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GOLD NANOPARTICLES: A POSSIBLE CURE FOR PANCREATIC CANCER
Julia McKay, , Mena, 1:00, Madeleine Braun, ,Sanchez, 5:00, Erin Cannon , Budny, 10:00
Abstract- Pancreatic cancer is particularly problematic across the world due to its high resistance to chemotherapy and radiation and the late stage in which the cancer is often diagnosed. By the time that many people discover they have the disease it is often too late for surgical intervention. Gold nanoparticles (AuNPs) could be a potential solution to this dilemma. AuNPs are a form of targeted drug delivery that transport drugs to the main tumor and metastasis site. AuNPs have properties such as microscopic size, biocompatibility, and high surface reactivity that allow them to effectively inhibit tumor cell reproduction and growth. This technology is projected to improve drug reception efficiency while providing a less invasive treatment as compared to those currently available. While this technology is theorized to have several positive effects on those who face pancreatic cancer, there are also some challenges with the development of these AuNPs. As with any new technology, there are several obstacles that those leading the development are facing. This includes, the elimination of long term cytotoxicity within the cell that may be caused by the use of gold nanoparticles. Possible solutions to these challenges are being investigated with the help of animal and clinical experiments. The goal of these experiments is to create a sustainable treatment option that could improve the quality of life for those with pancreatic cancer.
Key Words- AuNPs, gold nanoparticles, nanotechnology, pancreatic cancer, targeted drug delivery, therapeutic devices
NANOPARTICLES: POSSIBLY REVOLUTIONIZING CANCER TREATMENT
Pancreatic cancer is the fourth leading cause of cancer deaths in America. “It continues to have a survival rate of less than five percent over five years, with a median survival of only six months” . Pancreatic cancer is an aggressive and elusive disease that is typically diagnosed in the later stages when it is too late for surgical intervention to remove the tumor . This disease is often
viewed as incurable and, for that reason many scientists have chosen to direct their efforts towards finding a new treatment method. Scientists and engineers are exploring different forms of targeted drug delivery as possible remedies. One that has much promise is gold nanoparticles (AuNPs). They have several advantageous properties that allow them to function well within the body without causing harm. Researchers hope that when gold nanoparticle development is complete, their implications will improve the quality of life for thousands of people across the globe.
WHAT IS TARGETED DRUG DELIVERY?
Targeted drug delivery is a method of transporting medication to a patient in a manner that increases the concentration of the substance in some parts of the body while limiting it in others. This allows for healthy cells to remain unaffected by the medication. The development of targeted drug delivery systems is a sustainable approach in both chemical and biological engineering to transporting drugs throughout the body. In this context sustainability is the consideration of the whole system, in which the process of drug delivery will take place rather than just focusing on the process itself. The main vector for delivering these drugs are forms of biological nanotechnology, including nanoparticles. These nanoparticles are being designed to combat the significant side effects of traditional drug delivery methods. Targeted drug delivery systems have proven, through in vitro and in vivo trials, to function effectively within the human body. The developers of these currently researched drug delivery systems have taken many factors into account that simulate the human body such as fluctuating pH, temperature, and other chemical interactions.
The nanodrug delivery systems are very integrated and therefore require many different specialists. For example, biologists, chemists, and engineers all work together to make the best quality system possible. Dr. David A. Giljohann, an adjunct professor of chemical and biological engineering at Northwestern University, participates in research related to controlled drug release systems. In his professional paper on gold nanoparticles for medical applications he explained, “when implementing a targeted release system, the following design criteria for the system must be taken into account: the drug properties, side-effects of the drugs, the route taken for the delivery of the drug, the targeted site, and the disease” . The main method for transporting the drug delivery agent into the body is oral ingestion. Once it is absorbed it can enter the circulatory system and travel to its destination. After the drug has reached its specified target the system has completed its task. The primary goal of targeted drug delivery is to improve the efficacy of drug delivery while reducing the side effects. The advanced drug delivery systems currently being developed could potentially meet both of these goals.
APPLICATION AND IMPACTS RELATING TO PANCREATIC CANCER
Cancer cells replicate at a faster rate than normal cells and divide to form a cluster known as a tumor. Once this tumor has formed it is difficult to remove because it has already intertwined with vessels and other organs. Tumors caused by pancreatic cancer are especially risky because they easily metastasize, meaning that the cancer cells can spread to any part of the body through the lymph nodes and begin to grow there. Eventually this leads to the cancer taking over the entire body and the need for drastic treatment measures .
Currently, pancreatic cancer is considered by many to be an “incurable” disease. The difficulty in treatment of pancreatic cancer is caused by a variety of factors. The symptoms of this disease occur much later than other forms of cancer and often depend on the initial location of the cancerous cells within the pancreas. Unless a patient has a family history of pancreatic cancer, due to its hereditary nature, it is unlikely that they will be tested for the disease without the presence of symptoms. Testing is not done on the general public because there are limited options for a non-invasive or cost effective test that can easily be done prior to the appearance of symptoms . A lack of testing allows for the tumor to spread across the body and becomes so invasive that attempted removal of the tumor is rarely possible or effective.
The only current method to fully eradicate pancreatic cancer cells from the body is complete surgical resection. Due to the positioning of the pancreas in the body, it is a very difficult organ to surgically access . The location of the pancreas can be seen in Figure 1. Also, in order for the tumor metastasis site to be removed, surgeons must remove large portions of the pancreas, sometimes up to 95%. This greatly affects the health of the patient. While it is possible to live with only a small portion of the pancreas, it requires large lifestyle changes such as daily insulin injections and frequent hospital visits. Doctors must continuously monitor hormone levels and residual cell growth to ensure that the cancer does not return. According to Dr. Allyson Ocean, a respected oncologist at the Weil Cornell Medical Center, “the prognosis is poor even in patients who do have surgery, because it comes back about 85 percent of the time. At best, 25 to 30 percent of patients are alive five years after surgery” . These statistics are a harsh reality for those who battle pancreatic cancer, regardless of when they were diagnosed.
FIGURE 1 
Anatomical diagram of the human body
(pancreas in red)
Although surgical resection is the only potential “cure” for pancreatic cancer, there are many treatment methods currently in existence. Two of the most common therapeutic treatments are chemotherapy and radiation. However, these solutions tend to be relatively unsuccessful. The pancreas has one main blood supply, known as the greater pancreatic artery, through which chemical substances can travel to the pancreas. Thus, the probability of chemical injections into the bloodstream impacting the tumor is very low. During the process of chemotherapy or radiation treatment, a significant number of healthy cells are killed, due to the lack of specialized targeting agents. The molecules cannot efficiently locate the cancer cells and, as a result, end up killing a large number of healthy cells . Considering that the three main treatment options for other cancers are not sustainable for pancreatic cancer, and have major side effects, many have sought an alternative method to treating this disease. The most promising solution comes from targeted drug delivery systems.
For those with pancreatic cancer, nanotechnology provides a potential cure that has been previously unavailable. These patients often have to go through the painful and strenuous process and recovery of chemotherapy and radiation. Based on the potential impacts of this technology, scientists have chosen to further explore targeted drug delivery. The application of targeted drug for pancreatic cancer could potentially provide a better quality of life and survival rate than currently offered, thus theoretically providing a more sustainable option.
EXPLANATION OF GOLD NANOPARTICLES
The research behind nanoparticles stems from the naturally existing organic transportation agents within the body. These include proteins, liposomes, and polysaccharides. By observing functions of the compound, modern forms of nanotechnology have been developed to mirror the capabilities of these organic agents. Gold nanoparticles (AuNPs) are among the most studied and promising of nanotechnology. Successful animal testing and in vitro experiments on human cells have already taken place . Because of the biocompatibility of these nanoparticles many exciting applications are foreseen. The foremost of these applications is in targeted drug delivery.
In the days of the ancient Egyptians, it was believed that ingesting gold had medicinal properties. Many applications of gold have since been discovered and are currently being researched. Interest in this specific element, gold, is due to its biocompatibility and ideal properties. These properties include, being non-toxic, easily shaped, and never corroding or tarnishing. Gold is a good conductor of both heat and electricity. This is advantageous when it comes to dealing with the natural electric signals within the body. The surface chemistry of elemental gold is highly reactive with other substances . This allows for more versatility in the design of the nanoparticles and what they can deliver.
Unique Characteristics of Gold Nanoparticles
Gold nanoparticles have a variety of beneficial characteristics that allow them to perform efficiently within the body. The properties of elemental gold and the structure of the nanoparticle itself enable them to act as multimodal drug carriers . This means that they can be used not only to transport the medication, but also to image the disease internally, sensitize cells and potentially apply electromagnetic radiation to disease sites. These characterics allow for AuNPs to act as transporters of substances, when on their own in the body, prove to have poor cellular penetration, solubility, and pharmacokinetics, properties that relate to how pharmaceuticals move throughout the bloodstream to specific tissues and organs.
“AuNPs are one hundred times smaller than human cells and can offer unprecedented interactions” . Their size allows them to enter into the cell through the plasma membrane. The most commonly used nanoparticle is the nanosphere . Nanospheres have a large surface area where ligands can be attached and interactions can occur . This increases the likelihood that the nanoparticle will make it to the disease site and be accepted by the cell. Typically, foreign substances are rejected by the body. Therefore, scientists have been making alterations to the surface of nanoparticles that make them compatible with cancerous tissue to ensure that gold nanoparticles can overcome this obstacle.
Metallic nanoparticles are conductors which means that they have electrons scattered throughout the particle which tend to rest on the surface, but are free to move throughout the particle. It is this trait of AuNPs that allows them to not only be drug deliverers, but act as multimodal agents. Imaging of the cancer is crucial in predicting what treatment options are best suited for each patient's case, and dosage amounts to be delivered.
Drug Carriers to Tumor Sites
Gold nanoparticles as a form of targeted drug delivery perform the intended equivalent task as that of chemotherapy and radiation. The AuNPs transfer the same anti-cancer drugs as those currently used in chemotherapy such as emcitabine, carmustine, paclitaxel and doxorubicin to limit tumor growth, but they do it in a more direct and efficient manner . This minimizes side effects and long term damage to regions of the body.
The most important characteristic of the gold nanoparticle is its malleable design. There are multiple options for the shape of the nanoparticle, each with a different purpose. Overall, their structures have universal features. These include a center, where the gold is contained and surrounded by a compact protective layer. This is known as the Stern Layer. This is covered with a second biocompatible layer known as the Gouy layer. The Gouy layer is where the drug is attached using ligands. Ligands are molecules that are attached to a metal ion using coordinate bonding . This bonding can either be covalent or non-covalent. Often it occurs between a functional group and a ligand. This functional group is the drug that the nanoparticle is delivering. The structure of the gold nanoparticle is shown in Figure 2. The functional group keeps the ligand attached to the surface of the nanoparticle. The body now recognizes the nanoparticle and permits delivery of the drug.
FIGURE 2 
The complex structure of the Gold Nanoparticles with ligands, R-Group, and drug attached to the surface
Multiple factors can influence the performance of these ligands. Binding affinity of the targeting ligand is crucial for favorable interactions between the surface and the ligands. Binding affinity is the strength of the attractions between the ligand and the surface of the nanoparticle. If the ligand has a strong affinity, then it will be more likely to bond and aid in the drug delivery process. If there is low affinity of a ligand to its receptor, this limits targeting efficiency.
Another component that impacts the construction of this structure is the surface density of the ligands. The more densely packed the ligands are on the surface, the more they can penetrate the cancerous tissue. The nanoparticles will then be more effective in destroying the malignant cells. This activity is dependent upon the nanoparticles being delivered as one unit to the metastasis site. Targeted ligands need a long half-life to provide sufficient time for the drug to reach the target at therapeutic levels.
After all of the previous constraints are met pertaining to the structure of the ligand and the characteristics of the gold nanoparticle, the nanoparticle can finally reach its destination. Once there, the gold nanoparticle enters the cell through receptor-mediated endocytosis. This means that a small hole opens up in the plasma membrane and allows the particle to enter. It then closes up behind it so that nothing from inside of the cell can escape. The particle is now inside of the cancerous cell where it can finally perform its task, releasing the drug. The coating on the outer surface of the nanoparticle is able to partition hydrophobic molecules from surrounding aqueous medium . This tells the nanoparticle the correct time to release the drug, which in when it is either inside of the cell or just outside of it, depending on the delivery system. Once released, the drug travels throughout the cell and triggers apoptosis. This means that the cancer cell dies and the nanoparticle has completed its task .
Enhanced Permeability and Retention
In order for gold nanoparticles to effectively reach the site of the malignant cells, the properties of such cells must be studied in order to better understand nanoparticle-cell interactions. Due to the abnormally large presence of blood vessels within tumor cell clusters, the increased permeability of these blood vessels, made possible by loosely compacted vasculature, and lack of lymphatic drainage, nanoparticles are able to invade and accumulate in the tumor tissue . This is known as the Enhanced Permeability and Retention (EPR) Effect, which was first established by Matsumura and Maeda. Although these qualities, caused by EPR, generally improve delivery of chemotherapeutic agents to cells through nanoparticles, it only results in a maximum ten-fold increase in delivery in comparison to unaffected organs. This small increase is insufficient for achieving optimal therapeutic levels in patients suffering with cancer [8, 9]. This led scientists to utilize these traits of tumor tissue to passively target cancerous tissue in addition to other modifications on the nanoparticles themselves for active targeting to improve the levels of drug successfully delivered to the cancerous cells.