Cytotoxic effects and apoptosis induction of cisplatin-loaded iron oxide nanoparticles modified with chitosan in human breast cancer cells

  • Ali Morovati
  • Shahin AhmadianEmail author
  • Hanieh JafaryEmail author
Original Article


Cisplatin is widely used as an anticancer drug in chemotherapy of human cancers. In the field of cancer therapy, nanoparticles modified with biocompatible copolymers are suitable vehicles to effectively deliver smaller doses of hydrophobic drugs such as cisplatin in the body. In this study, we investigated whether cisplatin-loaded iron oxide nanoparticles (IONPs) modified with chitosan can exert cytotoxic effects in the human breast cancer cell line MDA-MB-231. IONPs was synthesized using eucalyptus leaf extract as a reducing and stabilizing agent. MDA-MB-231 cells were treated with different concentrations of cisplatin, cisplatin-IONPs and cisplatin-IONPs-chitosan for 24 h. Apoptosis was confirmed by flow cytometry, whereas The mRNA and protein expression of pro- and anti-apoptotic molecules were measured using Real time RT-PCR and western blotting. Treatment with both cisplatin-IONPs and cisplatin-IONPs-chitosan showed a significantly higher cytotoxic effect in comparison to the free drug alone in MDA-MB-231 cells. The levels of apoptosis in cells treated with a combination of cisplatin-IONPs-chitosan were significantly higher compared with cisplatin-IONPs and cisplatin alone. The results of this study showed that the interaction between cisplatin and iron oxide nanoparticles modified with chitosan could enhance responsiveness to cisplatin in breast cancer cells.


Cell viability Cytotoxicity Apoptosis Cisplatin Iron oxide nanoparticle 



The authors would like to acknowledge the financial support of the Research Council of the University of Tehran and Science and Research Branch, Islamic Azad University.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.


  1. 1.
    Dubey AK, Gupta U, Jain S (2015) Breast cancer statistics and prediction methodology: a systematic review and analysis. Asian Pac J Cancer Prev 16(10):4237–4245CrossRefGoogle Scholar
  2. 2.
    DeSantis CE, Fedewa SA, Sauer AG, Kramer JL, Smith RA, Jemal A (2016) Breast cancer statistics, 2015: convergence of incidence rates between black and white women. CA Cancer J Clin 66(1):31–42CrossRefGoogle Scholar
  3. 3.
    Heinemann V (2002) Gemcitabine plus cisplatin for the treatment of metastatic breast cancer. Clin Breast Cancer 3:S24–S29CrossRefGoogle Scholar
  4. 4.
    Florea A-M, Büsselberg D (2011) Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers 3(1):1351–1371CrossRefGoogle Scholar
  5. 5.
    Tsang RY, Al-Fayea T, Au H-J (2009) Cisplatin overdose. Drug Saf 32(12):1109–1122CrossRefGoogle Scholar
  6. 6.
    Blanco E, Shen H, Ferrari M (2015) Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol 33(9):941CrossRefGoogle Scholar
  7. 7.
    Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C et al (2010) A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther 18(9):1606–1614CrossRefGoogle Scholar
  8. 8.
    Singh R, Lillard JW Jr (2009) Nanoparticle-based targeted drug delivery. Exp Mol Pathol 86(3):215–223CrossRefGoogle Scholar
  9. 9.
    Panyam J, Labhasetwar V (2003) Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev 55(3):329–347CrossRefGoogle Scholar
  10. 10.
    Gupta AK, Gupta M (2005) Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 26(18):3995–4021CrossRefGoogle Scholar
  11. 11.
    Laurent S, Forge D, Port M, Roch A, Robic C, Vander Elst L et al (2008) Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem Rev 108(6):2064–2110CrossRefGoogle Scholar
  12. 12.
    Unsoy G, Yalcin S, Khodadust R, Gunduz G, Gunduz U (2012) Synthesis optimization and characterization of chitosan-coated iron oxide nanoparticles produced for biomedical applications. J Nanopart Res 14(11):964CrossRefGoogle Scholar
  13. 13.
    Kim J-H, Kim Y-S, Park K, Lee S, Nam HY, Min KH et al (2008) Antitumor efficacy of cisplatin-loaded glycol chitosan nanoparticles in tumor-bearing mice. J Control Release 127(1):41–49CrossRefGoogle Scholar
  14. 14.
    Ren T-N, Wang J-S, He Y-M, Xu C-L, Wang S-Z, Xi T (2011) Effects of SMYD3 over-expression on cell cycle acceleration and cell proliferation in MDA-MB-231 human breast cancer cells. Med Oncol 28(1):91–98CrossRefGoogle Scholar
  15. 15.
    Jun SY, Choi YH, Shin HM (2006) Siegesbeckia glabrescens induces apoptosis with different pathways in human MCF-7 and MDA-MB-231 breast carcinoma cells. Oncol Rep 15(6):1461–1467Google Scholar
  16. 16.
    Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C et al (2009) Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 115(2):359–363CrossRefGoogle Scholar
  17. 17.
    Group IALCTC (2004) Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350(4):351–360CrossRefGoogle Scholar
  18. 18.
    Min Y, Mao CQ, Chen S, Ma G, Wang J, Liu Y (2012) Combating the drug resistance of cisplatin using a platinum prodrug based delivery system. Angew Chem 124(27):6846–6851CrossRefGoogle Scholar
  19. 19.
    Hu C-MJ, Zhang L (2012) Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem Pharmacol 83(8):1104–1111CrossRefGoogle Scholar
  20. 20.
    Wagstaff AJ, Brown SD, Holden MR, Craig GE, Plumb JA, Brown RE et al (2012) Cisplatin drug delivery using gold-coated iron oxide nanoparticles for enhanced tumour targeting with external magnetic fields. Inorg Chim Acta 393:328–333CrossRefGoogle Scholar
  21. 21.
    Bisht S, Maitra A (2009) Dextran–doxorubicin/chitosan nanoparticles for solid tumor therapy. Wiley Interdiscipl Rev 1(4):415–425Google Scholar
  22. 22.
    Soares PI, Sousa AI, Ferreira IM, Novo CM, Borges JP (2016) Towards the development of multifunctional chitosan-based iron oxide nanoparticles: optimization and modelling of doxorubicin release. Carbohyd Polym 153:212–221CrossRefGoogle Scholar
  23. 23.
    Qi L, Xu Z, Jiang X, Li Y, Wang M (2005) Cytotoxic activities of chitosan nanoparticles and copper-loaded nanoparticles. Bioorg Med Chem Lett 15(5):1397–1399CrossRefGoogle Scholar
  24. 24.
    Qi L-F, Xu Z-R, Li Y, Jiang X, Han X-Y (2005) In vitro effects of chitosan nanoparticles on proliferation of human gastric carcinoma cell line MGC803 cells. World J Gastroenterol 11(33):5136Google Scholar
  25. 25.
    Babu A, Wang Q, Muralidharan R, Shanker M, Munshi A, Ramesh R (2014) Chitosan coated polylactic acid nanoparticle-mediated combinatorial delivery of cisplatin and siRNA/Plasmid DNA chemosensitizes cisplatin-resistant human ovarian cancer cells. Mol Pharm 11(8):2720–2733CrossRefGoogle Scholar
  26. 26.
    Thomadaki H, Scorilas A (2006) BCL2 family of apoptosis-related genes: functions and clinical implications in cancer. Crit Rev Clin Lab Sci 43(1):1–67CrossRefGoogle Scholar
  27. 27.
    Sanpui P, Chattopadhyay A, Ghosh SS (2011) Induction of apoptosis in cancer cells at low silver nanoparticle concentrations using chitosan nanocarrier. ACS Appl Mater Interfaces 3(2):218–228CrossRefGoogle Scholar
  28. 28.
    Cummings BS, Schnellmann RG (2002) Cisplatin-induced renal cell apoptosis: caspase 3-dependent and-independent pathways. J Pharmacol Exp Ther 302(1):8–17CrossRefGoogle Scholar
  29. 29.
    Matsumoto M, Nakajima W, Seike M, Gemma A, Tanaka N (2016) Cisplatin-induced apoptosis in non-small-cell lung cancer cells is dependent on Bax-and Bak-induction pathway and synergistically activated by BH3-mimetic ABT-263 in p53 wild-type and mutant cells. Biochem Biophys Res Commun 473(2):490–496CrossRefGoogle Scholar
  30. 30.
    Korbakis D, Scorilas A (2012) Quantitative expression analysis of the apoptosis-related genes BCL2, BAX and BCL2L12 in gastric adenocarcinoma cells following treatment with the anticancer drugs cisplatin, etoposide and taxol. Tumor Biol 33(3):865–875CrossRefGoogle Scholar
  31. 31.
    Kumar KA, Babu PP (2002) Mitochondrial anomalies are associated with the induction of intrinsic cell death proteins Bcl2, Bax, cytochrome c and in mice brain during experimental fatal murine cerebral malaria. Neurosci Lett 329(3):319–323CrossRefGoogle Scholar
  32. 32.
    Kang MH, Reynolds CP (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15(4):1126–1132CrossRefGoogle Scholar
  33. 33.
    Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26(9):1324CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
  2. 2.Department of Biochemistry, Institute of Biochemistry and BiophysicsUniversity of TehranTehranIran

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