Skip to main content

Oral Administration of Cryptotanshinone-Encapsulated Nanoparticles for the Amelioration of Ulcerative Colitis

Abstract

Background

Inappropriate macrophages phenotype transition contributes to the development of ulcerative colitis, and the poly (ethylene glycol)-block-poly (d, l-lactic acid) (PEG-PLA) nanoparticles delivery system can be utilized to improve the cryptotanshinone (CTS)-based therapy.

Methods

We used a single emulsification method to prepare CTS-encapsulated nanoparticles (NPCTS). The therapeutic efficacy of NPCTS was evaluated in dextran sulfate sodium (DSS)-induced colitis mice. Then the proportion of total macrophages and M2-like macrophages were assayed with flow cytometry, and the relative content of pro-inflammatory cytokines in the colon was detected with Western blot. Bone-marrow-derived macrophages (BMDMs) were induced into M1-like macrophages, which were further incubated with NPCTS to repolarize into M2 subtype.

Results

Cryptotanshinone could induce the transition of M1 subtype to M2 subtype as indicated by up-regulated expression of arginase 1 (ARG1), interleukin (IL)-10, and CD206. In vivo, orally administrated NPCTS accumulated in the colon-infiltrated macrophages in colitis mice. It further revealed that NPCTS significantly alleviated colitis symptoms as indicated by increased body weight and colon length, decreased tumor necrosis factor (TNF)-α, IL-1β, and IL-6 content in the colon, and diminished total macrophage proportion (CD45+CD11b+F4/80+) and up-regulated M2 proportion (CD45+CD11b+F4/80+CD206hi).

Conclusion

Oral administration of NPCTS could ameliorate ulcerative colitis with the conversion of M1-like macrophages to M2-like macrophages.

This is a preview of subscription content, access via your institution.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. Ashrafizadeh, M., A. Zarrabi, S. Orouei, S. Saberifar, S. Salami, K. Hushmandi, and M. Najafi. Recent advances and future directions in anti-tumor activity of cryptotanshinone: a mechanistic review. Phytother. Res. 35(1):155–179, 2021

    Article  Google Scholar 

  2. Bain, C. C., C. L. Scott, H. Uronen-Hansson, S. Gudjonsson, O. Jansson, O. Grip, M. Guilliams, B. Malissen, W. W. Agace, and A. M. Mowat. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 6(3):498–510, 2013

    Article  Google Scholar 

  3. Baumgart, D. C., and S. R. Carding. Inflammatory bowel disease: cause and immunobiology. Lancet. 369(9573):1627–1640, 2007

    Article  Google Scholar 

  4. Chang, J. T. Pathophysiology of inflammatory bowel diseases. N. Engl. J. Med. 383(27):2652–2664, 2020

    Article  Google Scholar 

  5. Domínguez Conde, C., and S. A. Teichmann. Deciphering immunity at high plexity and resolution. Nat. Rev. Immunol. 20(2):77–78, 2020

    Article  Google Scholar 

  6. Don, M. J., J. F. Liao, L. Y. Lin, and W. F. Chiou. Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway. Br. J. Pharmacol. 151(5):638–646, 2007

    Article  Google Scholar 

  7. Giacalone, G., N. Tsapis, L. Mousnier, H. Chacun, and E. Fattal. PLA-PEG nanoparticles improve the anti-inflammatory effect of rosiglitazone on macrophages by enhancing drug uptake compared to free rosiglitazone. Materials (Basel, Switzerland). 11(10):1845, 2018

    Article  Google Scholar 

  8. Gren, S. T., and O. Grip. Role of monocytes and intestinal macrophages in Crohn’s disease and ulcerative colitis. Inflamm. Bowel Dis. 22(8):1992–1998, 2016

    Article  Google Scholar 

  9. He, W., N. Kapate, C. W. T. Shields, and S. Mitragotri. Drug delivery to macrophages: A review of targeting drugs and drug carriers to macrophages for inflammatory diseases. Adv. Drug Deliv. Rev. 165:15–40, 2020

    Article  Google Scholar 

  10. Herrlinger, K. R., and E. F. Stange. 25 years of biologicals in IBD: what’s all the hype about? J. Intern. Med. 290:806–825, 2021

    Article  Google Scholar 

  11. Hine, A. M., and P. Loke. Intestinal macrophages in resolving inflammation. J. Immunol. 203(3):593–599, 2019

    Article  Google Scholar 

  12. Hnatyszyn, A., S. Hryhorowicz, M. Kaczmarek-Ryś, E. Lis, R. Słomski, R. J. Scott, and A. Pławski. Colorectal carcinoma in the course of inflammatory bowel diseases. Hered. Cancer Clin. Pract. 17:18, 2019

    Article  Google Scholar 

  13. Kobayashi, T., B. Siegmund, C. Le Berre, S. C. Wei, M. Ferrante, B. Shen, C. N. Bernstein, S. Danese, L. Peyrin-Biroulet, and T. Hibi. Ulcerative colitis. Nat. Rev. Dis. Primers. 6(1):74, 2020

    Article  Google Scholar 

  14. Li, H., C. Gao, C. Liu, L. Liu, J. Zhuang, J. Yang, C. Zhou, F. Feng, C. Sun, and J. Wu. A review of the biological activity and pharmacology of cryptotanshinone, an important active constituent in Danshen. Biomed. Pharmacother. 137:111332, 2021

    Article  Google Scholar 

  15. Liu, W., Z. Dong, K. Liu, Y. Lu, W. Wu, J. Qi, and Z. Chen. Targeting strategies of oral nano-delivery systems for treating inflammatory bowel disease. Int. J. Pharm. 600:120461, 2021

    Article  Google Scholar 

  16. Lu, J., D. Liu, Y. Tan, R. Li, X. Wang, and F. Deng. Thalidomide attenuates colitis and is associated with the suppression of M1 macrophage polarization by targeting the transcription factor IRF5. Dig. Dis. Sci. 1:1–10, 2021

    Google Scholar 

  17. Lv, Q., Y. Xing, Y. Liu, Q. Chen, J. Xu, L. Hu, and Y. Zhang. Didymin switches M1-like toward M2-like macrophage to ameliorate ulcerative colitis via fatty acid oxidation. Pharmacol. Res. 169:105613, 2021

    Article  Google Scholar 

  18. Moreira Lopes, T. C., D. M. Mosser, and R. Gonçalves. Macrophage polarization in intestinal inflammation and gut homeostasis. Inflamm. Res. 69(12):1163–1172, 2020

    Article  Google Scholar 

  19. Nebbia, M., N. A. Yassin, and A. Spinelli. Colorectal cancer in inflammatory bowel disease. Clin. Colon Rectal Surg. 33(5):305–317, 2020

    Article  Google Scholar 

  20. De Schepper, S., S. Verheijden, J. Aguilera-Lizarraga, M. F. Viola, W. Boesmans, N. Stakenborg, I. Voytyuk, I. Schmidt, B. Boeckx, I. DierckxdeCasterle, V. Baekelandt, E. GonzalezDominguez, M. Mack, I. Depoortere, B. De Strooper, B. Sprangers, U. Himmelreich, S. Soenen, M. Guilliams, P. VandenBerghe, E. Jones, D. Lambrechts, and G. Boeckxstaens. Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell. 175(2):400–415, 2018

    Article  Google Scholar 

  21. Shi, M., Z. Lin, L. Ye, X. Chen, W. Zhang, Z. Zhang, F. Luo, Y. Liu, and M. Shi. Estrogen receptor-regulated SOCS3 modulation via JAK2/STAT3 pathway is involved in BPF-induced M1 polarization of macrophages. Toxicology. 433:152404, 2020

    Article  Google Scholar 

  22. Shin, D. S., H. N. Kim, K. D. Shin, Y. J. Yoon, S. J. Kim, D. C. Han, and B. M. Kwon. Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer Res. 69(1):193–202, 2009

    Article  Google Scholar 

  23. Sung, H., J. Ferlay, R. L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, and F. Bray. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3):209–249, 2021

    Article  Google Scholar 

  24. Tang, S., X. Y. Shen, H. Q. Huang, S. W. Xu, Y. Yu, C. H. Zhou, S. R. Chen, K. Le, Y. H. Wang, and P. Q. Liu. Cryptotanshinone suppressed inflammatory cytokines secretion in RAW2647 macrophages through inhibition of the NF-κB and MAPK signaling pathways. Inflammation. 34(2):111–118, 2011

    Article  Google Scholar 

  25. Wang, J. L., Y. J. Gan, S. Iqbal, W. Jiang, Y. Y. Yuan, and J. Wang. Delivery of tacrolimus with cationic lipid-assisted nanoparticles for ulcerative colitis therapy. Biomater. Sci. 6(7):1916–1922, 2018

    Article  Google Scholar 

  26. Wang, L., H. Zhang, L. Sun, W. Gao, Y. Xiong, A. Ma, X. Liu, L. Shen, Q. Li, and H. Yang. Manipulation of macrophage polarization by peptide-coated gold nanoparticles and its protective effects on acute lung injury. J. Nanobiotechnol. 18(1):38, 2020

    Article  Google Scholar 

  27. Yin, Z., T. Ma, Y. Lin, X. Lu, C. Zhang, S. Chen, and Z. Jian. IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma. J. Cell Biochem. 119(11):9419–9432, 2018

    Article  Google Scholar 

  28. Zhang, J., Y. Zhao, T. Hou, H. Zeng, D. Kalambhe, B. Wang, X. Shen, and Y. Huang. Macrophage-based nanotherapeutic strategies in ulcerative colitis. J. Control Release. 320:363–380, 2020

    Article  Google Scholar 

  29. Zhu, W., J. Yu, Y. Nie, X. Shi, Y. Liu, F. Li, and X. L. Zhang. Disequilibrium of M1 and M2 macrophages correlates with the development of experimental inflammatory bowel diseases. Immunol. Invest. 43(7):638–652, 2014

    Article  Google Scholar 

Download references

Conflict of interest

Li Zhang, Longfei Yu and Yueguang Wei declare that they have no conflict of interest.

Ethical Approval

All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the Daqing Oilfield General Hospital. No human studies were carried out by the authors for this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Li Zhang.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Associate Editor Michael R. King oversaw the review of this article.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, L., Yu, L. & Wei, Y. Oral Administration of Cryptotanshinone-Encapsulated Nanoparticles for the Amelioration of Ulcerative Colitis. Cel. Mol. Bioeng. 15, 129–136 (2022). https://doi.org/10.1007/s12195-021-00711-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12195-021-00711-x

Keywords

  • Cryptotanshinone
  • PEG-PLA
  • Ulcerative colitis
  • Macrophage