ELECTRONIC SUBMISSION
FOR CONSIDERATION IN THE
UNIVERSITY OF TORONTO MEDICAL JOURNAL
Nanooncology: the breast cancer story
AUTHOR NAMES: Anjali Rastogi1 HBSc, MSc, MD Candidate 2012
AUTHOR AFFILIATIONS: 1 Faculty of Medicine, University of Toronto
CORRESPONDING AUTHOR EMAIL ADDRESS: anjali.rastogi@utoronto.ca
ABSTRACT
Breast cancer is the most common cancer in Canadian women. Despite advances in the
past decade, current diagnostic and treatment modalities remain limited. Nanomedicine may
overcome some drawbacks of conventional breast oncology. Based on their composition and
physical properties, different types of nanoparticles can be designed as drug delivery vehicles,
contrast agents and/or diagnostic devices. Their use allows for more accurate molecular
profiling of cancer biomarkers, improved in vivo tumour and sentinel node imaging and better
selective therapeutic targeting so that tumour exposure to antineoplastic drugs is maximized
while systemic exposure is minimized. The general principles of nanomedicine, role of
nanoparticles in breast cancer management, their current clinical uses, challenges and future
prospects are reviewed, all in relation to breast cancer specifically. Nanomedicine appears to be
a promising avenue by which breast oncology can advance.
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KEYWORDS: breast cancer; nanomedicine; nanooncology; diagnosis; treatment
MANUSCRIPT TEXT
The opportunity to use nanomedicine in breast oncology
Breast cancer is the most common cancer in Canadian women with approximately 23
000 women diagnosed annually. Despite screening and therapeutic advances, which have
decreased the age-standardized mortality rate for breast cancer in women by 25% since 1986,
more than 5000 Canadian women die from breast cancer every year. The majority are
diagnosed at early stages where five year relative survivals are 96% and 86% for stages I and II
respectively. Unfortunately, because of recurrence after successful treatment, the 20 year
relative survival is only around 70%.1
Diagnostic evaluation of a patient with suspected breast cancer includes breast imaging
and biopsy. However, current imaging modalities such as diagnostic full screen, full field digital
mammography or gadolinium enhanced contrast magnetic resonance imaging (MRI) remain
limited. Disadvantages of film screen mammography, for example, include difficulty imaging
components of the breast such as dense tissue and inability to manipulate images. 2 Current
treatments for breast cancer, including radiotherapy and chemotherapy, also remain limited.
Chemotherapeutic agents have characteristics that constrain their clinical use including water
insolubility, nonspecific biodistribution and targeting and systemic toxicity. Drug resistance can
develop shortly after initial treatment, limiting the efficacy of therapy.3
Thus, marked improvements in the diagnosis and treatment of breast cancer are
required. Nanomedicine overcomes some of the current drawbacks associated with
conventional breast oncology. In recent years, the funding for nanotechnology research in
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Canada and the rest of the world has increased dramatically. Since the implementation of the
U.S. national nanotechnology initiative with initial funding of more than US$400 million in 2000,
annual spending has now reached over US$2.3 billion in U.S., Europe, Japan, China, Korea and
Taiwan together. In Canada, funding for nanomedicine was realized recently through CIHR’s
Regenerative Medicine and Nanomedicine Initiative and NSERC’s Nano Innovation Platform
Awards.4 Nanomedicine is a rapidly growing field that operates at the same scale as biological
processes and thus has the potential to improve the prevention, detection, diagnosis and
treatment of diseases.
This paper reviews the fundamentals of nanomedicine and its role in the diagnosis and
treatment of breast cancer. It reviews approved clinical uses of nanoparticles, clinical trials that
are underway, challenges and future prospects, specifically in relation to breast cancer. It
highlights how this cancer has been the first to benefit as nanooncology progresses from
laboratory to bedside.
What is nanomedicine?
Nanotechnology is defined as the “intentional design, characterization, production, and
application of materials, structures, devices and systems by controlling their size and shape in
the nanoscale range (1 to 100nm).” 5 While nanomedicine involves the exploitation of the
properties of nanoparticles for the diagnosis and treatment of diseases at the molecular level,
nanooncology in particular involves developing nanoparticles for use in tumour imaging in vivo,
molecular profiling of cancer biomarkers and targeted drug delivery. 6
In order to understand how nanomaterials can be designed as drug delivery vehicles,
contrast agents and/or diagnostic devices, it is necessary to have a basic understanding of their
favourable properties. These properties include a high surface area to volume ratio, which
enables particle surfaces to be coated with biomolecules such as oligonucleotides or peptides
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for both improved biocompatibility and selective targeting of biologic molecules such as tumour
markers; alterable optical, magnetic, electronic and biologic properties; and the ability to be
engineered in different sizes, shapes and chemical compositions.7-9 Most nanoparticles can be
classified into three main types: 1) organic particles which use nonmetal atoms as the
predominant building material, 2) metallic particles and 3) semi-conducting particles that consist
of a mixture of metal and nonmetal atoms.7
Organic nanoparticles include liposomes, dendrimers, carbon nanotubes, emulsions and
other polymers. Liposomes are self-assembling closed colloidal structures composed of lipid
bilayers. They are being developed as antineoplastic drug delivery vehicles for different human
tumours. Liposomal formulations of the anthracyclines doxorubicin and daunorubicin (Doxil or
Caelyx, Myocet, DaunoXome), for example, have already been approved for the treatment of
metastatic breast cancer and Kaposi’s sarcoma.3,12-15 Dendrimers are branched nanostructures
and in addition to drug delivery, they are being used as MRI contrast agents. 16 Carbon
nanoparticles are being used for both drug delivery and sentinel-node visualization.7, 17, 18
Metallic nanoparticles include gold, supermagnetic (eg. iron oxide) particles and
nanoshells. Gold nanoparticles are solid metal particles conventionally coated with proteins,
oligonucleotides or drug molecules. They are being used for drug delivery, as are iron oxide
particles, and for in vitro diagnostics such as high throughput genomic detection.19 Iron oxide
particles are also being used as MRI contrast agents and have been approved for human use
(Feridex, Resovist).7,20,21 Nanoshells are dielectric cores covered by thin metallic shells, usually
gold. They are currently in phase I clinical trials for the treatment of recurrent head and neck
tumours.7, 22 Nanoshells are injected into these tumours and illumination with light of specific
wavelengths produces localized heating from electron excitation and subsequent cell death.
Semi-conducting nanoparticles include quantum dots. These are fluorescent, core-and-shell
structured nanoparticles that are under investigation for use in in vitro diagnostics.23
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Nanomedicine in diagnosing and imaging breast cancer
Molecular profiling
Around two thirds of breast cancers express hormone receptors.10 Diagnostic evaluation
of breast cancer includes assessing the expression of estrogen receptor (ER), progesterone
receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer cells.
This is necessary to identify patients who are likely to benefit from endocrine treatment such as
tamoxifen and/or anti-HER2 treatment (i.e. the monoclonal antibody trastuzumab).10 Recent
data suggest that response to chemotherapy may also correlate with hormone receptor
expression.24 Thus, therapeutic decisions depend on accurate molecular profiling of resected
breast cancer specimens. Prognostic information may also be garnered from profiling, though
data is insufficient to recommend using ER, PR and HER2 overexpression to determine
prognosis in patients with early breast cancer.25 The standard method of profiling in current
clinical practice is immunohistochemistry. However, its limitations include signal degradation,
the inability to detect different protein biomarkers on the same specimen and background noise
interfering with true quantitative assessment of expression.10, 26, 27 When combined with systems
such as automated image analyses immunohistochemistry can indeed precisely quantify
biomarker expression. However, these systems are not widely available.
Quantum dots have optical properties that can overcome some limitations associated
with conventional molecular profiling. Advantages of dots include extended photostability and
high intensity fluorescence, resulting in absence of photobleaching and improved diagnostic
sensitivity respectively.28 Moreover, individual quantum dots have unique fluorescence emission
peaks which can be easily detected and quantified by spectrometry. Different quantum dots can
be conjugated to different antibodies targeted to protein biomarkers in cancer cells and spectra
from several dots can be simultaneously quantified in a single breast tumour section.26,27,29,30
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Yezhelyev and colleagues developed a quantum-dot based assay that allows quantitative
detection of ER, PR and HER2 in paraffin-embedded cultured breast cancer cell lines and
clinical tissue sections. Quantitative expression of the biomarkers correlated with conventional
immunohistochemical analysis and semi-quantitative western blotting.29, 30
Along with immunohistochemical staining, HER2 overexpression can be assessed by
fluorescence in situ hybridization (FISH). The latter is the standard method for determining gene
amplification. Quantum dots have been used to improve the sensitivity of FISH. Dots have been
conjugated to DNA probes for HER2 and then incubated with breast cancer cells to detect
HER2 at levels of expression that are undetectable by conventional FISH.31
Therefore, using nanoparticles offers several advantages over conventional molecular
profiling, including the opportunity to simultaneously quantify several proteins on small tumour
specimens. This will eventually: 1) allow antineoplastic therapy, both adjuvant and for metastatic
disease, to be tailored to an individual patient’s tumour protein profile and 2) facilitate sensitive
monitoring of protein expression in cancer cells pre and post therapy to determine treatment
efficacy.26
In vivo tumour and sentinel node imaging
Initial evaluation of suspected breast cancer involves diagnostic bilateral mammography,
often supplemented with ultrasonography. While gadolinium contrast enhanced breast MRI
facilitates detection of occult cancer and extent of disease, its appropriate role in diagnostic
evaluation is unclear. A major disadvantage is its limited specificity due to enhancement of
benign breast lesions, leading to overtreatment and a shift away from breast preservation. 32 In a
meta-analysis of 44 studies, pooled specificity was reported as 72%.33
Several research groups have reported using nanoparticles for tumour imaging to
overcome some of the drawbacks of conventional contrast agents. Supermagnetic nanoparticles
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are being developed as MRI contrast agents because they leak through immature tumour
vasculature due to their nano-size, generate magnetic fields and amplify signal in surrounding
tumour tissue.10,26 To date, two iron-oxide based agents have been approved (not yet in
Canada) specifically for MR imaging of the liver: Resovist (generic name: ferucarbotran) and
Feridex (generic name: ferumoxide).10,19,20,26
Advantages of magnetic nanoparticles are high levels of accumulation in target tissue for
better diagnostic specificity, biocompatibility, low toxicity and their ability to be conjugated to
cancer specific ligands for earlier identification of tumours and peripheral metastases. 10,34
Sunderland and colleagues used ultrasmall superparamagnetic iron oxide nanoparticles
(USPION) in breast cancer rat models to enhance leaky microvasculature of breast carcinomas
which can correlate with tumour grade and differentiate them from benign breast lesions.35 At
the same time, Zhou and colleagues showed that luteinizing hormone-releasing hormone
(LHRH) conjugated USPION enhanced the MRI of LHRH receptor-expressing breast cancers
and lung metastases in mouse models.20 USPION have also been conjugated with anti-HER2
antibodies and have shown potential for simultaneous imaging and therapeutic targeting of
breast cancer.19,36
Note that while quantum dots conjugated to anti-HER2 antibodies have recently been
traced in vivo after injection into live breast tumour bearing mice, their use in human in vivo
imaging has so far been limited by toxicity from their heavy metal core. 37,38
After breast cancer is diagnosed, determining the spread of disease to axillary lymph
nodes is imperative. It is an important prognostic factor in early stage breast cancer and is best
detected by histologic examination of removed nodes. To avoid anatomic disruption caused by
axillary lymph node dissection, sentinel lymph node biopsy (SLNB) is routinely performed for
staging clinically node negative breast cancers intraoperatively.39,40 SLNB is based on the
premise that a primary tumour metastasizes to sentinel lymph nodes before involving other
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nodes. Current methods involve injecting blue dye or radioactive tracer around the tumour to
identify a sentinel node which is removed and examined for cancer cells. To ensure removal of
the appropriate sentinel nodes, all nodes with greater than 10% radioactivity of the most
radioactive node are removed. The greatest concern with SLNB is the potential for false
negative results.39
Quantum dots may offer a simpler and more precise method to trace nodes without the
use of blue dye or radioactive tracer. Due to their nano-size, the dots do not flow past a sentinel
lymph node.10 Song and colleagues showed that after injection of near-infrared quantum dots
into the skin of a breast tumour-bearing animal, lymphatic flow was followed to a sentinel lymph
node and its location was easily identified.41 Intense fluorescence, specific accumulation and
extended photostability all enable more precise and sensitive imaging of sentinel nodes over
longer time periods under a single near infrared light source.41 Improved in vivo imaging may in
turn improve the precision and safety of sentinel node biopsies.
In summary, breast MRI in its current state is used judiciously in the clinical management
of breast cancer because of its low specificity. Nanoparticles may increase the diagnostic
specificity of imaging tumours, particularly when bioconjugated to nanoparticles, leading to less
false positive rates and radiation exposure.
Nanomedicine in treating breast cancer
The majority of patients who relapse after definitive treatment of early stage or locally
advanced disease will relapse with metastatic disease rather than local recurrence.
Conventional cytotoxic chemotherapy for metastatic breast cancer includes anthracyclines such
as doxorubicin and taxanes such as paclitaxel.Trastuzumab is the preferred initial agent for
HER2- positive cancer.42
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Conventional anthracycline preparations are limited by poor target tissue penetration and
cardiotoxicity from high cumulative doses.43 To address these drawbacks, liposomal
anthracycline preparations have been developed. They are given intravenously and work via an
“enhanced permeability and retention effect,” a passive tumour targeting mechanism (as
opposed to active targeting which uses ligand-specific conjugated nanoparticles) where
nanoparticles, by virtue of their size, extravasate through leaky tumour vasculature and
accumulate in tumour tissue, along with the drug molecule they carry, for an extended time. 3,10
Since liposomes too large to be cleared renally, they are cleared by the mononuclear phagocytic
system comprised of macrophages in the liver and spleen.44
Two liposomal preparations of doxorubicin are being sold in Canada: Caelyx, a pegylated
form, and Myocet, an unpegylated form. Adding polyethylene glycol protects the liposomes from
detection by the mononuclear phagocytic system, reduces drug clearance and prolongs drug
exposure.44 However, pegylation also results in a side effect known as hand-foot syndrome
which involves redness, tenderness and peeling of the skin due to Caelyx accumulating in the
skin.45,46 Hand-foot syndrome limits the Caelyx dose that can be given compared with
conventional doxorubicin, making it difficult to substitute Caelyx for conventional doxorubicin in
the treatment regimen for breast cancer. Therefore, while Myocet is approved for treatment of
metastatic breast cancer in combination with cyclophosphamide, Caelyx is approved only for
treatment of ovarian cancer and multiple myeloma.10,45,46
Randomized trials show that both Myocet and Caelyx have similar efficacy compared to
free doxorubicin, but have significantly decreased cardiotoxicity (6% versus 21%) and
neutropenia, with no additional toxicities.46,47 Development of preparations in which liposomes
are also bioconjugated to tumour targeting moieties have the potential to further improve
doxorubicin’s therapeutic index. Recently, Weng and colleagues showed successful delivery of
doxorubicin-conjugated, quantum dot-labeled liposomes conjugated with anti-HER2 antibody to
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HER2 cancer cells in
vitro.47
These liposomes had efficient antineoplastic activity compared to
controls.47 They serve as an example of targeted drug delivery systems that involve
simultaneous imaging and treatment of breast cancer.
Conventional paclitaxel has a synthetic delivery vehicle known as Cremophor EL which is
used to overcome the drug’s poor water solubility.10 However, Cremophor EL is associated with
marked toxicity, severe hypersensitivity reactions, leaching of plastic from standard tubing used
for administration and decreased tumour cell penetration due to encapsulation of the drug.10,48,49
Extensive research has been done to alter paclitaxel’s administration. Nab-paclitaxel is an
organic nanoparticle preparation where albumin surrounds a core containing paclitaxel. 50 It is
approved in U.S. for treatment of metastatic breast cancer after failure of combination
chemotherapy or relapse within 6 months of adjuvant chemotherapy— prior therapy should
have included an anthracycline unless contraindicated. Compared to conventional paclitaxel,
nab-paclitaxel has selective tumour permeability and albumin-receptor-mediated transport which
result in higher tumour versus systemic drug concentrations.10, 26, 50 Thus, nab-paclitaxel has a
more favourable toxicity profile with no requirement for steroid premedication to minimize
hypersensitivity reactions and no requirement for special tubing. 50 In randomized phase III trials,
nab-paclitaxel was associated with a significantly higher response rate than cremophor-based
paclitaxel (33% versus 19%) and longer time to tumour progression (21.9 versus 16.1 weeks) in
patients with metastatic breast cancer. Despite the 49% higher paclitaxel dose, nab-paclitaxel
was not associated with any severe hypersensitivity reactions, although it had a higher rate of
sensory neuropathy which was temporary and reversible.50
Multidrug resistance (MDR) poses a barrier to effective chemotherapy. Breast cancer
cells overexpress P-glycoprotein (pgp), a drug efflux pump that desensitizes tumour cells to a
wide range of chemotherapeutic agents including anthracyclines and taxanes. Since the toxicity
of current pgp inhibitors prohibits their clinical use, research has turned towards inhibiting pgp
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expression to overcome MDR. One strategy involves the use of RNA interference to silent gene
expression. Nanoparticles may be useful in delivering siRNA safely and specifically to tumour
cells. Recently, Gao and colleagues loaded nanoparticles with plasmid iMDR1-pDNA and
transfected adriamycin resistant MCF-7/ADR cells and MDR human breast cancer xenografts in
mice. They found reversal of MDR, greater chemotherapeutic drug accumulation and
consequent greater tumour suppression in iMDR1-pDNA transfected cells.51
While nanoparticles are also being used in in vitro research for gene therapy and
targeted thermal ablation treatment of breast cancer, their role as drug carriers is the closest
nanooncology has come to the patient’s bedside. The examples of liposomal doxorubicin and
nab-paclitaxel show how nanoparticles can enhance drug accumulation in target tissue, provide
constant and stable drug release and decrease efflux pump-mediated drug resistance.3,10 All of
these can improve therapeutic outcome and minimize systemic toxicity associated with
antineoplastic agents.
Conclusion: challenges with nanoparticles and future prospects
To date, there is no conclusive evidence of human toxic reactions that are uniquely
caused by nanoparticles. A recent review concluded that the risks associated with nanoparticles
depend on their type.52 Some may be toxic due to their heavy metal composition and other
physical properties while others may have negligible toxicity. Quantum dots, for example, are
limited in in vivo imaging by their heavy metal cores.37,38 Of course, this toxicity does not restrict
their use in vitro for molecular profiling.
More than toxicity, the cost of nanoparticles is a major issue. Bayer Schering Pharma AG
abandoned the production of Resovist in 2009 because it could not compete with another liver
imaging agent Primovist. Liposomal doxorubicin and nab-paclitaxel are also more expensive
than their conventional counterparts. The cost of Myocet is around 50-60 times that of
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conventional doxorubicin. Aside from the cost of nanoparticles themselves, there are substantial
operating costs: special spectroscopy equipment, for example, is needed for quantum dot
molecular profiling.26
Current challenges for nanooncology include: balancing increased drug loading capacity
of nanoparticles with maintenance of their nano size, inability to simultaneously target both
tumour cells and tumour microenvironment and the lack of characterization of nanoparticle
elimination from human bodies.3 In the near future, research must focus on optimizing
nanoparticles: improving their structure, quantifying their tissue distribution and analyzing their
pharmacokinetic and pharmacodynamic properties.3 Long term, broader goals must include
demonstration of efficacy of nanoparticle-based therapeutics, cost-benefit analyses and
consideration of physiological and environmental side-effects, comparing them to our current
management options.
Today nanomedicine plays a small clinical role in the diagnosis and treatment of breast
cancer. Considering its ability to offer new treatment options and better diagnostic tools, it
appears to be one promising avenue by which breast oncology can advance. Once challenges
are overcome, nanoparticles are likely to play a significant role in personalized cancer medicine.
ACKNOWLEDGMENTS
The author would like to thank Raheem Peerani (1T2) for guidance.
CONFLICTS OF INTEREST
There are no conflicts of interest.
REFERENCES
[1]
Canadian Cancer Society/National Cancer Institute of Canada. Canadian Cancer
Statistics 2010. Toronto, Canada, 2010.
UTMJ ORIGINAL RESEARCH SUBMISSION
Page 12 of 16
ANJALI RASTOGI
[2]
Mahesh M. AAPM/RSNA physics tutorial for residents: digital mammography: an
overview. Radiographics. 2004;24(6):1747 -1760.
[3]
Chen Z. Small molecule delivery by nanoparticles for anticancer therapy. Trends in
molecular medicine. 2010;16(12):594-602.
[4]
Fenniri H. The Canadian Regenerative Medicine and Nanomedicine Enterprise
(CARMENE). Int J Nanomedicine. 2006;1(3):225–227.
[5]
Terminology for nanomaterials [Internet]. Publicly available specification 136. London:
British Standards Institute; c2007 [cited 2010 Dec 20]. Available from:
www.nanointeract.net/x/file/PAS%20136.pdf
[6]
Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer.
2005;5:161-171.
[7]
Kim BYS, Rutka JT, Chan WCW. Nanomedicine. NEJM. 2010;363:2434-2443.
[8]
Xia Y, Xiong YJ, Lim B, Skrabalak SE. Shape-controlled synthesis of metal nanocrystals:
simple chemistry meets complex physics? Angew Chem Int Ed Engl. 2009;48:60-103.
[9]
Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an
emerging platform for cancer therapy. Nat Nanotechnol. 2007;2:751-60.
[10]
Yezhelyev MV, Gao X, Xing Y, Al Hajj A, Nie S, O’Regan RM. Emerging use of
nanoparticles in diagnosis and treatment of breast cancer. Lancet Oncol. 2006;7:657-67.
[11]
Park JW. Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res.
2002;4:95-99.
[12]
Rosenthal E, Poizot-Martin I, Saint-Marc T, Spano JP, Cacoub P, DNX Study Group.
Phase IV study of liposomal daunorubicin (DaunoXome) in AIDS-related Kaposi
sarcoma. Am J Clin Oncol. 2002;25:57-59.
[13]
Rivera E, Valero V, Arun B, Royce M, Adinin R, Hoelzer K, Walters R, Wade JL, Pusztai
L, Hortobagyi GN. Phase II study of pegylated liposomal doxorubicin in combination with
gemcitabine in patients with metastatic breast cancer. J Clin Oncol. 2003;21:3249-3259.
[14]
Markman M. Pegylated liposomal doxorubicin in the treatment of cancers of the breast
and ovary. Expert Opin Pharmacother. 2006;7:1469-1474.
[15]
Rivera E. Current status of liposomal anthracycline therapy in metastatic breast cancer.
Clin Breast Cancer. 2003;4(2):S76-83.
[16]
Swenson S, Tomalia DA. Dendrimers in biomedical applications: reflections on the field.
Adv Drug Deliv Rev. 2005;57:2106-2129.
[17]
Bianco A, Kostarelos K, Prato M. Applications of carbon nanotubes in drug delivery. Curr
Opin Chem Biol. 2005;9:674-679.
UTMJ ORIGINAL RESEARCH SUBMISSION
Page 13 of 16
ANJALI RASTOGI
[18]
Pramanik M, Hyun Song K, Swierczewska M, Green D, Sitharaman B, Wang LV. In vivo
carbon nanotube-enhanced non-invasive photoacoustic mapping of the sentinel lymph
node. Phys Med Biol. 2009;54(11):3291-3301.
[19]
Nam JM, Thaxton CS, Mirkin CA. Nanoparticle-based bio-bar codes for the ultrasensitive
detection of proteins. Science. 2003;301:1884-1886.
[20]
Artemov D, Mori N, Okollie B, Bhujwalla ZM. MR molecular imaging of the Her-2/neu
receptor in breast cancer cells using targeted iron oxide nanoparticles. Magn Reson Med.
2003;49(3):403-408.
[21]
Zhou J, Leuschner C, Kumar C, Hormes JF, Soboyejo WO. Subcellular accumulation of
magnetic nanoparticles in breast tumours and metastases. Biomaterials.
2006;27(9):2001-2008.
[22]
Hirsch LR, Stafford RJ, Bankson JA, Sershen SR, Rivera B, Price RE, Hazle JD, Halas
NJ, West JL. Nanoshell-mediated near-infrared thermal therapy of tumours under
magnetic resonance guidance. Proc Natl Acad Sci USA. 2003;100:13549-13554.
[23]
Li J, Wu D, Miao Z, Zhang Y. Preparation of quantum dot bioconjugates and their
applications in bio-imaging. Curr Pharm Biotechnol.2010;11(6):662-671.
[24]
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Clarke M, Coates AS,
Darby SC, Davies C, Gelber RD, Godwin J, Goldhirsch A, Gray R, Peto R, Pritchard KI,
Wood WC. Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patientlevel meta-analysis of randomised trials. Lancet. 2008;371(9606):29-40.
[25]
Taucher S, Rudas M, Mader RM, Gnant M, Dubsky P, Bachleitner T, Roka S, Fitzal F,
Kandioler D, Sporn E, Friedl J, Mittlböck M, Jakesz R. Do we need HER-2/neu testing for
all patients with primary breast carcinoma? Cancer. 2003;98(12):2547.
[26]
Haq AI, Zabkiewicz C, Grange P, Arya M. Impact of nanotechnology in breast cancer
(Report). Expert review of anticancer therapy. 2009;4:1021-1028.
[27]
Tanaka T, Decuzzi P, Cristofanilli M, Sakamoto JH, Tasciotti E, Robertson FM, Ferrari
M. Nanotechnology for breast cancer therapy. Biomed. Microdevices. 2009;11(1):49-63.
[28]
Gao X, Cui Y, Levenson RM. In vivo cancer targeting and imaging with semiconductor
quantum dots. Nat Biotechnol. 2004;22:969-976.
[29]
Yezhelyev MV, Al Hajj A, Morris C, Marcus AI, Liu T, Lewis M, Cohen C, Zrazhevskiy P,
Simons JW, Rogatko A, Nie S, Gao X, O’Regan RM. In situ molecular profiling of breast
cancer biomarkers with multicolor quantum dots. Adv. Materials. 2007;19:3146-3151.
[30]
Xing Y, Chaudry Q, Shen C, Kong KY, Zhau HE, Chung LW, Petros JA, O'Regan RM,
Yezhelyev MV, Simons JW, Wang MD, Nie S. Bioconjugated quantum dots for
multiplexed and quantitative immunohistochemistry. Nat. Protoc. 2007;2(5):1152-1165.
[31]
Xiao Y, Telford WG, Ball JC, Locascio LE, Barker PE. Semiconductor nanocrystal
conjugates, FISH and pH. Nat Methods. 2005;2(10):723.
UTMJ ORIGINAL RESEARCH SUBMISSION
Page 14 of 16
ANJALI RASTOGI
[32]
Turnbull L, Brown S, Harvey I, Olivier C, Drew P, Napp V, Hanby A, Brown J.
Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised
controlled trial. Lancet. 2010;375(9714):563-71.
[33]
Peters NH, Borel Rinkes IH, Zuithoff NP, Mali WP, Moons KG, Peeters PH. Metaanalysis of MR imaging in the diagnosis of breast lesions. Radiology. 2008;246(1):11624.
[34]
Akerman ME, Chan WC, Laakkonen P, Bhatia SN, Ruoslahti E. Nanocrystal targeting in
vivo. Proc Natl Acad Sci USA. 2002;99:126117-126121.
[35]
Sunderland CJ, Steiert M, Talmadge JE, Derfus AM, Barry SE.Targeted nanoparticles for
detecting and treating cancer. Drug Dev Res. 2006;67:70-93.
[36]
Pan D, Lanza GM, Wickline SA, Caruthers SD. Nanomedicine: perspective and promises
with ligand-directed molecular imaging. Eur. J. Radiol. 2009;70(2):274-285.
[37]
Tada H, Higuchi H, Wanatabe TM, Ohuchi N. In vivo real-time tracking of single quantum
dots conjugated with monoclonal anti-HER2 antibody in tumors of mice. Cancer Res.
2007;67(3):1138-1144.
[38]
Hardman R. A toxicologic review of quantum dots: toxicity depends on physicochemical
and environmental factors. Environ Health Perspect 2006;114:165-172.
[39]
Mabry H, Giuliano AE. Sentinel node mapping for breast cancer: progress to date and
prospects for the future. Surg Oncol Clin N Am. 2007;16(1):55-70.
[40]
Latosinsky S, Dabbs K, Moffat F, Evidence-Based Reviews in Surgery Group. Canadian
Association of General Surgeons and American College of Surgeons Evidence-Based
Reviews in Surgery. 27. Quality-of-life outcomes with sentinel node biopsy versus
standard axillary treatment in patients with operable breast cancer. Randomized
multicenter trial of sentinel node biopsy versus standard axillary treatment in operable
breast cancer: the ALMANAC Trial. Can J Surg. 2008;51(6):483-485.
[41]
Song KH, Kim C, Maslov K, Wang LV. Noninvasive in vivo spectroscopic nanorodcontrast photoacoustic mapping of sentinel lymph nodes. Eur.J. Radiol. 2009;70(2):227231.
[42]
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ,
Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M. Efficacy and safety
of trastuzumab as a single agent in first-line treatment of HER2-overexpressing
metastatic breast cancer. J Clin Oncol. 2002;20:719-726.
[43]
Mordente A, Meucci E, Silvestrini A, Martorana GE, Giardina B. New developments in
anthracycline-induced cardiotoxicity. Curr Med Chem. 2009;16(13):1656-1672.
[44]
Malem Y, Loizidou M, Seifalian AM. Liposomes and nanoparticles: nanosized vehicles for
drug delivery in cancer. Trends Pharmacol Sci. 2009;30(11):592-599.
[45]
Batist G, Ramakrishman G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, Shah P,
Khojasteh A, Nair MK, Hoelzer K, Tkaczuk K, Park YC, Lee LW. Reduced cardiotoxicity
UTMJ ORIGINAL RESEARCH SUBMISSION
Page 15 of 16
ANJALI RASTOGI
and preserved antitumour efficacy of liposome-encapsulated doxorubicin and
cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a
randomized, multicenter trial of metastatic breast cancer. J Clin Oncol. 2001;19:14441454.
[46]
O’Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG,
Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast
Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial
of pegylated liposomal doxorubicin HCL (Caelyx/Doxil) versus conventional doxorubicin
for first-line treatment of metastatic breast cancer. Ann Oncol. 2004;15:440-449.
[47]
Weng KC, Noble CO, Papahadjopoulos-Sternberg B, Chen FF, Drummond DC, Kirpotin
DB, Wang D, Hom YK, Hann B, Park JW. Targeted tumor cell internalization and imaging
of multifunctional quantum dot-conjugated immunoliposomes in vitro and in vivo. Nano.
Lett. 2008;8(9):2851-2857.
[48]
Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremaphor EL: The drawbacks and
advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37:1590-1598.
[49]
Weiss RB, Donehower RC, Wiernik PH, Ohnuma T, Gralla RJ, Trump DL, Baker JR Jr,
Van Echo DA, Von Hoff DD, Leyland-Jones B. Hypersensitivity reactions from Taxol. J
Clin Oncol.1990;8:1263-1268.
[50]
Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M,
O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with
polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol.
2005;23:7794-7803.
[51]
Gao Y, Chen L, Zhang Z, Chen Y, Li Y. Reversal of multidrug resistance by reductionsensitive linear cationic click polymer/iMDR1-pDNA complex nanoparticles. Biomaterials.
2011;32:1738-1747.
[52]
Jain KK. Nanobiotechnology: Technologies, Markets and Companies. Basel, Switzerland:
Jain PharmaBiotech Publications; 2010.
UTMJ ORIGINAL RESEARCH SUBMISSION
Page 16 of 16