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SCIENCE CHINA Materials, Volume 61, Issue 10: 1325-1338(2018) https://doi.org/10.1007/s40843-018-9261-x

PEGylated carbon dot/MnO2 nanohybrid: a new pH/H2O2-driven, turn-on cancer nanotheranostics

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  • ReceivedFeb 7, 2018
  • AcceptedMar 21, 2018
  • PublishedApr 20, 2018

Abstract

The effect of tumor-targeted photodynamic therapy (PDT) was improved by designing nanotheranostics to promote oxygenation in a tumor microenvironment (TME) wherein hypoxia, acidosis, and the elevated levels of H2O2 are three main characteristics. In this study, a carbon dot (CD) PDT agent recently developed by our group was firstly applied as reducing agent to react with potassium permanganate for fabricating CDs/manganese dioxide (CDs/MnO2) composites, which were in turn modified with polyethylene glycol (PEG) to form water-soluble CDs/MnO2-PEG nanohybrids. In a normal physiological environment, the as-prepared nanohybrids exhibited quenched fluorescence, weak singlet oxygen generation, and low magnetic resonance imaging (MRI) signal. However, given the high sensitivity of MnO2 to the TME, the CDs/MnO2-PEG nanohybrids changed from an “off” to an “on” state with synchronously enhanced fluorescence, singlet oxygen generation, and MRI signal in the TME. In vitro and in vivo analyses have revealed that CDs/MnO2-PEG nanohybrids could be applied as TME-driven, turn-on nanotheranostics for the MR/fluorescence bimodal imaging-guided PDT of cancer. Moreover, complete clearance of CDs/MnO2-PEG nanohybrids from the body of mice was observed, indicating their low long-term toxicity and good biocompatibility. This work offers a new nanotheranostic candidate for modulating the unfavorable TME, particularly for the targeted PDT of cancer through precise positioning and oxygen generation.


Funded by

the National Natural Science Foundation of China(51472252,51572269)

and the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB17000000)


Acknowledgment

This work was supported by the National Natural Science Foundation of China (51472252 and 51572269), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB17000000).


Interest statement

The authors declare that they have no conflict of interest.


Contributions statement

Wang P and Ge J supervised the project. Chen S designed and carried out the experiments, analyzed the data and wrote the manuscript. Jia Q, Zheng X and Wen Y helped with the synthesis of the CDs/MnO2-PEG. Liu W and Zhang H helped with the photodynamic therapy.


Author information

Shiqing Chen is now a Master candidate at the Technical Institute of Physics and Chemistry, Chinese Academy of Sciences. Her current research focuses on the preparation of nanomaterials for phototherapy of cancer.


Jiechao Ge is currently a full professor at the Technical Institute of Physics and Chemistry, Chinese Academy of Sciences. His research interests mainly concentrate on the synthesis of nanomaterials and their applications in phototheranostics and photocatalysts.


Supplement

Supplementary information

Supporting data are available in the online version of the paper.


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  • Figure 1

    Characterizations of CDs/MnO2-PEG nanohybrids. (a) XPS spectrum of CDs/MnO2 nanohybrids. (b) A TEM image of CDs/MnO2-PEG nanohybrids (scale bar: 200 nm). (c) Zeta potentials of CDs, CDs/MnO2, and CDs/MnO2-PEG. (d) UV-vis spectra of KMnO4, CDs, and CDs/MnO2-PEG. (e) FL spectra of CDs/MnO2-PEG and CDs. (f) Optical photographs of CDs/MnO2-PEG in water, PBS, FBS, and DMEM at 0 d (top) and 7 d (bottom).

  • Scheme 1

    Schematic illustration of CDs/MnO2-PEG nanohybrids as a multimodal theranostics for the MR/FL imaging-guided PDT.

  • Figure 2

    pH/H O2-response of CDs/MnO2-PEG nanohybrids. (a) UV-vis-NIR spectra and (b) FL spectra of CDs/MnO2-PEG nanohybrids at pH 6.5 and 7.4, respectively. (c) Simultaneous O2 generation in acidic H2O2 solutions (10 mmol L−1) after adding different concentrations of (MnO2: 0, 50, and 100 mmol L−1) of CDs/MnO2-PEG. (d) Characteristic 1O2-induced signal in the ESR spectra after 635 nm laser irradiation (100 mW cm−2) under N2 atmosphere, in the absence of presence of H2O2 (100 µmol L−1). (e) T1-weighted MR images of various concentrations of CDs/MnO2-PEG solutions incubated at different pH values (7.4 and 6.5) for 6 h prior to MRI. (f) Concentration-dependent T1 relaxation rates. The longitudinal relaxivities (r1) were determined to be 0.4763 and 7.0674 (mmol L−1)−1 s−1 for CDs/MnO2-PEG nanohybrids at pH 7.4 and 6.5, respectively.

  • Figure 3

    In vitro imaging and PDT. (a) Confocal microscopy images of HeLa cells incubated with CDs/MnO2-PEG nanohybrids (200 μg mL−1) for 4 h and added with acidic H2O2 at a bright field and excitation at 635 nm (scale bar: 10 μm). (b) Confocal images of HeLa cells incubated with DCFH-DA, CDs/MnO2-PEG nanohybrids at pH 7.4 and 6.5 at different irradiation times (0, 3, 6, 10 min). (c) Relative viabilities of HeLa cells after incubation with CDs/MnO2-PEG nanohybrids for 24 h in the dark, at pH 7.4 and 6.5 upon light irradiation (635 nm,100 mW cm−2, 10 min) under N2 atmosphere, respectively. (d) Fluorescence images of calcein AM and PI co-stained HeLa cells incubated with CDs/MnO2-PEG nanohybrids (200 μg mL−1) at pH 7.4 and 6.5 with 635 nm irradiation (100 mW cm−2) for 0, 3, 6 and 10 min (scale bar: 150 μm).

  • Figure 4

    In vivo MR/FL imaging and biodistribution. (a) Time-dependent T1-weighted MR images (transverse section) and (b) T1-weighted MR signals of the tumor. (c) In vivo T1-weighted MR images (transverse section) of the kidney and liver in the same mouse. (d) T1-weighted MR signals of the liver in the same mouse. (e) T1-weighted MR signals of the kidney in the same mouse. (f) Time-dependent FL images of tumor-bearing nude mouse after an i.v. injection of CDs/MnO2-PEG nanohybrids (1 mg mL−1, 200 μL). (g) FL signals in the tumor before, 4, 8, 12, and 24 h p.i. of CDs/MnO2-PEG nanohybrids. (h) Ex vivo FL images of major organs and tumor dissected from the same mice at 12 h p.i. tumor, liver, spleen, kidney, heart and lung. (i) Time-dependent content of Mn in the ex vivo tumor and other organs after an i.v. injection of CDs/MnO2-PEG nanohybrids. Inset is the blood circulation curve of the CDs/MnO2-PEG nanohybrids in mice that was measured based on the content of Mn in blood at different time points p.i. Error bars are based on the standard deviation of three mice.

  • Figure 5

    In vivo PDT. (a) PA images of 4T1 solid tumors measured based on HBO2 at different time points p.i. of CDs/MnO2-PEG nanohybrids. (b) Average enhanced tumor vascular saturated O2 p.i. of CDs/MnO2-PEG nanohybrids. (c) Time-dependent tumor growth curves of mice (n = 5) observed after various treatments. (d) Relative body weights of the nude mice after different treatments. (e) Representative photographs of the four groups after different treatments. (f) H&E-stained tumor slices from different groups collected 24 h after light irradiation. (scale bar: 100 μm).

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