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Review
. 2014 May 28;114(10):5161-214.
doi: 10.1021/cr400425h. Epub 2014 Mar 10.

Upconversion nanoparticles: design, nanochemistry, and applications in theranostics

Guanying Chen  1 , Hailong Qiu, Paras N Prasad, Xiaoyuan Chen
Affiliations
Review

Upconversion nanoparticles: design, nanochemistry, and applications in theranostics

Guanying Chen et al. Chem Rev. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
Schematic illustration of the structure of this Review.
Figure 2
Figure 2
Principal UC processes for lanthanide-doped UCNPs: (a) excited-state absorption (ESA), (b) energy transfer upconversion (ETU), (c) cooperative sensitization upconversion (CSU), (d) cross relaxation (CR), and (e) photon avalanche (PA). The red, violet, and green lines represent photon excitation, energy transfer, and emission processes, respectively.
Figure 3
Figure 3
General strategies to achieve the high efficiency of UCNPs.
Figure 4
Figure 4
UC PL spectra of colloidal NaYF4 nanoparticles codoped with 2% Tm3+ and with various concentrations of Yb3+ ions (20–100%), under diode laser excitation at 975 nm. Their absorption spectra have been normalized at 975 nm for the 2F7/2 → 2F5/2 transition of Yb3+ ions, as displayed in the inset. Reprinted with permission from ref (36). Copyright 2010 American Chemical Society.
Figure 5
Figure 5
Schematic illustration of a cross section of core/shell structure and random energy migration among lanthanide ions in the core nanoparticles.
Figure 6
Figure 6
(a) The UC PL spectra of the ∼20 nm NaYbF4:0.5%Tm3+ core, and the ∼27 nm (NaYbF4:0.5%Tm3+)@CaF2 core/shell nanoparticles; the inset shows the corresponding absorption spectra of the core and the core/shell nanoparticles; (b) photographic images of cuvettes with suspensions of the NaYbF4:0.5%Tm3+ core and the (NaYbF4:0.5%Tm3+)@CaF2 core/shell nanoparticles (ref (38)); (c) UC emission spectra and digital photographs (inset) of ∼7 nm NaYF4:Yb3+/Tm3+ core and the NaYF4:Yb3+/Tm3+@CaF2 core/shell nanoparticles; and (d) UC emission spectra and digital photographs (inset) of the NaYF4:Yb3+/Ho3+ core and the NaYF4:Yb3+/Ho3+@CaF2 nanoparticles (ref (187)). The excitation wavelength is ∼980 nm. The excitation power density for (a) and (b) is around 0.3 W/cm2, while it is about 8 W/cm2 for (c) and (d). Reprinted with permission from refs (38) and (187). Copyright 2012 American Chemical Society and 2012 John Wiley and Sons.
Figure 7
Figure 7
Schematic illustration of the various strategies to manipulate the wavelength of emission in lanthanide-doped UCNPs.
Figure 8
Figure 8
Panel (I): UCPL of colloidal YF3 nanoparticles doped with (Ia) Er3+ ions of 0.5% and Yb3+ ions of 10- 90%; (Ib) Tm3+ ions of 2% and Yb3+ ions of 10–90%; (Ic) Er3+ ions of 0.5%, Tm3+ ions of 2%, and Yb3+ ions of 10–90%. The spectra in (Ia), (Ib), and (Ic) in order were normalized to the emissions of Er3+ ions at 520 nm, Tm3+ ions at 475 nm, and Tm3+ ions at 475 nm, respectively. Compiled UCPL images of colloidal nanoparticles of YF3 doped with (Id-h) Er3+ ions of 0.5% and Yb3+ ions of 10- 90%; (Ii-m) Tm3+ ions of 2% and Yb3+ ions of 10–90%; (In-r) Er3+ ions of 0.5%, Tm3+ ions of 2%, and Yb3+ ions of 10–90% (ref (184)). Panel (II): UC PL spectra of (IIa) NaYF4:Yb3+/Er3+ (18% and 2%), (IIb) NaYF4:Yb3+/Tm3+ (20% and 0.2%), (IIc) NaYF4:Yb3+/Er3+ (25–60% and 2%), and (IId) NaYF4: Yb3+/Tm3+/Er3+ (20%, 0.2%, and 0.2–1.5%) particles in ethanol. Compiled luminescent photos showing corresponding colloidal solutions of (IIe) NaYF4:Yb3+/Tm3+ (20% and 0.2%), (IIf-j) NaYF4: Yb3+/Tm3+/Er3+ (20%, 0.2%, and 0.2–1.5%), and (IIk-n) NaYF4: Yb3+/Er3+ (18–60% and 2%) (ref (82)). Reprinted with permission from refs (82) and (184). Copyright 2008 American Chemical Society and 2012 Royal Society of Chemistry Publishing.
Figure 9
Figure 9
Tuning upconversion through energy migration in UCNPs. (a) Schematic illustration of a lanthanide-doped NaGdF4@NaGdF4 core–shell nanoparticle for energy migration-mediated upconversion (X: activator ion); (b) proposed energy transfer mechanisms in the system; (c) upconversion fluorescence spectra of the as-prepared NaGdF4@NaGdF4 core–shell nanoparticles doped with different activators (activator emissions are highlighted with color) (ref (170)); and (d) the effective suppression of surface-related quenching mechanism in the NaGdF4@NaGdF4@NaYF4 UCNPs (ref (193)). Reproduced with permission from refs (170) and (193). Copyright 2011 Nature Publishing Group and 2012 American Chemical Society.
Figure 10
Figure 10
(a) Digital images of colloidal NaYF4:20%Yb3+,2%Ho3+ (green, left) nanoparticles and NaYF4:20%Yb3+,2%Ho3+,10%Ce3+ (red, right) under 970 nm diode laser excitation; and (b) cross-relaxation (CR) energy transfer diagrams of Ho3+, Yb3+, and Ce3+ ions as well as proposed UC mechanisms. Reproduced with permission from ref (86). Copyright 2009 IOP Publishing.
Figure 11
Figure 11
(a) Schematic illustration of a sandwich construct to tune the UCNPs’ emission color; (b) UC PL spectra of the sandwich-structured nanoparticles; (c) fluorescence intensity comparison of core, core–shell, and sandwich structured UCNPs; and (d) photographic images of multicolor UCNPs. Reproduced with permission from ref (216). Copyright 2013 Elsevier B.V.
Figure 12
Figure 12
(a) Schematic illustration of FRET-based lanthanide-doped core/shell NaYF4@silica UCNPs; (b) PL spectra of pure NaYF4:Yb3+/Tm3+@silica nanospheres (black line), and of NaYF4:Yb,Tm@silica nanospheres doped with FITC (green line) and QD605 (red line); (c) fluorescence spectra of pure NaYF4:Yb3+/Er3+@silica nanospheres (black line) and NaYF4:Yb3+/Er3+@silica nanospheres doped with TRITC (red line); (d) PL spectra of NaYF4:Yb3+, Er3+@silica nanospheres doped with different amounts of TRITC; (e) photographic images of UCPL of NaYF4:Yb3+/Tm3+ nanospheres (blue), UCPL of NaYF4:Yb3+/Er3+ nanospheres (yellow green), UCPL of NaYF4:Yb3+/Er3+ nanospheres through green and red filters; and (f) photographic images of UC PL of NaYF4:Yb3+/Tm3+@FITC-doped silica nanospheres (left), NaYF4:Yb3+/Er3+@TRITC-doped silica nanospheres (middle), and NaYF4:Yb3+/Tm3+@QD605-doped silica nanospheres (right). Reproduced with permission from ref (224). Copyright 2008 John Wiley and Sons.
Figure 13
Figure 13
Typical TEM images of lanthanide-doped (a) LuOF, (b) LaF3, (c) α-NaYF4, (d) NaYbF4, (e) β-NaEuF4 (refs (237, 245), and (246)) synthesized by the thermolysis method; (f) α-NaYF4:Yb3+, Er3+, (g) β-NaYF4:Yb3+, Er3+, (h) LaF3, (i) YF3, (j) α-NaYF4, synthesized by the hydro(solvo)-thermal method (refs (100) and (266)); (k–o) β-NaYF4 or CaF2 nanoparticles synthesized by the Ostwald-ripening method (refs (175, 224, 220, 215), and (231)). Reprinted with permission from refs (237, 245, 246, 100, 266, 175, 224, 220, 215), and (231). Copyright 2006 American Chemical Society, 2005 American Chemical Society, 2007 John Wiley and Sons, 2011 American Chemical Society, 2005 Nature Publishing Group, 2012 American Chemical Society, 2008 John Wiley and Sons, 2008 IOP Publishing, 2008 American Chemical Society, and 2013 John Wiley and Sons.
Figure 14
Figure 14
Schematic illustration of the growth of UCNPs using the thermolysis strategy. The metallic precursors decompose at high temperature to yield monomers, which are then crystallized and grow into monodispersed UCNPs.
Figure 15
Figure 15
Two strategies to produce hierarchical core/shell UCNPs.
Figure 16
Figure 16
Schematic illustration of general strategies used for surface engineering of UCNPs, which include ligand exchange, ligand oxidation, ligand removal, silanization, layer-by-layer assembly, and amphiphilic polymer coating.
Figure 17
Figure 17
Bioconjugation chemistry commonly utilized for UCNPs to couple with selected biomolecules. Reaction 1 describes the chemical reaction of carboxylic acid and primary amine group to produce an amide bond, while reaction 2 presents a covalent bond formation between a thiol group and a maleimide group. Reaction 3 illustrates the coupling reaction between two thiol groups to form a disulfide bond, while reaction 4 displays the reaction of an aldehyde group and an amine group to produce an imine bond.
Figure 18
Figure 18
Schematic illustration of biosensing and bioassay applications of UCNPs in diverse fields.
Figure 19
Figure 19
(A) Schematic of nanothermometer used to monitor the temperature profile created by heating a colloidal solution of NaYF4:Er3+,Yb3+ UCNPs in water with a NIR diode laser (980 nm, pump beam) and scanned with an Ar+ laser (488 nm, probe beam). (B) Confocal image of all of the visible upconverted luminescence under 980 nm excitation (left). Thermal image of the spot created by the 980 nm pump beam (right). (C) Optical transmission images of an individual HeLa cell at different temperatures and temperature-dependent property of the HeLa cell determined by UCNPs as a function of the applied voltage. The voltage determines the heating temperature of plate under the cells. Reprinted with permission from ref (351). Copyright 2010 American Chemical Society.
Figure 20
Figure 20
Schematic illustration of typical heterogeneous assays based on UCNPs: (a) sandwich-type assay; the optical response is proportional to the concentration of an analyte; and (b) competitive assay; the optical response is inversely proportional to the concentration of an analyte.
Figure 21
Figure 21
Schematic illustration of typical homogeneous assays based on UCNPs. (a) Assays utilizing a sandwich-type structure. These systems involve the use of UCNPs as energy donors and strong-absorbing materials as energy acceptors. The donors and acceptors are brought into close proximity by analytes. (b) Assays utilizing the inhibition of energy transfer process. (b, upper) The fluorophore utilized as the energy donor of UCNPs is initially deactivated by a linked quencher through a FRET process. The linkage between the fluorophore and the quencher can be cut off by an analyte (generally, an enzyme), restoring the PL of the fluorophore. (b, lower) The PL of UCNP, quenched by FRET or LRET to a quencher, can be recovered by analyte-induced separation of the quencher from the UCNP or elimination of quenchers’ strong absorption.
Figure 22
Figure 22
Schematic illustration of applications of UCNPs in high contrast bioimaging.
Figure 23
Figure 23
Cell viabilities of (a) human pancreatic cancer Panc 1 cells (ref (300)), (b) human nasopharyngeal epidermal carcinoma cells (KB cells) (ref (48)), and (c) human glioblastoma U87MG cells and human breast cancer MCF-7 cells incubated with UCA-RGD of different concentrations (ref (380)). (d) Serum biochemistry results obtained from mice injected with PAA-UCNPs 115 days postinjection (dose = 15 mg/kg, test) and mice receiving no injection (control). (e) Change in body weight obtained from mice injected with PAA-UCNPs (dose = 15 mg/kg, test) and without injection (control). These findings did not indicate a trend of toxicity. (f–q) Hematoxylin and eosin-stained tissue sections from mice injected with PAA-UCNPs 115 days postinjection (f, j, n, h, l, and p) and mice receiving no injection (g, k, o, i, m, and q). Tissues were harvested from heart (f, g), spleen (h, i), liver (m, k), lung (l, m), kidney (n, o), and blood smear (p, q) (ref (48)). Reprinted with permission from refs (300, 48), and (380). Copyright 2008 American Chemical Society, 2010 Elsevier B.V., and 2013 Nature Publishing Group.
Figure 24
Figure 24
(a) Pseudo color images of C. elegans after being deprived of food over various periods of time: the red color represents the brightfield and green for the UC emission of Y2O3:Yb3+/Er3+ UCNPs (ref (384)). (b) Comparison of mouse imaging after subcutaneous injection of (left) green-emitting QDs under UV excitation and (right) green-emitting NaYF4:Yb3+/Er3+ UCNPs under NIR excitation (ref (387)). (c) Multicolor sentinel lymph node imaging of a mouse using NIR-to-blue UCNPs of NaY0.78Yb0.2Tm0.02F4, NIR-to-green UCNPs of NaY0.78Yb0.2Er0.02F4, and NIR-to-red UCNPs of NaY0.78Yb0.3Er0.01F4.(ref (329)). (d) Sentinel lymph node imaging of a mouse using NIR-to-NIR UCNPs of LaF3:Yb/Tm (ref (331)). (e) PL imaging of blood vessels in the mouse ear following tail vein injection of Y2O3:Yb3+/Er3+ UCNPs using NIR excitation at 980 nm (ref (403)). (f) High-resolution cortical vasculature imaging using NIR-to-green dendritic UCNPs at various depths under cw NIR laser diode excitation (ref (404)). Reprinted with permission from refs (384, 387, 329, 331, 403), and (404). Copyright 2006 American Chemical Society, 2008 Elsevier B.V., 2010 Springer, 2011 Elsevier B.V., 2013 Elsevier B.V., 2009 Royal Society of Chemistry Publishing, and 2012 National Academy of Sciences.
Figure 25
Figure 25
(a,b) In vivo UC PL imaging of subcutaneous U87MG tumor (left hind leg, indicated by short arrows) and MCF-7 tumor (right hind leg, indicated by long arrows) bearing mice after intravenous injection of RGD-conjugated NaYF4:Yb3+/Tm3+ nanoparticles for (a) 1 h and (b) 24 h. The left, middle, and right columns are bright-field, UC PL, and overlay images, respectively. Intense UC PL signal was observed in the U87MG tumor, whereas no obvious signal was seen in the MCF-7 tumor. In vivo SNR = (IROI1 – IROI3)/(IROI2 – IROI3) where ROI 1 represents specific uptake region of interest; ROI 2 is nonspecific uptake region of interest; and ROI 3 is background region of interest (Figure 25 b) (ref (49)). (c,d). In vivo UC PL imaging of subcutaneous HeLa tumor-bearing athymic nude mice (right hind leg, pointed by white arrows) after intravenous injection of UCNPs-NH2 without FA (c) and UCNPs-FA (d), respectively. The left and right columns represent the bright-field images as well as the overlay of bright and UC PL images, respectively (ref (348)). Reprinted with permission from refs (49) and (348). Copyright 2009 American Chemical Society and 2009 Elsevier B.V.
Figure 26
Figure 26
Whole-body images of mouse injected with NaYF4:Yb3+/Tm3+ UCNPs; intact mouse (a), same mouse after dissection (b). The red color indicates emission from UCNPs; green and black show background as indicated by the arrows. The inset presents the PL spectra corresponding to the spectrally unmixed components of the multispectral image obtained with the Maestro system (ref (300)). (c) Whole-body images of a BALB/c mouse injected via tail vein with the hyaluronic acid-coated α-(NaYbF4:0.5% Tm3+)/CaF2 core/shell UCNPs. (d) Bright-field image of the pork tissue (side view), displaying the imaging depth; (e) UC PL image of the cuvette containing α-(NaYbF4:0.5% Tm3+)/CaF2 core/shell UCNPs covered with a pork tissue. The insets in (c) and (e) show the spectra of the NIR UC PL and background taken from the circled area (ref (38)). Reprinted with permission from refs (300) and (38). Copyright 2008 American Chemical Society and 2012 American Chemical Society.
Figure 27
Figure 27
A comparison of NaYF4:Yb3+/Tm3+ UCNPs (left column) and organic dyes (right column) in FDOT. (a,b) Three-dimensional rendering of the reconstructed fluorophores; the boxes indicate the position of the cross-sectional slices. (a) Reconstruction using UCNPs shows a smooth and uniform rendering. (b) Reconstruction using Rhodamine 6G shows several artifacts at the two ends of the fluorescent target (ref (414)). (c,d) Two-dimensional plots of the FDOT reconstructions with (c) the quadratically power-dependent NaYF4:Yb3+/Tm3+@NaYF4 UCNPs as contrast agents and (d) the linearly power-dependent DY-781 fluorophores, and their corresponding intensity profiles (line plots). The true depth was z = 7 mm, while the separation distance between the fluorescent tubes was set to 6 mm. The use of quadratic UCNPs clearly leads to reconstructions with higher spatial resolutions and qualities (ref (416)). Reprinted with permission from refs (414) and (416). Copyright 2009 American Institute of Physics and 2012 American Chemical Society.
Figure 28
Figure 28
(I a–c) The UC PL (I a), bright-field (I b), and merged (I c) images of a KB tumor-bearing mouse 1 h after intravenous injection of PEGylated multifunctional nanoparticles. (I d) Ex vivo UCPL imaging showing accumulation of multifunctional nanoparticles in the liver, spleen, tumor, bone, and lung of the injected mouse at 24 h post injection. T2-weighted images of KB-tumor bearing nude mice with (I e) and without (I f) injection of multifunctional nanoparticles. Multimodal UC PL (I g) and T2MR (I h) imaging for in vivo lymphangiography mapping using multifunctional nanoparticles (ref (63)). In vivo UCPL imaging of lymphatic system after injection with NaYF4:Yb3+/Tm3+@FexOy nanoparticles into a nude mouse at various time: (II a) 0 min, (II b) 10 min, and (II c) 20 min. (II f) T2-weighted and color-mapped MR images of various molar concentrations of NaYF4:Yb3+/Tm3+@FexOy nanoparticles. Deionized water (0 mg/mL) was the reference. (II g) Relaxation rate R2 (1/T2) versus various molar concentrations of hydrophilic NaYF4:Yb3+/Tm3+@FexOy nanoparticles at room temperature using a 3T MRI scanner. (II h) MR images of the armpit region after injection with NaYF4:Yb3+/Tm3+@FexOy nanoparticles and color-mapped coronal images of lymph node at various time (ref (425)). These figures are adapted from refs (63) and (425). Copyright 2011 John Wiley and Sons and 2011 Elsevier B.V.
Figure 29
Figure 29
In vivo UC PL imaging (I a) and X-ray imaging (I b) of mice after subcutaneous injection (left) without and (right) with NaGdF4:Yb3+/ Er3+. In vivo CT images of mice after subcutaneous injection with lanthanide-doped NaGdF4 UCNPs suspended in PBS. (II a) The photograph of the injected mouse; (II b,c) the transverse image of the back, the HU value of the injection site is 468; (II d,e) the transverse image of the buttock, the HU value of the injection site is 465. Reprinted with permission from ref (427). Copyright 2011 John Wiley and Sons.
Figure 30
Figure 30
(a) Schematic representation of preparation of 18F-labeled rare-earth (RE) materials and lymph node imaging mechanism. The 18F-labeling is by virtue of a reaction between RE ions and 18F. Entrance of lymphotropic materials into lymph nodes is mainly via nonselective endothelial transcytosis into the lymph nodes via the lymphatic system. PET imaging (b) and PET/CT imaging (c) of lymph node 30 min after subcutaneous injection of 18F-UCNPs. Thirty minutes after subcutaneous injection of 18F-UCNPs into the left paw footpad, the signal in lymph node quickly reached the peak intensity and maintained up to 60 min post injection, while as control free 18F ions injected into the right paw showed no lymphatic imaging ability. Reprinted with permission from ref (62). Copyright 2011 Elsevier B.V.
Figure 31
Figure 31
(I a) In vivo UC PL imaging of a nude mouse after injection with UCNP@SiO2-GdDTPA for 10 min. (I b) Ex vivo UC PL imaging of the same but sacrificed nude mouse. (I c) Ex vivo UC PL image of main organs of the sacrificed nude mouse. (II a–c) Serials of coronal CT images of Kunming mouse at different layers after injection of UCNP@SiO2-GdDTPA. (II e–g) Enlarged CT views of the abdomen. (III a,d) T1-weighted MRI images of liver (III a) and spleen (III d) at 0, 30, and 120 min after injection of UCNP@SiO2-GdDTPA. (III b,e) T1 distribution images of liver (III b) and spleen (III e) at 0, 30, and 120 min after injection of UCNP@SiO2-GdDTPA. (III c,f) Local colorized T1-weighted MR images of liver (III c) and spleen (III f) at 0, 30, and 120 min after injection of UCNP@SiO2-GdDTPA. Reprinted with permission from ref (422). Copyright 2012 Elsevier B.V.
Figure 32
Figure 32
Schematic representation of current approaches to construct UCNP-based drug delivery systems: (a) hydrophobic pockets, (b) mesoporous silica shells, and (c) hollow mesoporous-coated spheres. Reprinted with permission from ref (99). Copyright 2013 Elsevier B.V.
Figure 33
Figure 33
Schematic illustration of the UCNP-based drug delivery system. (a) As-synthesized oleic acid capped UCNPs; (b) C18PMH-PEG-FA functionalized UCNPs; (c) the loading of DOX on UCNPs; DOX molecules are physically adsorbed into the oleic acid layer on the nanoparticle surface by hydrophobic interactions; and (d) release of DOX from UCNPs triggered by decreasing pH. Reprinted with permission from ref (53). Copyright 2011 Elsevier B.V.
Figure 34
Figure 34
(a) Chemical design for uncaging d-luciferin and subsequent bioluminescence through the use of photocaged UCNPs. (b,c) Bioluminescent images of living mice that were treated with d-luciferin. (b) Left ellipse, injection with d-luciferin (20 mm, 20 mL); right ellipse, injection with photocaged nanoparticles without NIR light irradiation. (c) Left ellipse, injection with photocaged nanoparticles and irradiation with UV light for 10 min; right ellipse, injection with photocaged nanoparticles and irradiation with NIR light for 1 h. Comparison of (b) and (c) clearly indicates the NIR-induced release of d-luciferin in deep tissues. Reprinted with permission from ref (449). Copyright 2012 John Wiley and Sons.
Figure 35
Figure 35
Dual-targeted photothermal ablation of cancer cells. (a) The heating curves of water (○), UCNP-iron oxide nanocomposite (◇), and multifunctional nanoparticles (MFNPs) under 808 nm laser irradiation. (b) Relative viabilities of PEG-MFNP or FA-PEG-MFNP treated KB cells with or without 808 nm laser irradiation. (c) A UCPL image of HeLa cells in a culture dish after incubation with PEG-MFNP in the presence of magnetic field taken by the Maestro in vivo imaging system (980 nm excitation). Inset: A photo showing the experimental setup. A magnet was placed close to the cell culture dish. (d–f) Confocal images of calcein AM (green, live cells) and propidium iodide (red, dead cells) costained cells after magnetic targeted PTT. Images were taken at different locations in the culture dish: (1) far from the magnet (d), (2) in the middle (e), and (3) close to the magnet (f). (g) A digital photo of the cell culture dish after magnetic targeted PTT and trypan blue staining. (h–j) Optical microscopy images of trypan blue stained cells after magnetic targeted PTT. Reprinted with permission from ref (63). Copyright 2011 John Wiley and Sons.
Figure 36
Figure 36
(a) Representative gross photos of a mouse showing tumors (highlighted by dashed white circles) at 14 d after treatment with the conditions described for groups 1–4. Scale bars, 10 mm. (b) Tumor volumes in the four treatment groups at 6, 8, 10, 12, and 14 d after treatment to determine the effectiveness of the treatment in terms of tumor cell growth inhibition. (c) TUNEL staining of tissue sections from the treatment groups at 24 h after treatment to determine the effectiveness of the treatment in terms of tumor cell death by apoptosis. DAPI counterstaining indicates the nuclear region, and upconversion fluorescence imaging indicates the position of the injected UCNP-labeled cell (×400 magnification). Scale bar, 20 μm. (d) The apoptotic index charted as the percentage of TUNEL-positive apoptotic nuclei divided by the total number of nuclei visualized by counterstaining with DAPI obtained from counts of randomly chosen microscopic fields. Reprinted with permission from ref (64). Copyright 2012 Nature Publishing Group.
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