Session B3
Paper 120
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GOLD NANOPARTICLES AS A MORE EFFECTIVE FORM OF CANCER
TREATMENT AND DETECTION
Matthew O’Connor, [email protected], Sanchez 5:00: Arvind Venkatraman, [email protected], Sanchez 5:00
tumor suppressor genes and the proto-ocncogenes. The protooncogenes enable the cell to grow and divide under this
controlled cell cycle when they are activated. To ensure that
the system produces healthy, duplicate cells, a series of
checkpoints are passed during the growth of the cell. The job
of the tumor suppressor genes are to act as a checkpoint, in
order ensure that the cell does not carry any of the features
that lead to the creation of cancer. When they are activated,
tumor suppressor genes are able to both slow and stop the cell
cycle when there is an error in DNA replication, or when
division is happening too fast. It is then assessed whether the
DNA is repairable or not. If the DNA damage is harmful, the
cell has a programatic self death, known as apoptosis. Protooncogenes and tumor suppressor work together to in this
cycle to balance the speed and accuracy of division [3].
THE IMPORTANCE OF NANOPARTICLE IN
CANCER DRUG RESEARCH
As one of the most abundantly fatal diseases, cancer
continues to torment families and challenge the researchers of
the modern world. The human body is home to billions of
functional cells [1], all controlled by our nervous system. It
takes a single mutation in just one of these cells to turn a
patient’s life upside down. A cancerous cell is one that
bypasses apoptosis, and continues to divide uncontrollably.
This process is caused by many external variable factors as
well as genetic mutations. To our dismay, many of the
modern luxuries and technological innovations that bless our
present generations are simultaneously cursing us with
disease [1]. 2016 saw the highest cancer diagnoses rate in the
United States, in which .52% of the population was
diagnosed with some form of cancer [2]. We are all aware of
the every-day dangers of carcinogens, such as processed
foods, asbestos, tobacco, and radiation exposure, yet still
value the use of the technology over the health risk.
Despite the increased creation of new carcinogens over
the last decades, the medical field is combating this growth
with much more direct and aggressive ways to treat cancer
cells. Although the diagnostic rate is at an all time high, the
mortality rate is decreasing as a result to modern medicines.
The primary cancer treatments of the last decade have been
radiation therapy, chemotherapy, and surgery. However, as a
result of these procedures, both patients and their families
have suffered from much more than just the disease itself.
Each of these treatments take months to conduct, costs
thousands of dollars, and survival is not guaranteed. There
needs to be an efficient, cost effective solution to rid the
world of this disease. The introduction of the gold
nanoparticle as a direct local pharmaceutical delivery vehicle
is a major step in the right direction.
Gene Mutation
A gene mutation is an unintentional change that occurs
in the DNA sequence of the gene. A mutation can vary in
severity, but this creates a gene that does not have the exact
entitled function. Mutations in the genes that promote cell
growth can lead to one of the most widespread diseases
known to mankind, cancer [4]. When there is a mutation in
the tumor suppressor gene, this checkpoint is inactivated and
no longer useful. The cell is then able to undergo mitosis and
create duplicates of potentially harmful cells, and unable to
slow the rate at which this happens. A mutated protooncogene is known as an oncogene. An oncogene is a protooncogene that has been permanently activated and tells the
cell to divide at an uncontrolled rate. Both of these mutations
lead to the creation of tumors [5].
Tumors
A tumor is a collection of cells created by the mutated
genes. Since the cells are duplicated with error, the function
also has error. A tumor is a lump or growth in the body with
no function. Often times these growths are benign and are not
harmful to the body. In other situations, these tumors can
become harmful, blocking vital organ function, destroying
surrounding tissues, and spreading to other parts of the body.
ORIGIN OF CANCER CELLS
The cell cycle is a series of multiple steps which lead to
the growth, division, and replication of every cell. The
primary types of genes which guide the cell cycle are the
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University of Pittsburgh Swanson School of Engineering
Submission Date 03.31. 2017
Matthew O’Connor
Arvind Venkatraman
These harmful tumors are labeled as malignant and cancerous
[1]. Tumors are able to be seen through medical imaging to
be treated. However, through a process called metastasis, a
tumor may break away from its origin and be carried to other
body parts via the bloodstream or lymph system. This spreads
cancer through the body, creating multiple sources of where
tumors are located [1].
gamma ray frequencies into the specific cancer site. These
waves are delivered by either an external radiation beam or
from a radioactive material that is placed inside the body,
near the tumor site. The radiation waves are used to directly
alter the DNA of the targeted cells, killing them. Radiation
treatments can stop cancer growth in the target location,
however, they can also alter the DNA of neighboring cells,
promoting new cancer growths [8].
GLOBAL NEED TO COMBAT CANCER
Chemotherapy
Mutations to the tumor suppressor genes and the protooncogenes are seldom caused through inheritance, but rather
externalities. Our modern way of life has added many
carcinogenic externalities to this list. Everyday activities such
as smoking, using a cell phone, being in sunlight, and eating
our processed diets have direct correlation to altering the
DNA inside specific genes that will prevent cancer from
being created in the first place [4]. In addition, as people age,
they are more susceptible to new infections and at a higher
risk of cancer. As expected, with an increase of new
carcinogens and an aging population, we have seen global
increases in new cancer diagnosis rates. However, with
modern cancer therapies, we have also seen substantially
increased survival rates [6].
There is no consistent cure for cancer. We have many
treatments with marginal success rates, but no consistent cure
that can stop the division of cancerous cells, 100% of the
time. Because cancer is so invasive to the health of a patient,
it cannot go untreated. Modern treatment options are
expensive, potentially harmful, and do not always guarantee
success.
Chemotherapy is a prescription of medications that have
a specific goal of targeting cells of rapid growth. Because
cancer cells are dividing and uncontrolled rates, they are
targeted by these drugs. Chemotherapy is known to cure
patients of cancer in some cases, however, this can be over
the course of many years. A drug that can consistently kill
cancer cells is the ultimate goal. However, chemotherapy
comes at great costs [9].
Because chemotherapeutical medications target cells of
rapid growth rates, cancer cells are not singled out during
treatment. Other cells of rapid growth such as hair follicles
and stomach lining are killed in addition to the cancer cells.
This is what causes the patients to lose body hair, and the
corrosion of the stomach lining leads to unpleasant side
effects such as extreme vomiting, nausea, and diarrhea in
patients. On top of this, platelets, and red and white blood
cells are targeted. This means chemotherapy patients are now
also more susceptible to bleeding, fatigue, and have much
weaker immune systems. Thus, chemotherapy is an
extremely violent procedure to the human body after already
battling cancer itself. In addition to the short term cost of
patient health, chemotherapy costs a lot of time and money
from the patients to hope for results [9].
Surgery
Surgery is the most primitive, but sill an effective attack
on cancer cells. A surgical oncologist is the doctor who
performs cancer surgeries, by removing a tumor and
surrounding tissue. By taking the tumor and the surrounding
area completely out of the body, in theory the cancer should
have no more source. However, this method can leave small
traces of malignant cells still in the body. Surgery can also be
used to decrease tumor size to prevent blockage or more
damage from the withstanding tumor [7].
Human error constricts the accuracy of this operation by
only targeting what can be seen directly. Often times this
operation is done in partner with a chemotherapy or radiation
treatment. These therapies together have a devastating toll on
the health of the patient. Along side the health risks, the
financial burden is very heavy for patients who need
treatments, and often times more than one is needed [7].
The nanoparticle
A nanoparticle is a functional element that has been
sized down to the nanoscale. In case of the gold, a block of
gold will be crushed, milled, and ground before particles are
in the nanoscale. A sheet of paper is 100,000 nanometers for
comparison. In cancer treatment, these particles are gathered,
reacted, and equipped with organic compounds in order to
deliver pharmaceutical drugs to treatment locations. The gold
acts as a non-biodegradable transport vehicle for these
medicines, that navigates its way through the body of the
patient [10].
Particles are equipped with drugs designed to
specifically source and kill only cancer cells. Unlike
chemotherapy or radiation treatment, nanoparticle treatments
localizes the delivery of the medicines. This allows for a
dosage of medication to have a more precise impact on the
cancer cells themselves, and not neighboring healthy
cells[10]. This new form of technology is a much more
efficient way to deliver medications, and is a reduction in
Radiation Therapy
Radiation treatments are the least expensive and most
frequently used cancer therapy options. Radiation therapy
works by sending high concentrations of certain x-ray and
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Arvind Venkatraman
both the side effects and costs of other cancer treatment
options.
the spheres will not be used for photothermal therapy, the
high density will illuminate them more during imaging [14].
The best transporter of medication was the sphere shape. In
tests recorded in in vitro, the sphere saw the most uptake by
cancerous cells, over that of the rod and star in medicine
delivery. They also found the prime size for function to be the
50nm diameter gold nanosphere [11]. This variety of shapes
and functions only adds to the string versatility and ability of
the gold nanoparticles.
STRUCTURE OF GOLD NANOPARTICLES
Gold nanoparticles for functional cancer treatment are
on the scale of 20-100 nanometers. The varying size and
shape of each particle allows for different functions [11].
When used in cancer imaging, light waves are directed
through the body and expected to be absorbed by the gold
particles which are attached to a cancer cell. Each differently
sized nanoparticle gives a different percent of signal strength
at each wavelength. The trend shows larger particles
increasing activity at higher wavelengths, while smaller
particles react to shorter wavelengths [12]. This means that
for photo thermal therapy to have maximal results, it helps to
have the nanoparticles to be uniform in size in order to have
them all respond the same way to the same wavelength.
APPLICATION OF NANOPARTICLES
The previous nanotechnology used to screen cancer
cells incorporated iron oxide particles. These particles were
iron oxide in the core and were coated with a sugar like
substance called dextran. The dextran coating would allow
the particles to be taken in by normal healthy cells. When
inside the cells, the iron oxide particles would accumulate,
and changes in the iron oxide concentration would be
abundantly clear through comparing photos of before and
after MRI scans. The healthy cells will change to a black
color from the concentration of iron oxide particles they have
taken in. This leaves cancerous cells to be unchanged and
easier to identify and locate [15]. However, this process
brings health risks and limited accuracy.
A dosage of the iron oxide particles is given to a patient
based on body weight, and is expected to disperse equally
throughout the body [15]. This method is proven to show
results, however, there is room for error. There is no
guarantee that all healthy cells are going to absorb the same
amount of iron oxide. The injection of iron oxide does not
prescribe an equal distribution of nanoparticles being taken
up by cells. The results are not reliable because the iron oxide
uptakes for each cell are too variable.
For example, if there is a healthy cell that does not
absorb a nanoparticle, it will be seen as cancerous on the
screening, and a false diagnosis will be given. This means
that doctors will be attacking healthy cells with a
chemotherapy treatment that is even more harmful to the
patient. A much more precise diagnostic tool is needed to
ensure the health of the patient.
Structure
Although the gold nanoparticles vary in size, the basic
structure of nanoparticles are similar. At the core of each
particle is the gold. The gold acts as a non-organic vehicle to
attach organic molecules to. Metals are used as transport
vehicles because they are not biodegradable, allowing them
to not decompose in the body. Gold is most commonly used
for its behavior in the body. Unlike some metals like
platinum or chromium, gold remains non toxic to the body
until extreme volumes, and will not react with any organic
material inside the body. Gold is also very reactive to certain
rays that are used during cancer imagining and treatment [11]
At the center of the vehicle structure, the gold is
attached to the delivery medicine if there is one [11].
Surrounding the medicine is a layer of silica used to protect
the nanoparticle and medicine until delivery. A strong, acid
sensitive, covalent bond between the gold and the sulfur atom
of a delivery drug, keeps the vehicle together. The strength of
the bond keeps the vehicle in tact, while the acid sensitivity
of the bond acts as a timer for when it needs to break and
deliver[11]. Like all cells, there is a soluble biocompatible
outside layer. This is where antibodies and ligands are able to
be attached to the vehicle to track and enter cancer cells [13].
VERSATILITY OF THE GOLD
NANOPARTICLE
Shape
There are three major stages in the fight against cancer.
The first step is diagnosis, followed by therapy, and
treatment. The versatility of the gold nanoparticles allows
them to function effectively at each stage as necessary. In the
diagnostic stage, doctors are looking to find the source of the
cancer cells to see what they're combatting by looking at the
stage and any movement of a cancer from its origin.
The shape of each nanoparticle varies as well. The most
common shapes are the sphere, rod, and star, but other shapes
can be synthesized. In a study for in vitro for the delivery of
doxorubicin, these three main shapes were tested in
photothermal therapy under near infrared light. [14]. During
photo thermal therapy, the rod and star shaped nanoparticles
were the most aggressive on the cancer cells. The sphere
shared particles were least toxic to the cancer cells. However,
the spheres were found to have the most density. Although
Precision of Treatment
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Matthew O’Connor
Arvind Venkatraman
Through characteristics specific to the gold
nanoparticle, the gold nanoparticles are able to identify
cancer cells. Because gold is a metal, there are free electrons
moving throughout the atom. At certain wavelengths of light,
the electrons in gold atoms begin to oscillate at uniform
frequencies in a special property called surface plasmon
resonance [16]. This allows concentrations of the gold
particles that are attached to cancerous cells to be very
apparent in imaging screens, as they often become a red color
due to the heat change [12]. In gold particle imaging, only the
cancerous cells are illuminated. This is the contrary to how
the iron oxide treatment exclusively located concentrations of
healthy cells. Doctors are now able to see the exact location
of a cancer cell and provide a much more accurate diagnosis
than before.
In other forms of cancer therapy such as radiation and
chemotherapy, all cells, healthy and cancerous, are targeted.
Gold nanoparticles allow for a much more accurate treatment
of medicine to exclusively target cancer cells. Again this
precision of treatment, as seen previously in the use of gold
versus iron oxide for imaging, allows for an all around better
treatment. Gold is mainly used as the delivery element in
nanoparticle drug therapy because its surface is easily
manipulated. With help by the chemistry of sulfur atoms in
medicines, researchers are able to covalently bond medicines
and antibodies to the surface of the gold particle. Gold acts as
a successful delivery vehicle because inert gold will not react
with other molecules in a living body. This allows the
medicine to be delivered safely and the vehicle unchanged.
Next, the vehicle needs to find the cancer cell for delivery
In previous treatments, researchers tried to block these
ligand receptors which hinders the devision of a cancer cell,
allowing nothing to enter. However, the cells grow immune,
and this system serves inadequate over time [13]. With the
use of the properties of a ligand, a more advanced attack
method is to get an antibody or drug inside the cell, versus
just blocking the receptors. This is done with the use of a
nanoparticle as a transport vehicle. The properties of gold
allow it to make strong covalent bonds with the medicines
that are being delivered. This very compatible structure
allows researchers to disguise the vehicle and medicine under
a biocompatible outer layer upon which they can attach
appropriate ligands to gain entry into the cancer cell. Thus,
the nanoparticle is disguised and taken in by cancer cells.
Once inside, the nanoparticle delivers the medicine which is
able to kill the cell. A common drug to attach is Doxorubicin.
Very much like radiation and chemotherapy, Doxorubicin
will kill every cell it comes in contact with. This is why there
is a need for a vehicle to get the drug to a very specific
location inside of a cancer cell.
Specific Delivery
Whatever drugs that are being delivered need to know
when to be released from the vehicle. This is done through
the use of acid-sensitive bonds between the gold core and the
medicine. In an acidic environment these bonds will release
and the drugs will be free in the cell. The bloodstream has a
slightly basic pH of around 7.4, so the bonds hold while the
vehicle is in transport. This differs from inside the endosomes
of the cell which have a pH of about 4.5-6.5. Once the drug
has reached the endosomes, the bonds break and the drug is
transported throughout the cellular matrix, where it is
dispersed and kills the cell [12].
Tracking Cancer Cells
In the blood stream, healthy cells are attached to the
blood stream by a tight junction blood vessel which cannot be
accessed by a nanoparticle. However, the cancerous cells that
are attached to the bloodstream are bound by broken leaky
blood vessels. The creation of these leaky blood vessels are
unique to tumors and will lead right to the source.
Although unable to enter normal vessels, gold
nanoparticles are able to enter these broken vessels which
lead to the cancerous cells. In addition to only having access
to cancerous cells from the blood stream, the gold particles
can also be equipped to be attracted to a cancer cell. Cells are
equipped with an intracellular receptor inside the
phospholipid bilayer. The receptor receives ligands which act
as signals from other cells, but only specific ligands can bond
to the receptor site. Every cancer cell has a ligand receptor
which is unique to the population of malignant cells as a
whole. On the outside of the gold nanoparticle is the
biocompatible layer which holds the appropriate ligand to be
accepted into a cancer cell. This allows the vehicle to find the
specific receptor site and connect itself.
Photothermal Therapy
The versatility of gold nanoparticle treatment does not
stop there. The same process that is used to find the cancer
cells though imaging can be used to kill the cells as well. In
the imaging process, many gold particles are attracted to a
cancer cell and attach specific antibody to connect itself to
the cancer cell. In imaging, this process just illuminates the
location of a cancer cell. Next, a highly concentrated
lightwave at a specific wavelength is sent to the targeted area.
This is very similar to the imaging process but on a much
higher concentration. Using the surface plasmon resonance
phenomena, the electrons in the gold particle begin to
oscillate at a uniform frequency. This movement of electrons
is able to generate an extreme increase of heat in the particle
[16]. With several particles bonding to a cancer cell, the sum
of the temperature increase from all of the bonded
nanoparticles generating heat is enough to kill the cell. In
some cases, this heat is enough to melt rod shaped particles.
This is known as Photothermal Therapy [12].
Pharmaceutical Delivery
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Matthew O’Connor
Arvind Venkatraman
except this process may cause more damage than the initial
issue itself. A nanoparticle permeates the cell wall and
peacefully makes entry in a cell. In the case of a magnet, the
gold particle will take a straight path towards the attractive
source. This is not safe when dealing with healthy cells, for
the nanoparticle may rip the cell wall or displace the location
of the cell as a whole [17]. The best alternative is to find a
way to not manually retrieve the nanoparticles, but also
ensure there is no additional threat to health of the patient.
In order to not be harmful to a patient, a nanoparticle
must either find its own way out of a healthy cell, or be able
to safely decompose. When the particle kills a cancer cell, it
makes its way back into the blood stream and is excreted
from the body. There is no concern of the gold harming the
dead cell. The issue that is faced with using gold
nanoparticles on healthy cells is that they are not
biodegradable. This results in having potentially toxic
elements left inside cells. One way to reduce this concern
would be to use a biodegradable vehicle for transportation
[17].
HEALTH CONCERNS
The main risks that gold nanoparticles bring during
cancer treatment are through photothermal therapy. As seen
in photothermal therapy, gold particles will absorb an
extreme amount of light and generate corresponding heat as
they are stimulated. This generated heat is enough to kill the
cancer cells that the particles are attached to. Although most
of the accumulated sum of heat is directed towards the cancer
cell, all neighboring cells will also feel residual parts of this
heat. This puts healthy neighboring cells at risk of also
receiving the effect of photothermal therapy [12].
If as much as one nanoparticle extra is delivered in the
treatment dosage, there are complications of exciting extra
particles that are still free in the bloodstream, not attached to
anything. These non bonded particles are still subjected to the
same light rays and will excite in the same way, generating
the same heat, which can kill other healthy cells wherever
extra particles are in the body.
Non-Biodegradable Element
Comparison to Previous Nanoparticles
The gold nanoparticles are injected into the body and
have specific functions such as the local delivery of medicine
or the illumination of cancer cells. In addition to killing
cancer cells, gold particles can act as a vehicle to deliver
medication to not malignant cells. However, there is not a
safe way to retrieve the metal based particles after they have
done their job from healthy cells. As a result, traces of gold
are left in the body. As seen in the creation of gold
nanoparticles, an attraction to each other forms over time.
These particles will find each other and bond, creating a
larger flake of gold [12]. There is a concern that this process
will repeat in the human body, and become toxic due to the
nature of a metal substance over time. A larger flake of gold
magnifies the issues that can arise from a single gold
nanoparticle. A single nanoparticle is small enough to
permeate the cell wall, however, this may not be the case
when there are several particles bonded together. A cell may
struggle to excrete a higher concentration of the pure metal
substance as waste, leaving a large gold flake stuck in a cell
[17].
Although there are health concerns with the gold
nanoparticles, this gold technology is a huge step forward
from previous forms of nanoparticles. As previously
mentioned, some of the earlier nanoparticles were iron oxide
based vehicles with a coating made of dextran. However, the
iron oxide particles are toxic. An every day example of an
iron oxide is rust. Rust, when in contact to the blood stream,
can lead to infections such as tetanus. So directly injecting
iron oxide particles into patients with weaker immune
systems can lead to further complications than the cancer
itself. Because of its metallic features, large concentrations of
iron oxide will be harmful to healthy cells. However, there
needs to be a relatively high concentration of iron oxide
particles in the cell to have the imaging work properly [15]. If
the cell cannot dispose of all iron oxide waste, it will be
poisoned and die. Although the function in imaging using
iron oxide particles is very similar to that of the gold
particles, the cons outweigh the pros for using iron oxide.
Gold nanoparticles are able to show a much more accurate
and illuminated map of cancerous cells without any of the
heath risks of iron oxide.
Gold Nanoparticle Recovery
SUSTAINABILITY IN THE FUTURE
This concern is only applicable to gold nanoparticle
interactions with healthy cells. In a cell that the particle has
killed, the gold is left inside of a dead cell. There is no
concern to how a gold particle will effect the health of a dead
cell. As the cell decomposes, the gold particle will reenter the
bloodstream as an exclusively non organic vehicle, which
will be excreted by the waste systems.
One possible way to hypothetically retrieve a gold
nanoparticle from a healthy cell would be through magnetics.
Gold in its natural form is a magnetic element. Magnetic
recovery would be the simplest way to retrieve nanoparticles,
With the hundreds of different types of cancers, it is
very difficult to find a consistent cure or treatment that works
for all kind because cancer is such a broad category.
The use of gold nanoparticles in cancer treatment is still
in research. While many of the systems and applications are
functional, research still needs to be done to perfect this
technology before a public release. Gold Nanoparticles
sustain the quality of life for patients and their families. This
becomes evident though the results of cancer cell death and
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Matthew O’Connor
Arvind Venkatraman
financial burden. With the right equipment, gold
nanoparticles are inexpensive to manufacture and load with
the pharmaceutical drugs. As a chemotherapy treatment may
take years and cost around $30,000 on average, nanoparticle
treatment is seen to take extreme effect within 24 hours.
Nanoparticle treatment also dramatically reduces this
expensive price tag down to around $1,000 [18].
When nanoparticles begin to become a viable treatment
option for patients, other treatments will not become obsolete.
Surgery and radiation therapy are much more direct ways to
quickly reduce a tumor size. But for killing cancer cells and
protecting the patient, nanotechnology is far superior to either
of those treatments or chemotherapy.
With the introduction of gold nanoparticles to the practical
medical world, we will see the sustainability of life around
the world. As a much less expensive and much more effective
form of treatment, more patients can afford to get the help
they need. There is no consistent cure for cancer yet,
however, using gold nanoparticles as local drug vehicles is a
huge step in the right direction.
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ADDITIONAL SOURCES SECTION
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ACKNOWLEDGMENTS
We would like to thank Dr. Sanchez and the Freshman
Engineering program at the University of Pittsburgh’s
Swanson School of Engineering, for providing us with the
opportunity to conduct research paper on an interesting topic
we would have not otherwise learned about. We would also
like to thank the instructors at the writing center who gave
guidance along the way during our paper. We would also like
to thank my the peer reviewers who read over this paper for
grammatical issues prior to submission.
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