Skip to main content

Advertisement

SpringerLink
Log in

In Vitro Apoptosis Evaluation and Kinetic Modeling onto Cyclodextrin-Based Host–Guest Magnetic Nanoparticles Containing Methotrexate and Tamoxifen

  • Published:
BioNanoScience Aims and scope Submit manuscript

Abstract

Supramolecular carriers as a targeted drug delivery system have a significant role in managing the pharmacokinetics and pharmacodynamics of drugs. Therefore, in this project, we used cyclodextrin (CD) as a host molecule for tamoxifen (TMX) and methotrexate (MTX) to evaluate apoptosis mechanism and statistical patterns of release. The flow cytometry analysis showed that combination therapy by anticancer drugs was successful in apoptosis induction compared to free TMX and MTX. Also, real-time PCR and western blot analyses were performed to measure gene expression of Bak1, Bclx, and caspase-3 in estrogen and folate receptor-positive MCF-7 cell lines. All results confirmed that MNPs containing TMX and MTX can significantly increase Bak1/Bclx ratios plus the activity of caspase-3, while free MTX and free TMX showed no effects on triggering apoptosis after 24 h of exposure. According to results of pharmacokinetic studies onto TMX and MTX release, it is revealed that both models that consist of Sahlin-Peppas and Ritger-Peppas create the good fitting curves more than other statistical patterns at both low and high temperatures (37°C and 42°C). For this reason, activation parameters (ΔH‡, ΔS‡, and ΔG‡) were calculated to estimate the favorable model. The lower energy barrier indicates that the Sahlin-Peppas is the favorable model with both diffusion and relaxation process. Therefore, combination therapy by two anticancer drugs, TMX and MTX, utilizing cyclodextrin-based host–guest supramolecular magnetic nanoparticles (CD-MNPs) provided new results for induction of apoptosis and pharmacokinetic model.

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

Similar content being viewed by others

References

  1. Cheng, H., Fan, X., Wang, X., Ye, E., Loh, X. J., Li, Z., & Wu, Y.-L. (2018). Hierarchically self-assembled supramolecular host–guest delivery system for drug resistant cancer therapy. Biomacromolecules, 19(6), 1926–1938.

    Article  Google Scholar 

  2. Sargazi, A., Azhoogh, M., Allahdad, S., & Heidari Majd, M. (2018). Evaluation of supramolecule conjugated magnetic nanoparticles as a simultaneous carrier for methotrexate and tamoxifen. Journal of Drug Delivery Science and Technology, 47, 115–122. https://doi.org/10.1016/j.jddst.2018.07.006.

    Article  Google Scholar 

  3. Hu, Q.-D., Tang, G.-P., & Chu, P. K. (2014). Cyclodextrin-based host–guest supramolecular nanoparticles for delivery: From design to applications. Accounts of Chemical Research, 47(7), 2017–2025.

    Article  Google Scholar 

  4. Heidari Majd, M., Akbarzadeh, A., & Sargazi, A. (2017). Evaluation of host–guest system to enhance the tamoxifen efficiency. Artificial Cells, Nanomedicine, and Biotechnology, 45(3), 441–447. https://doi.org/10.3109/21691401.2016.1160916.

    Article  Google Scholar 

  5. Gurunathan, S., Kang, M.-H., Qasim, M., & Kim, J.-H. (2018). Nanoparticle-mediated combination therapy: Two-in-one approach for cancer. International Journal of Molecular Sciences, 19(10), 3264. https://doi.org/10.3390/ijms19103264.

    Article  Google Scholar 

  6. Sargazi, A., Kamali, N., Shiri, F., & Heidari Majd, M. (2018). Hyaluronic acid/polyethylene glycol nanoparticles for controlled delivery of mitoxantrone. Artificial Cells, Nanomedicine and Biotechnology, 46(3), 500–509. https://doi.org/10.1080/21691401.2017.1324462.

    Article  Google Scholar 

  7. Din, F. U., Aman, W., Ullah, I., Qureshi, O. S., Mustapha, O., Shafique, S., & Zeb, A. (2017). Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. International Journal of Nanomedicine, 12, 7291–7309. https://doi.org/10.2147/IJN.S146315.

    Article  Google Scholar 

  8. Saei, A. A., Barzegari, A., Majd, M. H., Asgari, D., & Omidi, Y. (2014). Fe3O4 nanoparticles engineered for plasmid DNA delivery to Escherichia coli. Journal of Nanoparticle Research, 16(8), 2521. https://doi.org/10.1007/s11051-014-2521-0.

    Article  Google Scholar 

  9. Salami, S., & Karami-Tehrani, F. (2003). Biochemical studies of apoptosis induced by tamoxifen in estrogen receptor positive and negative breast cancer cell lines. Clinical Biochemistry, 36(4), 247–253.

    Article  Google Scholar 

  10. Fodor, T., Szántó, M., Abdul-Rahman, O., Nagy, L., Dér, Á., Kiss, B., & Bai, P. (2016). Combined treatment of MCF-7 cells with AICAR and methotrexate, arrests cell cycle and reverses Warburg metabolism through AMP-activated protein kinase (AMPK) and FOXO1. PLoS One, 11(2), e0150232.

    Article  Google Scholar 

  11. Ghodsi, F., Shahraki, M., Habibi-Khorassani, S. M., Omidikia, N., & Heidari Majd, M. (2021). Kinetic modeling on mitoxantrone release from hyaluronic MNP as a drug delivery system. Chemical Methodologies, 5(1), 30–34. https://doi.org/10.22034/chemm.2021.118506.

    Article  Google Scholar 

  12. Mansouri-Torshizi, H., Zareian-Jahromi, S., Ghahghaei, A., Shahraki, S., Khosravi, F., & Heidari Majd, M. (2018). Palladium(II) complexes of biorelevant ligands. Synthesis, structures, cytotoxicity and rich DNA/HSA interaction studies. Journal of Biomolecular Structure and Dynamics, 36(11), 2787–2806. https://doi.org/10.1080/07391102.2017.1372309.

    Article  Google Scholar 

  13. Shahraki, S., Majd, M. H., & Heydari, A. (2019). Novel tetradentate Schiff base zinc(II) complex as a potential antioxidant and cancer chemotherapeutic agent: Insights from the photophysical and computational approach. Journal of Molecular Structure, 1177, 536–544. https://doi.org/10.1016/j.molstruc.2018.10.005.

    Article  Google Scholar 

  14. Shahraki, S., Shiri, F., Heidari Majd, M., & Dahmardeh, S. (2019). Anti-cancer study and whey protein complexation of new lanthanum(III) complex with the aim of achieving bioactive anticancer metal-based drugs. Journal of Biomolecular Structure and Dynamics, 37(8), 2072–2085. https://doi.org/10.1080/07391102.2018.1476266.

    Article  Google Scholar 

  15. Sargazi, A., Shiri, F., Keikha, S., & Majd, M. H. (2018). Hyaluronan magnetic nanoparticle for mitoxantrone delivery toward CD44-positive cancer cells. Colloids and Surfaces B: Biointerfaces, 171, 150–158. https://doi.org/10.1016/j.colsurfb.2018.07.025.

    Article  Google Scholar 

  16. Hashemzaei, M., Barani, A. K., Iranshahi, M., Rezaee, R., Tsarouhas, K., Tsatsakis, A. M., Wilks, M. F., & Tabrizian, K. (2016). Effects of resveratrol on carbon monoxide-induced cardiotoxicity in rats. Environmental Toxicology and Pharmacology, 46, 110–115.

    Article  Google Scholar 

  17. Sargazi, A., Barani, A., & Heidari Majd, M. (2020). Synthesis and apoptotic efficacy of biosynthesized silver nanoparticles using Acacia luciana flower extract in MCF-7 breast cancer cells: Activation of Bak1 and Bclx for cancer therapy. BioNanoScience. https://doi.org/10.1007/s12668-020-00753-x.

  18. Alarifi, S., Ali, H., & Saad Alkahtani, M. S. A. (2017). Regulation of apoptosis through bcl-2/bax proteins expression and DNA damage by nano-sized gadolinium oxide. International Journal of Nanomedicine, 12, 4541. https://doi.org/10.2147/IJN.S139326.

    Article  Google Scholar 

  19. Barar, J., Kafil, V., Majd, M. H., Barzegari, A., Khani, S., Johari-Ahar, M., Asgari, D., Cokous, G., & Omidi, Y. (2015). Multifunctional mitoxantrone-conjugated magnetic nanosystem for targeted therapy of folate receptor-overexpressing malignant cells. Journal of Nanobiotechnology, 13(1). https://doi.org/10.1186/s12951-015-0083-7.

  20. Shrestha, R., & Prajapati, S. (2019). Assessment of prescription pattern and prescription error in outpatient Department at Tertiary Care District Hospital, Central Nepal. Journal of Pharmaceutical Policy and Practice, 12, 16–16. https://doi.org/10.1186/s40545-019-0177-y.

    Article  Google Scholar 

  21. Siepmann, J., & Siepmann, F. (2008). Mathematical modeling of drug delivery. International Journal of Pharmaceutics, 364(2), 328–343. https://doi.org/10.1016/j.ijpharm.2008.09.004.

    Article  MATH  Google Scholar 

  22. Puhalla, S., Bhattacharya, S., & Davidson, N. E. (2012). Hormonal therapy in breast cancer: A model disease for the personalization of cancer care. Molecular Oncology, 6(2), 222–236. https://doi.org/10.1016/j.molonc.2012.02.003.

    Article  Google Scholar 

  23. Heidari Majd, M., Asgari, D., Barar, J., Valizadeh, H., Kafil, V., Abadpour, A., Moumivand, E., Mojarrad, J. S., Rashidi, M. R., Coukos, G., & Omidi, Y. (2013). Tamoxifen loaded folic acid armed PEGylated magnetic nanoparticles for targeted imaging and therapy of cancer. Colloids and Surfaces B: Biointerfaces, 106, 117–125. https://doi.org/10.1016/j.colsurfb.2013.01.051.

    Article  Google Scholar 

  24. Yaşar, P., Ayaz, G., User, S. D., Güpür, G., & Muyan, M. (2016). Molecular mechanism of estrogen-estrogen receptor signaling. Reproductive Medicine and Biology, 16(1), 4–20. https://doi.org/10.1002/rmb2.12006.

    Article  Google Scholar 

  25. Ducker, G. S., & Rabinowitz, J. D. (2017). One-carbon metabolism in health and disease. Cell Metabolism, 25(1), 27–42. https://doi.org/10.1016/j.cmet.2016.08.009.

    Article  Google Scholar 

  26. Spurlock III, C. F., Aune, Z. T., Tossberg, J. T., Collins, P. L., Aune, J. P., Huston III, J. W., Crooke, P. S., Olsen, N. J., & Aune, T. M. (2011). Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK. Arthritis and Rheumatism, 63(9), 2606–2616.

    Article  Google Scholar 

  27. Jalali, A., Zafari, J., Jouni, F. J., Abdolmaleki, P., Shirazi, F. H., & Khodayar, M. J. (2019). Combination of static magnetic field and cisplatin in order to reduce drug resistance in cancer cell lines. International Journal of Radiation Biology, 1–8.

  28. Senapati, S., Mahanta, A. K., Kumar, S., & Maiti, P. (2018). Controlled drug delivery vehicles for cancer treatment and their performance. Signal Transduction and Targeted Therapy, 3(1), 7. https://doi.org/10.1038/s41392-017-0004-3.

    Article  Google Scholar 

  29. Blackman, C. F., Benane, S. G., & House DE. (2001). The influence of 1.2 microT, 60 Hz magnetic fields on melatonin- and tamoxifen-induced inhibition of MCF-7 cell growth. Bioelectromagnetics, 22(2), 122–128. https://doi.org/10.1002/1521-186x(200102)22:2<122::aid-bem1015>3.0.co;2-v.

    Article  Google Scholar 

  30. Yuan, Y.-G., & Gurunathan, S. (2017). Combination of graphene oxide–silver nanoparticle nanocomposites and cisplatin enhances apoptosis and autophagy in human cervical cancer cells. International Journal of Nanomedicine, 12, 6537.

    Article  Google Scholar 

  31. Popgeorgiev, N., Jabbour, L., & Gillet, G. (2018). Subcellular localization and dynamics of the Bcl-2 family of proteins. Frontiers in Cell and Development Biology, 6, 13–13. https://doi.org/10.3389/fcell.2018.00013.

    Article  Google Scholar 

  32. Bauer, C., Hees, C., Sterzik, A., Bauernfeind, F., Mak’Anyengo, R., Duewell, P., Lehr, H.-A., Noessner, E., Wank, R., & Trauzold, A. (2015). Proapoptotic and antiapoptotic proteins of the Bcl-2 family regulate sensitivity of pancreatic cancer cells toward gemcitabine and T-cell–mediated cytotoxicity. Journal of Immunotherapy, 38(3), 116–126. https://doi.org/10.1097/CJI.0000000000000073.

    Article  Google Scholar 

  33. Suhaili, S. H., Karimian, H., Stellato, M., Lee, T.-H., & Aguilar, M.-I. (2017). Mitochondrial outer membrane permeabilization: A focus on the role of mitochondrial membrane structural organization. Biophysical Reviews, 9(4), 443–457. https://doi.org/10.1007/s12551-017-0308-0.

    Article  Google Scholar 

  34. Li, W., Shi, X., Xu, Y., Wan, J., Wei, S., & Zhu, R. (2017). Tamoxifen promotes apoptosis and inhibits invasion in estrogen-positive breast cancer MCF-7 cells. Molecular Medicine Reports, 16(1), 478–484.

    Article  Google Scholar 

  35. Sharifi, S., Barar, J., Hejazi, M. S., & Samadi, N. (2015). Doxorubicin changes Bax /Bcl-xL Ratio, caspase-8 and 9 in breast cancer cells. Advanced Pharmaceutical Bulletin, 5(3), 351–359. https://doi.org/10.15171/apb.2015.049.

    Article  Google Scholar 

  36. Cao, X., Hou, J., An, Q., Assaraf, Y. G., & Wang, X. (2020). Towards the overcoming of anticancer drug resistance mediated by p53 mutations. Drug resistance updates: Reviews and commentaries in antimicrobial and anticancer chemotherapy, 49, 100671. https://doi.org/10.1016/j.drup.2019.100671.

    Article  Google Scholar 

  37. Omer, S. A., & Fakhre, N. A. (2019). Three different spectrophotometric methods for simultaneous determination of pyriproxyfen and chlorothalonil residues in cucumber and cabbage samples. Journal of Spectroscopy, 2019, 8241625. https://doi.org/10.1155/2019/8241625.

    Article  Google Scholar 

  38. Dash, S., Murthy, P. N., Nath, L., & Chowdhury, P. (2010). Kinetic modeling on drug release from controlled drug delivery systems. Acta Poloniae Pharmaceutica, 67(3), 217–223

  39. Ritger, P. L., & Peppas, N. A. (1987). A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. Journal of Controlled Release, 5(1), 37–42. https://doi.org/10.1016/0168-3659(87)90035-6.

    Article  Google Scholar 

  40. Giri, B. R., Song, E. S., Kwon, J., Lee, J. H., Park, J. B., & Kim, D. W. (2020). Fabrication of intragastric floating, controlled release 3D printed theophylline tablets using hot-melt extrusion and fused deposition modeling. Pharmaceutics, 12(1). https://doi.org/10.3390/pharmaceutics12010077.

  41. Gull, N., Khan, S. M., Butt, O. M., Islam, A., Shah, A., Jabeen, S., Khan, S. U., Khan, A., Khan, R. U., & Butt, M. T. Z. (2020). Inflammation targeted chitosan-based hydrogel for controlled release of diclofenac sodium. International Journal of Biological Macromolecules, 162, 175–187. https://doi.org/10.1016/j.ijbiomac.2020.06.133.

    Article  Google Scholar 

  42. Higuchi, T. (1963). Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. Journal of Pharmaceutical Sciences, 52(12), 1145–1149. https://doi.org/10.1002/jps.2600521210

  43. Hixson, A. W., & Crowell, J. H. (1931). Dependence of reaction velocity upon surface and agitation. Industrial and Engineering Chemistry, 23(8), 923–931. https://doi.org/10.1021/ie50260a018.

    Article  Google Scholar 

  44. Habibi-Khorassani, S. M., Maghsoodlou, M. T., Talaiefar, S., Kazemian, A. M., & Aboonajmi, J. (2014). Full kinetics and a mechanistic investigation of the synthesis of tetrahydrobenzo [b] pyrans in the presence of sodium acetate as a catalyst by a one-pot three-component reaction. Letters in Organic Chemistry, 11(6), 413–421.

    Article  Google Scholar 

  45. Carvalho-Silva, V. H., Coutinho, N. D., & Aquilanti, V. (2019). Temperature dependence of rate processes beyond Arrhenius and Eyring: Activation and transitivity. Frontiers in Chemistry, 7(380). https://doi.org/10.3389/fchem.2019.00380

  46. Lente, G., Fábián, I., & Poë, A. J. (2005). A common misconception about the Eyring equation. New Journal of Chemistry, 29(6), 759–760. https://doi.org/10.1039/B501687H.

    Article  Google Scholar 

  47. Haroon, H., Gardazi, S. M. H., Butt, T. A., Pervez, A., Mahmood, Q., & Bilal, M. (2017). Novel lignocellulosic wastes for comparative adsorption of Cr (VI): Equilibrium kinetics and thermodynamic studies. Polish Journal of Chemical Technology, 19(2), 6–15.

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank the Deputy of Research and Technology of Zabol University of Medical Sciences and also Research Council of the University of Sistan and Baluchestan for all the support provided.

Author information

Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran

    Sayyed Mostafa Habibi Khorassani, Fatemeh Ghodsi, Mehdi Shahraki & Nematollah Omidikia

  2. Student Research Committee, Zabol University of Medical Sciences, Zabol, Iran

    Hamide Arezomandan

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran

    Mahmoud Hashemzaei

  4. Department of Medicinal Chemistry, Faculty of Pharmacy, Zabol University of Medical Sciences, Zabol, Iran

    Mostafa Heidari Majd

Authors
  1. Sayyed Mostafa Habibi Khorassani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fatemeh Ghodsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hamide Arezomandan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mehdi Shahraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nematollah Omidikia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mahmoud Hashemzaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mostafa Heidari Majd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mostafa Heidari Majd.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Research Involving Humans and Animals Statement

None.

Informed Consent

None.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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

Habibi Khorassani, S., Ghodsi, F., Arezomandan, H. et al. In Vitro Apoptosis Evaluation and Kinetic Modeling onto Cyclodextrin-Based Host–Guest Magnetic Nanoparticles Containing Methotrexate and Tamoxifen. BioNanoSci. 11, 667–677 (2021). https://doi.org/10.1007/s12668-021-00877-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12668-021-00877-8

Keywords

Search

Navigation