Advertisement

Polyelectrolyte Carboxymethyl Cellulose for Enhanced Delivery of Doxorubicin in MCF7 Breast Cancer Cells: Toxicological Evaluations in Mice Model

  • Vahid Shafiei-Irannejad
  • Mahdi Rahimi
  • Mojtaba Zarei
  • Roshan Dinparast-isaleh
  • Saman Bahrambeigi
  • Alireza Alihemmati
  • Salman Shojaei
  • Zarrin Ghasemi
  • Bahman YousefiEmail author
Research Paper
  • 185 Downloads

Abstract

Purpose

Chemotherapy as an important tool for cancer treatment faces many obstacles such as multidrug resistance and adverse toxic effects on healthy tissues. Drug delivery systems have opened a new window to overcome these problems.

Methods

A polyelectrolyte carboxymethyl cellulose polymer as a magnetic nanocarrier was synthesized for enhancing delivery and uptake of doxorubicin in MCF7 breast cancer cells and decreasing the adverse toxic effects to healthy tissues.

Results

The physicochemical properties of developed nanocarrier showed that it can be used in drug delivery purposes. The efficiency of the delivery system was assessed by loading and release studies. Besides, biological assays including protein-particle interaction, hemolysis assay, cytotoxicity study, cellular uptake, and apoptosis analysis were performed. All results persuaded us to investigate the cytotoxic effects of nanocarrier in an animal model by determining the biochemical parameters attributed to organ injuries, and hematoxylin and eosin (H&E) staining for histopathological manifestations. We observed that the nanocarrier has no toxic effect on healthy tissues, while, it is capable of reducing the toxic side effects of doxorubicin by more cellular internalization.

Conclusion

Chemical characterizations and biological studies confirmed that developed nanocarrier with permanent cationic groups of imidazolium and anionic carboxylic acid groups is an effective candidate for anticancer drug delivery.

KEY WORDS

enhanced drug delivery doxorubicin toxicity MCF7 breast cancer cells polyelectrolyte carboxymethyl cellulose 

Abbreviations

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

CK

Creatine kinase

CMC

Carboxymethyl cellulose

Cr

Creatinine

DAPI

4′,6-diamidino-2-phenylindole

DDS

Drug delivery systems

DEE

Drug encapsulation efficiency

DLE

Drug loading efficiency

DLS

Dynamic light scattering

DOX

Doxorubicin

DSC

Differential scanning calorimetry

EDTA

Ethylenediaminetetraacetic acid

EDX

Energy-dispersive X-ray spectroscopy

EPR

Enhanced permeability and retention

FBS

Fetal bovine serum

FTIR

Fourier transform infrared PLGA

LDH

Lactate dehydrogenase

MDR

Multidrug resistance

MFI

Mean fluorescent intensity

MNPs

Magnetic nanoparticles

MTT

3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphe-nyltetrazolium bromide

P-gp

P-glycoprotein

RPMI-1640

Roswell Park Memorial Institute 1640 growth medium

SEM

Scanning electron microscopy

TEM

Transmission Electron Microscopy

VSM

Vibrating-sample magnetometer

Ur

Urea

XRD

X-ray diffraction

Notes

Acknowledgments and Disclosures

We thank the Drug Applied Research Centre (DARC), Aging Research Institute, Physical Medicine and Rehabilitation Research Centre, Clinical Research Development Unit, Shohada Hospital, Tabriz University of Medical Sciences, Tabriz, Iran and Cellular and Molecular Research Centre, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran. The authors report no conflicts of interest.

References

  1. 1.
    Gottesman MM, Lavi O, Hall MD, Gillet JP. Toward a better understanding of the complexity of Cancer drug resistance. Annu Rev Pharmacol Toxicol. 2016;56:85–102.PubMedCrossRefGoogle Scholar
  2. 2.
    Shafiei-Irannejad V, Samadi N, Salehi R, Yousefi B, Zarghami N. New insights into antidiabetic drugs: possible applications in Cancer treatment. Chem Biol Drug Des. 2017;90:1056–66.PubMedCrossRefGoogle Scholar
  3. 3.
    Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13(10):714–26.PubMedCrossRefGoogle Scholar
  4. 4.
    Maeda H, Nakamura H, Fang J. The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev. 2013;65(1):71–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Liu Y, Fang J, Kim Y-J, Wong MK, Wang P. Codelivery of doxorubicin and paclitaxel by cross-linked multilamellar liposome enables synergistic antitumor activity. Mol Pharm. 2014;11(5):1651–61.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Jahanban-Esfahlan R, de la Guardia M, Ahmadi D, Yousefi B. Modulating tumor hypoxia by nanomedicine for effective cancer therapy. J Cell Physiol. 2018;233(3):2019–31.PubMedCrossRefGoogle Scholar
  7. 7.
    Rahimi M, Shojaei S, Safa KD, Ghasemi Z, Salehi R, Yousefi B, et al. Biocompatible magnetic tris (2-aminoethyl) amine functionalized nanocrystalline cellulose as a novel nanocarrier for anticancer drug delivery of methotrexate. New J Chem. 2017;41(5):2160–8.CrossRefGoogle Scholar
  8. 8.
    Zhang P, Li J, Ghazwani M, Zhao W, Huang Y, Zhang X, et al. Effective co-delivery of doxorubicin and dasatinib using a PEG-Fmoc nanocarrier for combination cancer chemotherapy. Biomaterials. 2015;67:104–14.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Rahimi M, Safa KD, Salehi R. Co-delivery of doxorubicin and methotrexate by dendritic chitosan-g-mPEG as a magnetic nanocarrier for multi-drug delivery in combination chemotherapy. Polym Chem. 2017;8(47):7333–50.CrossRefGoogle Scholar
  10. 10.
    Hennink W, Park K. The influence of polymer topology on pharmacokinetics. Elsevier; 2009.Google Scholar
  11. 11.
    Rahimi M, Shafiei-Irannejad V, Safa KD, Salehi R. Multi-branched ionic liquid-chitosan as a smart and biocompatible nano-vehicle for combination chemotherapy with stealth and targeted properties. Carbohydr Polym. 2018;196:299–312.PubMedCrossRefGoogle Scholar
  12. 12.
    Moon RJ, Martini A, Nairn J, Simonsen J, Youngblood J. Cellulose nanomaterials review: structure, properties and nanocomposites. Chem Soc Rev. 2011;40(7):3941–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Aouada FA, de Moura MR, Orts WJ, Mattoso LH. Preparation and characterization of novel micro- and nanocomposite hydrogels containing cellulosic fibrils. J Agric Food Chem. 2011;59(17):9433–42.PubMedCrossRefGoogle Scholar
  14. 14.
    Elumalai R, Patil S, Maliyakkal N, Rangarajan A, Kondaiah P, Raichur AM. Protamine-carboxymethyl cellulose magnetic nanocapsules for enhanced delivery of anticancer drugs against drug resistant cancers. Nanomed: Nanotechnol, Biol Med. 2015;11(4):969–81.CrossRefGoogle Scholar
  15. 15.
    Dai L, Yang T, He J, Deng L, Liu J, Wang L, et al. Cellulose-graft-poly (l-lactic acid) nanoparticles for efficient delivery of anti-cancer drugs. J Mater Chem B. 2014;2(39):6749–57.CrossRefGoogle Scholar
  16. 16.
    Lin J, Alexander-Katz A. Cell membranes open “doors” for cationic nanoparticles/biomolecules: insights into uptake kinetics. ACS Nano. 2013;7(12):10799–808.PubMedCrossRefGoogle Scholar
  17. 17.
    Lin J, Zhang H, Chen Z, Zheng Y. Penetration of lipid membranes by gold nanoparticles: insights into cellular uptake, cytotoxicity, and their relationship. ACS Nano. 2010;4(9):5421–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Wei L, Chen C, Hou Z, Wei H. Poly (acrylic acid sodium) grafted carboxymethyl cellulose as a high performance polymer binder for silicon anode in lithium ion batteries. Sci Rep. 2016;6:19583.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Zhang Y, Kohler N, Zhang M. Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake. Biomaterials. 2002;23(7):1553–61.PubMedCrossRefGoogle Scholar
  20. 20.
    Rahimi M, Safa KD, Alizadeh E, Salehi R. Dendritic chitosan as a magnetic and biocompatible nanocarrier for the simultaneous delivery of doxorubicin and methotrexate to MCF-7 cell line. New J Chem. 2017;41(8):3177–89.CrossRefGoogle Scholar
  21. 21.
    Azimi A, Majidinia M, Shafiei-Irannejad V, Jahanban-Esfahlan R, Ahmadi Y, Karimian A, et al. Suppression of p53R2 gene expression with specific siRNA sensitizes HepG2 cells to doxorubicin. Gene. 2018;642:249–55.PubMedCrossRefGoogle Scholar
  22. 22.
    Shafiei-Irannejad V, Samadi N, Yousefi B, Salehi R, Velaei K, Zarghami N. Metformin enhances doxorubicin sensitivity via inhibition of doxorubicin efflux in P-gp-overexpressing MCF-7 cells. Chem Biol Drug Des. 2018;91(1):269–76.PubMedCrossRefGoogle Scholar
  23. 23.
    Yousefi B, Samadi N, Baradaran B, Rameshknia V, Shafiei-Irannejad V, Majidinia M, et al. Differential effects of peroxisome proliferator-activated receptor agonists on doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. Cell Mol Biol (Noisy-le-Grand). 2015;61(8):118–22.Google Scholar
  24. 24.
    Shafiei-Irannejad V, Samadi N, Salehi R, Yousefi B, Rahimi M, Akbarzadeh A, et al. Reversion of multidrug resistance by co-encapsulation of doxorubicin and metformin in poly (lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles. Pharm Res. 2018;35(6):119.PubMedCrossRefGoogle Scholar
  25. 25.
    Shojaei S, Ghasemi Z, Shahrisa A. Cu (I)@ Fe3O4 nanoparticles supported on imidazolium-based ionic liquid-grafted cellulose: green and efficient nanocatalyst for multicomponent synthesis of N-sulfonylamidines and N-sulfonylacrylamidines. Appl Organomet Chem. 2017;31(11):e3788.CrossRefGoogle Scholar
  26. 26.
    Mir M, Yazdani Y, Asadi J, Khoshbin Khoshnazar AA. Survey on the possibility of utilizing gamma H2AX as a biodosimeter in radiation workers. Iran J Med Phys. 2015;12(1):14–21.Google Scholar
  27. 27.
    Yarmohamadi A, Asadi J, Gharaei R, Mir M, Khoshnazar AK. Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in breast cancer cell line. J Radiat Cancer Res. 2018;9(2):86.CrossRefGoogle Scholar
  28. 28.
    Yang F, Li G, He Y-G, Ren F-X, Wang G-x. Synthesis, characterization, and applied properties of carboxymethyl cellulose and polyacrylamide graft copolymer. Carbohydr Polym. 2009;78(1):95–9.CrossRefGoogle Scholar
  29. 29.
    Lim J, Yeap SP, Che HX, Low SC. Characterization of magnetic nanoparticle by dynamic light scattering. Nanoscale Res Lett. 2013;8(1):381.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Anbarasu M, Anandan M, Chinnasamy E, Gopinath V, Balamurugan K. Synthesis and characterization of polyethylene glycol (PEG) coated Fe3O4 nanoparticles by chemical co-precipitation method for biomedical applications. Spectrochim Acta A Mol Biomol Spectrosc. 2015;135:536–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Huang H, Lai W, Cui M, Liang L, Lin Y, Fang Q, et al. An evaluation of blood compatibility of silver nanoparticles. Sci Rep. 2016;6:25518.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Dobrovolskaia MA, Clogston JD, Neun BW, Hall JB, Patri AK, McNeil SE. Method for analysis of nanoparticle hemolytic properties in vitro. Nano Lett. 2008;8(8):2180–7.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Tso C-p, Zhung C-m, Shih Y-h, Tseng Y-M, Wu S-c, Doong R-a. Stability of metal oxide nanoparticles in aqueous solutions. Water Sci Technol. 2010;61(1):127–33.PubMedCrossRefGoogle Scholar
  34. 34.
    Corbo C, Molinaro R, Parodi A, Toledano Furman NE, Salvatore F, Tasciotti E. The impact of nanoparticle protein corona on cytotoxicity, immunotoxicity and target drug delivery. Nanomedicine. 2016;11(1):81–100.PubMedCrossRefGoogle Scholar
  35. 35.
    McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther. 2017;31(1):63–75.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Vahid Shafiei-Irannejad
    • 1
    • 2
  • Mahdi Rahimi
    • 3
    • 4
    • 5
  • Mojtaba Zarei
    • 6
  • Roshan Dinparast-isaleh
    • 1
  • Saman Bahrambeigi
    • 1
  • Alireza Alihemmati
    • 3
  • Salman Shojaei
    • 5
  • Zarrin Ghasemi
    • 5
  • Bahman Yousefi
    • 6
    Email author
  1. 1.Cellular and Molecular Research Center, Cellular and Molecular Medicine InstituteUrmia University of Medical SciencesUrmiaIran
  2. 2.Solid Tumor Research Center, Cellular and Molecular Medicine InstituteUrmia University of Medical SciencesUrmiaIran
  3. 3.Drug Applied Research CenterTabriz University of Medical SciencesTabrizIran
  4. 4.Aging Research Institute, Physical Medicine and Rehabilitation Research CentreTabriz University of Medical SciencesTabrizIran
  5. 5.Department of Organic and Biochemistry, Faculty of ChemistryUniversity of TabrizTabrizIran
  6. 6.Immunology Research CenterTabriz University of Medical SciencesTabrizIran

Personalised recommendations