Journal Home > Volume 12 , Issue 8
Nano Research 2019, 12(8): 1880-1887 https://doi.org/10.1007/s12274-019-2452-2
Research Article | Issue | Published: 29 November 2023

Zinc-substituted hemoglobin with specific drug binding sites and fatty acid resistance ability for enhanced photodynamic therapy

Show Author's Information Yiting Xu1,§,  Jiamei Xu1,§,  Xiaoxiao Hu1,§,  Xin Xia1,  Qian Dong1,  Zhangkun Liu1,  Zhuo Chen1,*( ),  Weihong Tan1,2
Molecular Science and Biomedicine Laboratory,State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Life Sciences, Aptamer Engineering Center of Hunan Province, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University,Changsha,410082,China;
Department of Chemistry, Departments of Physiology and Functional Genomics, Center for Research at the Bio/Nano Interface,UF Health Cancer Center, UF Genetics Institute and McKnight Brain Institute, University of Florida,Gainesville, Florida,32611,USA;

§Yiting Xu, Jiamei Xu, and Xiaoxiao Hu contributed equally to this work.

Keywords:
photodynamic therapy, natural metalloporphyrin protein carrier, specific drug binding sites, fatty acid resistance ability, hemin oxygenase-1 (HO-1)
Topics:
Nano biology
Cite this article:
Xu Y, Xu J, Hu X, et al. Zinc-substituted hemoglobin with specific drug binding sites and fatty acid resistance ability for enhanced photodynamic therapy. Nano Research, 2019, 12(8): 1880-1887. https://doi.org/10.1007/s12274-019-2452-2
Download citation
EndNote(RIS)
BibTeX

551

Views

16

Downloads

Citations

16

Crossref

0

WoS

14

Scopus

0

CSCD

Abstract Full text Electronic supplementary material About this article

Precisely designed protein-based nanodrugs, as a kind of colloidal drug system, have attracted significant attention in tumor therapy because of their refined drug loading ratio, controlled delivery efficacy and natural biocompatibility. However, most drugs are conjugated to the protein carriers randomly without specific binding sites. Moreover, such sites could easily be replaced by lipophilic molecules in the physiological environment and result in low delivery efficiency. With strong and specific binding locations especially comparatively narrow spatial binding sites and nonflexible structure, hemin (FePPIX)-free hemoglobin or apohemoglobin (apoHb), as a natural metalloporphyrin protein carrier, represents great potential in bioapplication. Therefore, we herein introduce a folate acid (FA) modified, zinc-substituted hemoglobin (ZnPHb-FA) as a naturally occurring protein matrix-based photosensitizer for cancer photodynamic therapy (PDT). Noncovalent inserted ZnPPIX molecules in apoHb possess an extremely stable property and significant recovered photoproperties with superior biocompatibility and phototoxicity, both in vitro and in vivo. This stability was verified by molecular docking analysis and calculation of binding constant, representing a total of five drug binding sites of apoHb for ZnPPIX molecules, four of which are energetically favorable (△G value of -11.9 kcal/mol), and one which is energetically acceptable (△G value of -9 kcal/mol). Folate acid modification has been shown to efficiently enhance the internalization and retention time of ZnPHb nanodrug. ZnPHb-FA is also an efficient depressor of hemin oxygenase-1 (HO-1), which could, in turn, lower the antioxidant ability of cancer cells by decreasing the production of bilirublin. Results in vitro and in vivo both indicated that the firmly combination of apoHb and ZnPPIX described here represents a novel and efficient protein nanodrug systems for cancer therapy.


menu
Abstract
Full text
Outline
Electronic supplementary material
About this article

Zinc-substituted hemoglobin with specific drug binding sites and fatty acid resistance ability for enhanced photodynamic therapy

Show Author's information Yiting Xu1,§, Jiamei Xu1,§, Xiaoxiao Hu1,§, Xin Xia1, Qian Dong1, Zhangkun Liu1, Zhuo Chen1,*( ), Weihong Tan1,2
Molecular Science and Biomedicine Laboratory,State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Life Sciences, Aptamer Engineering Center of Hunan Province, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University,Changsha,410082,China;
Department of Chemistry, Departments of Physiology and Functional Genomics, Center for Research at the Bio/Nano Interface,UF Health Cancer Center, UF Genetics Institute and McKnight Brain Institute, University of Florida,Gainesville, Florida,32611,USA;

§Yiting Xu, Jiamei Xu, and Xiaoxiao Hu contributed equally to this work.

Abstract

Precisely designed protein-based nanodrugs, as a kind of colloidal drug system, have attracted significant attention in tumor therapy because of their refined drug loading ratio, controlled delivery efficacy and natural biocompatibility. However, most drugs are conjugated to the protein carriers randomly without specific binding sites. Moreover, such sites could easily be replaced by lipophilic molecules in the physiological environment and result in low delivery efficiency. With strong and specific binding locations especially comparatively narrow spatial binding sites and nonflexible structure, hemin (FePPIX)-free hemoglobin or apohemoglobin (apoHb), as a natural metalloporphyrin protein carrier, represents great potential in bioapplication. Therefore, we herein introduce a folate acid (FA) modified, zinc-substituted hemoglobin (ZnPHb-FA) as a naturally occurring protein matrix-based photosensitizer for cancer photodynamic therapy (PDT). Noncovalent inserted ZnPPIX molecules in apoHb possess an extremely stable property and significant recovered photoproperties with superior biocompatibility and phototoxicity, both in vitro and in vivo. This stability was verified by molecular docking analysis and calculation of binding constant, representing a total of five drug binding sites of apoHb for ZnPPIX molecules, four of which are energetically favorable (△G value of -11.9 kcal/mol), and one which is energetically acceptable (△G value of -9 kcal/mol). Folate acid modification has been shown to efficiently enhance the internalization and retention time of ZnPHb nanodrug. ZnPHb-FA is also an efficient depressor of hemin oxygenase-1 (HO-1), which could, in turn, lower the antioxidant ability of cancer cells by decreasing the production of bilirublin. Results in vitro and in vivo both indicated that the firmly combination of apoHb and ZnPPIX described here represents a novel and efficient protein nanodrug systems for cancer therapy.

Keywords: photodynamic therapy, natural metalloporphyrin protein carrier, specific drug binding sites, fatty acid resistance ability, hemin oxygenase-1 (HO-1)

References(62)

1

Chen, G. Y.; Roy, I.; Yang, C. H.; Prasad, P. N. Nanochemistry and nanomedicine for nanoparticle-based diagnostics and therapy. Chem. Rev. 2016, 116, 2826-2885.
DOI Google Scholar
2

Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2007, 2, 751-760.
DOI Google Scholar
3

Elzoghby, A. O.; Samy, W. M.; Elgindy, N. A. Protein-based nanocarriers as promising drug and gene delivery systems. J. Control. Release 2012, 161, 38-49.
DOI Google Scholar
4

MaHam, A.; Tang, Z. W.; Wu, H.; Wang, J.; Lin, Y. H. Protein-based nanomedicine platforms for drug delivery. Small 2009, 5, 1706-1721.
DOI Google Scholar
5

Ahmad, R.; Deng, Y.; Singh, R.; Hussain, M.; Shah, M. A. A.; Elingarami, S.; He, N. Y.; Sun, Y. M. Cutting edge protein and carbohydrate-based materials for anticancer drug delivery. J. Biomed. Nanotechnol. 2018, 14, 20-43.
DOI Google Scholar
6

Einerson, N. J.; Stevens, K. R.; Kao, W. J. Synthesis and physicochemical analysis of gelatin-based hydrogels for drug carrier matrices. Biomaterials 2003, 24, 509-523.
DOI Google Scholar
7

Ruszczak, Z.; Friess, W. Collagen as a carrier for on-site delivery of antibacterial drugs. Adv. Drug Deliv. Rev. 2003, 55, 1679-1698.
DOI Google Scholar
8

Kratz, F. Albumin as a drug carrier: Design of prodrugs, drug conjugates and nanoparticles. J. Control. Release 2008, 132, 171-183.
DOI Google Scholar
9

Paliwal, R.; Palakurthi, S. Zein in controlled drug delivery and tissue engineering. J. Control. Release 2014, 189, 108-122.
DOI Google Scholar
10

Xu, Y.; Li, J. J.; Yu, D. G.; Williams, G. R.; Yang, J. H.; Wang, X. Influence of the drug distribution in electrospun gliadin fibers on drug-release behavior. Eur. J. Pharm. Sci. 2017, 106, 422-430.
DOI Google Scholar
11

Müller, S. K.; Wilhelm, I.; Schubert, T.; Zittlau, K.; Imberty, A.; Madl, J.; Eierhoff, T.; Thuenauer, R.; Römer, W. Gb3-binding lectins as potential carriers for transcellular drug delivery. Expert Opin. Drug Deliv. 2017, 14, 141-153.
DOI Google Scholar
12

Lohcharoenkal, W.; Wang, L. Y.; Chen, Y. C.; Rojanasakul, Y. Protein nanoparticles as drug delivery carriers for cancer therapy. Biomed Res. Int. 2014, 2014, 180549.
DOI Google Scholar
13

Wilhelm, S.; Tavares, A. J.; Dai, Q.; Ohta, S.; Audet, J.; Dvorak, H. F.; Chan, W. C. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 2016, 1, 16014.
DOI Google Scholar
14

Harwood, J. L. Fatty acid metabolism. Annu. Rev. Plant Physiol. Plant Mol. Biol. 1988, 39, 101-138.
DOI Google Scholar
15

Wenskowsky, L.; Schreuder, H.; Derdau, V.; Matter, H.; Volkmar, J.; Nazaré, M.; Opatz, T.; Petry, S. Identification and characterization of a single high-affinity fatty acid binding site in human serum albumin. Angew. Chem. , Int. Ed. 2018, 57, 1044-1048.
DOI Google Scholar
16

Zheng, Y. R.; Suntharalingam, K.; Johnstone, T. C.; Yoo, H.; Lin, W.; Brooks, J. G.; Lippard, S. J. Pt(Ⅳ) prodrugs designed to bind non-covalently to human serum albumin for drug delivery. J. Am. Chem. Soc. 2014, 136, 8790-8798.
DOI Google Scholar
17

Topete, A.; Alatorre-Meda, M.; Iglesias, P.; Villar-Alvarez, E. M.; Barbosa, S.; Costoya, J. A.; Taboada, P.; Mosquera, V. Fluorescent drug-loaded, polymeric-based, branched gold nanoshells for localized multimodal therapy and imaging of tumoral cells. ACS Nano 2014, 8, 2725-2738.
DOI Google Scholar
18

Peng, Y. B.; Zhao, Z. L.; Liu, T.; Li, X.; Hu, X. X.; Wei, X. P.; Zhang, X. B.; Tan, W. H. Albumin-As2O3 nanodrug with self-amplified folate receptor- targeting ability for chronic myeloid leukemia treatment. Angew. Chem. , Int. Ed. 2017, 56, 10845-10849.
DOI Google Scholar
19

Rajora, M. A.; Lou, J. W. H.; Zheng, G. Advancing porphyrin's biomedical utility via supramolecular chemistry. Chem. Soc. Rev. 2017, 46, 6433-6469.
DOI Google Scholar
20

Sahoo, S. K.; Sawa, T.; Fang, J.; Tanaka, S.; Miyamoto, Y.; Akaike, T.; Maeda, H. Pegylated zinc protoporphyrin: A water-soluble heme oxygenase inhibitor with tumor-targeting capacity. Bioconjugate Chem. 2002, 13, 1031-1038.
DOI Google Scholar
21

Regehly, M.; Greish, K.; Rancan, F.; Maeda, H.; Böhm, F.; Röder, B. Water-soluble polymer conjugates of ZnPP for photodynamic tumor therapy. Bioconjugate Chem. 2007, 18, 494-499.
DOI Google Scholar
22

Derycke, A. S. L.; De Witte, P. A. M. Liposomes for photodynamic therapy. Adv. Drug Deliv. Rev. 2004, 56, 17-30.
DOI Google Scholar
23

Luo, Z. Y.; Zheng, M. B.; Zhao, P. F.; Chen, Z.; Siu, F. M.; Gong, P.; Gao, G. H.; Sheng, Z. H.; Zheng, C. F.; Ma, Y. F. et al. Self-monitoring artificial red cells with sufficient oxygen supply for enhanced photodynamic therapy. Sci. Rep. 2016, 6, 23393.
DOI Google Scholar
24

Van Nostrum, C. F. Polymeric micelles to deliver photosensitizers for photodynamic therapy. Adv. Drug Deliv. Rev. 2004, 56, 9-16.
DOI Google Scholar
25

Zhang, K.; Zhang, Y. D.; Meng, X. D; Lu, H. T.; Chang, H.; Dong, H. F.; Zhang, X. J. Light-triggered theranostic liposomes for tumor diagnosis and combined photodynamic and hypoxia-activated prodrug therapy. Biomaterials 2018, 185, 301-309.
DOI Google Scholar
26

Liu, C. H.; Dong, H. F.; Wu, N. Q; Cao, Y.; Zhang, X. J. Plasmonic resonance energy transfer enhanced photodynamic therapy with Au@SiO2@Cu2O/ perfluorohexane nanocomposites. ACS Appl. Mater. Interfaces 2018, 10, 6991-7002.
DOI Google Scholar
27

Hu, D. R.; Zhong, L.; Wang, M. Y.; Li, H. H.; Qu, Y.; Liu, Q. Y.; Han, R. X.; Yuan, L. P.; Shi, Y.; Peng, J. R. et al. Perfluorocarbon-loaded and redox-activatable photosensitizing agent with oxygen supply for enhancement of fluorescence/photoacoustic imaging guided tumor photodynamic therapy. Adv. Funct. Mater. 2019, 29, 1806199.
DOI Google Scholar
28

Xin, J.; Wang, S. J.; Wang, J.; Wang, J. Z.; Fu, L.; Zhang, L. W.; Shen, L. J.; Zhang, Z. X.; Yao, C. P. Nanosystem integrated with photosensitizer and novel targeting chemotherapy agent for gastric cancer chemo-photodynamic combined therapy. J. Biomed. Nanotechnol. 2018, 14, 1430-1447.
DOI Google Scholar
29

Hardison, R. C. A brief history of hemoglobins: Plant, animal, protist, and bacteria. Proc. Natl. Acad. Sci. USA 1996, 93, 5675-5679.
DOI Google Scholar
30

Paoli, M.; Liddington, R.; Tame, J.; Wilkinson, A.; Dodson, G. Crystal structure of T state haemoglobin with oxygen bound at all four haems. J. Mol. Biol. 1996, 256, 775-792.
DOI Google Scholar
31

Dougherty, T. J. Gomer, C. J.; Henderson, B. W.; Jori, G.; Kessel, D.; Korbelik, M.; Moan, J.; Peng, Q. Photodynamic therapy. J. Natl. Cancer Inst. 1998, 90, 889-905.
DOI Google Scholar
32

Felsher, D. W. Cancer revoked: Oncogenes as therapeutic targets. Nat. Rev. Cancer 2003, 3, 375-380.
DOI Google Scholar
33

Agostinis, P.; Berg, K.; Cengel, K. A.; Foster, T. H.; Girotti, A. W.; Gollnick, S. O.; Hahn, S. M.; Hamblin, M. R.; Juzeniene, A.; Kessel, D. et al. Photodynamic therapy of cancer: An update. CA Cancer J. Clin. 2011, 61, 250-281.
DOI Google Scholar
34

Sternberg, E. D.; Dolphin, D.; Brückner, C. Porphyrin-based photosensitizers for use in photodynamic therapy. Tetrahedron 1998, 54, 4151-4202.
DOI Google Scholar
35

Jin, C. S.; Lovell, J. F.; Chen, J.; Zheng, G. Ablation of hypoxic tumors with dose-equivalent photothermal, but not photodynamic, therapy using a nanostructured porphyrin assembly. ACS Nano 2013, 7, 2541-2550.
DOI Google Scholar
36

Lovell, J. F.; Jin, C. S.; Huynh, E.; Jin, H. L.; Kim, C.; Rubinstein, J. L.; Chan, W. C. W.; Cao, W. G.; Wang, L. V.; Zheng, G. Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents. Nat. Mater. 2011, 10, 324-332.
DOI Google Scholar
37

Wang, S. S.; Yuan, F.; Chen, K.; Chen, G. J.; Tu, K. H.; Wang, H. J.; Wang, L. Q. Synthesis of hemoglobin conjugated polymeric micelle: A ZnPc carrier with oxygen self-compensating ability for photodynamic therapy. Biomacromolecules 2015, 16, 2693-2700.
DOI Google Scholar
38

Xu, X.; Cui, Y. C.; Bu, H. X.; Chen, J. M.; Li, Y.; Tang, G. P.; Wang, L. Q. A photosensitizer loaded hemoglobin-polymer conjugate as a nanocarrier for enhanced photodynamic therapy. J. Mater. Chem. B 2018, 6, 1825-1833.
DOI Google Scholar
39

Lepeshkevich, S. V.; Parkhats, M. V.; Stasheuski, A. S.; Britikov, V. V.; Jarnikova, E. S.; Usanov, S. A.; Dzhagarov, B. M. Photosensitized singlet oxygen luminescence from the protein matrix of Zn-substituted myoglobin. J. Phys. Chem. A 2014, 118, 1864-1878.
DOI Google Scholar
40

Key, H. M.; Dydio, P.; Clark, D. S.; Hartwig, J. F. Abiological catalysis by artificial haem proteins containing noble metals in place of iron. Nature 2016, 534, 534-537.
DOI Google Scholar
41

Delcanale, P.; Montali, C.; Rodriguez-Amigo, B.; Abbruzzetti, S.; Bruno, S.; Bianchini, P.; Diaspro, A.; Agut, M.; Nonell, S.; Viappiani, C. Zinc- substituted myoglobin is a naturally occurring photo-antimicrobial agent with potential applications in food decontamination. J. Agric. Food Chem. 2016, 64, 8633-8639.
DOI Google Scholar
42

Drummond, G. S.; Kappas, A. Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation. Proc. Natl. Acad. Sci. USA 1981, 78, 6466-6470.
DOI Google Scholar
43

Naveen, R; Akshata, K., Pimple, S.; Chaudhari, P. A review on albumin as drug carrier in treating different diseases and disorders. Der Pharm. Sin. 2016, 7, 11-15.
Google Scholar
44

Park, K. Albumin: A versatile carrier for drug delivery. J. Control. Release 2012, 157, 3.
DOI Google Scholar
45

Chen, Q.; Liu, Z. Albumin carriers for cancer theranostics: A conventional platform with new promise. Adv. Mater. 2016, 28, 10557-10566.
DOI Google Scholar
46

Tsuneshige, A.; Yonetani, T. Preparation of mixed metal hybrids. Methods Enzymol. 1994, 231, 215-222.
DOI Google Scholar
47

Trott, O.; Olson, A. J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010, 31, 455-461.
DOI Google Scholar
48

Hu, J.; Allen, R.; Rozinek, S.; Brancaleon, L. Experimental and computational characterization of photosensitized conformational effects mediated by protoporphyrin ligands on human serum albumin. Photochem. Photobiol. Sci. 2017, 16, 694-710.
DOI Google Scholar
49

Boaz, H.; Rollefson, G. K. The quenching of fluorescence. deviations from the stern-volmer law. J. Am. Chem. Soc. 1950, 72, 3435-3443.
DOI Google Scholar
50

Cai, C. Q.; Chen, X. M.; Ge, F. Analysis of interaction between tamoxifen and ctDNA in vitro by multi-spectroscopic methods. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2010, 76, 202-206
DOI Google Scholar
51

Yu, X. Y.; Liu, R. H.; Yi, R. Q.; Yang, F. X.; Huang, H. W.; Chen, J.; Ji, D. H.; Yang, Y.; Li, X. F.; Yi, P. G. Study of the interaction between N-confused porphyrin and bovine serum albumin by fluorescence spectroscopy. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2011, 78, 1329-1335.
DOI Google Scholar
52

Komatsu, T.; Wang, R. M.; Zunszain, P. A.; Curry, S.; Tsuchida, E. Photosensitized reduction of water to hydrogen using human serum albumin complexed with zinc-protoporphyrin IX. J. Am. Chem. Soc. 2006, 128, 16297-16301.
DOI Google Scholar
53

Gyulkhandanyan, A. G.; Ghazaryan, R. K.; Knyukshto, V. N.; Stasheuski, A. S.; Dzhagarov, B. M.; Gyulkhandanyan, G. V. Action of fatty acids on the binding capacity of porphyrins to blood proteins: I. Spectral investigations. Biol. J. Arm. 2012, 4, 80-84.
Google Scholar
54

Zhang, G. Y.; Wu, J.; Liu, Y. R.; Huang, L.; Qiao, J.; Liu, X.; Wei, J. Y.; Guan, Q. X. Effects of degree of substitution on stearic acid-modified Bletilla striata polysaccharides nanoparticles and interactions between nanoparticles and bovine serum albumin. Chin. Chem. Lett. 2018, 29, 1861-1864.
DOI Google Scholar
55

Valko, M.; Rhodes, C. J.; Moncol, J.; Izakovic, M.; Mazur, M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact. 2006, 160, 1-40.
DOI Google Scholar
56

Trachootham, D.; Alexandre, J.; Huang, P. Targeting cancer cells by ROS- mediated mechanisms: A radical therapeutic approach? Nat. Rev. Drug Discov. 2009, 8, 579-591.
DOI Google Scholar
57

Doi, K.; Akaike, T.; Fuji, S.; Tanaka, S.; Ikebe, N.; Beppu, T.; Shibahara, S.; Ogawa, M.; Maeda, H. Induction of haem oxygenase-1 by nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. Br. J. Cancer 1999, 80, 1945-1954.
DOI Google Scholar
58

Minetti, M.; Mallozzi, C.; Di Stasi, A. M. M.; Pietraforte, D. Bilirubin is an effective antioxidant of peroxynitrite-mediated protein oxidation in human blood plasma. Arch. Biochem. Biophys. 1998, 352, 165-174.
DOI Google Scholar
59

Maines, M. D. Heme oxygenase: Function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J. 1988, 2, 2557-2568.
DOI Google Scholar
60

Sardana, M. K.; Kappas, A. Dual control mechanism for heme oxygenase: Tin(Ⅳ)-protoporphyrin potently inhibits enzyme activity while markedly increasing content of enzyme protein in liver. Proc. Natl. Acad. Sci. USA 1987, 84, 2464-2468.
DOI Google Scholar
61

Zhang, W. S.; Contag, P. R.; Hardy, J.; Zhao, H.; Vreman, H. J.; Hajdena- Dawson, M.; Wong, R. J.; Stevenson, D. K.; Contag, C. H. Selection of potential therapeutics based on in vivo spatiotemporal transcription patterns of heme oxygenase-1. J. Mol. Med. (Berl. ) 2002, 80, 655-664.
DOI Google Scholar
62

Fang, J.; Sawa, T.; Akaike, T.; Akuta, T.; Sahoo, S. K.; Khaled, G.; Hamada, A.; Maeda, H. In vivo antitumor activity of pegylated zinc protoporphyrin: Targeted inhibition of heme oxygenase in solid tumor. Cancer Res. 2003, 63, 3567-3574.
Google Scholar
File
12274_2019_2452_MOESM1_ESM.pdf (3.2 MB)
Publication history
Copyright
Acknowledgements

Publication history

Received: 28 March 2019
Revised: 06 May 2019
Accepted: 03 June 2019
Published: 29 November 2023
Issue date: August 2019

Copyright

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Acknowledgements

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Nos. 21522501, 21521063, 31701249, and 31601125), Hunan Provincial Natural Science Foundation of China (Nos. 2018JJ1007 and 2018JJ3037), the keypoint research and invention program of Hunan province (No. 2017DK2011), and the Science and Technology Development Fund of Macao S.A.R (FDCT, 196/2017/A3).

Return