ADR-13004; No of Pages 14

Advanced Drug Delivery Reviews xxx (2016) xxxxxx

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

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

Stimuli responsive drug delivery systems based on nano-graphene for

cancer therapy
Kai Yang a,, Liangzhu Feng b, Zhuang Liu b,
a

School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education
Institutions, Medical College of Soochow University, Soochow University, Suzhou, Jiangsu 215123, China
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials & Devices, Collaborative Innovation Center of Suzhou Nano Science and
Technology, Soochow University, Suzhou, Jiangsu 215123, China

a r t i c l e

i n f o

Article history:
Received 19 January 2016
Received in revised form 13 April 2016
Accepted 18 May 2016
Available online xxxx
Keywords:
Nano-graphene
Drug delivery
Stimuli-responsive
Cancer therapy

a b s t r a c t
Nano-graphene as a class of two-dimensional sp2 carbon nanomaterial has attracted tremendous attentions in
various elds in the past decade. Utilizing its unique physical and chemical properties, nano-graphene has also
shown great promises in the area of biomedicine, for application in biosensing, imaging and therapy. In particular,
with all atoms exposed on its surface, nano-graphene exhibits ultra-high surface area available for efcient binding/loading of various biomolecules of interests, and has been widely used as multifunctional nano-carriers for
drug and gene delivery. In this review article, we will summarize the recent advances in the development of
nano-graphene as stimuli-responsive nano-carriers for drug delivery, as well as the applications of these smart
systems for cancer therapy.
2016 Elsevier B.V. All rights reserved.

Contents
1.
2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Endogenous stimuli-responsive drug delivery with graphene . . . . . . . .
2.1.
pH responsive drug delivery with graphene . . . . . . . . . . . .
2.2.
Redox-responsive drug delivery with graphene . . . . . . . . . . .
2.3.
Graphene-based drug delivery systems responsive to biomolecules . .
3.
Graphene-based drug delivery systems responsive to external physical stimuli
3.1.
Light-responsive drug delivery systems with graphene . . . . . . .
3.2.
Magnetic eld-responsive drug delivery systems with graphene . . .
3.3.
Temperature-responsive drug delivery systems with graphene . . . .
4.
Conclusion and prospects . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
While cancer has become the major global healthcare problem in
this century [1], cancer chemotherapy currently used in the clinic on
This review is part of the Advanced Drug Delivery Reviews theme issue on Graphenebased materials in nanomedicine.
Corresponding authors.
E-mail addresses: kyang@suda.edu.cn (K. Yang), zliu@suda.edu.cn (Z. Liu).

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0
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one side has severe side effects, and on the other side shows limited
and individually varied therapeutic responses [2,3]. With the hope to
overcome those existing problems (at least some of them) in current
cancer therapy strategies, various drug delivery systems (DDSs) have
been explored in the past few decades, aiming at cancer-targeted delivery and controlled release of therapeutic agents inside the lesion [47].
In particular, in order to further improve therapeutic specicity, different types of stimulus-responsive DDSs have been successfully designed
with the help of nanotechnology, and demonstrated to be effective by

http://dx.doi.org/10.1016/j.addr.2016.05.015
0169-409X/ 2016 Elsevier B.V. All rights reserved.

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

pre-clinic animal experiments in recent years [814]. An excellent

stimuli-responsive drug delivery carrier for cancer therapy should be
featured with not only excellent in vivo pharmacokinetic proles and
tumor homing ability, but also enhanced cell uptake and/or controlled
release of drugs selectively in the diseased region (e.g. cancer) under
stimulations, so as to achieve cancer-specic treatment with high
efcacy and reduced side effects [1517].
Graphene, as a class of two-dimensional (2D) nanomaterials, has
attracted extensive attention in various different elds including nanoelectronic devices, transparent conductors, energy and catalysis
[1823]. Owing to their intrinsic physical and chemical properties,
graphene, graphene derivatives and various graphene-based nanocomposites have also been widely explored in the area of biomedicine, for application in bio-sensing, bio-imaging, drug/gene delivery, different types
of cancer therapies, as well as tissue engineering [2434](Fig. 1). As far as
cancer theranostic applications are concerned, nano-graphene and its
derivatives with high near-infrared (NIR) absorbance could act as
photothermal agents for efcient photothermal therapy (PTT) of cancer
[3538]. With an extremely high specic surface area, graphene can be
loaded with various types of biomolecules with high efciencies for applications in drug delivery and gene transfection [25,3948]. Moreover,
various inorganic nanoparticles could be anchored onto the surface of
nano-graphene to offer additional optical and magnetic properties

which could be useful to provide contrast for in vivo tumor multimodal

imaging [36,4952]. In addition, functionalized nano-graphene labeled
with radionuclides such as 64Cu, 66Ga, 125I and 131I could nd interesting
applications in nuclear imaging and radiotherapy of cancer [5358]. Beyond graphene oxide, other graphene related nanomaterials including
graphene nanoribbons and graphene quantum dots have also been
used as nano-carriers for drug delivery in recent years [5963]. Meanwhile, many research groups including ours have investigated the
in vivo behaviors and toxicology of functionalized nano-graphene via different administration strategies [57,6469], and uncovered that the toxicity of nano-graphene could be closely related to its surface chemistry
and sizes. Nano-graphene with well-engineered surface coating and
small sizes exhibited no obvious toxic effect to treated mice in a reasonable dose range and could be gradually excreted from the body via urine
and feces [55,56,58,64,7074].
While the biomedical applications of graphene have been intensively reviewed in the past several years [26,28,64,7581], a review article
focusing on stimuli-responsive graphene-based nano-platforms for cancer therapy may still be needed in the community of nanomedicine. In
this article, therefore, we would like to discuss the development of
graphene-based stimulus-responsive DDSs for cancer therapy applications, a relatively focused direction with many latest interesting results
promising to the area of nanomedicine. As summarized in Table 1, nano-

Fig. 1. A scheme showing the exploration of nano-graphene in different elds of biomedicine.

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

Table 1
Drug delivery based on nano-graphene.
Graphene
composites

Drug

Stimuli
responsive

References

GO-PEG
GO-pluronic F127
GO-IONP
GO-Au
GO-Ag
GO-CuS
GO-sulfonic acid
GO-gelatin
GO-PNIPAM
GO-chitosan
GO-SS-mPEG
GO-chlorotoxin
GO-PEG-BPEI
GO-hyaluronic
acid (HA
GO-lipid
GO-DNA
GO-silica
GO-PDEA
GO-peptide-FA
GO-transferrin
GO-PEG

DOX, Ce6
DOX
DOX
DOX
DOX
DOX
DOX and CPT
DOX, MTX
CPT, DOX, IBU
CPT, DOX
DOX
DOX
DOX
DOX, Ce6, ICG

Light/pH
pH
Magnetic/pH
Light/ pH/Redox
Light
Light/pH
pH
pH
pH/thermo
pH
Redox
pH
Light
Light/pH

[24,25,88,136,161,162]
[101]
[82,83,98,141,146,163]
[49,91,124,164]
[140]
[165]
[43]
[102,166]
[152,153,167]
[104,105]
[85]
[103]
[86]
[47,108,109,111114]

DOX
DOX
DOX
CPT
CPT
Dihydroartemisinin
DOX

pH
ATP
Light/pH
pH
pH
pH
Furin

[101]
[87]
[90,139,168]
[97]
[106]
[107]
[88]

graphene functionalized with various types of surface coatings, or

anchored with inorganic nanoparticles, can be efciently loaded with
different therapeutic molecules via stacking and hydrophobic interactions [82,83]. Utilizing carefully designed conjugation chemistry,
or taking advantage of the inherent chemical properties of nanographene or the loaded therapeutic molecules, graphene-based DDSs
responsive to a number of endogenous stimuli such as pH, redox potential, and biomolecules of interests, have been widely explored [8489].
On the other hand, certain external physical stimuli, such as NIR light
and magnetic eld, could also be used to stimulate drug delivery by
graphene-based DDSs [9093]. This review would therefore bring an
overview of this interesting eld, and discuss future perspectives
in the development of multi-stimuli responsive DDSs with nanographene for cancer therapy.
2. Endogenous stimuli-responsive drug delivery with graphene
The controlled drug release within lesions plays an important role in
the eld of drug delivery. Recently, graphene-based DDSs responsive to
various endogenous stimuli including pH, redox potential, and biomolecules of interests, have been widely developed to enhance the
therapeutic efcacy and reduce the side effects of loaded drugs.
2.1. pH responsive drug delivery with graphene
pH sensitive DDSs, which are responsive to the abnormal change of
pH values in diseased sites such as ischemia, infection, inammation,
and cancer, have been widely explored for controllable drug release
[31,9496]. Since the tumor microenvironment is more acidic compared to normal tissues, exploiting acidic sensitive DDSs has been proven to be an effective strategy for tumor specic drug delivery. Under
acidic conditions, hydrophobic drugs such as doxorubicin (DOX) can
be protonated, which would weaken the stacking and hydrophobic
interactions between drug molecules and the graphene surface, realizing pH responsive drug release [43,9799].
In an early work related to graphene oxide (GO), GO with polyethylene glycol (PEG) functionalization was rstly reported by Dai and coworkers, and used as a 2D nano-carrier to load anticancer drug. In that
work, an antibody (anti-CD20, Rituxan) was conjugated to PEGylated
GO (GO-PEG) for targeted drug delivery with pH responsive release
prole [24]. After that, nano-graphene and its derivatives with

various surface coatings have been used for loading anticancer drugs
and pH dependent drug release. For example, Pluronic F127 was used
to functionalize nano-graphene (PF127/GO) via the hydrophobic interactions to confer its biocompatibility. The obtained PF127/GO nanocomposites exhibited high DOX loading capacity (289 %, w/w) and a pH
responsive drug release behavior [100]. Similar behaviors have also
been observed for lipid monolayer membrane functionalized graphene
sheets with DOX loading [101]. In another work, nano-graphene covalently functionalized pH-sensitive poly(2-(diethylamino) ethyl methacrylate) (PDEA) (GO-PDEA) was used to load camptothecin (CPT), a
water-insoluble anticancer drug, for fabrication of a pH responsive
drug release system [97]. Besides DOX and CPT, anticancer drugs methotrexate (MTX) and 5-uorouracil, (5-FU) were also loaded on the surface
of nano-graphene with different surface coatings for pH dependent drug
release [98,102].
In order to improve therapeutic efciency and reduce systemic side
effects, various ligands were used for targeted drug delivery with
graphene-based DDSs. Targeted peptide chlorotoxin-conjugated GO
(CTX-GO) sheets were prepared and applied for DOX loading (CTXGO/DOX) via noncovalent interactions. The DOX release was pHdependent and showed sustained-release properties [103]. Cyclic
RGD-modied chitosan functionalized graphene oxide (RC/GO) was
used for hepatocellular carcinoma-targeted therapy and imaging. The
DOX loaded RC/GO exhibited targeted drug transportation to hepatoma
cells and pH-responsive drug release [104]. In addition, Depan et al.
used folic acid conjugated chitosan to modify nano-graphene and applied it for DOX loading [105,106]. In recent work, dihydroartemisinin
(DHA) and transferrin dual-dressed nano-graphene oxide was synthesized and used for pH-triggered chemotherapy, signicantly enhancing
the specicity of tumor-targeted delivery [107]. Moreover, hyaluronic
acid (HA) has also been widely used to modify nano-graphene for
cancer-targeted specic delivery of an anti-cancer drugs via HA receptor
mediated endocytosis [108114].
To allow monitoring of pH-responsive drug release by imaging, in a
more recent work, multifunctional GO was developed for stimuliresponsive cancer therapy by Shi and co-workers [115]. In this work,
superparamagnetic Fe3O4 and paramagnetic MnOx nanoparticles
(NPs) were co-anchored onto the surface GO (FeMn-GO) by a double
redox strategy. DOX could be loaded onto the surface GO via stacking with high drug loading capacity. The DOX loaded FeMn-GO exhibited pH dependent drug release. More interestingly, it was found that
MnOx NPs appeared to be very sensitive to mild acidity, and would
disintegrate and produce Mn2+ ions under reduced pH, leading to the
enhanced T1-weighted and T2-weighted magnetic resonance (MR)
imaging contrast (Fig. 2). Therefore, such a strategy could be used to
monitor the pH-responsive drug release via T1-and T2-weighted MR
imaging during chemotherapy.
In recent years, charge-reversal nano-carriers, whose surface
charges could be converted from negative into positive under reduced
pH to promote their cellular uptake, has received considerable interests
in the eld of DDSs [84,116120]. A charge-reversal polyelectrolyte
and integrin V3 mono-antibody functionalized GO was developed
for targeted delivery and controlled DOX release [121]. In this
work, citraconic anhydride-functionalized poly(allylamine) (PAH-Cit),
a common charge-reversal polyelectrolyte, was conjugated with
polyethyleneimine (PEI) coated GO, which could be used to load DOX,
obtaining a GO-Abs/PAH-Cit/DOX nano-complex. Under acidic condition, the PAH-Cit/DOX would be converted to cationic PAH and release
DOX into cancer cells. In our recent work, we also developed chargereversal GO for drug delivery (Fig. 3a). In order to obtain chargereversibility, 2,3-dimethylmaleic anhydride (DA)-PAH was conjugated
together with PEG to modify GO, yielding GO-PEG-DA nanoconjugates
[84]. It was found that GO-PEG-DA exhibited very stable negative
charges under physiological pH at 7.4, but would be rapidly converted
into positively charged nano-carriers under a slightly acidic pH (e.g.
6.8), at which the cellular uptake of DOX loaded on GO-PEG-DA could

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

Fig. 2. pH-and reduction-responsive T1-weighted MR imaging based on FeMn-GO nanocomposites. (a) A schematic to show the disintegration of MnOx from Fe3O4 and MnOx
nanoparticles co-loaded GO nanocomposites in a mildly acidic environment. (b) In vitro dynamic measurement of T1-(b1b10 ) and T2-weighted (b11b20 ) MR images of FeMn-GO in
buffer solutions with different pH values (b1 and b11: 0 min, b2 and b12: 5 min, b3 and b13: 10 min, b4 and b14: 15 min, b5 and b15: 20 min, b6 and b16: 25 min, b7 and b17: 30 min, b8
and b18: 35 min, b9 and b19: 40 min, b10 and b20: 45 min; in each photo, left: pH = 6.0; right: pH = 7.4). (c & d) T1- (c) and T2- (d) weighted MR images of FeMn-GO in buffer
solutions at different pH values after soaking at 37 C for 4 h. (e & f) T1 (e) and T2 (f) relaxivity of the buffer suspensions of FeMn-GO after 4 h soaking under different pH values
(black line: 7.4 and red line: 6.0) at 37 C. (For interpretation of the reference to color in this gure legend, the reader is referred to the web version of this article.)
Adapted from Chen et al. [115]. Copyright 2014 Wiley-VCH.

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

Fig. 3. Tumoral acidic microenvironment responsive nano-graphene oxide for efcient cancer therapy overcoming drug resistance. (a) A schematic illustration of the acidic extracellular
environment-induced surface charge reverse of NGO-PEG-DA/DOX complex, its cellular uptake and intracellular acidic environment-triggered DOX release. (b) Confocal uorescence
microscopy observations of pH dependent cellular uptake of FITC-labeled NGO-PEG-DA and NGO-PEG-SA by MCF-7/WT cells. (c & d) Relative cell viabilities of drug-resistant MCF-7/
ADR cells incubated with NGO-PEG-DA/DOX, NGO-PEG-SA/DOX (a control without the pH-responsive charge reverse ability), and free DOX for 48 h at pH 6.8 (c) and pH 7.4 (d).
Adapted from Feng et al. [84]. Copyright 2014 Wiley-VCH.

be greatly enhanced (Fig. 3b). As a result, GO-PEG-DA/DOX under the

tumor microenvironment pH (e.g., pH 6.8) offered rather strong cell
killing efcacy towards drug-resistant MCF-7/ADR cells, which could
hardly be killed by free DOX under this pH (Fig. 3b-d). Therefore, pH responsive DDSs based on nano-graphene could be promising to enhance
the efcacy of conventional chemotherapy of cancer.
2.2. Redox-responsive drug delivery with graphene
It is known that the cellular redox environment is mainly regulated
by the level of glutathione (GSH) [122]. GSH is the thiol compound present in the cytoplasm of mammalian cells with high concentrations (5
10 mM) [123]. Deciency of GSH levels always leads to an increased
susceptibility to oxidative stress, while excess of GSH generally increases antioxidant capacity and oxidative stress resistance. Therefore,
the intracellular GSH may serve as a promising stimulus to trigger
drug release from DDSs. In a work by Shi, a shielded PEG shell was
used to modify nano-GO (NGO) via a disulde linkage, yielding NGOSS-mPEG nanoconjugates. For drug delivery, NGO-SS-mPEG loaded
with DOX via stacking could be internalized by cancer cells via endocytosis. In the presence of intracellular GSH, the disulde bond of
NGO-SS-mPEG was rapidly cleaved to release the loaded DOX at an elevated speed, realizing rapid GSH-mediated drug release for tumor chemotherapy (Fig. 4) [85]. In another work, NGO-Ag nanocomposites
were prepared for intercellular drug release which was monitored by
surface enhanced Raman scattering (SERS)-uorescence combined
spectroscopy. DOX was linked directly to the NGO-Ag nanocomposites
via disulde bonds, which can be cleaved by the intracellular GSH to
trigger the DOX release [124]. On the other hand, combined GSH and
light multi-responsive based on GO-BPEI-PEG nano-carrier would
signicantly improve the killing efciency against cancer cells [86].

Therefore, redox-responsive drug delivery will provide novel approaches and alternatives for cancer therapy.
In addition to the application of redox responsive surface modication to enable controllable drug release, in another work by our group,
we found that the biodegradation behaviors of GO could be regulated
by its redox-sensitive surface coating [57]. It was uncovered that GO
without surface coating, while being toxic to macrophages, could be
gradually degraded through enzyme induced oxidization by horseradish peroxidase (HRP). While GO coated with biocompatible macromolecules such as PEG or bovine serum albumin (BSA) exhibited no obvious
toxicity to cells, it could hardly be degraded by enzymes. In order to obtain biocompatible functionalized GO that can still undergo enzymatic
degradation, we conjugate PEG to GO via a cleavable disulde bond,
obtaining GO-SS-PEG with negligible toxicity and considerable degradability (Fig. 5). Therefore, redox responsive surface coating could not
only be used to fabricate smart graphene-based DDSs, but may also be
utilized to tune the biodegradation behaviors of GO.
2.3. Graphene-based drug delivery systems responsive to biomolecules
Beyond pH and redox responsive graphene-based DDSs, smart
graphene carriers responsive to specic biomolecules have also been reported [87,88]. In a recent work by Gu and co-workers, adenosine-5triphosphate (ATP), the primary energy molecule of cells, was chosen
as the intracellular trigger to enhance the release of loaded drug from
the GO nano-carrier responding to the intracellular ATP concentrations
[87]. In this work, they prepared GO-DNA hybrid nano-aggregates containing single-stranded DNA1, DNA2, the ATP aptamer and GO, the latter of which was used as nano-platform to load DOX. It was found that
the single-stranded DNA1 and DNA2 together with the ATP aptamer
could crosslink with each other on the surface of GO, effectively

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

Fig. 4. A schematic illustration of redox-sensitive DXR-loaded NGO-SS-mPEG for cancer cells chemotherapy. (a) PEG-shielded NGO with disulde linkage for prolonged blood circulation.
(b) Endocytosis of NGO-SS-mPEG in tumor cells via the EPR effect. (c) GSH trigger to induce PEG detachment. (d) Rapid drug release to kill cancer cells.
Adapted from Wen et al. [85]. Copyright 2012 Wiley-VCH.

inhibiting the release of DOX from GO nanosheets. In the presence of

ATP, the interaction of ATP and ATP aptamer would induce the dissociation of GO-DNA nano-aggregates, promoting DOX release from GO
nanosheets (Fig. 6).
In a following work from the same group, they developed furincleavable peptide conjugated PEGylated GO (TRAIL/DOX-fGO) as a
nano-platform to co-load a cell-membrane-targeted anticancer protein
and a chemotherapeutic agent for combination cancer treatment [88].
In this work, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a cell-membrane-targeted anticancer protein to induce
cell apoptosis, was conjugated to GO-PEG through furin cleaved peptide.
In the tumor, TRAIL could be released in the extracellular environment
through furin digestion of peptide linker to trigger cell apoptosis. On
the other hand, GO-PEG was also used as a nano-carrier to transport
DOX into cells for chemotherapy, which in combination with the
apoptosis-inducing effect of TRAIL could offer synergistic antitumor
activity.
3. Graphene-based drug delivery systems responsive to external
physical stimuli
In addition to endogenous stimuli, there have been a number of external physical stimuli potentially useful in DDSs such as light, magnetic
eld and temperature. Different from previously discussed smart DDSs
responsive to internal stimuli which may already exist inside the
tumor microenvironment, DDSs responsive to external physical stimuli
would only exert or show enhanced therapeutic functions under specific physical stimuli applied onto the tumor from the outside.
3.1. Light-responsive drug delivery systems with graphene
Photothermal therapy (PTT) has been widely used to directly kill
cancer cells using optical-absorbing nano-agents, which could generate
heat under near infrared (NIR) light irradiation. Up to date, a large variety of inorganic and organic nano-agents, including nano-graphene,
have been exploited as efcient photothermal agents for direct
photothermal ablation of cancers [36,37,125134]. Those studies have

been well summarized in a number of previously published review articles [27,29,135], and thus would not be detailed in this current review.
On the other hand, different from direct photothermal ablation of cancer cells with high-temperature heating (e.g. above 50 C), the mild
photothermal effect, which could elevate the tumor temperature to
4345 C and would not induce obvious cell death, has been found to
be a useful strategy to enhance the cell uptake of those NIR-absorbing
drug carriers and promote drug release for a more effective cancer
therapy.
In a series of work by our group and others, nano-graphene and its
derivatives have been demonstrated to be effective nano-carriers for
many aromatic therapeutic molecules [24,25,39]. In 2011, we found
that chlorine 6 (Ce6), a photosensitizer, could be effectively loaded
onto the surface of nGO-PEG via stacking and hydrophobic interactions. Interestingly, utilizing the high photothermal conversion capacity
of nGO-PEG, we found that a mild photothermal heating effect induced
by 808-nm laser irradiation could signicantly enhance the cell uptake
of Ce6 transported by nGO-PEG without inducing obvious cytotoxicity,
further enhancing the photodynamic therapy efcacy against cancer
cells [136]. In another work by our group, we found that nGO with covalent grafting of (PEG) and polyethyleneimine (PEI) could be promising
for photothermally controllable gene delivery. In this work, intriguing
results indicated that nGO-PEG-PEI could efciently transport the loaded plasmid DNA into cancer cells at ~43 C induced by 808-nm laser irradiation, resulting in greatly enhanced gene transfection efciency.
Moreover, by utilizing the small interfering RNA (siRNA) as the model
therapeutic nucleic acid, we found that such mild photothermal effect
could remarkably enhance its treatment outcome, rstly realizing
photothermally enhanced cancer gene therapy (Fig. 7) [93].
Owing to the intrinsic high photothermal conversion ability of nanographene, NIR laser irradiation could also be used to enhance drug release from the nano-carrier, realizing photothermally triggered drug release. In a recent work, reduced nano-graphene with PEG modication
could be used for resveratrol (RV) loading, forming NrGO/PEG-RV nanocomposites [137]. Under NIR laser irradiation for 3 min, RV released
from NrGO/PEG-RV was signicantly increased, subsequently contributing to enhanced cell apoptosis. In another work, Kim et al. used the

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

Fig. 5. The biodegradation of disulde-linked GO-SS-PEG. (a) Schematic illustration of the preparation of GO-SS-PEG. (b & c) UVvis-NIR spectra and inner photos of GO-SS-PEG samples
without (a) or with (b) dithiothreitol (DTT)-pretreatment, before and after HRP-induced biodegradation for 4 days. The absorbance peak at 420 nm was attributed to the HRP added into
different samples. (c) TEM images of DTT-pretreated GO-SS-PEG at day 0 (1 & 2) and day 4 (3 & 4).
Adapted from Li et al. [57]. Copyright 2014 Wiley-VCH.

PEG and BPEI co-functionalized rGO for drug delivery, and obtained
similar results [138]. Moreover, Huang and co-workers reported
targeting peptide (IP) conjugated mesoporous silica coated GO (GS)
for DOX loading, realizing in vitro synergic chemo-photothermal
therapy of glioma (Fig. 8a) [139]. NIR laser irradiation of GS not only
increased the temperature of GS nanocomposites but also signicantly
enhanced cell uptake and drug release. Besides, GO/Ag nanocomposites
functionalized with Asn-Gly-Arg (NGR) peptide conjugated DSPEPEG2000 was developed for targeted drug delivery, achieving
great in vivo tumor treatment effect in their animal tumor model experiments [140].
In order to further enhance the NIR absorbance of GO for a more effective cancer therapy, in a recent work, Song et al. found that small gold
nanorods could be loaded onto reduced GO, yielding rGO-AuNR vesicles
with remarkably amplied photoacoustic (PA) imaging performance
and photothermal effects [91]. Moreover, rGO-AuNR vesicle exhibited
high loading capacity for DOX due to the cavity of the vesicle and the

large surface area of rGO. In another successive work by the same

group, GO wrapped mesoporous silica nanoparticles (MSN) were developed for light-mediated drug release and aptamer-targeted cancer therapy (Fig. 8b) [90]. DOX was loaded into the MSN which was then
wrapped by negatively-charged GO, yielding MSN-DOX@GO nanocomposites. Afterwards, Cy5.5 labeled AS1411 aptamer (Cy5.5-AS1411) was
assembled on the surface of GO via the hydrophobic interactions and
stacking, with dramatic quenching of the Cy5.5 uorescence.
Under NIR laser irradiation, the photothermal heating effect induced
the expansion and vibration of GO, leading to the on-demand DOX release and uorescence recovery. In another work, GO-poly(allylamine
hydrochloride) (PAH) composite capsules were prepared and used as
novel nano-carriers to load anticancer drug DOX (doxorubicin) [92].
Upon NIR-laser irradiation, the microcapsules were ruptured in a
point-wise fashion due to local heating which in turn triggered the
release of the encapsulated anticancer drug doxorubicin (DOX) from
these capsules in a light-controllable prole.

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

Fig. 6. A schematic illustration of ATP-responsive DNA conjugated GO for controllable drug release.
Adapted from Mo et al. [87]. Copyright 2015 Elsevier.

Therefore, as nano-carriers with strong NIR absorbance, graphene

and its derivatives have shown great promises at light-responsive
DDSs. In particular, the mild photothermal heating induced by NIR
laser irradiation could enhance cell uptake of drugs with nanographene as the delivery carrier, remotely control the drug release, as
well as reduce the side-effect to normal tissues, further demonstrating
the NIR induced photothermal effect to be promising for external
stimulus responsive drug delivery.
3.2. Magnetic eld-responsive drug delivery systems with graphene
In the past few years, various graphene-based nanocomposites with
magnetic properties have also been used for applications in stimuliresponsive drug delivery. Iron oxide nanoparticles (IONPs) decorated
GO (GO-IONP) was rstly reported by Yang et al., and used as nanocarriers to load anticancer drug DOX for pH controllable DOX release
[141]. In the following work by the same group, folic acid (FA) as a
targeted ligand was covalently conjugated to GO-IONP nanocomposites
for dually targeted drug delivery by using the magnetic property of GOIONP and specic recognition ability of FA and its receptor [83], further
enhancing the loaded drug release into cancer cells. In our later work,
IONP-anchored GO with PEG functionalization for magnetically targeted
drug delivery was developed (Fig. 9a) [82]. It was found that cancer cells
incubated with GO-IONP-PEG-DOX under the magnetic eld showed
high DOX uptake, while little DOX uptake in cells far from the magnet
in the same culture dish was observed, demonstrating the magnetic
eld targeted drug delivery based on GO-PEG-IONP-DOX to enable selective killing of cancer cells localized inside the magnetic eld. Similarly, localized photothermal ablation of cancer cells in vitro could also be
realized using this agent (Fig. 9be). Such IONP-anchored GO functionalized with PEG could also be used for in vivo multimodal imaging guided photothermal therapy of cancer as demonstrated in another work by
our group [36]. Interestingly, our magnetic GO-nanocomposite could
serve as a nano-probe to monitor the tumor growth before and after
photothermal therapy (Fig. 9f).

It is known that magnetic nanoparticles in the presence of alternating magnetic eld would generate heat. Such a phenomenon has
been widely explored for magnetic hyperthermia cancer treatment
[142145]. Poly(vinyl alcohol) (PVP) functionalized GO was found to
be able to load both hydrophobic drug paclitaxel (PTXL) and hydrophilic
drug DOX with high loading efciencies and capacities [146]. Under an
alternating magnetic eld at 418 Oe (250 kHz), GO-IONP-PVP exhibited
hyperthermia effect and could be used for magnetic hyperthermia
against cancer. Therefore, with magnetic graphene nano-composites
as drug carriers, we could either apply a constant magnetic eld to locally enhance their tumor accumulation, or use an alternating magnetic
eld to induce tumor heating to achieve further enhanced cancer
therapy.
3.3. Temperature-responsive drug delivery systems with graphene
Besides light and magnetic responsive, thermal effect has also been
shown to be a useful stimulus for thermal responsive drug delivery
based on graphene and temperature sensitive polymers [147,148].
Poly(N-isopropylacrylamide) (PNIPAM) as one of the best-known
thermo-sensitive polymers with tunable critical solution temperature
(LCST) in water, has been widely used as a thermal responsive material
for controlled drug release [149151]. PNIPAM could be used to
functionalize nano-graphene via the click chemistry, obtaining GOPNIPA nanocomposites, which after loading with ibuprofen (IBU) or
CPT showed temperature dependent drug release proles [152,153].
In addition, poly(N-isopropylacrylamide) (PNIPA) and poly(ethylene
oxide) (PEO) nanoparticles (PNPs) were prepared and then assembled
onto 1-pyrenebutyric acid N-hydroxysuccinimide ester (PNHS)functionalized GO nanosheets for drug loading and temperaturedependent drug release [154]. Therefore, graphene-based DDSs containing thermo-sensitive polymers may be utilized as nano-carriers
responding to temperature changes, which could be induced by directly
heating (e.g. by water-pad), or by indirect hyperthermia effect such as
photothermal and magnetic hyperthermia effects as aforementioned.

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

Fig. 7. PEG and PEI dual-functionalized nano-graphene oxide for photothermally enhanced gene delivery. (a) A scheme showing the synthesis process of NGO-PEG-PEI conjugate and the
preparation of NGO-PEG-PEI/pDNA complex for efcient gene transfection. (b) A schematic illustration of photothermally enhanced gene delivery. (c) Confocal uorescence images of
enhanced green uorescent protein (EGFP) transfected HeLa cells treated with NGO-PEG-PEI at different N/P ratios for 20 min under various conditions including 37 C incubation,
43 C incubation, and 37 C incubation together with the 808-nm laser irradiation (0.5 W cm2). (d & e) The expression levels of Plk1 mRNA (d) and protein (e) as determined by
qRT-PCR and western blotting, respectively, in MDA-MB-435s cells after transfection with NGO-PEG-PEI/siRNA complexes at different N/P ratios with or without laser irradiation
(808 nm, 0.5 W cm2 , 20 min).
Adapted from Feng et al. [93]. Copyright 2013 Wiley-VCH.

4. Conclusion and prospects

Since its discovery, graphene with intrinsic physical and chemical
properties exhibit a wide range of potential applications in different
elds from physics, chemistry to biomedicine. For biomedical applications, nano-graphene with proper surface functionalization has been
widely used as nano-carriers for drug and gene delivery owning to its
ultra-high surface area. In this review article, we have summarized the
current advances of using nano-graphene for drug delivery in response

to different stimuli, particularly in the forms of endogenous stimuli and

physical stimuli. However, there are still a number of important tissues
to be resolved before we realize the real application of nano-graphene
in clinic.
Graphene-based DDSs responding to endogenous stimuli such as
pH, redox and biomolecules have been widely explored to realize
cancer-specic drug delivery, by taking advantage of the acidic tumor
microenvironment, the high intracellular GSH level, or the overexpression of specic types of enzymes in the tumor. However, the

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

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K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

Fig. 8. Photothermally triggered drug release from nano-graphene. (a) A scheme showing multifunctional mesoporous silica coated nano-graphene for combined chemo-photothermal
targeted therapy of glioma. (b) A schematic illustration of GO-wrapped DOX-loaded MSN bound with Cy5.5-labeled AS1411 aptamer, as well as the corresponding NIR light-controlled
intracellular drug release.
Adapted from Wang et al. [139] and Tang et al. [90]. Copyright 2013 American Chemical Society and 2015 Royal Society of Chemistry.

specicity of such internal stimuli may be limited, and the nonstimulated drug release in other tissues could also be a problem. Moreover, whether graphene is unique here and maybe replaced by other
conventional drug carriers for those applications is another question
to be answered.
In order to realize more specic and remotely controllable drug release, various external physical stimuli strategy including light and
magnetic eld could also be applied to stimulate graphene-based cancer
therapy. With strong NIR absorbance, graphene and its derivatives have
been widely explored for direct NIR-triggered photothermal therapy or

NIR-responsive drug delivery. When coupled with magnetic nanostructures, the obtained graphene-based magnetic nanocomposites would
acquire additional magnetic properties useful for magnetic eldenhanced tumor targeting or magnetic hyperthermia triggered drug release. Different from graphene-based DDSs responsive to endogenous
stimuli, those external stimulus responsive systems are based on the
unique physical properties of graphene-based nanomaterials. However,
the limited light penetration, even for NIR light, could be a major bottleneck for light-responsive therapies. On the other hand, although
magnetic eld has not tissue penetration limit, how to locally focus

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

11

Fig. 9. Magnetic graphene nanocomposite for drug delivery and imaging-guided cancer therapy. (a) A schematic illustration of DOX loaded GOIONPPEG. Inset: photos of GOIONPPEG
DOX in aqueous solutions with and without a magnet. (b) A scheme showing magnetic eld controlled in vitro photothermal therapy. A magnet was placed under the cell culture dish
during incubation. Confocal uorescence images of calcein AM (green, live cells) and PI (red, dead cells) co-stained cells after magnetically targeted photothermal ablation with the
images taken at three different locations in the culture dish: (c) right above the magnet; (d) close to the magnet; and (e) far from the magnet. (f) Monitoring of the therapeutic
response by MR imaging of tumor-bearing mice after i.v. injection with PEGylated magnetic graphene nanocomposite and exposed to the 808-nm NIR laser (upper). Non-irradiated
mice were used as the control (bottom). (For interpretation of the references to colors in this gure legend, the reader is referred to the web version of this article.)
Adapted from Ma et al. [82] and Yang et al. [36]. Copyright 2012 Springer-Verlag Berlin Heidelberg and 2012 Wiley-VCH.

sufciently strong magnetic eld specically on the tumor without

affecting its surrounding normal organs in a large human body may
require further improved techniques.
Despite numerous encouraging pre-clinical results reported in
recent years, the bench to bedside translation for graphene-based
nanomedicine remains to be a challenging task. Understanding the
potential toxicity and in vivo degradation/excretion behaviors of
nano-graphene may be of utmost importance for further development
of graphene-based nanomedicine. According to literature, nanographene without surface coating would induce signicant toxicity to
cells and animals, particularly pulmonary toxicity after intratracheal
instillation/intravenous injection, while well functionalized nanographene induced no obvious toxicity to treated cells/ animals [6567,
71,155157]. It is now widely accepted that the toxicity of nanographene may depend on its surface modication and sizes distribution [35,64,158]. However, although it has been well documented
that nano-graphene with ultra-small sizes and biocompatible surface coatings appeared to be quite safe in vitro to cells and in vivo

to animals [55,56,64,159], and naked GO could be gradually degraded

by enzymes over time [57,66,68,71,156,157,160], tremendous efforts
are still needed to persuade authorities and the public to accept the
use of graphene-based agents in the clinic.
Acknowledgments
This work was partially supported by the National Basic Research
Program of China (973 Program 2014CB931900), National Natural Science Foundation of China (81471716, 31400861), the National Natural
Science Foundation of Jiangsu Province (BK20140320), and a Project
funded by the Priority Academic Program Development of Jiangsu
Higher Education Institutions (PAPD).
References
[1] W.H. Organization, Cancer, Fact Sheet #297, 2011.
[2] J.L. Arias, Drug targeting strategies in cancer treatment: an overview, mini-rev,
Med. Chem. 11 (2011) 117.

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

12

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

[3] C. Mohanty, M. Das, J.R. Kanwar, S.K. Sahoo, Receptor mediated tumor targeting: an
emerging approach for cancer therapy, Curr. Drug Deliv. 8 (2011) 4558.
[4] J.A. Hubbell, A. Chilkoti, Nanomaterials for drug delivery, Science 337 (2012)
303305.
[5] S. Chandra, K.C. Barick, D. Bahadur, Oxide and hybrid nanostructures for therapeutic applications, Adv. Drug Deliv. Rev. 63 (2011) 12671281.
[6] S.J. Lee, H.S. Min, S.H. Ku, S. Son, I.C. Kwon, S.H. Kim, K. Kim, Tumor-targeting glycol
chitosan nanoparticles as a platform delivery carrier in cancer diagnosis and
therapy, Nanomedicine 9 (2014) 16971713.
[7] I. Brigger, C. Dubernet, P. Couvreur, Nanoparticles in cancer therapy and diagnosis,
Adv. Drug Deliv. Rev. 64 (2012) 2436.
[8] W. Xiao, X. Zeng, H. Lin, K. Han, H.-Z. Jia, X.-Z. Zhang, Dual stimuli-responsive
multi-drug delivery system for the individually controlled release of anti-cancer
drugs, Chem. Commun. 51 (2015) 14751478.
[9] D. Luo, K.A. Carter, A. Razi, J. Geng, S. Shao, D. Giraldo, U. Sunar, J. Ortega, J.F. Lovell,
Doxorubicin encapsulated in stealth liposomes conferred with light-triggered drug
release, Biomaterials 75 (2016) 193202.
[10] F.-F. Zheng, P.-H. Zhang, Y. Xi, J.-J. Chen, L.-L. Li, J.-J. Zhu, Aptamer/graphene quantum dots nanocomposite capped uorescent mesoporous silica nanoparticles for
intracellular drug delivery and real-time monitoring of drug release, Anal. Chem.
87 (2015) 1173911745.
[11] J.L. Paris, M.V. Cabanas, M. Manzano, M. Vallet-Regi, Polymer-grafted mesoporous
silica nanoparticles as ultrasound-responsive drug carriers, ACS Nano 9 (2015)
1102311033.
[12] S. Jin, J. Wan, L. Meng, X. Huang, J. Guo, L. Liu, C. Wang, Biodegradation and toxicity
of protease/redox/pH stimuli-responsive PEGlated PMAA nanohydrogels for
targeting drug delivery, ACS Appl. Mater. Interfaces 7 (2015) 1984319852.
[13] A.A. Hwang, B.-Y. Lee, D.L. Clemens, B.J. Dillon, J.I. Zink, M.A. Horwitz, pH-responsive
isoniazid-loaded nanoparticles markedly improve tuberculosis treatment in mice,
Small 11 (2015) 50665078.
[14] J. Du, L.A. Lane, S. Nie, Stimuli-responsive nanoparticles for targeting the tumor
microenvironment, J. Control. Release 219 (2015) 205214.
[15] W. Zhang, C. Gao, Recent advances in cell imaging and cytotoxicity of intracellular
stimuli-responsive nanomaterials, Sci. Bull. 60 (2015) 19731979.
[16] Y. Zhao, Sensing system for mimicking cancer celldrug interaction, Sci. Bull. 60
(2015) 12181219.
[17] D. Das, P. Ghosh, A. Ghosh, C. Haldar, S. Dhara, A.B. Panda, S. Pal, Stimulus-responsive,
biodegradable, biocompatible, covalently cross-linked hydrogel based on dextrin
and poly(N-isopropylacrylamide) for in vitro/in vivo controlled drug release, ACS
Appl. Mater. Interfaces 7 (2015) 1433814351.
[18] A.K.N. Geim, K. S., The rise of graphene, Nat. Mater. 6 (2007) 183191.
[19] K.S. Novoselov, A.K. Geim, S.V. Morozov, D. Jiang, Y. Zhang, S.V. Dubonos, I.V.
Grigorieva, A.A. Firsov, Electric eld effect in atomically thin carbon lms, Science
306 (2004) 666669.
[20] K.P. Loh, Q. Bao, G. Eda, M. Chhowalla, Graphene oxide as a chemically tunable
platform for optical applications, Nat. Chem. 2 (2010) 10151024.
[21] H. Wang, Y. Liang, T. Mirfakhrai, Z. Chen, H.S. Casalongue, H. Dai, Advanced asymmetrical supercapacitors based on graphene hybrid materials, Nano Res. 4 (2011)
729736.
[22] S. D.A.S. Dikin, E.J. Zimney, R.D. Piner, G. G.H.B.E. Dommett, S.T. Nguyen, R.S. Ruoff,
Preparation and characterization of graphene oxide paper, Nature (2007)
457460.
[23] X. Huang, X. Qi, F. Boey, H. Zhang, Graphene-based composites, Chem. Soc. Rev. 41
(2012) 666686.
[24] X. Sun, Z. Liu, K. Welsher, J.T. Robinson, A. Goodwin, S. Zaric, H. Dai, Nano-graphene
oxide for cellular imaging and drug delivery, Nano Res. 1 (2008) 203212.
[25] Z. Liu, J.T. Robinson, X.M. Sun, H.J. Dai, PEGylated nanographene oxide for delivery
of water-insoluble cancer drugs, J. Am. Chem. Soc. 130 (2008) 1087610877.
[26] L.Z. Feng, Z.A. Liu, Graphene in biomedicine: opportunities and challenges,
Nanomedicine 6 (2011) 317324.
[27] K. Yang, L. Feng, X. Shi, Z. Liu, Nano-graphene in biomedicine: theranostic applications, Chem. Soc. Rev. 42 (2013) 530547.
[28] H. Shen, L. Zhang, M. Liu, Z. Zhang, Biomedical applications of graphene,
Theranostics 2 (2012) 283294.
[29] L. Cheng, C. Wang, L. Feng, K. Yang, Z. Liu, Functional nanomaterials for
phototherapies of cancer, Chem. Rev. 114 (2014) 1086910939.
[30] C.-H. Lu, H.-H. Yang, C.-L. Zhu, X. Chen, G.-N. Chen, A graphene platform for sensing
biomolecules, Angew. Chem. Int. Ed. 48 (2009) 47854787.
[31] S. Goenka, V. Sant, S. Sant, Graphene-based nanomaterials for drug delivery and
tissue engineering, J. Control. Release 173 (2014) 7588.
[32] L. Wu, J. Wang, M. Yin, J. Ren, D. Miyoshi, N. Sugimoto, X. Qu, Reduced graphene
oxide upconversion nanoparticle hybrid for electrochemiluminescent sensing of
a prognostic indicator in early-stage cancer, Small 10 (2014) 330336.
[33] L. Feng, L. Wu, X. Qu, New horizons fro diagnosis and therapeutic applications of
graphene and graphene oxide, Adv. Mater. 168-186 (2013).
[34] L.Y. Feng, L. Wu, J.S. Wang, J.S. Ren, D. Miyoshi, N. Sugimoto, X.G. Qu, Detection of a
prognostic indicator in early-stage cancer using functionalized graphene-based
peptide sensors, Adv. Mater. 24 (2012) 125131.
[35] K. Yang, J. Wan, S. Zhang, B. Tian, Y. Zhang, Z. Liu, The inuence of surface
chemistry and particle size of nanoscale graphene oxide on photothermal therapy
of cancer using ultra-low laser power, Biomatreials 3 (2012) 22062214.
[36] K. Yang, L. Hu, X. Ma, S. Ye, L. Cheng, X. Shi, C. Li, Y. Li, Z. Liu, Multimodal imaging
guided photothermal therapy using functionalized graphene nanosheets anchored
with magnetic nanoparticles, Adv. Mater. 24 (2012) 18681872.
[37] K. Yang, S. Zhang, G. Zhang, X. Sun, S.-T. Lee, Z. Liu, Graphene in mice: ultra-high
in vivo tumor uptake and photothermal therapy, Nano Lett. 10 (2010) 33183323.

[38] J.T. Robinson, S.M. Tabakman, Y.Y. Liang, H.L. Wang, H.S. Casalongue, D. Vinh, H.J.
Dai, Ultrasmall reduced graphene oxide with high near-infrared absorbance for
photothermal therapy, J. Am. Chem. Soc. 133 (2011) 68256831.
[39] L. Feng, S. Zhang, Z. Liu, Graphene based gene transfection, Nanoscale 3 (2011)
12521257.
[40] S. He, B. Song, D. Li, C. Zhu, W. Qi, Y. Wen, L. Wang, S. Song, H. Fang, C. Fan, A
graphene nanoprobe for rapid, sensitive, and multicolor uorescent DNA analysis,
Adv. Funct. Mater. 20 (2010) 453459.
[41] L.A.L. Tang, J. Wang, K.P. Loh, Graphene-based SELDI probe with ultrahigh extraction and sensitivity for DNA oligomer, J. Am. Chem. Soc. 132 (2010) 1097610977.
[42] B.G. Choi, H. Park, T.J. Park, M.H. Yang, J.S. Kim, S.-Y. Jang, N.S. Heo, S.Y. Lee, J. Kong,
W.H. Hong, Solution chemistry of self-assembled graphene nanohybrids for highperformance exible biosensors, ACS Nano 4 (2010) 29102918.
[43] L. Zhang, J. Xia, Q. Zhao, L. Liu, Z. Zhang, Functional graphene oxide as a nanocarrier
for controlled loading and targeted delivery of mixed anticancer drugs, Small 6
(2010) 537544.
[44] L. Zhang, Z. Lu, Q. Zhao, J. Huang, H. Shen, Z. Zhang, Enhanced chemotherapy efcacy by sequential delivery of siRNA and anticancer drugs using PEI-grafted
graphene oxide, Small 7 (2011) 460464.
[45] Y. Zhu, S. Murali, W. Cai, X. Li, J.W. Suk, J.R. Potts, R.S. Ruoff, Graphene and graphene
oxide: synthesis, properties, and applications, Adv. Mater. 22 (2010) 39063924.
[46] G. Shim, J.-Y. Kim, J. Han, S.W. Chung, S. Lee, Y. Byun, Y.-K. Oh, Reduced graphene
oxide nanosheets coated with an anti-angiogenic anticancer low-molecularweight heparin derivative for delivery of anticancer drugs, J. Control. Release 189
(2014) 8089.
[47] W. Miao, G. Shim, C.M. Kang, S. Lee, Y.S. Choe, H.-G. Choi, Y.-K. Oh, Cholesteryl
hyaluronic acid-coated, reduced graphene oxide nanosheets for anti-cancer drug
delivery, Biomaterials 34 (2013) 96389647.
[48] W. Li, J. Wang, J. Ren, X. Qu, 3D graphene oxide-polymer hydrogel: near-infrared
light-triggered active scaffold for reversible cell capture and on-demand release,
Adv. Mater. 25 (2013) 67376743.
[49] C. Wang, J. Li, C. Amatore, Y. Chen, H. Jiang, X.-M. Wang, Gold nanoclusters and
graphene nanocomposites for drug delivery and imaging of cancer cells, Angew.
Chem. Int. Ed. 50 (2011) 1164411648.
[50] S.-H. Hu, Y.-W. Chen, W.-T. Hung, I.W. Chen, S.-Y. Chen, Quantum-dot-tagged reduced graphene oxide nanocomposites for bright uorescence bioimaging and
photothermal therapy monitored in situ, Adv. Mater. 24 (2012) 17481754.
[51] Y.-W. Chen, P.-J. Chen, S.-H. Hu, I.W. Chen, S.-Y. Chen, NIR-triggered synergic
photo-chemothermal therapy delivered by reduced graphene oxide/carbon/
mesoporous silica nanocookies, Adv. Funct. Mater. 24 (2014) 451459.
[52] W. Li, J.S. Wang, J.S. Ren, X.G. Qu, Near-infrared- and pH-responsive system for reversible cell adhesion using graphene/gold nanorods functionalized with i-motif
DNA, Angew. Chem. Int. Ed. 52 (2013) 67266730.
[53] H. Hong, Y. Zhang, J.W. Engle, T.R. Nayak, C.P. Theuer, R.J. Nickles, T.E. Barnhart, W.
Cai, In vivo targeting and positron emission tomography imaging of tumor vasculature with 66Ga-labeled nano-graphene, Biomaterials 33 (2012) 41474156.
[54] H. Hong, K. Yang, Y. Zhang, J.W. Engle, L. Feng, Y. Yang, T.R. Nayak, S. Goel, J. Bean,
C.P. Theuer, T.E. Barnhart, Z. Liu, W. Cai, In vivo targeting and imaging of tumor vasculature with radiolabeled, antibody-conjugated nanographene, ACS Nano 6
(2012) 23612370.
[55] K. Yang, H. Gong, X. Shi, J. Wan, Y. Zhang, Z. Liu, In vivo biodistribution and toxicology of functionalized nano-graphene oxide in mice after oral and intraperitoneal
administration, Biomaterials 34 (2013) 27872795.
[56] K. Yang, J.M. Wan, S.A. Zhang, Y.J. Zhang, S.T. Lee, Z.A. Liu, In vivo pharmacokinetics,
long-term biodistribution, and toxicology of PEGylated graphene in mice, ACS
Nano 5 (2011) 516522.
[57] Y. Li, L. Feng, X. Shi, X. Wang, Y. Yang, K. Yang, T. Liu, G. Yang, Z. Liu, Surface
coating-dependent cytotoxicity and degradation of graphene derivatives: towards
the design of non-toxic, degradable nano-graphene, Small 10 (2014) 15441554.
[58] L. Chen, X. Zhong, X. Yi, M. Huang, P. Ning, T. Liu, C. Ge, Z. Chai, Z. Liu, K. Yang,
Radionuclide I-131 labeled reduced graphene oxide for nuclear imaging guided
combined radio- and photothermal therapy of cancer, Biomaterials 66 (2015)
2128.
[59] X. Wang, X. Sun, J. Lao, H. He, T. Cheng, M. Wang, S. Wang, F. Huang, Multifunctional graphene quantum dots for simultaneous targeted cellular imaging and drug
delivery, Colloid Surf. B. 122 (2014) 638644.
[60] J.C. Qiu, R.B. Zhang, J.H. Li, Y.H. Sang, W. Tang, P.R. Gil, H. Liu, Fluorescent graphene
quantum dots as traceable, pH-sensitive drug delivery systems, Int. J. Nanomedicine
10 (2015) 67096724.
[61] S.M. Chowdhury, C. Surhland, Z. Sanchez, P. Chaudhary, M.A.S. Kumar, S. Lee, L.A.
Pena, M. Waring, B. Sitharaman, M. Naidu, Graphene nanoribbons as a drug
delivery agent for lucanthone mediated therapy of glioblastoma multiforme,
Nanomed-Nanotechnol. 11 (2015) 109118.
[62] X.J. Wang, X. Sun, J. Lao, H. He, T.T. Cheng, M.Q. Wang, S.J. Wang, F. Huang, Multifunctional graphene quantum dots for simultaneous targeted cellular imaging and
drug delivery, Colloid Surf. B. 122 (2014) 638644.
[63] C. Wang, C.Y. Wu, X.J. Zhou, T. Han, X.Z. Xin, J.Y. Wu, J.Y. Zhang, S.W. Guo, Enhancing cell nucleus accumulation and DNA cleavage activity of anti-cancer drug via
graphene quantum dots, Sci. Rep. 3 (2013).
[64] A. Bianco, Graphene: safe or toxic? The two faces of the medal, Angew. Chem. Int.
Ed. 52 (2013) 49864997.
[65] K. Yang, Y. Li, X. Tan, R. Peng, Z. Liu, Behavior and toxicity of graphene and its
functionalized derivatives in biological systems, Small 9 (2013) 14921503.
[66] S.K. Singh, M.K. Singh, P.P. Kulkarni, V.K. Sonkar, J.J.A. Gracio, D. Dash, Aminemodied graphene. Thrombo-protective safer alternative to graphene oxide
for biomedical applications, ACS Nano 6 (2012) 27312740.

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

[67] Y. Chang, S.-T. Yang, J.-H. Liu, E. Dong, Y. Wang, A. Cao, Y. Liu, H. Wang, In vitro
toxicity evaluation of graphene oxide on A549 cells, Toxicol. Lett. 200 (2011)
201210.
[68] W. Hu, C. Peng, M. Lv, X. Li, Y. Zhang, N. Chen, C. Fan, Q. Huang, Protein coronamediated mitigation of cytotoxicity of graphene oxide, ACS Nano 5 (2011)
36933700.
[69] G.M. Mutlu, G.R.S. Budinger, A.A. Green, D. Urich, S. Soberanes, S.E. Chiarella, G.F.
Alheid, D.R. McCrimmon, I. Szleifer, M.C. Hersam, Biocompatible nanoscale dispersion of single-walled carbon nanotubes minimizes in vivo pulmonary toxicity,
Nano Lett. 10 (2010) 16641670.
[70] S. Shi, K. Yang, H. Hong, H.F. Valdovinos, T.R. Nayak, Y. Zhang, C.P. Theuer, T.E.
Barnhart, Z. Liu, W. Cai, Tumor vasculature targeting and imaging in living mice
with reduced graphene oxide, Biomaterials 34 (2013) 30023009.
[71] X. Zhang, J. Yin, C. Peng, W. Hu, Z. Zhu, W. Li, C. Fan, Q. Huang, Distribution and biocompatibility studies of graphene oxide in mice after intravenous administration,
Carbon 49 (2011) 986995.
[72] K. Wang, J. Ruan, H. Song, J. Zhang, Y. Wo, S. Guo, D. Cui, Biocompatibility of
graphene oxide, Nanoscale Res. Lett. 6 (2011) 18.
[73] R. Kurapati, J. Russier, M.A. Squillaci, E. Treossi, C. Menard-Moyon, A. Esau Del
Rio-Castillo, E. Vazquez, P. Samori, V. Palermo, A. Bianco, Dispersibility-dependent biodegradation of graphene oxide by myeloperoxidase, Small 11 (2015)
39853994.
[74] D.A. Jasim, C. Menard-Moyon, D. Begin, A. Bianco, K. Kostarelos, Tissue distribution
and urinary excretion of intravenously administered chemically functionalized
graphene oxide sheets, Chem. Sci. 6 (2015) 39523964.
[75] C. Chung, Y.-K. Kim, D. Shin, S.-R. Ryoo, B.H. Hong, D.-H. Min, Biomedical applications of graphene and graphene oxide, Acc. Chem. Res. 46 (2013) 22112224.
[76] D. Bitounis, H. Ali-Boucetta, B.H. Hong, D.-H. Min, K. Kostarelos, Prospects and
challenges of graphene in biomedical applications, Adv. Mater. 25 (2013)
22582268.
[77] Y. Zhang, T.R. Nayak, H. Hong, W. Cai, Graphene: a versatile nanoplatform for biomedical applications, Nanoscale 4 (2012) 38333842.
[78] F.M.P. Tonelli, V.A.M. Goulart, K.N. Gomes, M.S. Ladeira, A.K. Santos, E. Lorencon,
L.O. Ladeira, R.R. Resende, Graphene-based nanomaterials: biological and medical
applications and toxicity, Nanomedicine 10 (2015) 24232450.
[79] Y.Q. Yang, A.M. Asiri, Z.W. Tang, D. Du, Y.H. Lin, Graphene based materials for biomedical applications, Mater. Today 16 (2013) 365373.
[80] S.C. Patel, S. Lee, G. Lalwani, C. Suhrland, S.M. Chowdhury, B. Sitharaman,
Graphene-based platforms for cancer therapeutics, Ther. Deliv. 7 (2016) 101116.
[81] S.F. Kiew, L.V. Kiew, H.B. Lee, T. Imae, L.Y. Chung, Assessing biocompatibility of
graphene oxide-based nanocarriers: a review, J. Control. Release 226 (2016)
217228.
[82] X. Ma, H. Tao, K. Yang, L. Feng, L. Cheng, X. Shi, Y. Li, L. Guo, Z. Liu, A functionalized
graphene oxideiron oxide nanocomposite for magnetically targeted drug delivery, photothermal therapy, and magnetic resonance imaging, Nano Res. 5 (2012)
199212.
[83] X. Yang, Y. Wang, X. Huang, Y. Ma, Y. Huang, R. Yang, H. Duan, Y. Chen, Multifunctionalized graphene oxide based anticancer drug-carrier with dual-targeting
function and pH-sensitivity, J. Mater. Chem. 21 (2011) 34483454.
[84] L. Feng, K. Li, X. Shi, M. Gao, J. Liu, Z. Liu, Smart pH-responsive nanocarriers based
on nano-graphene oxide for combined chemo- and photothermal therapy overcoming drug resistance, Adv. Healthcare Mater. 3 (2014) 12611271.
[85] H. Wen, C. Dong, H. Dong, A. Shen, W. Xia, X. Cai, Y. Song, X. Li, Y. Li, D. Shi,
Engineered redox-responsive PEG detachment mechanism in PEGylated nanographene oxide for intracellular drug delivery, Small 8 (2012) 760769.
[86] H. Kim, D. Lee, J. Kim, T.-i. Kim, W.J. Kim, Photothermally triggered cytosolic drug
delivery via endosome disruption using a functionalized reduced graphene
oxide, ACS Nano 7 (2013) 67356746.
[87] R. Mo, T. Jiang, W. Sun, Z. Gu, ATP-responsive DNAgraphene hybrid nanoaggregates
for anticancer drug delivery, Biomaterials 50 (2015) 6774.
[88] T. Jiang, W. Sun, Q. Zhu, N.A. Burns, S.A. Khan, R. Mo, Z. Gu, Furin-mediated sequential delivery of anticancer cytokine and small-molecule drug shuttled by graphene,
Adv. Mater. 27 (2015) 10211028.
[89] K. Yang, L. Feng, H. Hong, W. Cai, Z. Liu, Preparation and functionalization of
graphene nanocomposites for biomedical applications, Nat. Protoc. 8 (2013)
23922403.
[90] Y. Tang, H. Hu, M.G. Zhang, J. Song, L. Nie, S. Wang, G. Niu, P. Huang, G. Lu, X. Chen,
An aptamer-targeting photoresponsive drug delivery system using offon
graphene oxide wrapped mesoporous silica nanoparticles, Nanoscale 7 (2015)
63046310.
[91] J. Song, X. Yang, O. Jacobson, L. Lin, P. Huang, G. Niu, Q. Ma, X. Chen, Sequential drug
release and enhanced photothermal and photoacoustic effect of hybrid reduced
graphene oxide-loaded ultrasmall gold nanorod vesicles for cancer therapy, ACS
Nano 9 (2015) 91999209.
[92] R. Kurapati, A.M. Raichur, Near-infrared light-responsive graphene oxide composite multilayer capsules: a novel route for remote controlled drug delivery, Chem.
Commun. 49 (2013) 734736.
[93] L. Feng, X. Yang, X. Shi, X. Tan, R. Peng, J. Wang, Z. Liu, Polyethylene glycol and
polyethylenimine dual-functionalized nano-graphene oxide for photothermally
enhanced gene delivery, Small 9 (2013) 19891997.
[94] M. Stubbs, P.M.J. McSheehy, J.R. Grifths, C.L. Bashford, Causes and consequences of
tumour acidity and implications for treatment, Mol. Med. Today 6 (2000) 1519.
[95] J. Yu, X. Chu, Y. Hou, Stimuli-responsive cancer therapy based on nanoparticles,
Chem. Commun. 50 (2014) 1161411630.
[96] X. He, J. Li, S. An, C. Jiang, pH-sensitive drug-delivery systems for tumor targeting,
Ther. deliv. 4 (2013) 14991510.

13

[97] T. Kavitha, S.I.H. Abdi, S.-Y. Park, pH-sensitive nanocargo based on smart polymer
functionalized graphene oxide for site-specic drug delivery, Phys. Chem. Chem.
Phys. 15 (2013) 51765185.
[98] X. Fan, G. Jiao, L. Gao, P. Jin, X. Li, The preparation and drug delivery of a graphenecarbon nanotube-Fe3O4 nanoparticle hybrid, J. Mater. Chem. B. 1 (2013)
26582664.
[99] V.K. Rana, M.-C. Choi, J.-Y. Kong, G.Y. Kim, M.J. Kim, S.-H. Kim, S. Mishra, R.P. Singh,
C.-S. Ha, Synthesis and drug-delivery behavior of chitosan-functionalized graphene
oxide hybrid nanosheets, Macromol. Mater. Eng. 296 (2011) 131140.
[100] H. Hu, J. Yu, Y. Li, J. Zhao, H. Dong, Engineering of a novel pluronic F127/graphene
nanohybrid for pH responsive drug delivery, J. Biomed. Mater. Res. Part A 100A
(2011) 141148.
[101] J. Liu, S. Guo, L. Han, T. Wang, W. Hong, Y. Liu, E. Wang, Synthesis of phospholipid
monolayer membrane functionalized graphene for drug delivery, J. Mater. Chem.
22 (2012) 2063420640.
[102] J. An, Y. Gou, C. Yang, F. Hu, C. Wang, Synthesis of a biocompatible gelatin functionalized graphene nanosheets and its application for drug delivery, Mater. Sci. Eng. C
33 (2013) 28272837.
[103] H. Wang, W. Gu, N. Xiao, L. Ye, Q. Xu, Chlorotoxin-conjugated graphene oxide for
targeted delivery of an anticancer drug, Int. J. Nanomedicine 9 (2014) 14331442.
[104] C. Wang, B. Chen, M. Zou, G. Cheng, Cyclic RGD-modied chitosan/graphene oxide
polymers for drug delivery and cellular imaging, Colloid Surf. B. 122 (2014)
332340.
[105] D. Depan, J. Shah, R.D.K. Misra, Controlled release of drug from folate-decorated
and graphene mediated drug delivery system: synthesis, loading efciency, and
drug release response, Mater. Sci. Eng. C 31 (2011) 13051312.
[106] J. Tian, Y. Luo, L. Huang, Y. Feng, H. Ju, B.Y. Yu, Pegylated folate and peptidedecorated graphene oxide nanovehicle for in vivo targeted delivery of anticancer
drugs and therapeutic self-monitoring, Biosen. Bioelectron. 80 (2016) 519524.
[107] L. Liu, Y. Wei, S. Zhai, Q. Chen, D. Xing, Dihydroartemisinin and transferrin dualdressed nano-graphene oxide for a pH-triggered chemotherapy, Biomaterials 62
(2015) 3546.
[108] H.S. Jung, M.-Y. Lee, W.H. Kong, I.H. Do, S.K. Hahn, Nano graphene oxide
hyaluronic acid conjugate for target specic cancer drug delivery, RSC Adv. 4
(2014) 1419714200.
[109] H. Wu, H. Shi, Y. Wang, X. Jia, C. Tang, J. Zhang, S. Yang, Hyaluronic acid conjugated
graphene oxide for targeted drug delivery, Carbon 69 (2014) 379389.
[110] F. Li, S.-J. Park, D. Ling, W. Park, J.Y. Han, K. Na, K. Char, Hyaluronic acid-conjugated
graphene oxide/photosensitizer nanohybrids for cancer targeted photodynamic
therapy, J. Mater. Chem. B 1 (2013) 16781686.
[111] A.-A. Nahain, J.-E. Lee, J.H. Jeong, S.Y. Park, Photoresponsive uorescent reduced
graphene oxide by spiropyran conjugated hyaluronic acid for in vivo imaging
and target delivery, Biomacromolecules 14 (2013) 40824090.
[112] E. Song, W. Han, C. Li, D. Cheng, L. Li, L. Liu, G. Zhu, Y. Song, W. Tan, Hyaluronic
acid-decorated graphene oxide nanohybrids as nanocarriers for targeted and
pH-responsive anticancer drug delivery, ACS Appl. Mater. Interfaces 6 (2014)
1188211890.
[113] Y.A. Luo, X.L. Cai, H. Li, Y.H. Lin, D. Du, Hyaluronic acid-modied multifunctional Qgraphene for targeted killing of drug-resistant lung cancer cells, ACS Appl. Mater.
Interfaces 8 (2016) 40484055.
[114] W. Miao, G. Shim, G. Kim, S. Lee, H.J. Lee, Y.B. Kim, Y. Byun, Y.K. Oh, Image-guided
synergistic photothermal therapy using photoresponsive imaging agent-loaded
graphene-based nanosheets, J. Control. Release 211 (2015) 2836.
[115] Y. Chen, P. Xu, Z. Shu, M. Wu, L. Wang, S. Zhang, Y. Zheng, H. Chen, J. Wang, Y. Li, J. Shi,
Multifunctional graphene oxide-based triple stimuli-responsive nanotheranostics,
Adv. Funct. Mater. 24 (2014) 43864396.
[116] L. Li, W. Sun, J. Zhong, Q. Yang, X. Zhu, Z. Zhou, Z. Zhang, Y. Huang, Multistage
nanovehicle delivery system based on stepwise size reduction and charge reversal
for programmed nuclear targeting of systemically administered anticancer drugs,
Adv. Funct. Mater. 25 (2015) 41014113.
[117] S.-S. Han, Z.-Y. Li, J.-Y. Zhu, K. Han, Z.-Y. Zeng, W. Hong, W.-X. Li, H.-Z. Jia, Y. Liu, R.-X.
Zhuo, X.-Z. Zhang, Dual-pH sensitive charge-reversal polypeptide micelles for
tumor-triggered targeting uptake and nuclear drug delivery, Small 11 (2015)
25432554.
[118] Z. Zhou, Y. Shen, J. Tang, M. Fan, E.A. Van Kirk, W.J. Murdoch, M. Radosz, Chargereversal drug conjugate for targeted cancer cell nuclear drug delivery, Adv.
Funct. Mater. 19 (2009) 35803589.
[119] P. Xu, E.A. Van Kirk, Y. Zhan, W.J. Murdoch, M. Radosz, Y. Shen, Targeted chargereversal nanoparticles for nuclear drug delivery, Angew. Chem. Int. Ed. 46 (2007)
49995002.
[120] X. Liu, J. Xiang, D. Zhu, L. Jiang, Z. Zhou, J. Tang, X. Liu, Y. Huang, Y. Shen, Fusogenic
reactive oxygen species triggered charge-reversal vector for effective gene
delivery, Adv. Mater. (2015), http://dx.doi.org/10.1002/adma.201504288.
[121] T. Zhou, X. Zhou, D. Xing, Controlled release of doxorubicin from graphene oxide
based charge-reversal nanocarrier, Biomaterials 35 (2014) 41854194.
[122] N. Ballatori, S.M. Krance, S. Notenboom, S. Shi, K. Tieu, C.L. Hammond, Glutathione
dysregulation and the etiology and progression of human diseases, Biol. Chem. 390
(2009) 191214.
[123] R. Dringen, Metabolism and functions of glutathione in brain, Prog. Neurobiol. 62
(2000) 649671.
[124] H. Chen, Z. Wang, S. Zong, L. Wu, P. Chen, D. Zhu, C. Wang, S. Xu, Y. Cui, SERSuorescence monitored drug release of a redox-responsive nanocarrier based
on graphene oxide in tumor cells, ACS Appl. Mater. Interfaces 6 (2014)
1752617533.
[125] Q. Tian, F. Jiang, R. Zou, Q. Liu, Z. Chen, M. Zhu, S. Yang, J. Wang, J. Wang, J. Hu, Hydrophilic Cu9S5 nanocrystals: a photothermal agent with a 25.7% heat conversion

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015

14

[126]

[127]

[128]

[129]

[130]

[131]
[132]

[133]

[134]

[135]
[136]
[137]

[138]
[139]

[140]

[141]

[142]

[143]

[144]

[145]

[146]

K. Yang et al. / Advanced Drug Delivery Reviews xxx (2016) xxxxxx

efciency for photothermal ablation of cancer cells in vivo, ACS Nano 5 (2011)
97619771.
K. Yang, H. Xu, L. Cheng, C. Sun, J. Wang, Z. Liu, In vitro and in vivo near-infrared
photothermal therapy of cancer using polypyrrole organic nanoparticles, Adv.
Mater. 24 (2012) 55865592.
L. Cheng, K. Yang, Y. Li, J. Chen, C. Wang, M. Shao, S.-T. Lee, Z. Liu, Facile preparation of multifunctional upconversion nanoprobes for multimodal imaging
and dual-targeted photothermal therapy, Angew. Chem. Int. Ed. 50 (2011)
73857390.
L. Cheng, J. Liu, X. Gu, H. Gong, X. Shi, T. Liu, C. Wang, X. Wang, G. Liu, H. Xing, W.
Bu, B. Sun, Z. Liu, PEGylated WS2 nanosheets as a multifunctional theranostic agent
for in vivo dual-modal CT/photoacoustic imaging guided photothermal therapy,
Adv. Mater. 26 (2014) 18861893.
K. Yang, G. Yang, L. Chen, L. Cheng, L. Wang, C. Ge, Z. Liu, FeS nanoplates as a
multifunctional nano-theranostic for magnetic resonance imaging guided
photothermal therapy, Biomaterials 38 (2015) 19.
W. Lu, M.P. Melancon, C. Xiong, Q. Huang, A. Elliott, S. Song, R. Zhang, L.G. Flores II,
J.G. Gelovani, L.V. Wang, G. Ku, R.J. Stafford, C. Li, Effects of photoacoustic imaging
and photothermal ablation therapy mediated by targeted hollow gold nanospheres
in an orthotopic mouse xenograft model of glioma, Cancer Res. 71 (2011)
61166121.
H.K. Moon, S.H. Lee, H.C. Choi, In vivo near-infrared mediated tumor destruction by
photothermal effect of carbon nanotubes, ACS Nano 3 (2009) 37073713.
L. Cheng, K. Yang, Q. Chen, Z. Liu, Organic stealth nanoparticles for highly effective
in vivo near-infrared photothermal therapy of cancer, ACS Nano 6 (2012)
56055613.
Q. Chen, C. Liang, C. Wang, Z. Liu, An imagable and photothermal abraxane-like
nanodrug for combination cancer therapy to treat subcutaneous and metastatic
breast tumors, Adv. Mater. 27 (2015) 903910.
Q. Chen, C. Liang, X. Wang, J. He, Y. Li, Z. Liu, An albumin-based theranostic nanoagent for dual-modal imaging guided photothermal therapy to inhibit lymphatic
metastasis of cancer post surgery, Biomaterials 35 (2014) 93559362.
X. Song, Q. Chen, Z. Liu, Recent advances in the development of organic
photothermal nano-agents, Nano Res. 8 (2015) 340354.
B. Tian, C. Wang, S. Zhang, L. Feng, Z. Liu, Photothermally enhanced photodynamic
therapy delivered by nano-graphene oxide, ACS Nano 5 (2011) 70007009.
J. Chen, H. Liu, C. Zhao, G. Qin, G. Xi, T. Li, X. Wang, T. Chen, One-step reduction and
PEGylation of graphene oxide for photothermally controlled drug delivery, Biomaterials 35 (2014) 49864995.
H. Kim, W.J. Kim, Photothermally controlled gene delivery by reduced graphene
oxide-polyethylenimine nanocomposite, Small 10 (2014) 117126.
Y. Wang, K. Wang, J. Zhao, X. Liu, J. Bu, X. Yan, R. Huang, Multifunctional mesoporous silica-coated graphene nanosheet used for chemo-photothermal synergistic
targeted therapy of glioma, J. Am. Chem. Soc. 135 (2013) 47994804.
J. Shi, L. Wang, J. Zhang, R. Ma, J. Gao, Y. Liu, C. Zhang, Z. Zhang, A tumor-targeting
near-infrared laser-triggered drug delivery system based on GO@Ag nanoparticles
for chemo-photothermal therapy and X-ray imaging, Biomaterials 35 (2014)
58475861.
X. Yang, X. Zhang, Y. Ma, Y. Huang, Y. Wang, Y. Chen, Superparamagnetic graphene
oxideFe(3)O(4) nanoparticles hybrid for controlled targeted drug carriers, J.
Mater. Chem. 19 (2009) 27102714.
X. Chen, R. Klingeler, M. Kath, A.A. El Gendy, K. Cendrowski, R.J. Kalenczuk, E.
Borowiak-Palen, Magnetic silica nanotubes: synthesis, drug release, and feasibility
for magnetic hyperthermia, ACS Appl. Mater. Interfaces 4 (2012) 23032309.
B. Mehdaoui, A. Meffre, J. Carrey, S. Lachaize, L.-M. Lacroix, M. Gougeon, B.
Chaudret, M. Respaud, Optimal size of nanoparticles for magnetic hyperthermia:
a combined theoretical and experimental study, Adv. Funct. Mater. 21 (2011)
45734581.
Y. Yang, X. Liu, Y. Lv, T.S. Herng, X. Xu, W. Xia, T. Zhang, J. Fang, W. Xiao, J. Ding, Orientation mediated enhancement on magnetic hyperthermia of Fe3O4 nanodisc,
Adv. Funct. Mater. 25 (2015) 812820.
C. Blanco-Andujar, D. Ortega, P. Southern, S.A. Nesbitt, T. Nguyun Thi Kim, Q.A.
Pankhurst, Real-time tracking of delayed-onset cellular apoptosis induced by
intracellular magnetic hyperthermia, Nanomedicine 11 (2016) 121136.
A.K. Swain, L. Pradhan, D. Bahadur, Polymer stabilized Fe3O4graphene as an
amphiphilic drug carrier for thermo-chemotherapy of cancer, ACS Appl. Mater.
Interfaces 7 (2015) 80138022.

[147] A. Alexander, J. Ajazuddin, S. Khan, S. Saraf, Saraf, poly(ethylene glycol)poly(lactic-co-glycolic acid) based thermosensitive injectable hydrogels for biomedical applications, J. Control. Release 172 (2013) 715729.
[148] M.A. Ward, T.K. Georgiou, Thermoresponsive polymers for biomedical applications,
Polymers 3 (2011) 12151242.
[149] J. Ramos, A. Imaz, J. Forcada, Temperature-sensitive nanogels: poly(Nvinylcaprolactam) versus poly(N-isopropylacrylamide), Polym. Chem. 3
(2012) 852856.
[150] S.A. Jadhav, I. Miletto, V. Brunella, G. Berlier, D. Scalarone, Controlled post-synthesis
grafting of thermoresponsive poly(N-isopropylacrylamide) on mesoporous silica
nanoparticles, Polym. Adv. Technol. 26 (2015) 10701075.
[151] M.S. Heo, E.J. Seo, J.V. John, I.H. Jang, J.H. Kim, I. Kim, Synthesis of hyperbranched
polyglycidol-b-poly(N-isopropylacrylamide) using nitroxide-mediated polymerization for thermo-sensitive drug delivery system, J. Control. Release 213 (2015)
E80.
[152] S. Zhu, J. Li, Y. Chen, Z. Chen, C. Chen, Y. Li, Z. Cui, D. Zhang, Grafting of graphene
oxide with stimuli-responsive polymers by using ATRP for drug release, J.
Nanopart. Res. 14 (2012) 11321143.
[153] Y. Pan, H. Bao, N.G. Sahoo, T. Wu, L. Li, Water-soluble poly(N-isopropylacrylamide)graphene sheets synthesized via click chemistry for drug delivery, Adv. Funct.
Mater. 21 (2011) 27542763.
[154] H. Wang, D. Sun, N. Zhao, X. Yang, Y. Shi, J. Li, Z. Su, G. Wei, Thermo-sensitive
graphene oxidepolymer nanoparticle hybrids: synthesis, characterization, biocompatibility and drug delivery, J. Mater. Chem. B 2 (2014) 13621370.
[155] B. Li, J.Z. Yang, Q. Huang, Y. Zhang, C. Peng, Y.J. Zhang, Y. He, J.Y. Shi, W.X. Li, J. Hu,
C.H. Fan, Biodistribution and pulmonary toxicity of intratracheally instilled
graphene oxide in mice, NPG, Asia Mater. 5 (2013).
[156] M.C. Duch, G.R.S. Budinger, Y.T. Liang, S. Soberanes, D. Urich, S.E. Chiarella, L.A.
Campochiaro, A. Gonzalez, N.S. Chandel, M.C. Hersam, G.M. Mutlu, Minimizing oxidation and stable nanoscale dispersion improves the biocompatibility of graphene
in the lung, Nano Lett. 11 (2011) 52015207.
[157] S.K. Singh, M.K. Singh, M.K. Nayak, S. Kumari, S. Shrivastava, J.J.A. Gracio, D. Dash,
Thrombus inducing property of atomically thin graphene oxide sheets, ACS Nano
5 (2011) 49874996.
[158] H. Zhou, B. Zhang, J. Zheng, M. Yu, T. Zhou, K. Zhao, Y. Jia, X. Gao, C. Chen, T. Wei,
The inhibition of migration and invasion of cancer cells by graphene via the impairment of mitochondrial respiration, Biomaterials 35 (2014) 15971607.
[159] W. Miao, G. Shim, S. Lee, S. Lee, Y.S. Choe, Y.-K. Oh, Safety and tumor tissue accumulation of pegylated graphene oxide nanosheets for co-delivery of anticancer
drug and photosensitizer, Biomaterials 34 (2013) 34023410.
[160] Y. Li, Y. Liu, Y. Fu, T. Wei, L. Le Guyader, G. Gao, R.-S. Liu, Y.-Z. Chang, C. Chen, The
triggering of apoptosis in macrophages by pristine graphene through the MAPK
and TGF-beta signaling pathways, Biomaterials 33 (2012) 402411.
[161] W. Zhang, Z. Guo, D. Huang, Z. Liu, X. Guo, H. Zhong, Synergistic effect of chemo
photothermal therapy using PEGylated graphene oxide, Biomaterials 32 (2011)
85558561.
[162] M. Zhang, Y. Cao, Y. Chong, Y. Ma, H. Zhang, Z. Deng, C. Hu, Z. Zhang,
Graphene oxide based theranostic platform for T-1-weighted magnetic resonance imaging and drug delivery, ACS Appl. Mater. Interfaces 5 (2013)
1332513332.
[163] G. Wang, G. Chen, Z. Wei, X. Dong, M. Qi, Multifunctional Fe3O4/graphene oxide
nanocomposites for magnetic resonance imaging and drug delivery, Mater.
Chem. Phys. 141 (2013) 9971004.
[164] Y. Wang, L. Polavarapu, L.M. Liz-Marzan, Reduced graphene oxide-supported gold
nanostars for improved SERS sensing and drug delivery, ACS Appl. Mater. Interfaces 6 (2014) 2179821805.
[165] J. Bai, Y. Liu, X. Jiang, Multifunctional PEG-GO/CuS nanocomposites for nearinfrared chemophotothermal therapy, Biomaterials 35 (2014) 58055813.
[166] K. Liu, J.-J. Zhang, F.-F. Cheng, T.-T. Zheng, C. Wang, J.-J. Zhu, Green and facile synthesis of highly biocompatible graphene nanosheets and its application for cellular
imaging and drug delivery, J. Mater. Chem. 21 (2011) 1203412040.
[167] A. Kundu, S. Nandi, P. Das, A.K. Nandi, Fluorescent graphene oxide via polymer
grafting: an efcient nanocarrier for both hydrophilic and hydrophobic drugs,
ACS Appl. Mater. Interfaces 7 (2015) 35123523.
[168] D. He, X. He, K. Wang, Z. Zou, X. Yang, X. Li, Remote-controlled drug release from
graphene oxide-capped mesoporous silica to cancer cells by photoinduced pHjump activation, Langmuir 30 (2014) 71827189.

Please cite this article as: K. Yang, et al., Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy, Adv. Drug Deliv.
Rev. (2016), http://dx.doi.org/10.1016/j.addr.2016.05.015