Key words
carbon nanotubes - breast cancer cell line
Introduction
Cancer remain one of the greatest challenges faced across the world today. Deaths due
to cancer accounted for approximately 8.2 million in 2012, and breast cancer leading
to 521 000 deaths of all. According to American Cancer Society, the numbers of
diagnosed and death by invasive breast cancers in 2014 was estimated to be
respectively 232 670 and 40 000 [1].
Breast tumor remains the most common women malignant tumor throughout the world, and
also a major cancer death cause [2]. According
to American Cancer Society, it is the second main cause of cancer-related death in
The United State of America. The basic hallmark of breast tumor is the progression
and metastasis to several organs including liver, lung, bone and/or brain, which
leads to a multiple organ dysfunction, thereby increasing the incidence of death in
patients with breast cancer [3]
[4]. Metastasis occur when cancer cells leaves
the primary cancer site and travels to another organ through the blood vessels or
lymphatic system [5]
[6].
Nanomaterials possessing opto-thermal principles of transduction have been shown
promising for cancer therapy. Nanotubes (NTs) are suitable in this regards, such
that, they possess a high photo-thermal cell destruction and optical absorbance
efficiencies [7]
[8]. The quantity of light energy used is
fairly small as compared to other procedures, since the optical absorbance of NTs is
high in the 700–1 100 nm near-infrared (NIR) range. This has been used lately to
design several kinds of optical actuators and sensors based on the photo-mechanical
actuation of carbon nanotubes (CNTs) [9]
[10]
[11]. CNT [12] are regarded as a flawless materials for various uses [13], this ranges from field emission display
[14] to ultrastrong fibers [15]. Lately, CNT have received great attention
in the field of molecular biology [16], where
appropriately functionalized CNT can serve as vaccine and drug delivery systems
(DDS) [17] or protein transporters [18]. Due to the extensive π-π stacking reaction
between associated ligand and CNTs side walls, conjugation of ligand and
functionalization is possible [19]
[20], multi-component targeting using
photo-thermal cell destruction might lead to the improvement of micro-surgery,
cancer therapies, and cell repair [21].
The present study aims at reviewing the recent advances of carbon nanotubes
especially Single-walled carbon nanotube (SWNT) for improving targeted breast cancer
therapy.
Carbon Nanotubes
CNTs are cylindrical carbons made of benzene rings, they finds applications in
biology as protein and DNA detecting sensors, protein or vaccine carrier and
diagnostic tool for several kinds of serum samples for proteins discrimination [22]. These structure can also be produced from
graphite sheets where carbon atoms are located in the apexes of a hexagonal net.
They are chemically stable, possess high thermal and electrical conductance,
mechanical strength and surface area [23].
CNTs are completely insoluble in all solvents, which gives them toxicity and
health-related concerns. Nevertheless, introduction of chemical modification to CNTs
improves their solubility, and interaction with active molecules including proteins,
peptides, nucleic acids, proteins, and other therapeutic agents [24]. Anticancer drugs (methotrexate) or
antifungal agents (amphotericin B) have covalently been attached to CNTs with a
fluorescent agent (FITC). Drugs attached to CNTs have been shown efficient
internalized into the cells in comparison with drugs without CNTs [25]
[26]. The multiple CNTs surface modification
or tips of CNTs permits them to carry several molecules, and thus providing a
fundamental merit for cancer therapy. CNTs come in two principal forms; these are
the SWCNT and Multi-walled carbon nanotube (MWNTs) ([Fig. 1]). Targeted drug delivery using CNTs
have shown improvements by integrating molecules specific of the biological
receptors with these nanotubes [27]. In a
study, glycol-MWCNT were designed where glucosamine was covalently attached to the
carbon nanotube. These tubes exhibited sugar-like interaction with breast cancer
cells, hence assisting the biological molecules into the cells [28].
Fig. 1 Single-walled carbon nanotube (SWCNT) and multiwalled
carbon nanotube (MWCNT). Source: [50] [rerif].
Single-walled carbon nanotube
SWCNT is a newer type of nanomaterial possessing unique mechanical, electrical,
structural, and optical features which are promising for several biomedical
applications, including biosensors [29],
drug delivery transporters [30] and novel
biomaterials [31]. In the quest of
achieving a specific tumor cells targeting for photothermal ablation, SWNTs was
attached to folate for targeting the receptors of folate in folate positive
tumor cells [32]
[33] or noncovalently conjugated (through
adsorption) or indirectly through streptavidin-biotin conjugation [34] to antibodies targeting a specific
receptors on the tumor cells. The direct covalent conjugation for specific
cancer by targeting antibodies of SWNTs has also been studied [35], nevertheless, the application of such
antibody-SWNT conjugates for specific photothermal ablation of tumor cells with
NIR light has not been reported. Studies have also revealed that CNTs can
enhance the pharmacokinetic properties of drugs like Docetaxel, which are
insoluble and have low tissue permeability [36]. Needle-like structure of carbon nanotube ease internalization of
the biomolecules into the target cells. CNTs have been reported effective for
the administration of several antitumor drugs like topoisomerase I inhibitors,
platinum and anti-microtubule drugs, genes, siRNA, immunogenic compounds and
aptamers for anticancer treatments [37].
Multi-walled carbon nanotube
A MWNTs encompass an exclusive nanomaterial type that is remarkably durable and
electrically conductive owing to the high aspect ratio and chemistry of the
particles [38]
[39]. MWNTs are comparatively long, with a
cylindrical shaped-nanoparticles whose honeycomb structure produces high surface
area relative to their volume, and high porosity. The size of these pores ranges
from 4 and 30 nm in diameter [40]. The
particles are flexible and durable [41],
comparable to the extracellular matrix (ECM). Because of the importance of
cells’ physical microenvironment, the ability of MWNT to mimic the normal ECM
might be able to modify tumor cell behavior in a way that is hypothetically
clinically applicable.
Characteristics of Carbon Nanotubes as a Drug Delivery System
Characteristics of Carbon Nanotubes as a Drug Delivery System
Large surface area and thermal and electrical stability of carbon nanotubes allow the
attachment of various biological molecules to its surface, making them suitable
candidate to form drug delivery system. For example, Cationic fullerenes have
tendency to bind to anionic tumor cells hence providing affinity for targeted
delivery of the drugs [23] The conjugation
scheme of antibodies (Ab) is shown in [Fig.
2]. This strategy works fine for the attachment of specific and
non-specific Abs on the surface of the NT. TEM of the Ab conjugated SWCNT shows a
direct confirmation that the Ab were functionalized on the SWCNT on several sites,
as depicted in [Fig. 3]. This has been
confirmed in previous research using atomic force microscopy (AFM) and confocal
microscopy [42]. Since the NTs conjugated with
Abs were washed three times prior to imaging, it is predictable that all the Abs
aggregates are covalently LINKED to the CNTs. This depicted a greater number of Abs
molecules in a specific site, capable of attachment to SWCNT without any activity
loss for drug delivery.
Fig. 2 Conjugation schematic of SWNTs with mAbs. 1-pyrenebutanoyl succinimide was adsorbed on the NT via π–π stacking. The succinimidyl
ester can react with lysine side chain amines available on Abs to form amide bonds. PEG serves the purpose of insulator to hinder possible bio-fouling.
Source: [32] [rerif].
Fig. 3 TEM of the functionalization of mAbs aggregates specifi c
to IGF1 receptor in breast cancer cells. Each site comprising 10–25
Ab molecules. Source: [32] [rerif].
Carbon Nanotubes Improves Breast Cancer Therapy
Carbon Nanotubes Improves Breast Cancer Therapy
The improvement of efficient and novel DDS is critical for developing the
pharmacological profiles of several therapeutic molecules classes. Several DDS are
presently in use. Amongst nanomaterials, CNT have materialized as an effective tool
and new substitute for translocating and conveying therapeutic molecules. They can
act as a surface modifier using proteins, bioactive peptides, drugs and nucleic
acids for carrying the drugs they contain into the target organs and cells. Since
surface modified CNT are not immunogenic, and possesses a lower toxicity, such a
design is of a great potential in nanomedicine and bionanotechnology [43].
Singh et al. [44] synthesized and studied
paclitaxel loaded thiamine and riboflavin conjugated multi walled CNT (PTX-Tm-MWCNTs
and PTX-Rf-MWCNTs) for targeted delivery to MCF-7 breast cancer cell lines. They
found that PTX-Tm-MWCNTs and PTX-Rf-MWCNTs showed a great potential in breast cancer
treatment, however, more thorough findings are required in future.
Al Faraj et al. [45] fabricated a new
diagnostic and therapeutic method through doxorubicin-loaded SWCNTs, targeting
treatment of metastatic regions, they followed preferential improved and homing
therapeutic effects through noninvasive free-breathing bioluminescence imaging and
magnetic resonance imaging (MRI). The noninvasive MRI combination to localize
sensitively of cancer sites, through specific magnetic positioning that improves
nanocarriers magnetic targeting permitted increasing efficacy of treatment.
Molecular targeting and photodynamic therapy is promising for selective treatment of
tumor. Monoclonal antibodies that are specific to the HER2 and IGF1 cell surface
antigens can bind to SWCNT for targeting SWCNT on breast cancer cells for specific
near-infrared phototherapy. When this nanotube is conjugated with both the
receptors, there is a selective attachment to the breast cancer cells as compared to
those conjugated with non-specific antibodies.
Mashal et al. showed that SWCNTs is a probable dielectric contrast enhancer between
normal and malignant breast tumor microwave detection and enhances selective
malignant tissue heating for microwave hyperthermia treatment of breast cancer. This
study was the first step in the direction of fabricating functionalized,
cancer-targeting SWCNTs as theranostic (integrated therapeutic and diagnostic)
agents for microwave breast tumor diagnosis and treatment. It was observed that in
microwave heating studies, there was a significantly higher temperature increase in
SWCNTs containing mixtures. This increase in temperature was linearly scaled with
the efficient mixtures conductivity [46].
Metastasized cancerous cells lack contact inhibition where past studies have proposed
that restoration of these contact inhibition may restore the normal cells
properties. Dineshkumar et al. aimed at restoring the contact inhibition of cancer
cells with multi-walled CNTs. They analyzed the adhesion, proliferation, western
blots, autophagy assays, and immunochemical staining to evaluate E-cadherin
expression and adhesion. Breast cancer cells seeded on a MWCNT-collagen coated
surface showed an increased cell adhesion and decreased cell migration indicating an
upregulation of E-cadherin. This study provided an alternative approach to cancer
therapy [47].
Xiao et al., [48] investigated two unique
optical characteristics of SWNTs - very strong NIR absorbance and a very strong
Raman signals. HER2 IgY-SWNT complex was synthesized through covalently
functionalizing SWNTs with anti-HER2 IgY antibody to produce SWNTs possessing high
sensitivity and specificity for the IgY antibody. The complex formed was effectively
applied in vitro for the selective destruction and detection of
HER2-expressing breast cancer cells. Raman signal arising from tumor cells was
identified at the unicellular level. The uniqueness of this dual-function agent lies
in the fact that it needs no internalization by the tumor cells for achieving
selective photothermal ablation, and therefore offering the merit of being easily
extended to other tumor types. Conversely, more research is required for this
investigation to be applied in the clinical trials. In a recent study, polyethylene
glycol (for its physiochemical characteristics and biocompatibility) and
estradiol-E2 (estradiol receptors are over expressed in breast cancer cells) were
used for CNT modification and lobaplatin (third generation, platinum anticancer
drug) was loaded for the treatment of breast cancer. It was seen that incubating
cells after 72 h at the dose of 200 µg/ml of PEG-E2-CNT-lobaplatin significantly
inhibited the tumorigenic activity of the cells, without any toxic effects [49]
Conclusion
This review reveals the understanding of the relationship between cells and their
microenvironment. It has been shown that CNTs specifically SWNTs, can imitate the
natural ECM to facilitate the adhesion of cell and regulates the expression of gene.
This area of research offers a novel method of diagnosing and treating breast cancer
and should be considered for additional investigation to develop it towards clinical
use.
Contributors’ Statement
Dr. Mahdis Tajabadi: conceptualized and designed the study, drafted the initial
manuscript, and reviewed and revised the manuscript. Designed the data collection
instruments, collected data, carried out the initial analyses, and reviewed and
revised the manuscript. Coordinated and supervised data collection, and critically
reviewed the manuscript for important intellectual content.
