In Depth about Gold Nanoshells

Introduction

For thousands of years gold has been an important part of human civilization. Known since approximately 4000 B.C., gold was clearly prized and applied in ornamental decorations; roughly 1000 years later, gold was being used in fashionable jewelry. Soon, people began collecting gold for the aesthetic value and perceived worth of the metal. By 1500 B.C., gold was adopted as one of the world’s first currencies. In the United States, gold was not fully eliminated as a currency standard until 1971. The use of gold developed in other fields as well, finding promise in optics, electronics, and medicine. Some of the first recorded studies of using gold as a medical remedy came in 1927, when French researchers investigated colloidal gold, a solution of gold nanoparticles dispersed in a liquid, as a treatment for rheumatoid arthritis.¹ Today gold nanoparticles are being studied as a new method for fighting cancer.

Special gold nanoparticles called nanoshells are being investigated for uses in both imaging and destroying cancerous cells. Nanoshells can be engineered to target cancerous cells and at the same time designed to interact with specific wavelengths of light.² Depending upon the wavelength of incident light, nanoshells can either scatter or absorb light, creating applications as both a cancer imaging agent or therapeutic one. Several research groups have performed successful studies that prove nanoshells can be used to create high-resolution images of tumors as well as a precise treatment procedure that causes cell death in tumors. Currently researchers are awaiting FDA approval to begin clinical testing of these methods.³

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Gold Nanoshell Design

Gold has had a significant impact on the development of our culture, as well as some exciting and diverse uses. But why would we choose to use metals in our fight against cancer, and most of all, why gold?

Metals are a unique class of materials. One special attribute is the ability of metallic nanoparticles to strongly interact with electromagnetic waves (light, radio, x-ray, etc.). When electromagnetic waves, such as light, shine on a metallic nanoparticle, it can start an interaction known as surface plasmon resonance.⁴ During surface plasmon resonance, the electrons along the surface of the metallic nanoparticles are excited by the energy from the light and begin to oscillate. We are all familiar with resonance in many systems; it is the effect of maximum oscillation amplitude at particular frequency. You need to push a swing at a certain rate (frequency) to go as high as possible. Only at certain frequencies (notes) does a particular length of guitar string make an audible noise. Plasmons are quantized oscillations (waves) in the plasma (or electron gas) within a metal. These plasmons can oscillate very quicky and interact and even resonate with particular frequencies of light. Just as a length of guitar string is picked because it will resonate at a certain frequency, nanoshells can be made so that their surface plasmons will resonate at a certain frequency of light. Plasmon resonance is useful for fighting cancer because the increase in the magnitude of the oscillations effectively converts the incident light into heat and intensifies scattering effects.^{5, 6} In particular, gold and silver both display very strong surface plasmon resonance effects.⁷ Of these two metals, however, gold is far less dangerous to be used in the body.^{8, 9} The use of gold in medicine has been documented for over 50 years.¹⁰

So, not only does gold have useful physical properties, but it also has useful chemical properties that make it better for treating cancer than other potential materials. While the properties of gold are impressive and obviously important, it is really the structure of nanoshells that allow for progress in cancer treatment. What’s special about a nanoshell?

Nanoshells can come in many shapes and sizes, but all are composed of a core and a shell. The core is the interior part and the shell is the material coated around the core. In the case of a gold nanoshell the core is a ball of silica and the shell is a thin layer of gold. Gold nanoshells have similar properties to gold nanoparticles (plasmon resonance, scattering, etc.), but have the added benefit of being tunable to different wavelengths of light.¹¹ The human body only allows certain wavelengths of light to pass through the body; these wavelengths are outside the visible spectrum (colors we can see) and are near-infrared light. Gold nanoshells are tuned to these wavelengths of light so that they can trigger properties of nanoshells without opening the body.^6a

Gold nanoshells are also more efficient at converting EM waves to energy than nanoparticles. This is due to plasmon resonance along both the inner and outer surfaces of the shell, as opposed to a nanoparticle only having resonance along the outer surface.

Between the general structure of a nanoshell and using gold as a coating, scientists have been do some pretty amazing things. Specifically, they have been able to create drastic temperature differences at localized points in the body, sometimes causing a change as great as 35°C (95°F)!¹² While this is an amazing feat of modern science, producing these nanoshells can be quite tricky, and because they are being researched for use in medicine, it is especially important to control their production to ensure quality.

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Gold Nanoshells Fabrication

Over the past decade, nanoshells have been created with all sorts of dimensions, shapes, and sizes. Some look like balls, others resemble rods, and some are even shaped like eggs.¹³ Such particles may look and behave differently, but they are all made in a very similar way. The general process for fabricating nanoshells is:

1. Grow or obtain a nanoparticle sized dielectric core (such as spheres of silica, but they could be other similar compounds and different shapes).
2. Chemically treat the surface of the core to make it “sticky” and ready for growing gold from solution (this allows adding a gold shell to the core).
3. Grow gold “seed particles” on the surface of the core and then plate gold on top until a complete layer has formed (the seed particles will allow more gold to be coated on top to form a shell).¹⁴

While some of the more complicated nanoshell structures require additional steps for fabrication, almost all nanoshells share the above process. The process is very similar to creating paper-maché globes, where a balloon represents the core, and the paper strips represent the gold. It is easy to blow up the balloon (creating the core of a nanoshell), but not easy to start adding paper at first. However, once a few strips of paper have been successfully stuck to the balloon (the seed particles), it becomes easier and easier to add more paper (the coating gold).

Unfortunately, simply growing gold onto a core will not guarantee that the nanoshells are fit for our uses. There are many different factors to control and check before nanoshells can be efficiently used, including controlling shell thickness and adding surface coatings. Changing the shell thickness changes optical properties of the nanoshells. Adding surface coatings allows the nanoshells to target and interact with different things in the body.

The next step in creating viable nanoshells is to “tune” them to absorb specific wavelengths of light. Gold nanoshells have the property of absorbing a specific wavelength of light, but need to be tuned to absorb light in a more useful range. Tuning refers to the process of changing the dimensions of gold nanoshells to control the wavelength of light that is absorbed.¹⁵ Scientists are most interested in the ratio between the size of the gold layer and size of the inner core. Scientists have determined that this ratio determines what wavelength of light gets absorbed best. By having the ability to control this ratio, scientist can fabricate nanoshells that absorb ultraviolet, visible, or near infrared wavelengths of light.¹⁶

After creating the nanoparticle, researchers treat the nanoshells for a length of time with special chemicals to etch the shell size down in thickness. By doing this, the scientists make the surface of the nanoshell rough. By thinning and roughening the surface of the nanoshell, scientists change the absorbed wavelength of light from visible wavelengths into the near infrared, a spectrum of light which passes through the human body without causing any harm.^6b Controlling which wavelength of light is best absorbed is one of the most important features of nanoshells.

Tuning allows scientists to treat a batch of gold nanoshells and make them the dimensions they desire. Therefore they can take nanoshells of any size and bring them to the desirable dimensions. This allows scientists to make nanoshells faster because they can make them all the same size at the beginning and later tune them to their application. By changing the shell thickness, scientists are able to change the wavelength the nanoshells absorb to a more desirable one.^13a This is especially useful because now scientists can create the particles so that they react with what works best with the body.

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Gold Nanoshell Immunotargeting

Now that the gold nanoshells have been prepared, they need to find the cancer cells to connect to. Billions of gold nanoshells are injected into the blood stream and begin to travel through the body’s blood stream. Gold nanoshells are seen as foreign objects in the blood and will be targeted for removal. To help gold nanoshells navigate the blood stream, nanoshells are coated with poly(ethylene glycol), or PEG for short, which allows them to circulate the blood stream without being targeted for removal. This allows the nanoshells to travel in the bloodstream longer increasing the chance they come across cancer cells.^16a The biology of cancer cells also helps nanoshells find them.

Cancer cells grow faster than normal cells and because of it they are leaky and allow particles the size of the gold nanoshells to pass through them. The leakiness of the cancer cells require more blood to pass through them, so there is more chance that the nanoshells go their sooner.¹⁷ Because cancer cells grow faster than normal cells, cancer cells have more epidermal growth factor receptors (EGFR) than healthy cells.¹⁸ EGFR are on the surface of the cell and combine to things in the body that cause the cancer cell to grow. Nanoshells are coated with anitepidermal growth factor receptor, or anti-EGFR for short, which combine with the EGFR and bind the nanoshell to the cancer cell.¹⁹ Nanoshells will continue binding with the cancer cell until about 20 nanoshells are connected to each cancer cell.²⁰ At this point, the nanoshells are ready to start imaging and treating the cancer cells they are bound to.

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Gold Nanoshells Cancer Imaging

Early detection of cancer is often important for effective treatment. The best way to detect cancer early is to use effective imaging techniques to search for any potential dangers that might be developing in a patient. Unfortunately, current imaging methods are not clear enough to show the early signs of cancer and dangerous cell mutations that are required for doctors to identify problems. Current imaging methods use reflectance-based techniques similar to sonar and radar.²¹ These imaging methods all involve sending a signal into the body, and then wait for it to hit something and reflect back to where the signal began. Depending on how long it took the signal or how strong the signal was, the distance of the object causing the reflection is found.²² A significant problem with imaging methods today is that cancer cells do not reflect enough of the signal to be seen.^21a

One method that allows easier detection of cancer is to attach “markers” that target cancer cells. The markers outline or cover the cancer cell, showing both its size and shape. Markers are more reflective than the cancer cells, making the cells more noticeable than they otherwise are. Ideal markers are small, durable, biocompatible particles that only bind to the area of interest.²³ Gold nanoshells make excellent optical markers for cancer because they are small (on the nanoscale), inert (gold doesn’t react with the body’s biology), and can be fabricated to bind to cancer cells. It may seem strange to think that a nanoshell, which is too small to be seen with the human eye, can be used as an optical marker to show something much larger than them, yet their size, shape, and material give them unique optical properties.^2a Gold nanoshells are especially useful as biological markers because they can be tuned to scatter near-infrared light, which fits in the “water-window” of the body.²⁴

During their creation, gold nanoshells are made to be about 100x smaller than most cancer cells and coated with cell receptors that connect to cancer cells. When the nanoshells attach to the cancer cell, they bind to the outside of the cancer cell. Enough of the nanoshells will bind to a cancer cell that nanoshells will cover the cancer cell. Since the nanoshells are small and cover the cancer cell, imaging the nanoshells is just like imaging the cancer cell. Nanoshells are small enough to achieve a high quality image of the area they attach to. Also, nanoshells use their ability to redirect light to act as a reflector, allowing for a number of quick and efficient imaging techniques.

Due to their small size and dimensions, nanoshells have the ability to redirect light in many different directions, also known as scattering light. Nanoshells are tuned to scatter specific wavelengths of light when they are created. The scattered wavelength is determined by the size of the nanoshell and the intensity is enhanced due to the gold coating.²⁵ This property makes optical imaging of cancer cells effective. Sensors detect the brightness difference between the light that was sent out and the reflected light. From the change in brightness and the amount of time the light traveled, the depth of the nanoshell in the body can be determined.^25a The data is then formed into an image. Because the laser being used is a NIR laser, only the gold nanoshells reflect signal. This results in images with a high contrast between the cancerous and healthy tissue. Some specific imaging methods that use this process are Optical Coherence Tomography (OCT) and Reflectance Confocal Microscopy (RCM).

Imaging is useful because it allows the doctor to correctly determine which cells are healthy and which cells are cancerous. With the cancerous cells now identified, treatment can begin. The process that allows cancer cells to be imaged also allows cancer treatment. Fortunately, many of the properties that make nanoshells excellent markers also make them good agents for treating cancer.

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Gold Nanoshells Photo-thermal Ablation

Once the nanoshells are attached to the cancer cells, only laser light is needed to treat the cancer. Near infrared (NIR) light passes through the body and reaches the gold nanoshell.^11a The “tuned” gold nanoshells receives the NIR light and convert the light’s energy into heat, killing the cancer cells.^16b Nanoshells use surface plasmon resonance, or a wave-like excitation of electrons along the surface, to convert laser light into heat.^4a Because nanoshells are metallic on the outside and small in size, the laser light interacts with the shell, causing surface plasmon resonance. Electrons in the gold prefer to have low energy, so they give off any extra energy as heat to the surrounding environment, including the attached cancer cell.²⁶ Typically there are about 20 nanoshells attached to the cancer cell, working together to heat the cell.^20a This process causes the temperature of the cancer cell to increase 20°C to 35°C or 68°F to 95°F after 4-6 minutes of laser light exposure, causing the cell to almost double in temperature!^12a Nanoshells convert light to heat well enough that they can be used to heat up a space 1000 times larger than their size.²⁷ The transferred heat is strong enough to destroy the cancer cell. Healthy cells then consume the dead cancer cells through phagocytosis. When the process is done, only healthy cells remain and there are no traces of cancer.

The use of nanoshells to treat cancer has benefits over standard treatments today. Standard treatments such as chemotherapy, radiation therapy, and surgery are said to “destroy cancers cells with about as much precision as an atomic bomb.”^20b These treatments destroy cancer cells, but also many healthy cells in the process. Due to their small size, nanoshells have the ability to only heat up the attached cancer cell. This allows them to target and destroy cancer cells while minimizing the amount of damage done to healthy cells. Nanoshells also provide a less intrusive treatment option than traditional methods.²⁸ Once the nanoshells are injected into the blood stream and attach to the cancer cells, they are triggered from outside the body without any cutting or harmful radiation. The NIR light can pass harmlessly through most of the body and only interact with the nanoshells, causing them to heat up and destroy the cells they have attached to. However, if one component is missing, be it the NIR light, the nanoshells, or the cancer, nothing will happen.^16c

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Gold Nanoshells Extensions

Currently the use of gold nanoshells is restricted to lab settings. While the procedure is promising, it is not old enough or well studied enough to provide for clinical testing. However, proposals have been made to the FDA requesting approval for clinical trials of using gold nanoshells to image and ablate cancer.³

Gold nanoshells are not the only nanoscale-based cancer detection and treatments being investigated. Scientists across the world are using different kinds of nanoparticles to provide new imaging and cancer therapies. One of these alternative therapies uses iron nanoparticles to detect prostate cancer through combined use with MRI technology.^{29, 30} Other studies are investigating the use of gold nanoparticles (not nanoshells) to deliver anti-cancer drugs to specific cell sites.³¹ While the iron based prostate cancer detection method offers a more specific detection regimen, it does not provide a means to fight existing cancer, and immunotargeted nanoparticles run the risk of presenting anti-cancer drugs to healthy cells (something that is not desirable under any circumstance). No treatment is without cause for some concern, but certainly each new discovery offers promising contributions to the fight against cancer.

This research also lends itself to other applications outside of the realm of cancer. These applications include but are not limited to fusing tissue together without stitches³², providing new imaging techniques for cells and DNA³³, as well as acting as biomarkers for specific biological agents.³⁴

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Gold Nanoshells Conclusion

As mentioned in previous sections, as of 2007, gold nanoshells have not been tested in a clinical environment. However, they offer increasingly promising results in lab studies with no significant side effects. Gold nanoshells are fast becoming the forerunner of other nanomedicine technologies, and their success could provide medical professionals with some special tools to fight disease.

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