REVIEW
Cancer Therapy
Emerging Strategies of Nanomaterial-Mediated
Tumor Radiosensitization
Jiani Xie, Linji Gong, Shuang Zhu, Yuan Yong, Zhanjun Gu,* and Yuliang Zhao
Nano-radiosensitization has been a hot concept for the past ten years, and
the nanomaterial-mediated tumor radiosensitization method is mainly
focused on increasing intracellular radiation deposition by high atomic
number (high Z) nanomaterials, particularly gold (Au)-mediated radiation
enhancement. Recently, various new nanomaterial-mediated radiosensitive
approaches have been successively reported, such as catalyzing reactive
oxygen species (ROS) generation, consuming intracellular reduced glu-
tathione (GSH), overcoming tumor hypoxia, and various synergistic radio-
therapy ways. These strategies may open a new avenue for enhancing the
radiotherapeutic effect and avoiding its side effects. Nevertheless, reviews
systematically summarizing these newly emerging methods and their
radiosensitive mechanisms are still rare. Therefore, the general strategies
of nanomaterial-mediated tumor radiosensitization are comprehensively
summarized, particularly aiming at introducing the emerging radiosensitive
methods. The strategies are divided into three general parts. First, methods
on account of the intrinsic radiosensitive properties of nanoradiosensitizers
for radiosensitization are highlighted. Then, newly developed synergistic
strategies based on multifunctional nanomaterials for enhancing radio-
therapy efficacy are emphasized. Third, nanomaterial-mediated radiopro-
tection approaches for increasing the radiotherapeutic ratio are discussed.
Importantly, the clinical translation of nanomaterial-mediated tumor radio-
sensitization is also covered. Finally, further challenges and outlooks in this
field are discussed.
J. Xie, L. Gong, S. Zhu, Dr. Y. Yong, Prof. Z. Gu, Prof. Y. Zhao
CAS Key Laboratory for Biomedical Effects of Nanomaterials
and Nanosafety
Institute of High Energy Physics
Chinese Academy of Sciences
Beijing 100049, China
E-mail: zjgu@ihep.ac.cn
Prof. Z. Gu, Prof. Y. Zhao
College of Materials Science and Optoelectronic Technology
University of Chinese Academy of Sciences
Beijing 100049, China
Prof. Y. Zhao
CAS Center for Excellence in Nanoscience
National Center for Nanoscience and Technology of China
Chinese Academy of Sciences
Beijing 100190, China
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/adma.201802244.
DOI: 10.1002/adma.201802244
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1. Introduction
Over 14 million new cases and more
than 8 million cancer-caused deaths
were reported worldwide in 2012, and the
number of cancer-caused death per year
was projected to raise by 45% from 2007
to 2030 according to the World Health
Organization (WHO).[1,2] In today’s society,
despite the massive financial and intellec-
tual investments are put into the preven-
tion and treatment of cancer, cancer is still
one of the world’s leading causes of death
to threaten human health. Therefore, it is
highly desired to find better cancer thera-
peutic approaches to complement and
improve current cancer treatments.
Radiotherapy (RT) is such an effec-
tive cancer therapeutic tool and has been
extensively applied in current clinical
cancer therapy. According to the reports,
over 50% cancer patients are treated with
RT either alone or cooperated with other
types of therapies.[3–5] The therapeutic
rationale of RT is that high-energy ion-
izing radiations (such as X-rays and γ-rays)
directly interact with cellular DNA to cause
DNA damage (DNA is the major target
which determines the radiobiological
effects[3]), or indirectly, react with water
molecule to produce ROS (such as superoxide O2•−, hydrogen
peroxide H2O2, hydrogen radical H•, hydroxyl radical HO•, and
H2O•+) to destroy DNA or other cellular components to induce
cell apoptosis and necrosis.[6,7] As a classical cancer therapy
method, RT has its specific superiority, such as no tissue depth
restriction.[8] However, some intrinsic shortcomings of RT also
limit its long-term application, which mainly include three
aspects as follows: 1) The ionizing radiations used for killing
tumor may harm neighboring normal tissues and thus lead
to severe toxic side effects to body.[9] 2) The hypoxic nature
inside the tumor microenvironment (TME) may make tumor
cells resistant to radiation, ultimately resulting in the failure of
tumor eradication.[10,11] 3) Since elevated antioxidants seems to
be a general feature of cancer phenotype, antioxidant system
within cancer cells will prevent them against these damaging
effects through quenching excessive free radicals. For example,
the intracellular glutathione (GSH) concentration in cancer
cells is about four fold than that within normal cells,[12,13] which
has strong ability to scavenge the ROS before they arrival at the
target site and finally reduce the radiotherapeutic efficiency to
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a large extent. As a result, these defects discount the efficiency

of RT. Therefore, the purpose of radiosensitization aims to Jiani Xie is a graduate stu-
improve the RT therapeutic efficacy. dent of the Key Laboratory
In the last two decades, the rapid development of emerging for Biomedical Effects
advanced nanomaterials and nanobiotechnology provides a of Nanomaterials and
promising opportunity for tumor radiosensitization. A variety Nanosafety of the Institute of
of nanomaterials have been widely studied and applied in the High Energy Physics, Chinese
enhancement of radiotherapeutic efficacy attributed to their ver- Academy of Sciences, under
satile physicochemical properties, such as good biocompatibility, the supervision of Prof.
intrinsic radiosensitive activities, highly loading abilities of mul- Zhanjun Gu. She obtained
tiple types of drugs[14] as well as the enhanced permeability and her bachelor’s degree from
retention (EPR) effects in tumor tissue.[15] Previously, the nano- Sichuan Normal University,
material-mediated radiosensitization method is mainly focused China, in 2014. She is now
on enhancing the intracellular radiation energy deposition by studying the synthesis and biomedical applications of
high Z nanoradiosensitizers. In recent years, a large number of nanomaterials.
new nanoradiosensitizers and radiosensitive strategies are con-
tinuously proposed. These nanoradiosensitizers and radiosensi- Zhanjun Gu is a professor
tive strategies not only can enhance ionizing radiation energy in the Key Laboratory
deposition, but also have the ability to catalyze ROS genera- for Biomedical Effects
tion, manipulate the TME (such as reducing intracellular GSH of Nanomaterials and
concentration, converting low toxic intracellular H2O2 to high- Nanosafety of the Institute
active HO• as well as improving oxygen level in tumor) or tune of High Energy Physics,
the cell circle/signal pathway to make cancer cells more sensi- Chinese Academy of Sciences.
tive to radiation, and thus significantly enhance the RT thera- He obtained his Ph.D.
peutic efficacy and simultaneously reduce its side effects. For degree from the Institute of
example, the photocatalytic semiconductor nanoparticles can be Chemistry, Chinese Academy
activated by X-ray to facilitate ROS generation so as to enhance of Science, in 2007 under the
radiation effects.[16] Some of the nanomaterials have the ability direction of Prof. Jiannian
to deplete GSH in tumor and consequently prevent the scav- Yao. He carried out postdoctoral research at the University
enging of radiation-induced ROS from GSH, finally improving of Georgia in 2009 in the group of Prof. Zhengwei Pan.
the treatment outcomes.[17] A few iron (Fe)/copper (Cu)-based His current research interests focus on nanomaterials
nanomaterials can convert intracellular H2O2 into high reactive synthesis and biomedical applications.
HO• to damage cancer cells and thus enhance the RT thera-
peutic effects.[18,19] The nanomaterials with the ability of oxygen
level improvement can effectively overcome the tumor hypoxia Yuliang Zhao is the founder
to reduce radioresistance and eventually elevate radiation of the Key Laboratory
efficiency.[20] And some nanomaterials are able to arrest cancer for Biomedical Effects
cells at G2/M phase (the most sensitive phase to radiation) and of Nanomaterials and
hence enhance radiation sensitivity of cells.[21] Apart from these Nanosafety, and Professor
intrinsic radiosensitive properties, due to the large surface area and Deputy Director-General
and multifunction features, the nanoparticles can act as carriers of National Center for
for loading and delivering radiosensitive therapeutic agents Nanoscience and Technology
(such as some of the chemotherapeutic drugs, gene materials, of China. He was elected as a
photosensitizers (PSs), and photothermal agents) into tumors Member of Chinese Academy
to achieve synergistic RT sensitization effect. In addition, the of Sciences in 2017. His
nano­­particles with radioprotective function for healthy tissue can research interests focus on
also enhance the RT efficiency, because they can decrease side nanotoxicological chemistry and nanomedicine.
effects of RT to healthy tissues, and thus elevate the therapeutic
ratio under higher dose radiation.[5]
Currently, although plenty of new radiosensitive approaches to guide researchers to promote the development of this field.
based on nanomaterials are reported, most review articles still Therefore, in this review, we systematically sum up the gen-
focus on the high Z nanomaterials mediated radiosensitiza- eral strategies of nanomaterial-mediated radiosensitization
tion,[22–28] particularly Au-mediated RT enhancement.[3,29–43] by far, and narrate their radiosensitive principles and applica-
The systematic summarization of the newly emerging nano- tions. We divide these methods into three general parts: 1) The
material-mediated RT enhancement strategies, such as the enhancement of radiosensitivity by nanoradiosensitizers with
new nanoradiosentizers and radiosensitive methods men- intrinsic radiosensitive properties. 2) The improvement of the
tioned above, is still rare. Thus, it is necessary and important cancer therapeutic outcomes via synergy of other therapy and
to make a new summarization of the most recent advances in RT based on nanocarriers. 3) The elevation of the therapeutic
this field to review its growing tendency and more importantly, ratio through protecting healthy tissues from radiation-caused

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injury by nanoradioprotectors. Moreover, some nanoradio-
sensitizers have come into clinical transformation stage, indi-
cating the great potential of current nanoradiosensitizers on
clinical application. Thus, current state of the art of the clinical
translation of nanoradiosensitizers is also introduced in this
review. Finally, we further discuss the current challenges and
future research directions in this field. It is anticipated that
such a review article can assist researchers in understanding
the latest progresses of nanomaterial-based radiosensitization,
and encourage all of us to improve the existing approaches or
explore new ways for radiosensitization.
2. General Strategies of Nanomaterial-Mediated
Tumor Radiosensitization
2.1. The Intrinsic Radiosensitive Properties of
Nanoradiosensitizers for Tumor Radiosensitization
The multifunctional properties of nanomaterials make
them suitable for a wide range of biomedicine applications.
According to a series of studies, the nanomaterials with
intrinsic radiosensitive properties not only can enhance ion-
izing radiation energy deposition, but also have the ability to
catalyze ROS generation, regulate the TME, and manipulate
cancer cell circles/signal path ways to make cancer cells more
sensitive to radiation-induced damage. Herein, we summarize
the common intrinsic radiosensitive properties of the nanora-
diosensitizers as follows (Scheme 1): 1) The high Z nanomate-
rials can promote the radiation energy deposition in tumor to
increase the RT efficiency. 2) The semiconductor nanomaterials
with photocatalytic function can be activated by light to gen-
erate free radicals for enhancing radiation effects. 3) The Fe/
Cu-based nanomaterials with chemical catalytic properties can
catalyze H2O2 to produce toxic HO• for tumor radiosensitiza-
tion. 4) The nanomaterials which can deplete GSH in cancer
cells will prevent the consumption of ROS and thus improve
the RT effect. 5) The nanomaterials that raise the oxygen level
in the TME can overcome the tumor hypoxia and thus reduce
radioresistance to realize radiosensitization. 6) The nanomate-
rials which arrest cells at G2/M phase can enhance radiation
sensitivity of cells. In this section, we will detailedly introduce

Scheme 1. Scheme of the general intrinsic radiosensitive properties of nanoradiosensitizers. Energy deposition: Adapted with permission.[42]
Copyright 2017, Royal Society of Chemistry. Photocatalysis: Adapted with permission.[90] Copyright 2017, Wiley-VCH. Chemcatalysis: 1) iron oxide:
Adapted with permission.[18] Copyright 2016, Elsevier. 2) Cu3BiS3: Adapted with permission.[19] Copyright 2017, Royal Society of Chemistry. Depleting
intracellular GSH: Adapted with permission.[17] Copyright 2017, American Chemical Society. Improving tumor oxygen: Adapted with permission.[117]
Copyright 2017, Elsevier. Regulating cell cycle: Adapted with permission.[119] Copyright 2014, American Chemical Society.

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the radiosensitive mechanisms and applications of these kinds
of nanoradiosensitizers on RT enhancement.
2.1.1. Increasing the Intracellular Radiation Energy
Deposition by High Z Nanoradiosensitizers
The main mechanism for developing high Z nanoradiosensi-
tizers is on account of the difference in the energy absorbing
abilities between high Z nanomaterials and soft tissues. There
are much more X-ray energy absorption of high Z atoms in
nanoparticles than that of low Z atoms in soft tissues (soft
tissues are mainly consisted of organic matters with low Z),
allowing physical energy dose deposition enhancement in
the presence of high Z nanoparticles.[3] In a detailed process,
when ionizing radiation hits high Z nanoparticles, the high Z
atoms can absorb more photons to increase the local dose of
radiation in cells. Then, the interaction of photons with high
Z nanoparticles will induce the occurrence of multiple effects,
such as the Compton effect and photoelectric effect. These
effects can lead to various emissions, such as photoelectrons,
Compton electrons, and Auger electrons. Subsequently, the
emissive electrons either directly damage DNA or indirectly
interact with water to produce ROS to damage DNA to induce
cell apoptosis and necrosis (Scheme 2).[6,7,42]
Owing to the special radiosensitive effects of high Z nano-
materials, many researches have devoted great effort to apply
high Z nanomaterials with good biocompatibility and tumor
targeting ability for improving the therapeutic outcome of
RT. Here, we take the most popular high Z nanomaterials
(including Au-, gadolinium (Gd)-, bismuth (Bi)-, and tungsten
(W)-based nanomaterials) in the field of tumor radiosensitiza-
tion as paradigms to manifest the promising potential of high
Z nanoradiosensitizers on RT enhancement. What needs to be
specifically mentioned is that attributing to lots of works about
hafnium (Hf)-based nanomaterials for cancer radiosensitiza-
tion have entered clinical trials, we will introduce them at the
next section of “The clinical translation of nanomaterial-medi-
ated tumor radiosensitization,” and thus will not repeat the
statement about them here.
Au-based nanomaterials are the hottest researched radiosen-
sitizers due to their unique advantages such as chemical inert-
ness, highly biocompatibility, varied morphology for achieving
Scheme 2.  The schematic illustration of the RT enhancement effect by high Z nanoradiosensitizers.
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optimum delivery and effect, multiform modification of tar-
geting moieties for specifically delivering to the tumor tissue
and longer systemic circulation for providing the material with
enough time to be absorbed by tumor tissue.[7] A large amount
of articles about Au-induced tumor radiosensitization can be
searched.[44–58] For example, Zhang et al. prepared ultrasmall
GSH-Au nanomolecules for increasing the safety and efficacy
of RT.[48] The radiosensitization came from the direct interac-
tion between Au and radiation. When the GSH-Au nanomol-
ecules received high-energy radiation, they would become a
new source of radiation and emit high energy electrons to
cause radiochemicals (ionizations and free radicals) within the
cancer cells that could damage and kill the cells. Meanwhile,
the increased targeting specificity and tumor uptake of GSH-Au
nanomolecules in cancer cells via the improved EPR effect
could increase the accumulation of Au nanomolecules in cancer
cells and thus further enhance the radiosensitization effects.
Yang et al. reported the enhancement of RT on cancer cells by
lipid nanocapsules (NCs) mediated delivery of amphiphilic Au
nanoparticles (amph-NPs) into intracellular membranes.[46] As
seen in Figure  1a, the amph-NPs were embedded in the walls
of NCs and formed Au-NCs. And such a formation could pro-
mote the transfer of amph-NPs into intracellular membranes.
Clonogenic assays demonstrated that Au-NCs strengthened
radiotherapeutic killing of cancer cells compared to that of
radiation alone (Figure 1b,c). Zaki et al. used polymeric micelle-
encapsulated Au nanoparticles for RT enhancement, where the
median survival time of tumor-bearing mice treated by both
of the Au and radiation showed a 1.7-fold improvement com-
pared to that of mice receiving radiation alone.[45] Attributed to
the positive radiosensitive response of Au-based nanomaterials,
researchers attempted to evaluate the radiosensitive efficacy of
Au-based nanoradiosensitizers with different physicochemical
parameters (such as size and shape) so as to obtain the optimal
sensitization condition.[44,51,58,59] As a representative example,
Zhang et al. observed that 12.1 and 27.3 nm poly(ethylene
glycol) (PEG)-coated Au nanoparticles had higher radiosensi-
tive effects than 4.8 and 46.6 nm nanoparticles, which indicated
that the radiosensitization of the PEG-coated Au nanoparticles
was size-dependent.[44]
Gd is a lanthanide element with powerful high energy ioni-
zation radiation absorption ability and the Gd-based nano-
materials are widely developed as radiosensitizers in recent
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Figure 1.  a) Scheme of the structure of Au-NCs and amph-NPs. b) colonies assay of B16F10 cells after different treatments. c) Responding survival
fraction of B16F10 and 4T1 cells with different treatments. Adapted with permission.[46] Copyright 2014, American Chemical Society.

years.[60–68] As a paradigm, Le Duc et al. used ultrasmall Gd-
based nanoparticles (GBNs) to carry microbeam RT. The
radiosensitive effect of GBNs activated by X-ray microbeams
significantly improved the survival of rats bearing brain
tumors.[60] Miladi et al. studied the radiosensitive effect of GBNs
for human radioresistant head and neck squamous cell carci-
noma (HNSCC). Combining the GBNs with irradiation could
significantly decrease the HNSCC cell survival and delay tumor
growth.[64] Dufort et al. developed the Gd-based theranostic
nanoparticles (USRPs) for lung tumor radiosensitization.[62] An
effective radiosensitive effect of USRPs could be certified by the
longer mean survival time of 112 days for irradiated H358-Luc
lung tumor-bearing mice with USRPs treatment compared to
that of 77 days for the irradiated mice without USRPs treat-
ment. Most recently, Du et al. engineered the Gd-doped carbon
dots (Gd-doped CDs) for tumor RT treatment.[68] Compared to
treating tumor-bearing mice with radiation alone, injecting the
Gd-doped CDs to the mice during the radiation process remark-
ably inhibited the growth of the solid tumors. Consequently,
Gd-based nanomaterials could be envisioned as the powerful
radiosensitizers to assist RT.
Bi-based nanomaterials, such as Bi2S3, Bi2Se3 and Bi2O3, are
another hot materials in radiosensitization.[69–75] For example,
Yao et al. provided the first example of both in vitro and in vivo
to demonstrate the radiosensitive effect of Bi2S3/poly(lactic-co-
glycolic acid) (PLGA) nanocapsule against prostate cancer.[69] For
another example, Bi2Se3 has attracted wide attention in biomed-
ical applications due to the large X-ray absorption ability of Bi
and the effective anticancer activity of selenium (Se). Zhang et al.
reported a poly(vinylpyrollidone) (PVP)-coated Bi2Se3 nano-
plates for enhancing RT on cancer.[70] The net increase of
tumor weight was minimum after treating with Bi2Se3  + RT,
indicating that Bi2Se3 nanoparticles possess a strong radiation
enhancement effect. In addition, Du et al. recently synthesized
hyaluronic acid-modified bismuth oxide nanoparticles (HA-
Bi2O3 NPs) to use as adjuvants for cancer radiosensitization.[73]
The HA-Bi2O3 NPs with high X-ray attenuation efficiency exhib-
ited an ideal radiosensitivity to induce cell apoptosis and inhibit
tumor growth. Thus, Bi-based nanomaterials manifest the great
promise for RT enhancement.
W-based nanomaterials also hold the great attention in radio-
sensitization field in recent years.[76–79] For example, Yong et al.
reported a new ultrasmall bovine serum albumin (BSA)-coated
GdW10O36 nanoclusters (GdW10@BSA NCs) as radiosensi-
tizers for RT treatment.[76] The tumors of the mice in group
GdW10@BSA NCs + X-ray were thoroughly eliminated at
4 days and showed no recurrence in the subsequent 14 days,
indicating the strong sensitization effect of the NCs on RT.

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For another example, Shen et al. developed an ultrasmall coor-
dination polymer nanodot (CPN) by the coordination of gallic
acid (W-GA) and tungsten ions (WVI) (W-GA-PEG CPNs) for
enhancing RT.[77] Taking advantage of the radiosensitive func-
tion of W with strong X-ray absorption, the W-GA-PEG CPNs
greatly inhibited the tumor growth under X-ray exposure. As a
result, W-based nanomaterials also have the potential for tumor
radiosensitization.
2.1.2. Promoting ROS Generation through Photocatalysis
by Semiconducting Nanoradiosensitizers
Photocatalytic semiconductor nanomaterials have also been
exploited to enhance radiation effects, because they can be
activated by light to generate the toxic free radicals. In detail,
when the semiconductors are excited by light with energy levels
higher than their band gap, the electron-hole pairs are formed.
Subsequently, the free radicals will continuously generate from
these semiconductors via either oxidative pathway (involving
hole transfer to a donor (usually H2O) to form HO•) or reduc-
tive pathway (involving electron transfer to an acceptor (usually
O2) to form O2•−). As a result, the DNA or proteins in cancer
cells were damaged by the generated free radicals.[16,80,81] TiO2
and ZnO are typical semiconductors that can produce toxic free
radicals by photoactivation.[82,83] Previously, researchers applied
them in photodynamic therapy (PDT) due to their unique photo-
toxic effect that generates ROS upon the UV irradiation.[80,84–88]
Figure 2.  a,b) The diagrams of proposed “photoactivation mechanism” by Eu/Gd-doped ZnO nanoparticles and BSA-coated BiOI@Bi2S3 semiconductor
heterojunction nanoparticles under X-ray, respectively. a) Adapted with permission.[16] Copyright 2016, American Chemical Society. b) Adapted with
permission.[90] Copyright 2017, Wiley-VCH.
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For example, Zhang et al. investigated the combined application
of ZnO nanorods with anticancer agent daunorubicin (DNR)
in PDT.[80] The ZnO nanorods could not only act as the carrier
to deliver DNR for cancer therapy, but also further enhance
the inhibition of cancer cells under UV irradiation by photo-
catalysis. Recently, inspired by the ROS generation ability of
semiconductors under UV irradiation, researchers attempted to
design and fabricate one kind of special photocatalytic semicon-
ductor nanomaterial that could be excited by X-ray radiation to
generate ROS for improving RT treatment effect. For example,
Ghaemi et al. designed lanthanide-doped ZnO nanoparticles
(europium (Eu)/Gd-doped ZnO nanoparticles) to enhance the
RT of cancer.[16] The RT enhancement mechanism of this nano-
particle is illustrated in Figure  2a. Lanthanides could interact
with X-ray radiation, and an efficient relaxation of lanthanides
electronic excitation occurred via the transfer of excess energy
to ZnO nanoparticles. When the transferred energy levels were
higher than that of the ZnO band gap, electron–hole pairs were
formed and consequently ROS were generated and caused
DNA breakage in targeted cancer cells. For another example,
Townley et al. synthesized earth-doped TiO2 nanoparticles for
ROS generation in tumors to enhance RT.[81] When tumor was
treated with X-ray in the existence of such nanoparticles, the
tumor volume could be reduced by around half compared to
that of X-ray alone, which exhibited a good radiosensitization
effect.
In addition to lanthanides-doped semiconductor nanoparti-
cles, some of the other semiconductor nanocomposites were
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also used in photocatalysis-induced radiosensitization.[89,90] For
instance, BSA-coated BiOI@Bi2S3 semiconductor heterojunc-
tion nanoparticles (SHNPs) for radiosensitization have been
well investigated in treatment of hepatocellular carcinoma
by Guo et al.[90] On the one hand, since SHNPs contained the
high Z elements such as Bi and I, they possessed a strong
X-ray attenuation capability and thus was anticipated to be the
radiosensitive materials to increase radiation dose deposition
in tumor. On the other hand, owing to the photocatalytic semi-
conductor property, BiOI could be excited by X-ray to generate
the electron–hole pair that reacted with surrounding oxygen
or H2O molecules to produce ROS such as HO• and O2•− to
kill tumor. Importantly, superior to the conventional semicon-
ductor PSs, the formation of core–shell heterojunction structure
by coating Bi2S3 shell on the surface of BiOI could reduce the elec-
tron–hole recombination, and thus further increase the yield of
electron–hole pair, resulting in higher photocurrent and photo-
catalytic activity. As a result, the SHNPs could generate higher
level of ROS to damage DNA more effectively (Figure 2b).
by Fe2+/Fe3+ to produce a toxic, highly reactive HO•. These radi-
cals can lead to oxidative damage to cell components.[91]
The Haber–Weiss reaction process was presented as follows
Fe3+ + O2 •− → Fe 2+ + O2  (3)
Fe 2+ + H2O2 → Fe3+ + HO • + OH −  (4)
This reaction can occur in cells and is therefore a possible
source for oxidative stress.[92,93]
Based on the chemocatalysis of Fe-based nanomaterials,
Hauser et al. employed iron oxide nanoparticles to catalyze
H2O2 to form HO• for the enhancement of RT on A549 cells.
Moreover, the iron oxide nanoparticles were functionalized
with the TAT peptide (a cell penetrating peptide), which further
elevated the efficacy of radiation via increasing intracellular
concentrations and promoting lysosomal escape of the nano-
particles (Figure 3a).[18]

2.1.3. Promoting ROS Generation through

Chemocatalysis Processes of Fe/Cu-based
Nanoradiosensitizers

The H2O2 level within a tumor is overex-

pressed because of the fast metabolism of
cancer cells and insufficient blood supply.
Notably, it has approved that ionizing radia-
tion can increase production of the O2•−
and then these free radical are quickly con-
verted to H2O2 by superoxide dismutase (SOD).
This action further elevates H2O2 level in
cancer cells during the RT treatment. There-
fore, converting intracellular H2O2 into toxic
HO• by suitable catalytic agents under radia-
tion exposure becomes an effective way for
radiosensitization. Some Fe-based nanoma-
terials are such good catalysts. The detailed
radiosensitive process is as follow: the radia-
tion initially facilitates electron leakage
from the electron transport chain and thus
enhances the generation of the O2•−. Then,
the O2•− is converted to H2O2 by natural SOD.
Finally, the H2O2 is catalyzed by Fe-based
nanomaterials to form highly reactive HO• to
result in DNA damage.[18] The generation of
HO• by Fe-based nanoparticles is through the
Fenton’s reaction or Haber–Weiss reaction.
The catalytic process of Fenton’s reaction
was presented as follows

Fe 2+ + H2O2 → Fe3+ + HO • + OH −  (1)

Fe3+ + H2O2 → Fe 2+ + HOO • + H+  (2)

Figure 3.  a,b) Schematic illustration of the mechanism of radiosensitization by TAT-conjugated
iron oxide nanoparticles and TPGS-functionalized Cu3BiS3 nanocrystals, respectively. a) Adapted
This reaction happens in almost all Fe- with permission.[18] Copyright 2016, Elsevier. b) Adapted with permission.[19] Copyright 2017,
related vital processes. H2O2 can be catalyzed Royal Society of Chemistry.

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In addition to Fe-based nanoparticles, some studies have
demonstrated that Cu-based nanoparticles can act as Fenton-
like reagents for catalyzing the H2O2 substrate to produce
ROS.[94,95] Its catalytic mechanism is likely to followed Fenton-
like reaction[95]
Cu 2+ + H2O2 → Cu + + HOO • + H+  (5)
Cu + + H2O2 → Cu 2+ + HO • + OH −  (6)
Based on this principle, Du et al. designed the d-α-tocopherol
polyethylene glycol 1000 succinate (TPGS)-functionalized
Cu3BiS3 nanocrystals (NCs) (TPGS-Cu3BiS3 NCs) for the
enhanced RT treatment of deep-seated tumor cells.[19] Prof-
iting from the catalytic activity, high X-ray and near-infrared
(NIR) laser absorbable ability of TPGS-Cu3BiS3 NCs, the ther-
apeutic efficiency of RT was remarkable increased. As shown
in Figure 3b, the Cu2+ located on the surface of the NCs were
capable of catalyzing the intracellular H2O2 to generate highly
reactive HO• via Haber–Weiss and Fenton-like reactions to
destruct cancer cells. Meanwhile, attributing to the strong X-ray
absorbability of Bi element, TPGS-Cu3BiS3 NCs could deposit
more X-ray irradiation energy within tumor via generating pho-
toelectrons, Compton electrons and Auger electrons to induce
the emission of secondary electrons for radiosensitization.
Moreover, benefiting from the strong absorbance of NIR light
in the second NIR window, TPGS-Cu3BiS3 NCs could generate
hyperthermia under NIR irradiation and effectively improve
the tumor oxygenation so as to overcome the hypoxia-induced
radioresistance of tumors, thus further increasing the radiation
effect.
In addition to Fe and Cu, some of the elements with mul-
tiple redox states (such as cobalt (Co) and chromium (Cr))
have been proved that can also convert intracellular H2O2 into
toxic HO• via the Fenton-like reaction,[96] but have not yet been
widely applied into tumor radiosensitization. Thus, it is worth
exploring and evaluating the tumor radiosensitization effects
of the nanomaterials contained these elements to facilitate the
development of new nanoradiosensitizers.
2.1.4. Consuming Intracellular GSH by Nanoradiosensitizers
GSH, which contains thiol, is an important antioxidant
in vivo.[97] The overexpression of GSH is one of the major
obstacles on improving the efficiency of RT, because it can
reduce the amount of generated ROS before their arrival at
target site and consequently cause the radiation resistance
in tumor tissue.[98] Therefore, if a nanoparticle can deplete
GSH in tumors, it will powerfully overcome the GSH-asso-
ciated radioresistance and thus improve the RT therapeutic
effect.
Base on this property, Abdallah et al. realized the RT
enhancement on solid Ehrlich carcinoma-bearing mice
by Withania somnifera extract/Gd(III) oxide nanocom-
posite (WSGNC).[99] The experimental results showed a
remarkable decrease of GSH content in cancer tissues of
the tumor-bearing mice after treating mice with WSGNC
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combined with γ-radiation. Recently, Yong et al. designed a
chitosan-polyoxometalates-based radiosensitization platform
(GdW10@CS nanosphere) for enhanced radiation response
by reducing GSH level to improve ROS generation.[17] As
shown in Figure 4a, the GdW10@CS nanosphere was able to
consume GSH via the redox reaction between W6+ and GSH
to reduce the removal of the generated ROS. This mecha-
nism was verified by the Ellman’s assay, which evaluated
the oxidative stress level by the ratio of GSH and oxidized
glutathione (GSSG). As expected, the relative GSH level and
the GSH/GSSG ratio were significantly reduced after treat-
ment with GdW10@CS nanosphere in external analog and
cells (Figure 4b,c). Therefore, these results amply proved that
GdW10@CS nanosphere could effectively reduce GSH via
redox reaction to attenuate radioresistance so as to enhance
radiation response.
Up to now, a lot of nanomaterials have been reported to
be able to decrease GSH in cancer cells for cancer therapy,
but they are not yet used as radiosensitizers. Herein, we
also introduce some of them to inspire researchers to exploit
their function in tumor radiosensitization. Some oxidative
compounds are such suitable candidates to exhaust GSH.
For example, Platinum (Pt) (IV) pro-drugs can be reduced
to highly cytotoxic Pt(II) by high concentrations of GSH in
cancer cells. Taking advantage of this feature, Bi et al. suc-
cessfully fabricated CuS–Pt(IV) nanoparticles for cooperated
Pt drug-induced chemotherapy with CuS nanoparticles-medi-
ated photothermal therapy (PTT).[100] The MnO2 nanomaterial
also can be reduced by intracellular GSH so as to decrease the
level of GSH in cancer cells. For instance, chlorin e6 (Ce6)-
loaded MnO2 nanosheets and PLGA/hematoporphyrin mono-
methyl ether (HMME)@MnO2 nanoparticles were used to
strengthen PDT efficacy by reducing the intracellular GSH
level, respectively.[101,102] Moreover, the reduction of Cu2+ by
GSH can also lead to GSH depletion. Ju et al. reported Cu2+–
g-C3N4 nanosheets for PDT enhancement.[98] This system
could facilitate light-triggered ROS generation and reduce
intracellular GSH levels. In addition to direct reduce GSH by
oxidizing materials, accelerating GSH oxidation by the mate-
rials with corresponding catalytic activity is another effective
approach to indirectly promote the depletion of GSH. Yin
et al. reported that MoS2 was such a material to accelerate
GSH oxidation by catalytic reaction.[103] They used PEG-MoS2
nanoflowers (NFs) for antibacterial applications. It is known
that GSH is important in the bacterial antioxidant defense
system, because it can prevent damage of cellular components
caused by oxidative stress. Therefore, the accelerated GSH oxi-
dation to decrease GSH would more easily result in bacterial
death. It was proved that PEG-MoS2 NFs showed a time- and
temperature-dependent catalytic oxidation behavior to GSH,
and 808 nm irradiation induced hyperthermia could remark-
ably promote GSH oxidation at the presence of PEG-MoS2
NFs. Furthermore, the materials that can inhibit GSH syn-
thesizing enzymes are also able to decrease the GSH level in
cells. For instance, Valodkar et al. studied the in vitro cytotoxic
mechanisms of latex capped silver nanoparticles (LAgNPs) in
human lung carcinoma cells. It showed that LAgNPs resulted
in significant decrease of cellular GSH level by the inhibition
of GSH synthesizing enzymes.[104] Therefore, the continued
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Figure 4.  a) Schematic illustration of the mechanism of the GSH consumption. b) Relative GSH level after different treatment. c) GSH/GSSG ratios of
solution after different treatment in external analog and cells. Adapted with permission.[17] Copyright 2017, American Chemical Society.

efforts for developing and applying nanomaterials with GSH
down-regulated function on RT are significant for cancer
therapy.
2.1.5. Improving Tumor Oxygen Level by Nanoradiosensitizers
Since tumors grow in an exaggerated way, the tumor interior
becomes far beyond blood supply, which causes the largely sup-
pressed delivery of O2. Such an insufficient O2 supply cannot
meet the ever-increasing metabolic demands of the aggres-
sively proliferating tumor cells, bringing about the significant
hypoxia in TME and leading to the tumor resistance to ionizing
irradiation.[10,11,105,106] Thus, the nanoparticles which are able
to reduce the tumor hypoxia can effectively elevate the RT effi-
ciency. There are many nanoparticle-mediated approaches for
increasing oxygen levels in TME to overcome tumor hypoxia for
radiosensitization applications. As a typical paradigm, MnO2
can act as activator to trigger the decomposition of endog-
enous H2O2 in tumor to produce O2 for decreasing tumor
hypoxia, and thus realize tumor radiosensitization.[20,107–111]
For instance, Fan et al. used MnO2 nanosheets anchored with
upconversion nanoprobes (UCSMs) for therapy of the solid
tumors.[107] The oxygen generation was achieved by the redox
activity of MnO2 toward acidic H2O2, which allowed the effective
treatment of solid tumors through the oxygen-elevated syner-
getic RT. Similarly, Yi et al. constructed core-shell Au@MnO2
nanoparticles for improving RT efficacy.[20] On the one hand,
as a well-known radiosensitizer, Au nanoparticle could interact
with X-rays to generate charged particles for enhancing cancer
killing under RT. On the other hand, the MnO2 shell could act
as activator to trigger the decomposition of endogenous H2O2
in the tumor to produce O2 for overcoming hypoxia-induced
radioresistance. As a result, Au@MnO2-PEG nanoparticles
indicated remarkable enhancement of tumor therapeutic effi-
ciency during RT both in vitro and in vivo. As another typical
example, since hyperthermia can enhance tumor blood flow
and improve the overall tumor oxygenation to make tumor
more susceptible to radiation,[112] the nanoparticles that can
be used as photothermal agents to provide hyperthermia are
promising for radiosensitization, such as WS2 and Bi2S3.[113,114]
They can convert NIR into heat to increase the oxygen level in
TME so as to elevate the efficacy of RT. In addition, the nano-
particles that load catalase for promoting the generation of O2
or integrate with oxygen donator to release O2 in tumor have
been explored to overcome hypoxia-associated radioresist-
ance.[72,115–118] For example, Song et al. encapsulated catalase
within tantalum oxide (TaOx) nanoshells for enhancing RT.[115]
Among this bio-nanoreactor, high Z TaOx could concentrate
radiation energy into the tumor to increase DNA damage;

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Figure 5.  a) The schematic illustration of the oxygen-loaded TaOx@PFC-PEG nanodroplets for enhanced RT. b) Tumor growth inhibition curves of
mice with different treatments. c) Averaged tumors weights of mice with different treatments at the end of the experiment. d) TUNEL and H&E stained
images of tumor collected from different treated groups. Adapted with permission.[117] Copyright 2017, Elsevier.

meanwhile, catalase could rapidly decompose H2O2 into O2
to overcome hypoxia-induced radioresistance. Soon after, they
used TaOx nanoparticles to decorate onto perfluorocarbon
(PFC) nanodroplets (oxygen donator) for radiosensitization.[117]
As illustrated in Figure  5a, the as-prepared TaOx@PFC-PEG
nanoparticles could not only increase the X-ray absorption to
concentrate radiation energy by TaOx, but also act as an oxygen
donator to gradually release oxygen and elevate intracellular O2
by PFC. Consequently, remarkable enhancement of RT effect in
vivo is achieved by TaOx@PFC-PEG nanoparticles (Figure 5b–d).
Overall, it is meaningful to design antihypoxic nanoagents for
radiosensitization applications.
2.1.6. Regulating Cell Cycle by Nanoradiosensitizers
Cell cycle is a series of events which leads to DNA replica-
tion to generate two daughter cells. It consists of four distinct
phases: G1, S, G2, and M phase. The most sensitive phase to
radiation of the cell cycle is G2/M phase. Thus, the nanoparti-
cles which can arrest cancer cells at G2/M phase will enhance
radiation sensitivity of the cells. In recent years, the studies
about retention of cells in G2/M phase by nanoparticles have
gradually been reported. For example, Huang et al. employed
biocompatible BSA nanoparticles as carriers of organic sele-
nocompound with targeting ligand folate to improve the
efficiency of RT. This nanosystem could overcome radioresist-
ance by inhibiting the function of vascular endothelial growth
factor (VEGF), vascular endothelial growth factor receptor
2 (VEGFR2) and X-ray repair cross complementing pro-
tein 1 (XRCC-1) and eventually triggered G2/M phase arrest
and apoptotic signaling pathways.[119] Liu et al. confirmed
that antiepidermal growth factor receptor (EGFR) mono-
clonal antibody-conjugated hollow Au nanospheres (HGNs)
(anti-EGFR/HGNs) obviously elevated the ratio of HeLa
cells in G2/M phase.[21] When HeLa cells were treated with
naked HGNs and anti-EGFR/HGNs, the cells in the G2/M
phase increased remarkably while cells in the G0/G1 phase
decreased compared with the control, remarkably enhancing
radiation sensitivity of HeLa cells. As another typical example,
the glucose-capped Au nanoparticles and androgen receptor
shRNA-loaded nanoparticle also were reported to elevate radi-
osensitivity of cells via enhancing cycle arrest in cells at the
G2/M phase under ionizing radiation exposure, which observ-
ably enhanced the sensitivity of cells to radiation.[120,121] There-
fore, the exploitation of the nanomaterials with the ability to

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arrest cells at G2/M phase is promising for radiosensitization
application.
2.2. Nanomaterial-Mediated Synergetic RT for Tumor
Radiosensitization
Besides using the intrinsic radiosensitive properties of nanora-
diosensitizers to enhance the RT, nanomaterial-mediated syn-
ergistic RT is also a good option for tumor radiosensitization,
which employs nanoparticles as nanocarriers to delivery various
therapeutic drugs into tumors. An ideal delivery system needs
to satisfy the following requirements: delivering therapeutic
agents through the vasculature without drug leakage, selectively
accumulating and exerting therapeutic effect in tumor instead of
normal tissue to reduce undesired side effects.[122] Nanoparticle
is such an ideal drug delivery system due to its good biocom-
patibility, highly drug-loading abilities and EPR effects. When
using nanoparticles to delivery various radiosensitive thera-
peutic agents (such as some of the chemotherapeutic drugs,
gene materials, PSs, and photothermal agents) into tumors for
enhancing RT efficiency, these agents can not only exert their
own drug therapeutic function, but also render cells more sus-
ceptible to radiation-induced damage through different mech-
anisms, and thus achieve corresponding synergistic RT for
tumor radiosensitization. For example, the chemotherapeutic
drugs with the potential to arrest cell cycle at the radiosensi-
tive G2/M phase can afford synergetic chemotherapy with RT.
The gene materials that limit the expression of radioresistance-
linked proteins can realize synergetic gene therapy with RT. PSs
molecule with the ability to produce more ROS can attain syn-
ergetic PDT with RT. Moreover, the photothermal agents, which
generate heat to accelerate intratumoral blood flow to enhance
the tumor oxygenation so as to make the cells more sensitive to
RT, can accomplish synergetic PPT with RT.
In this section, we summarize the common nanomaterial-
mediated synergetic RT methods for tumor radiosensitization
(including synergy of chemotherapy with RT, synergy of gene
therapy with RT, synergy of PDT with RT, synergy of PPT with
RT and trimodal synergetic RT) (Scheme 3). The radiosensi-
tive mechanism and application of each kind of synergetic RT
strategy are concretely discussed.

Scheme 3.  The common methods of nanomaterial-mediated synergetic RT for tumor radiosensitization. Chemo&RT: Adapted with permission.[159]
Copyright 2014, Royal Society of Chemistry. PDT&RT: 1) Single excitation source: Adapted with permission.[207] Copyright 2015, Wiley-VCH. 2)
Two excitation sources: Adapted with permission.[202] Copyright 2016, Elsevier. Trimodal: Adapted with permission.[90] Copyright 2017, Wiley-VCH.
Gene&RT: Adapted with permission.[17] Copyright 2017, American Chemical Society. PTT&RT: Adapted with permission.[243] Copyright 2018, Ivyspring
International Publisher.

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2.2.1. Synergy of Chemotherapy with RT
At present, chemotherapy is still one of the major cancer treat-
ment approaches in the clinic besides surgery and RT.[123,124]
Some chemotherapy drugs, such as docetaxel (Dtxl),[125–130]
Paclitaxel (Ptxl),[131–134] curcumin,[135–140] tirapazamine
(TPZ),[141–143] cisplatin (CDDP),[144–146] doxorubicin (DOX),[147]
and mitomycin C (MMC),[148–150] have been verified to act as
radiosensitizers to boost the efficiency of RT through different
mechanisms. For instance, both Ptxl and curcumin can arrest
cells at the G2/M phase and thus enhance the RT.[138,151,152] Dtxl
also shows obviously radiosensitive activity, which is ascribed
to the retention of cells in the G2/M phase,[130] or the pro-
motion of ROS generation and the consumption of GSH in
cells.[153] CDDP can inhibit the repair of damaged DNA caused
by radiation,[154] thus enhancing RT therapeutic effects. More-
over, TPZ, a drug only active in hypoxic condition,[155] can be
reductively activated at low oxygen partial pressure to generate
toxic products and consequently damage the hypoxic cells.
Therefore, using nanoparticles to load and delivery radiosensitive
chemotherapeutic drugs into tumors for achieving chemo-
therapy/RT synergetic treatment is an effective approach for
tumor radiosensitization.
Up to now, various kinds of nanoparticles formulation of
radiosensitive drugs for increasing the efficacy of RT have
been designed.[125,141,150,156–178] For example, based on the
effective radiosensitization effect of chemodrug CDDP, Fan
et al. designed rattle-structured multifunctional upconversion
core/porous silica shell nanotheranostics (UCSNs) to deliver
CDDP into tumor cells for achieving chemotherapy/RT syn-
ergetic treatment.[158] The UCSNs-CDDP exhibited unambigu-
ously enhanced RT efficacy both in vitro and in vivo. Soon
afterward, they employed rattle-structured upconversion core/
mesoporous silica nanoparticles (RUMSNs) to transport radi-
osensitive drug MMC for chemotherapy and RT synergetic
therapy (Figure  6a).[150] Different from the former UCSNs-
CDDP system, the RUMSNs were conjugated with nuclear
localization signal ligands TAT that could facilitate the efficient

Figure 6. a) The scheme of the intranuclear radiosensitization by RUMSNs-TAT-MMC nanosystem. b,c) The cell viability of MCF-7 and MCF-7/
ADR cells after different treatments, respectively. d,e) The relative tumor volume of MCF-7 and MCF-7/ADR tumor-bearing mice with time after the
corresponding treatments, respectively. Adapted with permission.[150] Copyright 2015, Royal Society of Chemistry.

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transportation of nanoparticles into the cell nucleus. Therefore,
the RUMSNs-TAT system could directly transport the radiosen-
sitive drug MMC into the nucleus for the substantially elevated
chemodrug-sensitized RT under high energy X-ray exposure
compared to the extranuclear chemodrug-sensitized RT system.
As seen in Figure 6b–e, both MCF-7 and MCF-7/ADR cells in
vitro and in vivo could be effectively inhibited by RUMSNs-TAT-
MMC under X-ray radiation. In addition to intranuclear radio-
sensitive technique, if the nanocarriers can absorb high energy
ionizing radiation, both the nanocarriers and the radiosensitive
drugs will be able to serve as radiosensitizers, and thus the
therapeutic effect of RT will be further improved compared to
that of single chemodrug-radiosensitized method. For example,
Setua et al. developed multifunctional CDDP-tethered Au nano-
spheres for accomplishing chemotherapy/RT combined treat-
ment of glioblastoma multiforme (GBM).[159] On the one hand,
the chemotherapeutics agent CDDP that was delivered into
cancer cells by nanospheres could achieve chemodrug-sensi-
tized RT. On the other hand, both Au and Pt were high Z radio-
sensitizers. Herein, both the two sides efficiently demolished
the tumor cells. For another example, Liu et al. recently con-
structed a new type of nanoscale coordination polymers (NCPs)
on account of the Hf ions and acidic pH sensitive benzoic-
imine linker (BI-linker). Chloro(triphenylphosphine)gold(I)
(TPPGC, a chemotherapeutic drug) was then loaded into the
NCPs, forming an acidic sensitive degradation and drug
release nanoplatform.[170] In this system, the drug TPPGC could
cause mitochondrial damage as well as block the cell cycle of
cancer cells into radiosensitive phase, and high Z Hf ions could
act as radiosensitizers to deposit ionizing radiation energy into
tumors. As a result, the efficacy of RT was obviously improved.
2.2.2. Synergy of Gene Therapy with RT
Gene therapy refers to the guide of genetic materials into
the target cancer cells to regulate the apoptosis-linked gene’s
expression and corresponding biological signaling pathway to
kill the cancer cells. It is worth pointing out that since gene
therapy can fix abnormal genes (the roots of the diseases), it
has unparalleled superiority compared to the other traditional
therapeutic methods.
A lot of researches have shown the apparent links between
some genes and/or gene-induced proteins (such as p53, early
region 1A (E1A), survivin, VEGF and ataxia telangiectasia
mutated (ATM)[179–185]) and radiation, because these gene
materials can regulate the expression of radiation-related pro-
tein and thus get the goal of tumor radiosensitization. For
example, anti-ATM oligodeoxynucleotides and anti-survivin
siRNA are the common gene materials for radiosensitiza-
tion. Anti-ATM oligodeoxynucleotides can reduce expression
of ATM (ATM is a key protein to prevent the DNA damage
and activate DNA-repair following ionizing radiation) in
cells to increase sensitivity of the cells to radiation and thus
strengthen the apoptosis of cells.[112,186] For another example,
anti-survivin siRNA that limits the generation of survivin (an
important radioresistance-linked protein) can reverse radiation
resistance and achieve RT enhancement.[182,187] Therefore, the
combination of RT with gene drugs that limits the expression
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of radioresistance-linked proteins is also an effective method
for radiosensitization.
Yang et al. once used adenovirus-mediated transfer of siRNA
to inhibit survivin expression to enhance the sensitivity of
human non–small cell lung cancer (NSCLC) cells to radiation.
The results indicated that the synergistic effect of survivin-
targeting gene therapy and RT was significantly valid on cell-
growth inhibition than monotherapy for the NSCLC cells.[188]
However, the synergy of gene therapy with RT in this work
is performed without nanocarriers. It is known that deliv-
ering gene drug in vivo without carriers suffers from many
drawbacks, such as fast degradation in physiological environ-
ment, short half-life in plasma, bad targeting ability to lead
side effect, and inefficient translocation of substances into the
cytoplasm.[189] Therefore, it is significant to develop carriers
for gene drug delivery to overcome the aforementioned short-
comings. Nanomaterial with high drug-loading ability and
biocompatibility is such an ideal carrier. At present, the litera-
tures about using nanomaterials as carriers for achieving gene
therapy/RT synergistic treatment are coming in increasing
numbers.[17,121,181,190–197] For instance, Shen et al. used super-
paramagnetic dextran iron oxide nanoparticles to carry the E1A
gene and explored the effects of this system on radiosensitiza-
tion of human cervical cancer in nude mice.[181] They demon-
strated that this system increased p53 expression but inhibited
human epidermal growth factor receptor-2 (HER-2)/neu expres-
sion in xenograft tumor tissue and thus enhanced the tumor
radiosensitivity. As another example, Yong et al. employed
GdW10@CS nanosphere to deliver the hypoxia-inducible
factor-1α (HIF-1α) siRNA for enhanced radiation response,
which is also a typical instance of gene therapy/RT synergistic
treatment (Figure  7a).[17] On the one hand, the GdW10@CS
nanosphere could act as a radiosensitizer to promote enough
ROS generation under X-ray radiation. On the other hand,
HIF-1α siRNA could down-regulate HIF-1α expression to atten-
uate hypoxia-associated resistance and inhibit broken double-
stranded DNA restoration under RT. The two sides together
facilitated radiosensitization in hypoxic tumors. As shown in
Figure 7b, a significantly enhanced RT efficacy could be found
in the hypoxic BEL-7402 cells after treating with GdW10@
CSsiRNA nanospheres + X-ray compared to that of single X-ray
treatment. Furthermore, in vivo experiments showed sharp
tumor growth inhibition and no recrudescence in the GdW10@
CSsiRNA+X-ray treated group (Figure 7c), further suggesting the
prominent RT enhancement effect. Recently, Mizrachi et al.
encapsulated BYL719 (a phosphatidylinositol 3-kinase (PI3Kα)
inhibitor) into P-selectin-targeted nanoparticles and realized
RT efficacy enhancement by specific accumulation of BYL719
in HNSCC tumors.[196] The nanoparticle-targeted delivery of
BYL719 in HNSCC tumors not only enhanced RT therapeutic
outcome via tumor specific PI3K inhibition, but also avoided
side effects caused by systemic PI3K inhibition, thus offering a
novel effective strategy for tumor radiosensitization.
2.2.3. Synergy of PDT with RT
PDT, a potentially new approach to substitute conventional
cancer treatment methods, has attracted plentiful attention and
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Figure 7.  a) Schematic illustration of the synergistic gene therapy with RT for efficient radiosensitization by GdW10@CSsiRNA nanosphere. b) The
surviving fraction of BEL-7402 cells with various treatments, respectively. c) In vivo antitumor assay of BEL-7402 tumor-bearing mice after different
administrations. Adapted with permission.[17] Copyright 2017, American Chemical Society.

is widely researched in recent years. Its therapeutic mecha-
nism is as follow: when PSs are localized in cancer tissue, the
ground-state PSs molecules can be activated by appropriate
wavelength of light to induce ROS generation to destroy cancer
cells.[26,198–201] It is known that RT could also generate ROS
to damage DNA and cellular components. Hence, concurrent
integration of PDT with RT will remarkably increase the yield
of ROS than single RT, which destroy more cancer cells and
thus enhance the radiation effect.
The conventional nanomaterial-modulated PDT and RT
synergetic approaches need both the X-ray and laser as exci-
tation light source.[202–204] For example, Liu et al. employed
the PEGylated nanoscale metal organic framework (NMOF)
(NMOF-PEG) to achieve PDT/RT combined therapy under both
the X-ray and 661 nm laser exposure.[202] This nanoparticle com-
posed of Hf4+ and tetrakis (4-carboxyphenyl) porphyrin (TCPP)
PSs. Due to the strong X-ray absorbed ability of Hf4+ and effi-
cient singlet oxygen generation ability of TCPP PSs under laser
exposure, it was easy to realize PDT/RT synergistic treatment.
The study of in vivo therapy indicated that the mice treated
with NMOF-PEG + X-ray + laser showed remarkable inhibi-
tion of tumor growth, demonstrating the good treatment effect
of PDT/RT synergistic therapy than other mono-therapies. For
another example, Zhang et al. designed and fabricated a SnWO4
nanocrystal-conjugated upconversion nanoparticle (UCNP-
SnWO4). This nanoparticle could accomplish PDT/RT synergetic
treatment under both X-ray and 980 nm NIR light exposure.[204]
On the one hand, W and tin (Sn) (high Z atoms) with strong
X-ray attenuation capacity are excellent radiosensitizers. On the
other hand, SnWO4 could absorb the UV and blue light emitted
by the UCNP under 980 nm lasers and then was activated to
trigger the PDT process to generate ROS. Thus, the combina-
tion of the two processes would powerfully improve the ther-
apeutic efficiency. More interestingly, unlike traditional PSs
loading strategy that made plenty of molecular PSs to attach a
single UCNP core, which was not guaranteed that all PSs were
activated, this UCNP-SnWO4 nanocrystal was formed by using
amount of tiny UCNPs to covalently conjugate with one needle-
like SnWO4 core. Such an especial conformation allowed that
SnWO4 core was able to be activated by enough intensity of
UCNP-emitted light, and generate ROS in a “full-loaded” way,
which further boosted the treatment efficacy.
The aforementioned approach of nanoparticle-mediated PDT/
RT synergistic treatment requires both X-ray and laser irradiation
as excitation light source. Here, another effective and widely appli-
cable way that only need X-ray irradiation is introduced. It uses
scintillating nanoparticles to delivery PSs into tumors for PDT/
RT synergistic treatment. Because the scintillating nanoparticles
can transduce X-rays and/or γ-rays into visible lights and subse-
quently activate adjacent PSs, this synergistic process can achieve
under a single X-ray excitation source. This energy transfer idea
has been proposed by Chen et al. in 2006.[205] Shortly afterward,
they employed LaF3:Tb3+-meso-tetra(4-carboxyphenyl) porphine
nanoparticle conjugates to generate singlet oxygen following
X-ray irradiation, which was expected to be a promising thera-
peutic approach for deep cancer treatment.[206] Later, Zhang et al.
designed a core–shell Ce(III)-doped LiYF4@SiO2@ZnO-PEG
nanoparticles (SZNP) for combination of octahedral Ce(III)-doped

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Figure 8.  a) The scheme of the synthetic route of SZNPs and the mechanism of ionizing radiation-induced PDT. b) The change of relative tumor
volume of mice with time after different treatments. c) H&E staining of tumor tissue from mice after treatment with: i) saline, ii) SZNPs, iii) X-ray, and
iv) SZNPs + X-ray, respectively. Adapted with permission.[207] Copyright 2015, Wiley-VCH.

LiYF4 nanoscintillator (SCNP) with ZnO nanosemiconductor to
achieve PDT/RT synchronous treatment with reduced oxygen-
tension dependency.[207] As shown in Figure  8a, the SCNP was
excited by ionizing radiation and thus emitted lots of low-energy
photons for exciting ZnO surface-bound to form excitons
(the electron–hole pairs), and the excitons subsequently inter-
acted with water or O2 to obtain free radicals. Specially, the highly
biotoxic free radicals HO• were generated from the interaction
between the hole and water instead of O2, which diminished the
oxygen dependence for producing ROS. Meanwhile, ionizing radi-
ation had the intrinsic antitumor efficacy via directly interacting
with DNA or indirectly radiating water in tumors to produce
ROS to damage DNA. The two paths together afforded the syn-
ergy of PDT and RT for cancer treatment. As exhibited in animal
experiment (Figure 8b), when tumors treated with SZNPs + X-ray
radiation, the relative tumor volume were almost unchanged after
15 days, indicating the complete inhibition of tumor growth.
The result of hematoxylin and eosin (H&E) staining agreed well
with the tumor growth curve, which obviously indicated that the
tumor tissue was damaged after treating with SZNPs + X-ray
irradiation (Figure 8c). Recently, Clement et al. synthesized the
CeF3 nanoparticles conjugated with the verteporfin (VP) PSs via
electrostatic interaction. This nanoplatform was able to produce
singlet oxygen under X-ray irradiation.[208] This work experimen-
tally quantified the singlet oxygen quantum yield in scintillating
CeF3-VP conjugates as a result of the X-ray. The viability of pan-
creatic cancer cells treated with the nanoparticles and radiation
was clearly reduced, manifesting the good synergetic effect of
radiation-induced-PDT and RT by CeF3-VP conjugates. Most
recently, Lan et al. constructed the nanoscale metal–organic layers
(MOLs) for X-ray-induced PDT of colon cancer. The MOLs com-
posed by [Hf6O4(OH)4(HCO2)6] secondary building units (SBUs)
and [Ru(bpy)3]2+- or Ir[bpy(ppy)2]+-derived tricarboxylate ligands
(bpy = 2,2′-bipyridine, ppy = 2-phenylpyridine).[209] The Hf atoms
(high Z atom) could strong attenuate X-rays and transfer energy
to [Ru(bpy)3]2+ or Ir[bpy(ppy)2]+ ligands to induce PDT by pro-
ducing ROS, which availably afforded a superb anticancer efficacy
through PDT/RT synchronous treatment.
2.2.4. Synergy of PTT with RT
PTT has received wide application in recent years due to its
minimal invasion or noninvasion properties.[210] It utilizes

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heat generated from NIR optical absorbance agents to ablate
tumor.[113,211–213] Because of the minimal tissue absorption
and scattering within the NIR or biological window, NIR light
has greater depth of penetration in tissue, which is pivotal for
the utilization of PTT on biological cells and in vivo organ-
isms.[214–221] More interestingly, an appropriate level of hyper-
thermia generated by PTT can accelerate intratumoral blood
flow so as to improve the overall tumor oxygenation to over-
come the tumor hypoxia.[222] It is known that RT suffers from
resistance to hypoxic cells due to its oxygen dependence and
thus leads to anticancer failure. Therefore, when combing PTT
with RT, the heat generated from PTT can elevate the oxygen
level in cancer cells to make the cells more sensitive to radia-
tion, and thus the RT therapeutic effect is availably strength-
ened. Up to date, a large number of literatures about PTT and
RT synergetic therapy can be searched.[8,54,79,113,114,211,212,222–245]
And we roughly summarized the evolution trends of this syner-
getic strategy as follows.
Previously, nanomaterial-modulated synergetic PTT with RT
was achieved by decorating the photothermal agents on nano-
carriers. For example, Xiao et al. designed a multifunctional
core/satellite nanotheranostic (CSNT) through decorating
photothermal transducing agent ultrasmall CuS nanoparticles
onto the surface of silica-coated rare-earth upconversion nano­
particles.[222] The CuS nanoparticles absorbed NIR light and
converted it into heat for tumor thermal-ablation. Meanwhile,
the heat improved tumor oxygen and thus the RT treatment
effect was enhanced. Moreover, silica-coated rare-earth upcon-
version nanoparticles (NaYbF4: 2%Er3+/20%Gd3+@SiO2-NH2)
containing high Z elements also could induce a highly local-
ized radiation dose to strengthen radiation damage. Therefore,
CSNTs were the promising nanoplatform of PTT/RT syner-
gistic treatment for tumor radiosensitization.
Lately, the construction of nanocomposites by photothermal
transducing agents and radiation dose-enhancing agents
became another effective strategy for PTT/RT synergetic treat-
ment. For instance, Wang et al. integrated photothermal agent
MoS2 with radiation dose-enhancing agents Bi2S3 to form
MoS2/Bi2S3-PEG (MBP) composite nanosheets for cancer
therapy.[212] Among the MBP, the high X-ray attenuation effect
of Bi promoted the dose-enhancement during tumor RT, and
the strong NIR absorbance of MoS2 nanosheet framework
enabled the highly efficient photothermal ablation of tumors.
When the mice bearing 4T1 tumors were treated with MBP
nanosheets and subsequently exposed to 808 nm laser and
X-ray, a remarkable tumor therapeutic outcome of MBP
nanosheets could be obtained.
Recently, the nanomaterials that play both roles of photo-
thermal agents and radiosensitizers are widely researched due to
their multifunctional properties and simply synthetic methods,
such as Au,[223,224,227,231,239] WS2[8,113] Bi2S3,[114,233] Bi2Se3,[228,245]
ReS2,[240] Cu3BiS3,[236] and WO3−x[230] nanoparticles. The NIR
absorption ability of these nanoparticles allows them to act as
photothermal agents for producing significant heat to elimi-
nate tumor, and the high Z atom endows these nanoparticles
with the ability to serve as radiosensitizers for accumulating
more X-ray energy in cells. For example, Yong et al. reported
that ultra-small size WS2 dots could act as multifunctional
nanotheranostics for PTT/RT synergistic treatment.[8] The WS2
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dots were synthesized via a green and facile method of phys-
ical grinding and ultrasonication. For the in vitro experiment,
when the cells treated by WS2  + NIR + RT, it was obviously
observed that the cell survival fraction dramatically decreased.
Similarly, the mice treated with WS2 QDs + NIR + RT showed
the most efficient tumor growth delay. More worthy of men-
tion, the ultrasmall sizes WS2 QDs could be cleared out of the
body by renal excretions, greatly minimizing the side effects of
WS2 QDs to living organisms. For another example, as depicted
in Figure  9a, Wang et al. reported BSA-mediated synthesis of
Bi2S3 biocompatible nanoparticles for combined PTT/RT treat-
ments of cancers.[114] Attributing to the ultrasmall size and
good colloidal stability, the Bi2S3 nanoparticles possessed a long
blood circulation time and high tumor targeting ability, which
was greatly in favor of the therapeutic applications. As shown
in Figure 9b,c, the Bi2S3 nanoparticle-induced excellent PTT
and RT synergistic effects afforded the completely eradication
of tumors and 100% survival rate of tumor-bearing mice over
40 day after the treatments.
2.2.5. Trimodal Synergetic RT
Following the step of exploration for dual-modal synergetic cancer
RT, trimodal synergetic RT based on nanomaterials for tumor
radiosensitization has been gradually realized in recent years,
such as chemotherapy/PDT/RT,[246] chemotherapy/PTT/ RT[247]
and PTT/PDT/RT,[90,248,249] and so on. Fan et al. constructed the
sub-80 nm multifunctional rattle-structured Gd-UCNPs core/
mesoporous silica shell nanocomposites (UCMSNs) for the co-
delivery of hematoporphyrin (HP) and Dtxl to achieve chemo-
therapy/PDT/RT trimodal synergetic cancer therapy.[246] In this
UCMSNs-HP-Dtxl nanosystem, HP was applied as both PS and
radiosensitizer for PDT/RT synergetic therapy, and Dtxl was acted
as both chemotherapeutic agent and radiosensitizer for chemo-
therapy/RT synergetic therapy. As a result, such a UCMSNs-HP-
Dtxl nanosystem mediated trimodal synergetic therapy afforded
the complete tumor ablation. Recently, Qiu et al. employed single
ultrathin PVP-decorated W18O49 nanowires to realize PTT/PDT/
RT trimodal synergistic cancer therapy.[249] Three properties
endowed W18O49 nanowires with the above therapeutic func-
tions. First, W18O49 nanowire with high photothermal conver-
sion efficacy could serve as a photothermal agent.[250] Second,
the nanowires could be used as PSs to generate cytotoxic singlet
oxygen under the 980 nm laser excitation for PDT.[251] Third, the
high Z atom (W, Z = 74) enabled the nanowire with the potential
for local radiation dose enhancement. The In vivo experiments
showed the complete tumor clearance of mice treated with
W18O49  + NIR + RT after 4 days, and no recurrence within a 9
month follow-up, which demonstrated that trimodal PTT/PDT/
RT synergistic therapeutic effect between NIR-induced PDT/PTT
and RT was more available than that of RT therapy alone.
2.3. Radioprotection of Healthy Tissues by Nanomaterials for
Tumor Radiosensitization
When ionizing radiation is used for tumor treatment, the sur-
rounding healthy tissues may inevitably receive the radiation
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
Figure 9.  a) The scheme of synthetic process of BSA-stabilized Bi2S3 nanoparticles and the BSA-stabilized Bi2S3 nanoparticles for PTT/RT synergistic
therapy. b) The changes of relative tumor volume of mice with time under various treatments. c) The survival rates of mice after various treatments.
Adapted with permission.[114] Copyright 2016, Wiley-VCH.
energy, which leads to the side effects and thus decreases the
therapeutic ratio of RT. Therefore, the protection of healthy tis-
sues from the radiation-caused injury by nanoradioprotectors
to increase the radiotherapeutic ratio is another useful way
for nanomaterial-mediated tumor radiosensitization. Because
human tissues have 80% water, the major radiation damage is
caused by ROS generated from the interaction between water
and ionizing radiation.[252] Therefore, the general radioprotec-
tion reagents are free radical scavengers, which can scavenge
ROS in cells and thereby reduce the DNA damage. Up to now,
a lot of nanomaterials with free radical scavenge ability have
been reported, including graphene-based nanomaterials,[253,254]
fullerene-based nanomaterials,[255,256] bamboo charcoal nano­
particles,[257] graphdiyne nanoparticles,[258] cerium oxide
nanoparticles,[259–261] MoS2, WS2, WSe2, and Bi2Se3 nanoparti-
cles,[262–265] to name a few. Most of them have been utilized as
radioprotectors for radioprotection. As a paradigm example, Xie
et al. found that the biocompatible bamboo charcoal nanoparti-
cles have the potential applications in radioprotection.[257] They
evaluated the radioprotection activity of TPGS-functionalized
bamboo charcoal nanoparticles (TPGS-BCNPs) through the
intracellular ROS level assay and DNA damage assay (γ-H2AX
staining) in human umbilical vein endothelial cells (HUVECs).
It turned out that the intracellular ROS level and DNA damage
level of HUVECs in the TPGS-BCNPs + X-ray treated groups
were less than the single X-ray treated groups, revealing the
potential of TPGS-BCNPs on radiation protection of healthy
tissues. As another typical example, Zhang and co-workers
reported that cysteine-protected MoS2 and WS2 nanodots could
serve as radioprotectors due to their ROS scavenging ability in
vivo via the highly catalytic activity against H2O2 and O2.[262,263]
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The in vivo experiments indicated that surviving fraction of
mice was significantly increased under high-energy ionizing
radiation after the mice were treated with these quantum dots.
Moreover, the cysteine-protected MoS2 and WS2 nanodots could
protect the hematological system and DNA in bone marrow
cells of mice from high-energy rays. Furthermore, these
quantum dots could remove excessive 3,4-methylenedioxyam-
phetamine (MDA) and recover SOD in lung and liver of mice.
These results suggested that cysteine-protected MoS2 and WS2
nanodots have the potential to reduce radiation-caused injury
to normal organ and thus boost the therapeutic ratio of RT. In
addition, it is well known that Se is beneficial to human health
by involving in various important bioactivities, including radio-
protection. Based on this, Du et al. constructed a new versatile
radioprotector based on PVP- and selenocysteine (Sec)-mod-
ified Bi2Se3 nanoparticles (PVP-Bi2Se3@Sec NPs).[245] Particu-
larly, this Bi2Se3 nanoplatform could simultaneously enhance
RT efficacy in tumor and achieve radioprotection in healthy
tissues (Figure  10). On the one hand, the strong X-ray attenu-
ation ability of Bi atom and remarkable photothermal effect
of Bi2Se3 endowed this nanoplatform with the ability of PTT/
RT synergistic treatment. On the other hand, it is known that
Se could be incorporated into selenoproteins by the amino
acid Sec and subsequently catalyzed a wide range of electron-
transfer reactions for antioxidant defense and redox regulation
to reduce side-effects of RT for normal tissues. Therefore, the
traces of Se, which released from the PVP-Bi2Se3@Sec NPs
and entered the blood circulation system, could increase the
immune function (such as enhancing the SOD and GSH-Px
activity, improving the cytokines level, up-regulating number
of white blood cells and reducing marrow DNA suppression)
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
Figure 10.  Scheme of the therapeutic principle for simultaneously radiosensitization and radioprotection by PVP-Bi2Se3@Sec nanoparticles. Adapted
with permission.[245] Copyright 2017, Wiley-VCH.
and reduce the side-effects of ionizing radiation in body. Con-
sequently, the PVP-Bi2Se3@Sec NPs provided a promising
platform to simultaneously enhance RT in tumor and protect
normal tissue from radiation-induced side effect, which avail-
ably increased the radiotherapeutic ratio and thus accomplished
tumor radiosensitization.
3. The Clinical Translation of Nanomaterial-
Mediated Tumor Radiosensitization
For the sake of ultrasmall size and tailorable versatile physico-
chemical properties, nanomaterial and its related nanomedicine
is the emerging field utilized in clinic biomedical applications
to improve human health, especially in cancer diagnosis and
treatment. Over the last two decades, many prominent exam-
ples of multifunctional nanotheranostics have been used to
conquer kinds of cancer. The past decade has witnessed a dra-
matic increase in interest in the use of nanoparticles as radio-
sensitizers for RT. Herein, we want to analyze the state of art
of promising nanoradiosensitizers as well as their translation
from bench to bedside.
Nanomedicines are undergoing clinical translation for RT.
At present, some nanoradiosensitizers, especially the inorganic
nanoradiosensitizers, have made gratifying breakthroughs and
entered clinical trials for cancer RT (Table  1). Compared with
organic nanomaterials, there is some skepticism that inorganic
compounds are the underdog and hardly applied in biomedi-
cine. However, in recent years, some inorganic nanomate-
rials have been demonstrated to be promising candidates for
the enhancement of cancer radiation treatment. For example,
French company Nanobiotix developed a nanoradiosensitizer
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named NBTXR3, whose effective radiation sensitizing ingre-
dient is HfO2 nanoparticles.[266–270] HfO2 is relatively chem-
ical inert in biological media, which reduce its biotoxicity and
encourage its biomedical use. After being functionalized with
a negative surface charge, this nanosphere with average dia­
meter about 50 nm can be stabilized in an aqueous solution
at pH between 6 and 8.[268,271] More importantly, Hf is a high
Z atom (Z = 72), which enables it to be used as radiosensitive
agent.[266] HfO2 nanoparticles can serve as a radiosensitizer by
physical mechanism.[270,272] When HfO2 enters the tumor tis-
sues and is activated by external radiation beam, it can emit
high energy electrons and increase the electron density depos-
ited within irradiated tissues, resulting that the dose of X-ray
delivered to the tumor is magnified while the dose passing
through healthy tissues remains unchanged. This physical
interaction among high energy photons, HfO2 nanoparticles
and cancer cells can promote the generation of cytotoxic free
radicals and other ROS to destroy cancer cells through double-
stranded DNA damage,[266] and thus lead to the inhibition
of tumor growth. In addition, Monte Carlo simulation also
find that NBTXR3 enhances radiation doses ninefolds when
compared to water exposure alone.[268] The first human trial
showed that preoperative NBTXR3 with external beam RT is
a technically feasible therapeutic approach that yields encour-
aging radiological and pathologic responses in patients with
locally advanced soft tissue sarcoma of the extremity and trunk
wall.[272] In the stage of clinical trials, NBTXR3 has shown
better antitumor performance to many types of cancers, such as
soft tissue sarcoma (ClinicalTrials.gov; NCT02379845),[272–274]
head and neck cancer (NCT02901483),[6] prostate cancer
(NCT02805894),[275] rectal cancer (NCT02465593),[272] and liver
cancer (NCT02721056),[272] just to name a few.
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
Table 1.  Clinical translation of some nanoradiosensitizers.
Name ClinicalTrials.gov identifier Condition or disease
NBTXR3 NCT02721056 Liver cancer
NCT02805894 Prostate cancer
NCT01946867 Head and neck cancer
NCT01433068 Adult soft tissue sarcoma
NCT02379845 Adult soft tissue sarcoma
NCT02901483 Head and neck squamous cell carcinoma
NCT02465593 Rectal cancer
AGuIX NCT03308604 Gynecologic cancer
NCT02820454 Brain metastases
In addition, Tillement and co-workers find a nanoradiosen-
sitizer AGuIX to enhance the sensitization of brain tumor cells
to radiation.[276,277] This ultrasmall AGuIX nanoparticle displays
hydrodynamic diameters inferior to 5 nm, indicating that it can
be excreted through the kidney and avoiding biosafety prob-
lems. AGuIX is composed of Gd chelated polysiloxane, and
its chemical composition is anticipated to be Gd10Si40C200N50
O150Hx.[277–279] Gd resulted in a strong interaction with X-rays
and an increase of RT efficacy.[280] In addition, AGuIX can be
accumulated in tumoral tissue due to EPR effect,[281] further
promoting the RT efficacy. Preclinical animal experiments
show that AGuIX locally enhance the effect of RT in a variety
of tumor models and exert no significant toxicity to mice and
monkeys.[277,282] Several phases I clinical trials are ongoing in
patients with brain metastases (NCT02820454) to enhance the
sensitization of brain metastatic tumor cells to radiation.[283]
Also, AGuIX nanoparticles also have the potential to treat cer-
vical and liver cancer.[277,284] The safety, tolerability of doses
of AGuIX in combination with radiation and CDDP-based
chemotherapy in patients with locally advanced cervical cancer
are being evaluated in phase 1 clinical trials (NCT03308604).
Besides, according to the information of NH TherAguix com-
pany, the potential indications of AGuIX also include lung
cancer, esophageal carcinoma, head and neck tumor.
4. Conclusions and Future Perspectives
The rapid development and application of emerging advanced
nanomaterials in biomedicine provides a good opportunity to
enhance the efficiency of RT treatment. In this review, we sys-
tematically summarize the general strategies and corresponding
mechanisms of nanomaterial-mediated tumor radiosensitiza-
tion. It mainly consists of three aspects. The first is on account
of the intrinsic radiosensitive properties of nanoradiosensitizers
selves, which includes enhancing ionizing radiation energy dep-
osition, promoting ROS generation and modulating the TME to
make tumor more sensitive to radiation. The second is nanoma-
terial-mediated synergistic RT, which uses the nanoparticles to
load and delivery the radiosensitive drugs into tumor for cancer
treatment. These drugs can not only exert its own drug func-
tion, but also make cells more susceptible to radiation-induced
damage through different mechanisms. The third is to reduce
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side effects of normal organ by nanoradiopro-
tectors, which protects healthy tissues from
Clinical trial phase radiation-caused injury to improve the radio-
Phase I/II therapeutic ratio. Moreover, we also discuss
Phase I/II
the clinical translation of nanoparticle-medi-
ated radiosensitization. It is clear that the
Phase I
challenges still exist in the clinical translation
Phase I of the nanomaterials for RT enhancement
Phase II/III that we have to face and tackle:
Phase I/II
Phase I/II
1) The systematical investigations of the biosafety
and metabolism in vivo of nanomaterials. Owing
Phase I
to the relative large size and slow biodegrad-
Phase I able ability, nanoparticles have a relative longer
systemic circulation time and lower metabo-
lism rate than that of molecular drugs, which
endows the nanoparticles with enough time to exert their ther-
apeutic function in vivo. However, these characters are also
easy to induce their long-term retention and accumulation in
body and thus may cause harm to health. Therefore, the sys-
tematical investigations of their biosafety and metabolism in
vivo are vitally important to evaluate the prospect of their ra-
diosensitization applications. First, for the biosafety, although
short-term toxicity and biodistribution of nanomaterials have
been studied in some efforts, their long-term biological effects
and potential biosafety are largely unexplored.[285] Meanwhile,
due to plenty of the nanomaterials studied at the present stage
contain heavy metal elements, which have toxicity to a certain
extent, it is necessary to find more and better ways to reduce
their toxicity and improve their biocompatibility (such as the
utilization of suitable surface modifiers). Then, for the metas-
bolism issue, many of the nanomaterials are faced with the
problem of slower biodegradation compared to molecular
drugs. Accordingly, the efforts are needed to appropriately
improve the metabolic capacity of nanomaterials and/or
design and fabricate the new types of easily biodegradable
nano­materials. For instance, it can prepare the nanoparticles
with ultrasmall size to make them clear out of the body by
renal excretions. Moreover, the studies on clearance pathway,
immune behavior and other biological effects are still insuffi-
cient. Therefore, all these issues are of significance and should
be put in the first place to investigate so as to satisfy its future
radiosensitization application in the clinic.
2) The optimization of the physicochemical properties of nano­
materials for RT enhancement. In general, so many factors,
such as the composition, shape, size, synthesis method, sur-
face functional modification, and doses of nanoradiosensitiz-
ers, can affect the sensitization effect of RT. For instance, as
mentioned above, different size of Au-based nanoparticles
can lead to the different radiosensitive effect.[44,51,59] Moreover,
shape-dependent radiosensitive effect of Au nanostructures
was also reported.[58] Therefore, it is important to compare the
radiosensitive efficacy of nanomaterials with different phys-
icochemical parameters, and gain the optimal conditions to
obtain satisfying RT efficiency.
3) The deeper exploration of the mechanisms of radiosensitiza­
tion. Human organism is a complex system that numerous
physical, chemical and biological factors will influence the RT
efficiency when nanomaterials entered tumor region. Until
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com
now, researchers have devoted numerous efforts to explain the
mechanisms of various kinds of radiosensitization approach-
es, but most of the mechanisms are still limited at cellular
level, and the mechanisms that deep into molecular levels are
still rare. Therefore, it is necessary to deeper understand ra-
diosensitization mechanisms at molecular or gene levels.
4) The exploration of the optimal modality of synergistic RT. Al-
though there are various combined modalities for each kind
of synergistic RT, we cannot randomly combine these thera-
peutic strategies together, because the random combination
may not get the optimal synergistic anticancer efficiency. For
example, when we use PTT/RT for cancer treatment, whether
we offer NIR laser before X-ray or offer X-ray before NIR laser
or offer NIR laser and X-ray simultaneously, it still requires
us to explore thoroughly and choose the most suitable modal-
ity to get the optimal therapeutic efficiency. Therefore, it still
needs to spare no effort to find the optimal synergistic modal-
ity of synergistic RT.
5) The establishment of standardization of nanoradiosensitizers de­
sign and fabrication to satisfy the clinical translation. The bio-
logical effects and toxicological characteristics are drastically
different between nanodrug and molecular drugs for vary of
physical and chemical properties when they enter biological
tissue. Therefore, to make the nanoradiosensitizers suitable
for clinic translation, rationally preclinical protocols are ex-
traordinary demanded, and the guidance as well as stand-
ardization for nanoradiosensitizers design and fabrication
should be established.
6) The promotion of clinical translation of nanoradiosensitizers.
The current status of the development of nanoradiosensitiz-
ers is too many papers but too few clinic anticancer drugs.
The clinic translation of nanoradiosensitizers remains in a
dilemma. Therefore, efforts are needed to facilitate the clini-
cal translation of nanoradiosensitizers. In the era of nano-
medicine, this emerging and promising interdisciplinary
filed full of hope and will further promote the application of
nanomedicine for RT enhancement.
Acknowledgements
J.X. and L.G. contributed equally to this work. This work was supported
by the National Basic Research Program of China (2016YFA0201600,
2015CB932104), National Natural Science Foundation of China
(51772292, 31571015, 11621505, 11435002, and 21320102003), Youth
Innovation Promotion Association CAS (2013007), and Key Research
Program of Frontier Sciences CAS (QYZDJ-SSW-SLH022).
Conflict of Interest
The authors declare no conflict of interest.
Keywords
clinical translation, nanomaterial-mediated radiosensitization,
nanoradiosensitizers, radioprotection, synergistic radiotherapy
Received: April 9, 2018
Revised: June 8, 2018
Published online:
Adv. Mater. 2018, 1802244 1802244  (20 of 25)
www.advmat.de
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