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WIREs Nanomed Nanobiotechnol
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A brief account of nanoparticle contrast agents for photoacoustic imaging

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Photoacoustic imaging (PAI) is a hybrid, nonionizing modality offering excellent spatial resolution, deep penetration, and high soft tissue contrast. In PAI, signal is generated based on the absorption of laser‐generated optical energy by endogenous tissues or exogenous contrast agents leading to acoustic emissions detected by an ultrasound transducer. Research in this area over the years has shown that PAI has the ability to provide both physiological and molecular imaging, which can be viewed alone or used in a hybrid modality fashion to extend the anatomic and hemodynamic sensitivities of clinical ultrasound. PAI may be performed using inherent contrast afforded by light absorbing molecules such as hemoglobin, myoglobin, and melanin or exogenous small molecule contrast agent such as near infrared dyes and porphyrins. However, this review summarizes the potential of exogenous nanoparticle‐based agents for PAI applications including contrast based on gold particles, carbon nanotubes, and encapsulated copper compounds. WIREs Nanomed Nanobiotechnol 2013, 5:517–543. doi: 10.1002/wnan.1227 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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(a) The measured PA signal amplitude generated with and without AuNCs in rat blood at several wavelengths. Noninvasive PA imaging of a rat's cerebral cortex, (b) before the injection of AuNCs and (c) about 2 h after the final injection of nanocages, which is the peak enhancement point. (Reprinted with permission from Ref . Copyright 2007 American Chemical Society; Reprinted with permission from Ref .)
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SEM images of (a) Ag nanocubes and (b) AuNCs. The inset shows the corresponding TEM images of the same sample. (c) UV–vis spectra of the samples obtained by titrating Ag nanocubes with different volumes of 0.1 mM HAuCl4 solution. (Reprinted with permission from Ref . Copyright 2007 American Chemical Society)
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(a) PA signals generated from a Tygon® tube (I.D. 250 µm, O.D. 500 µm) filled with GNB and rat blood. The excitation light is of 764 nm wavelength. (b) PA spectrum of GNB and blood over a 740–820 nm range of NIR wavelengths. (c) Ratio of the peak‐to‐peak PA signal amplitudes generated from GNB to those of blood. (d) PA signal to noise ratio for the GNB and the control (no gold). Cross‐sectional PA image of a low density polyethylene (LDPE) tube (˜1 cc volume, I.D. ˜6 mm) filled with plasma clot: (e) control, (f) targeted with GNB using a curved array PA system (λ = 800 nm). (g) Control, (h) targeted with GNB using a photoacoustic breast scanner system (λ = 532 nm). (Reprinted with permission from Ref . Copyright 2009 Wiley Interscience)
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Porphysomes are optically active nanovesicles formed from porphyrin bilayers. (a) Schematic representation of a pyropheophorbide–lipid porphysome. The phospholipid headgroup (red) and porphyrin (blue) are highlighted in the subunit (left) and assembled nanovesicle (right). (b) Electron micrographs of negatively stained porphysomes (5% PEG‐lipid, 95% pyropheophorbide‐lipid). (c) Absorbance of the porphyrin–lipid subunits incorporated in porphysomes formed from pyropheophorbide (blue), zinc pyropheophorbide (orange) and bacteriochlorophyll (red) in PBS. (d) Resonance light scattering spectra ratio between gold nanorods and pyropheophorbide porphysomes. Nanorod and porphysome concentration was adjusted to have equal optical density at 680 nm. (e) Dynamic light scattering size profiles of indicated porphysomes recorded in PBS. (Reprinted with permission from Ref . Copyright 2011 Nature Publishing Group)
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Synthesis and physiochemical characterization of self‐assembled nanoparticles of copper neodecanoate. Schematic describing the preparation of copper‐enriched nanoparticles: (1) suspension of copper neodecanoate (1) in sorbitan sesquioleate, vigorously vortex and mixing, filter using cotton bed, vortex; (2) dissolve phospholipids in anhydrous chloroform and preparation of phospholipid thin film by slow evaporation of solvent at 45 °C under reduced pressure; (3) resuspension of the thin film in water (0.2 μM); (4) self‐assembly by high pressure homogenization at 4 °C, 20000 psi (141 MPa), 4 min; (5) dialysis (cellulosic membrane, MWCO 20 k); in box, characterization table for nanoparticles of copper neodecanoate. (Reprinted with permission from Ref . Copyright 2011 American Chemical Society)
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Noninvasive in vivo PA images of SLN in rat: For all PA images, the laser was tuned to 750 nm wavelength. (a) Control PA image acquired before polymeric nanoparticle injection. Bright parts represent optical absorption, here, from blood vessels (BV). (b) PA image (MAP) acquired immediately after the polymeric nanoparticle injection. (c) Post‐injection (35 min) PA image. (d) Post‐injection (110 min) PA imageBlood vessel (BV), lymph vessel (LV) and sentinel lymph node (SLN) are marked with arrows, and the SLN is visible in (b)–(d), however, invisible in (a). (e) Photograph of the rat after the hair was removed from the scanning region before taking the PA images. The scanning region is marked with a black dotted square. (f) Photograph of the rat with the skin removed after PA imaging. (g) Excised lymph node. Smallest tick: 1 mm. (h) PA signal enhancement in the SLN after the injection of polymeric nanoparticle as a function of post‐injection time. For (a)–(d): FOV = 25 mm × 24 mm, step size along the X direction = 0.2 mm, step size along the Y direction = 0.4 mm, total scan time = − 23 min. No signal averaging was used. (Reprinted with permission from Ref . Copyright 2011 Wiley Interscience)
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(a) TEM image of the polymeric micelles drop desposited over nickel brid, scale bar = 100 nm; (b) AFM image of the micelles drop deposited over glass; (c) physio‐chemical characterization table for a NIR‐polymer micelle; (d) dissolution of ADS‐832‐WS from micelle when incubated against rabbit plasma and human plasma albumin; (e) time‐dependent release of fumagillin from micelle. (Reprinted with permission from Ref . Copyright 2011 Wiley Interscience)
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Noninvasive in vivo PA images (maximum intensity projections, MIP) of the SLN in a rat. (a) Photograph of the rat with region of interest depilated before scanning. The scanning region is delineated by a black dotted square. (b) Baseline PA image acquired before NanoCuN injection. Bright regions represent inherent optical absorption from a blood vessel (BV). (c) PA image (MIP) acquired almost immediately after NanoCuN administration. (d) PA image 60 min post injection showing a marked signal enhancement corresponding to increased NanoCuN uptake by the node: blood vessel (BV) and sentinel lymph node (SLN) are marked with arrows. The SLN is visible in both (c) and (d), however not apparent in (b). (e) Photograph of the rat with the skin excised after PA imaging. For (b)–(d), FOV = 25 × 24 mm, step size along the X direction = 0.2 mm, step size along the Y direction = 0.4 mm, total scan time = ˜23 min. No signal averaging was used. (Reprinted with permission from Ref . Copyright 2011 American Chemical Society)
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(a) Hydrodynamic particle size distribution from DLS; (b) UV–vis spectrum of NanoCuN nanoparticles in water; (c) anhydrous state TEM image; (d, e) SEM images; (f) EDX spectrum of the selected area from the image in (e); (g) AFM image (deposited on glass substrate); shelf life stability of NanoCuN over 90 days from formulation; (i) dissolution of Cu over 3 days when incubated with saline and human plasma albumin. (Reprinted with permission from Ref Copyright 2011 American Chemical Society)
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Synthesis and characterization of theranostic polymeric micelles: (1) co‐self assembly of amphiphilic diblock copolymer and sorbitan monooleate, ADS‐832‐WS (a) and/or fumagillin (b), sonication, 25 °C, 1 min; (2) dialysis 10 kDa cellulosic membrane, nanopure water (0.2 μM). (Reprinted with permission from Ref . Copyright 2011 Wiley Interscience)
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Microscopic examination of FGF Matrigel subcutaneous explant from FVB/N‐TgN(TIE2LacZ)182Sato mice following injection (IV) of αvβ3‐targeted rhodamine labeled GNB‐M nanoparticles. These transgenic mice carry a β‐galactosidase reporter gene under the control of the murine Tek (Tie2) promoter. LacZ is expressed specifically in vascular endothelial cells in embryonic and adult mice. (a) H&E staining of the excised implant providing spatial orientation of the matrix with respect to skin and muscle. The red box region is further examined in panels b, c, and d. The blue box region is studied in more detail in panels e, f, and g. Panels b and e depict the accumulation of αvβ3‐targeted rhodamine nanoparticles in the red and blue tissue regions respectively. Note the brilliant and dense accumulation of NPs in panel b (red arrows) and little to no accumulation of particles in the panel e. Region. Panels c and f depict the staining of vascular endothelium for PECAM (CD34) in the red (c) and blue (f) regions of the matrigel plug. There was dense vascularity in both locations (Red arrows in c and turquoise arrows in f. Panels d and g depict the LacZ signal for β‐galactosidase under Tie2 promoter control. In panel d, no LacZ signal was appreciated, reflecting a paucity of mature microvessels. In contradistinction, there is strong LacZ signal in panel g. These results indicated that the αvβ3GNB nanoparticles were specifically targeted to angiogenic endothelial cells (PECAM +/Tie‐2−) and not to more mature microvessels, which were PECAM +, Tie‐2+. The data corroborated that PAT imaging with αvβ3‐targeted GNB specifically distinguished and enhanced the angiogenic neovasculature from new, but more matured and differentiated microvessels. (Reprinted with permission from Ref . Copyright 2010 by the Federation of American Societies for Experimental Biology)
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Single‐walled carbon nanotube argine–glyice–aspartic acid (SWNT‐RGD) tumor targeting in living mice. Ultrasound (gray) and photoacoustic (PA) (green) images of a vertical slice (white dotted line) through the tumors of mice injected with SWNT‐RGD (right column) and control plain SWNTs (left column). Subtraction images were calculated as 4 h post‐injection minus pre‐injection to remove tissue background signal from the PA image. Mice injected with SWNT‐RGD showed an averaged sevenfold PA signal increase in the tumor over mice injected with control untargeted SWNTs. The high PA signal in the mouse injected with plain SWNTs (indicated by the white arrow) is not seen in the subtraction image, suggesting that it is due to a large blood vessel and not SWNTs. (Reprinted with permission from Ref . Copyright 2007 Nature Publishing Group)
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(a) Schematic of single‐walled and multi‐walled carbon nanotubes (SWNT and MWNT, respectively). (b) Absorption spectra of SWNTs and golden carbon nanotubes (GNTs), and photoacoustic (PA) spectra of GNTs. Lines represent normalized optical spectra (left vertical axis) of GNTs in water (red curve), SWNTs in water (black curve) and water only (green curve) and the dots represent normalized PA signal amplitude (blue dots, right axis) of GNTs in water. The concentration of the SWNTs is ˜35 times higher than that of GNTs; hence 85‐ to 100‐fold enhanced NIR contrast is achieved by the hybrid GNTs. Reprinted with permission from Kim et al. (c) Optical absorption spectrum of SWNT‐RGD (black curve) and indocyanine green‐enhanced SWNT‐RDG (SWNT‐ICG‐RGD, green curve). The optical absorbance spectrum of plain SWNT‐RGD is relatively flat with slight gradual absorption decrease as the wavelength increase. However, by attaching a large number of ICG molecules to the SWNT surface, a 20‐fold increase in optical absorption results at 780 nm. (Reprinted with permission from Ref . Copyright 2010 American Chemical Society)
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Matrigel™ (0.75 mL) was implanted subcutaneously in nude mouse. The mouse was imaged photoacoustically 8–20 days after Matrigel™ implantation. (a) Photoacoustic (PA) maximum amplitude projection (MAP) image of the dotted area. This is a control image. After the control image was taken targeted gold nanobeacons (αvβ3GNB‐M) were injected intravenously using the tail vein. In a time course study (b–k), PA images were acquired with an interval of approximately 1/2 hour up to 5 h. (g) Three hour post‐injection PA image. Red arrows point to the angiogenic sprout (not visible in A). (k) Five hour post‐injection PA image. For all PA images λ = 767 nm, scale bar = 5 mm. (l) Digital photograph of a mouse implanted with Matrigel™ plug. Blue arrow points to the plug. The black dotted area was imaged. The smallest tick: 1 mm. (m) Digital photograph of the sacrificed mouse after all the image acquisition was over. The skin was removed to show the Matrigel™ plug (blue arrow). (Reprinted with permission from Ref . Copyright 2010 by the Federation of American Societies for Experimental Biology)
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In vivo noninvasive photoacoustic imaging of sentinel lymph nodes in rat (λ = 767 nm). (a–g) Scale bar is 5 mm, 150 mL of nanobeacons were injected intradermally in all the cases. GNB1: (a) Control PA image; (b) 5 min post‐injection image of GNB1 (5 mM). GNBP: (c) Control PA image. (d) Lymph node is not visible in a 60 min post‐injection image of GNBP (680 nM). GNBS: (e) Sagittal maximum amplitude projection (MAP) pre‐injection control image: Bright parts represent optical absorption from blood vessels, marked with red arrows. (f) PA image (MAP) acquired 5 min after GNBS injection (10 nM). SLNs are clearly visible, marked with green arrow. Lymphatic vessel is also visible, marked with blue arrow. (g) 20 min post‐injection PA image. (Reprinted with permission from Ref . Copyright 2010 Elsevier BV)
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(a) Increase of PA amplitude in the melanoma tumors after intravenous injection of [Nle4, D‐Phe7]‐a‐MSH‐ and PEG‐AuNCs (n = 4 mice for each group), respectively, for different periods of time. The PA signals increased up to 38 ± 6% for [Nle4, D‐Phe7]‐a‐MSH‐AuNCs while the maximum signal increase only reached 13 ± 2% for PEG‐AuNCs at a post‐injection time of 6 h (P < 0.0001). (b) The average number of AuNCs accumulated in the melanomas dissected at 6 h post injection for the two types of AuNCs as measured by ICP‐MS. Here Ntumor denotes the number of AuNCs per unit tumor mass (g). (Reprinted with permission from Ref . Copyright 2010 American Chemical Society)
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In vivo noninvasive PA time‐course coronal MAP images of B16 melanomas using [Nle4, D‐Phe7]‐a‐MSH‐ and PEG‐AuNCs. (a, e) a schematic of the [Nle4, D‐Phe7]‐a‐MSH‐ and PEG‐AuNCs. Time‐course PA images of the B16 melanomas after intravenous injection with 100 μL of 10 nM (b–d) [Nle4, D‐Phe7]‐a‐MSH‐ and (f–h) PEG‐AuNCs through the tail vein. The background vasculature images were obtained using the PA microscope at 570 nm (ultrasonic frequency = 50 MHz), and the melanoma images were obtained using the PA macroscope at 778 nm (ultrasonic frequency = 10 MHz). (Reprinted with permission from Ref . Copyright 2010 American Chemical Society)
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PA images of the axillary region of a rat taken (a) before and (b) 28 min after the injection of AuNCs. (c) The changes of PA signal amplitude as a function of the post‐injection time. After the injection, PA signals increased with time, which means gradual accumulations of the nanocages. (d–f) Depth capability of SLN mapping with AuNCs. The PA images were acquired after the injection of nanocages for: (d) 126 min with a total imaging depth of 10 mm by placing a layer of chicken breast tissue on the axillary region; (e) 165 min with a total imaging depth of 21 mm by adding another layer of chicken breast tissue; and (f) 226 min with a total imaging depth of 33 mm by using three layers of chicken breast tissue. The bars represent the optical absorption. BV, blood vessel. SLN, sentinel lymph node. (Reprinted with permission from Ref . Copyright 2009 American Chemical Society)
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Different classes of photoacoustic contrast agents.
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Multimodal optical utility of porphysomes. (a) Photothermal transduction. Solutions were irradiated with a 673 nm laser and imaged with a thermal camera. (b) Ratio of photoacoustic amplitudes (P.A.) measured for porphysomes and methylene blue_0.5% Triton X‐100 (mean_ s.e.m. from 10 measurements); det., detergent. (c) Photoacoustic images of tubing containing porphysomes and PBS measured_0.5% Triton X‐100. (d) Dual modality for photoacoustic contrast and activatable fluorescence. Top, lymphatic mapping. Rats were imaged using photoacoustic tomography before and after intradermal (i.d.) injection of porphysomes (2.3 pmol). Secondary lymph vessels (cyan), lymph node (red), inflowing lymph vessel (yellow) and 5 mm scale bar are indicated. Bottom, fluorescence activation after i.v. injection of porphysomes (7.5 pmol) in a KB xenograft‐bearing mouse. (Reprinted with permission from Ref . Copyright 2011 Nature Publishing Group)
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Top: Synthesis of GNBs (Dav = Number averaged (DLS); ζ = electrophoretic (zeta) potential; Hav = average height (AFM); PDI = polydispersity index (DLS)). Bottom: a general scheme showing the effect of particle size in facile lymphatic distribution. (Reprinted with permission from Ref . Copyright 2010 Elsevier BV)
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(a) TEM image of gold nanorods drop deposited over Ni‐grid; (b) TEM images of GNBR drop deposited over Ni‐grid; (c) AFM images of GNBR drop deposited over glass; (d) UV–vis spectrum of gold nanorods showing LSPR and TSPR bands at 750 nm and 530 nm, respectively. (Reprinted with permission from Ref . Copyright 2009 American Scientific Publishers)
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(a) Preparation of gold nanobeacons from octanethiol‐functionalized gold nanoparticles (AuNPs), x = 1–2 mol% phospholipid coating. (b) TEM image of gold nanobeacons (drop deposited over nickel grid, 1% uranyl acetate; scale bar: 100 nm). (c) AFM image of gold nanobeacons. Average height Hav = 10,151 nm. (d) UV/Vis spectroscopic profile. Solid blue line: gold nanobeacons; purple dashed line: octanethiol‐coated AuNPs. Spectra are not normalized. (Reprinted with permission from Ref . Copyright 2009 Wiley Interscience)
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In vivo multiplex two‐color photoacoustic (PA) detection of circulating tumor cells (CTCs). (a) The 10 nm magnetic NPs (MNPs) coated with amphiphilic triblock polymers, polyethylene glycol (PEG) and the amino‐terminal fragment of urokinase plasminogen activator (ATF). The 12 × 98 nm GNTs coated with PEG and folic acid. (b) PA spectra of ˜ 70 µm veins in mouse ear (open circles). Absorption spectra of the MNPs and GNTs (dashed curves) normalized to PA signals from CTC labeled with MNPs (black cricle) and GNTs (open circle). (c) The size of the primary breast cancer xenografts at different time stages of tumor development. (d) Average rate of CTCs in mouse ear vein. (Reprinted with permission from Ref . Copyright 2009 Nature Publishing Group)
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Photoacoustic (PA) detection of single‐walled carbon nanotube indocyanine green (SWNT‐ICG) in living mice. Vertical slices of ultrasound images (gray) and PA images (green) of mice injected subcutaneously with SWNT‐ICG‐RGD at concentrations of 0.82‐200 nm (dotted black line). The white dotted lines on the images illustrate the approximate edges of each inclusion. Quantitative analysis of the images estimated that 170 pm of SWNT‐ICG‐RGD gives the equivalent PA signal as the tissue background. (Reprinted with permission from Ref . Copyright 2010 American Chemical Society)
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