Hypoxia-Triggered Self-Assembly of Ultrasmall Iron Oxide Nanoparticles to Amplify the Imaging Signal of a Tumor

Article abstract of DOI:10.1021/jacs.0c10245

Hypoxia is a common phenomenon among most solid tumors that significantly influences tumor response toward chemo- and radiotherapy. Understanding the distribution and extent of tumor hypoxia in patients will be very important to provide personalized thera

Full text of DOI:10.1021/jacs.0c10245

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Hypoxia-Triggered Self-Assembly of Ultrasmall Iron Oxide
Nanoparticles to Amplify the Imaging Signal of a Tumor
Huige Zhou,# Mengyu Guo,# Jiayang Li,# Fenglan Qin, Yuqing Wang, Tao Liu, Jing Liu,
Zeinab Farhadi Sabet, Yaling Wang, Ying Liu, Qing Huo, and Chunying Chen*
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ABSTRACT: Hypoxia is a common phenomenon among most solid tumors that
significantly influences tumor response toward chemo- and radiotherapy. Under-
standing the distribution and extent of tumor hypoxia in patients will be very
important to provide personalized therapies in the clinic. Without sufficient vessels,
however, traditional contrast agents for clinical imaging techniques will have difficulty
in accumulating in the hypoxic region of solid tumors, thus challenging the detection
of hypoxia in vivo. To overcome this problem, herein we develop a novel hypoxia
imaging probe, consisting of a hypoxia-triggered self-assembling ultrasmall iron oxide
(UIO) nanoparticle and assembly-responding fluorescence dyes (NBD), to provide
dual-mode imaging in vivo. In this strategy, we have employed nitroimidazole
derivatives as the hypoxia-sensitive moiety to construct intermolecular cross-linking of
UIO nanoparticles under hypoxia, which irreversibly form larger nanoparticle
assemblies. The hypoxia-triggered performance of UIO self-assembly not only
amplifies its T2-weighted MRI signal but also promotes the fluorescence intensity of NBD through its emerging hydrophobic
environment incorporated into self-assemblies. In vivo results further confirm that our hypoxic imaging probe can display a prompt
MRI signal for the tumor interior region, and its signal enhancement performs a long-term effective feature and gradually reaches
3.69 times amplification. Simultaneously, this probe also exhibits obvious green fluorescence in the hypoxic region of tumor sections.
Accordingly, we also have developed a MRI difference value method to visualize the 3D distribution and describe the extent of the
hypoxic tumor region within the whole bodies of mice. Due to its notable efficiency of penetration and accumulation inside a
hypoxic tumor, our hypoxia imaging probe could also be considered as a potential candidate as a versatile platform for hypoxia-
targeted drug delivery, and meanwhile its hypoxia-related therapeutic efficacy can be monitored.
methods in clinical diagnostics,8 due to its excellent deep tissue
contrast and spatial resolution (50 μm). Contrast agents are
INTRODUCTION
■
Hypoxia, a characteristic feature of many types of solid tumors,
essential to distinguish lesions from healthy tissues from the
plays an important role in chemoresistance, radioresistance,
MRI images through rational designs.9 However, the
angiogenesis, and invasiveness.1,2 Notably, hypoxia is also an
restriction of penetration depth limits their further applications
independent prognostic factor for patients linked to poor
of imaging the central tumor region where hypoxia frequently
disease-free survival and local control.3 Due to the importance
occurs. Among the diverse contrast imaging agents, ultrasmall
of hypoxia, an accurate description of the hypoxic distribution
iron oxide nanoparticles (UIOs), having considerable pene-
and its extent in a tumor will help clinicians to obtain precise
information on tumor malignancy degree and then provide
tration efficacy in the tumor interior region,10 have been widely
used as T2-weighted MRI contrast agents due to their
personalized therapeutic strategies accordingly. Current clinical
homogeneous size distribution, good biocompatibility, and
methods, including oxygen microelectrodes4,5 and immuno-
easily functionalized surface.11 Moreover, the process of UIO
histochemistry,6,7 have been considered as gold standards to
self-assembly to alter the particle size and surface chemistry
provide local information on hypoxia for the exact oxygen
can dramatically enhance the transverse relaxation rate (R2) of
concentration and hypoxia-related biomarkers. However, these
treatments can be time-consuming and painful for patients.
Noninvasive and real-time approaches, providing on-site
information on hypoxia with unlimited penetration and high
Received: September 25, 2020
Published: January 4, 2021
resolution should be developed to visualize the three-
dimensional (3D) distribution of a hypoxic tumor.
In comparison with other imaging methods, magnetic
resonance imaging (MRI) is one of the best noninvasive
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Figure 1. (a) Principle of the UIO nanoparticle self-assembly that amplifies the signal of MRI and fluorescence triggered by hypoxia. Hypoxia-
responsive sensitivity of UIO-Pimo and UIO-B in vitro: (b) illustration of the formation principle of UIO-Pimo self-assembly under hypoxia
conditions; HPLC trace of the ligand Pimo (c) and the ligand B (d) after different treatments; (e) hydrodynamic size of solutions in (f−i) at 25
°C; TEM images of UIO-Pimo treated under hypoxia (f) and normoxia (g) and UIO-B treated under hypoxia (h) and normoxia (i), with NADPH
and nitroreductase at 37 °C for 1 h. Scale bar: 100 nm.
the surrounding water protons, finally resulting in MRI
promotion.12 Therefore, UIO-enhanced MRI has attracted
more and more interest for tumor diagnosis and therapy
through smart designs of stimuli-responsive UIO self-assembly,
including in situ self-assembly constructed by a pH-sensitive
study has introduced a self-assembled design of carbonic
anhydrase IX constructed nanofibers for hypoxia tumor
therapy,26 suggesting that the intelligent design of hypoxia-
responsive sensors should be important in constructing UIO
self-assembly.
DNA i-motif,13 an MMP 2/9 responsive click reaction,14
a
When the hypoxia-specific redox state and oxygen
concentration are considered, nitroimidazole compounds
containing a hypoxia-sensitive nitro moiety27 have been
intensely developed as hypoxia-sensitive probes with the signal
intensity changing along with the fluctuations of oxygen partial
pressure.28−33 Performing a series of bioreductions for its nitro
moiety, nitroimidazole exhibits excellent hypoxia binding and
normoxia deprivation capability that can be useful for the
evaluation of hypoxic degree in clinical experiments.34,35
Therefore, here we employ nitroimidazole derivatives as the
hypoxia-sensitive moiety (Pimo) in this study, which can
irreversibly bind to thiols and form stable reductive adducts in
the presence of NADPH and reductase under hypoxia. After
Pimo and cysteine were conjugated onto a UIO surface in a
certain ratio, we have developed a hypoxia imaging probe
(UIO-Pimo) that may covalently cross-link under hypoxia and
consequently afford larger UIO assemblies. Nanoparticle-
induced endothelial leakiness (NanoEL)36−38 and the
endothelial permeability and retention effect (EPR)39 could
help UIO-Pimo nanoparticles arrive at tumor tissues. Due to
its ultrasmall size, as illuminated in Figure 1a, UIO-Pimo could
penetrate into a solid tumor and arrive at its central region,
followed by the nitroimidazole group changing to hydroxyl-
caspase 3/7 managed condensation reaction,15 an integrin αvβ3
targeting accumulation,16 and a hyaluronidase and weak pH
triggered aggregation.10,17 Benefiting from their size effects for
permeability effects and MRI enhancement, UIO nanoparticles
can be considered as a promising platform for hypoxia stimuli-
responsive imaging.
The self-assembly or disassembly of nanoparticles, involving
serial changes in particle size, charge, and surface chemistry,
can significantly influence their physiochemical characteristics
and functions18 and endow them with a certain response
toward well-known tumor microenvironment conditions: e.g.
site-specific pH, redox potential, overexpressive enzymes,
etc.19−23 In situ self-assembly of small nanoparticles not only
results in considerable permeability efficacy but also may
enhance their accumulations in the targeting region with the
desired nanostructures. So far, current strategies have mainly
focused on progress in nanoparticle disassembly in hypoxia
diagnosis and therapy,24,25 whereas few works have discussed
the self-assembly performance of nanoparticles exclusively
responding to hypoxia stimulations. Manipulating hypoxia-
triggered UIO self-assembly and portraying the precise hypoxia
distribution in a solid tumor is still challenging. Our recent
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Figure 2. Hypoxia-responsive fluorescence enhancement in vitro and in vivo. (a) Illustration of the fluorescence-enhanced principle of UIO-Pimo
aggregation in hypoxic cells. (b) Fluorescence intensity (per mM NBD) of UIO-Pimo solutions under hypoxia and normoxia. (c) Statistics of green
fluorescence intensity in (d, e). Confocal fluorescence images of MDA-MB-231 cells after 3 h coincubation with (d) UIO-Pimo and (e) UIO-B. (f)
Confocal fluorescence images at different focal depths of the tumor spheroid. (g) Representative images of tumor tissues after staining HIF-1α. In
(d−g), NBD represents the fluorescence of UIO-Pimo (or UIO-B).
amine and then binding to cysteine under hypoxia.6 These
hypoxia-responding performances of self-assembly in UIO-
Pimo nanoparticles provide us with a good chance for these
nanoparticles to selectively target hypoxia and then gradually
accumulate, which consequently amplifies the T2-weighted
MRI signal of the hypoxic tumor. Accordingly, we have
developed a MRI difference value method using the changed
signal of MRI to visualize an in vivo 3D map of hypoxia in
mice. Meanwhile, a small molecule of 4-chloro-7-nitro-2,1,3-
benzoxadiazole (NBD) emitting stronger fluorescence in the
hydrophobic environment in comparison to the hydrophilic
environment could be considered as an assembly-responding
fluorescence dye.23 Thus, we incorporated NBD into our
manufactured hypoxia imaging probe to induce a fluorescence
promotion through the emerging hydrophobic environment in
self-assembly. On the basis of these designs, we may construct
a promising platform to provide dual-mode hypoxia imaging
through achieving hypoxia-triggered UIO self-assembly.
series of bioreductions for the nitroimidazolyl group in an
oxygen-dependent manner and may subsequently form a
reductive adduct with thiols in cells. Since its activated
intermediate of a nitro radical anion can be quickly depleted by
O2,6 this sensor exhibits a promising selectivity for hypoxic
cancer cells. Therefore, we further applied lysine as a linker to
conjugate this hypoxia sensor with NBD, a small fluorescent
dye, together affording our hypoxia-sensitive ligand A (Pimo)
(Scheme S2). In contrast, here we also prepared a control
ligand (B) with a similar chemical structure, only changing the
nitroimidazolyl group into a phenyl group (Schemes S3 and
S4).
To investigate the hypoxia-responding behaviors of Pimo,
here we mimicked physical conditions of hypoxic cancer cells
and implemented in vitro experiments through the process
described in Scheme S7. In the presence of NADPH and
nitroreductase, Pimo should be reductively activated and then
irreversibly bound to cysteine under a relatively low level of
oxygen tension. Thereafter, we analyzed the resulting adducts
by high-performance liquid chromatography (HPLC) and
mass spectral (MS) analyses. As shown in Figure 1c, an
emerging product can be clearly detected under hypoxia, which
exhibits a shorter retention time in the HPLC trace in
comparison to Pimo. This is because the reduction of its nitro
group changes the solubility11 (Scheme S6) and provides a
mass peak for its subsequent thiol adduct (Figure S7). Figure
1c and Figure S6 further convinces us that the reaction
happens exclusively under hypoxia, suggesting that Pimo is
RESULTS AND DISCUSSION
■
Design of Hypoxia-Sensitive Ligands. Because of their
unique respondence to hypoxia, nitroimidazole derivatives
have been currently explored for hypoxia-selective prodrugs
and imaging probes. Herein, we employed 1-(4-
(aminomethyl)piperidin-1-yl)-3-(2-nitro-1H-imidazol-1-yl)-
propan-2-ol (Scheme S1) as a hypoxia sensor, which contains a
nitroimidazolyl residue at the end. As illuminated in Figure 1b,
the underlying mechanism of its hypoxia sensitivity involves a
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Figure 3. UIO-Pimo can greatly elevate the MRI signal intensity of tumors through this hypoxia-triggered self-assembly strategy. (a) Relaxation
values and MR phantom images of UIO-Pimo and UIO-B under normoxia and hypoxia on a 7.0 T MR scanner, respectively (n = 3). Relaxation
values of MDA-MB-231 cells incubated with UIO-B and UIO-Pimo under (b) normoxia and (c) hypoxia. Inserts give the corresponding MR
phantom images (n = 3). (d) ICP-OES determined iron concentration of MDA-MB-231 cells incubated with UIO-B and UIO-Pimo under
normoxia and hypoxia, respectively (n = 3). (e) Change in signal intensity over time in the tumor (n = 3). R0 and Rt represent the relaxation values
before and after the injection of UIO-Pimo and UIO-B at the indicated time points, respectively. (f) Signal intensity of liver, spleen, and kidney
after the injection of UIO-Pimo (n = 3). (g) Representative images of tumor tissues by Prussian blue staining. (h) MRI images of in situ 4T1 tumor-
bearing mice after the intravenous injection of UIO-Pimo and UIO-B.
highly selective and sensitive to hypoxia conditions. As a
control, ligand B gives an inert performance under the same
conditions, so that no obvious change can be detected (Figure
1d).
(Scheme S9). TEM images (Figure 1g,i) exhibits the
nanostructure of UIO-Pimo/B under normoxia conditions,
with an average diameter of around 10 nm in dynamic light
scattering (DLS) (Figure 1e). As shown in Figure S11, UIO-
Pimo maintains a well-dispersed and uniform nanostructure for
at least 7 days in PBS buffer without any obvious change in the
hydrodynamic size. This phenomenon supports the notion that
these engineered UIO nanoparticles should be relatively stable,
so that they will not aggregate until certain specific
requirements are met. On treatment with NADPH and
reductase under hypoxic conditions, however, self-assembly
of UIO-Pimo NPs can be triggered due to conjugations of
cysteine and Pimo. Figure 1f reveals that the size of UIO-Pimo
self-assemblies has been significantly increased with hydro-
dynamic diameters of around 100 nm (Figure 1e); meanwhile,
UIO-B does not present similar alterations with decreasing
oxygen concentration (Figure 1h). To observe the influence of
the intracellular thiol groups on this hypoxia-triggered self-
assembly, certain amounts of GSH (Scheme S10) were added
into the reaction system. The results indicate that the self-
assemblies of UIO-Pimo can still occur under hypoxia
conditions even with the presence of 1 mM GSH (Figure
S12). It should be noted the hypoxia-triggered self-assembly of
UIO-Pimo NPs not only increases their overall sizes but also
changes their inner chemical environment between each
particle surface, providing a potential hypoxia imaging
platform.
Hypoxia-Triggered Self-Assembly of UIO-Pimo Nano-
particles. Encouraged by the remarkable sensitivity toward
hypoxia, we utilized Pimo ligands to achieve the hypoxia-
triggered self-assembly of UIO nanoparticles, which promised
the construction of a dual-mode hypoxia imaging platform.
After the successful preparation of poly(acrylic acid)-coated
UIO (UIO@PAA) nanoparticles (Figure S8), we covalently
conjugated ligand Pimo/B and cysteine onto the surface of
UIO nanoparticles through a facile reaction of 1-ethyl-3-(3-
(dimethylamino)propyl)carbodiimide hydrochloride/N-hy-
droxysuccinimide (EDC/NHS) (Scheme S5). The appear-
ances of an absorption peak (480 nm) and a fluorescence
signal (560 nm) suggest a successful modification (Figures S9
and S10). According to the calculated reaction efficiency, the
grafting percentages of cysteine and Pimo/B should be 22.5%
and 0.619%, respectively. As determined by a previous
method,10 one iron oxide nanoparticle contains 1120 cysteine
groups and 33 Pimo/B groups, in which the excess cysteine
guarantees sufficient cross-linking sites.
Whether intermolecular cross-linking of hypoxia-sensitive
ligands can induce effective self-assembly between different
nanoparticles (NPs) plays a crucial role in this project.
Therefore, in vitro experiments were executed to further
investigate the hypoxia sensitivity of UIO NP self-assembly
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Hypoxia-Triggered Fluorescence “Turn On”. When the
self-assemblies occurred, nanoparticles aggregated to a
condensed form; meanwhile, the interior of the self-assemblies
became more cohesive and squeezed out water molecules.
Therefore, the overall environment of the inner part in these
self-assemblies became more hydrophobic and “turn on” the
fluorescence of NBD (Figure 2a). To prove this assumption,
we examined in vitro and in vivo fluorescence intensities for
both UIO-Pimo and UIO-B nanoparticles. The solution of
UIO-Pimo nanoparticles shows a significantly increasing
fluorescence intensity under hypoxia (Figure 2b), indicating
that this hypoxia-triggered aggregation will package NBD
inside the self-assemblies to increase the signal of fluorescence.
However, the solution of UIO-B nanoparticles exhibits the
same level of fluorescence intensity under both hypoxia and
normoxia (Figure S13). This feature was also observed in
MDA-MB-231 cells (Figure 2d,e). Due to the formation of
larger self-assemblies (Figure S14), the fluorescence intensity
of NBD in the UIO-Pimo group is 203% higher than that of
UIO-B under hypoxia conditions (Figure 2c). In addition,
excessive cysteine on the UIO could help to amplify the
imaging signal (Figure S15). We also prepared tumor
spheroids (diameter about 500 μm) to observe the penetration
and aggregation of UIO-Pimo in the hypoxia region formed in
their centers.40 The UIO-Pimo group exhibits an obvious
clustering of green fluorescence in both the center and margin
of the tumor, proving that UIO-Pimo can effectively penetrate
into the tumor spheroids and aggregate in the hypoxic section
(Figure 2f and Figure S16). In contrast, the UIO-B group just
displays scattered green fluorescence in the margin region of
tumor spheroids and negligible clustering green fluorescence in
the center (Figure 2f and Figure S16).
To verify this hypoxia-responsive fluorescence in vivo, we
adopted a breast cancer xenograft bearing mouse model, in
which 4T1 cells have been injected subcutaneously into the fat
of Balb/c mice. After the average volume of tumors increased
to 1000 mm3, ensuring the formation of a hypoxic region
inside the tumor, the mice were treated with UIO-B and UIO-
Pimo i.v.. Immunostaining results of the tumor sections have
shown that UIO-Pimo treatment affords strong green
fluorescence and largely overlaps with the hypoxia biomarker
HIF-1α, indicating that the self-assemblies of UIO-Pimo may
target the hypoxic region and “turn on” the fluorescence
(Figure 2g). In contrast, the UIO-B group shows similar red
fluorescence of HIF-1α but negligible colocated green
fluorescence. This certifies that UIO-B nanoparticles can
neither aggregate in the hypoxic section nor increase the
fluorescence signal.
UIO-B just shows a slight change from normoxia (12.6 s−1) to
hypoxia (14.2 s−1). This hypoxia-responsive cross-linking
among nanoparticles can be completely finished after 1 h
(Figure S17), where the fast reaction speed gives the ultrasmall
nanoparticles a significant chance to productively accumulate
in the hypoxic region of the tumor. Thereafter, we measured
the MRI relaxation properties of MDA-MB-231 cells incubated
with UIO-B and UIO-Pimo under different conditions (Figure
3b,c). In comparison with normoxia groups, hypoxia groups
exhibit an elevated relaxation value (Figure 3c), together with
an increased intracellular iron concentration (Figure 3d).
Under hypoxic conditions, the relaxation value of UIO-Pimo
(139 s−1) is more than 2-fold greater than that of UIO-B (65
s−1). However, the iron concentration of the UIO-Pimo group
is just 0.43-fold higher than that of the UIO-B group. Thus, it
can be deduced that, in addition to improving cell uptake, the
formation of larger UIO-Pimo self-assemblies within hypoxic
cells (Figure S14) can greatly amplify the MRI signal.
Therefore, in vitro cell experiments have marked the potential
of UIO-Pimo for selectively aggregating under hypoxia
conditions and amplifying the MRI signal.
In vivo results further confirm that our hypoxic imaging
probe can display a prompt MRI signal for the tumor interior
region, and its signal enhancement performs a long-term
effective feature and gradually reaches 3.69-fold enhancement.
To fully prove the key concepts of this design, we carried out
animal experiments bearing hypoxic tumors, with the same
tumor model as for fluorescence in vivo experiments. Figure
3e,h demonstrates that the UIO-Pimo group has significantly
achieved a stronger MRI contrast in comparison to UIO-B in
the whole period of 8 h treatment. After the tumor was given
an intravenous injection for 1/2 h, the inner section of the
tumor in UIO-Pimo group obviously becomes darker,
indicating its rapid accumulation and penetration speed in
the tumor interior region. The relaxation value of UIO-Pimo
group at 2 h is almost 2-fold higher than that of Pre (1.88), and
this value keeps increasing up to 8 h (3.69), demonstrating the
long-term effective feature (≥6 h) (Figure 3e). In addition, the
enhanced relaxation change (3.69) at 8 h is 3.10-fold that of
UIO-B (1.19), illustrating the greatly enhanced MRI detection
sensitivity with this hypoxia-triggered self-assembly strategy.
The formation of UIO-Pimo self-assemblies can be further
confirmed by the occurrence of notably large blue areas stained
by Prussian blue in tumor tissue (Figure 3g). However, the
UIO-B group only exhibits dispersive blue dots in the tumor
section, because no self-assembly has occurred. In the absence
of a nitroimidazole group, UIO nanoparticles cannot aggregate
for hypoxia. Meanwhile, most of these UIO nanoparticles can
be degraded or excreted from liver, spleen, and kidney around
24 h after the injection (Figure 3f and Figure S18).
Hypoxia-Triggered T2-Weighted MRI Signal Enhance-
ment. One of the important characteristic features of UIO-
Pimo self-assembly should be the signal enhancement in T2-
weighted MRI, on the basis of the corresponding changes in
nanostructures and physiochemical surface environment
exclusively triggered by hypoxia.10,15,17 Subsequently, the size
enlargement in UIO-Pimo self-assembly promotes its accumu-
lation and retention time in the hypoxia region, which also
contributes to T2-weighted MRI enhancement. Here, we
measured the UIO-Pimo (or UIO-B) solution under different
oxygen conditions to confirm the ability of the amplified MRI
signal of UIO-Pimo self-assemblies in vitro (Figure 3a). UIO-
Pimo self-assemblies increase the relaxation value from 12.8 s−1
to 21.4 s−1, demonstrating that the transverse relaxations of
water protons could be significantly enhanced. In contrast,
Visualization of Tumor Hypoxia Distribution In Vivo
by MRI Difference Value Method. To describe the hypoxic
region and degree of tumor in three dimensions, here we
developed a MRI difference value method; the details are
shown in the Supporting Information. Considering the large
individual differences in tumors between each group, herein we
preferred to choose the tumor before injection (0 h) in the
UIO-Pimo group as the reference. Then the tumor region with
a relaxation time (at 8 h after the i.v. injection of UIO-Pimo)
changing more than a certain value is defined as the hypoxic
region and the greater the change, the more hypoxia. This
certain value is called a difference value and can be selected on
the basis of HIF-1α staining across the tumor tissue. On the
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Figure 4. Distribution of hypoxic regions within a tumor. Hypoxic area (dashed area) displayed by the MRI difference value method (a), the
immunofluorescence of HIF-1α antibody (b) and HE staining of Pimonidazole (c) about the cross-section of the tumor tissue at 8 h. (d) Rotation
images showing the in vivo distribution of hypoxia within the tumor in the whole body, calculated by the MRI difference value method. The yellow
circle indicates the tumor tissue.
basis of the HIF-1α staining result of the largest cross-section
of tumor tissue (Figure 4b), we tried three different difference
values (7, 14, and 28 ms) (Figure S19). However, the imaging
results of the MRI difference value method were consistent
with the distribution of the red fluorescence of HIF-1α in
Figure 4b only when 14 ms was chosen as the difference value.
To further evaluate the accuracy of this method, a cross-section
of the tumor was used to do the immunostaining with the
pimonidazole antibody (Figure 4c). Three hypoxia imaging
methods show largely overlapped sections, indicating the
precision of this MRI difference value method. Then, this
method was applied to show the distribution of hypoxic
regions within the whole mice (Figure 4d and Movie 1 in the
Supporting Information). We can observe the hypoxia region
from any angle with these 3D results and know the inner
information from the corresponding cross-section. This will
give a possibility for clinicians to choose the proper therapy
strategy. The results of CCK-8 (Figure S20) and H&E staining
of tissues (Figure S21) indicate the safety of UIO-B and UIO-
Pimo.
vessels. The remarkable hypoxia-response performance of
UIO-Pimo could be advantageous for its future applications
in monitoring hypoxia-related therapeutic effects. Moreover,
this smart design of hypoxia-sensitive ligands promises a broad
future for the hypoxia-triggered self-assembly strategy. We
hope that the current study will facilitate the development of
therapies and diagnoses related to hypoxic tumors through the
safe nanomaterials.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c10245.
■
sı
Details of the synthesis, TEM images, in vivo and in
vitro biocompatibility (PDF)
Three-dimensional (3D) distribution of hypoxic areas
within the whole body of 4T1 in situ tumor-bearing mice
calculated by the MRI difference value method, where
the color moves from blue to red to indicate the hypoxic
degree enhancement (MP4)
CONCLUSION
AUTHOR INFORMATION
Corresponding Author
■
■
In conclusion, we have constructed the novel hypoxia imaging
probe UIO-Pimo, which exclusively self-assembled to amplify
the hypoxia imaging signals of fluorescence and MRI in vitro
and in vivo. A MRI difference value method has been
developed to portray the 3D hypoxia region within the
tumor of the whole body, providing accurate information
about hypoxia to clinicians and helping them to choose a
better therapy method. Due to its outstanding penetration and
accumulation efficacy, this hypoxia-triggered self-assembly
strategy will also provide a method for overcoming difficulties
in delivering a drug to the hypoxic region without sufficient
Chunying Chen − CAS Key Laboratory for Biomedical Effects
of Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
of China; University of Chinese Academy of Sciences, Beijing
100049, People’s Republic of China; Research Unit of
Nanoscience and Technology, Chinese Academy of Medical
Sciences, Beijing 100021, People’s Republic of China; GBA
Research Innovation Institute for Nanotechnology,
Guangdong 510700, People’s Republic of China;
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orcid.org/0000-0002-6027-0315; Email: chenchy@
nanoctr.cn
of China; Research Unit of Nanoscience and Technology,
Chinese Academy of Medical Sciences, Beijing 100021,
People’s Republic of China; GBA Research Innovation
Institute for Nanotechnology, Guangdong 510700, People’s
Republic of China; orcid.org/0000-0002-6540-0473
Qing Huo − Department of Biomedical, College of Biochemical
Engineering, Beijing Union University, Beijing 100023,
People’s Republic of China
Authors
Huige Zhou − CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
of China; Research Unit of Nanoscience and Technology,
Chinese Academy of Medical Sciences, Beijing 100021,
People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10245
Mengyu Guo − CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
of China; University of Chinese Academy of Sciences, Beijing
100049, People’s Republic of China
Jiayang Li − CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
of China; Research Unit of Nanoscience and Technology,
Chinese Academy of Medical Sciences, Beijing 100021,
People’s Republic of China
Fenglan Qin − CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
of China
Yuqing Wang − CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
of China
Tao Liu − CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
of China
Jing Liu − CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
of China; orcid.org/0000-0002-8740-4600
Zeinab Farhadi Sabet − CAS Key Laboratory for Biomedical
Effects of Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
of China; University of Chinese Academy of Sciences, Beijing
100049, People’s Republic of China
Yaling Wang − CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
of China; Research Unit of Nanoscience and Technology,
Chinese Academy of Medical Sciences, Beijing 100021,
People’s Republic of China; GBA Research Innovation
Institute for Nanotechnology, Guangdong 510700, People’s
Republic of China; orcid.org/0000-0002-5845-5150
Ying Liu − CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety and CAS Center for
Excellence in Nanoscience, National Center for Nanoscience
and Technology of China, Beijing 100190, People’s Republic
Author Contributions
#H.Z., M.G., and J.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the Ministry of Science
and Technology of China (2016YFA0201600,
2016YFE0133100), the National Natural Science Foundation
of China (31871004, 51861145302), the Program for
International S&T Cooperation Projects of the Ministry of
Science and Technology of China (2018YFE0117200), the
Science Fund for Creative Research Groups of the National
Natural Science Foundation of China (11621505), the CAMS
Innovation Fund for Medical Sciences (CIFMS 2019-I2M-5-
018), the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB36000000), the CAS Key Research
Program for Frontier Sciences (QYZDJ-SSW-SLH022, ZDBS-
LY-SLH039), the Bureau of International Co-operation,
Chinese Academy of Sciences (GJHG1852), and the CAS
interdisciplinary innovation team.
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