Oxygen Vacancies Enhanced CeO2:Gd Nanoparticles for Sensing a

Subscriber access provided by the Henry Madden Library | California State University, Fresno

Article

Oxygen Vacancies-Enhanced CeO2:Gd Nanoparticles for Sensing Tumor Vascular Microenvironment by Magnetic Resonance Imaging Chulun Shao, Aijun Shen, Meng Zhang, Xianfu Meng, Chaolin Song, Yanyan Liu, Xiaolong Gao, PeiJun Wang, and Wenbo Bu ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.8b07387 • Publication Date (Web): 29 Nov 2018 Downloaded from http://pubs.acs.org on November 29, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

Oxygen

Vacancies-Enhanced

CeO2:Gd

Nanoparticles for Sensing Tumor Vascular Microenvironment by Magnetic Resonance Imaging Chulun Shao, †,‡ ,∥ Aijun Shen, §,

∥

Meng Zhang, †,‡ Xianfu Meng,⊥ Chaolin Song,⊥

Yanyan Liu,⊥ Xiaolong Gao,§ Peijun Wang,*,§ and Wenbo Bu*,†,⊥ †

State Key Laboratory of High Performance Ceramics and Superfine Microstructure,

Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, P.R. China. ‡University

of Chinese Academy of Sciences, Beijing, 100049 (P. R. China)

§Department

of Medical Imaging, Tongji Hospital, Tongji University, Shanghai,

200065 (P.R. China) ⊥Shanghai

Key Laboratory of Green Chemistry and Chemical Processes, College of

Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062 (P. R. China) KEYWORDS: CeO2:Gd nanoparticles, oxygen vacancies, tumor microenvironment, microvascular, DWI/DCE-PWI

1 ACS Paragon Plus Environment

ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 26

ABSTRACT: The specific characteristics of the tumor vascular microenvironment such as microvascular permeability and water diffusion have been demonstrated to play essential roles in the evaluation of infiltration of tumors. However, at present, there are few contrast agents (CAs) for magnetic resonance imaging (MRI) to enhance the sensitivity to acquire this vital information. Herein, we develop Gd doped (CeO2:Gd) nanoparticles as CA to detect the tumor vascular microenvironment with high sensitivity. The lattice oxygen vacancies on the surface of CeO2:Gd nanoparticles could bind considerable water molecules to improve the r1 value, achieving an excellent dynamic contrast-enhanced perfusion weighted imaging (DCE-PWI) performance for the measurement of microvascular permeability. The water molecules’ diffusion limited by oxygen vacancies of CeO2:Gd nanoparticles further enhance the diffusion-weighted magnetic resonance imaging (DWI) signal in vitro and in vivo. Excitingly, the strategy is not only essential for obtaining tumor vascular microenvironment information but also offers a way for further research of how to design magnetic resonance CAs.

Local characteristics of tumor microenvironment, such as water diffusion1 and microvascular permeability,2,3 are the main factors when evaluating the malignancy of tumors.4 Owing to the extreme complexity of the diffusion process in biological tissues, diffusion-weighted magnetic resonance imaging (DWI)5 is the optimal approach currently for the accurate detection of the water molecule movement in vivo.6 Additionally, to obtain precise information on the hemodynamics and microvascular permeability of tumor microvascular, the technique of dynamic contrast-enhanced perfusion weighted imaging (DCE-PWI) has been used in clinic recently.7 To collect the information by DCE-PWI, regarding the physiological tissue characteristics, it must be pre-injected small-molecule gadolinium chelates such as 2 ACS Paragon Plus Environment

Page 3 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

Gd-DTPA (Magnevist®) in clinic.8 However, Magnevist cannot promote the DWI sensitivity9 and causes the MRI artifacts in DWI,10 limiting its application in combined

DWI/DCE-PWI

to

get

full

information

about

tumor

vascular

microenvironment. Therefore, the design of the bifunctional contrast agents for both DWI/DCE-PWI sequences is significant and would provide a more convenient way for tumors malignancy detection. Judging from the principle of MRI, the lattice defects, such as the paramagnetic defects in the graphene quantum dots11,12 or oxygen vacancies13 on the surfaces of tungstate nanoparticles would influence the signal intensities of traditional T1-MRI sequences, which presents an another dimension on the excavation of functional nano-CAs. The apparent diffusion coefficient (ADC) value of water molecules movement in DWI requires limiting the moment of water molecules. As the widely used catalytic materials,14-16 cerium oxide-based nanomaterials have abundant oxygen vacancies on the surface, which are suitable to act as nano-CAs for DCE-PWI MRI. The oxygen vacancies of cerium oxide could bond the oxygen atoms of the water molecules around the nanoparticles17,18 and thereby amplify the r1 value.2 More importantly, the oxygen vacancies can limit the diffusion movement of water molecules, possibly leading to improved DWI signals. In this study, Gd3+-doped ultra-small CeO2 (CeO2:Gd) nanoparticles with surface oxygen vacancies19,20 were synthesized as the DWI/DCE-PWI nano-CAs. Oxygen vacancies on the CeO2:Gd nanoparticles can bond the water molecules to accelerate the proton relaxation of the water molecules to ensure a high r1 value (19.89 mM−1 s−1), which guarantees higher resolution DCE-PWI images than that of Magnevist at the same concentration of Gd3+. Moreover, our results showed that PEG-CeO2:Gd


ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 26

could increase the relative DWI signals strength at different b factors with lower magnetic susceptibility artifacts than Magnevist. As far as we know, this study firstly applied the defects-adjusted MRI strategy to design nano-CAs for preferable DCE-PWI and DWI information dynamically (Scheme 1). The defects-adjusted MRI strategy may provide a non-traditional approach for the design of MRI inorganic nano-CAs, demonstrating its bright prospects for the more sensitive tumor detection. RESULT AND DISCUSSION. Synthesis and Characterization of nano-CAs. The ultra-small Ce2S3:Gd nanoparticles were prepared by a single-source precursor thermal decomposition process,21,22

and

then

were

coated

with

a

layer

of

PEG-phospholipids

(DSPE-PEG)23,24 to become hydrophilic and improve biocompatibility. Finally, the PEG-CeO2:Gd nanoparticles were prepared by a hydrolysis reaction from PEG-Ce2S3:Gd. As shown in the transmission electron microscopy (TEM) images (Figure 1a), the Ce2S3:Gd nanoparticles displayed the average diameter about ~4 nm. As demonstrated in Figure S3 and Figure 1d, the X-ray powder diffraction (XRD) pattern indicated that the as-synthesized Ce2S3 (JCPDS No.27-0104) were successfully transformed into ultra-small Gd-doped CeO2 particles (JCPDS No.43-1002) after hydrolysis reaction. After that ultra-small PEG-CeO2:Gd nanoparticles were obtained, it was performed with the TEM image (Figure 1c) clearly showed the high uniformity of PEG-CeO2:Gd and still exhibiting excellent uniformity after PEG coating. Moreover, the Fourier transform infrared (FT-IR) spectra (Figure S2) indicated that DSPE-PEG had been successfully modified to the surface of CeO2:Gd.

23

Meanwhile, the energy-dispersive X-ray (EDX) spectrum

(Figure S1) demonstrated the presence of all basic elements in Ce2S3:Gd (Ce, Gd, and


Page 5 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

S) and CeO2:Gd (Ce, Gd, and O). As shown in Figure 2a, it was assumed that water molecules absorbed by oxygen vacancies cause the change of MRI signal. To further demonstrate, it is necessary to control the oxygen vacancy concentration on cerium oxide for MRI experiments. According to reports, the presence of Ce3+ in CeO2 based catalysts were generally related to the formation of oxygen vacancies, and larger amounts of oxygen vacancies are indicated by a higher concentration of Ce3+.25,26 Furthermore, the depletion of oxygen vacancies and the formation of Ce4+ in PEG-CeO2:Gd were adjustable by hydrogen's addition peroxide (H2O2).27 Therefore, we use different concentrations of H2O2 to reduce the oxygen vacancies content in PEG-CeO2:Gd to further study the relationship between the oxygen vacancies and the MR signal. The absorption spectra of PEG-CeO2:Gd nanoparticles was shown in Figure 2b. And, the significant red shifted of absorption spectra with the addition of different concentrations of H2O2 was shown in Figure 2c, which indicated the stoichiometric oxidation of the surface Ce3+ to Ce4+ according to previous reports.19,28-30 Before the in vitro MRI experiments, the PEG-CeO2:Gd samples were divided into five groups with different concentrations of H2O2. #1: 10 mM PEG-CeO2:Gd, #2: 100 μmol/L H2O2 + 10 mM PEG-CeO2:Gd, #3: 200 μmol/L H2O2 + 10mM PEG-CeO2:Gd, #4: 400 μmol/L H2O2 + 10 mM PEG-CeO2:Gd and #5: 1000 μmol/L H2O2 + 10 mM PEG-CeO2:Gd. Examination of Figures 2g and 2h depicted the O 1s X-ray photoelectron spectroscopy (XPS) of samples #1 and #5, respectively. Obviously, two kinds of oxygen species: the surface lattice oxygen (Olatt) and the surface absorbed oxygen (Oads) can be observed on the surface of CeO2:Gd. The Oads% (defined as Olatt / (Olatt + Oads)) increased after oxidation by H2O2 may cause by the adsorption of peroxide species (such as O22-) on the surface of nanoparticles. Figures 2d and 2e 5 ACS Paragon Plus Environment

ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 26

exhibited the XPS of Ce in samples #1 and #5, the presence of 8 peaks owing to Ce 3d3/2 and Ce 3d5/2, respectively. The relative Ce3+ concentration ratio decreased indicated a higher Ce4+ concentration in the surface of CeO2:Gd after the oxidation by H2O2, accompanied by the decrease of oxygen vacancies. It was further demonstrated by Raman spectra in Figure 2i. The strong peak at 465 cm−1 due to the vibrational mode with the F2g symmetry in CeO2 lattice.31 The 860 cm-1 peak of #5 can be attributed to stretching of the adsorbed peroxide species. Furthermore, the bands around the peaks at 570 cm-1 and 593 cm-1 for sample #1 and #5 are attributed to the defect-induced CeO2 modes mainly. Notably, the peak approximately 593 cm−1 is directly related to the concentration of oxygen vacancy, and the oxygen vacancy concentration in PEG-CeO2:Gd can be estimated by (I593/I465). Additionally, the I593/I465 of sample #5 (0.102) is lower than that of sample #1 (0.211), proving that the oxygen vacancy concentration in CeO2:Gd is deceased after oxidation by H2O2. Next, the r1 values of a series of aqueous PEG-CeO2:Gd samples containing different H2O2 concentrations were evaluated. According to Figure 3b, the signal intensities of the region of interest on each T1-weighted grayscale images were evaluated for quantitative analysis. No MRI contrast effect was found for PEG-CeO2 in Figure S5. The high magnetic resonance properties of PEG-CeO2:Gd can be attributed only to the influence of oxygen vacancies and Gd3+ ions. The longitudinal relaxivity of PEG-CeO2:Gd obtained from 3 T MRI scanner is 19.89 mM−1 s−1, which is larger than Magnevist. Meanwhile, with the decreasing the concentration of oxygen vacancy (Figure 3a) the r1 value decreased rapidly. Oxygen vacancies in PEG-CeO2:Gd can effectively enhance the contrast ability of MRI, which is confirmed by all the above results. Only utilized the ultrasmall nanoparticles for the traditional T1-MRI application 6 ACS Paragon Plus Environment

Page 7 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

cannot acquire functional information such as tumor vascular microenvironment. As one of main perfusion MRI techniques, DCE-PWI signals establish on measuring shortening of the spin lattice relaxation induced by contrast agents (for instance: Magnevist).32,33 Using CAs with high r1 value, such as PEG-CeO2:Gd, can enhance the signal to noise ratio of DCE-PWI. The permeability and microvessel density of tumor microvessels can be effectively reflected by DCE-PWI. Based on the above considerations, oxygen vacancies magnified PEG-CeO2:Gd nanoparticles can result in a higher resolution of the DCE-PWI images than that of Magnevist at the same concentration of Gd3+. As a functional imaging technique that is based on water molecules' diffusion, DWI has a higher detection sensitivity in tumor malignant than conventional structural imaging.4 The malignancy is one of the tumor diagnosis and treatment research focuses.34-38 DWI and DCE-PWI are often used together to the growth and metastasis of tumors by measure the density of tumor microvascular and microvascular permeability.33 To verify that the signal intensity of DWI can be strengthened by PEG-CeO2:Gd, due to the oxygen vacancies' affinity to the water molecules, 20 ml 10% Gelatin samples were used as vitro models and divided into 3 treatment groups. Various dispersion sensitive factors (b factors) and ADC values6 were applied to measure the effect of PEG-CeO2:Gd for DWI. As shown in Figure 3c, the Gelatin models containing PEG-CeO2:Gd appear brightest in the DWI images and darkest in ADC mapping, further proving that the oxygen vacancies of PEG-CeO2:Gd can restrict the diffusion of water. What's more, the images of PEG-CeO2:Gd group showed a lower magnetic artifact compared the Magnevist group at the same Gd3+ concentration. Thus, the utilized of PEG-CeO2:Gd may overcome the severe shortcoming of combination MR imaging sequences such as DCE-MRI with DWI. 7 ACS Paragon Plus Environment

ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 26

Toxicity Studies. Before intravitreal injection, the typical MTT method confirmed that PEG-CeO2:Gd had good biological safety at the cell level (Figure S6 and S7). Then, the toxicity of PEG-CeO2:Gd in vivo was investigated by blood biochemistry data and H&E-stained tissues, and these results (Figure S12 & S13) validate that PEG-CeO2:Gd has excellent biocompatibility for the further application. MRI Tests In Vivo. Due to the high relaxivity of PEG-CeO2:Gd, we explored the PEG-CeO2:Gd in magnetic resonance angiography (MRA) for blood vessels imaging besides tumor tissue. Figure 4a showed that the obtained images clearly reveal the blood vessels when PEG-CeO2:Gd were used instead of Magnevist as CAs in MRA imaging. While the mouse group injected with Magnevist fails to deliver clear images, showing no visible blood vessels at the same Gd dose. Next, the time-signal intensity curves of the PEG-CeO2:Gd and Magnevist-injected groups indicated PEG-CeO2:Gd can maintain the perfusion enhanced signal for a longer time (Figure S14), showing its potential for further DWI/DCE-PWI research. DCE-PWI can provide four significant pharmacokinetic parameters for microvascular permeability detection, such as volume transfer coefficient (Ktrans), blood plasma volume fraction (Vp), flux rate constant (kep) and extracellular volume fraction (Ve). Figure S9 showed the MR images of two groups before the injection of PEG-CeO2:Gd or Magnevist (I.V. 5 mg Gd3+ /kg at the rate of 0.1 ml/s for 1 ml), and it can be seen that the sizes of the two groups‘ tumors are close. As shown in Figure 4b, the tumor tissue of the PEG-CeO2:Gd group displayed a higher signal than that of the Magnevist group in the Ktrans, Ve and Vp mapping images, proving that the PEG-CeO2:Gd can enhance these signal better than Magnevist at the same Gd3+ concentration, while there is no noticeable difference in the images of kep (kep =


Page 9 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

Ktrans/Ve). Since kep is related to reflux of the contrast agent from the extracellular space back to the vessel, which due to the reduction of the contrast agent reflux caused by the EPR effect in the tumor area. Regarding the performance of DCE-MRI signal enhancement in the tumor area after the PEG-CeO2:Gd injection, it can be used for the more sensitive identification of benign and malignant tumors and obtaining the characteristics of the tumor microvessels. Due to oxygen vacancies on the surfaces of PEG-CeO2:Gd nanoparticles would inhibit the diffusion of water by the affinity of water molecules, PEG-CeO2:Gd can be a 'bridge' for DWI and DCE-PWI. The above experiments have proved the DCE-PWI effect of PEG-CeO2:Gd, and then we further studied their DWI capability in vivo. Subsequently, the DWI signal of the PEG-CeO2:Gd injected group demonstrated a dramatic strengthening effect in Figure 5a, with the relative signal strength increasing by 1.59 and 1.61 times at different b factors (b=500, b=1000), respectively. The DWI signal of the tumor tissue increased by 1.23 and 1.21 times (Figure 5b) after the injection of Magnevist caused by the blood vessel shrinkage in tumor tissue by Magnevist.33 To further confirm these results, ADC images of tumor tissues in mice injected with PEG-CeO2:Gd or Magenvec were measured. The darker signal in the ADC images represented the restricted movement of water diffusion. The relative reduction rate of ADC value after PEG-CeO2:Gd injection is 53.7%, which is lower than that of the Magnevist injected group (87.5%), further proving that PEG-CeO2:Gd can reduce the local water diffusion in tumor tissue (Figure 5c). To demonstrate evidence about PEG-CeO2:Gd promoting DWI signal in tumor with different size, we calculated signal of four groups of tumor-bearing mice ( Figure S16). Meanwhile, the above


ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 26

results about tumor microvessel environment were further confirmed by the immunofluorescence images (Figure S17) and immunohistochemical staining (Figure S18 - 20). The CD31 and α-SMA immunofluorescence images showed the permeability of vessels with different tumor size. The results indicated that the PEG-CeO2:Gd could enhance the DWI signal-noise ratio, even at the tissue with slightly diffusion-limited. Moreover, the immunohistochemical staining of antibody against angiopoietin-1 (Ang-1) and antibody against angiopoietin-2 (Ang-2) were then collected to assess the vascular density/permeability of microvessels. PEG-CeO2:Gd-injected group has a better DCE-PWI performance at the same vascular environment, which shows potential to precisely measure the tumor tissue and microvascular permeability for the detection in the future. CONCLUSION Our research provided a nano-CAs based on CeO2:Gd for DWI/DCE-PWI enhancement with low magnetic resonance artifacts. More importantly, this report describes what we believe to be the first attempt to apply the oxygen-vacancy enhanced DWI/DCE-PWI CAs for improving the sensitivity of detecting the tumor microvascular environment. The ultrasmall CeO2:Gd nanoparticles exhibited high DCE-PWI performance with exceptional r1 value, as well as desirable DWI ability by bonding to the oxygen atoms of the water molecules. The combination of anatomic, biologic,

and

hemodynamic

information

offered

by

DWI/DCE-PWI

with

PEG-CeO2:Gd makes it successful as an imaging tool to measure the metastasis of tumors. Furthermore, our synthetic strategy may provide a general route for the design of CAs rather than traditional dual-mode imaging agents. Besides, many other defects (e.g., paramagnetic defects, dislocations) besides the oxygen vacancies can potentially


Page 11 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

be used as a CAs designing tool for various MRI sequences. METHODS

Materials and Reagents. Oleylamine (80%-90%) were purchased from Sigma-Aldrich, Inc. Gadolinium nitrate hexahydrate (99.9%), Diethylammonium diethyldithiocarbamate (Ddtc), 2,2'-Bipyridyl (Bipy) and Cerium nitrate hexahydrate (99.9%)

were

purchased

from

Adamas Reagent Co., Ltd. DSPE-PEG

(thiol-polyethylene glycol) was obtained from Jenkem Technology Co., Ltd. Beijing. All chemical reagents were used directly without any purification. Characterization. Transmission electron microscopy (TEM) images were obtained with JEOL 200CX. X-ray diffraction (XRD) was performed using a Rigaku D/MAX-2250 V at Cu Kα (λ = 0.154056 nm) with the scanning rate of 6 ° min-1 in the 2θ range of 10-80 °. Agilent 700 Series inductively coupled plasma optical emission spectrometer (ICP-OES) was used to determine the concentration of elements. The Fourier transform infrared spectroscopy (FT-IR) spectra was obtained by a Nicolet 7000-C spectrometer with KBr pellets. Confocal laser scanning microscopy (CLSM) images were recorded by A1R+ (Nikon Corporation). The Micro-Raman spectra were obtained by using a DXR Raman Microscope (Thermal Scientific Corporation, USA) with 532 nm excitation wavelength. In Vitro MRI Tests. The T1 MR imaging experiments and in vitro DWI experiments of the samples with different concentrations were performed using a clinical MRI scanner (MagnetomVerio/Trio TIM, Siemens Healthcare, 3.0 T). To test the enhancement performance of the relaxation rate r1 of the surface oxygen vacancies of PEG-CeO2:Gd in vitro, PEG-CeO2:Gd at the given Gd concentrations of 0.00357, 0.00713, 0.01426, 0.0285, 0.057 and 0.114 mM were dispersed in 1 ml of dibasic 11 ACS Paragon Plus Environment

ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 26

sodium phosphate-citric acid buffer solution (pH = 7.4) and placed in centrifuge tubes (1.5

ml) for MRI scanning. To test the DWI signal enhancement of PEG-CeO2:Gd

in vitro, we have designed a 10% gelatin gel model to simulate tumor tissue. Gelatin models were divided into 3 groups including 20 ml gelatin gel and 10% 2 ml water, 2 ml nanoparticles or Magnevist (7 mg/ml Gd3+), respectively. The used DWI sequence with the following scan parameters: TE = 54 ms; TR = 2700 ms; slice gap = 0.3 mm; voxel size = 1.3×1.3×3.0 mm; slice thickness = 3.0 mm; flip angle = 180°; b factors = 0, 500, 1000 s/mm2; FOV = 150×75 mm; bandwidth = 825 Hz/Px; TA = 7 min 22 s. In Vivo DWI/DCE-PWI Test. A549 cells (106 in 100 μL) were injected into the Balb/c nude mice's right hind leg region subcutaneously to establish an A549 tumor model. For in vivo tests, DWI/DCE-PWI, A549-tumor-bearing mice were intravenously ( 5 mg Gd3+/kg) injected with PEG-CeO2:Gd or Magnevist by 64 G venous indwelling needle at the speed of 0.1 ml/s for 1 ml. Prior to the introduction of the contrast agent, different turn angles (flipangle) were used to repeatedly scan the region of interest, and the T1 values of normal tissue and tumor tissue points as a baseline by fitting calculation were obtained. After the introduction of CAs, the turn angle was set to flipangle =15 °, and the same area was scanned 40 times to obtain the relevant quantitative parameters and pseudo color. The scanning parameters of DCE-MRI are as follows: echo time (TE) = 2.46 ms; repetition time (TR) = 6.42 ms; slice gap =0.2 mm; flip angle = 15°; slice voxel size = 0.4×0.4×1.0 mm; field of view (FOV) = 71 ×71 mm; thickness = 1.0 mm; bandwidth = 260 Hz/Px; number of dynamics = 40; acquisition time (TA) = 5 min 9 s. ADC value was obtained by calculating the DWI signal at various dispersion sensitive factors (b factors) : ADC(x,y,z) = ln[S2(x,y,z)/S1(x,y,z)]/(b2-b1) (S1 and S2 are signal intensities under different diffused sensitive factors (b1 and b2)). After the injection of PEG-CeO2:Gd 12 ACS Paragon Plus Environment

Page 13 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

or Magnevist, and the nude mice in different groups were scanned with high resolve DWI at the same parameters (b = 0, 500, 1000). The scanning position was transversal and the scanning parameters for DWI are as follows: TR = 2700 ms; slice gap = 0.3 mm; TE = 54 ms; flip angle = 180°; voxel size = 1.3×1.3×3.0 mm; b factors = 0, 500, 1000 s/mm2; slice thickness = 3.0 mm; FOV = 150×75 mm; bandwidth = 825 Hz/Px; TA = 7 min 22 s.

Scheme 1. Schematic diagram of DWI and DCE-PWI signal in tumor tissue enhanced by PEG-CeO2:Gd. The absorption of oxygen atoms in water molecules by oxygen vacancies cause the water molecules diffusion constriction and promote the interactions between water molecules and Gd3+.


ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 26

Figure 1. (a) Schematic illustration of the synthesis process of ultrasmall PEG-CeO2:Gd nanoparticles. (b) TEM image of ultrasmall Ce2S3:Gd nanoparticles dispersed in cyclohexane. (c) TEM image of hydrophilic modified ultra-small PEG-CeO2:Gd.

(d) XRD patterns of PEG-CeO2:Gd.


Page 15 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

Figure 2. (a) Schematic diagram of water molecules abbsorbed by oxygen vacancies effect on the diffusion characteristics of water molecules and the interaction between water and the Gd3+ ions. (b) UV−vis−NIR absorption spectrum of PEG-CeO2:Gd in aqueous solution (inset: photograph of PEG-CeO2:Gd in aqueous solution). (c) UV−vis−NIR absorption spectra of the PEG-CeO2:Gd samples treated with various concentrations of H2O2. (d) Ce XPS patterns of sample #1 and #5. (e) Ce XPS patterns of sample #1 and #5. (f) XPS spectrum of Gd 3d. (g) O 1s XPS spectrum of sample #1. (h) O 1s XPS spectrum of #5. (i) Raman spectra of pure CeO2, sample #1 and #5.


ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 26

Figure 3. (a) The longitudinal relaxation rates of PEG-CeO2:Gd oxidized with with various concentrations of H2O2. (b) Corresponding T1-weighted MR images obtained from PEG-CeO2:Gd at various Gd3+ concentrations. (c) DWI phantom images of different b=0, 500, 1000 and ADC mapping obtained from PEG-CeO2:Gd group and Magnevist group, respectively. Image of first column is the 20 ml deionized water sample, while the second column is 20 ml 10% gelatin and the third column is gelatin contain PEG-CeO2:Gd or Magnevist (7 mg/ml Gd3+).


Page 17 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

Figure 4. (a) MRA images of BALB/c nude mice immediately after the intravenous administration of PEG-CeO2:Gd or Magnevist. (b) Pseudo color map for four parameters of DCE-PWI Mapping (Ktrans, kep, Ve, Vp) of BALB/c nude mice after injection with PEG-CeO2:Gd or Magnevist (I.V. 5 mg Gd3+/kg).


ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 26

Figure 5. (a) The DWI images and specific tumor tissue signals acquired from pre and after injection of PEG-CeO2:Gd with different b factors. (b) DWI images and signal enhancement of Magnevist group with the same b factors. (c) ADC mapping of tumor obtained from pre and after injection with PEG-CeO2:Gd or Magnevist. (d) Relative ADC value enhancement after PEG-CeO2:Gd or Magnevist injection.

ASSOCIATED CONTENT Supporting Information. Supplementary

Figures

(Figure

S1-S21),

and

characterization

data.

The 18

ACS Paragon Plus Environment

Page 19 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

Supplementary Information is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] *E-mail: [email protected] Author Contributions ∥ C. S. and A. S. contributed equally to this work. The authors declare no competing financial interest.

ACKNOWLEDGMENT This work has been financially supported by the China National Funds for Distinguished Young Scientists (Grant No. 51725202), the National Natural Science Foundation of China (Grant No. 51872094, 51702211, 81771889), the Shanghai Excellent Academic Leaders Program (Grant No.16XD1404000), the National Key R&D Program of China (2018YFA0107900) and the Key project of the Ministry of Science and Technology, China (Grant No.YS2017ZY040123).

The table of contents entry An oxygen vacancies enhanced DWI/DCE-PWI CA based on CeO2:Gd, which promote the number of bound water molecules on the nanoparticle surface to improve the r1 value, and has excellent DCE-PWI performance. With DWI signal enhancement due to oxygen vacancy’s affinity to the water molecules, CeO2:Gd can 19 ACS Paragon Plus Environment

ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 26

be suitable DWI/DCE-PWI CAs for provide a wealth of tumor vascular information.

REFERENCES (1) Padhani, A. R.; Liu, G.; Mukoh, D.; Chenevert, T. L.; Thoeny, H. C.; Takahara, T.;

Andrew,DJ.; Brian D.; Marc C.; David C.; Dima, V. H.; Gordon R.; Bachir,T.;

Peter C.;

Diffusion-Weighted Magnetic Resonance Imaging as a Cancer Biomarker:

Consensus and Recommendations. Neoplasia 2009, 11, 102-125. (2) Toy, R.; Hayden, E.; Camann, A.; Berman, Z.; Vicente, P.; Tran, E.; Meyers, J.; Pansky, J.; Peiris, P. M.; Wu, H. P.; Exner, A.; Wilson, D.; Ghaghada, K. B.; Karathanasis, E., Multimodal In Vivo Imaging Exposes the Voyage of Nanoparticles in Tumor Microcirculation. Acs Nano 2013, 7, 3118-3129. (3)

Yu, M. X.; Zhou, C.; Liu, L.; Zhang, S. R.; Sun, S. S.; Hankins, J. D.; Sun, X.

K.; Zheng, J., Interactions of Renal-Clearable Gold Nanoparticles with Tumor Microenvironments: Vasculature and Acidity Effects. Angew. Chem., Int. Ed. 2017, 56, 4314-4319. 20 ACS Paragon Plus Environment

Page 21 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

(4)

Di Costanzo, A.; Scarabino, T.; Trojsi, F.; Giannatempo, G. M.; Popolizio, T.;

Catapano, D.; Bonavita, S.; Maggialetti, N.; Tosetti, M.; Salvolini, U.; d'Angelo, V. A.; Tedeschi, G., Multiparametric 3T MR Approach to the Assessment of Cerebral Gliomas: Tumor Extent and Malignancy. Neuroradiology 2006, 48, 622-631. (5) Nougaret, S.; Tirumani, S. H.; Addley, H.; Pandey, H.; Sala, E.; Reinhold, C., Pearls and Pitfalls in MRI of Gynecologic Malignancy With Diffusion-Weighted Technique. Am J Roentgenol. 2013, 200, 261-276. (6) Kuang, F.; Ren, J.; Zhong, Q.; Liyuan, F.; Huan, Y.; Chen, Z., The Value of Apparent Diffusion Coefficient in the Assessment of Cervical Cancer. Eur Radiol. 2013, 23, 1050-8. (7) Bergamino, M.; Bonzano, L.; Levrero, F.; Mancardi, G. L.; Roccatagliata, L., A Review of Technical Aspects of T-1-weighted Dynamic Contrast-enhanced Magnetic Resonance Imaging (DCE-MRI) in Human Brain Tumors. Phys Medica. 2014, 30, 635-643. (8) Padhani, A. R., Dynamic Contrast-enhanced MRI in Clinical Oncology: Current Status and Future Directions. J Magn Reson Imaging. 2002, 16, 407-422. (9) Wang, C. L.; Chea, Y. W.; Boll, D. T.; Samei, E.; Neville, A. M.; Dale, B. M.; Merkle, E. M., Effect of Gadolinium Chelate Contrast Agents on Diffusion Weighted MR Imaging of the Liver, Spleen, Pancreas and Kidney at 3 T. Eur J Radiol. 2011, 80, E1-E7. (10) Qian, M.; Liu, X. H., The Effect of MRI Contrast Agent Gadolinium Diethy Lenetviamine-pentaacid on the Diffusion-weighed Imaging. Oncoradiology 2013, 031. 21 ACS Paragon Plus Environment

ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 26

(11) Wang, H.; Revia, R.; Wang, K.; Kant, R. J.; Mu, Q.; Gai, Z.; Hong, K.; Zhang, M., Paramagnetic Properties of Metal-Free Boron-Doped Graphene Quantum Dots and Their Application for Safe Magnetic Resonance Imaging. Adv. Mater. 2017, 29, 1605416. (12) Peng, J.; Guo, Y.; Lv, H.; Dou, X.; Chen, Q.; Zhao, J.; Wu, C.; Zhu, X.; Lin, Y.; Lu, W.; Wu, X.; Xie, Y., Superparamagnetic Reduced Graphene Oxide with Large Magnetoresistance: a Surface Modulation Strategy. Angew. Chem., Int. Ed. 2016, 55, 3176-80. (13) Ni, D.; Zhang, J.; Wang, J.; Hu, P.; Jin, Y.; Tang, Z.; Yao, Z.; Bu, W.; Shi, J., Oxygen Vacancy Enables Markedly Enhanced Magnetic Resonance Imaging-Guided Photothermal Therapy of a Gd(3+)-Doped Contrast Agent. ACS Nano 2017, 11, 4256-4264. (14) Hartmann, P.; Brezesinski, T.; Sann, J.; Lotnyk, A.; Eufinger, J. P.; Kienle, L.; Janek, J., Defect Chemistry of Oxide Nanomaterials with High Surface Area: Ordered Mesoporous Thin Films of the Oxygen Storage Catalyst CeO2-ZrO2. Acs Nano 2013, 7, 2999-3013. (15) Wen, C.; Zhu, Y.; Ye, Y. C.; Zhang, S. R.; Cheng, F.; Liu, Y.; Wang, P.; Tao, F., Water-Gas Shift Reaction on Metal Nanoclusters Encapsulated in Mesoporous Ceria Studied with Ambient-Pressure X-ray Photoelectron Spectroscopy. Acs Nano 2012, 6, 9305-9313. (16) Tamura, M.; Tomishige, K., Redox Properties of CeO2 at Low Temperature: The Direct Synthesis of Imines from Alcohol and Amine. Angew. Chem., Int. Ed. 2015, 54, 864-867.


Page 23 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

(17) Kowalski, P. M.; Meyer, B.; Marx, D., Composition, Structure, and Stability of the Rutile TiO2(110) Surface: Oxygen Depletion, Hydroxylation, Hydrogen Migration, and Water Adsorption. Phys. Rev. B 2009, 79, 115410. (18) Fronzi, M.; Piccinin, S.; Delley, B.; Traversa, E.; Stampfl, C., Water Adsorption on the Stoichiometric and Reduced CeO2(111) Surface: a First-principles Investigation. Phys. Chem. Chem Phys. 2009, 11, 9188-99. (19) Wang, Y. J.; Dong, H.; Lyu, G. M.; Zhang, H. Y.; Ke, J.; Kang, L. Q.; Teng, J. L.; Sun, L. D.; Si, R.; Zhang, J.; Liu, Y. J.; Zhang, Y. W.; Huang, Y. H.; Yan, C. H., Engineering the Defect State and Reducibility of Ceria Based Nanoparticles for Improved Anti-oxidation Performance. Nanoscale 2015, 7, 13981-90. (20) Ke, J.; Xiao, J. W.; Zhu, W.; Liu, H.; Si, R.; Zhang, Y. W.; Yan, C. H., Dopant-induced Modification of Active Site Structure and Surface Bonding Mode for High-performance Nanocatalysts: CO Oxidation on Capping-free (110)-oriented CeO2:Ln (Ln = La-Lu) Nanowires. J. Am. Chem. Soc. 2013, 135, 15191-200. (21) Zhao, F.; Sun, H. L.; Su, G.; Gao, S., Synthesis and Size-dependent Magnetic Properties of Monodisperse EuS Nanocrystals. Small 2006, 2, 244-8. (22) Zhou, X. Z.; Zhang, K. H. L.; Xiong, J.; Park, J. H.; Dickerson, J. H.; He, W. D., Size- and Dimensionality-dependent Optical, Magnetic and Magneto-optical Properties of Binary Europium-based Nanocrystals: EuX (X = O, S, Se, Te). Nanotechnol. 2016, 27, 192001. (23) Erogbogbo, F.; Yong, K. T.; Hu, R.; Law, W. C.; Ding, H.; Chang, C. W.; Prasad, P. N.; Swihart, M. T., Biocompatible Magnetofluorescent Probes:


ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 26

Luminescent Silicon Quantum Dots Coupled with Superparamagnetic Iron(III) Oxide. Acs Nano 2010, 4, 5131-5138. (24) Yu, B.; Wei, H.; He, Q.; Ferreira, C. A.; Kutyreff, C. J.; Ni, D.; Rosenkrans, Z. T.; Cheng, L.; Yu, F.; Engle, J. W., Efficient Uptake of 177Lu-Porphyrin-PEG Nanocomplexes

by

Tumor

Mitochondria

for

Multimodal-Imaging-Guided

Combination Therapy. Angew. Chem., Int. Ed. 2018, 57, 218-222. (25) Lv, L.; Zha, D. C.; Ruan, Y. J.; Li, Z. S.; Ao, X.; Zheng, J.; Jiang, J. J.; Chen, H. M.; Chiang, W. H.; Chen, J.; Wang, C. D., A Universal Method to Engineer Metal Oxide-Metal-Carbon Interface for Highly Efficient Oxygen Reduction. Acs Nano 2018, 12, 3042-3051. (26) Cafun, J. D.; Kvashnina, K. O.; Casals, E.; Puntes, V. F.; Glatzel, P., Absence of Ce3+ Sites in Chemically Active Colloidal Ceria Nanoparticles. Acs Nano 2013, 7, 10726-10732. (27) Kim, H. Y.; Lee, H. M.; Henkelman, G., CO Oxidation Mechanism on CeO(2)-supported Au Nanoparticles. J. Am. Chem. Soc. 2012, 134, 1560-70. (28) Lee, S. S.; Song, W. S.; Cho, M. J.; Puppala, H. L.; Nguyen, P.; Zhu, H. G.; Segatori, L.; Colvin, V. L., Antioxidant Properties of Cerium Oxide Nanocrystals as a Function of Nanocrystal Diameter and Surface Coating. Acs Nano 2013, 7, 9693-9703. (29) Karakoti, A. S.; Singh, S.; Kumar, A.; Malinska, M.; Kuchibhatla, S. V.; Wozniak, K.; Self, W. T.; Seal, S., PEGylated Nanoceria as Radical Scavenger with Tunable Redox Chemistry. J. Am. Chem. Soc. 2009, 131, 14144-5.


Page 25 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Nano

(30) Edwards, J. K.; Pritchard, J.; Lu, L.; Piccinini, M.; Shaw, G.; Carley, A. F.; Morgan, D. J.; Kiely, C. J.; Hutchings, G. J., The Direct Synthesis of Hydrogen Peroxide Using Platinum-Promoted Gold-Palladium Catalysts . Angew. Chem., Int. Ed. 2014, 53, 2381-2384. (31) Baron, M.; Abbott, H.; Bondarchuk, O.; Stacchiola, D.; Uhl, A.; Shaikhutdinov, S.; Freund, H. J.; Popa, C.; Ganduglia-Pirovano, M. V.; Sauer, J., Resolving the Atomic Structure of Vanadia Monolayer Catalysts: Monomers, Trimers, and Oligomers on Ceria. Angew. Chem., Int. Ed. 2009, 48, 8006-8009. (32) Youk, J. H.; Son, E. J.; Chung, J.; Kim, J. A.; Kim, E. K., Triple-negative Invasive Breast Cancer on Dynamic Contrast-enhanced and Diffusion-weighted MR Imaging: Comparison with Other Breast Cancer Subtypes. Eur. Radiol. 2012, 22, 1724-1734. (33) Ogura, A.; Hayakawa, K.; Miyati, T.; Maeda, F., The Effect of Susceptibility of Gadolinium Contrast Media on Diffusion-weighted Imaging and the Apparent Diffusion Coefficient. Acad. Radiol. 2008, 15, 867-872. (34) Chen, J.; Ding, J.; Xu, W.; Sun, T.; Xiao, H.; Zhuang, X.; Chen, X., Receptor and Microenvironment Dual-Recognizable Nanogel for Targeted Chemotherapy of Highly Metastatic Malignancy. Nano Lett. 2017, 17, 4526-4533. (35) Cong, Y.; Xiao, H.; Xiong, H.; Wang, Z.; Ding, J.; Li, C.; Chen, X.; Liang, X. J.; Zhou, D.; Huang, Y., Dual Drug Backboned Shattering Polymeric Theranostic Nanomedicine for Synergistic Eradication of Patient-Derived Lung Cancer. Adv. Mater. 2018, 30, 1706220.


ACS Nano 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 26

(36) Kwon, O. S.; Song, H. S.; Conde, J.; Kim, H. I.; Artzi, N.; Kim, J. H., Dual-Color Emissive Upconversion Nanocapsules for Differential Cancer Bioimaging In Vivo. Acs Nano 2016, 10, 1512-21. (37) Ma, P.; Xiao, H.; Yu, C.; Liu, J.; Cheng, Z.; Song, H.; Zhang, X.; Li, C.; Wang, J.;

Gu,

Z.;

Lin,

J.,

Enhanced

Cisplatin

Chemotherapy

by

Iron

Oxide

Nanocarrier-Mediated Generation of Highly Toxic Reactive Oxygen Species. Nano Lett. 2017, 17, 928-937. (38) Mi, P.; Kokuryo, D.; Cabral, H.; Wu, H.; Terada, Y.; Saga, T.; Aoki, I.; Nishiyama, N.; Kataoka, K., A pH-activatable Nanoparticle with Signal-amplification Capabilities for Non-invasive Imaging of Tumour Malignancy. Nat. Nanotechnol. 2016, 11, 724-30.


Oxygen Vacancies Enhanced CeO2:Gd Nanoparticles for Sensing a

Recommend Documents