Issue Report
Sophie Atkins
Is the use of gold nanoparticles for photothermal ablation a
better alternative to chemotherapy to treat cancer?
Problem:
‘Cancer is a malignant tumour the course of which is fatal; a degenerative disease in
which cells multiply uncontrollably and invasively, infiltrating adjacent tissues and often
spreading to other parts of the body’1. Around 309,500 people were diagnosed with
cancer in 2008 in the UK and cancer incidence rates have risen by 16% in males and by
34% in females since the late 1970s2. Although death rates as a result of cancer have
dropped significantly since the 1990s however there are areas that need to be improved,
therefore, earlier detection and new treatments need to be developed. In recent years
there have been many investigations into the use of nanoparticles to detect and treat
cancer. The only way cancer can be treated is by killing cancerous cells which prevents
them from multiplying and spreading. Chemotherapy works by killing the cells that divide
rapidly; this means that it also kills cells that divide rapidly under normal conditions such
as bone marrow and hair follicles. This results in a number of side effects such as
myelosuppresion (reduced production of blood cells) which in turn leads to
immunosuppression. Another side effect is alopecia (hair loss), which happens when hair
follicle cells are killed3. New medical strategies using nanotechnology are being
developed to target cancer cells and prevent damage to healthy cells; one of these
strategies is photothermal ablation which provides a more effective treatment with fewer
side effects.
What is photothermal therapy and what are gold nanoparticles?
Photothermal therapy uses nanoparticles to kill
cancerous cells without damaging neighbouring
healthy cells. This works because cancer cells die at
42˚C whereas normal cells die at 46˚C. The
nanoshells commonly used in this treatment are
approximately 30-50nm. The reason that gold
nanoparticles are used is that they are safer than other
metals and so do not cause as many side effects; they
also have good thermal absorption properties and can
therefore absorb large amounts of heat energy. The
nanoshells can be modified to improve their
Figure 1: Photothermal Ablation
1 The world of Biology P. William Davis, Eldra Pearl Solomon
http://info.cancerresearchuk.org/cancerstats/keyfacts/Allcancerscombined/
3
http://www.bupa.co.uk/individuals/health-information/directory/c/chemotherapy
2
1
Issue Report
Sophie Atkins
suitability to certain applications. ‘To enhance stability, prevent non-specific protein
adsorption, and increase circulation time in vivo the nanoshells were coated with
poly(ethylene glycol), PEG molecules self-assemble on the Nanoshell surface.’4
The Process of photothermal ablation:
Figure 15 shows the process of photothermal ablation. The nanoshells are linked to
antigens which target cancer cells which means that they seek out cancer cells and then
move into the cells. Near infrared light is then applied causing the nanoshells to heat up.
NIR is used due to its low absorbance by tissue chromophores such as haemoglobin and
water, therefore preventing damage to healthy tissue. Upon tumour laser irradiation NIR
light is absorbed by nanoparticles and heat generated. When the temperature of the
nanoparticles increases to above 42˚C denaturisation of proteins and impairment of DNA
and RNA synthesis starts and cell membrane rupture starts to occur killing the cancerous
cells6.
This was demonstrated in a recent study carried out on mice. A biodistribution study
confirmed that nanoshells delivered intravenously accumulated in the tumour cells of
mice which meant that a further investigation of photothermal ablation therapy could take
place. A total of 25 tumour bearing mice where used in this experiment. The mice were
injected with glioma cells and left for the cancer to develop. Once each of the tumours
had reached a diameter of 3-5.5mm the mice received intravenous injections via the tail
vein. Seven of the mice were intravenously injected with 100µl PEG-coated nanoshells,
8 mice received intravenous injections of saline solution; these mice were the sham
group. The remaining 9 mice were used as
a control group and received no injection.
After 6 hours to allow for circulation of the
nanoparticles/saline solution the mice were
anesthetized prior to the application of an
808nm NIR light laser for three minutes.
The tumours were then measured daily
following the treatment to track growth or
regression. The mice were monitored for
90 days or until the tumours reached 10mm
in diameter at which point the mice
Figure 2: Bar chart showing tumour measurements at 0 and 10 days
were euthanized.
4
http://westlab.rice.edu/download?fileType=publication&id=1437
5
http://www.cancer.gov/cancertopics/understandingcancer/nanodevices/AllPages
6
http://westlab.rice.edu/download?fileType=publication&id=1438
2
Issue Report
Sophie Atkins
Reliability and validity of the experiment:7
The total number of mice involved in the experiment was only 25. This is a fairly large
group which improves the reliability of the experiment. If a larger sample size was used
then the results would be better as a more accurate average could be taken with any
anomalous results discounted. The experiment was carried out in laboratory conditions,
controlling almost all of the variables thus improving the validity of the experiment. Only
albino female mice were used in the trial, which were aged between 5-6 weeks and
weighing between 15-20g each. ‘Each was shaved on the right dorsal flank prior to
subcutaneous inoculation with 1.5× 10 ⁵ (50 ml injection volume) CT26.WT murine colon
carcinoma tumour cells’8. The experiment was funded by the National Science
Foundation, an American government agency that funds scientific and engineering
research, it is a non-biased organisation. The National Science Foundation has put $69
million into nanoscale development and engineering. The experiment was carried out by
several scientists from the department of bioengineering at Rice University, the
department of electrical and computer engineering at Rice University and Nanospectra
Biosciences Inc., Texas, USA.
Figure 3: Kaplan-Meier graph, experiment 1
Results:
The experiment showed some very promising results. Figure 2 shows that the mice
treated with nanoparticle assisted photothermal therapy showed complete tumour
regression within 10 days, a huge difference to the average length of chemotherapy
treatment. The therapy showed a 100% survival rate (Figure 3) in those mice that
7
8
http://westlab.rice.edu/download?fileType=publication&id=1437
http://courses.engr.illinois.edu/ece398/sb/articles/12-6%20Halas-Cancer-LettersPhotothermal%20Ablation.pdf
3
Issue Report
Sophie Atkins
received the NAPT; however more research must be carried out before the treatment can
be proven. The mice treated with NAPT survived beyond the 90 days in which the trial
took place whereas none of the control group survived beyond 12 days, the mean
survival time was only 10.1 days. There was little difference in the survival time of the
sham group, the mean survival time for which was 12.5 days.
Further investigations:9
One of the scientists involved in the first experiment (‘Photo-thermal tumour ablation in
mice using near infrared-absorbing nanoparticles’) carried out in 2003 took part in a
second investigation on the same subject that took place in 2010. This investigation was
on a smaller scale, only 15 male mice were used in the study. The mice were injected
with the same amount of glioma cells and these cells were left until a tumour had grown
to the size of 3-5mm. At this point seven of the mice were intravenously injected with
nanoshells and the other eight were injected with nothing, no sham treatment group was
used this time. The results demonstrated a clear difference between the two groups as
shown in figure 4. In this experiment bioluminescent imaging was used to show the
tumour growth/regression throughout the trial, Figure 5 shows these images. The mouse
pictured in the first row received nanoshell assisted laser therapy and displayed complete
tumour regression without any signs of re-growth. The mouse in the second row received
exactly the same treatment but only responded partially, you can see that by day 20
there was reappearance of tumour cells. Visible scabs formed on the mice in row one
and two which is a sign that the nanoshell assisted laser therapy is effective as the
nanoshells heated up significantly. Finally the mouse in the third row did not receive
nanoshell assisted laser therapy and was
instead injected with saline solution
(having no effect on the mouse) the laser
did not produce enough heat to kill the
cancerous cells and so no tumour
regression was seen and eventually the
mouse had to be euthanized at day
twelve. None of the eight mice in the
control group survived beyond 24 days
and the mean survival for these mice was
Figure 4: Kaplan- Meier graph; experiment 2
only 13.3 days. By comparison four of the
seven mice in the nanoshell therapy group survived for the entire ninety days and
showed complete tumour regression with no recurrence. The research for this
9
http://westlab.rice.edu/download?fileType=publication&id=1438
4
Issue Report
Sophie Atkins
experiment was funded by the National Science Foundation and Hope Street Kids, a
charity that raises money to fight against childhood cancer.
Figure 5: Bioluminescent images showing tumour
size in a murine glioma model (9)
Implications:
There are many implications of this new development in cancer therapy. There has been
economic impact as a result of developing and trialling these new therapies; it is very
expensive to carry out research and to develop treatments prior to clinical use. In the
USA there are currently two major companies funding research, these are The National
Cancer Institute (part of the National Institute of Health) and The National Science
Foundation, both government run foundations. The National Science Foundation has put
$69million into research, the National Cancer Institute has a five year budget of
$144.3million to develop and translate cancer related nanotechnology research into
clinical practice. As they are both under control of the government it will be socially
beneficial as it means that the country as a whole benefits from anything that is
discovered, this also means that the treatment should be available to everyone,
depending on the cost of treatment. Treatment is likely to be expensive because of the
difficulty in fabricating the gold nanoshells, so the cost of treatment is unlikely to be
covered by the government this would mean that fewer people would receive the
treatment as they can’t afford it.10
10
http://www.tahan.com/charlie/nanosociety/course201/nanos/NH.pdf
5
Issue Report
Sophie Atkins
A further implication of the treatment is associated with the ethical issue of animal
cruelty. In order to test the therapy in vivo it must be carried out on a living organism,
such as an animal or person. Animal testing has created huge ethical debates as some
people believe that it is cruel and that it is poor medical practice. ‘Animal experimentation
involves the incarceration of animals- which itself causes intense psychological distresswho are poisoned, mutilated, given diseases and killed’.11 However it is still important to
carry out animal tests prior to a clinical trial to ensure that there are no fatal side effects.
Beneficial implications of Photothermal Ablation:
There are many benefits of photothermal ablation, especially in comparison to other
treatments available to treat cancer tumours at the moment. The first option to treat a
tumour at the moment is to surgically remove it, followed by chemotherapy and/or
radiation to kill any cancer cells. As mentioned previously there are quite a few side
effects with chemotherapy and surgery is not a very effective treatment as it can rarely
remove the whole tumour and is particularly dangerous when the tumour is formed in the
brain or the Central Nervous System. Photothermal ablation is less invasive and
destructive to neighbouring cells. For this reason there are fewer side effects in
comparison to those presented from surgery and chemotherapy. Chemotherapy also
damages bone marrow cells and therefore in turn lowers the body’s immunity as fewer
white blood cells are produced12, as the nanoshells used in photothermal ablation are
targeted to cancerous cells they do not damage healthy cells so the problem of
immunosuppression is avoided.
Risky implications of Photothermal Ablation:
There is ongoing research into the effects of prolonged or repeated exposure to
nanoshells in the body. A study carried out by James et al. found that nanoshells persist
in the body up to 28 days post injection without toxicity.’13 Further research must be
carried out to asses if there are any cytotoxic affects of nanoshells after prolonged
exposure to the body. One of the greatest risks presented by the development of this
therapy is that there are no known side effects to humans as yet; however the only know
side effect that was shown in the murine glioma model was the formation of a scab due
to the heat released by the nanoparticles when NIR was applied.14
11
http://www.uncaged.co.uk/vivisect.htm
http://en.wikipedia.org/wiki/Chemotherapy
13
http://westlab.rice.edu/download?fileType=publication&id=1438
14
http://westlab.rice.edu/download?fileType=publication&id=1438
12
6
Issue Report
Sophie Atkins
Alternative and Future Developments of Photothermal Ablation:
At the moment the only other available ways to treat cancer tumours are chemotherapy,
radiation and surgery. There are other therapies being developed to treat cancerous
tumours such as nanoparticle assisted drug delivery. Nanoparticle assisted drug deliver
works in a similar way to photothermal ablation, however the nanoshells carry a drug;
they are targeted to combine with antibodies that are attracted to cancer cells. This
means that the drug is delivered to cancer cells only resulting in fewer side effects cause
by the drug being carried in the nanoparticles.15
A biological problem with the therapy at the moment is the penetration depth and
strength of NIR through the human skull. ‘Light cannot penetrate the human skull so
treatment of human brain tumours with nanoshell mediated photothermal therapy with
need fiber optic laser probes to deliver the light energy.’16 A further development of the
therapy using fibre optic probes has been carried out on a brain tumour orthotopic canine
model. The experiment involved a cranial incision being made along the coronal ridge,
nanoshells were injected into the tumour, and a few hours later fibre optic probes were
inserted into the holes in the skull and the NIR therapy started. This treatment is far more
invasive in comparison to photothermal ablation used to treat surface tumours as it
involves drilling into the brain.17 However it could significantly improve brain tumour
survival rates if the therapy proves effective due to the significant risks of surgery to
remove brain tumours.
Evaluation of sources:
The report on the first experiment was published in Cancer Letters a journal owned by
the publisher Elsevier. Elsevier is a Dutch medical and scientific publisher that publishes
2,000 journals a year and has been since 1880. Cancer Letters is a peer reviewed
journal that has a good world reputation for publishing cancer research and the
development of new therapies. The experiment was funded by government organisations
so there was no vested interest thus improving the credibility. The report was published
in 2004 and so is fairly recent.
Cancer Research UK is the world leading cancer charity that is dedicated to saving lives
through research; it invests £332 million a year on research producing reliable
experimental data. Cancer Research is also a non-profit organisation that is entirely
funded by the public through donations, legacies, events and retail. The credibility is
improved as the charity has no vested interest in the research
15
http://www.benthamscience.com/ddf/samples/ddf1-1/0004DDF.pdf
http://westlab.rice.edu/download?fileType=publication&id=1438
17
http://144.206.159.178/FT/CONF/16425096/16425156.pdf
16
7
Issue Report
Sophie Atkins
Glossary:
Immunosuppression-The partial or complete suppression of the immune response of
an individual, induced to help the survival of an organ after a transplant. (Wikipedia)
Near Infrared light- is the portion of the infrared spectrum extending from roughly 0.75
to 5 millionths of a meter. (www.astronomydetectives.org/glossary.html)
Biodistribution- Biodistribution is a method of tracking where compounds of interest
travel in an experimental animal or human subject. (Wikipedia)
Glioma Cells- A glioma is a type of tumor that starts in the brain or spine. It is called a
glioma because it arises from glial cells. (Wikipedia)
Sham group- A placebo group
Bioluminescent imaging- Bioluminescence is the process of light emission in
living organisms. Bioluminescence imaging utilizes native light emission from one of
several organisms which bioluminescence. (Wikipedia)
Bibliography
Animal experimentation- The facts. 2010. http://www.uncaged.co.uk/vivisect.htm
(accessed January 24, 2012).
Cancer Research Statistics. December 7, 2011.
http://info.cancerresearchuk.org/cancerstats/keyfacts/Allcancerscombined/ (accessed
January 12, 2012).
Chemotherapy. July 2011. http://www.bupa.co.uk/individuals/healthinformation/directory/c/chemotherapy (accessed January 12, 2012).
Chemotherapy. July 2009. http://en.wikipedia.org/wiki/Chemotherapy (accessed January
25, 2012).
E. Day, P. Thompson, L. Zhang, N. Lewinski, N. Ahmed, R.Drezek, S. Blaney, J. West.
Nanoshell-mediated photothermal therapy improves survival in a murine glioma model.
Houston, Texas: Springer Science & Business Media, 2010.
Hui, Nicole Chia Poh. Nanomedicine and Cancer. Madison, Wisconsin, 2005.
J. Schwartz, A. Shetty, R. Price, R. Stafford, J. Wang, R. Uthamanthil, K. Pham, R.
McNichols, C. Coleman, J. Payne. Nanoparticle-assisted photothermal ablation of brain
tumor in an orthotopic canine model. Houston, Texas: Nanospectra Biosciences Inc.,
2009.
8
Issue Report
Sophie Atkins
Mandal, N. Praetorius & T. Engineered Nanoparticles in Cancer Therapy. Xavier
University of Louisiana, New Orleans, Louisiana: College of Pharmacy, 2006.
P. O'Neal, L. Hirsch, N. Halas, J. Payne, J. West. "Photo-thermal tumor ablation in mice
using near infrared-absorbing nanoparticles." Cancer Letters, 2004: 171-176.
Solomon, P. Davis & E. The World of Biology (3rd Edition). Orlando: Saunders College
Publishing, 1986.
What is nanotechnology? January 28, 2005.
http://www.cancer.gov/cancertopics/understandingcancer/nanodevices/AllPages
(accessed January 14, 2012).
9