Skip to main content
Log in

Self-assembled manganese phthalocyanine nanoparticles with enhanced peroxidase-like activity for anti-tumor therapy

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

The use of functional nanoparticles as peroxidase-like (POD-like) catalyst has recently become a focus of research in cancer therapy. Phthalocyanine is a macrocyclic conjugated metal ligand, which is expected to achieve a high POD-like catalytic activity, generating free radicals and inhibiting the proliferation of cancer cells. In this paper, we synthesized phthalocyanine nanocrystals with different structures through noncovalent self-assembly confined within micro-emulsion droplets, and manganese phthalocyanine (MnPc) possessing a metal-N-C active center was used as the building block. These nano-assemblies exhibit shape-dependent POD-like catalytic activities, because the emulsifier and MnPc co-mixed assembly reduced the close packing between MnPc molecules and exposed more active sites. The assembly had a water-dispersed nanostructure, which is conducive to accumulation at tumor sites through the enhanced permeability and retention effect (EPR). Because of a highly efficient microenvironmental response, the assembly showed higher catalytic activity only emerged under the acidic tumor-like microenvironment, but caused less damage to normal tissues in biomedical applications. In vivo and in vitro catalytic therapy tests showed excellent anti-tumor effects. This work explored a new way for the application of metal-organic macromolecules such as MnPc as nanozymes for catalytic tumor therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Gao, L. Z.; Zhuang, J.; Nie, L.; Zhang, J. B.; Zhang, Y.; Gu, N.; Wang, T. H.; Feng, J.; Yang, D. L.; Perrett, S. et al. Intrinsic peroxidase-like activity of ferromagnetic nanoparticles. Nat. Nanotechnol. 2007, 2, 577–583.

    Article  CAS  Google Scholar 

  2. Gao, L. Z.; Yan, X. Y. Nanozymes: An emerging field bridging nanotechnology and biology. Sci. China Life Sci. 2016, 59, 400–402.

    Article  Google Scholar 

  3. He, W. W.; Wamer, W.; Xia, Q. S.; Yin, J. J.; Fu, P. P. Enzyme-like activity of nanomaterials. J. Environ. Sci. Health, Part C:Environ. Carcinog. Ecotoxicol. Rev. 2014, 32, 186–211.

    Article  CAS  Google Scholar 

  4. Wei, H.; Wang, E. K. Nanomaterials with enzyme-like characteristics (nanozymes): Next-generation artificial enzymes. Chem. Soc. Rev. 2013, 42, 6060–6093.

    Article  CAS  Google Scholar 

  5. Wu, J. J. X.; Wang, X. Y.; Wang, Q.; Lou, Z. P.; Li, S. R.; Zhu, Y. Y.; Qin, L.; Wei, H. Nanomaterials with enzyme-like characteristics (nanozymes): Next-generation artificial enzymes (II). Chem. Soc. Rev. 2019, 48, 1004–1076.

    Article  CAS  Google Scholar 

  6. Wang, X. Y.; Hu, Y. H.; Wei, H. Nanozymes in bionanotechnology: From sensing to therapeutics and beyond. Inorg. Chem. Front. 2016, 3, 41–60.

    Article  CAS  Google Scholar 

  7. Huang, Y. Y.; Ren, J. S.; Qu, X. G. Nanozymes: Classification, catalytic mechanisms, activity regulation, and applications. Chem. Rev. 2019, 119, 4357–4412.

    Article  CAS  Google Scholar 

  8. Li, Y. Q.; Liu, J. W. Nanozyme’s catching up: Activity, specificity, reaction conditions and reaction types. Mater. Horiz. 2021, 8, 336–350.

    Article  CAS  Google Scholar 

  9. Chang, Y. Y.; Gao, S.; Liu, M.; Liu, J. W. Designing signal-on sensors by regulating nanozyme activity. Anal. Methods 2020, 12, 4708–4723.

    Article  CAS  Google Scholar 

  10. Chen, Z. J.; Huang, Z. C.; Sun, Y. M.; Xu, Z. L.; Liu, J. W. The most active oxidase-mimicking Mn2O3 nanozyme for biosensor signal generation. Chem. -Eur. J. 2021, 27, 9597–9604.

    Article  CAS  Google Scholar 

  11. Liu, B. W.; Liu, J. W. Surface modification of nanozymes. Nano Res. 2017, 10, 1125–1148.

    Article  CAS  Google Scholar 

  12. Huo, M. F.; Wang, L. Y.; Chen, Y.; Shi, J. L. Tumor-selective catalytic nanomedicine by nanocatalyst delivery. Nat. Commun. 2017, 8, 357.

    Article  Google Scholar 

  13. Wang, L. Y.; Huo, M. F.; Chen, Y.; Shi, J. L. Iron-engineered mesoporous silica nanocatalyst with biodegradable and catalytic framework for tumor-specific therapy. Biomaterials 2018, 163, 1–13.

    Article  CAS  Google Scholar 

  14. Liang, Q.; Xi, J. Q.; Gao, X. J.; Zhang, R. F.; Yang, Y. L.; Gao, X. F.; Yan, X. Y.; Gao, L. Z.; Fan, K. L. A metal-free nanozyme-activated prodrug strategy for targeted tumor catalytic therapy. Nano Today 2020, 35, 100935.

    Article  CAS  Google Scholar 

  15. Chen, Q. S.; Liu, Y. B.; Liu, J. B.; Liu, J. W. Liposome-boosted peroxidase-mimicking nanozymes breaking the pH limit. Chem. -Eur. J. 2020, 26, 16659–16665.

    Article  CAS  Google Scholar 

  16. Webb, B. A.; Chimenti, M.; Jacobson, M. P.; Barber, D. L. Dysregulated pH: A perfect storm for cancer progression. Nat. Rev. Cancer 2011, 11, 671–677.

    Article  CAS  Google Scholar 

  17. Bai, J.; Jia, X. D.; Zhen, W. Y.; Cheng, W. L.; Jiang, X. A facile ion-doping strategy to regulate tumor microenvironments for enhanced multimodal tumor theranostics. J. Am. Chem. Soc. 2018, 140, 106–109.

    Article  CAS  Google Scholar 

  18. Jana, D.; Wang, D. D.; Bindra, A. K.; Guo, Y.; Liu, J. W.; Zhao, Y. L. Ultrasmall alloy nanozyme for ultrasound- and near-infrared light-promoted tumor ablation. ACS Nano 2021, 15, 7774–7782.

    Article  CAS  Google Scholar 

  19. Cheng, G. H.; Zong, W.; Guo, H. Z.; Li, F. Y.; Zhang, X.; Yu, P.; Ren, F. X.; Zhang, X. L.; Shi, X. E.; Gao, F. et al. Programmed size-changeable nanotheranostic agents for enhanced imaging-guided chemo/photodynamic combination therapy and fast elimination. Adv. Mater. 2021, 33, 2100398.

    Article  CAS  Google Scholar 

  20. Jiao, L.; Ye, W.; Kang, Y. K.; Zhang, Y.; Xu, W. Q.; Wu, Y.; Gu, W. L.; Song, W. Y.; Xiong, Y. J.; Zhu, C. Z. Atomically dispersed N-coordinated Fe-Fe dual-sites with enhanced enzyme-like activities. Nano Res., in press, https://doi.org/10.1007/s12274-021-3581-y.

  21. Ranji-Burachaloo, H.; Gurr, P. A.; Dunstan, D. E.; Qiao, G. G. Cancer treatment through nanoparticle-facilitated fenton reaction. ACS Nano 2011, 12, 11819–11837.

    Article  Google Scholar 

  22. Huo, M. F.; Wang, L. Y.; Wang, Y. W.; Chen, Y.; Shi, J. L. Nanocatalytic tumor therapy by single-atom catalysts. ACS Nano 2019, 13, 2643–2653.

    CAS  Google Scholar 

  23. Zhu, Y.; Wang, W. Y.; Cheng, J. J.; Qu, Y. T.; Dai, Y.; Liu, M. M.; Yu, J. N.; Wang, C. M.; Wang, H. J.; Wang, S. C. et al. Stimuli-responsive manganese single-atom nanozyme for tumor therapy via integrated cascade reactions. Angew. Chem., Int. Ed. 2021, 60, 9480–9488.

    Article  CAS  Google Scholar 

  24. Lu, W. H.; Chen, J.; Kong, L. S.; Zhu, F.; Feng, Z. Y.; Zhan, J. H. Oxygen vacancies modulation Mn3O4 nanozyme with enhanced oxidase-mimicking performance for l-cysteine detection. Sens. Actuators B:Chem. 2021, 333, 129560.

    Article  CAS  Google Scholar 

  25. Yang, L. F.; Ren, C. C.; Xu, M.; Song, Y. L.; Lu, Q. L.; Wang, Y. L.; Zhu, Y.; Wang, X. X.; Li, N. Rod-shape inorganic biomimetic mutual-reinforcing MnO2-Au nanozymes for catalysis-enhanced hypoxic tumor therapy. Nano Res. 2020, 13, 2246–2258.

    Article  CAS  Google Scholar 

  26. Waldron, K. J.; Rutherford, J. C.; Ford, D.; Robinson, N. J. Metalloproteins and metal sensing. Nature 2009, 460, 823–830.

    Article  CAS  Google Scholar 

  27. Lv, M. Z.; Chen, M. X.; Zhang, R.; Zhang, W.; Wang, C. G.; Zhang, Y.; Wei, X. M.; Guan, Y. K.; Liu, J. J.; Feng, K. C. et al. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res. 2020, 30, 966–979.

    Article  CAS  Google Scholar 

  28. Signorella, S.; Palopoli, C.; Ledesma, G. Rationally designed mimics of antioxidant manganoenzymes: Role of structural features in the quest for catalysts with catalase and superoxide dismutase activity. Coord. Chem. Rev. 2018, 365, 75–102.

    Article  CAS  Google Scholar 

  29. Zhang, J. Y.; Lu, X. M.; Tang, D. D.; Wu, S. H.; Hou, X. D.; Liu, J. W.; Wu, P. Phosphorescent carbon dots for highly efficient oxygen photosensitization and as photo-oxidative nanozymes. ACS Appl. Mater. Interfaces 2011, 10, 40808–40814.

    Article  Google Scholar 

  30. Ding, H.; Hu, B.; Zhang, B.; Zhang, H.; Yan, X. Y.; Nie, G. H.; Liang, M. M. Carbon-based nanozymes for biomedical applications. Nano Res. 2021, 14, 570–583.

    Article  CAS  Google Scholar 

  31. Fan, K. L.; Xi, J. Q.; Fan, L.; Wang, P. X.; Zhu, C. H.; Tang, Y.; Xu, X. D.; Liang, M. M.; Jiang, B.; Yan, X. Y. et al. In vivo guiding nitrogen-doped carbon nanozyme for tumor catalytic therapy. Nat. Commun. 2011, 9, 1440.

    Article  Google Scholar 

  32. Zhao, R. S.; Zhao, X.; Gao, X. F. Molecular-level insights into intrinsic peroxidase-like activity of nanocarbon oxides. Chem. -Eur. J. 2015, 21, 960–964.

    Article  CAS  Google Scholar 

  33. Hiroto, S.; Miyake, Y.; Shinokubo, H. Synthesis and functionalization of porphyrins through organometallic methodologies. Chem. Rev. 2017, 117, 2910–3043.

    Article  CAS  Google Scholar 

  34. Park, J. M.; Hong, K. I.; Lee, H.; Jang, W. D. Bioinspired applications of porphyrin derivatives. Acc. Chem. Res. 2021, 54, 2249–2260.

    Article  CAS  Google Scholar 

  35. Gao, Z. G.; Li, Y. J.; Zhang, Y.; Cheng, K. W.; An, P. J.; Chen, F. H.; Chen, J.; You, C. Q.; Zhu, Q.; Sun, B. W. Biomimetic platinum nanozyme immobilized on 2D metal-organic frameworks for mitochondrion-targeting and oxygen self-supply photodynamic therapy. ACS Appl. Mater. Interfaces 2020, 12, 1963–1972.

    Article  CAS  Google Scholar 

  36. Ling, P. H.; Cheng, S.; Chen, N.; Qian, C. H.; Gao, F. Nanozyme-modified metal-organic frameworks with multienzymes activity as biomimetic catalysts and electrocatalytic interfaces. ACS Appl. Mater. Interfaces 2020, 12, 17185–17192.

    Article  CAS  Google Scholar 

  37. Cao-Milán, R.; Gopalakrishnan, S.; He, L. D.; Huang, R.; Wang, L. S.; Castellanos, L.; Luther, D. C.; Landis, R. F.; Makabenta, J. M. V.; Li, C. H. et al. Thermally gated bio-orthogonal nanozymes with supramolecularly confined porphyrin catalysts for antimicrobial uses. Chem 2020, 6, 1113–1124.

    Article  Google Scholar 

  38. Zheng, B. D.; He, Q. X.; Li, X. S.; Yoon, J.; Huang, J. D. Phthalocyanines as contrast agents for photothermal therapy. Coord. Chem. Rev. 2021, 426, 213548.

    Article  CAS  Google Scholar 

  39. Lo, P. C.; Rodríguez-Morgade, M. S.; Pandey, R. K.; Ng, D. K. P.; Torres, T.; Dumoulin, F. The unique features and promises of phthalocyanines as advanced photosensitisers for photodynamic therapy of cancer. Chem. Soc. Rev. 2020, 49, 1041–1056.

    Article  CAS  Google Scholar 

  40. Shi, W. J.; Ng, D. K. P.; Zhao, S. R.; Lo, P. C. A phthalocyanine-based glutathione-activated photosensitizer with a ferrocenyl boron dipyrromethene dark quencher for photodynamic therapy. ChemPhotoChem 2019, 3, 1004–1013.

    Article  CAS  Google Scholar 

  41. Ma, B. J.; Wang, S.; Liu, F.; Zhang, S.; Duan, J. Z.; Li, Z.; Kong, Y.; Sang, Y. H.; Liu, H.; Bu, W. B. et al. Self-assembled copper-amino acid nanoparticles for in situ glutathione “AND” H2O2 sequentially triggered chemodynamic therapy. J. Am. Chem. Soc. 2019, 141, 849–857.

    Article  CAS  Google Scholar 

  42. Xu, B. L.; Cui, Y.; Wang, W. W.; Li, S. S.; Lyu, C. L.; Wang, S.; Bao, W. E.; Wang, H. Y.; Qin, M.; Liu, Z. et al. Immunomodulation-enhanced nanozyme-based tumor catalytic therapy. Adv. Mater. 2020, 32, 2003563.

    Article  CAS  Google Scholar 

  43. Wang, J. F.; Zhong, Y.; Wang, X.; Yang, W. T.; Bai, F.; Zhang, B. B.; Alarid, L.; Bian, K. F.; Fan, H. Y. pH-dependent assembly of porphyrin-silica nanocomposites and their application in targeted photodynamic therapy. Nano Lett. 2017, 17, 6916–6921.

    Article  CAS  Google Scholar 

  44. Wang, D.; Niu, L. J.; Qiao, Z. Y.; Cheng, D. B.; Wang, J. F.; Zhong, Y.; Bai, F.; Wang, H.; Fan, H. Y. Synthesis of self-assembled porphyrin nanoparticle photosensitizers. ACS Nano 2018, 12, 3796–3803.

    Article  CAS  Google Scholar 

  45. Wang, X.; Wang, J. F.; Wang, J. H.; Zhong, Y.; Han, L. L.; Yan, J. L.; Duan, P. C.; Shi, B. Y.; Bai, F. Noncovalent self-assembled smart gold(III) porphyrin nanodrug for synergistic chemo-photothermal therapy. Nano Lett. 2021, 21, 3418–3425.

    Article  CAS  Google Scholar 

  46. Zhong, Y.; Wang, J. F.; Zhang, R. F.; Wei, W. B.; Wang, H. M.; Lu, X. P.; Bai, F.; Wu, H. M.; Haddad, R.; Fan, H. Y. Morphology-controlled self-assembly and synthesis of photocatalytic nanocrystals. Nano Lett. 2014, 14, 7175–7179.

    Article  CAS  Google Scholar 

  47. Zhang, N.; Wang, L.; Wang, H. M.; Cao, R. H.; Wang, J. F.; Bai, F.; Fan, H. Y. Self-assembled one-dimensional porphyrin nanostructures with enhanced photocatalytic hydrogen generation. Nano Lett. 2018, 18, 560–566.

    Article  CAS  Google Scholar 

  48. Zhong, Y.; Liu, S. H.; Wang, J. F.; Zhang, W. Z.; Tian, T.; Sun, J. J.; Bai, F. Self-assembled supramolecular nanostructure photosensitizers for photocatalytic hydrogen evolution. APL Mater. 2020, 8, 120706.

    Article  CAS  Google Scholar 

  49. Li, S. S.; Shang, L.; Xu, B. L.; Wang, S. H.; Gu, K.; Wu, Q. Y.; Sun, Y.; Zhang, Q. H.; Yang, H. L.; Zhang, F. R. et al. A nanozyme with photo-enhanced dual enzyme-like activities for deep pancreatic cancer therapy. Angew. Chem. 2019, 131, 12754–12761.

    Article  Google Scholar 

  50. Sun, J. X.; Yuan, Y. P.; Qiu, L. G.; Jiang, X.; Xie, A. J.; Shen, Y. H.; Zhu, J. F. Fabrication of composite photocatalyst g-C3N4-ZnO and enhancement of photocatalytic activity under visible light. Dalton Trans. 2012, 41, 6756–6763.

    Article  CAS  Google Scholar 

  51. Xing, H.; Ma, H.; Fu, Y.; Xue, M.; Zhang, X.; Dong, X.; Zhang, X. Preparation of g-C3N4/ZnO composites and their enhanced photocatalytic activity. Mater. Technol. 2015, 30, 122–127.

    Article  CAS  Google Scholar 

  52. Guo, D. H.; Shibuya, R.; Akiba, C.; Saji, S.; Kondo, T.; Nakamura, J. Active sites of nitrogen-doped carbon materials for oxygen reduction reaction clarified using model catalysts. Science 2016, 351, 361–365.

    Article  CAS  Google Scholar 

  53. Liang, H. W.; Zhuang, X. D.; Brüller, S.; Feng, X. L.; Müllen, K. Hierarchically porous carbons with optimized nitrogen doping as highly active electrocatalysts for oxygen reduction. Nat. Commun. 2014, 5, 4973.

    Article  CAS  Google Scholar 

  54. He, Y. H.; Liu, S. W.; Priest, C.; Shi, Q. R.; Wu, G. Atomically dispersed metal-nitrogen-carbon catalysts for fuel cells: Advances in catalyst design, electrode performance, and durability improvement. Chem. Soc. Rev. 2020, 49, 3484–3524.

    Article  CAS  Google Scholar 

  55. Chen, M. X.; Zhu, M. Z.; Zuo, M.; Chu, S. Q.; Zhang, J.; Wu, Y. E.; Liang, H. W.; Feng, X. L. Identification of catalytic sites for oxygen reduction in metal/nitrogen-doped carbons with encapsulated metal nanoparticles. Angew. Chem. Int. Edit. 2020, 132, 1644–1650.

    Article  Google Scholar 

  56. Song, Y. J.; Qu, K. G.; Zhao, C.; Ren, J. S.; Qu, X. G. Graphene oxide: Intrinsic peroxidase catalytic activity and its application to glucose detection. Adv. Mater. 2010, 22, 2206–2210.

    Article  CAS  Google Scholar 

  57. Tabor, E.; Poltowicz, J.; Pamin, K.; Basag, S.; Kubiak, W. Influence of substituents in meso-aryl groups of iron μ-oxo porphyrins on their catalytic activity in the oxidation of cycloalkanes. Polyhedron 2016, 119, 342–349.

    Article  CAS  Google Scholar 

  58. Xie, J. F.; Ma, G. F.; Ouyang, X. P.; Zhao, L. S.; Qiu, X. Q. Metalloporphyrin as a biomimetic catalyst for the catalytic oxidative degradation of lignin to produce aromatic monomers. Waste Biomass Valor. 2020, 11, 4481–4489.

    Article  CAS  Google Scholar 

  59. Antonangelo, A. R.; Westrup, K. C. M.; Burt, L. A.; Bezzu, C. G.; Malewschik, T.; Machado, G. S.; Nunes, F. S.; McKeown, N. B.; Nakagaki, S. Synthesis, crystallographic characterization and homogeneous catalytic activity of novel unsymmetric porphyrins. RSC Adv. 2017, 7, 50610–50618.

    Article  CAS  Google Scholar 

  60. Tovmasyan, A.; Carballal, S.; Ghazaryan, R.; Melikyan, L.; Weitner, T.; Maia, C. G. C.; Reboucas, J. S.; Radi, R.; Spasojevic, I.; Benov, L. et al. Rational design of superoxide dismutase (SOD) mimics: The evaluation of the therapeutic potential of new cationic mn porphyrins with linear and cyclic substituents. Inorg. Chem. 2014, 53, 11467–11483.

    Article  CAS  Google Scholar 

  61. Miriyala, S.; Spasojevic, I.; Tovmasyan, A.; Salvemini, D.; Vujaskovic, Z.; St Clair, D.; Batinic-Haberle, I. Manganese superoxide dismutase, MnSOD and its mimics. Biochim. Biophys. Acta (BBA)-Mol Basis Dis 2012, 1822, 794–814.

    Article  CAS  Google Scholar 

  62. Wang, X. H.; Li, L.; Song, F. Interplay of nanoparticle properties during endocytosis. Crystals 2021, 11, 728.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 21771055 and U1604139), the Zhongyuan High Level Talents Special Support Plan (No. 204200510010), and the Scientific and Technological Innovation Team in University of Henan Province (No. 20IRTSTHN001). J. Wang was supported by Henan University to visit the University of Waterloo.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Juewen Liu or Feng Bai.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Gao, S., Wang, X. et al. Self-assembled manganese phthalocyanine nanoparticles with enhanced peroxidase-like activity for anti-tumor therapy. Nano Res. 15, 2347–2354 (2022). https://doi.org/10.1007/s12274-021-3854-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-021-3854-5

Keywords

Navigation