The Role of Iron, Gold, and Silver-based Magnetic Nanoparticle Materials in Treating Breast

Cancer

Hermanto Quedarusman1, David Christorei Tooy1, Otto Sindra Tjhie1

1
Medical student of University of Sam Ratulangi

ABSTRACT

Breast cancer is the most diagnosed cancer in woman. It is estimated that there were nearly
1.4 million new cases of invasive breast cancer worldwide. Breast cancer is heterogenous
disease with different histological and biological features. There are many different
treatments of breast cancer, including chemotherapy. One of the therapies developed to treat
the breast cancer is magnetic nanoparticles. Magnetic nanoparticles are capable of producing
a hyperthermia condition and inducing the killing of cell when exposed to external AC
magnetic field. Magnetic nanoparticles can also become agents in drug delivery, a drug can
be coated with certain magnetic nanoparticle that is essential in protecting the drug and aiding
the drugs to enter targeting organ. There are many different magnetic nanoparticles, which
include iron oxide, silver, and gold nanoparticles. These magnetic nanoparticles have
different advantages and disadvantages in treating cancer. Some researches were able to show
the efficiency of magnetic nanoparticles.

Keyword: Breast cancer, Magnetic Nanoparticle, Iron oxide, Silver, Gold

I. Introduction

Now these days, women from all over the world are more susceptible to cancer
especially breast cancer since it is the most reported cancer incidence on them. A staggering
1.4 million new cases of invasive breast cancer are found worldwide. In United States alone,
it is estimated that 230,480 women were diagnosed with, and 39,520 women died from,
breast cancer in 2011. 1,2 For comparison, Japanese and Taiwanese woman have only one
fifth the risk of US women. The number of incidence among Asian and Pacific Islander
women have continued to increase at 1.5% per year, but still lower than the rates in white
women. 1 It is also known that less than 1% of breast cancers occur in women younger than
25 years of age. After age 30, there is a sharp increase in the incidence of breast cancer. 3
These numbers of occurrence take us to aim and evaluate the alternative therapeutic strategies
against cancer.

Breast cancer is a heterogeneous disease, comprising different histological and

biological features, clinical presentations, and behaviors. This differences cause varying
responses of therapy in breast cancer. Despite some improvements in early diagnosis,
approximately one of three breast cancer patients will suffer from metastatic disease.4

Chemotherapy is an effective option to treat cancers like breast cancer; however,

chemotherapy is always associated with side effects.2 Some of new therapies have been
proposed to overcome this predicament. One of which is hyperthermia therapy using
magnetic nanoparticles (MNPs). Nanoparticles are promising theranostic agents with
applications for tumor imaging and targeted cancer drug delivery. Nanoparticle formulations
take advantage of synergism of multiple imaging modalities to improve cancer diagnosis,
treatment, and to monitor the response of therapy.5

Magnetic nanoparticles can produce heat in tumor tissues and induce killing of
cancer cells under external AC magnetic field. This hyperthermia therapy requires large
amount of MNPs that are injected into tumor to obtain clinically needed thermal dose to
produce sufficient heat. There are three main processes of magnetic field alternating utilized
for arising the heat. These processes consist of hysteresis, Néel or Brown relaxation, and
frictional losses in viscous suspensions. The hysteresis process is led by the delay between
the magnetic field rotation and the magnetization rotation.Thus, the thermal energy is
produced when the area in the hysteresis loop is dissipated in the environment. In the
magnetic fluid thermotherapy, magnetic fluids containing magnetic nanoparticles are
delivered to the cancer and then heated by external alternating magnetic field, resulting in
hyperthermia of cancer tissue.6-8

There are many type of magnetic nanoparticles, including silver nanocrystal sensitize
magnetic nanoparticle, gold nanoparticle, and magnetic iron oxide nanoparticle.2,5,6,9 There
are some successes in conducting this therapy in cancer, but there are also some impediments.
The success of this therapy in killing tumor cell relies on its ability to elevate temperatures
above a certain threshold in the entire tumor with minimal damage to the surrounding healthy
tissue.10

In this study, we introduce the magnetic nanoparticles as alternative therapy in breast

cancer. We would figure out about the role of magnetic nanoparticles in treating breast
cancer, as well as the mechanism behind magnetic hyperthermia and drug delivery involving
the magnetic nanoparticles.

II. Breast cancer and magnetic nanoparticles

Breast cancer can be associated with the amplification and expression of the human
epidermal growth factor receptor (HER2) oncogene. This overexpression occurs in 25-40%
of cases and is associated with aggressive decease. HER2 is a trans-membranse tyrosin kinase
of the epidermal growth factor (EGF) receptor family. When the receptor is dimerized, it
leads to autophosphorylation and activation of heterodimer partners. The activated receptors
in turn recruit adaptor proteins which sequester substrates for downstream activation. HER2
signals through at least four major pathways, including the mitogen activated protein (Map)
kinase, phosphatidylinositol 3 kinase (PI3K/Akt), Phospholipase C, and signal transducers
and activators of transcription (STAT) pathways. The Map kinase pathway leads to the
activation of genes that promote cell proliferation. PI3K/Akt promotes down regulation of
several intermediates of apoptosis thereby promoting increased cell survival. Together these
effects provide a potential mechanism for the oncogenic role of HER2.11

Nanotechnology is a rapidly expanding field, encompassing the development of man-

made materials in the 5–200 nanometer size range. This dimension exceeds that of standard
organic molecules, but in the lower range it approaches the molecule of protein. The
nanoparticles have many properties, including optical, magnetic, electronic, and structural
properties. These properties make nano-sized particles very promising for a wide range of
biomedical applications such as cellular imaging, molecular diagnosis and targeted therapy
depending on the structure, composite and shape of the nanomaterials. 12, 13

There are many chemical methods in synthesizing magnetic nanoparticles. One of

the most commonly used are precipitation-based approaches, either by coprecipitation and
reverse micelle synthesis.14 Magnetic nanoparticles have some ways in treating cancer,
including magnetic heating and drug delivery. They can also be utilized in tumor imaging.

Figure 1. Schematic representation of magnetic nanoparticle applications7

III. Iron oxide magnetic nanoparticle

Magnetic iron oxide (IO) nanoparticle is one of the nanoparticles used in cancer
imaging and therapy. Magnetic iron oxide nanoparticles have a long blood retention time,
biodegradability, and low toxicity. The nanoparticles also have a large surface area and can
be engineered to provide a large number of functional groups for cross-linking to tumor
targeting ligands such as monoclonal antibodies, peptides, or small molecules for diagnostic
imaging or delivery of therapeutic agents.15
 There are some strategies in preparing the iron oxide nanoparticles. O\\ne of the
strategies is to utilize a water-in-oil microemulsion system with reverse micelles. For
maghemite (c-Fe2O3) and magnetite (Fe3O4) nanoparticles, this precipitation technique
requires alkalization of a solution of metal salt with subsequent hydrolysis in
microemulsions. The others strategies are to use sonochemical decomposition of iron
pentacarbonyl, thermal decomposition of other iron complexes, and by thermal
decomposition of iron pentacarbonyl followed by oxidation.12

Magnetic nanoparticles have heating potential which can be applied as hyperthermia

therapy. Since it has a distinct impact on the dosages that have to be applied to the tumor
region in order to achieve a reliable inactivation of target cells. It is defined by the amount of
heating delivered per unit mass and time as a consequence of the exposure of the
nanoparticles to an alternating magnetic field. This process is called magnetic hyperthermia
when temperatures up to 46°C are induced. If the temperature rising induced by magnetic
nanoparticles reached over 50°C, it is called magnetic thermoablation.16

The delivery of heating by IO nanoparticles is caused by the loss processes during

the reorientation of the magnetization in the magnetic field, or frictional losses in the case of
the nanoparticle being able to rotate in the surrounding medium. The heating potential is
determined by remagnetization processes according to a complicated interaction between
size, shape, and microstructure of nanoparticles. During exposure of those multidomain
nanoparticles to an alternating magnetic field, energy is supplied to assist the magnetic
moments to overcome the energy barrier, this process results in corresponding displacements
of the domain wall. Consequently, the magnetization of these materials will display typical
hysteresis curves and the delivered energy can be measured via the area between these
curves. In this context, heating potentials of maghemite particles as high as 1 kW/g have been
determined. Supermagnetic nanoparticles are preferred in newer research activities. The
superparamagnetic nanoparticles have better nanoparticle suspension features and they
exhibit only a single magnetic domain. The term ‘superparamagnetism’ is derived from the
fact that when the particles are comparatively small in size, the thermal energy is higher than
the energy barrier.16

IO magnetic nanoparticles can also be used to deliver the antibodies (ab) against
HER2 (anti-HER2 or anti-HER2/neu). This process involves polymer coated 30 nm IO that
was modified with anti-HER2 forming IO-Ab. In the research conducted by Hengyi Xu et al,
IO-Ab was showed to be able to increase the preferential capture of the cancer cells. That
made IO-Ab a potential contrast in MRI imaging of the HER2 overexpression in breast
cancer.17

IV. Silver nanoparticle

Recent study of nanoparticles on radiosensitivity of cancer cells has shown that silver
nanoparticles (AgNPs) could enhance the effectiveness of radiation treatment in killing
cancer cells. AgNPs have been studied extensively for their potential use in biological field
owing to the development of nanotechnology. AgNPs is also known to be cytotoxic in both
normal and cancer cells in mammals. One of the researches conducted to normal human lung
fibroblast cell and human glioblastoma cell showed that AgNPs had the capability to reduce
ATP content of the cell, causing the damage of mitochondria and it also could increase the
production of reactive oxygen species (ROS). The possible mechanism behind mitochondrial
toxicity and DNA damage was thought to be caused by the involvement of AgNPs in the
disruption of the mitochondrial respiratory chain, leading to production of ROS, and
interruption of ATP synthesis. The DNA damage was also thought to be augmented by the
deposition during interaction of AgNPs with the DNA, leading in cell cycle arrest in the
G2/M phase.6,18

A research conducted by Su Jin Kang et al19 showed that there is a role of nuclear
factor erythroid-derived 2-related factor (Nrf2) transcription factor in AgNPs-induced
cytotoxicity. When Nrf2 expression was blocked using the interring RNA expression in the
research, AgNPs treatment showed a substantial decrease in cell viability with the increase in
apoptosis and DNA damaged compared with the control cells. Heme oxygenase-1 was also
shown to be able to inhibit the cell death caused by AgNPs. The role of HO-1 in
cytoprotection against AgNPs was reinforced by results using pharmacological inducer of
HO-1: cobalt protoporphyrin-mediated HO-1 activation in the Nrf2i cells prevented AgNPs-
mediated cell death.

Silver colloids are most widely synthetized by chemical reduction of silver nitrate
(AgNO3). The process can be conducted by adding dextrose to AgNO3 solution to prepare an
aqueous solution containing Ag+. The continuing processes include the alkalization of the
solution using NaOH and the inducement of metal ions reduction by treating the solution in a
microwave oven for 60 seconds.18

AgNPs is capable of inducing heat to kill cancer cells. One of the possible
mechanisms behind the thermo-inducing killing of cancer cells is the enhancement of Bax
expression in cancer cells, which is correlated with cell apoptosis.6 Another hypothesis by
Lianke Liu et al6 suggested that the mechanism of thermosensitization by AgNOs might be
related to the release of Ag+ cation from silver nanostructures inside cells.

In the same research, AgNPs was also shown to be size dependent. There were three
different sizes used in the research, which were AgNPs of 20.6 ± 2.7 nm, 53.8 ± 7.6 nm, and
137.3 ± 43.0 nm. Cells showed highest thermo-sensitivity with AgNPs (20.6 ± 2.7nm) on
hyperthermia treatment, while the effect of AgNPs (53.8 ± 7.6nm) was weaker, and AgNPs
(137.3 ±43.0 nm) had the least effect.6

In the another research conducted by Seyed et al18, it was found that the combination
of subinhibitory concentration of tamoxifen and non-toxic concentration of Ag+ and AgNPs
is effective against tamoxifen-resistant T47D breast cancer. However, while the research
showed that tamoxifen combined with Ag+ and AgNPs was found to be cytotoxic to
tamoxifen-resistant cells. The Ag+ and AgNPs alone were proven ineffective as therapy to
tamoxifen-resistant cells. The results could have proven to be beneficial in chemotherapy of
breast cancer, since with such an approach, much lower doses of tamoxifen may produce the
same cytotoxic effect with less unwanted side effects. The advantage can also apply in
nanoparticle treatment itself, which means by using nanoparticles in non-toxic concentration,
the potential hazards in using the metallic nanoparticles can be avoided.

Dhermenda et al19 conducted a research regarding the safety of AgNPs. According to

their finding, the injection of AgNPs above 10 mg to animal blood could be potentially
dangerous to the recipient. The possible mechanism can be attributed to the increasing
binding probability with the cell surface when a higher dose is used. In dose levels of 40 and
20 mg/kg, AgNPs can bind with the cell surface and then they pass through the cell
membrane. It causes cell apoptosis and severe effect on human health. They can also disturb
red blood cells, division and development of other cells, and maturation of hemoglobin.

V. Gold nanoparticle

Gold nanoparticle has been a promising material due to its facile synthesis, surface
modification, optical tunability and biocompabillity for clinical setting. It has wide
biomedical applications, including imaging, drug delivery, and hyperthermia therapy. It
possesses unique optical property such as its strong absorption to light due to the surface
plasmon resonance (SPR) which converting absorbed light into localized heat by the electron
oscillation around the particle surface. As example, we discussed about the gold nanorods,
nanoshell, nanocage, and added gold-gold sulfide on our focus to see its role in breast cancer
treatment.20

V.1 Gold nanorods

Gold nanorods exhibit high absorption efficiency compared with nanoshells and have
the SPR at the same wave lenght. Thus, it is making gold nanorods conduct more effective
treatment at three times lower laser intensity. This is making the photothermal tumor
destruction easier even after the single dose of treatment.13

Gold nanorods have two distinctive advantages that making them more feasible for
clinical setting. First, the synthetic procedure is relatively facile compared with nanoshells
and nanocage. Gold nanorods use seed-mediated growth protocol to enable its production to
made high yield and high quality nanomaterials within 2 hours at room temperature.
Secondly, they possessed longer blood circulation times due to the anisotropic geometry,
such as the PEGylated gold nanorods that have over 17 hours blood half-life time in mice
from recent study.13

Recently in some researches, gold nanorods proved to be more capable of inducing

cell death in glioblastoma cells line with the combination of laser irradiation. The combined
laser irradiation with gold nanorods that had an axial diameter of 10 nm and a length of 41
nm decreased cells viabillity and comprimised cell membrane rather than just treating those
cells with laser irradiation or incubation with gold nanorods alone. In addition, these cells
showed signs of necrotic cell death, not apoptotical one. It was showed by the absence of
activated caspase-3-positive cells and no chromatin condensation antiactivated caspase-3
antibody and Hoechst dye staining.20
V.2 Gold nanoshell and nanocage

Gold nanoshells and nanocages are structural variation for optical tuning into the
NIR region (Figure 1). Gold nanoshell is composed of a silica core around 100 nm and a thin
shell of gold about few nanometers formed by aging the gold clusters attached on some
silicon core. By changing the shell thickness, we can control the SPR wave lenght of gold
nanoshells.13

Figure 2. Gold nanoshell and gold nanocage13

Decreasing the thickness of the gold shell from 20 to 5 nm leads to SPR red shift
about 300 nm, which is attributed to the increased coupling between the inner and outer shell
surface plasmons for thinner shell particles. Gold nanocages are a type of hollow and porous
gold nanostructures formed by a galvanic replacement reaction between silver nanocubes and
auric acid in aqueous solution. Common size of the nanocages is about 50 nm edge width
with few nanometers walls and holes for SPR wavelength around 800 nm. By controlling the
amount of auric acid solution, the SPR of gold nanocages could be tuned to NIR region with
specified wavelengths.13

V.3 Gold-gold sulfide

Gold-Gold sulfide (GGS) nanoparticle is a varian from gold based nanoparticle. GGS
–NPs have a quite smaller size (25–50 nm diameter) than silica-gold nanoshells (120–150 nm
diameter) while also used a drug carrier while minimal toxicity. In addition, GGS are strongly
absorb NIR wave lenght of light when penetrating deep tissue. Thus making it more suitable
for dual contrast to obtain high resolution image for gathering morphological and
physiological information besides being a therapeutic agent for in vivo cancer at the same
time.21

Recent study showed that GGS is making more promising imaging with multiphoton
microscopy than a conventional florophores. Two-photon microscopy is used in medical
imaging because its ability to provide sub-cellular resolution at the depth of several hundred
microns in tissue. The advantage from this approach is attributed due to the discovery that
rough surfaces of metal exhibit two photon induced resonance (TLP). This is enhancing the
signal’s brightness. As example, previous study demonstrated that nanorods TLP signals are
60 times brighter than a single rhodamine 6G molecul and nanoshells are nearly 140 times
brighter than florescent beads while displaying approximately brightness at the same rate as
nanorods.21

The main advantage of two-photon microscopy in medical imaging is the ability to

provide sub-cellular resolution at depths of up to several hundred microns in tissue. With
further development, multiphoton microscopy combined with dual imaging and therapy
GGS-NPs could provide an effective method to pinpoint and treat specific sites following
initial tumor detection with wide-field imaging modalities.21

GGS nanoparticle is suitable for making a pinpoint to the specific tumor cells and
treats them as well with just using multiphoton microscopy. Previous study shows that GGS
combined with coating anti-HER2 antibodies and pulsed NIR laser at low intensity targeting
SK-BR-3 breast carcinoma cells successfully induced the begining of membrane blebbing.
The membrane blebbing increased as well as the intensity of the laser because of the
photothermal ablation.21

VI. Conclusion

These iron oxide, silver and gold magnetic nanoparticle have been proven to be
effective for treating various cancer including breast cancer. Although different types of
materials have their own advantages and disadvantages. Iron oxide nanoparticle is useful
contrast for imaging by anti-HER2 antibody coating and it is also easily binded with the
antibody due to its large surface. AgNPs were found to be highly cytotoxic, which can cause
apoptosis to the cancer cells. AgNPs are also more efficient by combining them with Ag+ and
tamoxifen. Gold nanoparticles have more facile synthesis compared to other nanoparticles,
they also have an advantage in tuning the optical property. Nevertheless, gold nanoparticles
are more compatible when they are combined with irradiation and drug therapy. Due to the
researches regarding the benefit of magnetic nanoparticles, the possibility to treat breast
cancer is rising. Even though further study needs to be done.

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