International Journal of Pharmaceutics 603 (2021) 120644

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International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Review

Graphene-based materials: A new tool to fight against breast cancer

JinLing Zheng, DanDan Meng, Xing Zheng, Yan Zhang, HongFei Chen *
University of South China, No. 28 Changshengxi Road, Hunan 421001, China

A R T I C L E I N F O A B S T R A C T

Keywords: Breast cancer is one of the most common malignant tumors among women population on a global scale, with a
Graphene huge number of new cases and deaths each year. In recent years, there has been an increasing number of lit­
Graphene oxide eratures on the discovery and development of novel anti-breast cancer drugs and materials, aiming to increase
Breast cancer
the survival rate of breast cancer patients. One of the newest tools used for the therapy of breast cancer is
Identification
Delivery
graphene-based materials, which have ultra-high surface area as well as unique physical, chemical and me­
Treatment chanical properties. It is reported that graphene-based materials could induce apoptosis in cancer cells while
showing low toxicity due to their carbon structure. Therefore, they can be used as nano-drugs or biological
carriers to introduce small molecules such as nucleic acids, drugs, or photosensitizers into the human body to
achieve treatment goals. This article introduces the synthetic methods for graphene-based materials, as well as
the current status and the future prospects of graphene-based materials’ application in the treatment of breast
cancer.

1. Introduction
Breast cancer is one of the most prevalent malignant diseases glob­
ally, with more than 2 million new cases diagnosed in 2018, according to
WHO reports. There are many risk factors that lead to breast cancer,
including gender (Akram et al., 2017), lack of exercise (Protani et al.,
2010), Toxocara canis infection (Torre et al., 2015), diabetes (Flavia Zita
Francies et al., 2020), breast density (Momenimovahed and Salehiniya,
2019), and so on. For example, women are more likely to develop breast
cancer than men, on average one in eight women will get breast cancer.
Besides the role of gender, there is also a significant difference between
developed countries and developing countries in the mortality rate of
breast cancer patients. In developed countries the 5-year survival rate of
breast cancer patients is 80%; however, in developing countries the 5-
year survival rate is less than 40% (Eketunde, 2020; Ruiz-Manzano
et al., 2020), and consequently an estimated 60% of breast cancer-
related deaths occur in developing countries (Bojanic et al., 2020).
At the early stage of breast cancer, neoadjuvant therapy is commonly
applied, in addition to which the endocrine therapy, anti-Her-2 targeted
therapy, as well as combination therapy can also prolong the survival
time of patients. To improve the quality of patients’ life, some sub­
stantial progress has been made in the field of anti-breast cancer
research in recent years (Harbeck and Gnant, 2017). Among them, the
application of nanomaterials enables people to make improvements in
the efficacy of drugs, selective toxicity to cancer cells, and drug
targeting.
In recent years, graphene-based materials have gradually stepped
onto the stage of medical researching. Graphene is reported to exhibit
specific toxicity to cancer cells, which is caused by its carbon structure
(Gurunathan et al., 2014), and it is expected to be hypotoxic or nontoxic
to normal cells (Zuchowska et al., 2017). Therefore in the past few years,
graphene-based materials have been increasingly discussed and applied
in the medical field for anti-cancer, such as pancreatic cancer (Wu et al.,
2018; Yin et al., 2017), gastric cancer (Xu et al., 2019), colon cancer
(Baldea et al., 2020), cervical cancer (Wang et al., 2020) and so on.
The graphene-based materials were used to deliver drugs, nucleic
acid molecules or genes to the cancer cells to achieve the purpose of
inhibiting cancer (Fig. 1). Moreover, graphene-based materials are able
to absorb light in the near infrared region, so they can also be used in
photothermal therapy and photodynamic therapy (Orecchioni et al.,
2015). Up to now, the studies on graphene-based materials are still at an
early stage, and their application potential has not been well developed.
It is expected that the graphene-based materials can be used in many
fields, such as the research for batteries, supercapacitors, separation and
electrocatalysis (Huang et al., 2020), and the development of anti-
cancer drugs. As a new type of biological materials in medicine, there
is a lot of space for the development and utilization of graphene-based
materials. In this paper, we summarize the graphene-based materials’

* Corresponding author.
E-mail address: Hongfeich@163.com (H. Chen).

https://doi.org/10.1016/j.ijpharm.2021.120644
Received 18 January 2021; Received in revised form 11 April 2021; Accepted 21 April 2021
Available online 6 May 2021
0378-5173/© 2021 Elsevier B.V. All rights reserved.
J. Zheng et al.
Fig. 1. Coupling of small nucleic acid molecules, drugs or ligands with gra­
phenes, such as A graphene, B graphene oxide.
Fig. 2. Some properties of graphene.
application in anti-breast cancer therapies in recent years and give a
brief explanation of their future development as well as the problems
they are facing. The structures, synthesis, and biocompatibility of
graphene-based materials will also be introduced in detail.
2. Graphene
2.1. The structures and types of graphene
Graphene is a kind of single layer (Xu et al., 2013) carbon material
with a two-dimensional nanostructure (Ghanbarzadeh and Hamisheh­
kar, 2017), which exhibits unique topological properties with the hon­
eycomb lattice resonance structure (Zdetsis, 2020). Rahmanian and
colleagues reported that each carbon atom contains free π electrons,
which makes the two sides of the graphene’s structure be of higher
electron density, so the structure of graphene is more prone to electro­
philic substitution (Rahmanian et al., 2014). However, the precise
structure of graphene has always been controversial, which is
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International Journal of Pharmaceutics 603 (2021) 120644
immensely affected by the preparation methods and degree of oxidation
(Barar and Omidi, 2014).
Since the advent of graphene in 2004, many scientists were attracted
by its special structure and properties, and they applied the graphene to
various fields. Therefore, many derivatives of graphene have been
studied such as graphene oxide (GO) (Yazici et al., 2017), reduced
graphene (Wang et al., 2018), aminated graphene (Rabchinskii et al.,
2020), three-dimensional graphene (Ho et al., 2020), ferromagnetic
graphene (Alimohammadian and Sohrabi, 2020), element-doped gra­
phene (Gecim et al., 2020; Nguyen et al., 2020; Tian et al., 2015) and so
on. It is worth noting that although graphene, graphene oxide, and
reduced graphene belong to the same class of substance, their precise
structures are different, and they all have their own unique physical and
chemical properties.
Currently, the most studied graphene-based material in the
biomedical industry is graphene oxide, which may be attributed to its
oxygen-containing group. The surface of graphene oxide is rich in
functional groups such as carboxyl and hydroxyl groups, which is
conducive to the modification of small organic molecules on its surface
to obtain target complexes.
Graphene oxide is easily produced from graphite through oxidation,
in which some oxygen atoms were introduced into the aromatic C– –C
double bonds (Petrucci et al., 2019). Among all the nanostructured
materials, GO has a very high surface area that is highly functionalized
with oxygenated groups, which are beneficial for its thermal and
chemical stability. Also, the presence of oxygenated functional groups
such as hydroxyl and epoxy groups allow biochemical and bio­
conjugation reactions occurring on GO’s structure, and consequently
facilitate the functionalization of GO surface with proteins, antibodies
and DNA fragments (Raslan et al., 2020).
2.2. Special physical and chemical properties of graphene (Fig. 2)
2.2.1. Biocompatibility and toxicology
The emergence of a new type of material will bring new hope and
direction to medical chemistry research, but at the same time it will also
be accompanied by unanticipated potential risks. So are the graphene-
based materials.
It is found that various graphene-based materials could cross physi­
ological barriers to reach secondary organs that are distant from the
point of entry (Fadeel et al., 2018). Among them, graphene is proved
non-toxic to L929 cells, which close the wound by causing linear
migration of cells, therefore it is considered to be beneficial for tissue
damage recovery. Other research works had shown that graphene oxide
did not enter A549 cells, thus exhibited no obvious cytotoxicity.
However, graphene-based materials showed complexities in the as­
pects of biocompatibility and cytotoxicity. Whether they are biocom­
patible or cytotoxic depends on the size, distribution, dosage, shape,
layer number, purity, surface charge, surface dimensions, and surface
functional groups. Herein, several possible mechanisms for graphene-
based materials to produce cytotoxicity were enumerated simply: 1)
graphene-based materials are able to interact with the lipid tails, thereby
extracting or removing the hydrophobic cholesterol from the cellular
membrane to create surface pores, causing damage of the membrane, 2)
graphene compounds could pass through cell membranes easily and
stimulate excessive production of reactive oxygen species that leading to
mitochondrial disorders, 3) the release of lactate dehydrogenase (LDH)
causes cell membrane damage and leakage of cell contents, 4) graphene
materials enter the nucleus and directly interact with DNA to produce
genotoxic (Gurunathan and Kim, 2016; Liao et al., 2018), 5) graphene-
based materials cause immuno-inflammatory responses and activate
apoptotic pathways (IKK/IκBα/NF-κB and BAX/BCL-2) (Li et al., 2019).
Therefore, the exploration of new types of graphene-based materials,
structure modification, and the study of their biocompatibility system
with biological organisms are necessary.
Jian and colleagues did toxicology experiments on SMMC-7721 cells,
J. Zheng et al.
PC-12 cells and HL-7702 cells et al. and revealed that graphene-based
materials such as GQD, GQD-NH2, GQD-COOH and GOQD with
smaller particle size showed no obvious cytotoxicity. These materials
can be used for biomedical application safely as drugs carriers, as they
seem to be better than graphene, graphene oxide (GO) and reduced
graphene oxide (rGO) which elicit adverse effects. In addition, GO
showed more significant cytotoxicity than rGO (Li et al., 2019).
Erhan et al. studied an effective PEGylation method to improve
biocompatibility of graphene derivatives, they used poly (ethylene
glycol) methyl ether methacrylate (PEGMA), pyrenemethyl methacry­
late (PMA), methyl methacrylate (MMA), N, N, N’, N’’’, N’’-pentam­
ethyldiethylenetriamine (PMDETA), copper(I) bromide and ethyl 2-
bromo-2-methylpropionate (EiBr) to synthesize polymer P(PEGMA-co-
MMA-co-PMA). Then the polymer is reacted with graphene oxide to
obtain PEGylated reduced graphene oxide (PEG-rGO). Compared with
GO, the product PEG-rGO showed more blood compatible and better cell
viability (Demirel et al., 2020). Sharan et al. silanized GO with a com­
mon silanizing agent (3-aminopropyl) triethoxysilane to get the product
SiGO, and did viability testing on primary cell (HADF), normal trans­
formed cell line (NIH-3 T3) and cancerous cell line (MG-63). The results
showed that SiGO exhibited improved in vitro cytocompatibility,
reduced in vivo toxicity and better immunocompatibility than GO
(Vuppaladadium et al., 2020). Some biocompatibility improvement
research of graphene materials in the past five years is listed in Table 1.
2.2.2. Optical and Photoluminescence properties
Graphene-based materials exhibit the property of light absorption
due to special electronic structure, and the optical properties have a lot
to do with their shape and edge geometry. The absorption rate could
reach 2–3% from ultraviolet to infrared wavelength range (Chang and
Wu, 2013; Mansilla Wettstein et al., 2016). Deobrat et al. found the
holey graphene (HG) presents a strong and broad absorption in the
visible light region with the GW + BSE method (Singh et al., 2020).
Although graphene-based materials possess good optical properties, the
complete graphene materials do not show photoluminescence properties
due to lack of energy band gap. To make graphene materials emit light,
there are two ways: The first way is to create or induce energy gaps on
single-layer graphene, and the other way is to create defects on the
surface or edges of single-layer or multilayer graphene structures.
Graphene quantum dots are a unique existence (Cao et al., 2012).
Francesco et al. manufactured defect nitrogen-doped graphene, and
controlled the defect concentration of graphene-based materials by
Fig. 3. Some synthetic methods of graphene.
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International Journal of Pharmaceutics 603 (2021) 120644
metal decoration on anchoring sites to study on their harmonizable
optical properties (Buonocore et al., 2019). To our best knowledge, the
prominent related studies in the past five years are listed in Table 2.
2.2.3. Biodegradability
Since the discovery of graphene-based materials, they are expected
to be used in many fields as ideal carriers. Graphene-based materials
gradually entered the world of biomedicine in recent years due to their
good biocompatibility and low cytotoxicity. But another problem that
prevents them from being widely used in clinics is how to degrade them
in organism.
To solve this problem, some experts focused on improving the
biodegradability of graphene-based materials. Human myeloperoxidase
and eosinophil peroxidase are effective oxidases found to effectively
degrade graphene materials, such as graphene quantum dots (Martin
et al., 2019). Moreover, Rajendra et al. used recombinant human mye­
loperoxidase (hMPO) to act on single-layer and few-layer graphene. By
measuring G band images at different time points, researchers found
graphene can be degraded either by recombinant hMPO or by hMPO
(Kurapati et al., 2018). These researchers also reported that graphene
oxide can be degraded by recombinant eosinophil peroxidase (EPO) in
90 h treatment under a low concentration of hydrogen peroxide and
NaBr (Kurapati et al., 2020). Mukherjee et al. proved that neutrophils-
produced hMPO can degrade graphene oxide and the products are
non-toxic (Mukherjee et al., 2018), while hMPO can degrade graphene
nanoribbons too (Luan et al., 2020).
Based on the theory that graphene-based materials can be degraded
by horseradish peroxidase (HRP), Alberto et al. made a DNAZymes by
using supramolecular guanine-rich G-quadruplexes and hemin, and
found it has the same function of degrading graphene (Fadeel et al.,
2018; Kurapati and Bianco, 2018). This discovery makes it possible for
graphene-based materials to achieve synergistic degradation in the
body. Unlike the previous findings, Kun et al. demonstrated that gra­
phene with larger lateral dimensions (LLG, 330–630 nm) is mainly
concentrated in the liver and localized in Kupffer cells after intravenous
injection. Then red blood cells are induced to be damaged and swal­
lowed by Kupffer cells, which lead to the degradation of hemoglobin and
increase in iron ion concentration. However, the accumulation of iron in
Kupffer cells will trigger the Fenton reaction and promote the degra­
dation of graphene to CO2 (Lu et al., 2020). However, not all graphene
materials are able to enter the kidney, and therefore cannot be degraded
or excreted. Moreover, a very small part of graphene-based materials is
J. Zheng et al.
absorbed into the spleen, but studies have found that this phenomenon
does not cause damage to the body (Newman et al., 2020).
2.3. Synthesis of graphene (Fig. 3)
Graphene-based materials have always been favored by scientists
due to their diverse functions, so how to synthesize graphene has always
been one of the focuses of researchers. The conventional synthesis
methods that have been studied are: 1) mechanical exfoliation method,
2) graphite oxide-reduction method, 3) chemical vapor deposition
method, 4) the epitaxial growth method, 5) electrochemical methods, 6)
arc method, 7) organic synthesis method, etc (Hu et al., 2010). Here we
will introduce some of these methods briefly.
2.3.1. Mechanical exfoliation
The mechanical exfoliation method belongs to the top-down syn­
thesis of graphene that mainly peels off the graphene layer by layer from
the whole graphite, and is a purely physical technical method. There is
van der Waals gravity between the graphene thin layers, which is the
greatest resistance of this method, and it is often overcome by two
strategies: normal force and lateral force. Common mechanical peeling
techniques includes: 1) micromechanical cleavage, 2) sonication, 3) ball
milling, 4) fluid dynamics, 5) the detonation technique, 6) the super­
critical fluid assistance, and so on (Yi and Shen, 2015). In the traditional
concept, the mechanical peeling method is a high-quality, low-yield
graphene preparation method that cannot be produced on a large scale,
but a recent literature report broke this inertial thinking. Moon et al.
made the metal film be deposited on the graphite, and utilized the dif­
ference in toughness and binding energy of different metals and gra­
phene surfaces to control the number and thickness of graphene layers.
For example, gold film can exfoliate single-layer graphene, while
palladium, nickel, and cobalt can exfoliate different layers of multi-layer
graphene (Moon et al., 2020). The results of this research make the low-
cost, high-quality mechanical peeling method possible for mass
production.
2.3.2. Graphite oxide-reduction
The graphite oxide-reduction method uses the principle of redox
reaction to first oxidize graphite engendering oxygen-containing
graphite oxide with an oxidizing agent, and then reduce it to obtain
graphene after peel it off by external force. There are many oxidation
Fig. 4. The role of graphene-based nanomaterials in breast cancer.
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International Journal of Pharmaceutics 603 (2021) 120644
methods, including Hummers, Brodie and Staudenmaier. They have a
common feature that they are composed of a strong acid and an oxidant.
Brodie mainly uses fuming nitric acid and sodium chlorate to oxidize
graphite, Hummers mainly uses sulfuric acid and potassium perman­
ganate to prepare graphene oxide (Feicht et al., 2019), and Stau­
denmaier mainly oxidizes graphite with chloric acid oxidant and fuming
nitric acid (Moo et al., 2014). Reduction methods include chemical
reduction (Guo et al., 2021), thermal reduction (Vázquez-Sánchez et al.,
2019), electrochemical reduction (García-Argumánez et al., 2019),
photocatalytic reduction (Zhao et al., 2018), etc. The more important
point of this method is the selection and control of reaction conditions.
2.3.3. Chemical vapor deposition
Chemical vapor precipitation is a bottom-up graphene synthesis
method, which uses the accumulation of molecular modules to construct
target compounds. A flat substrate such as a metal film or a single crystal
is placed in a precursor such as ethylene, and the precursor is decom­
posed at high temperature and then annealed to deposit carbon atoms on
the surface of the substrate to form graphene. Finally, the metal is
removed by corrosion to obtain pure graphene. Alireza Dadkhah Teh­
rani et al. synthesized graphene monolayers on quartz substrate directly
by chemical vapor deposition (CVD) method at a temperature of 800 and
850 ◦ C. It is worth noting that they got graphene in excellent quality and
without using any catalyst. During the experiment they utilize ethanol as
the precursor and plasma cleaning to remove the oxide layer at a lower
cost (Dadkhah Tehrani et al., 2020).
2.3.4. Organic synthesis
Organic synthesis has been a research method for people to synthe­
size new substances from a long time ago. However, the more complex
and the larger the compounds’ molecules are, the more difficult they are
to synthesize. A tetraethynylbiphenyl core and ethynyl-substituted tet­
raphenylcyclopentadienones were used to synthesize nano-graphene by
iterating the Diels-Alder/dehydrogenation approach, as the nano-
graphene could be synthesized by cross-coupling, Diels-Alder, and
dehydrogenation reactions. Other researchers used cyclopentadienone
derivatives and alkynes to synthesize 222 graphite sheet by cyclo­
trimerization reaction of alkynes (Tran-Van and Wegner, 2014).
Although organic synthesis is difficult to achieve for compounds with
large molecular weights, its selectivity and sustainable production are
our motivation and goal for continuous exploration.
J. Zheng et al. International Journal of Pharmaceutics 603 (2021) 120644

Table 1
Research on improving the biocompatibility of graphene-based materials.
Graphene-based materials Characterization Cells Year Ref. Remarks

GPNM PNIPAM grafted GO (GPNM) exhibited better U87MG and 3T3-L1 2015 (Kundu et al., Poly(N-isopropylacrylamide)
biocompatibility than GO. 2015) (PNIPAM)
FGOns FGOns demonstrated excellent biocompatibility. s HaCaT and 3T3 2015 (Mahanta and Bovine α-lactalbumin
Paul, 2015) functionalized graphene oxide
(FGOns)
rGO (NAM-rGO) NAM-rGO showed excellent biocompatibility Mouse embryonic 2016 (Zhang and Nicotinamide (NAM)
fibroblast Gurunathan,
2016)
GO-DEX Nano-GO (GO-DEX) was biocompatible and 4T1 mammary 2016 (Alibolandi et al., Dextran (DEX)
nontoxic. carcinoma 2017)
COOH+/graphene and the COOH+/graphene and COOH functionalized L-929 2016 (Zhao et al., 2016) Physical ion implantation and
COOH functionalized graphene revealed improvement of chemical methods
graphene cytocompatibility and COOH+/ graphene exhibited
better.
GO-PAA Poly (Acrylic Acid) functionalization is Superior to J774A.1 2016 (Xu et al., 2016) Poly (acrylic acid)-functionalized
PEGylation. GO (GO-PAA)
GNP-C-PVA PVA considerably improved the biocompatibility. HFF-1 2016 (Pinto et al., Graphene nanoplatelets (GNP-C)
2016)
GO-CS The functionalization of GO with CS improved its RAW264.7RAW264.7 2017 (Yan et al., 2017) Chitosan (CS)
biocompatibility.
GO-PAMAM-GA The GO-PAMAM-GA hybrid exhibited greatly SMMC-7721 and HEK- 2018 (Liu et al., 2018a) The polyamidoamine (PAMAM)
enhanced biocompatibility. 293 dendrimer, glycyrrhetinic acid
(GA)

Graphene-based Characterization cells Year Ref. Remarks

materials

GO-CHI-HA GO-CHI-HA had lower cytotoxicity. NHBE cells 2018 (Liu et al., 2018b) Chitosan (CHI), hyaluronic acid
(HA)
GONH2 The biocompatibility of amino-functionalized GO in a Caenorhabditis elegans 2019 (Rive et al., 2019) Amino-functionalized GO (GONH2)
whole-organism had enhanced.
GO decorated Functionalisation of GO sheets nanocomposite with BJ1 normal skin 2019 (Khalil et al., 2019) Polyvinylpyrrolidone (PVP)
with PVP PVP improved the cell viability about 40~35% fibroblasts
Gd-rGONSS Gd-rGONSS improved the biocompatibility of humans 2019 (Chawda et al., 2019)
GO-PEG10K- The nanosized GO-PEG10K-6arm had a very low 293T and CAL27, MG63 2019 (Chai et al., 2019) Polyethylene glycol (PEG)
6arm toxicity and HepG2
Ag@S-GQDs Ag@S-GQDs improved biocompatibility data. HEK 293 2020 (Kadian et al., 2020) Sulfur-doped graphene quantum
dots (S-GQDs)
PLA/GO scaffolds PLA/GO scaffolds were biocompatible more efficiently MG-63 2020 (Belaid et al., 2020) Polylactic acid (PLA)
ErGO An enhancement in the biocompatibility of the CoCr J774A.1 2020 (Escudero et al., 2020) Electrochemically Reduced
with the ErGO films Graphene Oxide (ErGO)
SiGO Silanization improved biocompatibility of graphene HADF, NIH-3T3, and 2020 (Vuppaladadium
oxide MG-63 et al., 2020)
Lipid-rGO Lipid-rGO nanostructures had minimal impact on MDA-MB-231, MCF-7 2020 (Farell et al., 2020)
normal breast cells. and MCF-10A

Table 2
Research on photoluminescence properties of graphene-based materials.
Graphene-based materials Property Application or character Year Ref.

GQDs Photoluminescence Photodynamic therapy 2015 (Jovanovic et al.,

2015)
Graphene Photoluminescence Disease diagnosis as well as theranostics 2016 (He and Tian, 2016)
GO Photoluminescence Fluorescence imaging, NmPDT and NmPTT 2016 (Kalluru et al., 2016)
sGQDs Photoluminescence Optical pH sensing and optical sensing probes 2017 (Kumawat et al.,
2017)
ZnO/GO Photoluminescence Microstructural features can affect the photocatalytic 2019 (Haghshenas et al.,
2019)
CHMDA (hexamethylenediamine functionalized Intrinsic Flow cytometry technique and fluorescence microscopy 2019 (Potsi et al., 2019)
fluorographene) fluorescence imaging
N doped graphene and g-C3N4 quantum dots Photoluminescence The N- and O-rich edge groups can enhance the efficiency of 2019 (Gu et al., 2019)
photoluminescence
GQDs with microwave post-treatment Photoluminescence sensors and bioimaging 2020 (Huang et al., 2021)

Herein, other graphene synthesis methods will not be introduced in 2013).

detail and other graphene-based materials, such as graphene oxide,
reduced graphene, etc., can be obtained by performing related redox
reactions on graphene. Due to the discovery of the application of gra­
phene materials in biomedicine, they have gradually become the focus
of anti-tumor drug research. For example, graphene oxides prepared by
biological redox method and B-reduced graphene oxide are both dose-
dependently cytotoxic to MCF-7 breast cancer cells (Gurunathan et al.,
The development of graphene synthesis has made the application
range of graphene more extensive, and its development prospects will
also be better. In the process of studying graphene, we need to pay
attention to its biocompatibility, degradability in aqueous solution, and
flake size. Related studies have clarified that the size of graphene flakes
may affect cell viability (Feng et al., 2013). Since this research group
often conducts research on breast cancer, the anti-breast cancer aspects

5
J. Zheng et al. International Journal of Pharmaceutics 603 (2021) 120644

of graphene materials will be elaborated below. fact that circulating miRNA especially increases at the beginning of
cancer. miRNA-155 is a circulating miRNA, and people often use miR-
3. The role of graphenes in breast cancer (Fig. 4) 155 detection to diagnose early cancer patients and prognosis. The
biosensor made by connecting miR-155 gold nanoparticles-modified
Graphene biomaterials have been partially studied in the treatment graphene oxide (AuNPs-GO) to a glassy carbon electrode (GCE) can be
of breast cancer, there are related literatures reported on the detection used for early screening of breast cancer (Azimzadeh et al., 2016).
and treatment of breast cancer. Compared with other materials, Nitrogen-doped graphene quantum dots fluorescent probe—Folic
graphene-based materials have a very high surface area and highly acid receptors are overexpressed on breast cancer cells, which also allow
functionalized groups, which are beneficial for its structural stability. breast cancer cells to be specifically recognized by fluorescent probes.
Moreover, the functional groups improve its solubility in water and Graphene quantum dots are a kind of ultra-high area fluorescent mate­
polar solvents. In addition, the possibility of getting graphene-based rial. There are a large number of oxygen-containing groups on the sur­
materials easily and cheaply also renders this material very useful in face that can be well modified. Nitrogen-doped graphene quantum dots
electrochemical sensors. can provide more binding sites for the binding of folic acid. Therefore,
when the binding amount of folic acid increases, the amount of FA-N-
3.1. Early breast cancer recognition GQDs entering breast cancer also increases, and the labeled cells emit
stronger fluorescence, which is beneficial to the fluorescent diagnosis of
At present, breast cancer treatment can achieve better results breast cancer. Therefore, by controlling the amount of nitrogen doped in
compared with other cancers, and also the techniques and methods the graphene quantum dots, the intensity of fluorescence can be
appear to be more mature. According to American Cancer Society’s controlled to better detect cancer cells (Feng et al., 2020). Table 3 is the
statistics in the United States, from 1989 to 2017, the breast cancer last 5 years summary of the role of graphene in the early diagnosis of
death rate continues to decline, with a dramatical drop of 40% (DeSantis breast cancer.
et al., 2019). The reasons for this change in the treatment effect of breast
cancer may be the expansion of high-quality prevention, early detection
and treatment services. Most of the cured breast cancer patients could be 3.2. Small molecule delivery function
treated timely as the early detection, and if breast cancer can be diag­
nosed earlier, there would be more possibility of being cured. Therefore, Nucleic acid molecules not only play a role in the diagnosis and
the improvement of early detection technology of breast cancer is very recognition of breast cancer, but also in preventing breast cancer.
necessary for the improvement of the survival rate. However, most of them are unstable during in vivo transport. Therefore,
Currently, most medical researchers start from biomaterials and the it is of great significance to find a suitable biological carrier — the
unique characteristics of breast cancer, such as ERBB2, miRNAs, SKBR3 application of graphene materials is another major innovation in the
and folic acid receptors. As we mentioned above, graphene is a very field of medicine.
good biological carrier, and it is a kind of nanomaterials that has been The exploration of cancer treatment is getting more and more deeply.
more popular in recent years with good biocompatibility and unique Nowadays, nucleic acid therapy has gradually become the focus of
physical and chemical properties, which can be used as a carrier to application and an important direction of future exploration. The key to
transport unstable substances such as nucleic acid molecules into the the therapeutic application of nucleic acids is to have a safe and effective
body. Below we will introduce the role of graphene-based materials in delivery system. Polyethyleneimine (PEI) graphene oxide is a nano­
the early detection of breast cancer and its relationship with ERBB2, carrier that has been developed for gene delivery, but high dose of which
miRNAs, SKBR3 and folic acid receptors. Based on this principle, many shows high toxicity, limiting its application. According to research,
related biosensors and probes have emerged one after another. polyethylene glycol (PEG) is a long-chain hydrophilic polymer, which
DNA biosensor—ERBB2 (Her-2) is a protein receptor encoded by the
proto-oncogene on the long arm of human 17q chromosome, which Table 3
helps to control normal breast cancer cell growth, division and self- Graphene-based materials for early diagnosis of breast cancer.
repair. But the overexpression of ERBB2 gene can lead to the occur­ Graphene-based Type Recognition Year Ref.
rence of cancer, and even has a great relationship with cancer metastasis materials site or principle
and tumor growth. Therefore, ERBB2 is often used as a breast cancer Nanobiosensor RNA sensor miR-155 2016 (Azimzadeh
marker, and CD24 is also a carcinogenic marker. The DNA biosensor et al., 2016)
made by connecting two different DNA (ERBB2c and CD24c) gold Nanodot- Fluorescent It can be 2016 (Tao and
graphene nanoprobes disrupted in the Auguste,
nanoparticles modified graphene oxide (AuNPs-GO) to a glassy carbon oxide presence of 2016)
electrode (GCE) is used for early diagnosis of breast cancer (Saeed et al., complexes breast cells and
2017). In addition, there is also research on the principle of detecting give
and immunodiagnosing breast cancer biomarker ERBB2 through anti­ fluorescent
readouts
gen–antibody interaction, and prepared a selective, repeatable and
CD24-c/AuNPs- DNA sensor ERBB2 and 2017 (Saeed et al.,
stable microfluidic immunosensor for rapid detection of breast cancer GO/GCE, CD24 2017)
(Ali et al., 2016). ERBB2-c/
Graphene Raman probe—SKBR3 is a breast cancer cell line over­ AuNPs-GO/
expressing Her-2, to which bioconjugated graphene oxide selectively GCE
Au-Pt-Pd/rGO H2O2 sensor Detect and 2018 (Dong et al.,
targets. As the Raman probe based on bioconjugated graphene oxide can reduce H2O2 2018)
selectively recognize SKBR3 breast cancer cells, this type of Raman NFG/AgNPs/ Nano-genosensor miRNA-21 2018 (Salahandish
probe can be used for early diagnosis of breast cancer (Antwi-Boasiako PANI et al., 2018)
et al., 2017). BSA-GO Microwave- Enhance the 2019 (Yuan et al.,
induced MTAI contrast 2019)
RNA biosensor—miRNAs are newly emerging reliable biomarkers,
thermoacoustic of breast
short single-stranded ribonucleic acid molecules. They play important imaging (MTAI) tumors
regulatory roles in biological processes such as biological development, effectively
angiogenesis, cell proliferation, and apoptosis (Andorfer et al., 2011; Au-Pd/ rGO High- Detect H2O2 2019 (Dong et al.,
Ebert and Sharp, 2012). Circulating miRNA found in the blood is unique performance 2019)
sensor
to cancer patients, whose expression is also tissue-specific, based on the

6
J. Zheng et al. International Journal of Pharmaceutics 603 (2021) 120644

can improve the stability of graphene oxide and reduce toxicity. Poly­ used as a special material or carrier for phototherapy research. Below we
ethylene glycol (PEG) and octaalkylarginine (R8) on the basis of 10:1 will introduce two kinds of research related to optical treatment of
ratio and graphene oxide conjugation optimization result in a stable and breast cancer.
good bifunctional graphene oxide nanocomposite with the potential to Graphene quantum dots (GQDs) exhibit photoluminescence proper­
load plasmids and siRNA (Imani et al., 2018). ties (the largest emission ability in the near-infrared region) and mon­
Aptamers are a kind of molecular recognition probes, which are ooxygen 1O2 generation efficiency, so they have great potential in cancer
artificial single-stranded DNA or RNA sequences, with high affinity, treatment. However, because GQDs can be easily cleared by the renal
selectivity, and non-immunogenicity (Lyu et al., 2016; Yang et al., system in vivo, GQDs were embedded into hollow mesopore silica
2015). MUC1 is a good breast cancer marker, and it has been used nanoparticles (hMSN) and combined with PEG. hMSN is a silica material
clinically as a breast cancer target (Lv et al., 2013). Therefore, the approved by the FDA and is often used in the medical field. If doxoru­
nanocomplex formed by MUC1 aptamer and graphene oxide can selec­ bicin (DOX) is incorporated in the nanostructure, it would probably
tively induce breast cancer cell apoptosis (Bahreyni et al., 2017). Table 4 achieve a better anti-breast cancer effect (Yang et al., 2018).
is the last 5 years summary of the role of graphene in small molecule Nanographene oxide whose surface is modified by copper sulfide
delivery function for breast cancer. quantum dot has been irradiated by near-infrared (NIR) laser to enhance
As traditional chemotherapeutics have shown drug resistance in the the cytotoxic activity of the nanomaterial on MCF-7 breast cancer cells.
treatment of cancer, it is becoming more and more difficult to treat It is also a potential breast cancer treatment tool (Wang and Yan, 2019).
cancer with merely small-molecular drugs. Therefore, they are often The surface of graphene oxide is rich in negative charges, which can
combined with other treatment methods. Gene therapy is an innovation interact with cation-containing materials electrostatically. Methylene
in cancer treatment methods, which is treated from the source of the blue is a photosensitizer that can be adsorbed with graphene oxide, and
disease and has unquestionable superiority. In order to realize the using graphene oxide to transfer methylene blue photosensitizer can
combined application of gene therapy and drug therapy, researchers improve the MDA-MB-231 breast cancer treatment (Hosseinzadeh et al.,
consider using graphene oxide functionalized with polyamide den­ 2018).
drimer (PAMAM) as a nanocarrier for therapeutic drugs and genes. The The combination of poly(2-oxazoline) (POx) or poly (2-ethyl-2 oxa­
dendritic structure of polyamide dendrimers can encapsulate genes in it, zoline) (PEtOx) and graphene oxide can overcome the biological prob­
which can avoid the interference of enzymes in the body. Moreover, lems encountered by graphene oxide in the chemical photothermal
graphene oxide can load drugs and control their release, so GO-PAMAM treatment. Table 5 is the last 5 years summary of the role of graphene in
nanocomposites can load doxorubicin (DOX) and MMP-9 shRNA optical treatment of breast cancer.
plasmid at the same time to achieve effective treatment of breast cancer.
According to research, the effect of combination therapy is significantly 3.4. Drug treatment of breast cancer
better than single therapy (Gu et al., 2017).
In general, the current level of medical treatment for cancer is still in
its infancy, and the application and innovation of drugs have not yet
3.3. Optical treatment of breast cancer achieved a very good effect. Chemotherapy is a common method other
than surgery in the process of cancer treatment, but chemotherapy drugs
In recent years, photodynamic therapy (PDT), as an innovative often have very serious side effects. So medical workers still need to
exploration of tumor treatment, has occupied a certain position in the conduct further research on reducing toxic side effects and maintaining
medical research field with the characteristics of non-invasive, scarless, the efficacy of drugs. The use of carriers for targeted delivery is a
and fast healing. Because of graphene-based nanomaterials’ ability to breakthrough in this area of research. Moreover, graphene-based ma­
absorb light in the near infrared and have a large surface area, it can be terials have been a hot research spot in recent years and there have been
some related literatures reported that graphene-based nanomaterials
Table 4 were used as carriers to deliver drugs to enhance efficacy and reduce
Graphene materials deliver small molecule breast cancer treatment research. side effects.
Graphene- Characterization Small molecule Year Ref. Graphene nanomaterials can deliver gambogic acid (GA) to MCF-7
based type breast cancer cells, overcoming its poor solubility and low bioavail­
materials
ability, thereby more effectively inhibiting the growth of human breast
PEI-GO/ It could contribute to siRNA 2016 (Huang cancer cells in vitro (Saeed et al., 2014).
siCXCR4 targeted gene therapy to et al., The occurrence of cancer is inseparable from the formation of blood
suppress cancer 2016)
metastasis
vessels, so targeting tumor vasculature to generate markers is an effec­
rGON- It had a great potential to siRNA 2016 (Imani tive approach to target cancer cells. Anti-follicle stimulating hormone
PLPEG-R8 be used as a carrier for et al., receptor (FSHR) is abundant in tumor cells, and it is a highly selective
siRNA delivery 2016) tumor vascular marker. Therefore, the coupling of graphene oxide and
NS@GO- It activated the apoptotic miRNA-101 2018 (Assali
FSHR’s monoclonal antibody MAB can selectively target breast cancer,
PEG-(P-L- pathway and decreased et al.,
Arg) the viability of breast 2018) and the conjugate can be loaded with anti-cancer drugs to achieve the
cancer cell purpose of targeted treatment of breast cancer (Yang et al., 2016).
GO-R8/ It showed gene silencing survivin-siRNA 2018 (Wang Curcumin (cur) is a natural compound extracted from the spice
anti- and inhibition of tumor et al., turmeric. It has a polyphenol structure. In research, scientists found that
HER2 growth 2018)
(GRH)
it has anti-cancer and anti-oxidant effects. Both graphene oxide (GO)-
TRA/GO It induced oxidative anti-HER2 2019 (Xiao made-nanostructures and graphene quantum dots (GQDs) with curcu­
stress and actived antibody et al., min showed inhibition over the growth of breast cancer cells in a dose-
necroptosis. trastuzumab 2019) dependent manner, overcoming the shortcomings of curcumin itself,
(TRA)
and the latter one is more active than the former one (De et al., 2020).
GPCP/miR- It showed high in vivo miR-21 (miR- 2020 (Wu
21i/ICG anticancer efficiency 21i) et al., The graphene oxide magnetic nanocomposite material (GO-IOF)
2020) synthesized by the ferrofluid method can solve the aggregation problem
GO-APTES TP53 gene was expressed pEGFP-p53 2020 (Mirzaie of magnetic nanoparticles and has higher loading efficiency and mag­
51-fold in BT-20 cells et al., netic activity. Loading anastrozole (ANS) with it achieves better anti-
2020)
breast cancer effect (Chaudhari et al., 2014).

7
J. Zheng et al.
Table 5
Research on optical treatment of breast cancer with graphene materials.
Graphene-based Characterization
materials
GO-Ag It induced intracellular 1O2 production
MB–GO The MB-GO nanocomposite has good performance in photodynamic therapy (PDT)
CuSQDs-nGO It leaded to the cell apoptotic morphological variations and cell death
SGQDs-MB It induced oxidative stress and apoptotic damage
QrlGONPs-FA It showed significantly cytotoxic effects
nZVI/rGO@pDA It was effectively applied to the optical treatment of cancer and can target breast cancer
The nanocomposite formed by the combination of shape-selected
silver nanoparticles (AgNPs) and reduced graphene oxide has the
characteristics of strong resistance to breast cancer and low toxicity to
normal cells (Derakhshi et al., 2018).
Graphene oxide modified by folic acid, polyethyleneimine, and
heparin (GPFH) is a dual-targeting biomaterial that can selectively
target breast cancer with the anticancer drug doxorubicin (DOX). The
application of DOX@GPFH composite material and PI3K inhibitor GDC
can inhibit breast cancer metastasis to lung tissue and treat breast cancer
effectively (Li et al., 2018). Some researchers have also used graphene
oxide as a carrier of folic acid (FA) and doxorubicin to prepare polylactic
acid (PLA) composite microbubbles through multiple emulsification-
solvent evaporation methods, which can be used for breast cancer cell
targeting treatment and ultrasound diagnosis (Zhang et al., 2019).
Paclitaxel (PTX) is an anti-tumor drug with severe side effects and
low bioavailability (Bitounis et al., 2013). However, the targeted de­
livery of nanocomposite materials can effectively reduce its lethality to
normal human cells, so it is a promising research direction to find a
suitable transportation for paclitaxel carrier. Methyl acrylate (MA) is a
pH-sensitive and biocompatible synthetic polymer commonly used in
the medical field, and folate receptors exist in many tumor sites and are
overexpressed (Lin et al., 2013). Chemically synthesized folic acid-
coupled graphene oxide grafted methyl acrylate nanocarrier (GO-MA-
FA/PTX) is able to target paclitaxel into breast cancer, reduce the
toxicity of paclitaxel, and achieve the purpose of anti-breast cancer
(Vinothini et al., 2019).
At present, the treatment of breast cancer is still being explored, and
chemical drugs are still a major force, but most drugs have very serious
side effects. Graphene oxide is a very important nanomaterial. It is very
popular in the field of medicine and has a very large surface area and
various functional potentials. On this basis, graphene oxide and 5-FU are
made into gel nanocarriers, and then 5-FU is added to the synthesized
graphene oxide solution, and then L-arginine is used as a crosslinking
agent to make graphene oxide-L-arginine-5-FU nanogel. This gel is
sensitive to pH and can be used as a good tool for intelligent drug de­
livery and release, as it can achieve a good anti-breast cancer effect and
reduce the side effects of 5-FU on the body (Malekimusavi et al., 2019).
Platinum complexes is a very typical cancer chemotherapy drug, but
its acquired resistance, solubility, permeability and toxic side effects in
the body often limit its clinical application. Transferrin (Tf) coupled
nanographene oxide modified by polyethyleneimine showed good water
solubility, and the formed Tf-NGO nanosystem can be used as a carrier of
metallic platinum to deliver it to breast cancer cells and can inhibit the
proliferation, migration and invasion of breast cancer cells effectively
(Zhu et al., 2017). This is just a representative of the nanosystem for
metal complexes and other effective complexes can also be explored in
the same experiment.
In eukaryotes, mitochondria are very important organelles, which
can produce cell energy for cell growth and proliferation. Therefore,
mitochondria are a potential research object in anti-tumor research.
However, mitochondria have negative membrane potential and double
membranes, which are generally difficult to enter and penetrate. The
mitochondrial targeting ligand hypericin (HY) is a natural photosensi­
tizer, which can bind to the biological macromolecules on the tumor cell
membrane in the tumor microenvironment. Coupling both hypericin
8
International Journal of Pharmaceutics 603 (2021) 120644
Condition Year Ref.
Laser exposure 2017 (Shaheen et al., 2017)
Red LED irradiation 2018 (Hosseinzadeh et al., 2018)
Near-infrared (NIR) 2019 (Wang and Yan, 2019)
Visible light 2019 (Monroe et al., 2019)
Near-infrared (NIR) 2019 (Gadeval et al., 2019)
Near-infrared (NIR) 2020 (Lin et al., 2020)
(HY) and doxorubicin (DOX) to graphene oxide nanomaterials can cause
breast cancer cells to undergo apoptosis in vitro, and displays low
cytotoxicity to normal cells (Han et al., 2018).
The slow and sustained release of drugs in the focal tissues of the
body is the current exploration goal of researchers, which is particularly
important in cancer treatment. For the purpose of developing a
biocompatible carrier with sustained release behavior, the stable and
porous MIL-53 in metal organic frames (MOFs) was selected as the
polymer, because the interaction between polymers and nanoparticles is
relatively poor and particles are prone to occur polymerization, so
choose the method of directly synthesizing the polymer in the matrix to
overcome this shortcoming. In the carboxymethyl cellulose (CMC)/
graphene quantum dots (GQDs) matrix, MIL-53 was synthesized in situ,
and a new carrier material with good biocompatibility was obtained.
Studies have shown that loading doxorubicin (DOX) on MIL-53@CMC/
GQDs and using it to treat MDA-MB-231 breast cancer cells found a large
number of apoptosis and showed the controlled release behavior of
DOX. In consequence, the system has great potential to become a
medical clinical application (Pooresmaeil et al., 2020). Table 6 is a
summary of this effect.
3.5. Gene drug combination therapy for breast cancer
HSV-TK is a gene that can inhibit the growth of breast cancer, and
ganciclovir (GCV) which often has serious side effects in clinical appli­
cations is an anticancer drug that can be activated by HSV-TK to cause
cell death (Fillat et al., 2003). Hydroxyapatite (HAp) is a calcium
phosphate salt that is often used in drug delivery (Venkatesan et al.,
2011).
Therefore, some researchers have used nanocomposites (GO-HAp)
formed of graphene oxide and hydroxyapatite to connect tumor-specific
promoters (estrogen response elements ERRs and hypoxia response el­
ements HREs), HSV-TK genes and GCV, which is purposeful for intro­
duction of breast cancer cells, transfers the HSV-TK suicide gene,
inhibits the growth of breast cancer, and greatly reduces the cytotoxicity
to normal breast cells (Cheang et al., 2018).
4. Conclusion and outlook
In general, the discovery and application of graphene-based bio­
materials in the fight against breast cancer is a major breakthrough in
the world, and it also opens up a new direction for people in breast
cancer treatment. Graphene-based biomaterials help people to make
progress in the diagnosis of early breast cancer, increase the possibility
of cure for early breast cancer patients, and also contribute to the
treatment of breast cancer. Although the effects of graphenes on various
human systems have not been systematically studied, the surfaces of
graphenes are rich in carboxyl and hydroxyl groups, which facilitate
surface modification and absorb light in the near-infrared region. The
special biochemical and physical properties illustrate graphene-based
materials are a kind of biological materials with great potential, which
is worthy of our further exploration and research.
Graphene-based materials are still in a long-term exploration stage
and combining them with some metabolites of the body in the future
may change its biocompatibility and cytotoxicity. The three-position
J. Zheng et al.
Table 6
Research on graphene-based materials for breast cancer drugs or optical treatments.
Graphene-based Characterization
materials
NRGO-GNS@DOX It induced significant cytotoxicity in 4T1 breast
cancer cells
GOFA-DOX/HACPN A safe and efficient intratumoral drug delivery
system
GQDs@hMSN-PEG Excellent photoluminescent properties and (1O2)
generating efficiency
DOX@GPFH It down-regulated expression of matrix
metalloproteinase.
GO-PEG It increased the water solubility and targeting
sensitivity of DOX
POxylated GO It induced a stronger therapeutic effect than free
drug combination
GO-g-MA/FA It showed cytotoxic effect to breast cancer
DL-CNPs It induced the efficient inhibition of antitumor
activity
integration of gene, drugs and targeted formulation may greatly
enhance efficacy and reduce toxicity. In the future the sensitive release
of a small amount of multi-layer graphene-carrying drugs in vivo may be
a research direction.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
This study was supported by Hunan Provincial Natural Science
Foundation of China [2018JJ3456], Scientific Research Fund of Hunan
Provincial Education Department [17C1398], General project of Hen­
gyang Science and Technology Board [2016KJ62], Hunan Province
College Students Research Learning and Innovative Experiment Project
[2018478], and Teaching Research and Reform Project of University of
South China [2017XJG-YB43].
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