RESEARCH ARTICLE

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One-Minute Preparation of Iron Foam-Drug Implant for

Ultralow-Power Magnetic Hyperthermia-Based Combination
Therapy of Tumors in Vivo
Guangchao Xie, Bingjie Li, Xuejun Zhang, Jiaojiao Yu, and Shao-Kai Sun*

1. Introduction
The magnetic hyperthermia-based combination therapy (MHCT) is a powerful
tumor treatment approach due to its unlimited tissue penetration depth and Magnetic hyperthermia therapy (MHT)
is a promising thermal therapy method
synergistic therapeutic effect. However, strong magnetic hyperthermia and
for tumors, which has the merits of low
facile drug loading are incompatible with current MHCT platforms. Herein, an invasiveness, minimal side effects, and
iron foam (IF)-drug implant is established in an ultra-facile and universal way excellent tissue penetration, and has re-
for ultralow-power MHCT of tumors in vivo for the first time. The IF-drug alized great progress in fundamental
implant is fabricated by simply immersing IF in a drug solution at an research and clinical trials.[1] However, the
adjustable concentration for 1 min. Continuous metal structure of IF enables high temperature is essential for a single
MHT to eradicate tumors, which increases
ultra-high efficient magnetic hyperthermia based on eddy current thermal
the risk of potential damage to adjacent
effect, and its porous feature provides great space for loading various tissue.[2] In addition, the therapeutic effect
hydrophilic and hydrophobic drugs via “capillary action”. In addition, the IF of a single MHT is not ideal for whole
has the merits of low cost, customizable size and shape, and good tumor tissue due to its inhomogeneous
biocompatibility and biodegradability, benefiting reproducible and large-scale distribution of temperature.[3] To solve
these problems, tremendous efforts have
preparation of IF-drug implants for biological application. As a proof of
been devoted to magnetic hyperthermia-
concept, IF-doxorubicin (IF-DOX) is used for combined tumor treatment in based combination therapy (MHCT) by
vivo and achieves excellent therapeutic efficacy at a magnetic field intensity combining MHT with chemotherapy,
an order of magnitude lower than the threshold for biosafety application. The immunotherapy, and others, which has
proposed IF-drug implant provides a handy and universal method for the been regarded as a promising synergistic
fabrication of MHCT platforms for ultralow-power combination therapy. therapeutic strategy.[4] The MHCT not only
facilitates complete tumor eradication at
lower magnetic field intensities and smaller
drug doses, but also minimizes damage to surrounding healthy
tissues, thereby yielding a highly effective treatment outcome
while mitigating side effects.[1a,5]
G. Xie
Department of Diagnostic and Therapeutic Ultrasonography The current MHCT platforms can be divided into two cat-
Tianjin Medical University Cancer Institute and Hospital egories: magnetic nanoparticles (NPs) and liquid/solid metal
National Clinical Research Center of Cancer implant-based platforms.[1a,5–6] For the former, magnetic NPs
Key Laboratory of Cancer Prevention and Therapy (e.g., Fe3 O4 NPs, Fe2 O3 NPs, and Fe NPs) were synthesized with
Tianjin 300060, China
adjustable morphology and size, and their high specific surface
G. Xie, X. Zhang, J. Yu, S.-K. Sun
School of Medical Imaging area enabled highly efficient drug loading.[7] However, despite
Tianjin Medical University the elaborated design, tedious synthesis process, harsh reaction
Tianjin 300203, China conditions, and complex post-modifications, the magnetic NPs,
E-mail: shaokaisun@tmu.edu.cn which generate magnetic hyperthermia based on relaxation
B. Li loss and hysteresis loss mechanisms, can hardly own high
Department of Radiology and Tianjin Key Laboratory of Functional Imaging
magnetothermal capability.[8] As a result, repeated administra-
Tianjin Medical University General Hospital
Tianjin 300052, China tions and high-power alternating magnetic fields (AMF) are
required in magnetic NPs-based MHCT, severely hindering its
The ORCID identification number(s) for the author(s) of this article biological application. In contrast, metal implants with large size
can be found under https://doi.org/10.1002/advs.202307823 (millimeter-scale) and continuous metal structures can generate
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH. huge heat through eddy current thermal effect even in low-power
This is an open access article under the terms of the Creative Commons AMF, thus exhibiting powerful magnetothermal capability.[6g,9]
Attribution License, which permits use, distribution and reproduction in However, metal implants with dense structures and small spe-
any medium, provided the original work is properly cited.
cific surface areas often require further complex corrosion or
DOI: 10.1002/advs.202307823

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Scheme 1. Schematic illustration of 1-min preparation of iron foam-drug implant for ultralow-power MHCT of tumors in vivo. Upper panel: comparison
of different magnetic hyperthermia materials in terms of drug loading capability and magnetic hyperthermia capability. Magnetic nanoparticles: facile
drug loading process (√), low magnetothermal heating efficiency (×). Solid metal implant: complex drug loading process (×), high magnetothermal
heating efficiency (√). Iron foam implant: facile drug loading process (√), high magnetothermal heating efficiency (√).

electroplating strategies to achieve a limited drug loading, which
greatly increases the difficulty and reduces the efficiency of drug
loading. Therefore, it is urgent to develop a universal MHCT plat-
form with superior magnetothermal properties and convenient
and efficient drug-loading capability for tumor treatment.
Iron foam (IF) is a zero-valent iron block with a uniform
porous structure and is widely used in the fields of tail gas
purification, battery electrodes, electromagnetic wave shielding,
and biological scaffolds.[10] Continuous metal structure of IF
enables highly efficient magnetic hyperthermia like solid metal
based on eddy current thermal effect. Moreover, its abundant
pore structure provides a huge space for drug loading in a
simple adsorption method. Furthermore, it has the advantages
of low cost, customizable size and shape, and superior scale
production capability. Additionally, iron performs many impor-
tant physiological functions in the human body as an essential
trace element, ensuring the biosafety of IF for application in
vivo.[11] Besides, implant therapy is an indispensable treatment
method in clinics for tumor patients who must preserve vital
functional tissues, lose the opportunity or value of surgery, and
refuse radical surgery.[12] Therefore, IF with a porous structure
is expected to be an excellent substitute for magnetic NPs and
solid metal implants for MHCT.
Herein, the IF-drug implant was fabricated as a universal
platform for ultralow-power MHCT of tumors in vivo (Scheme
1). The implant was synthesized by immersing commercial
IF in the drug solution based on the “capillary action”, and
this preparation process can be finished in 1 min without the
need for any special equipment and conditions. The ultra-fast
and straightforward drug loading process, 1-min preparation,
significantly reduces energy and time consumption, enabling
this method to be used in a ready-to-use manner. The IF can
be employed to load various drugs including hydrophilic and
hydrophobic cargoes high efficiently, and drug loading had a
neglectable influence on magnetothermal capacity. Moreover,
IF has the advantages of low cost, customizable size and shape,
superior scale production capability, benefiting reproducible
and facile fabrication of various IF-drug implants. As a proof
of concept, the clinical chemotherapeutic drug of doxorubicin
(DOX) was selected to construct IF-DOX implant for in vivo
application. The IF-DOX implant achieved efficient combined
magnetic hyperthermia and chemotherapy efficacy of tumors in

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Figure 1. a) SEM image of IF. b) Photos of IF (2 × 2 × 2 mm) in DOX solution before and after shaking. c) Relationship between DOX loading mass of
IF and DOX solution concentration. d) Loading mass of IF for different drugs. e) Thermal images of IF with different sizes in AMF at different times. f)
Heating curves of IF with different sizes in AMF at different times. g) Heating and cooling curves of IF (2 × 2 × 2 mm) in AMF for 4 cycles. h) Heating
curves of IF-PBS (2 × 2 × 2 mm) and IF-DOX (2 × 2 × 2 mm) in AMF. i) Degradation rate of IF (2 × 2 × 2 mm) in H2 O and saline.

vivo under an ultralow-power magnetic field intensity (Happl ·fappl
= 3.78 × 108 A m−1 s−1 ) successfully, which is an order of magni-
tude lower than the threshold for biosafety application (Happl ·fappl
= 5 × 109 A m−1 s−1 ).[13] As far as we know, this is the first time
that the unification of exceptionally high magnetic hyperthermia
capacity and ultra-facile drug loading has been achieved.
2. Results and Discussion
2.1. Preparation and Characterization of IF-Drug Implant
Commercial IF has the merits of low cost, reproducible prepa-
ration, superior large-scale production capability, and can be
commercially customized according to the needs of the com-
position, size, and shape. As shown in Figure S1 (Supporting
Information), three kinds of IF cubes with different sizes were
customized in this experiment (2 × 2 × 2 mm, 2.5 × 2.5 × 2.5 mm,
and 3 × 3 × 3 mm), and the porosity was as high as 92.5%. The
scanning electron microscope (SEM) images of IF showed a
continuous network-like structure with micrometer-level pores,
which provides a huge space for loading cargo (Figure 1a). Due
to the continuous metal structure, the IF has a good electrical
conductivity of ≈2.11 х 105 S m−1 and can act as a good connector
in the circuit (Figure S2, Supporting Information), endowing
the generation of huge heat in an AMF through eddy thermal
effect. The IF can float on the surface after putting it into
liquid (DOX:6 mg mL−1 and water) due to its porous structure
(Figure 1b; Figure S3, Supporting Information), and they sink
quickly as liquid enters the internal pores of IF slightly shaking.
As IF possesses pores on the scale of several hundred microm-
eters, its mechanism for drug loading relies on the capillary
action of these pores with the solution. This is in contrast to

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the drug adsorption process in porous materials with nanosized
pores, which typically involves various physical and chemical in-
teractions between the porous materials and drug molecules. As
shown in Figure S4 (Supporting Information), the concentration
of the drug solution remained unaltered pre- and post-loading,
thereby confirming that IF facilitates drug loading through
simple capillary action. The liquid absorbed by IF can be stably
stored in the internal pores, and will not flow out casually (Figure
S5, Supporting Information). This phenomenon indicated IF
was capable of absorbing the surrounding liquid in a short time
based on the capillary action just like a sponge absorbs water.
The kinetics of liquid loading of IF (2 × 2 × 2 mm) was investi-
gated to understand the kinetics involved in loading various cargo
solutions into IF by the mass difference method. Figure S6 (Sup-
porting Information) shows that IF can quickly adsorb the liquid
and reach a stable state by immersing IF in water for 30 s, which
indicates IF has great potential in loading any drugs dissolved in
liquid. To investigate drug loading efficiency, different concen-
trations of DOX solutions were used to synthesize IF-DOX im-
plants, and the amounts of loaded DOX were quantified by UV–
vis absorption. As shown in Figure 1c, the DOX loading mass
in IF-DOX implant increased linearly with the enhancement of
DOX solution concentration. When the concentration of DOX
solution was 6 mg mL−1 (approach to its solubility), one IF can
load ≈48.21 μg of DOX. Besides the hydrophilic drugs like DOX,
there are many hydrophobic drugs in the clinic, and they can
be easily loaded in IF by dissolving them in individually biosafe
and benign solvents (PBS, dilute NaOH, water, ethanol, and oleic
acid) in the same manner. Totally, we studied the loading abil-
ity of IF toward various drugs including five chemotherapeutic
drugs and two immunoregulator drugs. As shown in Figure 1d,
one IF (2 × 2 × 2 mm) can load ≈313.12 μg Ara-C, 300.11 μg
PTX, 25.37 μg 5-FU, 154.77 μg R837, and 2.02 mg Mn2+ , respec-
tively. It is worth noting that solvents such as PBS (pH 6), dilute
NaOH (pH 8.5), H2 O, and oleic acid have good biosafety, and
the constructed IF-drug can be directly transplanted into living
organisms. When the solvent was ethanol, the constructed IF-
drug implant can be used after drying at room temperature. In
addition, Figure S7 (Supporting Information) demonstrates that
different IFs (2 × 2 × 2 mm) can load drugs with similar mass,
with a relative standard deviation (RSD) of 1.98%, proving the
excellent drug-loading reproducibility of IFs. These results indi-
cated IF can serve as a high-performance and universal carrier to
quantitatively load hydrophilic and hydrophobic drugs according
to the actual needs by simply tuning the concentration of drug
solution in a short time (1 min). The larger the solubility of the
drug, the higher the loading capacity of IF for the drug, so a high
drug loading capability can be achieved by dissolving the drugs
in benign and biosafe media.
Unlike the drug-loaded nanoparticles, which are intravenously
injected into the body and then will flow into the bloodstream,
the IF-DOX implant will be enveloped closely by the tumor tis-
sue after being implanted into the tumor site. Therefore, we in-
vestigate the release behavior of DOX in vitro by embedding the
IF-DOX implant into pork tissue. As shown in Figure S8 (Sup-
porting Information), half of the loaded DOX was released from
the IF-DOX implant in the pork tissue in the first 10 min, and
the majority of the remaining DOX was gradually released in 3 h.
Compared to the burst release of DOX in IF-DOX implant in so-
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lution, the IF-DOX implant exhibited a controlled release manner
due to the coating of surrounding tissues, which was beneficial
for local treatment.
2.2. Magnetothermal Performance of IF
Different from the traditional magnetic NPs which mainly pro-
duce heat through relaxation loss and hysteresis loss, IF with
a continuous metal structure generates heat mainly through
an efficient eddy current loss mechanism in AMF.[9c] First,
magnetothermal heating performance of IF with different sizes
was studied at an ultralow AMF (an order of magnitude
lower than the threshold for biosafety application (Happl ·fappl =
5 × 109 A m−1 s−1 )).[13] As shown in Figure 1e,f, the mag-
netic heating effect was obviously enhanced with the increase
of IF size in an ultralow magnetic field intensity (Happl ·fappl =
1.44 × 108 A m−1 s−1 ). The temperature of IF cubes with sides
of 2, 2.5, and 3 mm was raised by 26.3, 59.7, and 78.1 °C within
3 min, respectively. In addition, with the increase of magnetic
field intensity, the heating efficiency of IF was enhanced obvi-
ously. It is worth noting that even the smallest IF (2 × 2 × 2 mm)
showed a remarkable temperature increase by 93 °C within 3 min
under the condition of Happl ·fappl = 3.78 × 108 A m−1 s−1 (Figure
S9, Supporting Information). These results demonstrate that IF
had an outstanding magnetic heating efficiency. Besides, the sta-
bility of the heating capacity was studied by repeated heating and
cooling processes at an AMF (Happl ·fappl = 3.78 × 108 A m−1 s−1 ).
Figure 1g shows that there is no decline in elevated temperature
during four cycles, which proves good magnetothermal heating
stability of IF. Moreover, Figure S10 (Supporting Information)
shows that these different IFs (2 × 2 × 2 mm) exhibited similar
magnetothermal heating change under the same magnetic field
condition, with an RSD of 3.16%, which indicated the IF had ex-
cellent reproducibility of magnetothermal heating. Furthermore,
compared with CoFe2 O4 nanoparticles, one of the best magnetic
nanomaterials with good magnetocaloric effect reported in a pre-
vious study,[1b] whether they were in powder state or immersed
in H2 O IF both showed significantly better magnetothermal heat-
ing ability at the same magnetic field condition (Figure S11, Sup-
porting Information).
The unique advantage of MHT is the excellent tissue penetra-
tion depth.[1d] The magnetothermal heating capability of IF in
deep tissue was evaluated using fresh pig liver to reflect the tem-
perature change. As shown in Figure S12 (Supporting Informa-
tion), the color of the center at pig liver tissue with IF implant
changed from dark red to white after being heated in AMF for
6 min, which indicated the MHT with IF was capable of penetrat-
ing tissue deeply. However, in the PBS-injection group, there was
no color change in the center of the pig liver after heating in AMF
with the same power and time. In addition, the color of the ther-
mochromic material around the IF changed from light pink to
amaranth after heating in AMF, while free thermochromic ma-
terial had no obvious color change (Figure S13, Supporting In-
formation). These results proved that IF-based MHT exhibited
excellent tissue penetration ability.
Considering the large amount of liquid present in IF after
the formation of the IF-drug implant, we further evaluated the
magnetothermal performance of IF-PBS. The result indicated
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the IF-PBS also exhibits an excellent magnetothermal capability,
and the temperature evaluation can reach as high as 70 °C within
3 min under the condition of Happl ·fappl = 3.78 × 108 A m−1 s−1
(Figure 1h). Moreover, the magnetothermal performance of
IF-DOX implant after loading DOX was nearly the same as
that of IF-PBS, indicating that loading drugs did not affect the
heating of IF. These results proved that IF owned ultrahigh
efficient heating efficiency, excellent tissue penetration ability,
and good magnetothermal stability regardless of loading cargoes
or not, and had great potential for further biological application.
2.3. Degradation of IF in Vitro
To investigate the degradation of IF in vitro, IF was incubated in
water and saline. A large amount of flocculent rust was gener-
ated gradually indicating the degradation of IF during 60 days.
Quantitative analysis results revealed that IF (2 × 2 × 2 mm) de-
graded by 25.36% and 23.45% in water and saline, respectively
(Figure 1i). These results demonstrate that IF has good degrad-
ability in vitro.
2.4. Cytotoxicity of IF
Cytotoxicity of IF was evaluated using 4T1 cells by standard MTT
assay. Small magnets were placed on the outer side of the wells
to make IF stick to the inner side of the 96-well plates to avoid
mechanical compression damage caused by the weight of IF dur-
ing the incubation process (Figure S14, Supporting Information).
The cell viability of treated cells was over 81% after incubating
with one IF (2 × 2 × 2 mm) for 24 h, which demonstrated the low
cell toxicity of IF (Figure S15, Supporting Information).
2.5. Combination Therapy of Tumor Cells Using IF-DOX Implant
To investigate the therapeutic efficacy of IF-DOX in vitro, the vi-
abilities of 4T1 cells were determined after various treatments:
i) PBS, ii) PBS+AMF, iii) IF-PBS, iv) DOX, v) IF-DOX, vi) IF-
PBS+AMF, vii) IF-DOX+AMF. During the heating process in
AMF, the temperature of the PBS+AMF group did not rise
significantly, while the temperature of IF-PBS+AMF and IF-
DOX+AMF groups increased by ≈30 °C in 7 min (Figure 2a,b).
These results revealed the combination of IF and AMF can lead to
an obvious magnetothermal effect at the cellular level. The MTT
assay results revealed that almost all the cells were alive in the
PBS+AMF group, and 88% of cells survived in the IF-PBS group
(Figure 2c). However, there was significant cell death in the DOX,
IF-DOX, and IF-PBS+AMF groups, and only 60%, 57%, and 56%
of cells were alive, respectively. In contrast, only 25% of the cells
survived in the IF-DOX+AMF group, which proved that IF-DOX
had an excellent combined therapeutic effect of magnetic hyper-
thermia and chemotherapy on tumor cells. In addition, to study
the combined therapeutic effect of IF-DOX at the cellular level
more directly, the cells after different treatments were stained
with calcein-AM and PI. The fluorescent images indicated the IF-
DOX+AMF treatment led to the most obvious cell death among
these groups (Figure 2d). Moreover, the apoptosis of the cells af-
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ter different treatment were evaluated by flow cytometer after in-
cubation with Annexin V-FITC. As shown in Figure 2e, mod-
erate cell apoptosis can be found in the DOX group, IF-DOX
group, and IF-PBS+AMF group, and significant cell apoptosis
occurred in IF-DOX+AMF owing to the combined therapeutic
effect. These results indicated that IF-DOX implant in AMF pro-
vided highly efficient combined treatment efficacy at the cellular
level.
2.6. Biocompatibility Assessment of IF in Vivo
The in vivo biocompatibility of IF was evaluated on Kunming
mice through blood analysis, histopathological examination,
body weight monitoring, and degradation study. After being
treated with the IF implant, the serum biochemical indicators
of liver and kidney function of mice were all in the physiologi-
cal range and had no significant difference compared to those of
the blank group (Figure 3a). Furthermore, the indicators of blood
routine in the IF-implantation group were all at normal levels,
and there was no significant difference between the experimental
group and the control group (Figure S16, Supporting Informa-
tion). Inflammatory markers including tumor necrosis factor-𝛼
(TNF-𝛼) and interleukin-6 (IL-6) in serum did not significantly in-
crease, and the white blood cell count remained at a normal level,
which indicated that implantation of IF did not cause an obvious
inflammatory response (Figure S17, Supporting Information).
Moreover, there was no obvious difference in tumor markers of
alpha-fetoprotein (AFP) and carcino-embryonic antigen (CEA) in
the experimental group compared with the control group, which
revealed that IF did not exhibit tumorigenic effect (Figure S18,
Supporting Information). In addition, the hematoxylin and eosin
(H&E) staining images revealed that there was no obvious patho-
logical change in the major organs of mice treated with IF im-
plant (Figure 3b). Besides, there was no obvious difference in
body weight change between the IF-implantation group and the
blank group within 60 days (Figure 3c). At last, on the 60th day,
the IF implants in mice were collected, cleaned with water, and
dried. It could be seen that there was obvious rust on the surface
of the IF implant, and part of it became soft obviously (Figure 3d),
which indicated IF can degrade in vivo gradually. The quantita-
tive analysis by ICP-OES indicated IF degraded by ≈28% after
implantation in the body for 60 days (Figure S19, Supporting In-
formation). The above results indicated the IF implant had good
biocompatibility and could be used for various biological applica-
tions in vivo.
2.7. Computed Tomography (CT) Imaging of IF in the Tumor
Owing to the high density of iron in the IF implant, it has a
strong X-ray absorption ability, which makes it possible to en-
sure the successful implantation of the IF implant in the tumor
by CT imaging. To evaluate the CT imaging performance of IF
implants, IF-PBS and IF-DOX implants were implanted in the
tumors of mice, and the imaging of mice was performed using a
clinical CT scanner. The CT images showed that IF has good CT
imaging ability and the position of IF in the tumors can be seen
very clearly, which enabled CT imaging-guided MHCT (Figure 4).
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Figure 2. a) Thermal images of 4T1 cells with various operations. b) Heating curves of 4T1 cells with various operations. c) Cell viability of 4T1 cells after
various operations. Statistical analysis was determined by one-way ANOVA; **** p < 0.0001. d) Fluorescence images of 4T1 cells after various operations.
e) Cell apoptosis status of 4T1 cells analyzed by flow cytometry.

2.8. Drug Release of IF-Drug in Vivo
Indocyanine green (ICG) with intense near-infrared (NIR) flu-
orescence was employed as a model drug to replace DOX to
evaluate the drug release from IF-drug implant in vivo. Fluo-
rescent imaging revealed that ICG consistently maintained a
high retention effect throughout the 72-h period due to the
controlled release from the implant and dense structure of tu-
mor tissue, and then slowly diffused out of the tumor tis-
sue as time progressed (Figure S20, Supporting Information).
These results indicated the drugs in IF-drug implants could
efficiently accumulate within the tumor, facilitating an effec-
tive therapeutic outcome while reducing potential toxic side
effects.

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Figure 3. a) Serum biochemical indicators of Kunming mice after subcutaneous implantation of IF at various times. b) H&E staining results of vital
organs of Kunming mice after subdermal implantation of IF at different times. c) Body weight change of Kunming mice after subdermal implantation of
IF at different times. d) SEM images of IF dissected from Kunming mice after subdermal implantation at various times.

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Figure 4. CT images of mice before and after intratumoral implantation of a) IF-PBS and b)IF-DOX in tumor.
2.9. Combination of Magnetic Hyperthermia and Chemotherapy
Using IF-DOX for Tumors in Vivo
To assess the combined therapeutic effect of IF-DOX implant
of tumors, 4T1 tumor-bearing mice were exposed to various
treatments including: i) PBS, ii) PBS+AMF, iii) Sham, iv) IF-
PBS, v) DOX, vi) IF-DOX, vii) IF-PBS+AMF, viii) IF-DOX+AMF
(Figure 5a). The MHT in vivo
was performed under an ultralow-power magnetic field
(Happl ·fappl = 3.78 × 108 A m−1 s−1 ), which was an order of mag-
nitude lower than the threshold value of biosafety applications
(Happl ·fappl = 5 × 109 A m−1 s−1 ).[13] As shown in Figure 5b,c,
the temperature of the tumor surface increased by ≈18 °C in the
IF-PBS+AMF and IF-DOX +AMF groups, while there was no
obvious temperature elevation for tumors in PBS+AMF group
exposed to the AMF, indicating the excellent magnetothermal
performance of IF in vivo. Then the sizes of tumors in vari-
ous groups were monitored for 15 days. Figure 5d-g shows that
there is no significant tumor inhibition effect in Sham group,
PBS+AMF group, and IF-PBS group. The DOX group, IF-DOX
group, and IF-PBS+AMF group showed significant tumor sup-
pression but did not result in complete tumor elimination. In
contrast, the tumors in the IF-DOX+AMF group were destroyed
seriously and most of them were completely eliminated, which
proved that IF-DOX had an excellent combined therapeutic ef-
ficacy. In addition, Figure S21 (Supporting Information) shows
that the tumors treated in the IF+DOX+AMF group were elim-
inated, which exhibited a similar therapeutic effect compared to
IF-DOX+AMF. Nevertheless, the treatment of IF+DOX+AMF
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will involve two operations when applied in deep tissues. More
importantly, this strategy can hardly be used in tumor treatment
with hydrophobic drugs. Therefore, IF-DOX+AMF is a superior
strategy for tumor treatment compared to IF+DOX+AMF. Be-
sides, there was no significant alteration observed in the mass of
IF before and after treatment, thereby suggesting that a certain
degree of heating does not exert any influence on the structural
integrity of IF (Figure S22, Supporting Information). The above
results confirmed that the IF-DOX implant can serve as an excel-
lent MHCT platform for ultralow-power magnetic hyperthermia
and chemotherapy of tumors in vivo.
3. Conclusion
In summary, we developed 1-min preparation of IF-drug implant
for ultralow-power MHCT of tumors in vivo. The continuous
metal structure of IF guaranteed highly efficient magnetother-
mal capability based on the eddy current loss mechanism, and
its porous structure enabled loading drugs in an ultra-facile man-
ner via capillary action. In addition, IF has the merits of low cost,
customizable size and shape, superior scale production capabil-
ity, and good biocompatibility and biodegradability. More impor-
tantly, The IF-drug implant is a universal platform capable of
loading various hydrophilic and hydrophobic drugs by choosing
appropriate and biosafe solvents. Besides, the intense X-ray at-
tenuation capability of IF makes it a CT imaging visible implant.
We took IF-DOX as an example to investigate the therapeutic ef-
fect of IF-drug implants in vivo and achieved CT imaging-guided
highly efficient combination therapy of tumors under an ultralow
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Figure 5. a) Schematic diagram of combined magnetothermal therapy and chemotherapy for tumors using IF-DOX in vivo. b) Thermal images of 4T1
tumor-bearing mice with different operations. c) Heating curves of 4T1 tumor-bearing mice with different operations. d) Representative photos of 4T1
tumor-bearing mice with various operations for 15 days. e) Photos of tumors dissected from mice with different treatments on the 15th day. f) Tumor
growth curves of mice after various operations for 15 days. g) The weight of tumors dissected from mice after different treatments on the 15th day.
Statistical analysis was determined by one-way ANOVA; **** p < 0.0001, ** p < 0.01, and * p < 0.5.

magnetic field intensity. Our proposed IF-drug implant solves the
incompatible problem of highly efficient magnetic hyperthermia
and facile drug loading and lays down a convenient and universal
MHCT platform for tumor therapy in vivo.
4. Experimental Section
Reagents and Materials: The ultrapure water used throughout the
studies was provided by Hangzhou Wahaha Group Co., LTD. (Hangzhou,
China). Doxorubicin hydrochloride (DOX), paclitaxel (PTX), cytarabine
(Ara-C), 5-fluorouracil (5-FU), imiquimod (R837), and manganese chlo-
ride (MnCl2 ·4H2 O) were provided by Shanghai Aladdin Reagent Co., LTD.
(Shanghai, China). Iron foam (IF) was bought from Kunshan Jiayisheng
Electronics Co., LTD. (Kunshan, China). Thermochromic material was ob-
tained from Shenzhen HUANCAIBS Co., LTD. (Shenzhen, China).
Characterization of IF: The morphological and structural characteris-
tics of IF were observed by scanning electron microscopy (SEM, Zeiss,
Germany). The electrical conductivity of IF was characterized by a physical
property measurement system (PPMS-9, America). The drug loading abil-
ity of IF was determined by UV–vis absorption spectra by a UV-3600 plus
spectrophotometer (Shimadzu, Japan). The mass of Mn2+ loaded with IF
was quantified by an inductively coupled plasma optical emission spec-
trometer (ICP-OES, Thermo Fisher, Germany). The temperature monitor-
ing of IF was determined by a thermal camera (Teledyne FLIR, America).
Preparation of IF-Drug: To investigate the kinetics of liquid loading of
IF (2 × 2 × 2 mm) by the mass difference method, the mass of IFs was
weighed and divided into two groups. In one group, the IFs were immersed
in water by gently shaking and incubated for 30 s, 1, 3, 5, and 10 min. In the
other group, the IF was exposed to ultrasonic treatment for 30 s, 1, 3, 5, and
10 min after immersing them in water. Finally, IFs with different treatments
were collected and weighed, and the mass difference of IF before and after
treatment was determined.

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The drug loading capability of IF (2 × 2 × 2 mm) was investigated by
immersing the IF (2 × 2 × 2 mm) in DOX solution with different concen-
trations (PBS, pH 6; 0, 1, 2, 3, 4, and 6 mg mL−1 ) for 1 min. Then the IF
was taken out and added in 3 mL PBS to release the loading DOX. The
relationship between the drug loading mass of IF and drug concentration
was determined by UV–vis absorption spectra.
To investigate the loading capability of IF for different drugs
(chemotherapeutic drugs: Ara-C, PTX, 5-FU, immunoregulator drugs:
R837, Mn2+ ), the IFs (2 × 2 × 2 mm) were added into the drug solutions
with high concentrations and gently shaken for 1 min (Ara-C solution
(H2 O, 40 mg mL−1 ), PTX solution (ethanol, 40 mg mL−1 ), 5-FU solution
(dilute NaOH, pH 8.5, 3 mg mL−1 ), R837 solution (oleic acid, 50 °C,
20 mg mL−1 ), MnCl2 ·4H2 O (1000 mg mL−1 )). Then the IFs were removed
from the drug solutions and placed in 3 mL of corresponding solvents,
and gently shaken to release the drugs in IFs. The mass of each drug that
IF can load was measured by the UV–vis absorption spectra (Ara-C, PTX,
5-FU, R837) and ICP-OES (Mn2+ ).
To investigate the reproducibility of drug loading of IF, the IF
(2 × 2 × 2 mm) was immersed in DOX solution (PBS, pH 6, 6 mg mL−1 )
for 1 min. Then the IF was taken out and added in 3 mL PBS to release the
loading DOX. The drug loading mass of IF was determined by absorption
spectra. The drug loading experiment was repeated 8 times.
Drug Release of IF-Drug Implant in Vitro: To investigate the drug re-
lease of IF-drug implant in vitro, the IFs (2 × 2 × 2 mm) were immersed in
DOX solution (PBS, pH 6, 6 mg mL−1 ) for 1 min, and then the IF-DOX im-
plant was taken out and implanted in pork tissue for different time (0, 10,
30 min, 1, 3, 6, 12, 24, and 48 h) to release the loading DOX. Thereafter the
IF-DOX implants were collected and added into 3 mL PBS to completely
release residual DOX. After the solution was filtrated with a membrane
filter (pore size, 0.22 μm), the amount of residual free DOX in IF was de-
termined by UV–vis absorption spectra.
Magnetothermal Properties of IF: To study the magnetothermal prop-
erties of IF with different sizes (2 × 2 × 2 mm, 2.5 × 2.5 × 2.5 mm, and
3 × 3 × 3 mm), IFs were put in an alternating magnetic field (AMF, fre-
quency: 312 kHz, H = 0.46 kA m−1 , Happl ·fappl = 1.44 × 108 A m−1 s−1 )
and heated for 3 min, and the temperature monitoring of IF was decided
by a thermal camera. In addition, the magnetothermal capability of IF
(2 × 2 × 2 mm) was investigated by placing the IF (2 × 2 × 2 mm) in
the AMF under different magnetic field intensities (frequency: 312 kHz,
Happl ·fappl = X × 108 A m−1 s−1 , X = 1.44, 2.4, and 3.78) for 3 min,
and the thermal camera was also used to record the temperature change.
Moreover, the stability of the magnetic hyperthermia was studied by re-
peated heating and cooling processes in an AMF (frequency: 312 kHz, H =
1.21 kA m−1 , Happl ·fappl = 3.78 × 108 A m−1 s−1 ). In brief, IF (2 × 2 × 2 mm)
was placed in an AMF for 3 min, and then the AMF was turned off. After
the temperature of IF dropped to the initial temperature, the AMF was
turned on for 3 min again. The temperature monitoring was determined
by a thermal camera throughout four cycles of heating/cooling processes.
To study the reproducibility of magnetothermal heating with IF, the IF
(2 × 2 × 2 mm) was placed in an AMF (frequency: 312 kHz, Happl ·fappl
= 1.44 × 108 A m−1 s−1 ) for 3 min, and the temperature was monitored by
a thermal camera. The heating experiment was repeated 8 times. Besides,
the heating capacity of the IF was further compared with one of the best
magnetic nanomaterials with a good magnetocaloric effect reported in a
previous study.[1b] The IF (2 × 2 × 2 mm) and cobalt ferrite (CoFe2 O4 )
nanoparticles (powder or immersed in solution) were placed in an AMF
(frequency: 312 kHz, Happl ·fappl = 1.44 × 108 A m−1 s−1 ) for 3 min, and
their temperatures were monitored by a thermal camera.
To study the tissue penetration capability of IF-based MHT, the IF was
implanted into the center of a fresh cube-shaped pig liver (≈2 × 2 × 2 cm)
coated with pork tissue with a size of ≈8 cm. The pig liver coated with
pork tissue was heated in an AMF (frequency: 312 kHz, H = 2.2 kA m−1 ,
Happl ·fappl = 6.86 × 108 A m−1 s−1 ) for 6 min. Then the pig liver was cut
in half to observe the color change. In the control group, 10 μL PBS was
injected into the central position of pig liver tissue, and other operations
were carried out the same as above. In addition, the IF (2 × 2 × 2 mm)
was buried in a centrifuge tube filled with thermochromic material (light
pink to amaranth at >60 °C) and implanted in pork tissue with the sizes
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of 8 cm. Then the pork tissue was placed in an AMF for 6 min (frequency:
312 kHz, H = 2.2 kA m−1 , Happl ·fappl = 6.86 × 108 A m−1 s−1 ).
To study the magnetothermal ability of IF before and after loading
drugs, IFs (2 × 2 × 2 mm) immersed in PBS and DOX (6 mg mL−1 ) solu-
tion were placed in AMF (frequency: 312 kHz, H = 1.21 kA m−1 , Happl ·fappl
= 3.78 × 108 A m−1 s−1 ) for 3 min, and the temperature monitoring was
determined by the thermal camera.
Degradation of IF in Vitro: The degradation of IF in vitro was investi-
gated by the mass difference method. The IF was weighed and added to
1 mL of water and saline at room temperature for different time durations
(0, 3, 10, 20, 40, and 60 days). Then the IF was taken out, washed with
water, dried, and weighed, and the degradation degree of IF in various so-
lutions was determined.
Cytotoxicity of IF: 4T1 cells were used to study the cytotoxicity of IF
by standard MTT assay. 4T1 cells were seeded into cell culture plates and
cultured in a cell incubator for 24 h. The old medium was thrown, and the
adherent cells were washed using PBS. Then 180 μL new medium and the
IF (2 × 2 × 2 mm) were added, and a small magnet was placed on the
outer side of the 96-well plates to make IF stick to the inner side of the
wells to reduce the damage to cells caused by mechanical compression.
After incubating for different time durations (6, 12, and 24 h), the IF, small
magnet, and old medium were removed and the treated cells were washed
using PBS. Then 200 μL new medium and 10 μL thiazole blue (5 mg mL−1 )
were added and co-incubated for 4 h. At last, the supernatants in the cells
were thrown away and 120 μL Dimethylsulfoxide (DMSO) was added to
dissolve formazan. The cell viabilities were determined by measuring the
absorbance of the solution (490 nm) in each well using a microplate reader
(BioTek, USA).
In Vitro Combination Therapy Using IF-DOX: To investigate the com-
bination therapy effect of IF-DOX in vitro, 4T1 cells were cultured on
cell culture plates in a cell incubator for 24 h. After removing old media
and washing using PBS, the 4T1 cells were subjected to different treat-
ments: i) PBS group: 180 μL new medium and 10 μL PBS; ii) PBS+AMF
group: 180 μL new medium and 10 μL PBS and putting in AMF for 7 min;
iii) IF-PBS group: 180 μL new medium and one IF-PBS; iv) DOX group:
180 μL new medium and 10 μL DOX (3.8 μg); v) IF-DOX group: 180 μL
new medium and one IF-DOX (DOX: 3.8 μg); vi) IF-PBS+AMF group:
180 μL new medium and one IF-PBS and putting in AMF for 7 min; vii)
IF-DOX+AMF group: 180 μL new medium and one IF-DOX (DOX: 3.8 μg)
and putting in an AMF for 7 min. The parameters of AMF used in cel-
lular therapy were as follows: frequency = 362 kHz, H = 1.01 kA m−1 ,
Happl ·fappl = 3.66 × 108 A m−1 s−1 . It is worth noting that to eliminate
mechanical compression damage caused by the weight of IF, small mag-
nets were placed on the outer side of the 96-well plates after heating in the
AMF to make the IF attach to the inner side wall of the wells. The cells were
placed in a cell incubator and incubated for 24 h, and then the small mag-
nets, IF, and old medium were removed. After washing with PBS, 200 μL of
new medium and 10 μL of thiazole blue (5 mg mL−1 ) were added and co-
incubated for 4 h. At last, the supernatants in the cells were thrown away
and 120 μL DMSO was added to dissolve the generating formazan. The
cell viabilities were determined by measuring the absorbance of the solu-
tion (490 nm) in each well using a microplate reader. In addition, to study
the combined killing effect of the IF-DOX on cells more directly, the cells
with different treatments were stained using calcein-AM and PI and ob-
served under a fluorescence microscope to analyze the survival status of
the treated cells. Moreover, to further analyze the apoptosis status of cells
in each treatment group, the cells were incubated with Annexin V-FITC and
determined by flow cytometry.
Biocompatibility of IF in Vivo: All animal-associated experiments were
conducted in accordance with the guidelines of the Animal Care and Use
Committee of Tianjin Medical University and obtained approval from the
Animal Care and Use Committee of Tianjin Medical University (SYXK:
2019-0004). Kunming mice (≈20 g, SPF Biotechnology Co., Ltd., Beijing,
China) were used to evaluate the biocompatibility of IF in vivo by blood
analysis, histopathological examination, body weight monitoring, and
degradation study. Blood and serum were collected at different time dura-
tions (3, 10, 20, 40, and 60 days) after subcutaneous transplantation of IF
for blood analysis. The analyzed indicators included liver function indexes
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(Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Al-
bumin (ALB) and total protein (TP)), kidney function indicators (serum
creatinine (CREA), urea (Urea) and Uric Acid (UA)), inflammatory markers
(tumor necrosis factor-𝛼 (TNF-𝛼) and interleukin-6 (IL-6)), tumor markers
(alpha fetoprotein (AFP) and carcino-embryonic antigen (CEA)) and blood
routine indicators (leukocyte count (WBC), lymphocyte count (Lymph#),
monocyte count (Mon#), neutrophil number (Gran#), lymphocyte per-
centage (Lymph%), monocyte percentage (Mon%), neutrophilic granulo-
cyte percentage (Gran%), erythrocyte count (RBC), hemoglobin (HGB),
hematocrit (HCT), mean corpuscular volume (MCV), mean erythrocyte
hemoglobin content (MCH), mean corpuscular-hemoglobin concentra-
tion (MCHC), red blood cell distribution width (RDW), platelet count
(PLT), mean platelet volume (MPV), platelet distribution width (PDW),
plateletcrit (PCT)). At the same time, major organs (heart, liver, spleen,
lung, and kidney) of Kunming mice in different groups were dissected and
carried out with Hematoxylin and Eosin (H&E) staining. In addition, the
body weight change of Kunming mice in IF implanted group and control
group was monitored within 60 days. Besides, IFs implanted under the
skin of mice at different time points were dissected, washed, dried, and
analyzed by ICP-OES and SEM.
CT Imaging of IF in Tumors: 4T1 tumor-bearing Balb/c mice (≈20 g,
SPF Biotechnology Co., Ltd., Beijing, China) were used to evaluate the CT
imaging capability of IF. Balb/c mice were subcutaneously inoculated with
tumor cells on the right back, and in vivo experiments were carried out
when the diameter of the tumor grew to ≈5–7 mm. The CT imaging was
performed using a CT scanner in the clinic (Erlangen, Germany) after IF-
PBS and IF-DOX were transplanted into the tumor of Balb/c mice. The
tube voltage was 80 kV, and the volume render (VR) method was adopted
to reconstruct 3D images based on CT images.
Drug Release of IF-Drug Implant in Vivo: To investigate the drug release
behavior in vivo, ICG with intense near-infrared (NIR) fluorescence was
chosen as a model drug to replace DOX to explore the drug release from
IF-drug implant in vivo. After implantation of IF (2 × 2 × 2 mm) or IF-
ICG (ICG: 0.08 μg) in the tumor, the mice were imaged by a small animal
fluorescent imaging system at different time points.
Combined Magnetic Hyperthermia and Chemotherapy of Tumors Using
IF-DOX in Vivo: 4T1 tumor-bearing mice were used to study the com-
bined therapeutic efficacy of IF-DOX in vivo. The mice were randomly di-
vided into 8 groups for different treatments (n = 5): i) PBS group: intratu-
moral injection of 10 μL PBS; ii) PBS+AMF group: intratumoral injection
of 10 μL PBS and heated in AMF for 6 min; iii) Sham group; iv) IF-PBS
group: implantation of IF-PBS in tumor; v) DOX group: intratumoral in-
jection of 10 μL DOX (48 μg); vi) IF-DOX group: implantation of IF-DOX
(DOX: 48 μg) in tumor; vii) IF-PBS+AMF group: implantation of IF-PBS
in the tumor, and heated in an AMF for 6 min; viii) IF-DOX+AMF group:
implantation of IF-DOX (DOX: 48 μg) in the tumor, and heated in an AMF
for 6 min. The parameters of AMF used in vivo therapy were as follows:
frequency = 312 kHz, H = 1.21 kA m−1 , Happl ·fappl = 3.78 × 108 A m−1 s−1 .
Additionally, as the preparation of IF-DOX is extremely simple, a ready-to-
use strategy was adopted for combined therapy of tumors in vivo. From the
preparation of the implant, transplantation into the live tumor, and wound
closure, to the initiation of magnetothermal therapy, this entire process
took less than 5 min. Besides, after implantation of IF in the tumor and
wound closure, the mice were instantly placed in an AMF for magnetother-
mal heating. All mice were carried out with the same process.
The temperature monitoring of mice during the heating process in AMF
was using a thermal camera. The mice in each group were monitored for
15 days and tumor length and width were determined by a digital caliper
every 3 days. Tumor volume was defined as volume = length × width2 /2. In
addition, the IF was initially weighed prior to treatment, subsequently ex-
tracted, cleaned, dried, and then reweighed for the purpose of comparing
the mass changes before and after treatment.
Supporting Information
Supporting Information is available from the Wiley Online Library or from
the author.
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Acknowledgements
This work was supported by the National Natural Science Foundation
of China (82071982 and 21934002), the Natural Science Foundation of
Tianjin City (19JCJQJC63700), and Tianjin Science and Technology Bureau
Multi-investment Fund Project Youth Project (21JCQNJC01880).
Conflict of Interest
The authors declare no conflict of interest.
Data Availability Statement
The data that support the findings of this study are available from the cor-
responding author upon reasonable request.
Keywords
combination treatment, facile drug loading, iron foam, low-power mag-
netic hyperthermia
Received: October 17, 2023
Revised: December 10, 2023
Published online: January 2, 2024
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