Skip to main content
SpringerLink
Log in

Targeted Delivery of Metformin Against Lung Cancer Cells Via Hyaluronan-Modified Mesoporous Silica Nanoparticles

  • Original Article
  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

Metformin (Metf), a biguanide widely used to manage type 2 diabetes mellitus, has recently entered the spotlight as a hopeful anti-tumor agent. In this work, because of the hyaluronic acid (HA) capability to specifically target CD44 receptors over-expressed on the surface of non-small lung cancer cells, a tumor-targeted drug delivery nanocarrier-based HA-coated mesoporous silica nanoparticles (MSNs) have been used for active targeting and efficient delivery of Metf. For this purpose, the synthesized MSNs-HA were characterized using BET, FE-EM, DLS, and FTIR. Confocal microscopy was applied to show the enhanced cellular uptake of the FITC-labelled MSNs-HA compared to MSNs without HA coating. MTT and qPCR results also revealed superior cytotoxicity and pro-apoptotic effects of Metf-loaded MSNs-HA (Metf@MSNs-HA) against the A549 lung cancer cells compared to the free Metf and MSNs@Metf due to the efficient CD44-targeting capability and delivery of Metf@MSNs-HA. Besides, it was demonstrated that Metf@MSNs-HA could effectively trigger the AMP-activated protein kinase α (AMPKα) pathway and inhibit the mammalian target rapamycin (mTOR), increasing the growth suppression. In conclusion, this preliminary work disclosed the great potential of Metf@MSNs-HA in targeted therapy of lung cancer cells.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

References

  1. Low, Z. Y., Farouk, I. A., & Lal, S. K. (2020). Drug repositioning: New approaches and future prospects for life-debilitating diseases and the COVID-19 pandemic outbreak. Viruses, 12(9), 1058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Alibakhshi, A., et al. (2016). An update on phytochemicals in molecular target therapy of cancer: Potential inhibitory effect on telomerase activity. Current Medicinal Chemistry, 23(22), 2380–2393.

    Article  CAS  PubMed  Google Scholar 

  3. Javidfar, S., et al. (2018). The inhibitory effects of nano-encapsulated metformin on growth and hTERT expression in breast cancer cells. Journal of Drug Delivery Science and Technology, 43, 19–26.

    Article  CAS  Google Scholar 

  4. Jafari-Gharabaghlou, D., et al. (2018). Combination of metformin and phenformin synergistically inhibits proliferation and hTERT expression in human breast cancer cells. Iranian Journal of Basic Medical Sciences, 21(11), 1167.

    PubMed  PubMed Central  Google Scholar 

  5. Chatran, M., et al. (2018). Synergistic anti-proliferative effects of metformin and silibinin combination on T47D breast cancer cells via hTERT and cyclin D1 inhibition. Drug Research, 68(12), 710–716.

    Article  CAS  PubMed  Google Scholar 

  6. Aljofan, M., & Riethmacher, D. (2019). Anticancer activity of metformin: a systematic review of the literature. Future Science OA, 5(8), FSO410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ugwueze, C. V., et al. (2020). Metformin: a possible option in cancer chemotherapy. Analytical Cellular Pathology, 2020.

  8. Wink, K. C., et al. (2016). Improved progression free survival for patients with diabetes and locally advanced non-small cell lung cancer (NSCLC) using metformin during concurrent chemoradiotherapy. Radiotherapy and Oncology, 118(3), 453–459.

    Article  PubMed  Google Scholar 

  9. Fatehi Hassanabad, A., & MacQueen, K. T. (2021). Molecular mechanisms underlining the role of metformin as a therapeutic agent in lung cancer. Cellular Oncology, 44(1), 1–18.

    Article  CAS  Google Scholar 

  10. Ahmadi, S., et al. (2021). Efficient osteoblastic differentiation of human adipose-derived stem cells on TiO2 nanoparticles and metformin co-embedded electrospun composite nanofibers. Journal of Drug Delivery Science and Technology, 66, 102798.

    Article  CAS  Google Scholar 

  11. Cetin, M., & Sahin, S. (2016). Microparticulate and nanoparticulate drug delivery systems for metformin hydrochloride. Drug Delivery, 23(8), 2796–2805.

    Article  CAS  PubMed  Google Scholar 

  12. Pourpirali, R., et al. (2021). Prolonged proliferation and delayed senescence of the adipose-derived stem cells grown on the electrospun composite nanofiber co-encapsulated with TiO2 nanoparticles and metformin-loaded mesoporous silica nanoparticles. International Journal of Pharmaceutics, 604, 120733.

    Article  CAS  PubMed  Google Scholar 

  13. Zavari-Nematabad, A., et al. (2017). Development of quantum-dot-encapsulated liposome-based optical nanobiosensor for detection of telomerase activity without target amplification. Analytical and Bioanalytical Chemistry, 409(5), 1301–1310.

    Article  CAS  PubMed  Google Scholar 

  14. Naseri, N., et al. (2018). An update on nanoparticle-based contrast agents in medical imaging. Artificial Cells, Nanomedicine, and Biotechnology, 46(6), 1111–1121.

    Article  CAS  PubMed  Google Scholar 

  15. Serati-Nouri, H., et al. (2020). Biomedical applications of zeolite-based materials: A review. Materials Science and Engineering: C, 116, 111225.

    Article  CAS  PubMed  Google Scholar 

  16. Mellatyar, H., et al. (2018). 17-DMAG-loaded nanofibrous scaffold for effective growth inhibition of lung cancer cells through targeting HSP90 gene expression. Biomedicine & Pharmacotherapy, 105, 1026–1032.

    Article  CAS  Google Scholar 

  17. Mashayekhi, S., et al. (2020). Curcumin-loaded mesoporous silica nanoparticles/nanofiber composites for supporting long-term proliferation and stemness preservation of adipose-derived stem cells. International Journal of Pharmaceutics, 587, 119656.

    Article  CAS  PubMed  Google Scholar 

  18. Samadzadeh, S., et al. (2021). An implantable smart hyperthermia nanofiber with switchable, controlled and sustained drug release: Possible application in prevention of cancer local recurrence. Materials Science and Engineering: C, 118, 111384.

    Article  CAS  PubMed  Google Scholar 

  19. Tang, L., et al. (2021). Nanoparticle-mediated targeted drug delivery to remodel tumor microenvironment for cancer therapy. International Journal of Nanomedicine, 16, 5811.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Taleghani, A. S., et al. (2021). Mesoporous silica nanoparticles as a versatile nanocarrier for cancer treatment: A review. Journal of Molecular Liquids, 328, 115417.

    Article  CAS  Google Scholar 

  21. Li, T., et al. (2019). Recent advancements in mesoporous silica nanoparticles towards therapeutic applications for cancer. Acta Biomaterialia, 89, 1–13.

    Article  CAS  PubMed  Google Scholar 

  22. Ahir, M., et al. (2020). Delivery of dual miRNA through CD44-targeted mesoporous silica nanoparticles for enhanced and effective triple-negative breast cancer therapy. Biomaterials Science, 8(10), 2939–2954.

    Article  CAS  PubMed  Google Scholar 

  23. Ricci, V., et al. (2018). Hyaluronated mesoporous silica nanoparticles for active targeting: Influence of conjugation method and hyaluronic acid molecular weight on the nanovector properties. Journal of Colloid and Interface Science, 516, 484–497.

    Article  CAS  PubMed  Google Scholar 

  24. Mo, X., et al. (2021). Hyaluronic acid-functionalized halloysite nanotubes for targeted drug delivery to CD44-overexpressing cancer cells. Materials Today Communications, 28, 102682.

    Article  CAS  Google Scholar 

  25. Chen, C., et al. (2018). pH-responsive nanoreservoirs based on hyaluronic acid end-capped mesoporous silica nanoparticles for targeted drug delivery. International Journal of Biological Macromolecules, 111, 1106–1115.

    Article  CAS  PubMed  Google Scholar 

  26. Ghosh, S., et al. (2021). Targeted delivery of curcumin in breast cancer cells via hyaluronic acid modified mesoporous silica nanoparticle to enhance anticancer efficiency. Colloids and Surfaces B: Biointerfaces, 197, 111404.

    Article  CAS  PubMed  Google Scholar 

  27. Yu, M., et al. (2013). Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells. Nanoscale, 5(1), 178–183.

    Article  CAS  PubMed  Google Scholar 

  28. Chen, Z., et al. (2013). Bioresponsive hyaluronic acid‐capped mesoporous silica nanoparticles for targeted drug delivery. Chemistry–A European Journal, 19(5), 1778–1783.

    Article  CAS  PubMed  Google Scholar 

  29. Sábio, R. M., et al. (2019). New insights towards mesoporous silica nanoparticles as a technological platform for chemotherapeutic drugs delivery. International Journal of Pharmaceutics, 564, 379–409.

    Article  PubMed  Google Scholar 

  30. Almalik, A., et al. (2017). Hyaluronic acid coated chitosan nanoparticles reduced the immunogenicity of the formed protein corona. Scientific Reports, 7(1), 1–9.

    Article  CAS  Google Scholar 

  31. Jafari, S., et al. (2019). Mesoporous silica nanoparticles for therapeutic/diagnostic applications. Biomedicine & Pharmacotherapy, 109, 1100–1111.

    Article  CAS  Google Scholar 

  32. Shukla, S. K., et al. (2019). Metformin-encapsulated liposome delivery system: An effective treatment approach against breast cancer. Pharmaceutics, 11(11), 559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rasouli, S., et al. (2020). Synergistic anticancer effects of electrospun nanofiber-mediated codelivery of curcumin and chrysin: Possible application in prevention of breast cancer local recurrence. Journal of Drug Delivery Science and Technology, 55, 101402.

    Article  CAS  Google Scholar 

  34. Liu, K., et al. (2015). Hyaluronic acid-tagged silica nanoparticles in colon cancer therapy: Therapeutic efficacy evaluation. International Journal of Nanomedicine, 10, 6445.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Fang, Z., et al. (2019). Hyaluronic acid-modified mesoporous silica-coated superparamagnetic Fe3O4 nanoparticles for targeted drug delivery. International Journal of Nanomedicine, 14, 5785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gao, C., et al. (2020). Metformin induces autophagy via the AMPK-mTOR signaling pathway in human hepatocellular carcinoma cells. Cancer Management and Research, 12, 5803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lu, G., et al. (2021). The effects of metformin on autophagy. Biomedicine & Pharmacotherapy, 137, 111286.

    Article  CAS  Google Scholar 

  38. Entezari, M., et al. (2022). AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation. Biomedicine & Pharmacotherapy, 146, 112563.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the “Department of Thoracic Surgery, Leshan People’s Hospital” for their kind cooperation.

Author information

Authors and Affiliations

  1. Department of Thoracic Surgery, Leshan People’s Hospital, Leshan, 614000, China

    Fan Zhang, Wei Liu, Yonggui Long & Huali Peng

Authors
  1. Fan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yonggui Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huali Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FZ and WL: methodology, investigation, data curation, original draft preparation. YL: writing – review and editing, formal analysis. HP: supervision, conceptualization, writing – review and editing.

Corresponding author

Correspondence to Huali Peng.

Ethics declarations

Ethical Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

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

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, F., Liu, W., Long, Y. et al. Targeted Delivery of Metformin Against Lung Cancer Cells Via Hyaluronan-Modified Mesoporous Silica Nanoparticles. Appl Biochem Biotechnol 195, 4067–4083 (2023). https://doi.org/10.1007/s12010-022-04289-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-022-04289-6

Keywords

Search

Navigation