Developments in Gold Nanoparticles and Cancer Therapy

Catalyst Volume 9

Abstract

Nanotechnology has recently produced several breakthroughs in localized cancer therapy. Specifically, directing the accumulation of gold nanoparticles (GNPs) in cancerous tissue enables the targeted release of cytotoxic drugs and enhances the efficacy of established cancer therapy methods. This article will give a basic overview of the structure and design of GNPs, the role of GNPs in drug delivery and localized cancer therapy, and the challenges in developing and using GNPs for cancer treatment.

Introduction

Chemotherapy is currently the most broadly utilized method of treatment for most subtypes of cancer. However, cytotoxic chemotherapy drugs are limited by their lack of specificity; chemotherapeutic agents target all of the body’s most actively dividing cells, giving rise to a number of dangerous side effects.¹ GNPs have recently attracted interest due to their ability to act as localized cancer treatments—they offer a non-cytotoxic, versatile, specific targeting mechanism for cancer treatment and a high binding affinity for a wide variety of organic molecules.² Researchers have demonstrated the ability to chemically modify the surfaces of GNPs to induce binding to specific pharmaceutical agents, biomacromolecules, and malignant cell tissues. This allows GNPs to deliver therapeutic agents at tumor sites more precisely than standard intravenous chemotherapy can. GNPs also increase the efficiency of established cancer therapy methods, such as hyperthermia.³ This article will briefly cover the design and characteristics of GNPs, and then outline both the roles of GNPs in cancer therapy and the challenges in implementing GNP-based treatment options.

Design and Characteristics of Gold Nanoparticles

Nanoparticle Structure

To date, gold nanoparticles have been developed in several shapes and sizes.⁴ Although GNPs have also successfully been synthesized as rods, triangles, and hexagons, spherical GNPs have been demonstrated to be one of the most biocompatible nanoparticle models. GNP shape affects accumulation behavior in cells.⁴ A study by Tian et. al. found that hexagonal GNPs produced a greater rate of vesicular aggregation than both spherical and triangular GNPs.

Differences in GNP shape also cause variation in surface area and volume, which affects cellular uptake, biocompatibility, and therapeutic efficiency.⁴ For example, GNPs with greater surface area or more vertices possess enhanced cell binding capabilities but also heightened cell toxicity. Clearly, GNP nanoparticles must be designed with respect to their intended function.

Nanoparticle Surface Modification

In order to target specific cells or tissues, GNPs must undergo a ligand attachment process known as surface modification. The types of ligand particles attached to a GNP affect its overall behavior. For example, ligand particles consisting of inert molecular chains can stabilize nanoparticles against inefficient aggregation.⁵ Polyethylene glycol (PEG) is a hydrocarbon chain that stabilizes GNPs by repelling other molecules using steric effects; incoming molecules are unable to penetrate the PEG-modified surface of the GNPs.⁵ Certain ligand sequences can enable a GNP to strongly bind to a target molecule by molecular recognition, which is determined by geometric matching of the surfaces of the two molecules.⁵

Tumor cells often express more cell surface receptors than normal cells; targeting these receptors for drug delivery increases drug accumulation and therapeutic efficacy.⁶ However, the receptors on the surface of tumor cells must be exclusive to cancerous cells in order to optimize nanoparticle and drug targeting. For example, most tumor cells have integrin receptors.⁷ To target these residues, the surfaces of the therapeutic GNPs can be functionalized with the arginine-glycine-aspartic acid (RGD) sequence, which binds to key members within the integrin family.⁸ Successful targeting can lead to endocytosis and intracellular release of the therapeutic elements that the GNPs carry.

An important factor of GNP therapy is the efficient targeting and release of remedial agents at the designated cancerous site. There are two types of GNP targeting: passive and active. In passive targeting, nanoparticles accumulate at a specific site by physicochemical factors (e.g. size, molecular weight, and shape), extravasation, or pharmacological factors. Release can be triggered by internal factors such as pH changes or external stimuli such as application of light.² In active targeting, ligand molecules attached to the surface of a GNP render it capable of effectively delivering pharmaceutical agents and large biomacromolecules to specific cells in the body.

Gold Nanoparticles in Localized Cancer Therapy

Hyperthermia

Hyperthermia is a localized cancer therapy in which cancerous tissue is exposed to high temperatures to induce cell death. Placing gold nanoparticles at the site of therapy can improve the efficiency and effectiveness of hyperthermia, leading to lower levels of tumor growth. GNPs aggregated at cancerous tissues allow intense, localized increases in temperature that better induce cell death. In one study on mice, breast tumor tissue containing aggregated GNPs experienced a temperature increase 28°C higher than control breast tumor tissue when subjected to laser excitation.⁹ While the control tissue had recurring cancerous growth, the introduction of GNPs significantly increased the therapeutic temperature of the tumors and permanently damaged the cancerous tissue.

Organelle Targeting

GNPs are also capable of specifically targeting malfunctioning organelles in tumor cells, such as nuclei or mitochondria. The nucleus is an important target in localized cancer therapy since it controls the processes of cell growth, proliferation, and apoptosis, which are commonly defective in tumor cells. Accumulation of GNPs inside nuclei can disrupt faulty nuclear processes and eventually induce cell apoptosis. The structure of the GNP used to target the nucleus determines the final effect. For example, small spherical and “nanoflower”-shaped GNPs compromise nuclear functioning, but large GNPs do not.¹⁰

Dysfunctional mitochondria are also valuable targets in localized therapy as they control the energy supply of tumor cells and are key regulators of their apoptotic pathways.¹⁰ Specific organelle targeting causes internal cell damage to cancerous tissue only, sparing normal tissue from the damaging effects of therapeutic agents. This makes nuclear and mitochondrial targeting a desirable treatment option that merits further investigation.

Challenges of Gold Nanoparticles in Localized Cancer Therapy

Cellular Uptake

Significant difficulties have been encountered in engineering a viable method of cellular GNP uptake. Notably, GNPs must not only bind to a given cancer cell’s surface and undergo endocytosis into the cell, but they must also evade endosomes and lysosomes.¹⁰ These obstacles are present regardless of whether the GNPs are engineered to target specific organelles or release therapeutic agents inside cancerous cells. Recent research has demonstrated that GNPs can avoid digestion by being functionalized with certain surface groups, such as polyethylenimine, that allow them to escape endosomes and lysosomes.¹⁰

Toxic Effects on Local Tissue

The cytotoxic effects of GNPs on local cells and tissues remain poorly understood.¹¹ However, recent research developments have revealed a relationship between the shapes and sizes of GNPs and their cell toxicities. Larger GNPs have been found to be more cytotoxic than smaller ones.¹² Gold nanospheres were lethal at lower concentrations, while gold nanostars were less toxic.¹³ While different shapes and sizes of GNPs can be beneficial in various localized cancer therapies, GNPs must be optimized on an application-by-application basis with regard to their toxicity level.

Conclusion

Gold nanoparticles have emerged as viable agents for cancer therapy. GNPs are effective in targeting malignant cells specifically, making them less toxic to normal cells than traditional cancer therapies. By modifying their surfaces with different chemical groups, scientists can engineer GNPs to accumulate at specific tumor sites. The shape and size of a GNP also affect its behavior during targeting, accumulation, and cellular endocytosis. After accumulation, GNPs may be used to enhance the efficacy of established cancer therapies such as hyperthermia. Alternatively, GNPs can deliver chemotherapy drugs to tumor cells internally or target specific organelles inside the cell, such as the nucleus and the mitochondria.

Although some research has shown that GNPs themselves do not produce acute cytotoxicity in cells, other research has indicated that nanoparticle concentration, shape, and size may all affect cytotoxicity. Therefore, nanoparticle design should be optimized to increase cancerous cell death but limit cytotoxicity in nearby normal cells.

References

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Nomming on Nanotechnology: The Presence of Nanoparticles in Food and Food Packaging

Catalyst Volume 9

Nanotechnology is found in a variety of sectors—drug administration, water filtration, and solar technology, to name a few—but what you may not know is that nanotechnology could have been in your last meal.

Over the last ten years, the food industry has been utilizing nanotechnology in a multitude of ways.¹ Nanoparticles can increase opaqueness of food coloring, make white foods appear whiter, and even prevent ingredients from clumping together.¹ Packaging companies now utilize nano-sized clay pieces to make bottles that are less likely to break and better able to retain carbonation.² Though nanotechnology has proven to be useful to the food industry, some items that contain nanoparticles have not undergone any safety testing or labeling. As more consumers learn about nanotechnology’s presence in food, many are asking whether it is safe.

Since the use of nanotechnology is still relatively new to the food industry, many countries are still developing regulations and testing requirements. The FDA, for example, currently requires food companies that utilize nanotechnology to provide proof that their products won’t harm consumers, but does not require specific tests proving that the actual nanotechnology used in the products is safe.² This oversight is problematic because while previous studies have shown that direct contact with certain nanoparticles can be harmful for the lungs and brain, much is still unknown about the effects of most nanoparticles. Currently, it is also unclear if nanoparticles in packaging can be transferred to the food products themselves. With so many uncertainties, an activist group centered in Washington, D.C. called Friends of the Earth is advocating for a ban on all use of nanotechnology in the food industry.²

However, the situation may not require such drastic measures. The results of a study last year published in the Journal of Agricultural Economics show that the majority of consumers would not mind the presence of nanotechnology in food if it makes the food more nutritious or safe.³ For example, one of the applications of nanotechnology within the food sector focuses on nanosensors, which reveal the presence of trace contaminants or other unwanted microbes.⁵ Additionally, nanomaterials could be used to make more impermeable packaging that could protect food from UV radiation.⁵

Nanotechnology could also be applied to water purification, nutrient delivery, and fortification of vitamins and minerals.⁵ Water filters that utilize nanotechnology incorporate carbon nanotubes and alumina fibers into their structure, which allows microscopic pieces of sediment and contaminants to be removed from the water.⁶ Additionally, nanosensors made using titanium oxide nanowires, which can be functionalized to change color when they come into contact with certain contaminants, can help detect what kind of sediment is being removed.6 Encapsulating nutrients on the nanoscale-level, especially in lipid or polymer-based nanoparticles, increases their absorption and circulation within the body.⁷ Encapsulating vitamins and minerals within nanoparticles slows their release from food, causing absorption to occur at the most optimal part of digestion.⁴ Coatings containing nano-sized nutrients are also being applied to foods to increase their nutritional value.⁷ Therefore, there are many useful applications of nanoparticles that consumers have already shown to support.

While testing and research is an ongoing process, nanotechnology is already making food safer and healthier for consumers. The FDA is currently studying the efficacy of nanotechnology in food under the 2013 Nanotechnology Regulatory Science Research Plan. Though the study has not yet been completed, the FDA has stated that in the interim, it “supports innovation and the safe use of nanotechnology in FDA-regulated products under appropriate and balanced regulatory oversight.”^8,9 As nanotechnology becomes commonplace, consumers can also expect to see an increase in the application of nanotechnology in food and food packaging in the near future.

References

1. Ortiz, C. Wait, There's Nanotech in My Food? http://www.popularmechanics.com/science/health/a12790/wait-theres-nanotechnology-in-my-food-16510737/ (accessed November 9, 2015).
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Nano-Materials with Giga Impact

Catalyst Volume 9

What material is so diverse that it has applications in everything from improving human lives to protecting the earth? Few materials are capable of both treating prolific diseases like diabetes and creating batteries that last orders of magnitude longer than industry standards. None are as thin, lightweight, and inexpensive as carbon nanotubes.

Carbon nanotubes are molecular cylinders made entirely of carbon atoms, which form a hollow tube just a few nanometers thick, as illustrated in Figure 1. For perspective, a nanometer is one ten-thousandth the width of a human hair.¹ The first multi-walled nanotubes (MWNTs) were discovered by L. V. Radushkevich and V. M. Lukyanovich of Russia in 1951.² Morinobu Endo first discovered single-walled nanotubes (SWNTs) in 1976, although the discovery is commonly attributed to Sumio Iijima at NEC of Japan in 1991.^3,4

Since their discovery, nanotubes have been the subject of extensive research by universities and national labs for the variety of applications in which they can be used. Carbon nanotubes have proven to be an amazing material, with properties that surpass those of existing alternatives such as platinum, stainless steel, and lithium-ion cathodes. Because of their unique structure, carbon nanotubes are revolutionizing the fields of energy, healthcare, and the environment.

Energy

One of the foremost applications of carbon nanotubes is in energy. Researchers at the Los Alamos National Laboratory have demonstrated that carbon nanotubes doped with nitrogen can be used to create a chemical catalyst. The process of doping involves substitution of one type of atom for another; in this case, carbon atoms were substituted with nitrogen. The synthesized catalyst can be used in lithium-air batteries which can hold a charge 10 times greater than that of a lithium-ion battery. A key parameter in the battery’s operation is the Oxygen Reduction Reaction (ORR) activity, which is a measure of a chemical species’ ability to gain electrons. The ORR activity of the nitrogen-doped material complex is not only the highest of any non-precious metal catalyst in alkaline media, but also higher than that of precious metals such as platinum.⁵

In another major development, Dr. James Tour of Rice University has created a graphene-carbon nanotube complex upon which a “forest” of vertical nanotubes can be grown. This base of graphene is a single, flat sheet of carbon atoms ‒ essentially a carbon nanotube “unrolled.” The ratio of height-to-base in this complex is equivalent to that of a house on a standard-sized plot of land extending into space.⁶ The graphene and nanotubes are joined at their interface by heptagonal carbon rings, allowing the structure to have an enormous surface area of 2000 m² per gram and serve as a high potential storage mechanism in fast supercapacitors.⁷

Healthcare

Carbon nanotubes also show immense promise in the field of healthcare. Take Michael Strano of MIT, who has developed a sensor composed of nanotubes embedded in an injectable gel that can detect several molecules. Notably, it can detect nitrous oxide, an indicator of inflammation, and blood glucose levels, which diabetics must continuously monitor. The sensors take advantage of carbon nanotubes’ natural fluorescent properties; when these tubes are complexed with a molecule that then binds to a specific target, their fluorescence will increase or decrease.⁸

Perhaps the most important potential application for carbon nanotubes in healthcare lies in their cancer-fighting applications. In the human cell, there is a family of genes called HER2 that is responsible for the regulation of growth and proliferation of cells. Normal cells have two copies of this family, but 20-25% of breast cancer cells have three or more copies, resulting in quickly-growing tumor cells. Approximately 40,000 U.S. women are diagnosed every year with this type of breast cancer. Fortunately, Huixin He of Rutgers University and Yan Xiao of the National Institute of Standards and Technology have found that they can attach an anti-HER2 antibody to carbon nanotubes to kill these cells, as shown in Figure 2. Once inserted into the body, a near-infrared light at a wavelength of 785 nm can be reflected off the antibody-nanotube complex, indicating where tumor cells are present. The wavelength then increases to 808 nm, at which point the nanotubes absorb the light and vibrate to release enough heat to kill any attached HER2 tumor cells. This process has shown a near 100% success rate and leaves normal cells unharmed.⁹

Environment

Carbon nanotube technology also has environmental applications. Hui Ying Yang from Singapore has developed a water-purification membrane made of plasma-treated carbon nanotubes which can be integrated into portable, rechargeable, and inexpensive purification devices the size of a teapot. These new purifications devices are ideal for developing countries and remote locations, where large industrial purification plants would be too energy- and labor-intensive. Unlike other portable devices, this rechargeable device utilizes a membrane system that does not require a continuous power source, does not rely on thermal processes or reverse osmosis, and can filter for organic contaminants found in brine water - the most common water supply in these developing and rural areas.¹⁰

Oil spills may no longer be such devastating natural disasters either. Bobby Sumpter of the Oak Ridge National Laboratory demonstrated that doping carbon nanotubes with boron atoms alters the curvature of the tubes. Forty-five degree angles form, leading to a sponge-like structure of nanotubes. As these tubes are made of carbon, they attract hydrocarbons and repel water due to their hydrophobic properties, allowing the tubes to absorb up to 100 times their weight in oil. Additionally, these tubes can be reused, as burning or squeezing them was shown to cause no damage. Sumpter and his team used an iron catalyst in the growth process of the carbon nanotubes, enabling a magnet to easily control or remove the tubes from an oil cleanup scenario.¹¹

Carbon nanotubes provide an incredible opportunity to impact areas of great importance to human life - energy, healthcare, and environmental protection. The results of carbon nanotube research in these areas demonstrate the remarkable properties of this versatile and effective material. Further studies may soon lead to their everyday appearance in our lives, whether in purifying water, fighting cancer, or even making the earth a better, cleaner place for everyone. Big impacts can certainly come in small packages.

References

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3. Ecklund, P.; et al. Ugliengo, P. In International Assessment of Carbon Nanotube Manufacturing and Applications, Proceedings of the World Technology Evaluation Center, Inc. Baltimore, MD, June, 2007.
4. Nanogloss. The History of Carbon Nanotubes – Who Invented the Nanotube? http://nanogloss.com/nanotubes/the-history-of-carbon-nanotubes-who-invented-the-nanotube/#axzz3mtharE9D (accessed Sep 14, 2015).
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9. Understanding Nano. Combining Nanotubes and Antibodies for Breast Cancer 'Search and Destroy' Missions. http://www.understandingnano.com/nanomedicine-nanotubes-breast-cancer.html (accessed Sep 22, 2015).
10. Understanding Nano. Plasma-treated nano filters help purify world water supply. http://www.understandingnano.com/nanotube-membranes-water-purification.html (accessed Sep 24, 2015).
11. Sumpter, B. et al. Covalently bonded three-dimensional carbon nanotube solids via boron induced nanojunctions. Nature [Online] 2012, doi: 10.1038/srep00363. http://www.nature.com/articles/srep00363 (accessed Mar 06, 2016).
12.  Huixin, H. et al. Anti-HER2 IgY antibody-functionalized single-walled carbon nanotubes for detection and selective destruction of breast cancer cells. BMC Cancer 2009, 9, 351.