Skip to main content

Advertisement

SpringerLink
Log in

Co-Loading of Cisplatin and Methotrexate in Nanoparticle-Based PCL-PEG System Enhances Lung Cancer Chemotherapy Effects

  • Original Paper
  • Published:
Journal of Cluster Science Aims and scope Submit manuscript

Abstract

Since the anticancer drugs exhibited a variety of inhibitory mechanisms in cancer cells, the use of two or more anticancer drugs may have excellent therapeutic effects, particularly in drug-resistant tumors. In this study, the efficient entrapment of two clinically used single-agent drugs, Cisplatin (CDDP) and Methotrexate (MTX) is reported against lung cancer cell lines. Biodegradable polymeric nanoparticles perform to be a favorable environment-responsive controlled drug release system. MTX@CDDP were simultaneously encapsulated into the biodegradable poly (ε-caprolactone) (PCL) modified poly (ethylene glycol) (PEG) copolymer. The spherical nanoparticle was identified via scanning electron microscopy (SEM). Additionally, the antitumor activity and apoptosis induction of designed duel drug-loaded vectors were assessed against A549 cell lines by qRT-PCR, MTT assay, and DAPI staining. The nanoformulation loaded with MTX@CDDP statistically reduced the cell activity of A549. The results indicate that MTX@CDDP-loaded PCL-PEG nanoparticles can be further utilized for treating non-small-cell lung cancer as a promising therapeutic approach.

Graphical Abstract

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

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

Similar content being viewed by others

References

  1. A. Anwar and N. Waheed (2015). Galactosemia: clinical manifestations, diagnosis and outcome of early management. Ann Pak Inst Med Sci. 11 (4), 190–194.

    Google Scholar 

  2. A. Waheed, A. Gupta, and P. Patel (2015). Targeted drug delivery systems for lung cancer. PharmaTutor. 3 (2), 38–42.

    Google Scholar 

  3. L. Chen, A. Nan, N. Zhang, Y. Jia, X. Li, Y. Ling, et al. (2019). Circular RNA 100146 functions as an oncogene through direct binding to miR-361-3p and miR-615-5p in non-small cell lung cancer. Molecular cancer. 18 (1), 1–8.

    Article  PubMed  PubMed Central  Google Scholar 

  4. P. C. Huber, C. H. Maruiama, and W. P. Almeida (2010). Glicoproteína-P, resistência a múltiplas drogas (MDR) e relação estrutura-atividade de moduladores. Química Nova. 33 (10), 2148–2154.

    Article  CAS  Google Scholar 

  5. S. Niu, G. R. Williams, J. Wu, J. Wu, X. Zhang, H. Zheng, et al. (2019). A novel chitosan-based nanomedicine for multi-drug resistant breast cancer therapy. Chemical Engineering Journal. 369, 134–149.

    Article  CAS  Google Scholar 

  6. Ke. Xj, Y. F. Cheng, N. Yu, and Q. Di (2019). Effects of carbamazepine on the P-gp and CYP3A expression correlated with PXR or NF-κB activity in the bEnd 3 cells. Neuroscience letters. 690, 48–55.

    Article  CAS  Google Scholar 

  7. J. M. Albano, L. N. de Morais Ribeiro, V. M. Couto, M. B. Messias, G. H. R. da Silva, M. C. Breitkreitz, et al. (2019). Rational design of polymer-lipid nanoparticles for docetaxel delivery. Colloids and Surfaces B: Biointerfaces. 175, 56–64.

    Article  CAS  PubMed  Google Scholar 

  8. W. Chearwae, S. Anuchapreeda, K. Nandigama, S. Ambudkar, and P. Limtrakul (2004). Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder. Biochemical Pharmacology. 68 (10), 2043–2052.

    Article  CAS  PubMed  Google Scholar 

  9. P. Zarogoulidis, D. Petridis, C. Ritzoulis, K. Darwiche, D. Spyratos, H. Huang, et al. (2013). Establishing the optimal nebulization system for paclitaxel, docetaxel, cisplatin, carboplatin and gemcitabine: back to drawing the residual cup. International Journal of Pharmaceutics. 453 (2), 480–487.

    Article  CAS  PubMed  Google Scholar 

  10. H. Xiao, R. Qi, T. Li, S. G. Awuah, Y. Zheng, W. Wei, et al. (2017). Maximizing synergistic activity when combining RNAi and platinum-based anticancer agents. Journal of the American Chemical Society. 139 (8), 3033–3044.

    Article  CAS  PubMed  Google Scholar 

  11. J. Shen, Y. Zhu, H. Shi, and Y. Liu (2018). Multifunctional nanodrug delivery systems for platinum-based anticancer drugs. Progress in Chemistry. 30 (10), 1557–1572.

    CAS  Google Scholar 

  12. K. Nejati-Koshki, A. Akbarzadeh, and M. Pourhassan-Moghaddam (2014). Curcumin inhibits leptin gene expression and secretion in breast cancer cells by estrogen receptors. Cancer Cell International. 14 (1), 1–7.

    Article  Google Scholar 

  13. R. B. Weiss and M. C. Christian (1993). New cisplatin analogues in development. Drugs. 46 (3), 360–377.

    Article  CAS  PubMed  Google Scholar 

  14. Jamieson E. Lippard (1999). SJ Chem. Rev. 99, 2467.

    Article  CAS  Google Scholar 

  15. T. Boulikas, A. Pantos, E. Bellis, and P. Christofis (2007). Designing platinum compounds in cancer: structures and mechanisms. Cancer Ther. 5, 537–583.

    Google Scholar 

  16. R. Sharma, P. Tobin, and S. J. Clarke (2005). Management of chemotherapy-induced nausea, vomiting, oral mucositis, and diarrhoea. The lancet oncology. 6 (2), 93–102.

    Article  CAS  PubMed  Google Scholar 

  17. S. M. Sancho-Martínez, L. Prieto-García, M. Prieto, J. M. Lopez-Novoa, and F. J. López-Hernández (2012). Subcellular targets of cisplatin cytotoxicity: an integrated view. Pharmacology amd Therapeutics. 136 (1), 35–55.

    Article  CAS  Google Scholar 

  18. A. Kim, J.-E. Lee, W.-S. Jang, S.-J. Lee, S. Park, H. J. Kang, et al. (2012). A combination of methotrexate and irradiation promotes cell death in NK/T-cell lymphoma cells via down-regulation of NF-κB signaling. Leukemia research. 36 (3), 350–357.

    Article  CAS  PubMed  Google Scholar 

  19. Z. Pan, G. Yang, H. He, G. Zhao, T. Yuan, Y. Li, et al. (2016). Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: a prospective and single-arm study. International Journal of Cancer. 139 (8), 1864–1872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. I. D. Goldman and L. H. Matherly (1985). The cellular pharmacology of methotrexate. Pharmacology & Therapeutics. 28 (1), 77–102.

    Article  CAS  Google Scholar 

  21. P. Parashar, C. B. Tripathi, M. Arya, J. Kanoujia, M. Singh, A. Yadav, et al. (2019). A synergistic approach for management of lung carcinoma through folic acid functionalized co-therapy of capsaicin and gefitinib nanoparticles: enhanced apoptosis and metalloproteinase-9 down-regulation. Phytomedicine. 53, 107–123.

    Article  CAS  PubMed  Google Scholar 

  22. Y. Pan, N. G. Sahoo, and L. Li (2012). The application of graphene oxide in drug delivery. Expert Opinion on Drug Delivery. 9 (11), 1365–1376.

    Article  CAS  PubMed  Google Scholar 

  23. I. Brigger, C. Dubernet, and P. Couvreur (2012). Nanoparticles in cancer therapy and diagnosis. Advanced Drug Delivery Reviews. 64, 24–36.

    Article  Google Scholar 

  24. G. Stoter, T. Splinter, J. Child, S. Fosså, L. Denis, A. Van Oosterom, et al. (1987). Combination chemotherapy with cisplatin and methotrexate in advanced transitional cell cancer of the bladder. The Journal of Urology. 137 (4), 663–667.

    Article  CAS  PubMed  Google Scholar 

  25. D. A. Corral, A. Sella, C. A. Pettaway, R. J. Amato, D. M. Jones, and J. Ellerhorst (1998). Combination chemotherapy for metastatic or locally advanced genitourinary squamous cell carcinoma: a phase II study of methotrexate, cisplatin and bleomycin. The Journal of Urology. 160 (5), 1770–1774.

    Article  CAS  PubMed  Google Scholar 

  26. H. Ma, C. He, Y. Cheng, Z. Yang, J. Zang, J. Liu, et al. (2015). Localized co-delivery of doxorubicin, cisplatin, and methotrexate by thermosensitive hydrogels for enhanced osteosarcoma treatment. ACS Applied Materials & Interfaces. 7 (49), 27040–27048.

    Article  CAS  Google Scholar 

  27. M. Avella, F. Bondioli, V. Cannillo, E. Di Pace, M. E. Errico, A. M. Ferrari, et al. (2006). Poly (ε-caprolactone)-based nanocomposites: Influence of compatibilization on properties of poly (ε-caprolactone)–silica nanocomposites. Composites Science and Technology. 66 (7–8), 886–894.

    Article  CAS  Google Scholar 

  28. N. Asadi, N. Annabi, E. Mostafavi, M. Anzabi, R. Khalilov, S. Saghfi, et al. (2018). Synthesis, characterization and in vitro evaluation of magnetic nanoparticles modified with PCL–PEG–PCL for controlled delivery of 5FU. Artificial Cells, Nanomedicine, and Biotechnology. 46 (sup1), 938–945.

    Article  CAS  PubMed  Google Scholar 

  29. J. S. Suk, Q. Xu, N. Kim, J. Hanes, and L. M. Ensign (2016). PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Advanced Drug Delivery Reviews. 99, 28–51.

    Article  CAS  PubMed  Google Scholar 

  30. M. Chidambaram, R. Manavalan, and K. Kathiresan (2011). Nanotherapeutics to overcome conventional cancer chemotherapy limitations. Journal of Pharmacy & Pharmaceutical Sciences. 14 (1), 67–77.

    Article  Google Scholar 

  31. P. Soltantabar, E. L. Calubaquib, E. Mostafavi, M. C. Biewer, and M. C. Stefan (2020). Enhancement of loading efficiency by co-loading of doxorubicin and quercetin in thermoresponsive polymeric micelles. Biomacromolecules. 21 (4), 1427–1436.

    Article  CAS  PubMed  Google Scholar 

  32. E. Mostafavi, P. Soltantabar, and T. J. Webster (2019). Nanotechnology and picotechnology: A new arena for translational medicine. Biomaterials in Translational Medicine: Elsevier, p. 191–212.

  33. E. Mostafavi, D. Medina-Cruz, K. Kalantari, A. Taymoori, P. Soltantabar, and T. J. Webster (2020). Electroconductive nano-biomaterials for tissue engineering and regenerative medicine. Bioelectricity. 2 (2), 120–149.

    Article  PubMed  PubMed Central  Google Scholar 

  34. P. Parashar, C. B. Tripathi, M. Arya, J. Kanoujia, M. Singh, A. Yadav, et al. (2018). Biotinylated naringenin intensified anticancer effect of gefitinib in urethane-induced lung cancer in rats: favourable modulation of apoptotic regulators and serum metabolomics. Artificial Cells, Nanomedicine, and Biotechnology. 46 (sup3), S598–S610.

    Article  CAS  PubMed  Google Scholar 

  35. S. Fekri Aval, A. Akbarzadeh, M. R. Yamchi, F. Zarghami, K. Nejati-Koshki, and N. Zarghami (2016). Gene silencing effect of SiRNA-magnetic modified with biodegradable copolymer nanoparticles on hTERT gene expression in lung cancer cell line. Artificial Cells, Nanomedicine, and Biotechnology. 44 (1), 188–193.

    Article  CAS  PubMed  Google Scholar 

  36. E. Adlravan, K. Nejati, M. A. Karimi, H. Mousazadeh, A. Abbasi, and M. Dadashpour (2021). Potential activity of free and PLGA/PEG nanoencapsulated nasturtium officinale extract in inducing cytotoxicity and apoptosis in human lung carcinoma A549 cells. Journal of Drug Delivery Science and Technology. 61, 102256.

    Article  CAS  Google Scholar 

  37. J. Yang, S.-B. Park, H.-G. Yoon, Y.-M. Huh, and S. Haam (2006). Preparation of poly ɛ-caprolactone nanoparticles containing magnetite for magnetic drug carrier. International Journal of Pharmaceutics. 324 (2), 185–190.

    Article  CAS  PubMed  Google Scholar 

  38. S. Rasouli, S. Davaran, F. Rasouli, M. Mahkam, and R. Salehi (2014). Positively charged functionalized silica nanoparticles as nontoxic carriers for triggered anticancer drug release. Designed Monomers and Polymers. 17 (3), 227–237.

    Article  CAS  Google Scholar 

  39. K. Nejati-Koshki, M. Mesgari, E. Ebrahimi, F. Abbasalizadeh, S. Fekri Aval, A. A. Khandaghi, et al. (2014). Synthesis and in vitro study of cisplatin-loaded Fe3O4 nanoparticles modified with PLGA-PEG6000 copolymers in treatment of lung cancer. Journal of Microencapsulation. 31 (8), 815–823.

    Article  CAS  PubMed  Google Scholar 

  40. E. Akbari, H. Mousazadeh, Z. Sabet, T. Fattahi, A. Dehnad, A. Akbarzadeh, et al. (2021). Dual drug delivery of trapoxin A and methotrexate from biocompatible PLGA-PEG polymeric nanoparticles enhanced antitumor activity in breast cancer cell line. Journal of Drug Delivery Science and Technology. 61, 102294.

    Article  CAS  Google Scholar 

  41. H. Mousazadeh, Y. Pilehvar-Soltanahmadi, M. Dadashpour, and N. Zarghami (2020). Cyclodextrin based natural nanostructured carbohydrate polymers as effective non-viral siRNA delivery systems for cancer gene therapy. Journal of Controlled Release. 330, 1046–1070.

    Article  PubMed  CAS  Google Scholar 

  42. S. Amirsaadat, D. Jafari-Gharabaghlou, S. Alijani, H. Mousazadeh, M. Dadashpour, and N. Zarghami (2021). Metformin and Silibinin co-loaded PLGA-PEG nanoparticles for effective combination therapy against human breast cancer cells. Journal of Drug Delivery Science and Technology. 61, 102107.

    Article  CAS  Google Scholar 

  43. S. Oh, E. Xiaofei, D. Ni, S. D. Pirooz, J.-Y. Lee, D. Lee, et al. (2011). Downregulation of autophagy by Bcl-2 promotes MCF7 breast cancer cell growth independent of its inhibition of apoptosis. Cell Death & Differentiation. 18 (3), 452–464.

    Article  CAS  Google Scholar 

  44. E. A. Musgrove, C. E. Caldon, J. Barraclough, A. Stone, and R. L. Sutherland (2011). Cyclin D as a therapeutic target in cancer. Nature Reviews Cancer. 11 (8), 558–572.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research reported in this publication was supported by Elite Researcher Grant Committee under award number [971185] from the National Institutes for Medical Research Development (NIMAD), Tehran, Iran.

Author information

Authors and Affiliations

  1. Department of Medical Biotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran

    Elahe Akbari & Hanieh Mousazadeh

  2. Department of Chemistry, Sayyed Jamaleddin Asadabadi University, Asadabad, Iran

    Younes Hanifehpour

  3. Department of Chemical Engineering, Northeastern University, Boston, MA, 02115, USA

    Ebrahim Mostafavi

  4. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Peyman keyhanvar & Abolfazl Akbarzadeh

  5. Universal Scientific Education and Research Network (USERN), Tabriz, Iran

    Abolfazl Akbarzadeh

  6. Higher Education Institute of Rab-Rashid, Tabriz, Iran

    Elahe Akbari

  7. Department of Chemistry, Shahrood Branch, Islamic Azad University, Shahrood, Iran

    Majid Mohammadhosseini

  8. Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran

    Kazem Nejati

  9. Physiology Research Center and Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Hamidreza Pazoki-Toroudi

  10. Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Armita Mahdavi Gorabi

Authors
  1. Elahe Akbari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hanieh Mousazadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Younes Hanifehpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ebrahim Mostafavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Armita Mahdavi Gorabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazem Nejati
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peyman keyhanvar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hamidreza Pazoki-Toroudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Majid Mohammadhosseini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Abolfazl Akbarzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abolfazl Akbarzadeh.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests. The authors alone are responsible for the content and writing of this article.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akbari, E., Mousazadeh, H., Hanifehpour, Y. et al. Co-Loading of Cisplatin and Methotrexate in Nanoparticle-Based PCL-PEG System Enhances Lung Cancer Chemotherapy Effects. J Clust Sci 33, 1751–1762 (2022). https://doi.org/10.1007/s10876-021-02101-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10876-021-02101-9

Keywords

Search

Navigation