sagawa, shiori - COSMOS

Structure, Synthesis, Functions, Applications, and
Modification of Gold Nanoshells
COSMOS 2011
Cluster 8: Chemistry of Life
Shiori Sagawa

Abstract
Gold nanoshells are dielectric cores surrounded by thin gold layers. They are well known
for their unique optical properties, explained by plasmon hybridization theory as well as quantum
mechanics calculations. Their optical attributes are applied in a variety of aspects, including
visual enhancement and cancer therapy. Not only can they can absorb and scatter light of great
intensities, but the wavelengths absorbed and scattered by gold nanoshells range extensively
from visible to far infrared. Furthermore, the scattered light can have controlled wavelengths.
Among many applications, this paper focuses on the use of nanoshells in cancer diagnosis and
therapy, including imaging enhancement for early detection, photo-thermal ablation, and
inhibition of pro-angiogenic growth factor. In addition to properties and applications of gold
nanoshells, their structure, synthesis, and modification using gold-copper-64 alloys are
explained.
Background
Gold nanoshells, varying from 30nm to 120nm in diameter (Rasch, 2009), are
dielectric cores surrounded by thin, uniform layers of gold, giving rise to concentric spheres
(Brinson, 2008). As it can be inferred from their name, nanoshells are classified as a type of
nanomaterial because they are usually less than 100nm in diameter and their optical properties,
which they are mostly known for, arise from their nano-scale size.
Traditionally, gold nanoshells are assembled in the following process. To begin
with, oxide nanoparticles, such as silica, are functionalized with aminopropyltriethoxy or
methoxysilane to attach gold particles to the surface. After functionalization, gold nanoparticles
are bound to the surface. This is followed by reduction of Au 3+ (aq) → Au 0 (s) on the surface of the

nanoparticle. This process allows gold particles to merge and create a thin layer, giving rise to a
complete nanoshell structure (Brinson, 2008).
As previously stated, gold nanoshells have unique optical properties. Gold
nanoshells have the ability to absorb and scatter a great quantity of light in a relatively wide
range, varying from visible to far infrared (Brinson, 2008). The wavelength of the light can also
be controlled by modifying the layer to core ratio (Brinson, 2008), making the nanoshells very
practical. Although this optical attribute has been confirmed with quantum mechanics
calculations as shown in the study by E. Prodan and P. Nordlander (Prodan and Nordlander,
2003), the concept can also be explained by the plasmon hybridization model. In gold
nanoshells, both gold layers and cores exhibit plasmonic properties (Prodan, 2003), indicating
that they have oscillating electron clouds. Since each component contains plasmons and is close
to each other, plasmons interact (Prodan, 2003). As they interact, or “hybridize,” they produce 2
resonances (Prodan, 2003) shown in the picture below.
(Prodan, 2003)
The two resonances are symmetric or bonding plasmon, denoted as ω– in the picture above,
which is a lower energy state that responds strongly to incident light, and asymmetric or

antibonding plasmon, denoted as ω+ in the picture above, which is a higher energy state that
responds weakly to incident light (Prodan, 2003). Absorption and scattering of light causes
change in energy, which is exhibited as change in the state. Since layer-core ratio determines
how well plasmons interact, it determines the energy states of plasmonic resonances. Thus, the
wavelength of the absorbed and scattered light depends on the layer-core ratio, making gold
nanoshells tunable with respect to the relative sizes of the core and layer.
This unique feature of gold nanoshells is exploited in numerous applications, including
those in cancer therapy. One application is cancer imaging. With current methods, which involve
reflectance-based techniques, it is very difficult to detect early forms of cancer due to unclear
images caused by insufficient reflection by cancer cells (NCLT, 2008). To cope with this
weakness, gold nanoshells can be used as markers to enhance images. First, gold nanoshells are
attached specifically to cancer cells. This is achieved by attaching structures that bind to proteins
that are over-expressed in cancer cells, such as HER2 in breast cancer (NCLT, 2008). Then,
nanoshells scatter light, which is processed to derive the depth of the cancer tissue (NCLT,
2008). Since nanoshells scatter light of greater intensity compared to cancer cells, the image is
enhanced (NCLT, 2008). The small size of nanoshells in comparison to cancer tissues allows
them to accurately express the size and shape of cancer cells (NCLT, 2008). Furthermore, they
can achieve high quality images because a very large number of them cover the cancer tissue
(NCLT, 2008). Their tunable property also allows one to shine light of specific wavelength, near
infrared, which causes no harm to the human body (NCLT, 2008). This technique allows for
clearer images, leading to early detection of cancer, which is very significant for effective
treatment.

Another method in which the optical properties of gold nanoshells can be used in cancer
therapy is photo-thermal ablation, a process in which gold nanoshells bound to cancer cells are
used to turn laser into a significant quantity of heat, killing cancer cells (Lal, 2008). First, gold
nanoshells are dispatched specifically to cancer cells. This can be achieved by the process
described in the paragraph above or by only injecting nanoshells into the blood stream since new
blood vessels created by cancer cells are abnormal with large gaps, enhancing permeability and
retention, which eventually brings a great majority of nanoshells to cancer cells (Lal, 2008).
Next, near infrared light with wavelengths of 700nm to 1100 nm are directed to the area of
treatment (Lal, 2008). Near infrared light is most effective because it minimizes water absorption
and is most transmissive with respect to blood and tissue (Lal, 2008). When the light passes
through gold nanoshells, it causes plasmon resonance, in which nanoshells get excited and gain
energy. Since electrons prefer to be at a lower energy level, nanoshells release the gained energy
as heat, causing the temperature of a cancer cell to increase (NCLT, 2008). Within 4 to 6 minutes
of exposure to laser, 37.4 ± 6.6 °C increase, sufficient to ablate cancer cells, was observed (Lal,
2008), confirming efficiency.
The effectiveness of the photo-thermal ablation using nanoshells was shown by the study
of Surbhi Lal, Susan E. Clare, and Naomi J. Halas. In the study, mice were given one of the three
treatments: laser followed by gold nanoshells injection, laser followed by saline injection, and no
treatment (Lal, 2008). The results are shown in the figure below:

(Lal, 2008)
As shown above, there was a significant difference in tumor size; complete ablation was
observed in the treatment group while growth was observed on other groups (Lal, 2008). A
significant difference was observed in the survival rate as well (Lal, 2008), proving the
effectiveness of photo-thermal ablation. 100% survival rate in the treatment group (Lal, 2008)
also signifies that the treatment does not have immediate lethal side effects, showing that healthy
tissues are not lethally damaged.
Another property of gold nanoshells is the inhibition of pro-angiogenic growth factor,
also known as VEGF165, which causes abnormal growth, migration, and survival of cancer cells
(Patra, 2010). This property was exhibited experimentally; pro-angiogenic growth factor-induced

proliferation of human umbilical vein endothelial cells was inhibited in the presence of gold
nanoshells with FeCo cores. No inhibition was observed in VEGF165-induced growth in the
absence of gold nanoshells as well as in the non-VEGF165-induced growth in the presence of
gold nanoshells, which also indicated the non-toxicity of FeCo core gold nanoshells (Patra,
2010). Using this property, nanoshells can be used as an improved replacement for the toxic antiangiogenic
agents used today to halt the growth, migration, and survival of cancer cells (Patra,
2010).
Purpose
The purpose of the modification is to create improved nanoshells that can be used both to
detect and treat cancer.
Method and Discussion
In order to create improved nanoshells with applications in both diagnosis and therapy in
cancer, an alloy of gold and copper-64 is used as an outer layer, replacing pure gold. Copper-64
is a radioactive element, decaying via positron emission with a half-life of approximately 12.7
hours (Starkewolf, 2011). The radioactivity along with its plasmonic property allow this device
alone to conduct high-quality imaging as well as photo-thermal ablation.
Although gold-copper-64 nanoparticles do not currently exist, gold-copper nanoparticles
have been synthesized in many studies, including the study by Motl and co-workers (Motl,
2010). The synthesis involved a combination of HAuCl 4·3H 2 O and Cu(acac) 2 (Motl, 2010), so
synthesis of gold-copper-64 nanoparticles can be achieved by using Cu(acac) 2 with copper-64
when synthesizing nanoparticles. Then, using those gold-copper nanoparticles, nanoshells can be

synthesized using a process similar to that of gold nanoshells, which involves functionalization
of the shell, binding of nanoparticles, and reduction to merge the nanoparticles into a single layer
(Brinson, 2008).
Because copper-64 is a positron emitting radionuclide, the modified nanoshells can be
used as tracers in an imaging technique called positron emission tomography or PET
(Starkewolf, 2011), which creates images based on gamma rays produced in positron emitting
radionuclides (Pieterman, 2010). Nanoshells would be designed specifically to target the
cancerous cells by allowing nanoshells to bind to overly-expressed proteins in cancer tissues
(Pieterman, 2010). Since copper-64 has relatively short half-life and is a positron emitting
radionuclide (Starkewolf, 2011), PET can detect the gamma ray, creating images (Pieterman,
2010). PET can produce one of the highest resolution images today, which would allow for
earlier detection of cancer (Pieterman, 2010).
In addition to the radioactivity, plasmonic property is likely to be retained by goldcopper-64
nanoshells. First, both gold and copper are plasmonic elements (Motl, 2010). Since
alloys often retain the properties of pure metals, it is anticipated that the alloy would be
plasmonic as well. Secondly, in the study by Motl and co-workers, gold-copper nanoparticles
retained plasmonic properties (Motl, 2010), suggesting a high likelihood of the retention of the
property in nanoshells. Also observed in the study was a shift in the spectrum of light absorbed
and scattered toward lower energies (Motl, 2010). Even though the shift is highly probable in
nanoshells, a drastic effect is not expected since the shift in nanoparticles only consisted of
100nm or
in proportion (Motl, 2010), suggesting that it is likely that nanoshells can still be
tuned to near infrared, the least harmful and most effective type of light for cancer therapy. Thus,
it is expected that the shift would not be an issue. Although experiments are required to affirm

the retention as well as lack of drastic shift, the optical properties would allow gold-copper-64
nanoshells to be used in cancer therapy through photo-thermal ablation.
As discussed previously, the use of gold-copper-64 nanoshells would allow for the
execution of both cancer detection and therapy with one device, increasing efficiency. First,
nanoshells are dispatched specifically to cancer cells. Then, using PET, a high-quality image of
cancer cells can be obtained, allowing for an early diagnosis. Then, after imaging, lasers can be
applied to the area of interest so that nanoshells, which were used as PET tracers, can now be
used to practice photo-thermal ablation of cancer cells.
Conclusion
With early detection through enhanced imaging, photo-thermal ablation, and inhibition of
pro-angiogenic growth factor, gold nanoshells have great possibilities for cancer diagnosis and
therapy. In order to improve the efficiency and quality of the process, gold-copper-64 alloy was
used as a replacement for the gold outer layer, adding radioactivity while keeping the plasmonic
properties. The modification allows a single type of nanoparticle to achieve diagnosis as well as
therapy since gold-copper-64 nanoshell can be used in PET and photo-thermal ablation.
However, experiments are required to confirm the radioactivity and optical properties of goldcopper-64
nanoshells.
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