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Current Medicinal Chemistry, 2017, 24, 1-24 1
REVIEW ARTICLE
0929-8673/17 $58.00+.00 © 2017 Bentham Science Publishers
Recent Developments of Phototherapy Based on Graphene Family
Nanomaterials
Baomei Zhang1, Yang Wang1, Jiyong Liu2,* and Guangxi Zhai1,*
1Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012,
China
；
2Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai
200433, China
A R T I C L E H I S T O R Y
Received: May 28, 2016
Revised: September 29, 2016
Accepted: October 14, 2016
DOI: 10.2174/092986732366616101
9141817
Abstract: Graphene-based nanomaterials have drawn abundant interest in various fields such
as biomedicine in recent years. Thanks to the ultra-high surface area of single-layered gra-
phene, higher molecular loading is obtained. In addition, easy modifications were acquired
because of its ample oxygen-content functional groups. Owing to its excellent physical–
chemical properties, graphene-based nanomaterials have been widely explored as novel nano-
vectors for disease theranostics. In this article, we gave a comprehensive review of graphene-
based nanomaterials, including introduction about different members of graphene family
nanomaterials (GFNs), various modifications, toxicity and biomedical applications of gra-
phene-based derivatives. More attentions were given to phototherapy in this paper. The
mechanisms of photothermal and photodynamic therapy were also offered. Finally, the pros-
pects and challenges of the graphene-based nanomaterials were discussed in this review.
Keywords: GFNs, modifications, toxicity, biomedical applications, phototherapy, multifunctional nanoformula-
tions.
1. INTRODUCTION
Cancer, a tough issue, has been hard to tackle until
now. Recently, in clinical cancer therapy, apart from
surgery and radiation therapy, chemotherapy is still one
of the most common and effective methods but with
low therapeutic efficacy and severe adverse effects due
to the inactivation and non-specific distribution of
drugs in the whole body [1]. The severe negative side
effects of chemotherapy limit the dosage administered.
Rapid clearance of drugs from the body needs frequent
dosing and this also leads to patients’ poor compliance.
In addition, multidrug resistance (MDR) derived from
tumor cells is also a major issue in chemotherapy.
Apart from chemotherapy, phototherapy also exists,
composing of photothermal therapy (PTT) and pho-
todynamic therapy (PDT) which are non-invasive. To
*Address corresponding to these authors at the Department of
Pharmaceutics, College of Pharmacy, Shandong University, 44
Wenhua Xilu, Jinan 250012, China; Tel.: (86) 531-88382015;
E-mail: professorgxzhai@126.com; Department of Pharmacy,
Changhai Hospital, Second Military Medical University, Shanghai
200433, China; Tel.: (86) 21-31162308;
E-mail: liujiyong@gmail.com
date, a variety of inorganic nanomaterials including
gold nanomaterials [2], MoS2 [3, 4], and graphene [5,
6] have been widely studied as PTT nanoagents. The
combination of chemotherapy and phototherapy, with
synergistic anti-cancer effect, is better than a single
therapy. However, specifically killing the cancer cells
with no damage to normal non-cancerous cells is chal-
lenging, but can be obtained by using nanotechnology
[7]. Usually, nanotechnology can be applied to trans-
port drugs to specific sites by using active targeting
ligands such as folic acid (FA) and hyaluronic acid
(HA). However, these active targeting ligands are not
unique to the tumor cells, this marker-assisted drug
delivery systems (DDSs) have a chance to get misdi-
rected, leading to unavoidable side effects. Therefore,
using environmental stimulation to control or guide the
release of drugs systemically is the purpose when de-
veloping the next-generation treatment.
Graphene, a rising material star, has invoked hot
talks since its first discovery in 2004 [8] due to its in-
comparable physicochemical properties, such as a high
fracture strength, excellent electrical and thermal con-
2 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Zhang et al.
ductivity, fast mobility of charge carriers, large specific
surface area and biocompatibility [9-14]. So far, single-
layered graphene has been the thinnest material in the
world (about 0.35 nm in height) with sp2-hybridized
carbon atoms, structured with a honeycomb two-
dimensional (2-D) crystal lattice. In 2010, the Noble
Prize was awarded to Novoselov KS and Geim AK
who devoted their efforts to the study of graphene.
Thanks to its unparalleled physical–chemical proper-
ties, graphene-based derivatives are considered to be an
ideal material for a broad range of applications, ranging
from quantum physics, nano-electronics, energy re-
search to medical imaging, tissue engineering, drug
delivery and so on [15-23]. Besides, graphene itself
possesses photothermal conversion effect, so an in-
creasing number of people chose graphene family
nanomaterials (GFNs) as PTT agents. What’s more,
GO-based nanomaterials were also used to deliver pho-
tosensitizers (PSs) for PDT.
In this review, we offered a comprehensive discus-
sion about graphene-based nanomaterials, including
different members of GFNs, various modification
methods, toxicity (in vitro and in vivo) and biomedical
applications. Finally, the prospects and challenges
about graphene derivatives were also discussed.
2. CLASSIFICATION OF GRAPHENE-BASED
NANOMATERIALS
Generally, GFNs were classified by oxygen content,
mainly including graphene, graphene oxide (GO) and
reduced graphene oxide (rGO). The hydrophobility of
graphene makes it hard to be modified. As a result, it is
rarely used in nanomedicine. While GO and rGO with
better dispersibility are easy to be modified, so they
have been wildly used in biomedical applications [24].
The structure of GO and rGO is shown as Fig. (1).
GO, with ample oxygen-content groups such as car-
boxylate group, epoxide and hydroxyl groups, was de-
rived from graphene by hummers’ method[25]. It was
the oxidation process that destroyed its π-π conjugated
system. Therefore, its electronical and optical conduc-
tivity were lower than graphene, while its water dis-
persibility was better, resulting in decreased cytotoxic-
ity. [26].
rGO, a lower oxygen-content graphene derivative,
was derived from GO through a reduction process with
the help of hydrazine or other reducing agents and the
hydroxyl and epoxy groups of GO were converted into
carbon-carbon double bonds [27, 28]. It was the reduc-
tion process that restored its π-π conjugated system, so
the optical absorbance and electrical conductivity of
rGO were better than that of GO but the hydrophilicity
and the surface charge of rGO were relatively poor
[29]. Another advantage of rGO was the higher pho-
tothermal conversion efficacy which could be used for
PTT[30]. Based on the above discussion, the electrical
conductivity of rGO was superior to GO but inferior to
graphene. However, as to water-solubility, rGO was
superior to graphene but inferior to GO.
Apart from the GFNs discussed above, chemically
modified GO, for example pegyalted GO (PEG-GO),
was also the member of GFNs. The chemically modi-
fied GFNs, also called functionalized GO, would be
discussed more comprehensively in the following part.
Fig. (1). The structure of A) GO and B) rGO.
Recent Developments of Phototherapy Current Medicinal Chemistry, 2017, Vol. 24, No. 00 3
3. MODI FICATIONS OF GRAPHENE-BASED
NANOMATERIALS
GO or rGO was stable in water for a long time but
aggregated quickly in physiological environment,
which led to severe cytotoxicity. So modifications were
urgent if graphene-based nanomaterials were used for
biomedical applications. Modifications were classified
into covalent and non-covalent modifications. There
were many differences between these two modification
modes. Covalent modifications were formed via
chemical reactions which might destroy the original
structures of GO-based derivatives and this modifica-
tion was more stable in physiological solution. While
non-covalent modifications were formed through Van
der Waals force or hydrophobic interactions. This
method would maintain its original structures and was
easy to do. However, non-covalent modifications were
not as stable as covalent modifications in physiological
solution. These two modification methods would be
discussed in detail in the following parts.
3.1. Covalent Modifications
The oxygen-content functional groups of graphene-
based nanomaterials were used to make covalent modi-
fications. Many biocompatible polymers such as PEG
[24, 26], polyacrylic acid (PAA) [31], chitosan (CS)
[32], FA [33], HA [34], poly(vinyl alcohol) (PVA)
[35], polyethylenimine (PEI) [36], dextran (DEX) [37],
and L-Cysteine [38] were used to functionalize GFNs.
Generally, after modification, the toxicity was de-
creased. As one study showed [26], the in vivo toxicity
between GO and PEG-GO was different. The fatality in
the GO-treated group was 100%, but all the mice
treated with PEG-GO nanosheets were survived. Most
of the modifications were through the formation of am-
ide bond between the -COOH group of GO and the -
NH2 group of polymers, while some modifications
were via free radical polymerization [31]. Apart from –
COOH, epoxide (-O-) and hydroxyl groups (-OH) were
also exploited for covalent chemical modifications
[39].
Most of the above-mentioned modifications were
occurred between GO and polymers directly, while
some reactions between GO and polymers needed a
linker, for example disulfide bond (-S-S-) [40]. GO was
dispersible in water for a long storage time but aggre-
gated quickly in phosphate-buffered saline (PBS) and
cell medium. PEGylation of the GO was designed by
conjugating amino-terminated PEG to carboxylated
GO sheets through a -S-S-. Thanks to the -S-S-, the
prepared NGO-SS-mPEG had high stability in physio-
logical solution with little cytotoxicity. Also the release
of the loaded drug could be accelerated as a result of
the high GSH level in tumor environment.
3.2. Non-Covalent Modifications
Besides the above talking covalent modifications,
non-covalent modifications were also made by many
research groups [41-48]. Heparin was used to function-
alize graphene[44] to improve its stability, without any
precipitation or aggregation even after 6 months’ stor-
age. And at the same time, anticoagulant activity of
heparin was still preserved after conjugation with gra-
phene. Water-dispersible poly (lactide)–poly (ethylene
glycol) (PLA–PEG) copolymer was firstly synthesized
and then was used to stabilize GO aqueous dispersions
via simply mixing [45]. The as-made GO/PLA–PEG
possessed high colloidal stability in the presence of
high concentrations of NaCl (higher than physiological
concentrations). And thus the cytotoxicity was de-
creased. The interactions between GFNs and polymers
were usually hydrophobic interactions, π–π stacking,
hydrogen bonding interactions and electrostatic interac-
tions [7]. All the modifications were in order to im-
prove the solubility and biocompatibility of graphene
derivatives.
4. TOXICITY OF GRAPHENE-BASED NANO-
MATERIALS
Toxicity was an issue that no one could neglect be-
fore making graphene-based nanomaterials into
nanomedicine. The toxicity included in vitro and in
vivo aspects. So far the agreement of their toxicity has
not been achieved because it was related to many fac-
tors. Some research groups [49-52] exploited computer
simulation and theoretical analysis to study the trans-
membrane translocation mechanisms of these two-
dimensional nanomaterials. How graphene interacted
with cell membrane was related to the fundamental bio-
logical responses and was thereby one critical issue
should be resolved before further applications of gra-
phene in nanomedicine. In the following part, the in
vitro cytotoxicity and in vivo toxicity were discussed in
detail.
4.1. In Vitro Cytotoxicity
Recently, an increasing number of researchers gave
their efforts to the study of graphene-based nanomate-
rials’ cytotoxicity [48, 53-57]. But a consensus was
hard to obtain. Some thought the cytotoxicity was re-
lated to the physicochemical properties of GO-based
derivatives, such as surface charge, size, particulate
4 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Zhang et al.
state, residual precursors and surface functional groups
[53]. Some thought the cytotoxicity was associated
with cell types [58]. And others thought that the cyto-
toxicity was also related to the detection method. The
mostly used cytotoxicity assay--MTT method, perhaps
was not suitable for the study of carbon-based nanoma-
terials [59]. The production of reactive oxygen species
(ROS) was the major mechanism of cytotoxicity [60].
As to in vitro cytotoxicity, different researchers chose
different cell types such as A549 cell [61, 62], HeLa
cell [63], MCF-7 cell [58], HCT-116 cell [24], HepG2
cell [58], PC12 cell [64], Red blood cells [53, 65], hu-
man glioma cell lines (U118, U87) [66], murine RAW
264.7 macrophages[67] and so on. So, they sometimes
obtained different conclusion.
Mu et al. [54] synthesized protein-coated GO
nanosheet (PCGO) and studied its subcellular loca-
tions, cell surface adhesion, and cellular uptake mecha-
nisms. They discovered that the celluar uptake of
PCGO was size-dependent and energy-dependent.
Small PCGO nanosheets entered cells mainly via
clathrin-mediated endocytosis, and larger size of
PCGO enhanced phagocytotic cellular uptake. These
findings would promote biomedical and toxicologic
studies of graphene-based derivatives and also offer
comprehensive understanding of interactions between
two-dimensional nanostructures and biological sys-
tems. Wang et al. [68] demonstrated that the toxicity of
GO to human fibroblast cells was dose-dependent.
When the dose of GO was higher than 50µg/mL, the
toxicity was obvious. Liao et al. [53] studied the blood
compatibility of different graphene-based derivatives
using in vitro hemolysis. As to GO samples, they found
that GO with smaller size exhibited higher hemolytic
activity than that of GO with larger size. However,
covering GO sheets with CS would eliminate their
hemolytic activity. The aggregated graphene sheets
(GS) showed lower hemolytic rate than that of GO
samples. The cytotoxicity to adherent skin fibroblasts
was studied via WST-8 viability assays. The results
from WST-8 viability assays and ROS data confirmed
that the aggregated GS particles were more cytotoxic
than GO to human skin fibroblast cells and generated
more ROS in human skin fibroblast cells. In this study,
the toxicity was related to their surface chemistry such
as size or coating.
4.2. In Vivo Toxicity
Without doubt, attention should be given to not only
in vitro cytotoxicity, but also the in vivo profile (includ-
ing absorption, distribution, metabolism and excretion)
of graphene-based nanomaterials. The in vivo pharma-
cokinetics, toxicology, and long-term biodistribution of
PEGylated nanographene sheets (PEG-NGS) in mice
were studied in one paper [69]. The biodistribution and
blood circulation of PEG-NGS were investigated by
125I labeling method. Blood analysis and histology ex-
aminations were used to explore its toxicity in vivo.
The results indicated that the PEG-NGS mainly accu-
mulated in reticuloendothelial system (RES) including
liver and spleen after intravenous administration, and it
could be gradually eliminated through renal or fecal
excretion. No evident toxicity was found even when
the tested dose reached 20 mg/kg. Therefore, surface
modification was very important for the sake of reduc-
ing the toxicity. Apart from the intravenous administra-
tion route[69, 70], there were also inhalation[71], oral
and intraperitoneal administration route[72]. Solutions
of aggregated graphene, GO and pluronic dispersed
graphene were administered directly into the lung of
mice and their lung toxicity was compared. The results
demonstrated that GO increased the rate of mitochon-
drial respiration and the production of ROS, and also
induced severe inflammation and active apoptotic. All
these led to severe and persistent lung injury. In the
contrary, the toxicity of pristine graphene was signifi-
cantly reduced and further decreased when pristine
graphene was functionalized with block copolymer
Pluronic. Perhaps oxidation process of graphene was a
major contributor to its pulmonary toxicity[71]. The
fate of GO derivatives in animals after oral administra-
tion and intraperitoneal (i.p.) injection was studied
[72]. In the study, GO, nGO-PEG (smaller size), RGO-
PEG and nRGO-PEG (smaller size) were synthesized.
And then compared their toxicity after different ad-
ministration route (oral feeding or i.p. injection). The
results suggested that PEG-GO derivatives could not be
adsorbed by organs and quickly cleared after oral ad-
ministration. In contrast, after i.p. administration, PEG-
GO derivatives could be endocytosed by phagocytes in
the RES system in a size- and surface coating-related
manner. Despite of the long-term retention of GO and
PEG-GO in the mouse body after i.p. administration,
no significant toxicity was noticed. The in vivo toxicity
was closely related to their surface coating, size, and
importantly, the administration routes. Other research-
ers explored whether GO would cause damage to eye-
sight [73]. The administration route was intravitreal
injection. Ocular examination and histologic examina-
tion were done in different time point. The obtained
results showed that GO intravitreally injected eyes had
negligible influence on eyeball appearance, eyesight,
intraocular pressure (IOP), and histologic photos, pro-
Recent Developments of Phototherapy Current Medicinal Chemistry, 2017, Vol. 24, No. 00 5
viding productive information for the clinical diagnosis
of GO in ophthalmology. What is more, some chose
intraperitoneal injection to explore the safety risks as-
sociated with GO material that might be interacting
with living tissues [74]. No inflammation or granuloma
was formed (at the dose of 50 µg/animal) in vivo after
intraperitoneal injection.
Apart from the above talking in vivo toxicity of gra-
phene derivatives, other studies focused on the effect
caused by graphene derivatives on offsprings [75]. In
the study, different sizes of rGO nanosheets were ad-
ministered at diverse doses and the impacts on female
reproductive performance were investigated. What is
more, the health of the first, second and third litters of
offspring was also studied. The outcomes indicated that
the influences of rGO nanosheets on female reproduc-
tive performance and the health of offspring were af-
fected by administration time and doses. In addition,
the short- and long-term influences of high-dose rGO
on mouse behaviors after oral administration were in-
vestigated in another paper[76]. The investigated
mouse behaviors included general locomotor activity
level, exploratory and anxiety behaviors, balance and
neuromuscular coordination, and learning and memory
abilities. Their findings suggested that a high dose of
rGO nanosheets administrated through oral would
cause a short-term decrease in locomotor activity and
neuromuscular coordination but had no influences on
the anxiety-like, exploratory, or spatial learning and
memory behaviors.
5. APPLICATIONS OF GRAPHENE-BASED NA-
NOMATERIALS
Owing to the excellent physical–chemical proper-
ties, various biomedical applications of GFNs were
unceasingly emerging in order to tackle cancer with
better efficacy and little adverse effects. External and
endogenous stimuli-responsive DDSs using graphene-
based nanomaterials were reviewed in one article [77].
In the following part, the applications of GFNs in
nanomedicine would be introduced comprehensively.
And more attentions would be given to phototherapy in
this review.
5.1. Drug or Gene Delivery
Graphene was the thinnest material with a very
large surface area. So its drug loading [25, 78, 79] was
greatly higher than the traditional nanocarriers such as
micelles, liposomes and so on. As we know, GO with
higher oxygen-content was stable in water but easy to
aggregate in physiological environment, so modifica-
tions (covalent or non-covalent modifications)[80]
were very urgent for its clinical use. Nanoscale gra-
phene oxide (NGO) was functionalized by branched,
biocompatible PEG and finally obtained NGO-PEG.
The synthesized NGO-PEG possessing high aqueous
solubility was very stable in physiological solutions
including serum [24]. The prepared NGO-PEG was
used to deliver aromatic, water insoluble drug SN38, a
camptothecin (CPT) analogue, via noncovalent interac-
tion. The NGO-PEG-SN38 nanocomplex presented
enhanced water-solubility and maintained the high effi-
cacy of free SN38. The anti-cancer efficacy exceeded
that of irinotecan by 2-3 orders of magnitude. Shen et
al [81] used PEG-GO to deliver protein with high pay-
load via non-covalent interactions. This nano-carrier
would protect proteins from enzymatic hydrolysis and
keep their biological functions in physiological envi-
ronment. Besides the physical drug-loaded mechanism,
the drug could also be loaded via covalent bonds [31].
1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was se-
lected as a model drug and covalently linked to PAA-
GO via esterification. This DDS boosted the thermal
stability of BCNU and significantly prolonged its blood
circulation.
Apart from the above talking single-drug delivery
system, graphene-based nanocarrier was also used for
co-delivery systems. Co-delivery systems, which were
used to deliver two or more different drugs to the tumor
site simultaneously, could be utilized to enhance anti-
cancer efficacy compared with single-drug delivery
system. The NGO was firstly modified by sulfonic acid
groups, followed by covalent modifications by FA
molecule and the final product was FA-NGO [33]. The
FA-NGO had ability to specifically target MCF-7 cells,
human breast cancer cells with FA receptors. In addi-
tion, the FA-NGO was used to co-deliver two antican-
cer drugs, doxorubicin (DOX) and CPT through π-π
stacking and hydrophobic interactions. This co-delivery
system had much higher cytotoxicity to MCF-7 cells
than that of single-drug delivery system. Co-delivery
systems of chemotherapeutic drugs or genes have also
been widely reported recently [82-84] to solve MDR
more effectively. CS modified GO (GO-CS) with better
aqueous solubility and biocompatibility was obtained
[32]. Through π-π stacking and hydrophobic interac-
tions, the GO–CS was exploited to deliver a hydropho-
bic anticancer drug CPT with an excellent loading ca-
pacity and remarkably improved cytotoxicity to HepG2
and HeLa cell lines in comparation with free drug.
Meanwhile, GO–CS had the capability to condense
plasmid DNA into stable nanoparticles (NPs). The ob-
tained GO–CS/pDNA NPs exhibited excellent transfec-
6 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Zhang et al.
tion efficiency in HeLa cell. Based on the above dis-
cussion, the prepared GO–CS nanocarrier was able to
load and deliver both gene and anticancer drug. An-
other example of co-delivery systems of chemothera-
peutic drug and gene was done by Wang et al. [83].
They firstly synthesized chemically reduced graphene
oxide (CRGO) sheets and then functionalized them
with CS to co-deliver DOX and DNA. The loaded
DOX and DNA could be efficiently targeted to the tu-
mor tissue due to the EPR effect.
5.2. Phototherapy
Phototherapy is a non-invasive and excellent
method for cancer therapy with prominent anti-cancer
effect. In the following parts, two phototherapy meth-
ods based on GFNs would be discussed in detail.
5.2.1. PTT
Usually, PTT made use of the generated heat de-
rived from an optical-absorbing agent under NIR-light
irradiation, and thus leading to a high local temperature
to kill cancer cells. Based on the mechanisms of cancer
cell death, PTT could be categorized into two classes as
shown in Fig. (2). Mild temperature increases (i.e. hy-
perthermia, 43–50 oC) usually proceeded through apop-
totic pathways and were well known to interfere vari-
ous normal cell functions, giving rise to enhanced
membrane permeability, better cellular uptake, meta-
bolic signaling disruption, dysfunctional membrane
transport and so on[85, 86]. What’s more, the capacity
of tumor cells to restore such damages was reduced
(versus normal cells). Because of the mild influence
and minimal adverse effects, the mild hyperthermic
therapy was typically prolonged / recurrent and the ef-
ficacy could usually be dramatic. While, the so-called
“ablative’’ treatments were referred as larger, more
rapid temperature enhancements (＞50 oC), usually
accompanying with necrotic cell death via destroying
cellular membrane. In these cases, destruction of cell
membrane was predominant, and also accompanying
with cavitation and subsequent physical disruption of
organelles. In the past several decades, many classes of
nanomaterials possessing intrinsic strong NIR absor-
bance have been used as photothermal agent, such as
gold nanostructures, carbon nanomaterials, CuS NPs,
Pd nanosheets, and so on [87-93]. Recently, many re-
searchers have paid numerous attentions to graphene-
based nanomaterials for PTT [94-113]. For example,
GO and rGO had intrinsic high NIR absorbance, exhib-
iting potential in cancer PTT [114, 115].
Liu and his research group[116] firstly utilized a
fluorescent labeling (Cy7) method to study the in vivo
behaviors of nanographene sheets (NGS) with PEG
coating (NGS-PEG). In the study, NGS-PEG was
firstly synthesized and then its bio-distribution study
was carried out. The results indicated ultrahigh tumor
Fig. (2). Schematic of two mechanisms about PTT.
Recent Developments of Phototherapy Current Medicinal Chemistry, 2017, Vol. 24, No. 00 7
accumulation of NGS-PEG and this might be due to the
EPR effect in tumor tissue. Motivated by the ultra-
efficient passive tumor targeting of NGS-PEG and its
high photothermal conversion efficacy, they then im-
plemented the in vivo PTT test. After 24h injection of
NGS-PEG, the tumor on each mouse was irradiated by
NIR laser (808nm, 2 W/cm2). The surface temperature
of tumor in NGS-PEG injected group reached ~50°C.
However, only 2°C temperature increase of un-injected
mice was achieved. rGO, compared with GO, had bet-
ter NIR absorption capability and thus had higher PTT
efficiency. Dai H and his group[115] synthesized
nanosized rGO (nano-rGO) sheets with noncovalent
PEGylation. It possessed high photothermal conversion
efficacy and excellent biocompatibility. The average
lateral dimension of single-layered nano-rGO was ~20
nm and it exhibited 6-fold higher NIR absorption than
that of PEG-GO. A targeting peptide bearing the Arg-
Gly-Asp (RGD) motif was attached to nano-rGO. The
RGD motif offered active targeting property in
U87MG cancer cells and significant effective photoab-
lation of cancer cells in vitro. The advantages of this
synthesized compound were a low administrated dose
(~20mg/L) and a low power density (0.6 W/cm2).
U87MG cells treated with nano-rGO-RGD and NIR
light were completely damaged while all other groups
indicated near 100% viability. The nano-rGO-RGD had
great potential for cancer PTT. What is more, as a po-
tential photothermal agent on a large scale, the low cost
of nano-rGO also made it attractive compared with
gold and SWNT. Another example of PTT was rGO-
PEG [117]. In the study, nGO-PEG (23nm), RGO-PEG
(65nm) and nRGO-PEG (27nm) were fabricated and
labeled by 125I for accurately assessing the in vivo bio-
distribution of these nanomaterials. RGO was a symbol
of reduced GO and nRGO was a symbol of ultra-small
RGO. 125I-nGO-PEG, 125I-RGO-PEG and 125I-nRGO-
PEG at the same dose (4 mg/kg) were intravenously
injected into Balb/c mice and blood was drawn at pre-
set time points. The pharmacokinetics of GO-
derivatives revealed that RGO-PEG and nRGO-PEG
showed remarkably prolonged half-life, which enabled
the nanomaterials to repeatedly pass through tumor
blood vasculatures and this was in favor of passive tar-
geting through the EPR effect. Activated by the high
tumor passive targeting capacity of nRGO-PEG and its
strong photothermal conversion efficacy, they then im-
plemented the in vivo PTT studies. Ten mice bearing
4T1 tumors were intravenously injected with nRGO-
PEG, nGO-PEG (20 mg/kg) and then the tumors were
irradiated with NIR laser (808 nm, 0.15 W/cm2, 5min)
or without irradiation. The results were that mice
treated with nRGO-PEG and NIR irradiation survived
over 100 days without tumor re-growth. This demon-
strated the excellent in vivo PTT efficacy of nRGO-
PEG. Owing to the effective tumor passive targeting
capacity and strong NIR absorbance, nRGO-PEG had
great potential as a superb photothermal agent that real-
ized admirably efficient oncotherapy by using an ul-
tralow laser power density (0.15 W/cm2), which was an
order of magnitude lower than that of what was usually
applied for PTT.
In conclusion, rGO possessed better PTT efficacy
than GO. And the uptake of GO-based nanomaterials
might be size-dependent (the smaller the size was, the
better the cell uptake was). In addition, the surface
chemistry certainly would affect the PTT efficacy of
graphene-based nanomaterials.
5.2.2. PDT
PDT was a valid cancer treatment modality that de-
stroyed targeted cells in the presence of oxygen and
light with minimal invasiveness. PDT has several ad-
vantages in comparision with conventional therapies
such as noninvasiveness, specificity and the ability to
treat patients with repeated dosages without exceeding
total dose limitations (in contrast with radiotherapy). In
addition, the fast healing process of PDT led to the lack
of associated side effects [118]. So, studies about PDT
were unceasing emerging [119-133]. Generally, PDT
process needed three elements to produce singlet oxy-
gen: a PS, oxygen, and appropriate light. PS absorbed a
photon and was promoted into excited singlet state
when it was exposed to an appropriate light. The en-
ergy of the excited singlet state could be dissipated
through either thermal decay or the fluorescence emis-
sion. Alternatively, the excited singlet state could move
to a lower-energy excited triplet state through
intersystem crossing. In the excited triplet state, the PS
could produce reactive species via two mechanisms:
Type I and Type II processes. In the processes of type
I, the excited triplet state PS transferred an electron to
different receptor molecules, resulting in the produc-
tion of free radical including the superoxide anion, hy-
drogen peroxide, or hydroxyl radical [134]. In Type II
processes, the excited triplet state PS reacted directly
with oxygen, generating reactive singlet oxygen. Type
II PDT processes were most important for PDT and the
produced singlet oxygen was responsible for the dam-
age of the targeted tissue. Significant oxidative stress
was derived from the interaction between singlet oxy-
gen and cellular components including lipids, amino
acid residues, and nucleic acids, and thus cellular death
8 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Zhang et al.
occurred [125]. The mechanism of PDT could be
briefly explained by the Fig. (3).
GO could enable targeted PS delivery to specific
cells via receptor-mediated endocytosis by the help of
targeting ligands. In order to deliver a PS molecule
Chlorin e6 (Ce6) to specific cells, FA-GO-Ce6 was
synthesized for targeted PDT [135]. The cytotoxicity
study indicated that FA-GO was non-toxic in vitro. Ac-
cording to the study, the FA-GO-Ce6 could specifically
bond the FA-receptors, and then be internalized by re-
ceptor-mediated endocytosis via the deformation of cell
membrane, and finally disperse in the cytoplasm of
MGC803 cells. From the results of in vitro PDT effect,
tumor MGC803 cells treated with FA-GO-Ce6 and la-
ser irradiation (632.8 nm He-Ne laser, ~30 mW/cm2)
generated a concentration-dependent cytotoxicity,
which was dramatically different from non-irradiated
group. The non-irradiated group showed the cell viabil-
ity was more than 80%, suggesting that without light
exposure, the prepared FA-GO-Ce6 had little even no
influences on tumor cells. Regarding to the irradiated
group, about 90% loss of cell viability was obtained,
indicating a remarkable PDT efficacy. These results
suggested that the FA-GO-Ce6 had a high potential for
targeted PDT. Another example of targeted PDT was
HA-GO-Ce6 [136]. GO nanosheets was modified by
biocompatible and biodegradable HA (HA-GO). The
HA-GO had increased colloidal stability and biocom-
patibility. And then HA-GO was used to load the PS-
Ce6, finally obtained HA-GO/Ce6. In the study, HA
offered active targeting property which could specifi-
cally target the cancer cells with over-expressed HA
receptors, and thus tremendously enhancing cellular
uptake of the loaded PS. The photoactivity of Ce6
loaded on the surface of HA–GO nanocarriers was
largely quenched in aqueous solution so as to ensure its
biocompatibility. However, the photoactivity of Ce6
was rapidly recovered after its release following cellu-
lar uptake. Finally, the PDT capacity of the HA–
GO/Ce6 nano-hybrids was about ten-fold enhanced in
contrast with that of free Ce6. What’s more, there was
an example of dual-targeted nanohybrids. Wu et al.
[137] demonstrated a cellular and subcellular targeted
strategy to improve PDT efficacy without adverse side
effects. They fabricated PEG-functionalized and FA-
modified NGO (PEG-FA-NGO) and used it to incorpo-
rate a cationic porphyrin derivative (MitoTPP). FA was
used for cellular targeting and the hydrophobic cation
ensured its release from NGO at a lower pH and thus
obtained mitochondria-targeting ability. Laser confocal
microscope results demonstrated that this dual-targeted
nanosystem could be preferably internalized by the
cancer cells with over-expressed folate receptor, and
released its cargo MitoTPP, which subsequently accu-
mulated in mitochondria. After exposure on light irra-
Fig. (3). Schematic of the mechanism about PS-induced PDT
Abbreviations: PS, photosensitizer; ROS, reactive oxygen species. *Indicates activated state.
Recent Developments of Phototherapy Current Medicinal Chemistry, 2017, Vol. 24, No. 00 9
diation, the liberated MitoTPP molecules produced
singlet oxygen and caused oxidant destruction to mito-
chondria. Cell viability assays suggested that this dual-
targeted nano-hybrids exhibited much better photody-
namic cytotoxicity toward FA-positive cancer cells.
Apart from the above talking targeted PS delivery
by GO-based nanomaterials, there also existed target-
activatable delivery of PS by GO-based nanomaterials.
For example, Cho et al. [138] proposed a target-
activatable delivery system with a cleavable disulfide
linker (GO–SS–Ce6) which was redox-responsive and
this was used as an activatable PDT agent. In this
nanohybrid, both the NIR fluorescence and the singlet
oxygen production activities of the loaded Ce6 were
activated by intracellular redox environment (glu-
tathione [GSH]). GSH, molecular switch, was used to
trigger PS release. Even upon light irradiation, GO–
SS–Ce6 was non-fluorescent and non-phototoxic be-
cause of the fluorescence resonance energy transfer at
the interfaces between GO and PS at a close proximity.
Once the GO–SS–Ce6 was internalized into cancer
cells, disulfide bonds were quickly cleaved due to the
high level of GSH, then leading to the release of Ce6
from the surface of GO nanocarrier and finally its pho-
totoxicity was recovered. This GO-based activatable
theranostic DDS might provide new techniques for tar-
geting NIR fluorescence imaging and PDT of cancers.
Another example of this target-activatable delivery of
PS by graphene-based nanomaterials was done by Du
et al. [139]. As we have known that pre-quenching and
specific activation of PS were highly demanded in PDT
to circumvent off-target effect derived from non-
specific activation and poor targeting selectivity of PS.
In their study, nanographene materials as a distinct π-
conjugated planar system were exploited as a robust
platform for temporarily quenching of the loaded PS.
Through a disulfide linker, Ce6 was loaded onto the
surface of graphene quantum dot (GQD) or GO. This
formed nanohybrid presented tremendous fluorescence
quenching and trivial phototoxicity, even after expo-
sure on light irradiation. However, the photoactivity of
PS could be recovered to a large extent in the presence
of GSH. In the presence of reducing agent, the disul-
fide linker was cleaved, and the photoactivity of Ce6
was recovered. Compared with GO nanosystem with
larger sizes (around 200 nm), GQD nanosystem pre-
sented obviously boosted tumor accumulation through
EPR effect. The in vivo anti-tumor test exhibited com-
pletely tumor eradication for the group treated with the
GQD nanosystem, indicating the potential application
of this new anti-tumor therapy strategy. This study can
be overviewed by Fig. (4).
Fig. (4). A) The structure of target-activatable delivery of Ce6. B) The passive targeting (EPR effect) and active targeting
(GSH-induced release of Ce6) lead to enhanced PDT efficacy. (a) Minimum extr avasation of NPs to normal tissue. (b) In-
creased drug accumulating in tumor sites due to the EPR effect.
10 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Zhang et al.
5.3. Synergy Therapy Based on Phototherapy
5.3.1. The Combined PTT and PDT
Traditional anti-tumor techniques possessed many
limitations and usually failed to obtain completely tu-
mor eradication. So, multimodal anti-cancer therapy
with synergistic or combined effect of two or more dif-
ferent therapeutic modalities was a potential avenue to
boost anticancer therapy efficacy and decrease the un-
desirable adverse systemic effect [140]. Phototherapy,
including PTT and PDT, referred to a non-invasive
therapeutic approach with excellent merits including
remote controllability, low systemic toxicity and im-
proved selectivity [141]. Combining these two pho-
totherapy modality into one system could exceed the
single therapeutic response of each system and lead to
improved therapeutic effect. Many researchers have
devoted themselves to explore the combination of PTT
and PDT to treat cancers and achieved many harvests
[142-146]. And the following part were the examples
of PTT-PDT.
Abhishek Sahu et al. [147] synthesized Pluronic
coated GO and used it to deliver methylene blue (MB).
The final synthesized drug loaded nanocomplex was
Pluronic/GO-MB. Firstly, they studied the photother-
mal conversion efficacy of Pluronic/GO (10 mg/mL)
by exposing it to NIR laser (808 nm, 2 W/cm2). The
temperature of Pluronic/GO was rapidly increased by
17 ℃ in 3 min. While the temperature increase of water
was negligible (only 2℃). Secondly, the bio-
distribution study was carried out and the results
showed that pluronic/GO was significantly uptaken by
tumor and liver with very low amount in spleen. And
finally, taking tumor volume as a reference, the in vivo
therapeutic index of PDT, PTT and PDT-PTT com-
bined therapy was evaluated. After 24 h post-injection,
tumor tissues were irradiated with a 650 nm laser to
make PS generate singlet oxygen for PDT. After 48 h
post-injection, all groups received PTT using NIR laser
(808 nm, 2 W/cm2), the real-time temperature change
of the tumor tissue was recorded by an IR thermal im-
aging system. The results showed that only the PTT-
PDT combined therapy group obtained remarkably en-
hanced in vivo anti-tumor therapeutic efficiency, indi-
cating complete eradication of tumor. In addition, Liu
et al. [148] synthesized GO-PEG-Ce6 nanocomplex
and used it for combined PTT-PDT. They uncovered
that GO had high NIR absorbance and high photother-
mal conversion efficacy. So it was able to generate lo-
cal heating under NIR irradiation. In the experiment,
cells were treated with GO-PEG-Ce6 and irradiated for
20 min by NIR (808nm, 0.3 W/cm2). In such NIR laser
doses, only mild heating was achieved without leading
to significant cell death. The cells were then irradiated
by 660 nm laser (15 J/cm2) and the cellular uptake of
GO-PEG-Ce6 was significantly elevated after the NIR
irradiation in contrast to cells incubated without NIR
light. The NIR laser irradiation was able to obviously
improve the cellular uptake of GO-PEG-Ce6 by 2-3
folds likely because of the increased cell membrane
permeability at a mildly higher temperature that de-
rived from the photothermal conversion of GO-PEG.
These data showed the potential of exploiting GO in
combined phototherapies.
Apart from the above talking PTT-PDT, target-
activatable delivery of PS by GO-based nanomaterials
was another choice for the combined PTT-PDT. Selec-
tively unloading the PS at a specific site has shown
great advantages for cancer therapy. The advancements
of a target-activatable ‘‘smart’’ platform were its high-
affinity and specificity. For example, Cho et al. [149]
prepared a potential hyaluronidase (HAdase)-
activatable GO–HA–Ce6 nanocomplex and used it for
different tumor cells with over-expressed HAdase. This
was a novel enzyme-activatable GO–PS nanocomplex
as a biologically tunable theranostic agent and could be
used for photo-induced cancer therapy. The fluores-
cence intensity of HA–Ce6 was drastically quenched
after loaded onto the surface of GO. However, when
exposed to HAdase, the loaded HA–Ce6 was degraded
into small fragments, triggering the rapidly release of
Ce6 from the GO surface. And thus, the quenched Ce6
fluorescence was well recovered and induced tremen-
dous enhancement in singlet oxygen generation. In vi-
tro cell viability assays suggested remarkably enhanced
PDT efficacy with GO–HA–Ce6, in contrast to both
free Ce6 and HA–Ce6 conjugate. This enhancement
was related to the highly boosted cellular uptake of
GO-based nano-carriers due to EPR effect. Subse-
quently, by the help of lysosomal HAdase, more singlet
oxygen generation was activated. On the other hand,
owing to the intrinsic NIR-light-absorption properties
of GO-based nanomaterials, they would be sufficient to
offer efficient anticancer activity related to hyperther-
mic therapies. Therefore, the potential of GO–HA–Ce6
as a PTT agent was estimated. After the exposure to
810 nm laser (4.0 W/ cm2), gradually increased tem-
perature of GO–HA–Ce6 suspension was observed and
remained at a plateau value (50℃). In contrast, there
were no temperature changes in laser-irradiated HA–
Ce6. The in vitro cell viability assays suggested that the
temperature increases derived from GO–HA–Ce6 sus-
pension caused 33% cell death. However, cells incu-
bated with free Ce6 and HA–Ce6, PTT had no influ-
Recent Developments of Phototherapy Current Medicinal Chemistry, 2017, Vol. 24, No. 00 11
ences on cell viability. These results emphasized the
hyperthermic effects of PTT (810 nm, 4.0 W /cm2). In
particular, the combination of 810/670 nm for com-
bined PTT-PDT seemed to be a promising effective
treatment for cancer compared with PDT or PTT only.
5.3.2. The Combined Chemotherapy and PTT
Nowadays, the combination therapy of chemother-
apy and PTT has been integrated by more and more
researchers [150-160]. Recent developments of the
combined chemotherapy and PTT (chemo-PTT) were
briefly discussed in Table 1. And the following parts
were several examples of Chemo-PTT.
Graphene had shown great potential in both PTT
and drug loading. Zhang et al. [161] developed DOX-
loaded PEG-NGO (NGO-PEG-DOX) to realize chemo-
therapy and PTT simultaneously. In in vivo antitumor
study, the treatments included three groups: free DOX,
NGO-PEG＋NIR laser and NGO-PEG-DOX＋NIR
laser. After different treatments, enhanced antitumor
efficacy and reduced adverse effect were reported only
in the group where mice were treated with NGO-PEG-
DOX+NIR laser. Almost all mice in NGO-PEG-
DOX＋NIR laser group achieved completely tumor
eradication 1 day after NIR irradiation, leaving black
scars on the original tumor sites. What is more, the tu-
mors did not re-grow during the experiment. These re-
sults indicated that the combined chemotherapy and
PTT was better than single chemotherapy or PTT. Fur-
thermore, according to the systematic toxicity study,
the combined treatment displayed reduced adverse side
effects compared to free DOX. Bai et al. [162] pre-
pared a nanocarrier of CuS NPs-decorated GO func-
tionalized with PEG (PEG-GO/CuS) and used it as a
synergistic therapy tool to treat cervical cancer. The
PEG-GO/CuS nanocomposites possessed high pho-
tothermal conversion efficiency, high drug loading and
excellent biocompatibility. Regarding to the in vitro
cell cytotoxicity tests, the cytotoxicity of PEG-
GO/GuS/DOX＋NIR laser was about 1.3 and 2.7-fold
than that of PEG-GO/CuS and free DOX due to PEG-
GO/CuS-mediated photothermal ablation and cytotox-
icity of light-triggered DOX release. Apart from the in
vitro cytotoxicity study, they also conducted the in vivo
anti-tumor test. The combined chemotherapy and PTT
of PEG-GO/CuS/DOX nanocomposites significantly
inhibited mouse’s cervical tumor growth. Overall,
compared with only chemotherapy or PTT, the com-
bined treatment showed better anti-tumor therapeutic
efficacy both in vitro and in vivo. These findings high-
lighted the potential of the highly versatile multifunc-
tional NPs in biomedical application.
Besides the above talking chemo-PTT, the targeted
delivery of GO-based nanocomposite for combined
chemo-PTT was also unceasingly emerging. For exam-
ple, Yang and his team [163] fabricated a nanocom-
plex, aptamer-gold NP-hybridized GO (Apt-
AuNP−GO), to realize targeted treatment for tumor via
combined chemo-PTT. Owing to the specific interac-
tions between the MUC1-binding-aptamer and the
MUC1 (type I transmembrane mucin glycoprotein) on
cell membrane, the synthesized Apt-AuNP−GO nano-
complex could selectively target MUC1-positive MCF-
7 cell. Besides, Apt-AuNP−GO had a high photother-
mal conversion capability which could be used for
PTT, and it was able to produce photothermal thera-
peutic efficacy on MCF-7 cells at an ultralow concen-
tration (1.74µg/mL) without inducing adverse side ef-
fects to normal cells. However, the efficiency of PTT
could frequently be reduced because of the production
of heat shock proteins (HSPs). HSPs could protect cells
from heat stress and maintain homeostasis [164, 165].
HSPs could be rapidly activated once heat stress oc-
curred, which allowed them to effectively protect
against heat-induced toxicity [166, 167]. Therefore,
they utilized the HSP70 inhibitor (VER-155008) to
validate the proposed therapeutic approach. The syner-
gistic effect of PTT and HSPs inhibitors was excellent.
The relative viability of MCF-7 cells co-treated with
Apt-AuNP−GO (1.74 µg/mL) coupled with NIR laser
irradiation and VER-155008 decreased to 39%, much
lower than that of cells treated with Apt-AuNP−GO
coupled with NIR laser irradiation (57%) and VER-
155008 (96%). A synergistic chemo-photothermal
therapeutic effect was observed when using hyperther-
mia and HSP70 inhibitor, resulting in a significant en-
hancement of breast cancer cell death. Hou et al. [168]
modified GO with HA (HA-GO) and used it to load
mitoxantrone (MIT). Since HA could specifically bind
to various cancer cells with over-expressed CD44 re-
ceptor, HA was selected to modify GO, and thus HA-
GO possessed with good biocompatibility and physio-
logical stability. Active tumor-targeting ability and
passive tumor-targeting ability could also be obtained
in this system. In addition, the photothermal conversion
of GO could be utilized for PTT. The HA-GO
nanosheets could significantly facilitate specific uptake
by cancer cells via receptor-mediated endocytosis. Ad-
ditionally, MIT/HA-GO exhibited long-circulation time
and preferentially accumulation in tumors, which re-
sulted in improved anti-tumor efficacy. More impor-
tantly, compared with chemotherapy or PTT alone,
treatment of mice with MIT/HA-GO followed by NIR
laser irradiation (808nm, 2W/cm2) demonstrated excel-
12 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Zhang et al.
Table 1. Recent developments of chemo-PTT
GO-based nanomate-
rials
Model drug
NIR dose
Hights
Ref
PEG-GO/CuS
DOX
980nm, 1W/cm2
Excellent biocompatibility; High drug loading; Excellent
anti-cancer efficacy.
[162]
SiO2@GN-Serum
DOX
980nm,1W/cm2
High photothermal conversion efficiency and excellent
biocompatibility; High drug loading; pH-responsive and
NIR-triggered drug release.
[171]
Poloxamer 188-GO
DOX, IRI
808nm,3W/cm2
Developed a dual-in-dual synergistic therapy with a high
drug loading efficacy and pH-responsive drug release;
Achieved better combined chemo-photothermal therapy.
[172]
GSPI
DOX
808nm,6W/cm2
Heat-stimulative, pH-responsive, and sustained drug re-
lease; Advanced chemo-photothermal synergistic targeted
therapy with high stability and a high loading efficiency.
[173]
GO-CS
DTX
808nm,2.5W/cm2
High stability in physiological environments; Significant
tumor cell inhibition by the combination of chemotherapy
and PTT; The as-made DTX-GO/CS gel could achieve
selective killing of cancer cells in localized regions in vivo
with minimal side effects.
[174]
Apt-AuNP−GO
VER-155008
808nm,3W/cm2
A high light-to-heat conversion capability and biocompati-
bility; High therapeutic effects against breast cancer with
targeted combined chemo-PTT treatment.
[163]
HA-GO
MIT
808nm,2W/cm2
High drug loading efficiency and biocompatibility of the
as-made nanocarrier; Greater antitumor effect via receptor-
mediated endocytosis.
[168]
FA–NGO–PVP
DOX
808nm,2W/cm2
The as-prepared FA–NGO–PVP exhibited ultrahigh drug
loading ratio of anticancer drug and splendid biocompati-
bility; The efficient chemo-photothermal targeted therapy
via receptor-mediated endocytosis and reduced adverse
effect.
[169]
NGO-SS-PEG
DOX
808nm,2W/cm2
Remarkable drug loading efficiency and a rapid drug re-
lease from NGO-SS-PEG conjugates with sheddable PEG
upon the stimulus of high GSH levels; An outstanding
combined chemo-photothermal therapeutic efficacy.
[170]
Apt-GO-AuNP
DOX
__
The DOX-loaded GO-AuNP-Apt system showed heat-
stimulative and sustained release characteristics; The as-
prepared GO-Au-Apt/DOX nanocomposites could selec-
tively attach to cancer cells, and greatly enhance the tar-
geted chemo-PTT to these cancer cells when exposed to
NIR light.
[155]
NGO-HA-AuNR
DOX
808nm,4W/cm2
Higher phototherm al efficiency than AuNRs; The capabil-
ity of targeting hepatoma Huh-7 cells; pH-responsive and
NIR light-triggered drug-release properties; Ultra-efficient
chemo-photothermal anti-cancer efficacy.
[175]
rGO/CJ-PEGBT
DOX
810nm,7×10−2W/mm3
Enhanced biocompatibility, synergic anticancer effects and
high specificity; Efficiently killing cancer cells both via a
selective laser beam thermoablation and hyperthermia-
triggered chemotherapy due to its outstanding hyperthermic
effect and pH sensitivity.
[176]
GN = graphene nanosheet; IRI= irinotecan; GSPI= targeting peptide (IP)-modified mesoporous silica-coated graphene nanosheet; CS = chitosan; DTX = do-
cetaxel; Apt = aptamer; MIT = mitoxantrone; PVP = polyvinylpyrrolidone; AuNR = gold nanorods; CJ-PEGBT = biotinylated inulin-doxorubicin conjugate.
lent anti-tumor efficacy with the tumor growth inhibi-
tion of 93.52%. Yang et al. [169] fabricated FA-GO for
cancer targeted chemo-PTT. GO was firstly functional-
ized by polyvinylpyrrolidone (PVP) and then by FA,
finally achieved FA-GO-PVP. The synthesized FA–
NGO–PVP was confirmed to be a pH-responsive nano-
Recent Developments of Phototherapy Current Medicinal Chemistry, 2017, Vol. 24, No. 00 13
carrier and used to deliver DOX with a high loading
ratio more than 100%. FA was used to target the over-
expressed folate receptors on surface of numerous can-
cer cell. The results of in vitro cytotoxicity study exhib-
ited that the cell inhibition rate of FA–NGO–
PVP/DOX + NIR group, free DOX group and FA–
NGO–PVP/DOX group were 90%, 70.3% and 70.9%,
respectively. Taken together, this study demonstrated
that making the targeted delivery and combined
chemo-PTT in one system might be a promising strat-
egy to improve the anticancer efficacy with reduced
drug resistance.
Apart from the above talking chemo-PTT, there also
existed target-activatable DDS for combined chemo-
PTT. H. Xiong et al. fabricated a redox-sensitive bio-
degradable PEGylated nanographene oxide (NGO-SS-
PEG/DOX) for efficiently chemo-PTT [170]. And they
made a comparative study between non-biodegradable
PEGylated nanographene oxide (NGO-PEG/DOX) and
biodegradable NGO-SS-PEG/DOX. Even though
NGO-PEG was superior to NGO, PEG modification
adversely inhibited the drug release as a diffusion bar-
rier, which had hampered its biological application.
According to the in vitro cytotoxicity study, with DOX
concentration of 10 mg/L, the inhibition rate of the
NGO-SS-PEG/DOX+NIR group and NGO-
PEG/DOX+NIR group were 90% and 79%, respec-
tively. It would be possible that the DOX release from
NGO-SS-PEG/DOX under NIR irradiation was more
rapid than that of NGO-PEG/DOX due to the cleavage
of disulfide bond, thereby resulting in the detachment
of PEG. According to the intracellular DOX-release
experiments, a rapid drug release from NGO-SS-PEG
conjugates with a detachable PEG was obtained due to
the high levels of GSH inside A549 cells. And so,
compared to NGO-PEG/DOX, NGO-SS-PEG/DOX
with NIR laser revealed increased cytotoxicity to A549
cells. Altogether, this study suggested that using NGO-
SS-PEG as a nano-vector for co-delivery of drug and
heat to tumor tissues might be an ideal strategy to pro-
mote chemo-PTT with less adverse effects.
5.3.3. The Combined Chemotherapy and PDT
Previous studies indicated that GO-based deriva-
tives could be used to load PS, such as hypocrellin A,
for PDT. However, the anticancer activity of the loaded
PS was obviously decreased [177]. Thus, making che-
motherapy and PDT in one system might solve this
problem and increase anticancer activity. What is more,
P-gp mediated drug efflux could be inhibited by PDT
process [178], so that the tumor drug resistance could
be reversed. For example, Shen et al. [179] selected
hypocrellin A as a PS and 7-ethyl-10-
hydroxycamptothecin (SN-38) as a chemotherapeutic
model drug, they were co-loaded onto GO and the
nano-system was used for combination of PDT and
chemotherapy. In vitro cytotoxicity results exhibited
that the combination therapy displayed a synergistic
anti-proliferative efficacy in contrast with single PDT
or chemotherapy. In another study, Miao et al. [180]
synthesized PEG-grafted GO (pGO) as a multimodal
nano-vector for co-delivery of PS (Ce6) and synergistic
anticancer drug (DOX). Ce6/DOX/pGO was finally
fabricated and the synergistic anticancer effect was
studied. With the help of pGO, the boosted cellular up-
take of DOX was obtained as shown in the in vitro cel-
lular uptake test and higher tumor accumulation in the
in vivo study. All these might contribute to the en-
hanced synergistic anticancer efficacy. The results of
the in vivo anticancer study manifested that under
660nm LED light, compared to the untreated mice, a
31% and 73% reduction in tumor volume were ob-
tained in the Ce6/pGO-treated group and the
Ce6/DOX/pGO-treated group, respectively. The com-
bined chemotherapy and PDT might be a novel poten-
tial therapeutic strategy for treating cancer.
5.4. Imaging-Guided Theranostics Based on Pho-
totherapy
Theranostics, realizing diagnostics and therapies in
single system, has become a new concept in the battles
with various major diseases such as cancer. The inte-
gration of imaging and therapy for imaging-guided,
visualized cancer therapy might be a better therapeutic
modality. In vivo molecular imaging of a tumor can
provide great therapeutic advantages in cancer remedy
such as visualizing the region of a tumor in a non-
invasive manner and improving patients’ compliance.
Thanks to the intrinsic photoluminescence (PL) of GO-
based derivatives, they could be used for live cell imag-
ing in the NIR region with negligible background[25].
Fluorescent dyes, such as Cy7, Hilyte647 or rhodamine
B were selected as imaging probes and they were in-
corporated on the GO to realize simultaneous visualiza-
tion and evaluation of the internalization of the loaded
agents into the target area [116, 181, 182]. However,
most fluorescent molecular dyes were not suitable for
medical applications due to their inherent toxicity and
photobleaching. In addition, NPs with the dual func-
tionalities (diagnosis and therapy of cancers) included
super paramagnetic NPs (Fe3O4, etc)[183, 184], gold
NPs [85, 185] and those of carbon materials (e.g. car-
bon dots, carbon nanotube, fullerenes and nanogra-
phene)[25, 186, 187] could be used for imaging with
14 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Zhang et al.
little inherent toxicity. What is more, optical imaging
could achieve detection at a subcellular resolution and
thus was capable of identifying cancers at their very
early stage [188]. In the following parts, different type
of imaging-guided theranostics would be discussed.
Imaging-guided PTT was firstly introduced. Re-
cently, many researchers have been studied on imag-
ing-guided PTT [189-192]. Yang et al. synthesized 131I-
rGO-PEG and used it for nuclear imaging guided com-
bined radiotherapy (RT) and PTT for cancer therapy.
rGO exhibited strong NIR absorbance at a low power
density (0.5 W/cm2 in vitro; 0.2 W/cm2 in vivo). Under
NIR light irradiation, rGO could trigger significant
photothermal heating for tumor. What is more, 131I was
able to emit high-energy X-ray and this could induce
cancer killing due to the radio ionization effect. How-
ever, 131I-rGO-PEG induced no obvious toxicity to
normal tissues at the demanded dose and this was con-
firmed by the toxicology studies. As revealed by
gamma imaging emitted from 131I, the in vivo behaviors
of the fabricated 131I-rGO-PEG were investigated, sug-
gesting that it possessed efficient passive tumor
accumulation and long-term blood circulation. By
utilizing this imaging-guided combined PTT and RT,
effective eradication of tumors was attained in the in
vivo anti-tumor experiments. Liu et al. [116]
synthesized nanographene sheet (NGS) functionalized
with PEG (NGS-PEG) and then used Cy7 (NIR
fluorescent dye) to label NGS-PEG, finally obtained
NGS-PEG-Cy7. They studied the in vivo behaviors of
PEG-NGS by fluorescence imaging for the first time
and discovered surprisingly high tumor accumulation
of NGS-PEG in different xenograft tumor models,
likely due to the EPR effect of cancerous tumors. PEG-
NGS appeared to be an excellent in vivo tumor PTT
agent with insignificant toxicity to the treated mice.
Another example of imaging-guided PTT was
GO/BaGdF5/PEG [193]. In this study, BaGdF5 NP was
used as a potential dual mode MR/CT imaging contrast
agent. In order to study the photothermal conversion
efficacy of GO/BaGdF5/PEG, the aqueous solutions of
GO/BaGdF5/PEG with various concentrations were
irradiated by NIR laser (808nm, 0.4 W/cm2). Compared
to water, without evident temperature increase,
GO/BaGdF5/PEG solutions showed significant tem-
perature increases in a concentration- and irradiation
time-dependent manner, suggesting that the
GO/BaGdF5/PEG was a potential nanoagent for PTT.
Thanks to Ba and Gd, the GO/BaGdF5/PEG had MR
and CT imaging property. Activated by the brilliant
MR/CT imaging results and excellent in vitro PTT effi-
cacy of GO/BaGdF
5/PEG, the photothermally in vivo
anti-tumor test was carried out under accurate imaging
and finally obtained remarkable anti-tumor effect.
Imaging-guided PDT was then discussed in this
part. Photodynamic theranostics with the spatiotempo-
ral specificity and minimum invasiveness, was an
emerging attractive anti-tumor method that possessed
PS fluorescence imaging and PDT at the same time
[194, 195]. Under the light irradiation of appropriate
wavelengths, PS could emit fluorescence through the
relaxation of the excited singlet state PS back to the
ground state, which could be used for the photo-
diagnosis of disease. Real-time visualization of in vivo
PS delivery and biodistribution were obtained. Addi-
tionally, the absorbed photon energy could be trans-
ferred to surrounding oxygen molecules, leading to the
generation of ROS such as singlet oxygen and free
radicals, which could cause destruction or death of
cancer cells [196]. Recently, researchers have inte-
grated GO-based derivatives and PS into one system
for fluorescence imaging guided PDT [135, 148, 197].
However, the dramatic fluorescence quenching of the
loaded PSs on the GO-based nanomaterials limited
their application as photo-diagnostics. Chen et al. [198]
proposed a new photo-theranostic nanoplatform based
on sinoporphyrin sodium (DVDMS) PS-loaded GO-
PEG (GO-PEG-DVDMS) for elevated imaging guided
PDT. DVDMS, a porphyrin dimer salt, was a new type
of PS with high yield of fluorescent emission for can-
cer theranostic and its appropriate wavelength was 615-
625nm [199]. Most fascinatingly, 100% in vivo tumor
eradication was received after intravenous injection of
GO-PEG-DVDMS (2 mg/kg of DVDMS, 50 J), with
no loss of body weight, no tumor recurrence or other
noticeable adverse effects. The results of the in vivo
fluorescence imaging displayed that GO-PEG-DVDMS
was mainly distributed in tumor site thanks to the
strong EPR effects. The life spans of mice in the con-
trol groups, DVDMS laser groups and GO-PEG-
DVDMS laser groups were 12 days, 22 days and longer
than 30 days, respectively. The results from the in vivo
PDT indicated that laser irradiation (630nm) alone or
GO-PEG-DVDMS or DVDMS with no laser irradia-
tion did not inhibit tumor growth. The histology ex-
amination results indicated that the long-circulating
GO-PEG-DVDMS did not cause appreciable toxicity to
the treated animals. All these highlighted the admirable
potential of GO-PEG-DVDMS for integrating nano-
drug delivery, in vivo imaging, and PDT into a single
system and achieving high cancer therapy efficacy.
In this part, imaging-guided PTT and PDT was dis-
cussed [200]. The obtained UCNPs-NGO/ZnPc nano-
Recent Developments of Phototherapy Current Medicinal Chemistry, 2017, Vol. 24, No. 00 15
composites were fabricated by covalently grafting core-
shell structured upconversion nanoparticles (UCNPs)
to NGO via bi-functional PEG, and then phthalo-
cyanine (ZnPc) was loaded onto NGO. This nanocom-
posites not only were be exploited as upconversion lu-
minescence (UCL) imaging probes for disease diagno-
sis, but also could produce singlet oxygen under light
activation which was used for PDT. Also the UCNPs-
NGO/ZnPc could efficiently and rapidly converted the
NIR light energy into thermal energy which was used
for PTT. Prior to the theranostic application of UCNPs-
NGO nanoplatform, the in vitro cytotoxicity of
UCNPs-NGO was assessed using a traditional MTT
assay. The cell viability was higher than 90% even at a
high concentration of 320 µg/mL. Good biocompatibil-
ity and low cytotoxicity implied that UCNPs-NGO
could serve as a theranostic probe for simultaneous
UCL imaging and combinatorial PDT/PTT for cancer
therapy. For synergistically boosted anti-cancer effi-
cacy of the combined PDT-PTT, Hela cells were incu-
bated in 80µg/mL UCNPs-NGO/ZnPc nanocomposites
for 24h and then exposed to NIR light (808 nm, 2
W/cm2). Subsequently, cells were irradiated by 630 nm
laser (50mW/cm2). The cell viability was remarkably
reduced to 15%, which is much lower than 50% (PDT
only) and 75% (PTT only). The remarkably improved
therapeutic effect might be attributed to the photother-
mal effect of graphene that could not only “cook” the
tumor cells but also improve PS agent delivery for bet-
ter photodynamic tumor cell killing. From the study of
the UCL imaging, they found that UCNPs-NGO was a
promising candidate for cancer cellular labeling and
imaging. The capability of UCNPs-NGO nanocompo-
sites for high contrast UCL imaging in vivo was also
proved. These results highlighted that integration of
these functionalities endowed UCNPs-NGO/ZnPc with
the potential for cancer theranostics. UCNPs-
NGO/ZnPc nanocomposites herein had great potential
as a theranostic probe for UCL image-guided combina-
torial PDT/PTT of tumor. Recently, a research group
made a new study about imaging-guided PTT and
PDT[201]. In the study, they reported a mild one-pot
synthesis of core@shell structured NPs including Au
core and GO nanocolloid (GON) shell. GON was used
as a reducing and stabilizing agent. In order to improve
its biocompatibility, the Au@GON NPs were then PE-
Gylated, finally forming PEG-Au@GON NPs. And
then, a PS, zinc phthalocyanine (ZnPc) was loaded on
the PEG-Au@GON NPs. In this system, Au NPs was
vital important component in this system because they
could not only improve photothermal conversion effi-
cacy for PTT but also offer Raman signal for surface
enhanced Raman scattering (SERS) imaging based on
its localized surface plasmon resonance (LSPR) prop-
erty. The feasibility of PEG-Au@GON NPs served as a
Raman probe was confirmed by the study about Raman
imaging of PEG-Au@GON NPs in HeLa cells, they
found that Raman signal was obviously observed from
the HeLa cells treated with PEG-Au@GON NPs and
633nm laser irradiation. No Raman signal was found in
the control HeLa cells with no treatment. From the
study about the estimation of combinational therapeutic
efficiency of PTT and PDT based on ZnPc-PEG-
Au@GON NPs, they uncovered that the cell viability
of combinational PTT and PDT (808nm, 0.67 W/cm2,
20 min; 660nm, 0.2 W/cm2, 10 min) was 6.8%, lower
than PTT (29.3%) or PDT (11.4%) only. It was the
simple synthetic process and multifunctionality that
made PEG-Au@GON NP a potential multimodal
therapeutic platform.
5.5. Multi-Functional Nanocarriers Based on GFNs
Indiscriminate toxicity toward healthy tissues or the
limited ability to penetrate into tumor tissue in a sig-
nificantly high concentration was a major obstacle of
most chemotherapeutic agents. Therefore, to develop a
targeted DDS which could efficiently transport drug to
specific tumor site was highly desirable. Apart from the
above talking of the combined therapy of PTT and
PDT, chemotherapy and PTT, chemotherapy and PDT,
smarter DDSs (multifunctional therapy) was also syn-
thesized. The structure of multi-functional nano-
formulations was depicted as Fig. (5).
An example of multifunctional nanocarrier based on
graphene-based nanomaterials was done by Olena Ta-
ratula et al. [202]. A novel low-oxygen graphene
nanosheets (LOGr) were chemically functionalized by
polypropylenimine generation 4 (PPIG4) dendrimers
and used to deliver a PS--phthalocyanine (Pc), finally
forming LOGr-Pc-PPIG4. LOGr-Pc-PPIG4 was then
modified by PEG and luteinizing hormone-releasing
hormone (LHRH) peptide to acquire biocompatibility
and tumor-targeting, respectively. LOGr nano-sheets
had a low density of oxygen-containing groups (similar
to rGO) with 40-fold stronger light absorption than
GO. Because the fabricated LOGr nanosheets were eas-
ily dispersed in water and exhibited largely preserved
intrinsic properties of graphene, LOGr nanosheets
demonstrated strong and nearly wave-length-
independent NIR absorption, with no need of a post-
reduction process. Moreover, the synthesized nano-
formulation acted as a theranostic agent, producing ef-
ficient ROS, fluorescence emission, and heat upon light
16 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Zhang et al.
Fig. (5). Structure schematic of multi-functional nano-formulations （Imaging-guided combined therapy of PTT, PDT and che-
motherapy).
activation, to identify and destroy ovarian cancer cells
in a noninvasive way with excellent anti-cancer effect.
This novel theranostic platform (LOGr-Pc-LHRH) in-
tegrated PDT, PTT and imaging into a single nanosys-
tem for combinatorial ovarian cancer therapy. Owing to
its effective delivery and protective system for LOGr
(PTT) and Pc (PDT), LOGr-Pc-LHRH exhibited pro-
nounced theranostic properties for applications in im-
aging and phototherapy treatment of unresected ovarian
cancer tumors. Zhang et al. [203] synthesized a imag-
ing-guided tumor-targeting NIR laser-triggered DDS
(GO@Ag-DOX-NGR) based on GO@Ag NPs for
chemo-PTT. NGR was the Asn-Gly-Arg peptide motif
that could target CD13 isoform and be used as a tumor
active targeting ligand. Firstly, they studied the NIR-
controlled release of DOX from GO@Ag-DOX-NGR,
and they uncovered that the release of DOX from
GO@Ag-DOX-NGR was in a NIR power density- and
NIR time-double-dependent manner. An obviously
faster release of loaded DOX was observed in
GO@Ag-DOX-NGR/NIR group than that of no NIR
group. In the 24th hour, 48.3% of the total loaded DOX
was released from the GO@Ag-DOX-NGR stimulated
by NIR, while only 13.8% of the drug was released in
no NIR group. Secondly, they studied the photothermal
conversion efficacy of the GO@Ag-DOX-NGR and
found that after NIR irradiation for 5 min, the tempera-
ture of GO@Ag-DOX-NGR sample obviously in-
creased by 18.3 ℃ when the concentration was 10
mg/mL and the temperature increase was also in a con-
centration-dependent manner. While the samples of
water and GO increased by 1.9℃ and 7.6℃, respec-
tively. The above result revealed that GO@Ag-DOX-
NGR was an efficient photothermal agent in cancer
treatment. And thirdly, they investigated its anti-tumor
efficacy in vivo and found that the tumor bearing mice
treated with GO@Ag-DOX-NGR/NIR had tumor
growth inhibition (TGI) of 83.9%, which was signifi-
cantly more effective than the other groups (GO@Ag-
DOX and GO@Ag-DOX-NGR). Finally, they revealed
that the GO@Ag-DOX-NGR showed a great potential
as the contrast agent for X-ray imaging. In summary, a
multifunctional tumor targeting DDS (GO@Ag-DOX-
NGR) was successfully developed and it showed tumor
targeting property, excellent chem-photothermal thera-
peutic efficacy, NIR-controlled drug release and X-ray
imaging ability. Wang et al. [204] fabricated a target-
ing peptide-modified magnetic graphene-based
mesoporous silica (MGMSPI) and exploited it as a
multifunctional theranostic nanoplatform. In the study,
IL-13 peptide (IP) was selected as the glioma-targeting
ligand. This synthesized nanocomposite integrated
MRI-imaging, dual-targeting and chemo-photothermal
glioma therapy into one system. The excellent proper-
Recent Developments of Phototherapy Current Medicinal Chemistry, 2017, Vol. 24, No. 00 17
ties of this nano-formulations included: (1) strong NIR
absorbance of the rGO (PTT), (2) water dispersibility
and biocompatibility due to PEG coating, (3) large
transverse relaxivity (r2) aroused by the dispersed
Fe3O4 NPs (imaging), (4) high drug loading efficiency
and sustained release of DOX (chemotherapy), (5) high
selectivity offered by magnetic targeting and receptor-
mediated active targeting, (6) pH and photothermal
responsive release of the loaded DOX. All of these
properties would present a multifunctional theranostic
nanoplatform for imaging-guided effective glioma
therapy.
CONCLUSION AND PERSPECTIVES
GO, a rising material star, has attracted tremendous
interests from all over the world due to its incompara-
ble physicochemical properties. But it led to severe
toxicity deriving from its instability in physiological
environment. So modifications (covalent or non-
covalent modifications) were vital important to solve
its toxicity issue before its clinical use. Applications of
graphene-based nanomaterials, including drug/gene
delivery, PTT, PDT, combination therapy and multi-
functional therapy, were summarized in this paper.
Graphene-based nanomaterials have been hot talks in
the last decades and will have a better future in
nanomedicine.
Regarding toxicity, including in vitro and in vivo
level, there is still a long way to go. The in vitro cyto-
toxicity was in relation with so many factors (sizes,
surface modifications, morphology, purity, cell types
and so on) that no agreement was achieved at present.
What’s more, the in vivo toxicity was also complicated,
associated with dose, administration route, administra-
tion time and so on. So far, the mechanism of its ab-
sorption, distribution, metabolism and excretion
(ADME) have still been unclear. The in vivo fate of
these graphene-based nanocarriers after local/systemic
administration remained a puzzle. Clear understanding
of in vivo and in vitro behavior of different GFNs was
beneficial to expand their applications in biomedical
fields.
Owing to the bigger surface area of graphene de-
rivatives, their drug loading efficacy was higher than
that of traditional nanoformulations. With ample oxy-
gen groups, modifications with biocompatible poly-
mers or targeting ligand were easy to make so as to
enhance the biocompatibility and targeting effect. Be-
sides, excellent photothermal conversion efficacy of
GFNs made them ideal for PTT. After loading PS on
the surface, PDT was obtained. Labeling these nano-
carrier with fluorescent dye or imaging probe, ther-
anostics (the integration of diagnostics and therapies)
were achieved. Integrating chemotherapy, PTT, PDT,
targeting therapy and image guiding into one system,
multifunctional nano-formulations were obtained. All
these applications were so promising that an increasing
number of people would spare no efforts to make fur-
ther studies.
So far, the studies about graphene-based nanomate-
rials have expanded exponentially but yet are still at its
starting point. The advances in the biomedical applica-
tions are so thrilling and inspiring but we are incapable
to deny the great challenges. One of the major trouble
is toxicity. With the synergistic efforts from scientists
with different major, further explorations of graphene-
based derivatives in biomedicine will be propelled.
AUTHOR CONTRIBUTIONS
The manuscript was written through contributions
of all authors. All authors have given approval to the
final version of the manuscript.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
This work is partly supported by the Natural Sci-
ence Foundation of Shandong Province, China
(ZR2011HM026).
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PMID: 2 77 74874
