H2O2-Responsive MB–BSA–Fe(III) Nanoparticles as Oxygen Generators for MRI-Guided Photodynamic Therapy

  • Wen-Yao Zhen
  • Jing Bai
  • Xiao-Dan Jia
  • Lie Wu
  • Xiu-E Jiang
Original Paper


The local tumor hypoxia has become one of the main obstacles for photodynamic therapy (PDT).To break through this barrier, the fabrication of O2-evolving nanoplatform has been more significant. Herein, the uniform methylene blue (MB)–bovine serum albumin (BSA)–Fe(III) nanoparticles (MB–BSA–Fe(III) NPs) were successfully synthesized by biomineralization approach. MB–BSA–Fe(III) NPs show high loading capacity of MB, and Fe(ΙΙΙ) has excellent catalytic performance towards abundant H2O2 in cancer cells to generate O2, overcoming tumor hypoxia. All these combination effects remarkably increase the therapeutic efficiency of PDT, resulting in almost complete destruction of cancer cells. Most importantly, MB–BSA–Fe(III) NPs exhibit T2- magnetic resonance imaging, which have the potential for precise visualization of the tumor location. Our results demonstrate that MB–BSA–Fe(III) is a novel H2O2-responsive and O2-evolving nanoplatform and it has great potential for clinical applications such as cancer diagnosis, treatment or drug delivery.


Photodynamic therapy Biomineralization H2O2-responsive O2 generator Photosensitizer Magnetic resonance imaging 

1 Introduction

For the past few decades, cancer has turned into one of the leading causes of modality, and more effort has to be devoted to seek a practicable approach to treat cancer [1, 2]. Photodynamic therapy (PDT) has been proven effective for treating different types of tumor [3, 4] because of its noninvasive nature, less inflammatory side effect, negligible drug resistance and low systemic toxicity [5]. PDT produces toxic reactive oxygen species (ROS) such as 1O2 through using a nontoxic photosensitizer (PS) and specific wavelength light in the presence of oxygen, and induces cell death [6]. However, tumor hypoxia greatly limits the efficiency of PDT [7]. The design and synthesis of nanomaterials with an efficient O2-evolving property and high loading capacity of PS are of great significance but still challenging.

Recently, multifunctional nanoparticles fabricated by employing biomineralization approach have attracted much attention in biomedical and multimodal imaging applications [8]. Protein has abundant active groups, which offer great possibility to integrate organic molecules and trigger the formation of metal ions into ion complex at mild temperature [9, 10]. In addition, albumin-mediated nanomaterials showed good biocompatibility, high diagnostic agent delivery capacity, robust stability, excellent water solubility and good reproducibility, and have potential for medical diagnosis and treatment [11]. Consequently, it is sensible to prepare multifunctional nanomaterials through biomineralization approach.

Methylene blue (MB) is a member of the photosensitizer (PS) family, which has been used for PDT because of excellent photochemical properties for generating 1O2 [12]. Meanwhile, MB is also a fluorescent agent that can emit NIR fluorescence for imaging. In this work, we synthesized uniform MB–bovine serum albumin (BSA)–Fe(III) nanoparticles (MB–BSA–Fe(III) NPs) through biomineralization; MB was successfully loaded onto BSA–Fe(III) NPs through hydrophobic interaction and covalent bond. In addition, MB–BSA–Fe(III) NPs exhibit T2-weighted magnetic resonance imaging (MRI), which shows great potential for precise visualization of the tumor location and microstructure. Most importantly, the above associated functions of the biocompatible MB–BSA–Fe(III) NPs can generate abundant O2 in H2O2-rich cancer micro-environment (100 µM to 1 mM) [13] and overcome tumor hypoxia by breaking through hypoxia-associated resistance of PDT (Scheme 1).
Scheme 1

Schematic illustration of synthesis and therapeutic mechanisms of MB–BSA–Fe(III) NPs

2 Experimental Section

2.1 Chemicals and Reagents

Bovine serum albumin (BSA), 1,3-diphenylisobenzofuran (DPBF), methyl thiazolyl tetrazolium (MTT), methylene blue (MB), FeCl3 and NaOH were purchased from Aladdin Reagents Company (Shanghai, China). Ethanol, H2O2 (30%) were obtained from Beijing Chemical Reagents Company (Beijing, China). Dulbecco’s modified Eagle’s medium (DMEM) was purchased Thermo Scientific (Beijing, China). [Ru(dpp)3]Cl2 (RDPP), calcein acetoxymethyl ester (Calcein AM), propidium iodide (PI) and 2,7-dichlorofluorescein diacetate (DCFH-DA) were obtained from Sigma–Aldrich (MO, America). Standard fetal bovine serum (FBS) was purchased from Tianjin Haoyang Biological Manufacture Co. Ltd. (Tianjin, China). Dimethyl sulfoxide (DMSO) was obtained from Tianjin Concord Technology. The deionized (DI) water was generated using a Millipore–Milli-Q system (Billerica, MA). All the chemicals were used without additional purification.

2.2 Characterizations

The morphology of MB–BSA–Fe(III) NPs and BSA–Fe(III) NPs was investigated by transmission electronic microscope (TEM, H-600 electron microscope, Hitachi, Japan). Fourier transform infrared (FTIR) spectra were measured on a Nicolet 520 FTIR spectrometer (Nicolet) equipped with a germanium attenuated total reflection (ATR) accessory, DTGS KBr detector, and KBr beam splitter (Thermo Fisher Scientific, USA). UV-1700 spectrophotometer (Shimadzu, Japan) was utilized to obtain UV–Vis absorption spectra. The concentration of metallic element was measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES, Thermo Scientific Xseries 2, Thermo Fisher Scientific, USA). The portable dissolved oxygen meters (JPBJ-608, INESA, China) were utilized to monitor the concentration of dissolved oxygen.

2.3 Preparation of MB–BSA–Fe(III) NPs and BSA–Fe(III) NPs

To prepare MB–BSA–Fe(III) NPs, BSA (1 g) was dissolved in deionized water (36 mL), and 1 mL of FeCl3 aqueous solution (100 mM) was added into the above mixture under vigorous stirring. Then, MB aqueous solution (0.5 mg mL−1, 1 mL) was added dropwise into the mixture, then, NaOH solution (2.0 M) was applied to regulate pH (pH 12) and the mixture was stirred at 25 °C for 12 h in dark. Finally, the mixture was further dialyzed (membrane cutoff Mw: 100 KD) against deionized water for 24 h to remove excess precursors. The preparation process of BSA–Fe(III) NPs is similar to MB–BSA–Fe(III) NPs, and only the MB was not required during the preparation process. The precise concentration of MB loaded onto MB–BSA–Fe(III) NPs was detected by the UV–Vis spectrophotometer. The exact concentrations of Fe were detected by ICP–AES.

2.4 Extracellular Generation of O2

25 mL of MB–BSA–Fe(III) NPs aqueous solution (3 mg mL−1, [MB] = 5.89 µg mL−1) was added into 25 µL of H2O2 (30%) under vigorous stirring at room temperature. The dissolved oxygen meter was inserted into the above solution to detect the concentration of O2 every 10 s. MB–BSA–Fe(III) NPs aqueous solution without the addition of H2O2 served as control.

2.5 Extracellular 1O2 Detection

DPBF was employed to evaluate the 1O2 generation of MB–BSA–Fe(III)-NPs by UV–Vis absorption spectra. 10 µL of DPBF solution (10 mM in ethanol) was added into 890 µL of ethanol solution containing different concentrations of H2O2 (0, 40, 80 and 100 µM). Then, the mixture was transferred into a 10 mm-cuvette. The cuvette was irradiated with a 650 nm laser for 10 min (0.1 W cm−2) after the addition of MB–BSA–Fe(III) NP aqueous solution (2 mg mL−1, [MB] = 3.92 µg mL−1, 100 µL). The absorbance of DPBF at 410 nm was recorded every 2 min. The group without H2O2 and laser illumination served as control.

2.6 In Vitro Dark Cytotoxicity of MB–BSA–Fe(III) NPs

HeLa cells (5 × 103 cells per well) were seeded onto 96-well plates and incubated in 5% CO2 at 37 °C for 24 h. Then, 200 µL of MB–BSA–Fe(III)NP solution with different concentrations (0, 0.2, 0.4, 1, 1.5, 2 mg mL−1 in culture medium) were added into each well, and the cells were continued to be cultured for another 24 h. Cells were washed twice with PBS, and then 100 µL of MTT solution (0.5 mg mL−1 MTT in PBS, pH 7.4) was added into each well. Then, cells were incubated for another 4 h and the PBS was abandoned. The intracellular formazan crystals were dissolved by adding 100 µL of DMSO. The absorbance was recorded at 570 nm by a plate reader, and the cell viability was determined by comparing cells with control group.

2.7 The Detection of Intracellular O2

The intracellular production of O2 was measured with RDPP by confocal laser fluorescence scanning microscope (CLSM). HeLa cells (2.5 × 104 cells per dish) were seeded onto culture dishes and incubated at 37 °C in 5% CO2 for 24 h. Then, the cells were incubated with 1.5 µM RDPP suspended in medium for another 4 h. After that, each culture dish was washed with PBS for three times and further incubated with 1 mL of MB–BSA–Fe(III) NP solution (1.2 mg mL−1 in culture medium, [MB] = 2.4 µg mL−1), BSA–Fe(III) NP solution (1.2 mg mL−1 in medium) and free MB solution (2.4 µg mL−1) for 24 h. The cells without treatment served as control group. Finally, the cells were washed with PBS for three times, and fluorescence images were obtained with CLSM using an excitation of 488 nm and the emission of 600–700 nm.

2.8 The Generation of Intracellular 1O2

Intracellular 1O2 were detected by DCFH-DA. HeLa cells (2.5 × 104 cells per dish) were seeded onto culture dishes in 5% CO2 at 37 °C for 24 h. Then, cells were treated with 1 mL of MB–BSA–Fe(III) NP solution (1.2 mg mL−1 in medium, [MB] = 2.4 µg mL−1), BSA–Fe(III) NPs solution (1.2 mg mL−1 in medium) and free MB solution (2.4 µg mL−1) for 24 h. Finally, the cells were washed with PBS for three times and illuminated with a 650 nm laser (0.1 W cm−2) for 15 min. The cells without treatment acted as control. After 24 h, the cells were washed with PBS for three times and incubated with 1 mL of DCFH–DA solution (0.2 µM in PBS) for 30 min. Fluorescence of the cells were imaged with CLSM using an excitation of 488 nm, and the emission was collected between 510 and 560 nm.

2.9 In Vitro Photodynamic Therapy Effect

HeLa cells (2.5 × 103 cells per well) were seeded onto 96-well plates and incubated in 5% CO2 at 37 °C for 24 h. Then, the cells were treated with free MB (2.4 µg mL−1) and MB–BSA–Fe(III)–NPs (1.2 mg mL−1, [MB] = 2.4 µg mL−1) medium solutions. After 24 h, the cells were washed with PBS for three times, and 200 µL of fresh medium was added into each well. The cells were irradiated with the 650 nm laser at 0.1 W cm−2 for 15 min. The cells without treatment served as control. After 24 h, the cell viability was detected by MTT assay and investigated on a CLSM after co-staining with Calcein AM (40 nM) and PI (4.5 μM) for 20 min.

2.10 In Vitro MRI

MB–BSA–Fe(III) NPs were dissolved in 1 mL of deionized water with different concentrations in terms of the molar concentration of Fe (0.002, 0.004, 0.008, 0.016, 0.032, 0.064 mM). The relaxation time (T2) and transversal phantom images of MB–BSA–Fe(III)-NP solutions were recorded by a 3.0 T clinical MRI scanner (Philips, The Netherlands).

3 Results and Discussion

3.1 Synthesis and Characterization of MB–BSA–Fe(III)-NPs

MB–BSA–Fe(III) NPs were fabricated through biomineralization method according to the previous report with slight modifications (Scheme 1) [14]. BSA has abundant active groups such as carboxyl, thiol and amino groups that can coordinate with Fe3+ to form BSA–Fe3+ complex by adding FeCl3 to BSA solution dropwise. Afterwards, MB was added and successfully conjugated with BSA via the formation of amide bond and hydrophobic interaction. Finally, NaOH was mixed with the above mixture, which can transform BSA into unfolded status and facilitate the growth of metal oxide nanoclusters [15]. During the growth process, BSA can sterically stabilize and protect nanoparticles. The prepared MB–BSA–Fe(III) NPs were characterized by transmission electron microscopy (TEM). As shown in Fig. 1a, monodispersed MB–BSA–Fe(III) NPs exhibit sphere-like morphology with a uniform size of 21.2 nm and good monodispersity in PBS and cell culture medium (Figure S1). The hydrodynamic size (Fig. 1b) of MB–BSA–Fe(III) NP is 28.21 nm and the zeta potential is − 19.7 mV (Fig. 1c). The The FTIR spectrum of MB–BSA–Fe(III) NPs shows the amide I and II bands of protein at about 1657 and 1530 cm−1, indicating the presence of BSA on MB–BSA–Fe(III) NPs (Fig. 1d). From ICP–AES result, the mass concentration of Fe element in MB–BSA–Fe(III) NP is 8.93 µg mg−1. Furthermore, the UV–vis spectrum of MB–BSA–Fe(III) NPs shows a maximal absorption peak at 703 nm (Fig. 1e), which is red-shifted compared to the characteristic peak of free MB at 665 nm possibly due to the hydrophobic interaction between MB and BSA. The loading content of MB is 1.96 μg mg−1 (Figure S2). Above results demonstrate the successful preparation of MB–BSA–Fe(III) NPs.
Fig. 1

a TEM image and photograph (inset) of MB–BSA–Fe(III) NPs. b Hydrodynamic diameter of MB–BSA–Fe(III) NPs measured by dynamic light scattering (DLS). c Zeta potential of MB–BSA–Fe(III) NPs. d FTIR spectra of MB–BSA–Fe(III) NPs, BSA–Fe(III) NPs and BSA. e UV–Vis absorption spectra of free MB, BSA–Fe(III) NPs and MB–BSA–Fe(III) NPs. f Oxygen generation in MB–BSA–Fe(III) NPs solution (3 mg mL−1) with or without H2O2

3.2 Catalase-Like Activity of MB–BSA–Fe(III) NPs

In recent years, nanozymes have appealed to growing researchers, so the construction of artificial enzyme has great importance. Several studies have reported that Fe(III) with catalase-like activity can decompose H2O2 to generate O2 [16]. Here, to verify the catalase-like activity of MB–BSA–Fe(III) NPs, we next measured the time-dependent production of O2 in the MB–BSA–Fe(III) NPs solution upon addition of 1 mM H2O2 with an oxygen meter (Fig. 1f). More and more amount of O2 was detected with time relative to the control suspension without H2O2, suggesting that MB–BSA–Fe(III) NPs can greatly enhance the generation of O2.

3.3 Photodynamic Effect of MB–BSA–Fe(III) NPs

Encouraged by the potential that O2-evolving property of MB–BSA–Fe(III) NPs, MB–BSA–Fe(III) NPs may enhance the generation of 1O2 [17].To evaluate the PDT effect of MB–BSA–Fe(III) NPs, DPBF was used to detect 1O2 generation, which can irreversibly react with 1O2 and result in the decrease of its absorption intensity at 410 nm [18]. As seen in Fig. 2, the absorbance of DPBF in the MB–BSA–Fe(III) NP solution decreases with the increase of concentration of H2O2 and illumination time. Specifically, the absorbance of DPBF in the MB–BSA–Fe(III) NP solution containing 100 µM H2O2 could decrease gradually to 60% within 10 min of illumination (650 nm, 0.1 W cm−2), while MB–BSA–Fe(III) NPs without the addition of H2O2 could only decrease to 79%. Above results illustrate that MB–BSA–Fe(III) NPs can facilitate the production of 1O2 in response to the addition of H2O2.
Fig. 2

Consumption of DPBF over time due to the generation of 1O2: a 0.2 mg mL−1 of MB–BSA–Fe(III) ([MB] = 0.4 µg mL−1) only, 0.2 mg mL−1 of MB–BSA–Fe(III) with laser in the presence of b 0 µM, c 40 µM, d 80 µM and e 100 µM H2O2. f Consumption of DPBF triggered by 0.2 mg mL−1 of MB–BSA–Fe(III) with laser at different concentrations of H2O2

3.4 CAT-Like Property and Synergistic Photodynamic Efficacy of MB–BSA–Fe(III) NPs in HeLa Cells

To evaluate the biomedical application potential of MB–BSA–Fe(III) NPs, their cytotoxicity was first measured. It can be easily observed from Fig. 3 that no toxic effect can be observed on the HeLa cells treated with MB–BSA–Fe(III) NPs up to 2 mg mL−1 ([MB] = 3.92 µg mL−1) for 24 h, suggesting MB–BSA–Fe(III) NPs have excellent biocompatability.
Fig. 3

Viability of HeLa cells treated with MB–BSA–Fe(III) NPs at different concentrations (0, 0.1, 0.2, 0.4, 1, 1.5, 2 mg mL−1) under dark

Then, the generation of O2 within HeLa cells was also proved, cells were preincubated with O2 probe RDPP for 4 h, and cells were further incubated with MB–BSA–Fe(III) NPs (1.2 mg mL−1, [MB] = 2.4 µg mL−1). The fluorescence of RDPP within MB–BSA–Fe(III) NPs treated cells completely diminishes at 24 h compared with that in control and MB treated cells (Fig. 4a), indicating MB–BSA–Fe(III) NPs could effectively overcome the hypoxia of cancer cells. Finally, the 1O2 in HeLa cells produced by MB–BSA–Fe(III) NPs under 650 nm laser irradiation was measured using DCFH-DA, which can emit green fluorescence because of 1O2 oxidation [19]. As seen in Fig. 4b, very strong fluorescence in the cells treated with MB–BSA–Fe(III) NPs can be observed after irradiation (650 nm, 0.1 W cm−2), suggesting the synergy between the generation of O2 and incorporated MB in enhancing the production of 1O2.
Fig. 4

a The evolution of O2 indicated by O2 probe RDPP within HeLa cells treated with culture medium only, BSA–Fe(III) NPs, free MB and MB–BSA–Fe(III) NPs for 24 h. b The intracellular ROS generation probed with DCFH-DA after HeLa cells were incubated with culture medium only, BSA–Fe(III) NPs, free MB and MB–BSA–Fe(III) NPs under illumination (650 nm, 0.1 W cm−2) for 15 min. All of the scale bars are 75 µm

To assess the PDT effect of MB–BSA–Fe(III) NPs compared with free MB, HeLa cells were treated with different samples. As shown in Fig. 5a the cells viability slightly decreases by 83.3% after cell treated with free MB plus the illumination (650 nm, 0.1 W cm−2), whereas a remarkable decrease to 33.7% is found after treatment with MB–BSA–Fe(III) NPs and illumination. To visually investigate the killing capacity, live and dead cells were stained with calcein AM (green fluorescence) and propidium iodide (PI, red fluorescence), respectively. In Fig. 5b, nearly no cell death can be observed in the MB–BSA–Fe(III) NPs treated group, which is similar to cell treated with free MB under irradiation for 15 min (650 nm, 0.1 W cm−2). However, the cells treated with MB–BSA–Fe(III) NPs under irradiation exhibit obvious death. These results indicate that MB–BSA–Fe(III) NPs are biocompatible under dark conditions, but they will in situ generate O2 by decomposing endogenous H2O2 inside the cancer cell, facilitating the process that breaks through hypoxia-associated resistance of PDT.
Fig. 5

Photodynamic efficiency of HeLa cells in the presence of culture medium, laser (650 nm, 0.1 W cm−2, 15 min) only, free MB (2.4 µg mL−1), MB/Laser, MB–BSA–Fe(III) (1.2 mg mL−1, [MB] = 2.4 µg mL−1) and MB–BSA–Fe(III)/Laser, evaluated by a standard MTT assay and b CLSM (viable cells were stained with calcein AM, and dead cells were stained with PI). All of the scale bars are 75 µm

3.5 Imaging Properties of MB–BSA–Fe(III) NPs

Fe-contained nanomaterials have been used as contrast agents for MRI [20]. Therefore, we investigated the imaging performance of MB–BSA–Fe(III) NPs through measuring the transverse-MR relaxivity and the T2-weighted MRI by a 3.0 T clinical MRI scanner. The MR images of MB–BSA–Fe(III) NP aqueous solution displays concentration-dependent brightness and darkness effects (Fig. 6). The transverse (r2) relaxivity is 16.11 s−1 mM−1, suggesting that MB–BSA–Fe(III) NPs can be a prospective T2-contrast agent.
Fig. 6

The transversal relaxation rate and T2-MRI of MB–BSA–Fe(III) NPs aqueous solutions versus the concentration of MB–BSA–Fe(III) NPs (in terms of Fe)

4 Conclusion

In summary, we have successfully synthesized MB–BSA–Fe(III) NPs by biomineralization approach, which could cleave H2O2 to generate O2, overcoming tumor hypoxia and thus enhancing PDT efficiency. Moreover, MB–BSA–Fe(III) NPs have great biocompatibility, uniform morphology and high loading capacity of MB. Most importantly, MB–BSA–Fe(III) NPs exhibit excellent T2-contrast effect in MRI, which shows great potential for precise visualization of the tumor location. The above combination effects significantly increase the therapeutic efficiency of PDT, leading to destruction of almost all cancer cells. This proof of concept might provide a novel H2O2-responsive and O2-evolving nanoplatform for more efficient PDT, radiotherapy sensitization and increasing the effect of chemotherapy.



This work was financially supported by the National Natural Science Foundation of China (21675149, 21505130, 21705146), the Science and Technology Development Program of Jilin Province (20150519014JH, 20170414037GH, 20170520133JH), and the Key Research Program of Frontier Sciences, CAS (QYZDY-SSW-SLH019).

Supplementary material

41664_2018_50_MOESM1_ESM.docx (86 kb)
Supplementary material 1 (DOCX 85 kb)


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Copyright information

© The Nonferrous Metals Society of China 2018

Authors and Affiliations

  • Wen-Yao Zhen
    • 1
    • 2
  • Jing Bai
    • 1
  • Xiao-Dan Jia
    • 1
  • Lie Wu
    • 1
  • Xiu-E Jiang
    • 1
    • 2
  1. 1.State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchunChina
  2. 2.University of Science and Technology of ChinaHefeiChina

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