Download the application of ph sensing nanoprobes to carcinoma detection

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THE APPLICATION OF PH SENSING NANOPROBES TO CARCINOMA
DETECTION AND IMAGING
Rachel Lau, [email protected], Mahboobin 10:00, Chloe Feast, [email protected], Mahboobin 10:00
Abstract---Current methods of tumor imaging fall short in
producing a distinct representation of cancerous cells. A
recent technological advance that addresses the
shortcomings of previous methods of tumor imaging is the pH
sensing nanoprobe. The topic of this paper is the use of pH
sensing nanoprobes, such as the PINS nanoprobe, to detect
and image epithelial cancer cells exhibiting acidosis. These
nanoprobes detect tumor sites more accurately than other
methods of cancer detection, providing doctors with an
intricate internal map of a patient’s case before and during
surgery.
By examining journal articles that focus on carcinomas
and pH detecting nanoprobes, as well as recent research in
this field, we will detail the specific mechanisms of this
technology that give doctors an upper hand when compared
to previously used detection and imaging technologies. After
explaining the current and future applications of this pH
sensing nanoprobes, we will examine the limitations of this
technology and the questions it raises with regards to
sustainability in the areas of public health and
biodegradability of byproducts. Through this objective lens,
we will prove that pH sensing nanoprobes provide an effective
method of detecting cancerous epithelial cells and guiding
surgeons through operations on malignant tumors that will
significantly and sustainably benefit the oncological field.
Key Words—Carcinoma detection, Fluorophores, NIR
Fluorescence Imaging, pH sensing nanoprobe, PINS
nanoprobe, Tertiary amine groups, Tumor acidosis
INTRODUCTION TO PH SENSING
NANOPROBES
PH sensing nanoprobes represent the intersection of
technological innovation and practical, real-world
application. Capitalizing on an abnormal pH balance between
the intracellular fluid of a cancer cell and its surroundings, pH
sensing nanoprobes offer a new method of imaging tumors
precisely. An article by Tian Zhao, Gang Huang, Yang Li,
Shunchun Yang, Saleh Ramezani, Zhiqiang Lin, Yiguang
Wang, Xinpeng Ma, Zhiqun Zeng, Min Luo, Esther de Boer,
Xian-Jin Xie, Joel Thibodeux, Rolf A. Brekken, Xiankai Sun,
University of Pittsburgh, Swanson School of Engineering 1
Submission Date: 03.31.2017
Baran D. Sumer, and Jinming Gao, all of the Biomedical
Engineering News section of the scientific journal Nature details
the behaviors and possibilities of pH sensing nanotechnology
[1]. The same article asserts that once administered in the
body, the nanoprobes fluoresce in regions where pH levels
have fallen below the normal homeostatic range, allowing for
more accurate visualization of cancerous growths and
improvements in real time guided surgery. Such benefits are
best reaped when the nanoprobe is applied to skin cancer
patients, as pH sensing nanoprobes are most effective when
used to identify and image epithelial cancer cells [1]. Given
that skin cancer is a highly common form of cancer, yet also
easily treatable when found early enough, it can be seen that
pH sensing nanoprobes have the potential to greatly improve
the way the medical field currently addresses this disease.
Even in light of the numerous benefits of pH sensing
nanoprobes compared to other methods of carcinoma
detection, the sustainability of this technology must be taken
into account to provide a holistic evaluation of pH sensing
nanoprobes. The potential improvements to quality of life of
cancer patients and biodegradability of byproducts are offset
by uncertainties about public health in the future which make
the sustainability of pH sensing nanoprobes another important
aspect to consider. A thorough analysis of the benefits and
drawbacks of this new technology will shed light on the net
positive gain that we can expect from continued development
of pH sensing nanoprobe technology going forwards.
THE IMPORTANCE OF SKIN CANCER AS
A FOCUS
Few people will find their lives untouched by cancer at
some point. Cancer is a disease well-known to most, perhaps
because there are such a broad range of cancer types that
affect upwards of 14.5 million people in the United States
alone, according to the National Cancer Institute [2]. While
there are many different forms of this disease, this paper
addresses the most common and easily treated type where a
new technology would have the greatest impact—skin cancer.
According to the Skin Cancer Foundation website, in recent
years, skin cancer has become the most prominent cancer
diagnosis throughout the United States. Common types of
skin cancer such as basal cell and squamous cell carcinomas
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Chloe Feast
affect around half of Americans by the time they reach
retirement age [3]. In addition, the American Cancer Society
asserts that basal and squamous cell cancers “can be cured
with fairly minor surgery or other types of local treatments”
[4]. While these types of carcinomas are common in the
United States today, with proper detection, they are usually
treated and cured successfully, speaking to the need for
precise carcinoma detection that pH sensing nanoprobes can
provide.
extracellular environment is known as cellular acidosis [5].
pH sensing nanoprobe technology operates using the
principles of acidosis, detecting and imaging tumors based on
the body’s own indicators of cancerous cells.
Shortcomings of Previous Detection Methods
Numerous processes of tumor detection and imaging
have been developed to capitalize on the characteristics that
set normal and cancer cells apart. Knowledge of the
drawbacks of other cancer detection and imaging
technologies is essential to understanding the significance of
pH sensing nanoprobes as a precise method of carcinoma
detection. Until recently, the most common methods of
tracking cancer cells included biomarker tracking and
Positron Emission Tomography (PET) scans. The
aforementioned article by T. Zhao et. al., in the scientific
journal Nature details both technologies. Biomarker based
detection traces biomarkers, or biological molecules, that are
specific to cancer cells. These include receptors on the
membranes of cells, and certain antigens that exist in the
presence of tumors [1]. Each type of body tissue displays
variations of cell biomarkers [1]. Additionally, the Nature
article states that biomarkers vary throughout a population
because of phenotypic and genetic differences [1]. For this
reason, imaging based solely on cell-biomarkers is not the
most effective method of cancer detection because it does not
account for such tissue and individual differences.
In response to discrepancies in genetic display of cellbiomarkers, other researchers have focused on imaging using
PET scans which track increased glucose consumption in
cancerous cells. According to T. Zhao et. al. PET scans take
advantage of the Warburg effect, a tendency for cancerous
tissue producing lactic acid to exhibit a high glucose uptake
[1]. The PET scans capture areas of the body demonstrating
elevated glucose consumption levels. One drawback of this
method, however, is the naturally high consumption of
glucose in some bodily tissues gives rise to false positives.
This causes extra areas to light up on the PET scan. In addition
to false positives, T. Zhao explains that PET detection also
produces relatively unclear pictures which are little help
during surgery of delicate areas [1]. In light of the drawbacks
of other cancer detection methods, pH sensing technology for
carcinomas is a worthwhile focus for the healthcare field.
CHARACTERIZATION AND DETECTION
OF CANCER
The prevalence of cancer in our society strengthens a
demand for new methods of cancer detection and imaging.
Cancer imaging techniques rely upon a variety of biological
indicators of cancer cells to image tumors, however potential
for false positives and imprecision of the final image render
some of these methods undesirable. Before a comparison can
be drawn between pH sensing nanoprobes and pre-existing
forms of tumor imaging, the basic biological indicators of
cancer cells must be examined. This knowledge allows for the
development of a basic understanding of cancer detection
technology.
Identifiable Characteristics of a Cancer Cell
On a cellular level, cancerous cells can be identified by
unusual pH levels, and the abnormal behaviors induced by
those pH levels. Specifically, an article on tumor hypoxia by
Johanna Chiche, Ph.D. in cellular biology, reports that “recent
techniques using nuclear magnetic resonance 31P
spectroscopy…have confirmed the capacity of tumor cells to
acidify the extracellular environment and to maintain a rather
neutral/alkaline pH” [5]. Thus, this tumor acidosis process
serves as an indicator for cancer-cell detection, as stated by
Chiche [5]. In sum, the consistent trend towards an acidic
environment around cancer cells allows for successful tumor
detection via pH levels.
As a tumor develops it begins to exhibit hypoxia, or
oxygen deficiency, which increases the acidity of the
environment around the malignant cells. Chiche explains this
phenomenon in detail. Consumption of resources in blood
surrounding tumors, glycolysis, and lactic acid production all
contribute to a decrease in oxygen concentration near the
cancer cell. In response to decreased oxygen content, a proton
gradient forms [5]. The high concentration of H+ ions outside
of the cell is what decreases the pH of the extracellular fluid.
The body attempts to respond to the imbalance in pH by
producing other acidic or basic compounds, but this results in
the malfunction of cellular proteins. Na+/H+ exchangers in
the cell membrane work overtime to prevent the cell’s
concentration of H+ ions from increasing, which would lower
pH and acidify the cell. Chiche states that this process of
neutralizing the intracellular fluid while acidifying the
Improved Detection Using pH Sensing Technology
Nanotechnology has risen to the top of the hotlist of
scientific research, and its specific application to the field of
cancer is of great interest. Tuan Vo-Dinh of the Departments
of Biomedical Engineering and Chemistry at Duke University
explains in his article “Nanosensing at the Single Level” that
nanoprobes and nanosensors can be injected into the
bloodstream to carry out processes in vivo, or in the body.
Equipped with bioreceptors on fiber tips, much like nerve
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endings on finger-tips, sensors can seek out varying pH levels
indicative of cancer cells [6]. The probes can cause on-site
fluorescence once cancerous tissue is located, and deliver a
clear image of the affected area.
Delving into deeper applications of this technology is the
successful development of the PINS nanoprobe. The PINS
nanoprobe has been proven by T. Zhao and his colleagues to
be most effective when applied to superficial tissues
[1]. Carcinomas such as skin cancer include defective basal
and squamous cell groups that turn into tumors inside
superficial tissues [1]. Herein lies the connection between pH
sensing nanoprobes and a focus on skin cancer. In sum, the
PINS nanoprobe is most effective when dealing with skin
cancers, see Figure 1 below.
understanding both the administrative procedures and
functional components of this type of nanotechnology. With
the applications of precision carcinoma imaging and real-time
guided surgery in mind, the specific details of pH sensing
nanoprobes will be addressed to explain why these significant
benefits are possible. Specific examination of the PINS
nanoprobe, a new near infrared resonance fluorescence
imaging probe, will provide a view of this pH sensing
nanotechnology in operation.
Introducing pH Sensing Nanoprobe Technology to the
Body
Before examining how pH sensing nanoprobes activate
and fluoresce in response to low extracellular pH, it is
important to address how they are administered. To be able to
properly image cancerous growths in the body, pH sensing
nanoprobes must be introduced to the bloodstream via an
intravenous injection. According to the article published in
Nature by T. Zhao et al., this injection must take place twentyfour hours prior to the imaging process [1]. This provides
sufficient time for the nanoprobes to circulate throughout the
body and activate in areas of abnormally low pH. After the
twenty-four-hour period, T. Zhao et al. report that the
fluorescent response of pH sensing nanoprobes can be picked
up by clinical cameras such as the SPY Elite [1]. Thus,
hospital technology on the market can be used in conjunction
with these nanoprobes, increasing their appeal as a method of
precise imaging.
In addition to a twenty-four-hour time restriction,
Quentin le Masne de Chermont, Ph.D. in nanotechnology
applied to biology, addresses the steps that must be taken in
response to auto fluorescence when administering a
nanoprobe. He asserts that the nanoparticles must also be
treated with ultraviolet light prior to injection to protect
against the interference of auto fluorescence in the body [7].
Furthermore, in an article examining tissue auto fluorescence,
Monica Monici of the Centre of Excellence in Optronics in
Florence, Italy explains that auto fluorescence is a natural
occurrence within cells whereby external radiation excites
molecules within lysosomes and mitochondria, causing body
cells to fluoresce [8]. In other words, organelles within body
cells absorb energy and emit light, preventing the formation
of a clear image using nanoprobes. However, treatment of
probes prior to injection protects against the impeding effects
of auto fluorescence.
FIGURE 1 [1]
Comparisons of PET Scans of Tumors
This image from the article by T. Zhao et al., published
in the respected scientific journal Nature, compares PET
scans of tumors based on glucose consumption and
fluorescence scans based on abnormal pH levels. While these
images depict non-superficial tumors, they serve as an
effective comparison to human superficial tumors because
mice are so small. On the left of the above figure is a white
light photo as the human eye would see tumors of two sizes
in subject mice. The middle set contains PET scans of the
same mice. At first glance, these shots are incredibly blurry in
comparison to the photos on either side. Additionally, extra
tissues light up as indicated by the overlaying black arrows,
displaying false positives in areas that also consume high
amounts of glucose. The right panel consists of images taken
after injection of the PINS nanoprobe. One can see that the
tumors glow in high definition, and that no excess areas
fluoresce [1]. Therefore, PINS and the group of pH sensing
nanoprobes it represents stands as the imaging method in this
test that produces the most useful results.
TECHNOLOGY UNDERLYING THE PH
SENSING NANOPROBE
PH sensing nanoprobes evidently present a unique and
precise new method of imaging tumors in comparison to
previously used glucose consumption or biomarker tracking
strategies. As such, attention should be devoted to
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and any activated nanoprobe occurs because of an abnormally
low pH.
FIGURE 2 [9]
Effect of Auto Fluorescence on Performance of
Fluorophores
The leftmost image from an article in the journal
Biophotonics International shows a fluorescent probe with no
auto fluorescence correction [9]. The right image shows a
fluorescent probe that has been corrected for the auto
fluorescence of the cells it is imaging [9]. The difference
between images produced with unexcited and excited
nanoprobes seen in Figure 2 highlights the importance of
treating the probes to maintain the clarity and the precision
benefits of pH sensitive tumor detection.
Components of the PINS Nanoprobe
In addition to understanding the administrative and
corrective procedures associated with this nanotechnology, it
is important to understand the parts of the nanoprobe and their
respective functions. One of the important characteristics of
this technology according to the article by T. Zhao et. al. is its
ability to “transform pH from an analogue biologic signal to
a discrete exponentially amplified output” [1]. The two
components of the pH sensing nanoprobe essential to this
function are the fluorescent dye and tertiary amine group.
Tertiary amine groups detect the “biologic signal” discussed
in the Nature article by turning on and off in response to
irregular extracellular pH values [1]. What sets this
technology apart is that once detected, pH irregularities
produce a local, traceable response via the excitation of a
fluorescent dye molecule. This fluorescence reaction allows
external imaging devices such as clinical cameras to be used
to image cancerous growths based on extracellular pH.
FIGURE 3 [1]
Graph of the PH Sensitivity of PINS Nanoprobe
The above graph from T. Zhao and his colleague’s
experiment on the PINS nanoprobe highlights the sensitivity
of the probe to pH. As environmental pH drops below 6.9
there is a rapid shift in the nanoprobe from no fluorescence to
complete fluorescence. As can be seen in Figure three, there
are two distinct active and inactive states of the PINS
nanoprobe that mimic “transistor like responses,” as
identified by T. Zhao et. al. in the experiment [1]. Thus, the
nanoprobe exhibits either an off or on state based on
environmental pH, allowing for precise imaging that responds
to very small changes in these pH values.
Imaging with Fluorophores
Detection with pH Responsive Amines
The pH sensing capabilities of these nanoprobes would
be wasted without a mechanism to track and express the
observed pH variations. This mechanism comes in the form
of a fluorophore, otherwise known as a fluorescent molecule.
Fluorophores operate on the basis of excitation and emission
of electrons. As expressed in an article on fluorescent probes
from the Thermo Fisher corporate website, once in the body,
an external source of energy must be applied to the fluorescent
probe to excite fluorophore electrons [11]. This external
energy source causes the probe’s fluorophore electrons to
jump to a higher energy level. In the time before the electrons
decay back down to ground state, the same Thermo Fisher
article asserts that “energy is dissipated by molecular
collisions” [11]. In other words, the electrons lose energy
through interactions with other molecules in their excited
state. This loss may be observed in Figure 4 where the energy
of the electron in its excited state is portrayed as a downward
sloping curve.
As discussed previously, hypoxia in cancerous cells
induces an acidic extracellular pH that may be detected by pH
sensitive nanoprobes. In looking at the range of pH values
sensed by the PINS nanoprobes in specific, an appreciation
for the precision of pH sensing nanoprobes in general may be
obtained. It is important to note that the amine groups
included in pH sensing nanoprobes are responsible for
responding to changes in pH that delve below a certain
transition pH value.
Given that pH sensing nanoprobes are injected into the
bloodstream, the pH of blood is a significant consideration
when evaluating the range of pH values that activate the
nanoprobe. One key detail that allows for proper function of
this nanotechnology is that, according to an article on bodily
pH by Rich Rodriguez M.D., the typical pH of blood is 7.4
[10]. This is significantly higher than the pH of 6.9 at which
the PINS nanoprobe is activated [1]. Thus, the normal pH
conditions of the body will not activate the PINS nanoprobe,
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FIGURE 5 [1]
Survival Rates of Mice Receiving Various Types of
Guided Surgery
Figure 5 from an article published by T. Zhao et.al
presents survival rates of mice operated on with different
methods over 160 days. The Tumor Acidosis Guided Surgery
(TAGS) in red demonstrated the highest survival rates of mice
over the 160 day period when compared with white light
surgery and other debulking methods [1]. In Figure 5, it can
be seen that TAGS using the PINS nanoprobe generated the
highest survival rates in the mice of the experiment. This
particular experiment from the journal Nature using the PINS
nanoprobe with mice found “13 out of 18 animals (72%)
showing cures 150 [days] post-operatively” with a p value of
less than 0.0001 [5]. According to author Stanley E. Lazic in
his publication on Experimental Design for Laboratory
Biologists, a p value below 0.05 indicates a statistically
significant difference between two sets of data [12]. As such,
because evaluation of this experiment’s data produced a p
value lower than 0.05, it can be concluded that TAGS
statistically significantly increases survival rates in mice in
the period following surgery when compared with other
methods of guided surgery.
Experiments such as these are an important early step in
analyzing the effectiveness of pH sensing nanoprobes.
Though the subjects of this experiments were mice, the
insight gained from the results allows projections to be made
on the future effectiveness of this technology in
humans. Evidence that this technology provides a significant
benefit when compared to other forms of guided surgery is
important to consider when assessing whether or not to bring
this technology to market.
FIGURE 4 [11]
Diagram of Electron Excitation in Fluorophores
Figure 4 diagrams the process of excitation and emission
of fluorophore electrons. The energy dissipation that occurs
in the excited electron is important because it allows scans to
distinguish between the light applied to the system and the
light emitted by the system [11]. As can be seen in Figure 4,
The light emitted by the decaying electron has less energy
than the light applied to the system, and therefore may be
isolated when performing a scan. The production of precise
images with pH sensing nanoprobes is possible because only
nanoprobes activated by regions of abnormally low pH will
emit this lower energy light in this process
APPLICATIONS OF THE PINS
NANOPROBE
With its unique pH sensing and fluorescing mechanisms,
the PINS nanoprobe serves as an excellent example
highlighting the potential of pH sensing nanoprobes. Looking
at the success of the PINS nanoprobe in animal trials so far,
the future prospects of pH sensing nanoprobes in the
healthcare market may be extrapolated.
Guided Surgery in Animal Trials
One of the major benefits of using pH sensing
nanoprobes to image tumors is the potential for real time
guided surgery with higher postoperative survival rates. The
precise images produced with this technology help surgeons
identify and remove all parts of a tumor, leaving no traces that
would facilitate a return of the cancer in question. To observe
these higher postoperative survival rates that accompany
guided surgery with pH sensing nanoprobes, we must look to
animal trials. In the experiment performed by T. Zhao et. al.,
pH sensing nanoprobes were shown to increase survival rates
in experiments on mice with head and neck cancer [1].
Future Applications in Human Trials
While pH sensing nanoprobes such as the PINS
nanoprobe have demonstrated considerable success in animal
trials with mice, there are still many steps that must be taken
before this technology may be used to image tumors and guide
surgery in humans. One of the most significant barriers at
present is the approval of the Food and Drug Administration
(FDA). Ultimately, pH sensing nanoprobes need to be
deemed safe for human use. The purpose of this technology is
to help with the detection and treatment of individuals with
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cancer, and if the technology produces net negative effects in
the body then it is unfit for medical application.
According to the FDA’s website, a biologic like pH
sensing nanoprobes must be approved by the Center for
Biologics Evaluation and Research branch, a multi-step
process that starts with the technology submitting an
“Investigational New Drug application (IND)” [13]. This
must occur before any clinical trials may be performed on
humans to ensure the safety and wellbeing of participants in
such trials. Thus, the next step for this technology would be
obtaining an IND to move into a phase of clinical trials.
In this process, the benefits, including tumor acidosis
guided surgery and more accurate imaging, must be weighed
against the risks of this technology. For example, in the article
by T. Zhao et. al., one of the risks presented in the PINS
nanoprobe animal trials were “temporary body weight loss
and an acute toxicity response at high doses” [1]. In addition,
according to an article on effect of nanomaterials on public
health from the University of Plymouth by R.D. Handy and
B.J. Shaw, some studies have identified an association
between “manufactured nanomaterials” and oxidative stress,
or the alteration of a cellular response to injury by the
presence of oxygen radicals [15]. Thus, the harmful effects of
high concentrations of nanoprobes and a potential link
between nanomaterials and oxidative stress in cells are two of
the largest public health concerns raised when evaluating this
technology. An IND will determine whether these risks are
small enough to allow for clinical trials, or whether the
technology is unsafe for human use. In sum, significant
investigation must still be performed on pH sensing
nanoprobes before human clinical trials even become an
option.
Medicine’s Medline Plus website, PET scans have a degree
of risk resulting from the usage of x-ray scans that expose the
body to potentially cancer causing radiation [16]. If the risk
of imaging with pH sensing nanoprobes is smaller or equal to
such a risk of PET scans, and there are significant advantages
of precision imaging and guided surgery that accompany pH
sensing nanoprobes, then pH sensing nanoprobes can be
considered
sustainable.
Unfortunately,
this
risk
contextualization will only be possible as continued research
is performed on pH sensing nanoprobes.
Clearly, there is much additional research needed before
pH sensing nanoprobe technology can become available on
the market. Despite this, the promise that pH sensing
nanoprobes have shown in animal trials prompts continued
investigation into the benefits of human use moving forwards.
Sustainability of Nanoprobes with Respect to Public
Health
One of the most substantial limitations of pH based
cancer detection is a restriction on the types of cancer that
may be imaged. According to T. Zhao et. al., regions of the
body that normally demonstrate a pH lower than the 7.4 of
most bodily fluids will fluoresce under pH sensing
nanoprobes even if there is no cancer present [1]. As such, pH
sensing nanoprobes cannot be used to detect or image cancers
in areas of the body with a naturally low pH, which Rich
Rodriguez M.D identifies as the stomach or small intestine
[10]. While pH sensing nanoprobes produce significantly
clearer and more focused images of tumors in areas of the
body with a normal pH of around 7.4, they cannot be used
with respect to acidic areas of the body.
Another restriction on the use of pH sensing nanoprobes
is the depth to which the light needed for activation of the
nanoprobes will penetrate. One of the reasons that T. Zhao et.
al. asserts that pH sensing nanoprobes are best used for
carcinoma or skin cancer detection is that the light used in the
fluorescing procedure does not need to penetrate many layers
of bodily tissue to reach the areas in which cancer is being
identified [1]. While this method is successful for skin cancer
detection, in subjects larger than the mice specimen used in
ANALYZING THE BENEFITS AND
LIMITATIONS OF PH SENSING
NANOPROBES
When compared with methods of imaging such as PET
scans or biomarker detection, pH sensing nanoprobes
demonstrate a significant improvement boasting clearer
images and the opportunity for applications such as guided
surgery in the future. Though these are some obvious benefits,
certain biological limitations and ethical considerations must
also be taken into account to produce a holistic understanding
of all sides of this nanotechnology.
Limitations of PH Sensing Nanoprobes in Cancer
Detection
For pH sensing nanoprobes to be considered sustainable,
their long-term effects on public health have to be evaluated
beyond the standards required for the initiation of clinical
trials with an IND. In this context, sustainability is
maximizing the improvements to quality of life of skin cancer
patients through more precise imaging and guided surgery
possibilities, while minimizing future health risks that could
be incurred by insufficient investigation into long term bodily
effects. There are undeniable concerns about public health
that must be addressed before pH sensing nanoprobes can be
proclaimed sustainable.
To satisfy this definition, the risk of using pH sensing
nanoprobes must be minimized. It is important to recognize,
however, that there is always an inherent risk associated with
introducing a foreign device to the body. Therefore, an
accurate measure of risk in this situation is a comparison
between the risks of imaging with pH sensing nanoprobes and
an alternate imaging technology such as a PET scan.
According to an article from the U.S. National Library of
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trials so far, it is important to recognize that the light required
to cause fluorescence in pH sensing nanoprobes cannot
penetrate deep enough into the body to image certain organs.
Thus, even in light of the advantages of pH sensing
nanoprobes, there are still significant limitations on the types
of cancer that can be imaged based on location in the body
and pH of the region in question.
As briefly mentioned earlier, concerns about oxidative
stress and temporary body weight loss in mice receiving the
probes are significant concerns about the sustainability of pH
sensing nanoprobes with respect to public health. On the other
hand, increased environmental safety supports the sustainable
application of pH sensing nanoprobes. In an environmental
context, the term sustainability is the capacity for such a
technology to exist without detrimentally affecting the
environment around it because of its “green” characteristics.
An article by Adah Almutairi, Steven J. Guillaudeu, Mikhail
Y. Berezin, Samuel Achilefu, and Jean M. J. Frechet, all of
the College of Chemistry at University of California,
Berkeley, highlights such environmental benefits of a
nanoprobe nearly identical to PINS, apart from some
structural differences [18]. The article details another nearinfrared (NIR) nanoprobe that operates by activating
fluorophores and is “especially promising for imaging
applications because of [its] … biodegradable structure” [18].
The article explains the process which creates a completely
biodegradable nanoprobe in a form resembling that of a
dendrite, for effective outreach into isolated areas. A core
structure consisting of pentaerythritol, a biodegradable
organic compound, composes the backbone of this specific
nanoprobe [18]. The environmentally friendly capabilities of
this technology stem from its organic structure, allowing pH
sensing nanoprobes to be environmentally sustainable. With
future implementation of this technology, this biodegradable
structure assures that pH sensing nanoprobes will not
contribute to the production of additional biohazard waste in
hospitals, thereby sustaining the cleanliness of medical
byproducts. In sum, while there are potential health concerns
associated with this technology that necessitate additional
research, many positive aspects exist with respect to
biodegradability which provide grounds for sustainable
development.
Social Impact and Ethical Considerations
In addition to the drawbacks regarding imaging potential
for different cancer types, there are many issues within the
social realm that complicate uses of nanotechnology. While
the technology behind pH sensing nanoprobes yields copious
amounts of benefits, Patrick Lin, an author for “The
Scientist,” asserts that it can lead to conflicts between
religion, society, and personal backgrounds in a population
[17]. These conflicts shall be considered in accordance with
the overall positive impact of cancer detection.
With advancing cancer detection, the biggest social
impact is what Lin calls “personal” issues [17]. Members of
the public may oppose the use of such technology because of
resulting increases in population as well as assimilation of
unnatural processes into the body. The article describes an
increase in population as negatively affecting social security,
retirement, and other types of general welfare [17]. In
summation, Lin points out that some may disagree with the
development of pH sensing nanotechnology for cancer cells
because of worries that increased population will put strain on
the world’s resources.
In addition to population concerns, the use of such
technology raises questions about the extent to which
medicine should be allowed to interfere in the body. Lin
suggests that in the long term, new nanotechnology devices
are paving the road towards doctors “playing the hand of
God” [17]. With a technology as in need of further
development as pH sensing nanoprobes, social barriers
stemming from opinions on the correct allocation of
government funds for such research could be a problem
moving forwards. As the world becomes more
technologically advanced, those wary of losing touch with
natural processes will always exist. However, equally as
steadfast is the presence of skin cancer and a demand for new
technology to improve patients’ lives. The American Cancer
Society, a large cancer research organization, states that
“Different approaches might be used to treat basal cell
carcinoma, and squamous cell carcinoma… Fortunately, most
of these cancers...can be cured with fairly minor surgery or
other types of local treatment” [4]. The ease of treating skin
cancer is a reason to look for more accurate means of
detection, regardless of minor social backlash that might
occur.
Benefits Prove Importance to Health-Care Field on a
Global Scale
As earlier discussed, cancer is a worldwide phenomenon,
and skin cancer is one of the most prevalent varieties.
Developing pH sensing nanoprobes for imaging and guided
surgery is important even if the same technology cannot trace
all cancers universally. To actualize these goals, members of
the engineering and health fields must develop new
technologies affordably. Unfortunately, little information
exists at present on the cost for specific nanosensors such as
PINS. However, a better understanding of the cost sources of
using this imaging method can be achieved by analyzing
components behind the technology.
In regards to the cost of implementing pH method
imaging in hospitals, the new SPY Elite camera appears as a
promising product. T. Zhao et. al. mention SPY Elite cameras
in reference to detailed analysis of nanosensor injection levels
in their article on the PINS nanoprobe [1]. The corporate
Nanoprobe Byproducts and Environmental Impact
7
Rachel Lau
Chloe Feast
website for NOVADAQ, a fluorescence imaging company,
states that “SPY Elite is the first and most advanced
fluorescence imaging system that enables surgeons
performing
open
procedures...to
visualize...tissue
intraoperatively” [19]. As such, many sources suggest this
camera as a necessary requirement for imaging with pH
sensing nanoprobes, making it an additional cost to take into
account. Like the nanoprobes, there is little listed on the cost
of SPY Elite, but hospitals would need to invest in the camera
to properly apply pH sensing nanoprobe technology.
However, the investment would soon pay off. This imaging
system would make surgery significantly safer due to the
clarity of the images produced. Safer surgery is also cheaper
surgery, as costs arising as a result of complications are
minimized. Therefore, this system in combination with the
proved efficiency of pH nanosensors makes for an extremely
successful imaging process.
While new cameras pose a potentially respectable initial
cost, the use of SPY Elite and nanosensors such as PINS
should lower the cost to patient on the average. This occurs
because PINS nanoprobes can produce such a detailed image
that receiving patients would require less additional testing.
Additionally, the nanoprobes themselves are relatively
inexpensive. An article by multiple researchers of the
University of California, L.A. Nanosystems Institute analyzes
data recorded using plasmonic nanosensors, and references
them as being very low-cost [20]. Furthermore, the visual
produced in combining SPY Elite cameras with PINS
nanoprobes should decrease surgical complications.
NOVADAQ’s website for SPY Elite advertising cites that
these avoidable surgical complications lead to mass cell death
in localized regions [19]. These complications cause longer
term expenses, but can be avoided via improved healthcare
[19]. Therefore, application of pH sensing nanoprobes would
admittedly require an initial expense, but overall would make
detection and treatment more affordable, and more easily
implemented for many affected with skin cancer.
environment. Biodegradable nanoprobe structures mean that
helping people does not come at the cost of hurting the
environment—rather it contributes to environmental
sustainability while simultaneously improving the lives of
those affected with skin cancer.
Given the opportunity to improve detection and imaging
of skin cancer, one of the most common forms of cancer that
affects individuals worldwide, it is logical to employ such
technologies. Overall, pH sensing nanoprobes are a
worthwhile pursuit. Though they are still in early stages of
development, the potential to improve the lives of so many
individuals affected with skin cancer justifies many, if not all,
of the costs going forward.
SOURCES
[1] T. Zhao et al. “A transistor-like pH nanoprobe for tumour
detection and image-guided surgery.” 12.19.2016. Accessed
1.11.2017. http://www.nature.com/articles/s41551-016-0006
[2] “Cancer Statistics.” National Cancer Institute.
3.14.2016.
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https://www.cancer.gov/aboutcancer/understanding/statistics
[3] “Skin Cancer Facts and Statistics.” Skin Cancer
Foundation. 6.8.2016. Accessed 1.11.2017.
http://www.skincancer.org/skin-cancer-information/skincancer-facts#indoor
[4] “Basal and squamous cell skin cancer treatment.”
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Cancer
Society.
5.10.2016.
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[5] J. Chiche et. al. “Tumour hypoxia induces a metabolic
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[7] Q. le Masne de Chermont et. al. “Nanoprobes with nearinfrared persistent luminescence for in vivo imaging.”
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[8] M. Monici. “Cell and Tissue Autofluorescence Research
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PH SENSING NANOPROBES MOVING
FORWARD
Throughout this paper the various pros and cons of pH
sensing nanoprobes for carcinoma detection have been
addressed to present a complete assessment of this
technology. While bringing pH sensing nanoprobes to a
hospital setting means much additional research, new
equipment costs, and a lengthy process of FDA approval, the
potential improvements in the detection and imaging of skin
cancer justify this investment of time, effort, and money in the
long run. When compared with other methods of carcinoma
detection, there is no doubt that pH sensing nanoprobes
provide an element of precision and potential for guided
surgery that will vastly improve the lives of skin cancer
patients when applied in the medical field. Yet, even while
helping cancer patients, this technology does not hurt the
8
Rachel Lau
Chloe Feast
http://www.livestrong.com/article/442195-the-overall-ph-ofbody-fluid/
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[12] S. Lazic. “What exactly is a p-value?” Experimental
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[20] Z. Ballard et. al. “Computational Sensing Using LowCost and Mobile Plasmonic Readers Designed by Machine
Learning.” ACS Publications. 1.27.2017. Accessed 3.3.2017.
http://pubs.acs.org/doi/abs/10.1021/acsnano.7b00105.
ACKNOWLEDGEMENTS
We would like to thank Grace Bova, our co-chair, for all of
her help.
We would also like to thank the Swanson School of
Engineering for providing us with the knowledge to undertake
our project.
Lastly, we would like to thank our friends for supporting us
throughout our long, collaborative process.
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