Recent Advances in Inorganic Nanoparticle-Based NIR

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Review

Recent Advances in Inorganic Nanoparticle-Based NIR Luminescence Imaging: Semiconductor Nanoparticles and Lanthanide Nanoparticles Dokyoon Kim, Nohyun Lee, Yong Il Park, and Taeghwan Hyeon Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.6b00654 • Publication Date (Web): 08 Dec 2016 Downloaded from http://pubs.acs.org on December 11, 2016

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Bioconjugate Chemistry

Recent

Advances

Luminescence

in

Imaging:

Inorganic

Nanoparticle-Based

Semiconductor

Nanoparticles

NIR and

Lanthanide Nanoparticles

Dokyoon Kim1, Nohyun Lee2, Yong Il Park3* and Taeghwan Hyeon1,4*

1

Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Republic of Korea.

2

School of Advanced Materials Engineering, Kookmin University, Seoul 02707, Republic of Korea.

3

School of Chemical Engineering, Chonnam National University, Gwangju 61186, Republic of Korea.

4

School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Republic of Korea.

*To whom correspondences should be addressed. E-mail: [email protected] and [email protected]

ACS Paragon Plus Environment


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ABSTRACT Several types of nanoparticle-based imaging probes have been developed to replace conventional luminescent probes. For luminescence imaging, near-infrared (NIR) probes are useful in that they allow deep tissue penetration and high spatial resolution as a result of reduced light absorption/scattering and negligible autofluorescence in biological media. They rely on either an anti-Stokes or a Stokes shift process to generate luminescence. For example, transition metal-doped semiconductor nanoparticles and lanthanide-doped inorganic nanoparticles have been demonstrated as anti-Stokes shift-based agents that absorb NIR light through two- or three-photon absorption process and upconversion process, respectively. On the other hand, quantum dots (QDs) and lanthanide-doped nanoparticles that emit in NIR-II range (~1000 to ~1350 nm) were suggested as promising Stokes shift-based imaging agents. In this review, we summarize and discuss the recent progress in the development of inorganic nanoparticle-based luminescence imaging probes working in NIR range.


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1. INTRODUCTION Imaging probes, also known as contrast agents, are chemical compounds used to enhance visibility in molecular imaging. Various imaging probes have been developed and applied widely in a range of imaging modalities to label target molecules (or target organs), enabling high detection sensitivity and image contrast. Since the use of the imaging probes allows the acquisition of more detailed structural and functional information, they have become essential for biological analysis and disease diagnosis. Recently, many types of imaging tools and probes have been developed for imaging and diagnosis at cellular or even at molecular level. Representative imaging probes include fluorescent dyes for optical imaging,1,2 Gd3+-chelates for magnetic resonance imaging (MRI),3

iodinated compounds for X-ray computed tomography (CT), and radioisotopes for

positron emission tomography (PET)4 and single photon emission computed tomography (SPECT).5 Most of imaging probes used in clinical settings are organic or metal-organic compounds, and their utilities are limited due to intrinsic physical properties (e.g., photobleaching of fluorescent dyes and low magnetic moment of Gd3+-chelates) and insufficient physiological properties (e.g., short circulation time). Nanotechnology has led to the development of new types of imaging probes with improved physical properties. Especially, inorganic nanoparticles have attracted much interest from various research fields due to their unique physical and chemical properties arising from their nanoscale dimensions. They exhibit extraordinary optical, magnetic, and electrical properties, which can be used to improve the sensitivity of biological imaging.6-9 As an example, fluorescent semiconductor quantum dots (QDs) and magnetic nanoparticles have been evaluated for use as imaging contrast agents. Since QDs (e.g., CdSe/ZnS) show good optical and chemical stability and easily tunable emission depending on their size, they have been studied as robust, multicolor fluorescent tags in optical imaging.7,10 Magnetic



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nanoparticles (e.g., iron oxide nanoparticles) have been utilized as T2 MRI contrast agents, resulting in improved detection sensitivity compared with conventional or clinical MRI contrast agents.11-14 Despite these potential benefits of inorganic nanoparticles, they are not used widely in the clinical setting because of their disadvantages, including potential cadmium toxicity in human body (for cadmium-containing QDs), photo-induced damages from excitation source (e.g., ultraviolet (UV) light), low tissue penetration, and decreased image contrast against background autofluorescence. Magnetic nanoparticles fail to compete against the Gd-based T1 MRI contrast agents owing to negative contrast effects and magnetic susceptibility artifacts in T2-weighted imaging mode; therefore, only very few products are now clinically approved. To overcome the limitations of typical nanoparticle-based probes, several new types of luminescent nanoparticles have been developed as next-generation imaging probes. The depth of tissue penetration can be increased by utilization of near infrared (NIR) light. Thus, either NIR-absorbing anti-Stokes or NIR-to-NIR Stokes luminescent process is used to take advantage of the NIR window region (e.g., deep tissue penetration, low background noise, and low phototoxicity).15 Although several reviews on nanoparticle-based luminescence imaging have already been published,16-19 this review focuses on the recent progress on the NIR luminescent nanoparticle imaging probes. We cover the development of anti-Stokes shift-based nanoparticles utilizing NIR excitation. Then, we discuss the recent progress in Stokes shiftbased nanoparticles emitting NIR-II light (~1000 to ~1350 nm).

2. NIR-based luminescent nanoparticles


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Fluorescence imaging generally exhibits good temporal and spatial resolution with high detection sensitivity. However, noninvasive fluorescence imaging can be compromised by poor tissue penetration of excitation/emission light and decreased spatial resolution due to light scattering. Therefore, there have been attempts to develop alternative luminescent materials to overcome the limitations of current fluorescence imaging probes. The use of NIR as either an excitation source or emission light may be a solution to this limitation. NIR is significantly less absorbed by biological components compared with visible or infrared light. For example, hemoglobin strongly absorbs visible photons, and water strongly absorbs infrared photons. Thus, in the NIR window, tissue penetration depth could be greatly increased, and image contrast (or sensitivity) could also be improved by the reduced background autofluorescence and light scattering.15 Recently, several semiconductor nanoparticles and lanthanide nanoparticles have been developed so as to absorb or emit NIR for bioimaging.

2.1. Doped semiconductor nanoparticles for multi-photon imaging Anti-Stokes shift is referred to as a process that shorter wavelength is emitted by a molecule that absorbs longer excitation light. One of the advantage of anti-Stokes shift process is that NIR can be used as an excitation sources for visible-light emitting fluorophore. Representative photophysical processes of anti-Stokes emission include multiphoton absorption, second-harmonic generation, and upconversion.20 Among these processes, multiphoton absorption has been widely studied for the last two decades, and multiphoton microscopy and fluorescent probes are commercially available in the field of bioimaging. Compared with conventional confocal microscopy, multiphoton microscopy can improve the spatial resolution because the excitation can be localized only in the focal volume. By changing the focal plane, high-contrast three-dimensional images are readily obtained. In



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addition, the localized excitation of multiphoton microscopy can reduce the photobleaching of the fluorophores outside the beam focus and decrease the photo-induced damages of biological samples. To date, many fluorescent small molecules have been studied as multi-photon imaging probes. Although some commercial probes, such as rhodamine B, are known to have high two-photon absorption cross-section (~200 Goeppert-Mayer [GM]), their low photostability (e.g., photobleaching) is problematic and prevents repeated excitation and long-term imaging. Therefore, inorganic nanomaterials have been investigated to replace the molecular multi-photon probes because nanomaterials are usually resistant to photobleaching. Various types of inorganic nanoparticles, including semiconductor QDs,21 quantum rods,22 noble metal nanoparticles (e.g., gold nanorods and gold nanostars),23,24 carbon dots (e.g., graphene dots),25,26 and perovskite nanocrystals,27 have been widely investigated as probes for multi-photon imaging. Among these materials, semiconductor QDs exhibit prominent features, such as good photostability, narrow and tunable emission wavelength, and relatively high two-photon absorption cross-sections. Cadmium-containing QDs (e.g., CdSe/CdS/ZnS) have been successfully applied as two-photon imaging probes; however, potential toxicity from cadmium restricts their utility. To address this issue, cadmium-free semiconductor nanoparticles doped with metal ions (e.g., ZnS:Mn or ZnSe:Mn) have been developed for multi-photon imaging due to their low toxicity.28-30 Since ZnS:Mn nanoparticles exhibit a three-photon absorption cross-section that is 4 orders of magnitude larger than those of UV fluorescent dyes, they can be excited by 920-nm NIR pulsed laser.30 Moreover, the Mn2+ dopant ions in ZnS:Mn nanoparticles induce the red-shift of emission light from blue (430 nm) to orange (580 nm), enabling more efficient light escape from the tissues (Figure 1a). Three-photon imaging usually shows better spatial resolution compared with two-photon imaging because the three-photon imaging dramatically reduces the out-of-


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focus excitation and background fluorescence. The resulting signal-to-noise ratio is much enhanced when compared with that of two-photon imaging. NIR (~900 nm) excitation also allows much deeper tissue penetration than red-light excitation (~600 nm, common in twophoton imaging). These features of the three-photon imaging allow higher resolution and greater imaging depth for in vivo fluorescence imaging. For example, in a recent report, three-photon imaging of tumor vasculature was carried out using ZnS:Mn nanoparticles and compared with the result of one-photon and two-photon imaging performed with fluorescein isothiocyanate (FITC) molecules.30 Multi-photon imaging showed a highly resolved tumor vascular structure, while single-photon imaging did not. Additionally, three-photon imaging exhibited better resolution than two-photon imaging (Figure 1b).



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Figure 1. ZnS:Mn nanoparticles excited by two-photon and three-photon absorption. (a) Energy diagram of ZnS:Mn nanoparticles. Three-photon absorption of ZnS in NIR region or two-photon absorption of Mn2+ in NIR-II region induces orange (580 nm) emission. (b) Comparison between three-photon imaging of ZnS:Mn nanoparticles and two-photon imaging of FITC. Three-photon imaging showed better spatial resolution. (c) Slope obtained from the log-log plot of luminescence intensity (580 nm) at different excitation range. A change in slope from 3 to 2 indicates switching mechanism from three-photon to two-photon absorption. Reprinted with permission from refs 30 and 31.

While multi-photon excitation in the range of 700 to 1000 nm dramatically increases tissue penetration, light scattering by biological tissue still limits the further penetration of the light. To minimize the light scattering, NIR-II window in the range of 1000 to 1350 nm is suitable for in vivo fluorescence imaging. Recently, ZnS:Mn nanoparticles, which were also used as a three-photon imaging probe, were shown to have superior two-photon absorption properties when irradiated with an NIR-II light (Figure 1c).31 Instead of the two-photon excitation (~600 nm) of ZnS nanoparticles, direct two-photon excitation (1050–1310 nm) of the Mn2+ ions with a large two-photon absorption cross-section (265 GM per nanoparticle) was used (Figure 1a). Owing to the deeper light penetration of the NIR-II light, the larger anti-Stokes shift (450 nm or more), and the larger two-photon absorption cross-section, ZnS:Mn nanoparticles can facilitate the high-resolution deep-tissue imaging. Although multi-photon absorption cross-section is dramatically improved by development of doped-semiconductor nanoparticles, the overall efficiency of the multiphoton imaging is still very low, and expensive high-power femtosecond pulsed laser is usually required as an excitation source for successful imaging. In addition, long data acquisition time is needed because images are obtained by scanning samples with the laser


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focused on the samples. Therefore, the development of doped-semiconductor nanoparticles with high multi-photon efficiency as well as the development of rapid imaging techniques with high resolution are still required for the wide application of the multi-photon imaging.

2.2. Lanthanide-doped upconverting nanoparticles Among anti-Stokes shifting processes, upconversion has recently attracted great attention due to its superior emission efficiency.32 Compared with multi-photon absorption, upconversion exhibits several distinct features, including sequential photon absorption through real intermediate electronic states of lanthanide ions. The photophysical mechanism involving real intermediate states results in a long luminescence lifetime (up to several hundred microseconds) and much higher emission efficiency than those of multi-photon absorption based on virtual intermediate states.33,34 Consequently, upconverting nanoparticles (UCNPs) can be successfully excited with a compact continuous-wave laser diode with a relatively low-power density instead of an expensive high-power pulsed laser. As a result, upconverting imaging can be carried out using a wide-field microscopy, which facilitates a much faster imaging rate without the need for sample scanning.35,36 Combined with the unique optical properties of UCNPs,37,38 fast image acquisition of wide-field imaging, and low photodamage by NIR, real-time long-term tracking of UCNPs in live cells could be possible at a rate of 20 fps.35,39 In addition, combination of nonscanning wide-field imaging of UCNPs with the sectioning capability of confocal microscopy enables rapid (imaging rate: ~1 s-1) and background-free three-dimensional (3D) live-cell imaging (Figure 2).40 Minimization of background autofluorescence by NIR excitation combined with the image reconstruction process may allow us to eliminate the out-of-focus background. This rapid, high-contrast 3D imaging by wide-field microscopy may be advantageous for real-time tracking of the distribution and dynamics of UCNPs in living cells (Figure 2b).



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Figure 2. Fast and background-free 3D live cell imaging using UCNPs. (a) Schematic of wide-field epi-fluorescence microscopy with z-sectioning. The out-of-focus luminescence induces blurs in the raw images. (b) Raw epi-fluorescence image (left) and its 3D reconstructed image (middle). UCNPs (green) were internalized in HeLa cells, whose nuclei were stained with red. Right is a 3D trajectory of a single UCNP in a HeLa cell. Reprinted with permission from ref 40.

In addition to long-term cellular imaging, UCNPs are also ideal probes for in vivo optical imaging. The low background autofluorescence and deeper light penetration of NIR excitation enable the high-contrast whole-body luminescence imaging. To date, the visible light emitting UCNPs (e.g., Er3+/Yb3+- or Ho3+/Yb3+-doped systems) have been applied successfully in various animal models.41-43 However, image contrast can be further improved by NIR emitting UCNPs (e.g., Tm3+/Yb3+-doped systems that emit 800 nm NIR following


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excitation at 980 nm) because both the excitation and emission lights are in NIR range.44,45 Time-gated imaging using the long luminescence lifetime of UCNPs may further enhance the image contrast by separating luminescence of UCNPs from scattered light by the body.46 Time-gated imaging utilizes pulsed excitation and time-delayed signal acquisition to remove short-lived background signals (several nanoseconds of lifetime) (Figure 3a). Although UCNPs exhibit autofluorescence-free high-contrast imaging capability, time-gated imaging allows more enhanced image quality without interference from scattered light (Figures 3b and 3c). The time-gated method has facilitated at least one order of magnitude higher detection sensitivity than the conventional system using optical filters.46 The pulsed excitation also showed negligible heating effect compared with the continuous 980 nm excitation (Figure 3d).

Figure 3. Time-gated in vivo upconversion luminescence imaging. (a) Diagram of time-gated imaging mode. Following the pulse excitation, a short-delay is applied to acquire only the long-lived luminescence signal. (b) Left is the luminescence image of a mouse with subcutaneous injection of UCNPs, obtained by the filter-based method. Right is the time-



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gated luminescence image of the same mouse. (c) Left is a bright-field image of a mouse with subcutaneous injection of UCNPs. Middle is the time-gated luminescence image. Right is the time-gated luminescence image with the bright-field LED illumination. The time-gated imaging mode resulted in more enhanced image quality without interference from scattered light. (d) Comparison of the heating effect between continuous wave (CW) mode and timegated luminescence (TGL) mode. TGL mode showed the negligible heating effect. Reprinted with permission from ref 46.

Conventional Yb3+-doped UCNPs are usually excited by a 980-nm laser; at around 980 nm, water molecules absorb the photons, resulting in an increase of temperature. The heating effect of the 980-nm laser is mild in most cellular imaging, and may not induce significant toxicity.35 However, the 980-nm laser may induce thermal damages of tissues when a high-power laser is used for in vivo imaging. Thus, the excitation wavelength of UCNPs should be controlled in order to minimize the heating effect caused by the incident laser. In one study, a 915-nm laser was used instead of the 980-nm laser.47 Additionally, in a recent work, Nd3+ was introduced to conventional Yb3+-doped UCNPs as a new sensitizer excited at ~800 nm.48-50 Despite the presence of an additional energy transfer step from Nd3+ to Yb3+, overall upconversion efficiency is comparable to that of conventional Yb3+-doped UCNPs because Nd3+ ions show one order of magnitude higher absorption cross-section at 800 nm than Yb3+ at 980 nm. Moreover, energy absorption by water molecules at around 800 nm is much lower than that at 980 nm, thus minimizing the light-induced damages during continuous in vivo imaging. Because the optical properties of UCNPs is depends on the energy level of lanthanide ions, their excitation width is very narrow. To expand the excitation wavelength range of UCNPs, organic NIR dyes have been used as an antenna to collect NIR photons. Zou et al.


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reported that UCNPs coated with NIR dyes could be excited at 740–850 nm to induce upconversion.51 Such broad band absorption feature may allow the flexible choice of excitation source, i.e., not limiting the choice to excitation sources at 980 or 800 nm.51-53 The use of NIR dyes as an antenna also enhances the overall emission efficiency (~3300-fold) as a result of increased photon absorption.51,54 Besides the NIR dyes, other antenna materials with high photon absorptivity, such as NIR QDs and plasmonic nanostructures, can be used to overcome the low photon absorption of lanthanide elements in UCNPs.55,56 Temperature also can affect the upconversion luminescence properties since it is related with the phonon relaxation (also called lattice vibration) of lanthanide ions. Some lanthanides (e.g., Er3+) have energy level gaps of only a few hundred wavenumbers and are therefore sensitive to thermal agitation. This temperature-responsive upconversion luminescence can be utilized to monitor temperature changes. For example, the emission intensity ratio of 525 and 545 nm was monitored to determine thermal changes in a single HeLa cell with a resolution of about 0.5 K.57 In addition, stimulus-responsive upconversion luminescence also could be used to detect electrical and magnetic signals.58,59

2.3. NIR-II-emitting nanoparticles As described in previous part, reduced light scattering from NIR-II photons results in deeper light penetration and enhanced image resolution, enabling real-time imaging of the brain vasculature without removing the skull.56 Several probe materials, including carbon nanotubes,60,61 NIR QDs (e.g., Ag2S, Ag2Se),62-66 and lanthanide-doped nanoparticles,67 have been successfully applied for in vivo imaging through single-photon absorption. Hong et al. carried out whole-body imaging using single-walled carbon nanotubes (SWNTs) in the NIR-II region, which enabled high image contrast of mouse vessels and rapid, real-time monitoring.61 Compared with images obtained with IRDye-800 (emission peak at



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~800 nm), images obtained with SWNTs in the NIR-II range exhibit improved spatial resolution and more detailed vascular structures (Figure 4a). However, despite this strong potential of NIR-II imaging, the low fluorescence quantum yield of SWNTs is always a bottleneck. As an alternative, NIR-emitting QDs, which exhibit high quantum yields, may facilitate the development of brighter fluorescent probes in the NIR-II region. However, many of these QDs contain toxic elements,56 such as cadmium, lead, mercury, and arsenic, which are unsuitable for clinical applications. Recently, Ag2S QDs have been applied as brighter NIR-II-emitting probes having low toxicity.62-66 PEGylated Ag2S QDs have a quantum yield of approximately 15.5%, which is 5.6 times higher than that of SWNTs.65 Additionally, Ag2S QDs are highly biocompatible, as demonstrated by their lack of cytotoxicity, whereas CdSe@ZnS QDs have been shown to suppress cell growth severely. By controlling particle size, the emission wavelength of Ag2S QDs can be tuned in NIR-II region from 1000 to 1400 nm. Thus, Ag2S QDs have been shown to have potential as NIR-II imaging probes in cellular and small animal imaging (Figure 4b).66


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Figure 4. In vivo mouse imaging in the NIR-II region. (a) Left is absorption spectrum of SWNT-IRDye-800 (black dashed line), emission spectrum of IRDye-800 (green line) and SWNT (red line). Right is NIR-I and NIR-II fluorescence images of a mouse injected with SWNT-IRDye-800. NIR-II fluorescence image showed clearer mouse vasculature. (b) Realtime monitoring of angiogenesis from tumor-bearing mouse. PEGylated Ag2S QDs were injected to the mouse intraveneously. The red arrows indicate the tumor-induced angiogenesis, and the white arrow indicates the tumor. Right bottom is the images of the tumor extracted from the mouse. The formation of tumor vascular structures was clearly visualized. Reprinted with permission from refs 61 and 66.

Lanthanide-doped

nanoparticles

(NaYF4:Yb3+/Ln3+@NaYF4

core@shell

nanoparticles, where Ln = Er, Ho, Tm or Pr), which have been described as UCNPs in the previous section, can also be applied as NIR-II emitting probes.67 Lanthanide-doped upconverting nanoparticles always emit visible light (through the anti-Stokes shift) and NIRII light (through the Stokes shift) together (Figure 5a). Due to the unique optical properties of upconverted visible emission, NIR-II emitting features of the lanthanide-doped nanoparticles have not been studied extensively. However, these nanoparticles have recently been investigated as a new type of NIR-II-emitting probes as an alternative to SWNTs.67 For tumor tissues containing melanin, approximately 80% of NIR-II light is transmitted through 0.5 cm tissue, while less than 0.4% of NIR light (wavelength shorter than 1000 nm) is transmitted. The reduced scattering effects of NIR-II emission (at 1525 nm) have also been shown in comparison with 808-nm light. Due to the decreased scattering and increased transmittance, Er3+-doped nanoparticles (emission at 1525 nm) show deeper tissue penetration than the 808-nm light, and the nanoparticles were readily detected through 1 cm of phantom tissue (Figure 5b). Unlike the broad emission peaks of SWNTs, the ladder-like



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energy levels of lanthanides exhibit narrow emission widths (Figure 5a), allowing multispectral imaging with minimal spectral overlapping (Figure 5c).

Figure

5.

Lanthanide-doped

naoparticles

(NaYF4:Yb3+/Ln3+@NaYF4

core@shell

nanoparticles, where Ln = Er, Ho, Tm or Pr) as NIR-II emitting probes. (a) NIR-II emission spectra and energy diagram of lanthanide-doped nanoparticles. (b) Superior tissue transmission of NIR-II emission (1525 nm) compared with NIR emission (808 nm). (c) Multispectral imaging of tumor using NIR-II emitting probes. Narrow emission peaks from Er-and Ho-doped nanoparticles were clearly distinguished. Reprinted with permission from ref 67.


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3. CONCLUSION Several new types of nanoparticle imaging probes recently have been developed to overcome the limitations of conventional imaging probes, such as luminescent dye molecules. To utilize NIR excitation/emission, nanoparticles have been designed to use anti-Stokes or Stokes shift processes. For anti-Stokes-emitting nanoparticles, doped-semiconductor nanoparticles (for three-photon or two-photon imaging) and lanthanide-doped nanoparticles (for upconversion imaging) have been shown to enable high-resolution whole-body images with low toxicity, high signal-to-noise ratios, deep tissue penetration, and rapid image acquisition. For Stokes-emitting nanoparticles, NIR QDs and lanthanide nanoparticles working in NIR-II range may have applications as potential imaging agents yielding highintensity signals. However, to improve the utility of these materials, further advances are needed to overcome the intrinsic low quantum yield of multi-photon imaging systems and the low photon absorption of lanthanide elements.



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AUTHOR INFORMATION

Corresponding Authors *E-mail: [email protected] and [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS T.H. acknowledges the financial support from IBS (IBS-R006-D1). Y.I.P. was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science, ICT & Future Planning) (No. 2016R1A4A1012224).


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Table of Contents Graphic


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Figure 1. ZnS:Mn nanoparticles excited by two-photon and three-photon absorption. (a) Energy diagram of ZnS:Mn nanoparticles. Three-photon absorption of ZnS in NIR region or two-photon absorption of Mn2+ in NIR-II region induces orange (580 nm) emission. (b) Comparison between three-photon imaging of ZnS:Mn nanoparticles and two-photon imaging of FITC. Three-photon imaging showed better spatial resolution. (c) Slope obtained from the log-log plot of luminescence intensity (580 nm) at different excitation range. A change in slope from 3 to 2 indicates switching mechanism from three-photon to two-photon absorption. Reprinted with permission from refs 30 and 31. 175x156mm (150 x 150 DPI)



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Figure 2. Fast and background-free 3D live cell imaging using UCNPs. (a) Schematic of wide-field epifluorescence microscopy with z-sectioning. The out-of-focus luminescence induces blurs in the raw images. (b) Raw epi-fluorescence image (left) and its 3D reconstructed image (middle). UCNPs (green) were internalized in HeLa cells, whose nuclei were stained with red. Right is a 3D trajectory of a single UCNP in a HeLa cell. Reprinted with permission from ref 40. 172x118mm (150 x 150 DPI)


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Figure 3. Time-gated in vivo upconversion luminescence imaging. (a) Diagram of time-gated imaging mode. Following the pulse excitation, a short-delay is applied to acquire only the long-lived luminescence signal. (b) Left is the luminescence image of a mouse with subcutaneous injection of UCNPs, obtained by the filterbased method. Right is the time-gated luminescence image of the same mouse. (c) Left is a bright-field image of a mouse with subcutaneous injection of UCNPs. Middle is the time-gated luminescence image. Right is the time-gated luminescence image with the bright-field LED illumination. The time-gated imaging mode resulted in more enhanced image quality without interference from scattered light. (d) Comparison of the heating effect between continuous wave (CW) mode and time-gated luminescence (TGL) mode. TGL mode showed the negligible heating effect. Reprinted with permission from ref 46. 206x122mm (150 x 150 DPI)



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Figure 4. In vivo mouse imaging in the NIR-II region. (a) Left is absorption spectrum of SWNT-IRDye-800 (black dashed line), emission spectrum of IRDye-800 (green line) and SWNT (red line). Right is NIR-I and NIR-II fluorescence images of a mouse injected with SWNT-IRDye-800. NIR-II fluorescence image showed clearer mouse vasculature. (b) Real-time monitoring of angiogenesis from tumor-bearing mouse. PEGylated Ag2S QDs were injected to the mouse intraveneously. The red arrows indicate the tumor-induced angiogenesis, and the white arrow indicates the tumor. Right bottom is the images of the tumor extracted from the mouse. The formation of tumor vascular structures was clearly visualized. Reprinted with permission from refs 61 and 66. 200x128mm (150 x 150 DPI)


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Figure 5. Lanthanide-doped naoparticles (NaYF4:Yb3+/Ln3+@NaYF4 core@shell nanoparticles, where Ln = Er, Ho, Tm or Pr) as NIR-II emitting probes. (a) NIR-II emission spectra and energy diagram of lanthanidedoped nanoparticles. (b) Superior tissue transmission of NIR-II emission (1525 nm) compared with NIR emission (808 nm). (c) Multispectral imaging of tumor using NIR-II emitting probes. Narrow emission peaks from Er-and Ho-doped nanoparticles were clearly distinguished. Reprinted with permission from ref 67. 178x176mm (150 x 150 DPI)



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Table of Contents Graphic 166x100mm (150 x 150 DPI)


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Recent Advances in Inorganic Nanoparticle-Based NIR

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