Combined hyperthermia and chemotherapy

as a synergistic anticancer treatment

Dai Cao Phung, Hanh Thuy Nguyen, Thi

Thu Phuong Tran, Sung Giu Jin, Chul
Soon Yong, Duy Hieu Truong, Tuan
Hiep Tran & Jong Oh Kim
Journal of Pharmaceutical
Investigation

ISSN 2093-5552
Volume 49
Number 5

J. Pharm. Investig. (2019) 49:519-526

DOI 10.1007/s40005-019-00431-5

1 23
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 Author's personal copy
Journal of Pharmaceutical Investigation (2019) 49:519–526 Online ISSN 2093-6214
https://doi.org/10.1007/s40005-019-00431-5 Print ISSN 2093-5552

REVIEW

Combined hyperthermia and chemotherapy as a synergistic

anticancer treatment
Dai Cao Phung1 · Hanh Thuy Nguyen1 · Thi Thu Phuong Tran2 · Sung Giu Jin3 · Chul Soon Yong1 · Duy Hieu Truong4 ·
Tuan Hiep Tran5,6 · Jong Oh Kim1 

Received: 15 October 2018 / Accepted: 6 March 2019 / Published online: 19 March 2019
© The Korean Society of Pharmaceutical Sciences and Technology 2019

Abstract
To date, hyperthermia and chemotherapy have been widely investigated in the field of anticancer nanomedicine. However,
in many cases, the efficacy of monotherapies have been limited owing to the heterogeneity of cancers and the acquired drug
resistance. Noteworthy, hyperthermia has been demonstrated to offer numerous advantages when integrated with chemo-
therapy in nanoplatforms, namely increased accumulation of drugs in tumor site, enhanced cellular uptake, inhibition of
DNA repair, and accelerated drug cytotoxicity against cancer cells. These evidences suggest a promising anticancer syner-
gistic effect of hyperthermia and chemotherapy. This review will discuss the underlying mechanisms of action of chemo-
hyperthermia combination therapy, and especially the strategies of design of advanced nanocarriers to effectively co-deliver
hyperthermia and chemotherapeutic agents to the tumor based on various types of materials.

Keywords  Hyperthermia · Chemotherapy · Nanomedicine · Combined therapy

Introduction

Expanded knowledge on cancer at different levels, including

molecular, cellular, and physiological levels, has promoted a
Dai Cao Phung and Hanh Thuy Nguyen contributed equally. tremendous progress in cancer treatment in the last decade
(Kemp et al. 2016). In a clinical point of view, surgical inter-
* Duy Hieu Truong vention, radiation therapy, and chemotherapy are reliable
truongduyhieu@duytan.edu.vn
treatment options that may provide great hope for cancer
* Tuan Hiep Tran patients (Hu et al. 2016). In addition, surgery followed by
trantuanhiep@tdt.edu.vn
radiation therapy appears to be a good combined therapy for
* Jong Oh Kim managing developed tumors. However, apart from inoper-
jongohkim@yu.ac.kr
able cancerous tissue, the spread of cancer cells from the
1
College of Pharmacy, Yeungnam University, 280 Daehak‑ro, primary organ to the whole body has also been reported as
Gyeongsan 38541, Republic of Korea a severe problem in surgical treatment, and preservation of
2
The Institute of Molecular Genetics of Montpellier, CNRS, adjacent healthy cells is not possible in radiation therapy.
Montpellier, France Chemotherapy is considered a new hope for cancer treat-
3
Department of Pharmaceutical Engineering, Dankook ment owing to its efficacy and convenience, but it still has
University, 119 Dandae‑ro, Dongnam‑gu, Cheonan 31116, a long journey to achieve satisfactory outcomes because it
Republic of Korea is accompanied by side effects associated with overdose,
4
Institute of Research and Development, Duy Tan University, genetic heterogeneity of cancers, and drug resistance (Teo
Da Nang, Vietnam et al. 2016).
5
Department for Management of Science and Technology Developments in nanotechnology, particularly nanomedi-
Development, Ton Duc Thang University, Ho Chi Minh City, cine, offer a potential solution for anticancer treatment, in
Vietnam
which a nanovehicle carries multiple components for diag-
6
Faculty of Pharmacy, Ton Duc Thang University, nosis and therapeutic purposes (Liang et al. 2016). This
Ho Chi Minh City, Vietnam

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advanced technique has inspired researchers to integrate
many combination models, such as dual chemotherapy,
chemotherapy, and gene therapy (He et al. 2016; Kemp
et al. 2016). In this review, hyperthermia combined with
chemotherapy is reported as a promising trend in the field
of innovative combined anticancer therapy.
Enhancement of chemotherapy
through combination with hyperthermia
Hyperthermia has been developed as an anticancer treat-
ment for several decades. This therapy involves high-tem-
perature-induced changes in cells, particularly cancer cells.
Normal cells can tolerate a temperature of up to 42–45 °C,
whereas cancerous cells are more vulnerable to this condi-
tion (Hervault and Thanh 2014). In fact, at a temperature
that high, cancer cells start to undergo apoptosis, which
allows easy, natural elimination of cancer cells. Cancer
cells become more vulnerable at a temperature of 46 °C;
they will be destroyed by the heat, which is a process called
thermoablation, and undergo necrosis. The mechanisms
underlying the direct thermoablation and death of cancer
cells at high temperature remain to be elucidated. Several
studies have reported that denaturation of membrane and
cytoplasmic proteins could be considered the cause of cell
destruction (Lepock 2003). Moreover, oxygen and nutrient
deprivation may also occur because the damaged structure of
tumor vasculature at high temperature leads to fluctuation in
tumor microenvironmental factors, which ultimately results
in cell death. Currently, magnetic fluid hyperthermia (MFH)
and photothermal therapy (PTT) are the major hyperther-
mic strategies for treating cancer. MFH employs an external
alternative magnetic field (AMF) to navigate magnetic nano-
particles to various directions, which then followed by heat
release, whereas PTT uses photo-absorbing agents to convert
light to heat, inducing thermal ablation and subsequent death
of cancer cells. Considering the advantages of hyperther-
mia carriers, many researchers have developed methods to
integrate them with chemotherapy in order to improve the
efficacy of chemotherapy (Cheng et al. 2014). The published
mechanism of the chemotherapy-promoting effect of hyper-
thermia is worth re-mentioning. In detail, besides directly
ablating cancer cells, heat may also trigger drug release,
especially in cases of thermosensitive vehicles. Thus, an
anticancer drug can be controlled to release at a designated
position such that normal cells can be saved, whereas can-
cer cells can be specifically killed. On the contrary, heat
can also provide more energy for the carriers to boost their
interaction with the cell membrane. Energy-dependent path-
ways, including the clathrin- and caveolae-mediated endo-
cytosis and micropinocytosis, are involved in the increase
of cell membrane permeability at high temperature, thereby
13
D. C. Phung et al.
increasing the internalization of drugs and carriers (Cheng
et al. 2014).
Combination of photothermal therapy
and chemotherapy
PTT is established on the basis of photo-absorbing agents
that absorb energy from light and convert it to heat. In order
to penetrate deeply into biological tissues and effectively
generate heat, PTT must be supported by photothermal
agents that exhibit high absorbance in the near-infrared
(NIR) region. Moreover, to improve therapeutic efficacy, the
safety of the surrounding cells should also be considered. In
the following subsections, we provide a broad picture of the
improvement of chemotherapy through combination with
PTT using various types of nanomaterials.
Inorganic substance‑based nanomaterials
Gold‑based nanomaterials
Owing to its cytotoxic effect, gold nanorod (GNR) surface
was modified to strengthen not only its stability but also its
targeting moiety (Choi et al. 2012; Dickerson et al. 2008).
In addition, the shell covering of GNR could be utilized
as a multifunctional chamber for carrying anticancer drugs.
The most commonly used technique involves introduction
of poly(ethylene glycol) on the surface via 11-mercaptound-
ecanoic acid. The PEG layer could prolong the existence of
drug carriers in the physiological system and consequently
support drugs, such as paclitaxel, to efficiently kill cancer
cells. Moreover, NIR laser plays an important role as the
generator of heat for directly ablating the cells and indi-
rectly supporting burst release of the drug (Ren et al. 2013).
Another option that could be considered is a mixture of
GNR and drug-loaded nanoparticles inside a gel. An inject-
able nanocomposite hydrogel containing PEGylated GNRs
and paclitaxel-loaded chitosan polymeric micelles (PTX-M)
was intratumorally injected under exposure to laser irradia-
tion. PTX-M/GNR/gel provided the solution in sustaining
and localizing drug to the tumor then eliminating tumors
cells productively (Zhang et al. 2016).
In this point of view, several studies reported a polymer
that covalently binds to the GNR surface (Chen et al. 2013;
Peralta et al. 2015). After the binding, a drug is able to incor-
porate into the polymer matrix via hydrophobic interaction.
Peralta et al. attached human serum albumin into the outer
layer of GNR, whereby paclitaxel can be localized. After
15 min of NIR light (λ = 808 nm; power intensity = 2 W/
cm2) irradiation to PAC-AuNR-HSAPs-treated cancer cells,
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Combined hyperthermia and chemotherapy as a synergistic anticancer treatment 521

~ 94% of the cells was killed, whereas without irradiation, nanoparticles, forming Se@Au@mSiO2, which could be
only ~ 82% was killed (Peralta et al. 2015). a multifunctional nanoplatform for combined application
In another approach, the polymer layer is simply grafted with chemotherapeutic, chemoprevention, and photother-
onto the GNR surface by hydrophobic and electrostatic mal therapies (Fig.  1a). The triple combination therapy
interaction, whereby a drug is similarly dispersed. In detail, using Se@Au@mSiO2/DOX nanoparticles exhibited an
core/shell hybrid nanospheres were fabricated with GNR as enhanced anticancer efficacy for treating metastatic breast
the core and poly(N-isopropyl acrylamide-co-methacrylic cancer (Ramasamy et al. 2018).
acid) as the shell, followed by the addition of 5-fluorouracil Gold nanoshells (GNSs) are fabricated essentially
(5-FU) by electrostatic interactions. This system was char- through the seed-mediated growth method in which small
acterized and confirmed to be pH and temperature-sensitive.
The cumulative release of 5-FU from the nanospheres was
observed to be markedly increased in a mild acidic medium
and greater under NIR light irradiation (808 nm), which
subsequently inhibit tumor growth in vitro and in vivo (Jin
et al. 2015).
The electrostatic interaction concept also was employed
using the layer by layer technique. Hollow microcapsules
loaded with GNRs were multi-layered using chitosan as a
cationic polymer and sodium alginate as an anionic poly-
mer. Next, for targeting purposes, the carrier was conjugated
with folic acid, which can release doxorubicin (DOX) at a
higher rate at high temperature. Similar to heat-induced cell
death, FA-MC@GNRs/DOX is a promising design strat-
egy for tumor-targeted imaging and synergistic combined
therapy (Chen et al. 2015). Li et al. (2014) was interested
in attaching a drug on a GNR-polymer hybrid carrier via a
covalent bond. Specifically, poly(ethylene glycol)-attached
PAMAM G4 dendrimers (PEG@PAMAM) were first
covalently linked to the surface of mercaptohexadecanoic
acid-functionalized gold nanorod (MHA-AuNR), and this
was followed by conjugation of the anticancer drug DOX
to the dendrimer layer using an acid-labile-hydrazone link-
age to obtain PEG@DOX@PAMAM@AuNR particles.
The release of the drug is dramatically improved following
induction of acidic environment and heat generated by NIR
laser irradiation. The carrier exhibited great performance
in inhibiting cancerous cell growth in vitro and in vivo,
showing the synergistic effect of photothermal ablation and
chemotherapy (Li et al. 2014).
Beside polymers, mesoporous silica is also very com-
monly used as a platform for carrying drugs (Monem et al.
2014; Poudel et al. 2018; Ramasamy et al. 2018; Shen et al.
2013; Tang et al. 2012; Zhang et al. 2012). A mesoporous Fig. 1  a Schematic presentation of selenium-capped Au@mSiO2/
DOX (Se@Au@mSiO2/DOX) for NIR-responsive chemo-photo-
silica-capped gold nanorod (Au@mSiO2) was synthesized thermal therapy (Ramasamy et  al. 2018, licensed under a Creative
via a single-step coating method, and CTAB molecules on Commons Attribution 4.0 International License). b Schematic illus-
the surface of the GNRs served as an organic template for tration of multifunctional drug-loaded gold nanoshells for synergistic
the deposition of a mesoporous silica coating. The large, cancer therapy. The novel nanostructure comprises three key parts to
achieve multidimensional therapeutic efficacy: (1) an anti-EGFR anti-
specific surface area of mesoporous silica guarantees a high body, cetuximab (CET), as a targeting moiety and signal transduction
drug-payload, whereas GNR provides heat following NIR inhibitor, (2) a gold nanoshell possessing a photothermal effect due to
exposure. Their integration paves the road for drug delivery plasmon resonance upon illumination by NIR laser, and (3) DOX as a
in response to thermo/near-infrared laser irradiation with chemotherapeutic agent. These three components, which are incorpo-
rated into PLGA nanoparticles, provide synergistic tumoricidal effi-
improved therapeutic efficacy. Furthermore, the surface of cacy (Yang et al. 2009) (Reprinted with permission from Yang et al.
GNRs could be functionalized by nano-selenium overcoat 2009. Copyright© 2009 John Wiley and Sons)

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522 D. C. Phung et al.

seed GNPs are attached to the dielectric core and then grown and II windows, individual uses of CNT as a photothermal
to form a shell via reduction process. By modifying the ratio carrier (Moon et al. 2009) and drug delivery system (Liu
of core radius to shell thickness, the plasmonic properties of et al. 2009) are well-known. Afterward, many researchers
the carrier could be adjusted for light of certain wavelength have reported impressive results of the combination of both
(Hwang et al. 2014). In this concept of structure, the drug is uses. Zhang et al. coated single walled carbon nanotubes
loaded to the inner template before the gold shell is grown (SWCNT) by Evans Blue (EB), an azo dye that can bind
outside. Yang et al. incorporated DOX into PLGA nano- to mixture of albumin/PTX at high affinity. The SWCNT/
particles as a template and used cetuximab as a therapeutic EB/albumin/PTX exhibited strong NIR absorbance and
and targeting moiety (Fig. 1b). Combined chemotherapy and achieved the chemo/thermal therapeutic effect. To restrain
photothermal therapy can be applied to this system for treat- tumor growth, the system released heat and drug more effec-
ing human epithelial cancer systemically and locally (Yang tively than chemo- or photothermal therapy alone (Zhang
et al. 2009). Using similar strategy, Wang et al. recruited et al. 2015). In contrast, Wang et al. used CNT with tumor-
polyethyleneimine-b-poly(2- diisopropylamino/2-mercap- targeting peptide and DOX to generate a drug delivery sys-
toethylamine) ethyl aspartate as a polymer template and fur- tem (Fig. 2a). The effect this combined therapy with drug
ther evaluated the effect of the carrier in vivo using DOX and heat on the cell in vitro and in vivo was investigated in
and photo-heat converted by GNSs (Wang et al. 2016b). comparison with individual therapies. The heat generated
In another design, Liu and Wang employed mesoporous
silica as a drug-loaded core (Liu et al. 2011a; Wang et al.
2016a). The controllable NIR plasmonic GNSs are able to
internalize cancer cell or tumor region, and then generate
heat for ablation and drug release, indicating a synergistic
effect. Taking advantages of lipid for loading hydrophobic
drugs, Luo et al. developed cancer targeting photothermal
and pH-responsive nanocarriers, GNS-coated oleanolic acid
liposomes (GNOLs) mediated by chitosan. The NIR assisted
drug release can be easily and selectively activated locally
because the light is controllable spatially and in real-time.
The experimental results verified that the GNOLs with NIR
irradiation achieved more potent antitumor effects in vitro
and in vivo than those of other oleanolic acid formulations
(Luo et al. 2016).

Carbon based‑nanomaterials

Since their discovery, carbon-based materials have gained

prominent attention in nanotechnology development. Among
them, ­sp2 bonded carbons, such as graphene oxide (GO)
and carbon nanotube (CNT), possess a great potential of
application in nanomedicine (Liu et al. 2011b). GO and CNT
can penetrate cells via endocytosis. Hence, they could be
a promising carrier for delivering drugs to kill cancerous
cells. In addition, they are able to convert energy from NIR
laser to heat, which is useful for PTT (Shen et al. 2012). The
hydrophobic nature of carbon-based materials with workable
functional groups allowed drugs to bind to their surface via
hydrophobic interaction and covalent conjugation. Moreo-
ver, those functional groups can also be modified with poly-
mers or targeting moieties, which can improve the aqueous Fig. 2  a The preparation method of the SWNT-PEI and SWNT-PEI/
solubility and efficacy of the carriers in the body (Valentini DOX/NGR drug delivery systems (Wang et  al. 2013) (Reprinted
et al. 2013). with permission from Wang et  al. 2013. Copyright© 2013 Springer
CNT has attracted interest for application in detection, Nature). b Schematic diagram showing the antitumor activity of dual
drug-loaded graphene oxide (doxorubicin and irinotecan-loaded GO;
monitoring and therapy of diseases including cancer. Owing GO-DI) (Tran et  al. 2015) (Reprinted with permission from Tran
to the broad absorbance spectrum, covering both the NIR I et al. 2015. Copyright© 2015 American Chemical Society)

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Combined hyperthermia and chemotherapy as a synergistic anticancer treatment 523
under NIR laser irradiation not only directly ablated cancer
cells but also induced a burst of drug release, resulting in
extraordinary therapeutic effect (Wang et al. 2013).
On the contrary, GO sheets with unique physical and
chemical properties have attracted tremendous attention
since 2004. Several years later, the number of publications
on this strategy has dramatically increased with the expan-
sion of its bio-application, including drug delivery, cancer
therapies, and biosensing (Feng and Liu 2011). Feng et al.
developed GO in conjugation with two types of polymers,
biocompatible polyethylene glycol (PEG) and positively
charged poly(allylamine hydrochloride) (PAH). This pro-
carrier was subsequently modified with 2,3-dimethylmaleic
anhydride (DA), which is negatively charged to maintain
stability at physiological pH of 7.4, but is positively charged
in acidic environment. This unique property could enhance
the uptake of a carrier into cells, leading to a higher car-
rier activity. Besides photothermal effect, the system also
improved therapeutic treatment (Feng et al. 2014).
The advantage of chemotherapy and photothermal ther-
apy could be elevated to the next level with a “dual in dual”
concept. In detail, each therapy can be fabricated as a pro-
combination, such as dual drugs and photothermal therapy,
dual-photothermal therapies, or chemotherapy. Thapa et al.
successfully developed DOX-loaded, lateral, nanodimen-
sional (~ 53.0 nm), zwitterion-coated gold-graphene oxide
stealth nanoparticles through a vibrating nozzle approach
(AuGO@ZC-DOX) to combine chemo-photothermal ther-
apy for cancer treatment (Thapa et al. 2018a). The nano-
platforms showed acidic microenvironment-responsive DOX
release profiles, minimized macrophage opsonization, and
strong conversion of NIR light to heat, resulting in promis-
ing anticancer effect in a PANC-1 xenograft mouse model.
Furthermore, the vibrating nozzle approach shows great
potential for efficient built-to-order manufacturing of mul-
tifunctional nanotherapeutics.
In another study, Gautam et al. developed an on-demand,
scalable nanoplatform that incorporated titanium peroxide
Fig. 3  Schematic illustration of CuS@Gel–DOX NPs for combined PAT imaging, tumor-selective chemotherapy and PTT (Zha et  al. 2013)
(Reprinted with permission from Zha et al. 2013. Copyright© 2013 Royal Society of Chemistry)
(yTiO2), GO, DOX (D), and PEG (P) in a spray to form
GO-yTiO2@DP (Gautam et al. 2018). The continuous-flow
production of multifunctional nanocarriers by the aero-
hydro-aero approach without interruption could improve
drug-loading and provide an appropriate combination for
chemo-phototherapy. GO-yTiO2@DP showed greater drug
release and higher photothermal activity than those of GO@
DP formulation, leading to higher anticancer efficiency
both in vitro and in vivo (Gautam et al. 2018). Using other
approach, we recruited the synergistic effect of DOX and
irinotecan as dual drugs to a system with GO as a template.
Dual drug-loaded GO in combination with laser irradiation
caused higher cytotoxicity than that caused by the adminis-
tration of a free single drug as well as of a combination of
drugs and blank GO in various cancer cells, especially in
MDA-MB-231 resistant breast cancer cells (Fig. 2b). Moreo-
ver, the system affected intrinsic signals that activate several
cell death pathways instead of only causing thermo-ablation
(Tran et al. 2015).
Other inorganic materials
CuS nanoparticles have been revealed to be a potential
platform of photothermal therapy. Currently, researchers
are attempting to improve their effect by adding anticancer
drugs. CuS nanoparticles were incorporated into the tem-
plate along with drugs. Zha et al. stabilized CuS with DOX-
conjugated gelatin (Fig. 3). The uniform gel exhibited an
excellent performance in generating heat under irradiation
with NIR laser and releasing drugs to kill cancer cells. The
synergistic effect of chemo-thermo therapies was reported to
be superior than that of each therapy alone (Zha et al. 2013).
In a more recent study, Lu et  al. proposed the stable
and highly dispensed PEGylated mesoporous silica-coated
copper sulfide nanocomposites in aqueous solution. The
formulated nanoparticles were later equipped with DOX,
which is dramatically released following NIR exposure. The
results of in vitro cytotoxicity testing indicated that these
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524
nanocomposites have potential biomedical applications (Lu
et al. 2015). The photothermal-chemo therapies also inspired
chemists to develop many other materials that have poten-
tials to generate NIR-induced heat and incorporate drugs,
such as PEGylated ­MoS2 nanosheets (Liu et al. 2014), Pd
nanosheet-covered hollow mesoporous silica nanoparticles
(Fang et al. 2012), Pd nanoparticles-decorated GO (Thapa
et al. 2018b), and bismuth selenide nano spherical-sponge
(Li et al. 2016).
Organic substance‑based materials
In the other side of the material science field, organic materi-
als are considered as photothermal agents. These materials,
alone or in combination, provide scientists with more options
to maximize their efficacy and minimize their adverse effect.
In the past decades, cyanine derivatives have been investi-
gated mainly as dyes for fluorescent imaging. Those deriva-
tives strongly absorb light in the NIR region and convert
light energy to heat. These organic dyes, including indocya-
nine (ICG), IR780, and IR825, are usually deposited on the
liposome, polymer, and mesoporous silica nanoparticles, and
subsequently used as photothermal agent. In a recent study,
Nguyen et al. fabricated a temperature-sensitive liposome
containing docetaxel as an anticancer drug and ICG as a
photothermal agent (Fig. 4). This system not only enhanced
the stability of ICG but also employed it effectively to gener-
ate heat. The resulting increase in temperature was reported
to improve drug release in the presence of NIR laser irra-
diation. Ultimately, heat induced by NIR exposure and the
localized docetaxel burst release directly ablated and killed
cancer cells via apoptosis in vitro and in vivo (Nguyen et al.
2017). Chen and co-workers recognized the natural binding
Fig. 4  Schematic illustration of the combined antitumor activity of
hyperthermia and chemotherapy using low temperature-sensitive
liposome (LTSL) containing docetaxel (DOC) and indocyanine green
(ICG) (Nguyen et al. 2017) (Reprinted with permission from Nguyen
et al. 2017. Copyright© 2017 Tayer & Francis Online)
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D. C. Phung et al.
of polydopamine nanospheres (PDAs) to iron ion and fab-
ricated a carrier with high-efficiency photothermal con-
version. PDA complex was introduced not only to directly
damage tumors by heat but also to manipulate DOX release
by controlling an on-demand, NIR-responsive delivery of
chemotherapy (Chen et al. 2016).
Magnetic nanomaterials‑based
hyperthermia combined with chemotherapy
Magnetic hyperthermia was induced through dynamic
response of magnetic particles to an external AMF. The
mechanisms include relaxation and hysteresis loss. The
relaxation, including Néel and Brownian relaxation, induced
heat generation by changing the direction of magnetic
moments relative to crystal lattice (internal dynamics) and
physical rotation of particles within an environment medium
(external dynamics), respectively (Bai et al. 2014). For effec-
tive hyperthermia therapy, magnetic nanoparticles should be
distributed at a sufficient concentration to the cancer site.
Thermo-responsive polymers and lipids are popular materi-
als for fabricating thermo-chemo therapies. At very first state
of this strategy, Pradhan et al. designed a carrier with com-
bined biological and physical effects, which employs heat-
inducing magnetic nanoparticles and DOX. Attracted by
the external force of magnetic field, the carrier was able to
travel to tumor site and then interact with the cell membrane
via folate receptor. AMF-induced increase in temperature
resulted in direct cell death and controlled drug release, kill-
ing cancer cells (Pradhan et al. 2010). In a more recent study,
Li et al. designed a cancer cell-specific-targeting magnetite
nanocrystal core with polynucleotide shell, which carried
5-fluorouracil (5-FU) and anti-human epidermal growth fac-
tor receptor 2 (anti-HER2) antibody. The carrier could reach
80 °C after 50 s of irradiation in magnetic field in vitro,
leading to a strong drug release. This synergistic effect of
hyperthermia-induced ablation and drug release promoted
tumor remission in vivo (Li et al. 2013).
Conclusions
In this review, an overview of combined anticancer treat-
ment with hyperthermia and chemotherapy has been sum-
marized. Development of material engineering continues
to foster more-advanced ideas, one of which is the syner-
gistic use of heat and chemotherapy for treating cancer.
Although significant advancements have made, several
limitations with respect to these nanosystems are yet to
be addressed. Similar to other nanosystems, those carri-
ers need to be optimized to overcome product-process-
ing period and physiological barriers, such as long-term
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Combined hyperthermia and chemotherapy as a synergistic anticancer treatment 525
physical stability, matching in vitro–in vivo profiles, pro-
longed in vivo lifespan, tumor accumulation, and intracel-
lular delivery in tumor cells. In this specific concept, the
other concern should be taken care is the potential safety
of carriers, particularly the un-biodegradable ones which
could be harmful for extended periods of time after admin-
istration. In term of photothermal therapy, the scientists
also have to face limited light penetration depth of NIR
laser that could leave them out of body door. While the
required high concentration of magnetic nanoparticle and
radio frequency raised another concern from the sight of
clinic. The key advantage of this combination is the suffi-
cient accumulation of carriers in tumor cells, which allows
subsequent stimulation of hyperthermia by an external fac-
tor and release of chemotherapy. Along with advancing
individual therapy, imagine-guiding may serve as a useful
tool for determining the distribution and kinetics of carri-
ers within the body. Finally, although further studies need
to be conducted, the co-delivery system of hyperthermia
and chemotherapy holds a great prospect. It is worthwhile
to invest much more attention and effort in this efficient
combined cancer treatment.
Acknowledgements  This research was supported by National Research
Foundation of Korea (NRF) Grants funded by the Korea government
(MSIP) (No. 2018R1A2A2A05021143) and by the Medical Research
Center Program (2015R1A5A2009124) through the NRF funded by
MSIP.
Compliance with ethical standards  tothermal therapy. Colloids Surf B Biointerfaces 128:498–505
Conflict of interest  All authors declare that they have no conflict of
interest.
Human and animal rights  This article does not contain any studies with
human and animal subjects performed by any of the authors.
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