Skip to main content
Log in

Mitoxantrone-Loaded PLGA Nanoparticles for Increased Sensitivity of Glioblastoma Cancer Cell to TRAIL-Induced Apoptosis

  • Original Article
  • Published:
Journal of Pharmaceutical Innovation Aims and scope Submit manuscript

Abstract

Purpose

Malignant glioma cells are generally insensitive to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. In this research, we designed a system containing mitoxantrone (MTX) which is loaded into poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) in order to increase sensitivity of glioblastoma cancer cell to TRAIL plasmid.

Methods

PLGA NPs were prepared using a water-in-oil-in-water (W/O/W) double emulsification and solvent evaporation technique and characterized. Synergistic cytotoxicity effect was assessed by both MTT and annexin V-FITC and PI analysis against GL-261 cancer cell line.

Result

The combination treatment with PLGA-MTX and TRAIL plasmid showed more cytotoxic effect on GL-261 cancer cell line (cell viability = 16%) compared to MTX-PLGA alone (cell viability 38%) and TRAIL alone (cell viability = 87%).

Conclusion

It concluded that PLGA-MTX can be considered a potential agent to sensitize glioblastoma cancer cell to TRAIL.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Adamson C, Kanu OO, Mehta AI, Di C, Lin N, Mattox AK, et al. Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin Investig Drugs. 2009;18(8):1061–83.

    Article  CAS  PubMed  Google Scholar 

  2. Urbańska K, Sokołowska J, Szmidt M, Sysa P. Glioblastoma multiforme–an overview. Contemp Oncol. 2014;18(5):307.

    Google Scholar 

  3. Finbloom JA, Aanei IL, Bernard JM, Klass SH, Elledge SK, Han K, et al. Evaluation of three morphologically distinct virus-like particles as nanocarriers for convection-enhanced drug delivery to glioblastoma. Nanomaterials. 2018;8(12):1007.

    Article  PubMed Central  Google Scholar 

  4. Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: state of the art and future directions. CA: Cancer J Clin. 2020;70(4):299-312.

  5. Gottesman MM. Mechanisms of cancer drug resistance. Annual Review of Medicine 2002:615-27.

  6. Von Karstedt S, Montinaro A, Walczak H. Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer. 2017;17(6):352.

    Article  Google Scholar 

  7. Zhong HH, Wang HY, Li J, Huang YZ TRAIL-based gene delivery and therapeutic strategies. Acta pharmacologica Sinica. 2019:1-13.

  8. Stuckey DW, Shah K. TRAIL on trial: preclinical advances in cancer therapy. Trends Mol Med. 2013;19(11):685–94.

    Article  CAS  PubMed  Google Scholar 

  9. Kelly MM, Hoel BD, Voelkel-Johnson C. Doxorubicin pretreatment sensitizes prostate cancer cell lines to TRAIL induced apoptosis which correlates with the loss of c-FLIP expression. Cancer Biol Ther. 2002;1(5):520–7.

    Article  PubMed  Google Scholar 

  10. Ebrahimian M, Taghavi S, Ghoreishi M, Sedghi S, Farzad SA, Ramezani M, et al. Evaluation of efficiency of modified polypropylenimine (PPI) with alkyl chains as non-viral vectors used in co-delivery of doxorubicin and TRAIL plasmid. AAPS PharmSciTech. 2018;19(3):1029–36.

    Article  CAS  PubMed  Google Scholar 

  11. Pishavar E, Ramezani M, Hashemi M. Co-delivery of doxorubicin and TRAIL plasmid by modified PAMAM dendrimer in colon cancer cells, in vitro and in vivo evaluation. Drug Dev Ind Pharm. 2019;45(12):1931–9.

    Article  CAS  PubMed  Google Scholar 

  12. Kim I, Byeon HJ, Kim TH, Lee ES, Oh KT, Shin BS, et al. Doxorubicin-loaded porous PLGA microparticles with surface attached TRAIL for the inhalation treatment of metastatic lung cancer. Biomaterials. 2013;34(27):6444–53.

    Article  CAS  PubMed  Google Scholar 

  13. Unterkircher T, Cristofanon S, Vellanki SH, Nonnenmacher L, Karpel-Massler G, Wirtz CR, et al. Bortezomib primes glioblastoma, including glioblastoma stem cells, for TRAIL by increasing tBid stability and mitochondrial apoptosis. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;17(12):4019–30.

    Article  CAS  Google Scholar 

  14. Senbabaoglu F, Cingoz A, Kaya E, Kazancioglu S, Lack NA, Acilan C, et al. Identification of mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme. Cancer Biol Ther. 2016;17(5):546–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boiardi A, Silvani A, Eoli M, Lamperti E, Salmaggi A, Gaviani P, et al. Treatment of recurrent glioblastoma: can local delivery of mitoxantrone improve survival? J Neurooncol. 2008;88(1):105–13.

    Article  CAS  PubMed  Google Scholar 

  16. Janssens S, Mooter GVD, inventorsPreparation method for solid disupersions 2009.

  17. Xin Y, Qi Q, Mao Z, Zhan X. PLGA nanoparticles introduction into mitoxantrone-loaded ultrasound-responsive liposomes: in vitro and in vivo investigations. Int J Pharm. 2017;528(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  18. Aghebati-Maleki A, Dolati S, Ahmadi M, Baghbanzhadeh A, Asadi M, Fotouhi A, et al. Nanoparticles and cancer therapy: perspectives for application of nanoparticles in the treatment of cancers. J Cell Physiol. 2020;235(3):1962–72.

    Article  CAS  PubMed  Google Scholar 

  19. Groneberg DA, Giersig M, Welte T, Pison U. Nanoparticle-based diagnosis and therapy. Curr Drug Targets. 2006;7(6):643–8.

    Article  CAS  PubMed  Google Scholar 

  20. Li J, Sabliov C. PLA/PLGA nanoparticles for delivery of drugs across the blood-brain barrier. Nanotechnol Rev. 2013;2(3):241–57.

    Article  CAS  Google Scholar 

  21. Kapoor DN, Bhatia A, Kaur R, Sharma R, Kaur G, Dhawan S. PLGA: a unique polymer for drug delivery. Ther Deliv. 2015;6(1):41–58.

    Article  CAS  PubMed  Google Scholar 

  22. Acharya S, Sahoo SK. PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Adv Drug Deliv Rev. 2011;63(3):170–83.

    Article  CAS  PubMed  Google Scholar 

  23. Yang Z, Gao D, Cao Z, Zhang C, Cheng D, Liu J, et al. Drug and gene co-delivery systems for cancer treatment. Biomaterials science. 2015;3(7):1035–49.

    Article  CAS  PubMed  Google Scholar 

  24. Ebrahimian M, Taghavi S, Mokhtarzadeh A, Ramezani M, Hashemi M. Co-delivery of doxorubicin encapsulated PLGA nanoparticles and Bcl-xL shRNA using alkyl-modified PEI into breast cancer cells. Appl Biochem Biotechnol. 2017;183(1):126–36.

    Article  CAS  PubMed  Google Scholar 

  25. Hafezi Ghahestani Z, Alebooye Langroodi F, Mokhtarzadeh A, Ramezani M, Hashemi M. Evaluation of anti-cancer activity of PLGA nanoparticles containing crocetin. Artif Cells Nanomed Biotechnol. 2017;45(5):955–60.

    Article  CAS  PubMed  Google Scholar 

  26. Hashemitabar S, Yazdian-Robati R, Hashemi M, Ramezani M, Abnous K, Kalalinia F. ABCG2 aptamer selectively delivers doxorubicin to drug-resistant breast cancer cells. J Biosci. 2019;44(2):39.

    Article  PubMed  Google Scholar 

  27. Rao S, Morales AA, Pearse DD. The comparative utility of viromer RED and lipofectamine for transient gene introduction into glial cells. BioMed research international. 2015.

  28. Perego P, Boiardi A, Carenini N, De Cesare M, Dolfini E, Giardini R, et al. Characterization of an established human, malignant, glioblastoma cell line (GBM) and its response to conventional drugs. J Cancer Res Clin Oncol. 1994;120(10):585–92.

    Article  CAS  PubMed  Google Scholar 

  29. Wohlfart S, Khalansky AS, Gelperina S, Maksimenko O, Bernreuther C, Glatzel M, et al. Efficient chemotherapy of rat glioblastoma using doxorubicin-loaded PLGA nanoparticles with different stabilizers. PLoS ONE. 2011;6(5):e19121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hashemi M, Shamshiri A, Saeedi M, Tayebi L, Yazdian-Robati R. Aptamer-conjugated PLGA nanoparticles for delivery and imaging of cancer therapeutic drugs. Archives of Biochemistry and Biophysics. 2020:108485.

  31. Malinovskaya Y, Melnikov P, Baklaushev V, Gabashvili A, Osipova N, Mantrov S, et al. Delivery of doxorubicin-loaded PLGA nanoparticles into U87 human glioblastoma cells. Int J Pharm. 2017;524(1–2):77–90.

    Article  CAS  PubMed  Google Scholar 

  32. Agarwal S, Mohamed MS, Mizuki T, Maekawa T, Kumar DS. Chlorotoxin modified morusin–PLGA nanoparticles for targeted glioblastoma therapy. Journal of Materials Chemistry B. 2019;7(39):5896–919.

    Article  CAS  PubMed  Google Scholar 

  33. Zambaux M, Bonneaux F, Gref R, Maincent P, Dellacherie E, Alonso M, et al. Influence of experimental parameters on the characteristics of poly (lactic acid) nanoparticles prepared by a double emulsion method. J Control Release. 1998;50(1–3):31–40.

    Article  CAS  PubMed  Google Scholar 

  34. Hafezi Ghahestani Z, Alebooye Langroodi F, Mokhtarzadeh A, Ramezani M, Hashemi M. Evaluation of anti-cancer activity of PLGA nanoparticles containing crocetin. Artificial cells, nanomedicine, and biotechnology. 2017;45(5):955–60.

    Article  CAS  PubMed  Google Scholar 

  35. Bhardwaj A, Kumar L, Mehta S, Mehta A. Stimuli-sensitive systems-an emerging delivery system for drugs. Artificial cells, nanomedicine, and biotechnology. 2015;43(5):299–310.

    Article  CAS  PubMed  Google Scholar 

  36. Gutsche S, Krause M, Kranz H. Strategies to overcome pH-dependent solubility of weakly basic drugs by using different types of alginates. Drug Dev Ind Pharm. 2008;34(12):1277–84.

    Article  CAS  PubMed  Google Scholar 

  37. Alibolandi M, Ramezani M, Sadeghi F, Abnous K, Hadizadeh F. Epithelial cell adhesion molecule aptamer conjugated PEG–PLGA nanopolymersomes for targeted delivery of doxorubicin to human breast adenocarcinoma cell line in vitro. Int J Pharm. 2015;479(1):241–51.

    Article  CAS  PubMed  Google Scholar 

  38. Nakayama M, Akimoto J, Okano T. Polymeric micelles with stimuli-triggering systems for advanced cancer drug targeting. J Drug Target. 2014;22(7):584–99.

    Article  CAS  PubMed  Google Scholar 

  39. Roberts R, Smyth JW, Will J, Roberts P, Grek CL, Ghatnekar GS, et al. Development of PLGA nanoparticles for sustained release of a connexin43 mimetic peptide to target glioblastoma cells. Mater Sci Eng, C. 2020;108:110191.

    Article  CAS  Google Scholar 

  40. Choi Y, Yoon HY, Kim J, Yang S, Lee J, Choi JW, et al. Doxorubicin-loaded PLGA nanoparticles for cancer therapy: molecular weight effect of PLGA in doxorubicin release for controlling immunogenic cell death. Pharmaceutics. 2020;12(12):1165.

    Article  CAS  PubMed Central  Google Scholar 

  41. Senapati S, Mahanta AK, Kumar S, Maiti P. Controlled drug delivery vehicles for cancer treatment and their performance. Signal Transduct Target Ther. 2018;3(1):1–19.

    CAS  Google Scholar 

  42. Charbgoo F, Taghdisi SM, Yazdian‐Robati R, Abnous K, Ramezani M, Alibolandi M. Aptamer‐incorporated nanoparticle systems for drug delivery. Nanobiotechnology in Diagnosis, Drug Delivery, and Treatment. 2020:95-112.

  43. Alebooye LF, Hafezi GZ, Alibolandi M, Ebrahimian M, Hashemi M. Evaluation of the effect of crocetin on antitumor activity of doxorubicin encapsulated in PLGA nanoparticles. 2016.

  44. Kamali H, Khodaverdi E, Hadizadeh F, Yazdian-Robati R, Haghbin A, Zohuri G. An in-situ forming implant formulation of naltrexone with minimum initial burst release using mixture of PLGA copolymers and ethyl heptanoate as an additive: In-vitro, ex-vivo, and in-vivo release evaluation. J Drug Deliv Sci Technol. 2018;47:95–105.

    Article  CAS  Google Scholar 

  45. Natsume A, Yoshida J. Gene therapy for high-grade glioma: current approaches and future directions. Cell Adh Migr. 2008;2(3):186–91.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Yuan X, Gajan A, Chu Q, Xiong H, Wu K, Wu GS. Developing TRAIL/TRAIL death receptor-based cancer therapies. Cancer Metastasis Rev. 2018;37(4):733–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dorsey JF, Mintz A, Tian X, Dowling ML, Plastaras JP, Dicker DT, et al. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and paclitaxel have cooperative in vivo effects against glioblastoma multiforme cells. Mol Cancer Ther. 2009;8(12):3285–95.

    Article  CAS  PubMed  Google Scholar 

  48. Lee AL, Wang Y, Pervaiz S, Fan W, Yang YY. Synergistic anticancer effects achieved by co-delivery of TRAIL and paclitaxel using cationic polymeric micelles. Macromol Biosci. 2011;11(2):296–307.

    Article  CAS  PubMed  Google Scholar 

  49. Ehrhardt H, Wachter F, Grunert M, Jeremias I. Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis. Cell death & disease. 2013;4(6):e661-e.

  50. Xu L, Qu X, Luo Y, Zhang Y, Liu J, Qu J, et al. Epirubicin enhances TRAIL-induced apoptosis in gastric cancer cells by promoting death receptor clustering in lipid rafts. Mol Med Rep. 2011;4(3):407–11.

    CAS  PubMed  Google Scholar 

  51. Wu XX, Kakehi Y, Mizutani Y, Kamoto T, Kinoshita H, Isogawa Y, et al. Doxorubicin enhances TRAIL-induced apoptosis in prostate cancer. Int J Oncol. 2002;20(5):949–54.

    CAS  PubMed  Google Scholar 

  52. Wu XX, Ogawa O, Kakehi Y. TRAIL and chemotherapeutic drugs in cancer therapy. Vitamins & Hormones. 67: Elsevier; 2004. p. 365-83.

  53. Dyer M, MacFarlane M, Cohen GM. Barriers to effective TRAIL-targeted therapy of malignancy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2007;25(28):4505–6.

    Article  Google Scholar 

  54. Wang X, Wei X, Zhang H. Role of protein ubiquitination and its functional importance. SCIENTIA SINICA Vitae. 2015;45(11):1074–82.

    Article  Google Scholar 

  55. Fulda S. Inhibitor of apoptosis proteins as targets for anticancer therapy. Expert Rev Anticancer Ther. 2007;7(9):1255–64.

    Article  CAS  PubMed  Google Scholar 

  56. Jeong JK, Moon MH, Seo JS, Seol JW, Park SY, Lee YJ. Hypoxia inducing factor-1α regulates tumor necrosis factor-related apoptosis-inducing ligand sensitivity in tumor cells exposed to hypoxia. Biochem Biophys Res Commun. 2010;399(3):379–83.

    Article  CAS  PubMed  Google Scholar 

  57. Wang K, Kievit FM, Jeon M, Silber JR, Ellenbogen RG, Zhang M. Nanoparticle-mediated target delivery of TRAIL as gene therapy for glioblastoma. Adv Healthcare Mater. 2015;4(17):2719–26.

    Article  CAS  Google Scholar 

  58. Jiang X, Fitch S, Wang C, Wilson C, Li J, Grant GA, et al. Nanoparticle engineered TRAIL-overexpressing adipose-derived stem cells target and eradicate glioblastoma via intracranial delivery. Proc Natl Acad Sci. 2016;113(48):13857–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Financial support of this study was provided by Mashhad University of Medical Sciences (Grant Number: 951839).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Zahra Salmasi or Rezvan Yazdian-Robati.

Ethics declarations

Conflict of Interest

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hashemi, M., Abnous, K., Balarastaghi, S. et al. Mitoxantrone-Loaded PLGA Nanoparticles for Increased Sensitivity of Glioblastoma Cancer Cell to TRAIL-Induced Apoptosis. J Pharm Innov 17, 207–214 (2022). https://doi.org/10.1007/s12247-021-09551-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12247-021-09551-8

Keywords

Navigation