane tilting, were discovered in which the rotational behaviors of nanorods were remarkably different, as shown in Figure 9c, indicating different interactions for the two biomolecules with their membrane receptors.82

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These demonstrations indicate that the study of single-particle orientational and rotational tracking with anisotropic nanoparticles during biological events is only at an early stage. We believe that the underlying mechanisms governing the observed rotational behaviors in different biological functions will be elucidated in future.

Perspective Anisotropic plasmonic nanoparticles showing unique optical features due to the shape-dependent localized surface plasmon resonance have attracted more and more interest in various fields such as physics, chemistry, biology and biomedicine. Great progress in LSPR sensing and optical imaging using such particles has been made in the past years. Various types of anisotropic plasmonic nanoparticles have been proposed as label-free and ultrasensitive nanosensors for biochemical detection and dynamic monitoring at the single-particle level. By utilizing the anisotropic optical properties, novel approaches have been developed in polarization light imaging for revealing the 3D rotation dynamics in biological processes with details that were not previously possible. These achievements demonstrated the promising prospect of anisotropic nanoparticles imaging. However, there are still great challenges to be addressed in future. For example, as toxic surfactants are used in the synthetic processes of most anisotropic nanoparticles, present techniques for modifying anisotropic nanoparticles and reducing cellular toxicity still need to be improved for biological investigations. Also, when applied to LSPR sensing, the adsorption or binding of single molecules on

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anisotropic nanoparticles is still difficult to be detected and requires complex methodology. Another common drawback of these ultrasensitive analysis methods is the low throughput such that only a few of these methods have been implemented for practical applications. Regarding medical applications, the major problem for photothermal therapy with anisotropic nanoparticles is the poor efficiency in vivo resulting from the low selectivity when targeting tumors. Finally, the spatio-temporal resolution of existing optical imaging methods needs to be further improved in biological studies. Thus, there is plenty of room for new ideas for research in optical imaging of anisotropic nanoparticles for many years to come.

Biographies Ms. Yinhe Peng received her B.S. degree from Hengyang Normal University in 2012. She is currently a postgraduate student in the group of Professor Yan He and Professor Edward S Yeung at Hunan University. Her research interest focuses on the synthesis of plasmonic nanoparticles and applications of single-particle imaging. Ms. Lan Peng received her B.S. degree from Hunan University in 2013. She is pursuing her M.S. degree under the supervision of Professor Yan He at Hunan University. Her current research mainly focuses on developing new strategies for optical detection at single-particle level with dark-field microscopy. Ms. Hui Li received her B.S. degree in chemistry from Anqing Normal University in 2013. She is now pursuing her M.S. degree under the supervision of Professor. Yan He at Hunan University. Her research work focuses on the assembly of noble metal nanoparticles, plasmonic sensing and imaging. Dr. Bin Xiong is currently an assistant researcher in the College of Chemistry and Chemical Engineering at Hunan University. He received his B.S. degree in 2008 and Ph.D. degree in 2013 under the co-supervision of Professor Yan He and Professor Edward S Yeung, in the Department of Chemistry at Hunan University. He was a research associate in the group of Professor Hongkai Wu at Hong Kong University of Science and Technology before moving to his current position in 2014. His current

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research involves preparation of novel nanomaterials, optical sensing and imaging at single-particle and single-cell level. Dr. Yan He is a professor in the College of Chemistry and Chemical Engineering at Hunan University. He received his B.S. degree in 1995 from Peking University and his Ph.D. degree in 2001 from the University of Iowa under the supervision of Professor Lei Geng. After working as a PostDoc research associate in the group of Professor Edward S. Yeung at Ames Lab and Iowa State University from 2002 to 2005, he joined Hunan University in 2005. His current research focuses on single molecule plasmonic imaging and their applications in biological research. Dr. Edward Yeung is a Distinguished Professor Emeritus at Iowa State University. He also hold Chair Professorships at Hunan University, PRC, and at National Taiwan University, Taiwan. He received his A.B. degree from Cornell University and his Ph.D. degree from the University of California, Berkeley. Since then, he has been a member of the faculty at Iowa State University. He was a former associate editor of Analytical Chemistry. His research interests span single-molecule detection, genomic analysis, fundamentals of chromatography, and biological imaging.

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Acknowledgement This work was supported by NSFC 21127009, NSFC 91027037, NSFC 21221003, Natural Science Foundation of Hunan Province 13JJ1015, and Hunan University 985 fund.

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Figure 1. (a) Schematic illustration of the interaction of polarized light and gold nanorods to form the electronic coherent surface plasmon resonance (SPR) oscillation. The electric field (E) of incident light (propagating along the k direction) induces coherent collective oscillation of conduction band electrons with respect to the positively charged metallic core. (b) Calculated extinction spectra of gold nanorods with varying aspect ratios using Gans theory with the medium dielectric constant fixed at a value of 1.33, and the corresponding color change of gold nanorods colloids. Reprinted with permission from ref 53. Copyright 2014 Royal Society of Chemistry. (c) Sensitivity of gold nanorods with different aspect ratios. (d) Calculated longitudinal and transverse oscillation scattering spectra of single gold nanorod. Inset: Polar plot of polarization modulation resulting from the longitudinal oscillation mode.

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Figure 2. (a) UV–visible spectra of the gold nanotriangles with increasing edge lengths (normalized at the LSPR maximum). Reprinted with permission from ref 43. Copyright 2007 Macmillan Publishers Ltd. (b) UV-visible spectra taken from the silver nanocubes and gold nanocages. The surface plasmon resonance peak of the gold nanocages is tunable throughout the visible and near-IR regions by titrating the silver nanocubes with different volumes of HAuCl4 solution added. Adapted from ref 44. Copyright 2014 American Chemical Society.

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Figure 3. (a) Schematic diagram of dark-field microscopy. (b) Real-time monitoring of the in-situ growth of a single Ag@Hg nanoalloy from a silver nanorod by dark-field scattering microscopy. Adapted from ref 66. Copyright 2013 American Chemical Society. (c) Schematic diagram of total internal reflection scattering microscopy. (d) Influence of dielectric substrate on the far-field scattering patterns of gold nanorods under total internal reflection white light illumination. Left to right are the schematic diagram, scattering pattern, and intensity line-sectional profile for a gold nanorod on glass slide, respectively. The bottom is the corresponding diagrams for a single gold nanorod on a gold film. Adapted from ref 74. Copyright 2012 American Chemical Society.

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Figure 4. (a) Schematic diagram of differential interference contrast microscopy, (b) Changes in DIC image patterns of a Au nanorod as a function of azimuthal angle. Four different image patterns appear for the tilted Au nanorod: dark part on the left (R1), bright part down (R2), dark part right (R3), and bright part up (R4). Reprinted with permission from ref 83. Copyright 2012 Wiley-VCH. (c) Schematic diagram of two-photon luminescence imaging microscopy. (d) Merged two-photon luminescence image and transmission image of HepG2 cells after incubation with gold nanobranches. Adapted from ref 86. Copyright 2014 American Chemical Society.

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Analytical Chemistry

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Figure 5. (a) Diagram of total internal reflection setup with a magnified view of the flow cell. Inset: The plasmonic wavelength shift at the heart of the sensing principle. Reprinted from ref 115. Copyright 2012 American Chemical Society. (b) Schematic representation of the reversible conformational changes calmodulin undergoes in response to changing calcium concentration and the induced λmax changes. Reprinted from ref 47. Copyright 2011 American Chemical Society. (c) Dark-field image showing specific protein-target interaction (top left), the binding of target proteins to nanoparticles covered by proteins producing a shift in the plasmon resonance (top right), and binding affinity of multiple protein-protein interactions (bottom), where the solid lines correspond to the best fit of a Langmuir equation to the experimental data, respectively. Reprinted from ref 125. Copyright 2014 American Chemical Society.

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Analytical Chemistry

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Figure 6. (a) Dark-field color images and the corresponding background-subtracted spectral images for endogenous H2S imaging in HepG2 cells without (upper panel) and with (middle panel) the pretreatment of human insulin, and the corresponding observed (hollow dots) and fitted (lines) time courses of ∆λmax shifts. Reprinted with permission from ref 126. Copyright 2013 Macmillan Publishers Ltd. (b) Scheme of electrocatalytic oxidation of H2O2 on the surface of gold nanorods in KNO3 and KCl solutions respectively, the applied triangular wave potential for the electrocatalytic oxidation and the simultaneous plasmonic scattering spectral peak shift of single nanorod, respectively. Reprinted from ref 129. Copyright 2014 American Chemical Society.

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Analytical Chemistry

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Figure 7. (a) Schematic illustration for the influence of the modification of rifampicin on cell uptake of gold nanorods. Reprinted with permission from ref 155. Copyright 2014 American Chemical Society. (b) 18F-FDG PET/CT co-registered images of mice intravenously administrated with either saline or gold nanocages, followed by laser treatment. (1) A saline-injected mouse prior to laser irradiation; (2) A nanocage-injected mouse prior to laser irradiation; (3) A saline-injected mouse after laser irradiation; and (4) A nanocage-injected mouse after laser irradiation. The white arrows indicated the tumors that were exposed to the diode laser at a power density of 0.7 Wcm-2 for 10 min. Reprinted with permission from ref 176. Copyright 2010 Wiley-VCH.

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Analytical Chemistry

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Figure 8. (a) Five-dimensional patterning and readout. Normalized two-photon-excited luminescence raster scan of 18 patterns encoded in the same area using two laser light polarizations and three different laser wavelengths. Patterns were written in three layers spaced by 10 µm. The size of all images is 10×10 µm, and the patterns are 75 ×75 pixels. Reprinted with permission from ref 182. Copyright 2009 Macmillan Publishers Ltd. (b) Demonstration of 3D orientation-unlimited polarization encryption, the red arrows indicate the five configured polarization orientations used for the information encryption at out-of-plane angle θ with respect to the z axis and in-plane angle β with respect to the x axis. The bottom panel shows the raster scanning two-photon fluorescence images of five patterns retrieved at corresponding polarization orientations. Scale bar, 10 µm. Reprinted with permission from ref 183. Copyright 2012 Macmillan Publishers Ltd.

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Analytical Chemistry

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Figure 9. (a) Schematic illustration of planar illumination microscopy. Reprinted from ref 40. Copyright 2011 American Chemical Society. (b) Schematic diagram for cell sidewall imaging with dual-channel polarization dark-field microscopy and calculated errors of the azimuth angle (black) and the polar angle (red) under cell top and cell sidewall respectively. Adapted from ref 42, Copyright 2014 American Chemical Society. (c) Simulations and experimental data for 3D modes for adsorption of particles onto cell membrane surfaces. From left to right: computer simulated traces of a single gold nanorod; the corresponding normalized bright and dark differential interference contrast intensities; examples of 100 consecutive images and the corresponding bright and dark differential interference contrast intensities, respectively. Reprinted with permission from ref 82. Copyright 2013 Wiley-VCH.

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Anisotropic plasmonic nanoparticles can be imaged at the single-particle level by dark-field microscopy to elucidate cellular events in real time.

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Recent advances in optical imaging with anisotropic plasmonic nanoparticles.

Recent advances in optical imaging with anisotropic plasmonic nanoparticles. - PDF Download Free
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