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THERAPEUTICS

Gold Nanorods Mediate Tumor Cell Death by Compromising Membrane Integrity

Folate-conjugated gold nanorods targeted to tumor cell surfaces produced severe membrane damage upon near-infrared irradiation. Photoinduced injury to the plasma membrane resulted in a rapid increase in intracellular calcium with subsequent disruption of the actin network, featured prominently by the formation of membrane blebs.


L. Tong, Y. Zhao, T. B. Huff, M. N. Hansen, A. Wei, J.-X. Cheng
 

Advanced Materials Volume 19, Issue 20 , Pages3136 - 3141

 

Hyperthermic effects of gold nanorods on tumor cells

Plasmon-resonant gold nanorods, which have large absorption cross sections at near-infrared frequencies, are excellent candidates as multifunctional agents for image-guided therapies based on localized hyperthermia. The controlled modification of the surface chemistry of the nanorods is of critical importance, as issues of cell-specific targeting and nonspecific uptake must be addressed prior to clinical evaluation. Nanorods coated with cetyltrimethylammonium bromide (a cationic surfactant used in nanorod synthesis) are internalized within hours into KB cells by a nonspecific uptake pathway, whereas the careful removal of cetyltrimethylammonium bromide from nanorods functionalized with folate results in their accumulation on the cell surface over the same time interval. In either case, the nanorods render the tumor cells highly susceptible to photothermal damage when irradiated at the nanorods' longitudinal plasmon resonance, generating extensive blebbing of the cell membrane at laser fluences as low as 30 J/cm².

Huff, Terry B; Tong, Ling; Zhao, Yan; Hansen, Matthew N; Cheng, Ji-Xin; Wei, Alexander

Nanomedicine, Volume 2, Number 1, February 2007 , pp. 125-132(8)

http://www.chem.purdue.edu/awei/publications/Wei42.pdf

Gold Nanoparticles Target Cancer

Nanoparticles with unique optical properties, facile surface chemistry, and appropriate size scale are generating much enthusiasm in molecular biology and medicine. Noble metal, especially Au, nanoparticles have immense potential for cancer diagnosis and therapy on account of their surface plasmon resonance (SPR) enhanced light scattering and absorption. Conjugation of Au nanoparticles to ligands specifically targeted to biomarkers on cancer cells allows molecular-specific imaging and detection of cancer. Additionally, Au nanoparticles efficiently convert the strongly absorbed light into localized heat, which can be exploited for the selective laser photothermal therapy of cancer. We discuss recent advances in the study and use of selectively targeted Au nanospheres in cancer photodiagnostics and photothermal therapy. By changing the shape or composition of Au nanoparticles, the SPR can be tuned to the near-infrared region, allowing in vivo imaging and photothermal therapy of cancer. The use of Au nanorods and silica-Au core-shell nanoparticles for in vivo cancer detection and therapy is discussed.

Prashant K. Jain, Ivan H. El-Sayed, and Mostafa A. El-Sayed

 Nanotoday FEBRUARY 2007 | VOLUME 2 | NUMBER 1

http://www.nanotoday.com/pdfs_nanotoday_01_2007/nano_v2_1_review01.pdf

Photothermal reshaping of gold nanorods prevents further cell death

The combined use of phosphatidylcholine passivated gold nanorods (PC-NRs) and pulsed near-infrared (near-IR) irradiation resulted in cell death. Pulsed near-IR laser irradiation also induced reshaping of PC-NRs into spherical nanoparticles. Since reshaped particles showed no absorption in the near-IR region, successive laser irradiation did not affect cells. Photo-reshaping of PC-NRs is expected to be advantageous in preventing unwanted cell damage following destruction of target cells.

Hironobu Takahashi et al

2006 Nanotechnology 17 4431-4435


 

Biomedical applications of plasmon resonant metal nanoparticles

The strong optical absorption and scattering of noble metal nanoparticles is due to an effect called localized surface plasmon resonance, which enables the development of novel biomedical applications. The resonant extinction, which can be tuned to the near-infrared, allows the nanoparticles to act as molecular contrast agents in a spectral region where tissue is relatively transparent. The localized heating due to resonant absorption, also tunable into the near-infared, enables new thermal ablation therapies and drug delivery mechanisms. The sensitivity of these resonances to their environment leads to simple affinity sensors for the detection of low-level molecular analytes. Coupled with their general lack of toxicity, these applications suggest that noble metal nanoparticles are a highly promising class of nanomaterials for new biomedical applications.

Hongwei Liao, Colleen L Neh & Jason H Hafner

Nanomedicine August 2006, Vol. 1, No. 2, Pages 201-208

IMAGING (Two Photon Luminescence, Optical Coherence Tomography, Photoacoustic Imaging)

In vitro and in vivo two-photon luminescence imaging

Gold nanorods excited at 830 nm on a far-field laser-scanning microscope produced strong two-photon luminescence (TPL) intensities, with a cos4 dependence on the incident polarization. The TPL excitation spectrum can be superimposed onto the longitudinal plasmon band, indicating a plasmon-enhanced two-photon absorption cross section. The TPL signal from a single nanorod is 58 times that of the two-photon fluorescence signal from a single rhodamine molecule. The application of gold nanorods as TPL imaging agents is demonstrated by in vivo imaging of single nanorods flowing in mouse ear blood vessels.

Haifeng Wang, Terry B. Huff, Daniel A. Zweifel, Wei He, Philip S. Low, Alexander Wei, and Ji-Xin Cheng
 

15752–15756  PNAS  November 1, 2005  vol. 102  no. 44

http://www.chem.purdue.edu/jcheng/pdf%20files/nanorods%20PNAS%202005.pdf

Plasmon-resonant nanorods as multimodal agents for two-photon luminescent imaging and photothermal therapy

Plasmon-resonant gold nanorods have outstanding potential as multifunctional agents for image-guided therapies. Nanorods have large absorption cross sections at near-infrared (NIR) frequencies, and produce two-photon luminescence (TPL) when excited by fs-pulsed laser irradiation. The TPL signals can be detected with single-particle sensitivity, enabling nanorods to be imaged in vivo while passing through blood vessels at subpicomolar concentrations. Furthermore, cells labeled with nanorods become highly susceptible to photothermal damage when irradiated at plasmon resonance, often resulting in a dramatic blebbing of the cell membrane. However, the straightforward application of gold nanorods for cell-specific labeling is obstructed by the presence of CTAB, a cationic surfactant carried over from nanorod synthesis which also promotes their nonspecific uptake into cells. Careful exchange and replacement of CTAB can be achieved by introducing oligoethyleneglycol (OEG) units capable of chemisorption onto nanorod surfaces by in situ dithiocarbamate formation, a novel method of surface functionalization. Nanorods with a dense coating of methyl-terminated OEG chains are shielded from nonspecific cell uptake, whereas nanorods functionalized with folate-terminated OEG chains accumulate on the surface of tumor cells overexpressing their cognate receptor, with subsequent delivery of photoinduced cell damage at low laser fluence.

Terry B. Huff, Matthew N. Hansen, Ling Tong, Yan Zhao, Haifeng Wang, Daniel A. Zweifel, Ji-Xin Chenga, and Alexander Wei

http://www.chem.purdue.edu/awei/publications/SPIE2007_6448-11.pdf

Plasmon-resonant gold nanorods as low backscattering albedo contrast agents for optical coherence tomography
 

Plasmon-resonant gold nanorods are demonstrated as low backscattering albedo contrast agents for optical coherence tomography (OCT). We define the backscattering albedo, a , as the ratio of the backscattering to extinction coefficient. Contrast agents which modify a within the host tissue phantoms are detected with greater sensitivity by the differential OCT measurement of both a and extinction. Optimum sensitivity is achieved by maximizing the difference between contrast agents and tissue. Low backscattering albedo gold nanorods (14× 44 nm; λ max = 780 nm) within a high backscattering albedo tissue phantom with an uncertainty in concentration of 20% (randomized 2±0.4% intralipid) were readily detected at 82 ppm (by weight) in a regime where extinction alone could not discriminate nanorods. The estimated threshold of detection was 30 ppm.
 

Amy L. Oldenburg, Matthew N. Hansen, Daniel A. Zweifel, and Alexander Wei, Stephen A. Boppart
 

24 July 2006 / Vol. 14, No. 15 / OPTICS EXPRESS 6724

http://www.opticsexpress.org/abstract.cfm?id=92241

Cancer Cells Assemble and Align Gold Nanorods Conjugated to Antibodies to Produce Highly Enhanced, Sharp, and Polarized Surface Raman Spectra: A Potential Cancer Diagnostic Marker

Human oral cancer cells are found to assemble and align gold nanorods conjugated to anti-epidermal growth factor receptor (anti-EGFR) antibodies. Immunoconjugated gold nanorods and nanospheres were shown previously to exhibit strong Rayleigh (Mie) scattering useful for imaging. In the present letter, molecules near the nanorods on the cancer cells are found to give a Raman spectrum that is greatly enhanced (due to the high surface plasmon field of the nanorod assembly in which their extended surface plasmon fields overlap), sharp (due to a homogeneous environment), and polarized (due to anisotropic alignments). These observed properties can be used as diagnostic signatures for cancer cells.

Xiaohua Huang, Ivan H. El-Sayed, Wei Qian, and Mostafa A. El-Sayed
 

Nano Lett., 2007, 7, (6), pp 1591–1597

Gold Nanorods Coated with Multilayer Polyelectrolyte as Contrast Agents for Multimodal Imaging

Gold nanorods coated with multilayer polyelectrolyte is reported as a biocompatible optical probe with capability for dark-field imaging and for electron microscopy of cancer cells. Transferrin (Tf) was conjugated to the polyelectrolyte-coated nanorods for targeted in vitro delivery to cancer cells. Dark-field imaging was used to confirm the receptor-mediated uptake of nanorods into HeLa cells, which is known to overexpress the transferrin receptor (TfR). Minimal uptake was observed with untargeted nanorods. Electron microscopy was used to confirm that the intracellular uptake of the nanorods predominantly occurred via the Tf-TfR interaction and the nanorods localized in vesicular structures such as endosomes.

 
Hong Ding, Ken-Tye Yong, Indrajit Roy, Haridas E. Pudavar, Wing Cheung Law, Earl J. Bergey, and Paras N. Prasad

J. Phys. Chem. C, 111 (34), 12552 -12557, 2007. 10.1021

Optical coherence tomography with plasmon resonant nanorods of gold

We explored plasmon resonant nanorods of gold as a contrast agent for optical coherence tomography (OCT). Nanorod suspensions were generated through wet chemical synthesis and characterized with spectrophotometry, transmission electron microscopy, and OCT. Polyacrylamide-based phantoms were generated with appropriate scattering and anisotropy coefficients (30 cm−1 and 0.89, respectively) to image distribution of the contrast agent in an environment similar to that of tissue. The observed signal was dependent on whether the plasmon resonance peak overlapped the source bandwidth of the OCT, confirming the resonant character of enhancement. Gold nanorods with plasmon resonance wavelengths overlapping the OCT source yielded a signal-to-background ratio of 4.5 dB, relative to the tissue phantom. Strategies for OCT imaging with nanorods are discussed.

Timothy S. Troutman, Jennifer K. Barton, and Marek Romanowski

Optics Letters, Vol. 32, Issue 11, pp. 1438-1440

IN-VIVO Developments

Controlling the Cellular Uptake of Gold Nanorods

Gold nanorods coated with cetyltrimethylammonium bromide (CTAB, a cationic micellar surfactant used in nanorod synthesis, were rapidly and irreversibly internalized by KB cells via a nonspecific uptake mechanism. Internalized nanorods near the cell surface were monitored by two-photon luminescence (TPL) microscopy and observed to migrate toward the nucleus with a quadratic rate of diffusion. The internalized nanorods were not excreted but formed permanent aggregates within the cells, which remained healthy and grew to confluence over a 5-day period. Nonspecific nanorod uptake could be greatly reduced by displacing the CTAB surfactant layer with chemisorptive surfactants, particularly by the conjugation of poly(ethylene glycol) chains onto nanorods using in situ dithiocarbamate formation.

Terry B. Huff, Matthew N. Hansen, Yan Zhao, Ji-Xin Cheng, and Alexander Wei

Langmuir 2007, 23, 1596-1599

http://www.chem.purdue.edu/awei/publications/Wei43.pdf

PEG-modified gold nanorods with a stealth character for in vivo applications

Gold nanorods prepared in hexadecyltrimethylammonium bromide (CTAB) solution are expected to provide novel materials for photothermal therapy and photo-controlled drug delivery systems. Since gold nanorods stabilized with CTAB show strong cytotoxicity, we developed a technique to modify these with polyethyleneglycol (PEG) for medical applications. PEG-modification was achieved by adding mPEG-SH in the CTAB solution, then, excess CTAB was removed by dialysis. PEG-modified gold nanoparticles showed a nearly neutral surface, and had little cytotoxicity in vitro. Following intravenous injection into mice, 54% of injected PEG-modified gold nanoparticles were found in blood at 0.5 h after intravenous injection, whereas most of gold was detected in the liver in the case of original gold nanorods stabilized with CTAB.
 

Takuro Niidome , Masato Yamagata , Yuri Okamoto , Yasuyuki Akiyama , Hironobu Takahashi , Takahito Kawano , Yoshiki Katayama , Yasuro Niidome
 

OPTICAL FILTERS, POLARIZERS, AND NON-LINEAR OPTICS

Optical properties of nanometer-sized gold spheres and rods embedded
in anodic alumina matrices

This letter discusses theoretical studies of optical properties of gold nanospheres and nanorods with various aspect ratios; these are embedded in a porous anodic alumina matrix. The nanoparticles have potential applications in optical filters and sensors. In recent years, the interaction of light at metal/dielectric interfaces that leads to the formation of surface plasmon waves at specific frequencies has been the focus of intense research. The structures of interest for plasmonics are small metallic particles, wires, rods, and thin films that act as dipole oscillators and whose plasmon frequencies are in or near the visible spectral range. The interesting cases are usually those in which the plasmon lines incur minimal interference from interband optical transitions. In these cases, the surface plasmon resonances are usually dependent on the size, shape, and degree of particle-to-particle coupling; furthermore, they are also dependent on the dielectric properties of the metal from which the nanoparticles are made, and the dielectric properties of the matrix into which the nanoparticles are embedded.

V. G. Stolerua and E. Toweb
 

APPLIED PHYSICS LETTERS VOLUME 85, NUMBER 22 29 NOVEMBER 2004

http://www.mseg.udel.edu/images/projects/Stoleru/apl_85_5152.pdf

Optical Control and Patterning of Gold-Nanorod-Poly(vinyl alcohol) Nanocomposite Films

Gold nanorods with well-defined aspect ratios are homogeneously incorporated within poly(vinyl alcohol) thin films and subsequently aligned by heating and stretching the nanocomposite films.  The spatial alignment of the nanorods is directly proved using transmission electron microscopy.  The polarization-dependent optical response of the rods is measured and compared with a dipole model.  Excellent agreement is found.  Additionally, irradiation of the film with nanosecond laser pulses (1064 nm) leads to selective reshaping of the nanorods into nanospheres, and we demonstrate that this effect can be used to micropattern optical structures into the films.

Jorge Perez-Juste, Benito Rodriguez-Gonzalez, Paul Mulvaney, and Luis M. Liz-Marzan

Adv. Funct. Materials 2005, 15, 1065-1071

Spectrally-selective Gold Nanorod Coatings for Window Glass

The unique optical properties of gold nanorods, which exhibit tuneable absorption as a function of their aspect ratio, suggest that they might have potential applications in coatings for solar control on windows. Here we explore the properties of coatings produced by attaching gold nanorods to the surface of glass. Such coatings can attenuate solar radiation effectively, even at very low gold contents, but the figure-of-merit, Tvis/Tsol, of our experimental coatings was close to unity, indicating that they are not spectrally selective, However, calculations are presented to show how coatings comprised of a blend of rods with aspect ratios of greater than 3 can produce coatings with Tvis/Tsol of up to at least 1.4. The maximum value possible for perfectly spectrally-selective coating in sunlight is 2.08. Unfortunately, the practical realization of such coatings requires the further development of reliable methods to scale up the production of gold nanorods of longer aspect ratios.

Xu, X.; Gibbons, T.H.; Cortie, M.B.

Gold Bulletin, Volume 39, Number 4, December 2006 , pp. 156-165(10)

Second harmonic generation from resonantly excited arrays of gold nanoparticles

We show that second harmonic generation from lithographically prepared arrays of symmetric gold nanorods can be increased by two orders of magnitude by choosing the nanoparticle size to be resonant with the 800-nm wavelength of the 50-fs pump laser. The angular variation of the second-harmonic yield, which is defined by the pitch of the nanorod array, can be predicted using standard diffraction theory. This in turn makes it possible to bound approximately the relative contributions of dipole and quadrupole oscillations to the total second-harmonic yield; the two contributions appear to be of similar magnitude. Resonant ultrafast irradiation also changes the nanorod morphology, apparently due to surface melting and refreezing. At higher fluence, the intensity dependence of the second-harmonic yield changes from quadratic to cubic, an indication that the reshaping influences the mechanism of second-harmonic generation.

 
McMahon, M.D.; Ferrara, D.; Bowie, C.T.; Lopez, R.; Haglund Jr., R.F.

Applied Physics B, Volume 87, Number 2, April 2007 , pp. 259-265(7)

Light propagation in nanorod arrays

We study the propagation of TM- and TE-polarized light in two-dimensional arrays of silver nanorods of various diameters in a gelatin background. We calculate the transmittance, reflectance and absorption of arranged and disordered nanorod arrays and compare the exact numerical results with the predictions of the Maxwell–Garnett effective-medium theory. We show that interactions between nanorods, multipole contributions and formations of photonic gaps affect strongly the transmittance spectra that cannot be accounted for in terms of the conventional effective-medium theory. We also demonstrate and explain the degradation of the transmittance in arrays with randomly located rods as well as the weak influence of their fluctuating diameter. For TM modes we outline the importance of the skin effect, which causes the full reflection of the incoming light. We then illustrate the possibility of using periodic arrays of nanorods as high-quality polarizers.

A I Rahachou and I V Zozoulenko

DIAGNOSTICS

Nanoparticles in biomolecular detection

The use of nanoparticles as labels in biomolecular detection in place of conventional molecular fluorophores has led to improvements in sensitivity, selectivity, and multiplexing capacity. Nevertheless, further simplification is needed to take these technologies from the laboratory to point of care. Here, we summarize the latest developments in the use of nanoparticles as labels, especially in bioaffinity sensors for the detection of nucleic acids and proteins.

Natalia C. Tansil and Zhigiang Gao

Nanotoday Feb 2006

Comparing the influence of gold nanorods and -discs on the spontaneous decay rate of Eu-chelate dye
 

Nanometre-sized metal structures support localized surface plasmons associated with the collective oscillations of conduction band electrons. These modes can give rise to a drastic enhancement of local electromagnetic fields close to the surface of the structures. As a consequence, the fluorescence properties of molecules in that near field zone become strongly modified. In this paper, we investigate the modifications of the de-excitation processes in Eu-chelate dye for various nanoparticle sizes and shapes. By this coupling, in the electronic de-excitation process the corresponding radiative and non-radiative rates can be enhanced by orders of magnitude with respect to the free-space case. When the plasmon resonance overlaps well with the molecule's fluorescence emission frequency the interacting molecules show a dramatically shortened fluorescence lifetime but an enhanced signal amplitude. This is a valuable mechanism for new labelling techniques in biosciences and for modifications of OLED emission properties.


Reil, Frank; Gerber, Sebastian; Krenn, Joachim R.; Leitner, Alfred

Journal of Optics A: Pure and Applied Optics, Volume 9, Number 9, September 2007 , pp. S437-S442(1)

Light scattering from gold nanorods: tracking material deformation

We demonstrate the use of optical patterns, produced by resonant Rayleigh scattering from gold nanorods, as markers by which local deformations can be measured using image correlation techniques. While the use of optical data, in this case from dark-field microscopy, to generate deformational field information (displacements and strains) is not new, the use of the light scattered from gold nanorods as the correlated pattern is new, and has the potential to enable smaller scale measurements even over large deformations. We find excellent agreement between the measured and theoretical deformation and strain fields for two sample polymers with gold nanorod markers. The gold nanorod surface can be modified to make biocompatible nanomaterials, which will be useful for examining mechanical effects in biological tissue.

Christopher J Orendorff et al

2005 Nanotechnology 16 2601-2605  

http://www.iop.org/EJ/abstract/0957-4484/16/11/022

Hybrid Microgels Photoresponsive in the Near-Infrared Spectral Range

We report for the first time a photothermally responsive composite material based on polymer microgel particles doped with gold nanorods. We used the dependence of the longitudinal surface plasmon of the gold nanorods on their aspect ratio to synthesize nanoparticles with strong absorption in the near-IR spectral range (in the "water window"). The nanoparticles were incorporated in the interior of temperature-responsive poly(N-isopropylacrylamide-acrylic acid) microgels. Upon irradiation at = 810 nm, hybrid microgel particles doped with Au nanorods underwent a strong deswelling phase transition. These photothermally responsive microgels can be used to carry and release small molecules (e.g., small protein molecules and drugs).

Ivan Gorelikov, Lora M. Field, and Eugenia Kumacheva

J. Am. Chem. Soc., 126 (49), 15938 -15939, 2004

SENSORS

Pushing the Limits of Mercury Sensors with Gold Nanorods
 

The method presented here provides a direct way to determine mercury in tap water samples at the parts-per-trillion level. Its outstanding selectivity and sensitivity results from the well-known amalgamation process that occurs between mercury and gold. The entire procedure takes less than 10 minutes. No sample separation and/or sample pre-concentration is required. The only step prior to mercury determination consists of mixing the water sample with a gold nanorod solution in sodium borohydride. The analytical figures of merit demonstrate precise and accurate analysis at the parts-per-trillion level. The limit of detection (6.6x10-13 g.L-1) shows excellent potential for monitoring ultra-low levels of mercury in water samples.

F.E. Hernandez, M. Rexand and A.D. Campiglia

Anal. Chem., 78 (2), 445 -451, 2006

Imaging and Manipulation of Gold Nanorods with an Atomic Force Microscope

Designed fabrication of nanostructures requires progress on a number of fronts in research and development. The ability to synthesize, deposit, and position nanometer scale materials is important for the development of this technology. We report here on studies of deposition and manipulation of electrochemically prepared, micelle-capped Au nanorods deposited on silicon dioxide (SiO2) surfaces. A thiol-terminated silane (3-mercaptopropylmethyldimethoxysilane, MPMDMS) was used as an active interface for gold nanorod assembly. A scanning force microscope (SFM) was used to image and manipulate individual Au nanorods. It was found that mechanical movement of the rods depends on the location of the pushing point along the rod.

Shuchen Hsieh, Sheffer Meltzer, C. R. Chris Wang, Aristides A. G. Requicha, Mark E. Thompson, and Bruce E. Koel