Gold nanocages (AuNCs) represent a novel class of nanostructures invented by Younan Xia and his co-workers in 2002.[1] They can be considered as single-crystal nanoboxes with empty interiors and porous walls. The wall thickness of a gold nanocage can be controlled in the range of 1-10 nm to tune its absorption/scattering peak throughout the visible and near infrared (the transparent window of soft tissue). Significantly, Younan Xia demonstrated that such a complex nanostructure can be synthesized using a simple and elegant method based on the galvanic replacement reaction between silver nanocubes and chloroauric acid in water. The AuNCs are truly multifunctional: They have strong absorption/scattering powers with the resonance peak positions precisely tunable from 500 to 1200 nm. As a result, AuNCs are ideal contrast agents for imaging modalities such as optical coherence tomography (OCT) and photoacoustic tomography (PAT). Furthermore, the surface of AuNCs can be routinely derivatized with all sorts of functional groups using the well-established gold-thiolate monolayer chemistry. This ability allows one to easily build a well-controlled interface to interact with any biological system of interest. When these AuNCs are attached to the surfaces of cancer cells, the photothermal conversion provides an effective and selective means to destroy cancer cells. By coating the surface of AuNCs with smart polymers or filled with phase-change materials, the AuNCs serve as a new class carriers for drug delivery, with which life-saving medicines can be delivered and released at the site of interest and on demand.

Synthesis

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TEM images of Ag nanocubes template and Au nanocages, and photograph of Vials containing Au nanocages prepared with the addition of different volumes of 0.1 mM HAuCl4(aq) solution.

AuNCs can be prepared via the galvanic replacement reaction between Ag templates and HAuCl4, which is driven by the difference in electrochemical potential between Ag/Ag+ (0.80 V) and Au/AuCl4- (1.00 V).[2]


3Ag(s) + AuCl4ˉ (aq) → Au(s) + 3Ag+(aq) + 4Cl-(aq)


Upon mixing with aqueous HAuCl4, the Ag nanocubes were observed to go through four major stages of morphological and structural changes: (i) initiation of Ag dissolution from a site with poor protection, such as a defect on the side face of a cube with sharp corners or the corner(s) of a cube with truncated corners; (ii) dissolution of bulk Ag from the interior of the particle through the initial site(s) and concurrent deposition of Au on the rest of the surface; (iii) formation of a nanobox (for a sharp cube) or nanocage (for a truncated cube) with uniform wall thickness due to alloying between Au and Ag; (iv) dealloying of Ag to generate pores on the walls of the nanobox, which eventually led to the formation of AuNCs.[3]

Typical AuNCs are composed of a Au/Ag alloy. If necessary, the remaining Ag can be selectively removed using aqueous etchants based upon Fe(NO3)3, NH4OH, or H2O2.[4][5] During this treatment, nanoboxes are converted into thin-walled nanocages, accompanied by red shifts in the localized surface plasmon resonance (LSPR) peak. Alternatively, the surface of a Au/Ag alloyed nanobox or nanocage can be covered with pure Au through electroless deposition, together with a blue shift for the LSPR peak.[6]

Morphologies

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SEM and TEM (inset) images of morphological changes of Ag nanocubes with sharp coners converting into AuNCs
 
SEM and TEM (inset) images of morphological changes of Ag nanocubes with truncated coners converting into AuNCs

The Ag template-engaged galvanic replacement reaction is run like a titration, with HAuCl4 solution (for Au-based nanocages) being controllably added to a boiling suspension of Ag nanocubes. The morphological and compositional changes at various stages of replacement can be monitored using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and elemental analysis.

AuNCs derived from Ag nanocubes with sharp corners

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Typically, Ag nanocubes with sharp corners experience four morphologies during transforming into AuNCs: (a) Ag nanocubes with single crystals, (b) a pinhole on one of the six faces, (c) hollow interior of the nanobox, (d) porous nanocages.[7]

AuNCs derived from Ag nanocubes with truncated corners

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AuNCs with pores specifically localized at all the corners can be achieved by using truncated Ag nanocubes as a template. [8] The difference from Ag nanocubes with sharp corners is attributed to poly(vinyl pyrrolidone) (PVP), the stabilizing polymer present during reaction, which interacts most strongly with {100} facets of Ag.[9] For Ag nanocubes with sharp corners, all surfaces are passivated equally with PVP; however, for Ag nanocubes with truncated corners, the {111} corners are poorly passivated in comparison to the {100} faces. These unprotected corners become primary sites for Ag dissolution, while Au deposition still occurs at the {100} faces. Thus, cubic nanocages with pores at all corners are produced.

Multiple-walled nanoshells and nanorattles

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Various hollow Au-containing nanostructures such us nanorings,[10] triangular nanorings,[11] prism-shaped nanoboxes,[12] and single-walled nanotubes can be prepared by replacing the Ag nanocubes with other Ag nanostructures. Multiplewalled nanoshells and nanorattles (i.e., nanostructures consisting of shells and movable solid cores) were also demonstrated. To prepare these nanostructures, a Ag layer is deposited on Au/Ag nanoshells (or solid Au/Ag particles for nanorattles) synthesized by galvanic replacement. These coated nanostructures then undergo a second galvanic replacement reaction to generate another shell. In this way, hollow Matrioshka-like structures can be prepared.

Properties

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Top panel, vials containing AuNCs prepared by reacting Ag nanocubes suspension with different volumes of HAuCl4 solution. Lower panel, the corresponding UV-visible absorbance spectra of Ag nanocubes and AuNCs.
 
Gold nanostructures can be conjugated with a wide veriety of functional moieties.

Optical properties

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One of the most interesting and powerful properties of gold nanostructures is localized surface plasmon resonance (LSPR). When a Au nanostructure is illuminated with an electromagnetic wave, its conduction electrons will be driven by the electric field to collectively oscillate relative to the lattice of positive ions, creating intense peaks (both scattering and absorption) at resonant wavelengths. For in vivo applications, Au nanostructures must have LSPR peaks in the near-infrared (NIR) region ranging from 700 to 900 nm. In this so-called transparent window, light can penetrate deeply into soft tissues due to a great reduction in absorption from hemoglobin and water in the blood and in scattering by the tissue.[13] For conventional Au colloids with a solid structure and a spherical shape, their LSPR peaks are typically limited to the visible region. Only those Au nanostructures with specific nonspherical morphologies (e.g., rod, rice, multipod, and star) or a hollow structure (e.g., shell, box, and cage) can have LSPR peaks in the NIR region.

The LSPR peak position of the AuNCs is tunable throughout the visible and into the near-infrared by reacting Ag nanocubes suspension with different volumes of HAuCl4 solution. This observation makes AuNCs attractive for colorimetric sensing and biomedical applications.

Controllable surface chemistry

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The surface of gold is well-known for forming strong, stable gold-thiolate bonds (Au-S, ≈ 50 kcal/mol) to molecules with thiol (-SH) or disulfide groups (S-S).[14] This binding has been extensively studied with self-assembled monolayers (SAMs), where molecules (typically long-chain alkanethiols) generate highly ordered monolayers when they adsorb onto a gold surface. This well-characterized binding has been used extensively to add functionality to gold surfaces and gold nanostructures. By carefully choosing the functional group at the distal end of the molecule, it is possible to design and generate a well-defined interface to interact (or not interact) with cells and biomolecules in specific ways.

Potential properties

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In addition to their obvious features, such as hollow interiors and porous walls, AuNCs have a range of hidden qualities that make them unique for theranostic applications: (i) they are single crystals with good mechanical flexibility and stability, as well as atomically flat surfaces; (ii) they can be routinely produced in large quantities with wall thicknesses tunable in the range of 2-10 nm with an accuracy of 0.5 nm; (iii) their hollow interiors can be used for encapsulation; (iv) their porous walls can be used for drug delivery, with the release being controlled by various stimuli; (v) their sizes can be readily varied from 20 to 500 nm to optimize biodistribution, facilitate particle permeation through epithelial tissues, or increase drug loading; (vi) their LSPR peaks can be dominated by absorption or scattering to adapt to different imaging modalities; (vii) other noblemetals such as Pd and Pt can be incorporated into the walls during a synthesis to maneuver their optical properties.

Applications

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Imaging and Diagnosis

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The development of new and early cancer diagnostic techniques is contributing to an increase in cancer survival rates. Still, for this trend to continue, new or improved methods for early detection must continue to be explored. Thus, scientists are both improving the resolution of conventional imaging techniques and developing new imaging modalities. The value of these platforms could be increased through integration with appropriate contrast enhancement agents, and AuNCs, with the extraordinarily large scattering and absorption cross sections,[15] are superb optical tracers or contrast agents for imaging modalities such as dark-field microscopy, optical coherence tomography (OCT), photoacoustic tomography (PAT), and multiphoton luminescence-based detection.

1. Optical coherence tomography (OCT)

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Optical coherence tomography (OCT) and spectroscopic optical coherence tomography (SOCT) are promising diagnostic tools for noninvasive, in vivo imaging, providing the micrometer resolution necessary to distinguish differences between cancerous and healthy tissues.[16][17] These systems are based on a Michelson interferometer, which measures the interference signal between the backscattered light of a sample and a reference. Thus, image contrast arises primarily from the intrinsic scattering and absorption of light by tissue, but AuNCs, with their large absorption/scattering crosssections, could enhance this effect. To demonstrate the potential utility of AuNCs as OCT contrast enhancement agents, a tissue phantom was prepared to which AuNCs (LSPR tuned to 716 nm) were incorporated to one half at a nanomolar concentration.[18][19] OCT and SOCT were conducted using a 7-fs Ti:sapphire laser with a center wavelength of 825 nm and a bandwidth of 155 nm. Imaging revealed greater light attenuation from the side containing Au nanocages. These results imply the AuNCs represent a new class of absorption contrast agents for OCT imaging.

2. Photoacoustic tomography (PAT)

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PAT is a powerful hybrid imaging modality that combines the merits of both optical and ultrasonic imaging techniques, including strong optical absorption contrast and high ultrasonic spatial resolution. The contrast mechanism is based on differences in optical absorption. Xia group has used PAT to image the cerebral cortex of a rat before and after three successive administrations of PEG-ylated AuNCs.[20] An enhancement of the brain vasculature, up to 81%, was observed, and the photograph of an open skull revealed that the anatomical features of the vasculature matched well with those revealed by PAT. Moreover, when compared with Au nanoshells, the AuNCs appear to be more effective contrast enhancement agents for PAT, which is likely related to their larger absorption cross-section and more compact size.[21] In a recent study, AuNCs were used as optical tracers for PA mapping of sentinel lymph nodes (SLN).[22] Such capability is a prerequisite for SLN biopsy (the standard procedure for axillary staging in breast cancer patients), where it is essential to precisely locate the SLN before a biopsy needle can be inserted for sample collection. Compared to the conventional methods, PA mapping based on AuNCs shows a number of attractive features: noninvasiveness, strong optical absorption in the near-infrared region (for deep penetration), and the accumulation of AuNCs with a higher concentration than the initial solution for the injection. In an animal model, SLN can be identified as deep as 33 mm below the skin surface with good contrast by using AuNCs as optical tracers. This depth is greater than the mean depth of SLN in human beings.

3. Two-photon microscopy

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Au nanostructures can be excited optically, resulting in photoluminescence (PL) emission. The PL emission arose from a recombination of the photoexcited electrons in the s-p conduction band with holes in the d-band of metal surface such as Au, Cu, and Ag. This phenomenon is more pronounced for Au nanostructures, especially when they are excited by a laser in resonance with the LSPR peak in a two-photon configuration. Xia group has demonstrated the use of two-photon microscopy as a convenient tool to directly examine the uptake of antibody-conjugated and PEGylated AuNCs by U87MGwtEGFR cells. They have also correlated the results from two-photon microscopy with the data obtained by inductively coupled plasma mass spectrometry. Combined together, the results indicate that the antibody-conjugated AuNCs were attached to the surface of the cells through antibody-antigen binding and then internalized into the cells via receptor-mediated endocytosis. The cellular uptake process was dependent on a number of parameters, including incubation time, incubation temperature, size of the AuNCs, and the number of antibodies immobilized on each nanocage.[23]

Therapeutic Applications

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1. Cancer targeting

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Selectively delivering therapies to malignant tissues is of paramount importance in cancer treatment because it is a promising route to minimize damage to healthy tissue and consequently the harsh side effects from current broad-based treatments. Both passive and active targeting have been explored for delivering nanoparticles to a tumor site. Xia group has quantitatively assessed the passive targeting of AuNCs functionalized with PEG in a tumor mouse model.[24] The distribution of AuNCs in various organs indicates that there were very few AuNCs in normal tissue (0.95 ± 0.24 % ID/g and 0.98 ± 0.45% ID/g at 24 h postinjection formuscle and fat, respectively), while the amount of AuNCs in tumor increased from 0.8 ±0.1 % ID/g at 1 h postinjection to 3.4 ± 0.9 % ID/g at 24 h postinjection. They also compared the passive and active targeting efficiencies of AuNCs for melanomas by in vivo PA imaging.[25] For active targeting, the AuNCs were derivatized with [Nle4, D-Phe7]-α-melanocyte-stimulating hormone or [Nle4, D-Phe7]-α-MSH, a peptide that can selectively bind to the α-MSH receptors overexpressed on melanoma. The enhancement of PA signal in the melanoma was much stronger for the [Nle4, D-Phe7]-α-MSH-AuNCs (up to 36%) than for the PEG-AuNCs (up to 14% only), demonstrating an enhanced uptake of AuNCs by the tumor due to active targeting. Further ICP-MS analyses of the Au content also confirmed this dramatic increase.

2. Photothermal cancer treatment

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The heat generated from photothermal effect can also be used directly for therapy due to a process known as hyperthermia. When cells are exposed to a temperature above 42 °C (typically for several minutes), they can be irreversibly damaged due to protein denaturing and membrane disruption.

Xia group has demonstrated in vitro photothermal destruction of breast cancer cells targeted with immuno-AuNCs.[26] AuNCs 45 nm in edge length were selected because of their predicted large absorption cross-section. Their LSPR was tuned to 810 nm. SK-BR-3 cells were treated with these immuno-AuNCs then irradiated with an 810 nm laser at a power density of 1.5 W/cm2 for 5 min. The treated cells were stained with calcein-AM and ethidium homodimer-1 so that live cells fluoresce green and dead cells fluoresce red. This analysis revealed a well-defined zone of cellular death consistent with the laser spot size. Cells irradiated under the same conditions but without immuno-AuNCs treatment maintained viability. At power densities less than 1.5 W/cm2, the cells treated with immuno-AuNCs maintained viability. This threshold for cellular destruction is lower than that reported for Au nanoshells (35 W/cm2) and Au nanorods (10 W/cm2), which is likely due to the larger absorption cross-section of AuNCs or their greater concentration on cell surfaces. In addition to fluorescence imaging, flow cytometry was also used to quantify the cellular damage caused by the photothermal effect under different experimental conditions, including a range of power densities and irradiation times.[27]

Most recently, the efficacy of photothermal cancer treatment in vivo was examined by treating tumor-bearing mice.[28] The mice with a tumor on both flanks were divided into two groups ( n = 4 per group) with Group 1 being administrated intravenously with 100 μ L of 10 mg/mL (15 n M or 9 × 1012 particles per mL) PEGylated AuNCs and Group 2 being administrated with 100 μ L saline. At 72 h post injection, the tumor on the right flank of each mouse was irradiated with a 808-nm diode laser at a power density of 0.7 W/cm2 for 10 min. During the treatment, the tumors of mice injected with PEGylated AuNCs were rapidly heated to temperatures over 55 °C. In contrast, the saline-injected mice showed much less local temperature increases with maximum surface temperature < 40 °C during the laser irradiation. To evaluate the treatment response, [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) was used to monitor the changes in metabolic activity before and after photothermal therapy. For mice injected with AuNCs, there was a remarkable reduction in FDG uptake for the tumor on the right flank at 24 h post-treatment compared with no treatment. In contrast, the tumor on the left flank (without laser treatment) showed no significant difference for the FDG uptake at 0 and 24 h. The signal of the right tumor was then normalized to that of the left tumor to minimize the variation of FDG uptake at different time points. The normalized values suggest a decrease in metabolic activity by 70%. For the control, the normalized value of FDG uptake showed no change before and after treatment.

3. Controlled release of drug

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AuNCs have been used as a novel class of delivery vehicles by taking advantage of their hollow interiors, porous walls, and tunable LSPR properties. These features are particularly interesting for theranostic applications because AuNCs can be monitored with optical imaging techniques while the drug is released at the targeted site.

In one study, the surface of AuNCs was functionalized with thermally responsive polymers to control the release with NIR laser irradiation or high-intensity focused ultrasound (HIFU).[29][30] The surface of AuNCs was coated with poly(N-isopropylacrylamide) (pNIPAAm) or its derivatives by means of Au-thiolate bonding. The polymer chains can change conformation in response to temperature variation at a point known as the low critical solution temperature (LCST). The LCSTs of the smart polymers can be tuned from 32 to 50 ℃ through the incorporation of different amounts of acrylamide. When the AuNCs are irradiated by a NIR laser overlapping with the LSPR peak, the light will be absorbed and converted into heat through the photothermal effect. The polymer chains will collapse as the temperature increases beyond the LCST, opening the pores and thus releasing the preloaded drugs. When the laser is turned off, the temperature will drop and the polymer chains will relax back to the extended state, terminating the release. The smart polymer-coated AuNCs can thus release drug molecules with high temporal/spatial resolutions in a controlled manner.

References

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  1. ^ Sun, Y.; Mayers, B. T.; Xia, Y. (2002). "Template-Engaged Replacement Reaction: A One-Step Approach to the Large-Scale Synthesis of Metal Nanostructures with Hollow Interiors". Nano Letters. 2 (5): 481–485. doi:10.1021/nl025531v.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Skrabalak, S. E.; Au, L.; Li, X. and Xia, Y. (2007). "Facile synthesis of Ag nanocubes and Au nanocages". Nature Protocols. 2 (9): 2182–2190. doi:10.1038/nprot.2007.326.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Xia, Y.; Li, W.; Cobley, C. M.; Chen, J.; et al. (2011). "AuNCs: From Synthesis to Theranostic Applications". Accounts of Chemical Research. doi:10.1021/ar200061q. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  4. ^ Lu, X.; Au, L.; McLellan, J. M.; Li, Z.-Y.; Marquez, M. and Xia, Y. (2007). "Fabrication of Cubic Nanocages and Nanoframes by Dealloying Au/Ag Alloy Nanoboxes with an Aqueous Etchant Based on Fe(NO3)3 or NH4OH". Nature Letters. 7 (6): 1764–1769. doi:10.1021/nl070838l.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Zhang, Q.; Cobley, C. M. Zeng, J.; Wen, L.-P.; Chen, J. and Xia, Y. (2010). "Dissolving Ag from Au−Ag Alloy Nanoboxes with H2O2: A Method for Both Tailoring the Optical Properties and Measuring the H2O2 Concentration". Journal of Physical Chemistry C. 114 (14): 6396–6400. doi:10.1021/jp100354z.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Sun, Y.; Xia, Y. (2002). "Increased sensitivity of surface plasmon resonance of gold nanoshells compared to that of gold solid colloids in response to environmental changes". Analytical Chemistry. 74 (20): 5297–5305. doi:10.1021/ac0258352.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Sun, Y.; Xia, Y. (2004). "Mechanistic study on the replacement reaction between silver nanostructures and chloroauric acid in aqueous medium". Journal of the American Chemical Society. 126 (12): 3892–3901. doi:10.1021/ja039734c.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Chen, J.; McLellan, J. M.; Siekkinen, A.; Xiong, Y.; Li, Z.-Y.; Xia, Y. (2006). "Facile synthesis of gold-silver nanocages with controllable pores on the surface". Journal of the American Chemical Society. 128 (46): 14776–14777. doi:10.1021/ja066023g.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Sun, Y.; Mayers, B.; Herricks, T.; Xia, Y. (2003). "Polyol synthesis of uniform silver nanowires: A plausible growth mechanism and the supporting evidence". Nano Letters. 3 (7): 955–960. doi:10.1021/nl034312m.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Sun, Y.; Mayers, B.; Herricks, T.; Xia, Y. (2007). "Mechanistic studies on the galvanic replacement reaction between multiply twinned particles of Ag and HAuCl4 in an organic medium". Journal of the American Chemical Society. 129 (6): 1733–1742. doi:10.1021/ja067800f.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Zhang, Q.; Li, W.; Wen, L.-P.; Chen, J.; and Xia, Y. (2010). "Facile synthesis of Ag nanocubes of 30 to 70 nm in edge length with CF3COOAg as a precursor". Chemistry: A European Journal. 16 (33): 1733–1742. doi:10.1002/chem.201000341.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Chen, J.; Claus, C.; Laforest, R.; Zhang, Q.; Yang, M.; Gidding, M.; Welch, M. and Xia, Y. (2010). "Gold nanocages as photothermal transducers for cancer treatment". Small. 6 (7): 811–817. doi:10.1002/smll.200902216.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Weissleder, R. (2001). "A clearer vision for in vivo imaging". Nature Biotechnology. 19: 316–317. doi:10.1038/86684.
  14. ^ Love, J.; Estroff, L.; Kriebel, J.; Nuzzo, R. and Whitesides, G. (2005). "Self-Assembled Monolayers of Thiolates on Metals as a Form of Nanotechnology". Chemical Reviews. 105 (4): 1103–1170. doi:10.1021/cr0300789.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Cho, E. C.; Kim, C.; Zhou, F.; Cobley, C.M.; Song, K. H.; Chen, J.; Li, Z.;Wang, L. V.; Xia, Y. (2009). "Measuring the optical absorption cross sections of Au-Ag nanocages and Au nanorods by photoacoustic imaging". Journal of Physical Chemistry C. 113 (21): 9023–9028. doi:10.1021/jp903343p.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ Huang, D.; Swanson, E. A.; Lin, C. P.; Schuman, J. S.; Stinson, W. G.; Chang, W.; Hee, M. R.; Flotte, T.; Gregory, K.; Puliafito, C. A. (1991). "Optical coherence tomography" (PDF). Science. 254 (5035): 1178–1181. doi:10.1126/science.1957169.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Fujimoto, J. G. (2003). "Optical coherence tomography for ultrahigh resolution in vivo imaging" (PDF). Nature Biotechnology. 21 (11): 1361–1367. doi:10.1038/nbt892.
  18. ^ Chen, J.; Saeki, F.; Wiley, B.; Cang, H.; Cobb, M. J.; Li, Z.-Y.; Au, L.; Zhang, H.; Kimmey, M. B.; Li, X.; Xia, Y. (2005). "AuNCs: Bioconjugation and their potential use as optical imaging contrast agents". Nano Letters. 5 (3): 473–477. doi:10.1021/nl047950t.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Cang, H.; Sun, T.; Chen, J.; Wiley, B. J.; Xia, Y.; Li, X. (2005). "AuNCs as potential contrast agents for spectroscopic and conventional optical coherence tomography". Optics Letters. 30 (22): 3048–3050. doi:10.1364/OL.30.003048.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Yang, X.; Skrabalak, S. E.; Li, Z.-Y.; Xia, Y.; Wang, L. V. (2007). "Photoacoustic tomography of a rat cerebral cortex in vivo with au nanocages as an optical contrast agent". Nano Letters. 7 (12): 3798–3802. doi:10.1021/nl072349r.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Wang, Y.; Xie, X.; Wang, X.; Ku, G.; Gill, K. L.; O’Neal, D. P.; Stocia, G.; Wang, L. V. (2004). "Photoacoustic tomography of a nanoshell contrast agent in the in vivo rat brain". Nano Letters. 4 (9): 1689–1692. doi:10.1021/nl049126a.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Song, K. H.; Kim, C.; Cobley, C. M.; Xia, Y.; Wang, L. V. (2009). "Near-Infrared Gold Nanocages as a New Class of Tracers for Photoacoustic Sentinel Lymph Node Mapping on a Rat Model". Nano Letters. 9 (1): 183–188. doi:10.1021/nl802746w.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ Au, L.; Zhang, Q.; Cobley, C. M.; Gidding, M.; Schwartz, A. G.; Chen, J. and Xia Y. (2010). "Quantifying the cellular uptake of antibody-conjugated Au nanocages by two-photon microscopy and inductively coupled plasma mass spectrometry". ACS Nano. 4 (1): 35–42. doi:10.1021/nn901392m.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Chen, J.; Yang, M.; Zhang, Q.; Cho, E. C.; Cobley, C. M.; Claus, C.; Kim, C.; Wang, L.; Welch, M. J.; Xia, Y. (2010). "Gold Nanocages: A Novel Class of Multifunctional Nanomaterials for Theranostic Applications". Advanced Functional Materials. 420 (21): 3684–3694. doi:10.1002/adfm.201001329. {{cite journal}}: Text "http://onlinelibrary.wiley.com/doi/10.1002/adfm.201001329/pdf" ignored (help)CS1 maint: multiple names: authors list (link)
  25. ^ Kim, C.; Cho, E. C.; Chen, J.; Song, K. H.; Au, L.; Favazza, C.; Zhang, Q.; Cobley, C.M.; Gao, F.; Xia, Y.;Wang, L. V. (2010). "In vivo molecular photoacoustic tomography of melanomas targeted by bioconjugated AuNCs". ACS Nano. 4 (8): 4559–4564. doi:10.1021/nn100736c.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ Chen, J.; Wang, D.; Xi, J.; Au, L.; Siekkinen, A.; Warsen, A.; Li, Z.-Y.; Zhang, H.; Xia, Y.; Li, X. (2007). "Immuno gold nanocages with tailored optical properties for targeted photothermal destruction of cancer cells". Nano Letters. 7 (5): 1318–1322. doi:10.1021/nl070345g.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ^ Au, L.; Zheng, D.; Zhou, F.; Li, Z.-Y.; Li, X.; Xia, Y. (2008). "A quantitative study on the photothermal effect of immuno AuNCs targeted to breast cancer cells". ACS Nano. 2 (8): 1645–1652. doi:10.1021/nn800370j.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Chen, J.; Glaus, C.; Laforest, R.; Zhang, Q.; Yang, M.; Gidding, M.; Welch, M. J.; Xia, Y. (2010). "AuNCs as photothermal transducers for cancer treatment". Small. 6 (7): 811–817. doi:10.1002/smll.200902216.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ Mustafa, S. Y.; Cheng, Y.; Chen, J.; Cobley, C.M.; Zhang, Q.; Rycenga,M.; Xie, J.; Kim, C.; Song, K. H.; Schwartz, A. G.; Wang, L. V.; Xia, Y. (2009). "Gold nanocages covered by smart polymers for controlled release with near-infrared light". Nature Materials. 8 (12): 935–939. doi:10.1038/NMAT2564.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ Li,W.; Cai, X.; Kim, C.; Sun, G.; Zhang, Y.; Deng, R.; Yang,M.; Chen, J.; Achilefu, S.;Wang, L. V.; Xia, Y. (2011). "AuNCs covered with thermally-responsive polymers for controlled release by high-intensity focused ultrasound". Nanoscale. 3 (4): 1724–1730. doi:10.1039/c0nr00932f.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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