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The Optimized Formulation of Tamoxifen-Loaded Niosomes Efficiently Induced Apoptosis and Cell Cycle Arrest in Breast Cancer Cells

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Abstract

The aim, as proof of concept, was to optimize niosomal formulations of tamoxifen in terms of size, morphology, encapsulation efficiency, and release kinetics for further treatment of the breast cancer (BC). Different assays were carried out to evaluate the pro-apoptotic and cytotoxicity impact of tamoxifen-loaded niosomes in two BC cells, MDA-MB-231 and SKBR3. In this study, tamoxifen was loaded in niosomes after optimization in the formulation. The formulation of niosomes supported maximized drug entrapment and minimized their size. The novel formulation showed improvement in storage stability, and after 60 days only, small changes in size, polydispersity index, and drug entrapment were observed. Besides, a pH-dependent release pattern of formulated niosomes displayed slow release at physiological pH (7.4) and a considerable increase of release at acidic pH (5.4), making them a promising candidate for drug delivery in the BC treatment. The cytotoxicity study exhibited high biocompatibility with MCF10A healthy cells, while remarkable inhibitory effects were observed after treatment of cancerous lines, MDA-MB-231, and SKBR3 cells. The IC50 values for the tamoxifen-loaded niosomes were significantly less than other groups. Moreover, treatment with drug-loaded niosomes significantly changed the gene expression pattern of BC cells. Statistically significant down-regulation of cyclin D, cyclin E, VEGFR-1, MMP-2, and MMP-9 genes and up-regulation of caspase-3 and caspase-9 were observed. These results were in correlation with cell cycle arrest, lessoned migration capacity, and increased caspase activity and apoptosis induction in cancerous cells. Optimization in the formulation of tamoxifen-loaded niosomes can make them a novel candidate for drug delivery in BC treatment.

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References

  1. Jia Y, et al. KLF4 overcomes tamoxifen resistance by suppressing MAPK signaling pathway and predicts good prognosis in breast cancer. Cell Signal. 2018;42:165–75.

    Article  CAS  PubMed  Google Scholar 

  2. Sarhadi M, Aryan L, Zarei M. The estrogen receptor and breast cancer: a complete review. CRPASE: Transactions of Applied Sciences. 06(04):309–14

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2016;66(1):7–30.

    Article  PubMed  Google Scholar 

  4. Shaker DS, Shaker MA, Hanafy MS. Cellular uptake, cytotoxicity and in-vivo evaluation of Tamoxifen citrate loaded niosomes. Int J Pharm. 2015;493(1-2):285–94.

    Article  CAS  PubMed  Google Scholar 

  5. Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.

    Article  CAS  Google Scholar 

  6. Schmid P, et al. Fulvestrant plus vistusertib vs fulvestrant plus everolimus vs fulvestrant alone for women with hormone receptor–positive metastatic breast cancer: the MANTA phase 2 randomized clinical trial. JAMA Oncol. 2019;5(11):1556–63.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hanker AB, Sudhan DR, Arteaga CL. Overcoming endocrine resistance in breast cancer. Cancer Cell. 2020;37(4):496–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Molani S, Madadi M, Williams DJM. Investigating the effectiveness of breast cancer supplemental screening considering radiologists' bias. 2020. medRxiv, https://doi.org/10.1101/2020.12.16.20248373.

  9. Ibrahim AB, et al. Evaluation of tamoxifen and simvastatin as the combination therapy for the treatment of hormonal dependent breast cancer cells. Toxicol Rep. 2019;6:1114–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pinkerton JV. Selective estrogen receptor modulators in gynecology practice. Clin Obstet Gynecol. 2021;64(4):803–12. https://doi.org/10.1097/GRF.0000000000000647.

  11. Barani M, et al. Evaluation of carum-loaded niosomes on breast cancer cells: physicochemical properties, in vitro cytotoxicity, flow cytometric, DNA fragmentation and cell migration assay. Sci Rep. 2019;9(1):1–10.

    Article  CAS  Google Scholar 

  12. Birgani NB. Effect of carboplatin loaded niosomal nanoparticles on ovarian cancer cells. EC Pharmacol Toxicol. 2018;6:423–8.

    Google Scholar 

  13. Morello KC, Wurz GT, DeGregorio MW. Pharmacokinetics of selective estrogen receptor modulators. Clin Pharmacokinet. 2003;42:361–72.

  14. Grilli G. Tamoxifen (TAM): the dispute goes on. Ann Ist Super Sanita. 2006;42(2):170.

    CAS  PubMed  Google Scholar 

  15. Farrar MC, Jacobs TF. Tamoxifen. 2021 Jul 19. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.

  16. Herrscher H, Leblanc J, Petit TJBC. Agranulocytosis induced by tamoxifen in a breast cancer patient. Breast Care. 2020;15(1):72–4.

    Article  PubMed  Google Scholar 

  17. Makvandi P, et al. Drug delivery (nano) platforms for oral and dental applications: tissue regeneration, infection control, and cancer management. Adv Sci (Weinh). 2021;8(8):2004014.

    Article  CAS  Google Scholar 

  18. Patra JK, et al. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnology. 2018;16(1):71.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shad PM, Karizi SZ, Javan RS, Mirzaie A, Noorbazargan H, Akbarzadeh I, Rezaie H. Folate conjugated hyaluronic acid coated alginate nanogels encapsulated oxaliplatin enhance antitumor and apoptosis efficacy on colorectal cancer cells (HT29 cell line). Toxicol in Vitro. 2020;65:104756.

    Article  CAS  PubMed  Google Scholar 

  20. Heydari Sheikh Hossein H, et al. Functionalization of magnetic nanoparticles by folate as potential MRI contrast agent for breast cancer diagnostics. Molecules. 2020;25(18):4053.

    Article  PubMed Central  Google Scholar 

  21. Boran G, et al. Synergistic effect of graphene oxide and zoledronic acid for osteoporosis and cancer treatment. Sci Rep. 2020;10(1):1–12.

    Article  Google Scholar 

  22. Delfi M, et al. Self-assembled peptide and protein nanostructures for anti-cancer therapy: targeted delivery, stimuli-responsive devices and immunotherapy. Nano Today. 2021;38:101119.

    Article  CAS  PubMed  Google Scholar 

  23. Makvandi P, et al. Gum polysaccharide/nanometal hybrid biocomposites in cancer diagnosis and therapy. Biotechnol Adv. 2021;48:107711.

    Article  CAS  PubMed  Google Scholar 

  24. Day CM, et al. Novel tamoxifen nanoformulations for improving breast cancer treatment: old wine in new bottles. Molecules. 2020;25(5):1182.

    Article  CAS  PubMed Central  Google Scholar 

  25. Molani S, Madadi M, Wilkes WJO. A partially observable Markov chain framework to estimate overdiagnosis risk in breast cancer screening: incorporating uncertainty in patients adherence behaviors. Omega. 2019;89:40–53.

    Article  Google Scholar 

  26. Akbarzadeh I, et al. Preparation, optimization and in-vitro evaluation of curcumin-loaded niosome@ calcium alginate nanocarrier as a new approach for breast cancer treatment. Biology (Basel). 2021;10(3):173.

    CAS  Google Scholar 

  27. Moghaddam FD, et al. Delivery of melittin-loaded niosomes for breast cancer treatment: an in vitro and in vivo evaluation of anti-cancer effect. Cancer Nanotechnol. 2021;12(1):1–35.

    Google Scholar 

  28. Amale FR, et al. Gold nanoparticles loaded into niosomes: A novel approach for enhanced antitumor activity against human ovarian cancer. Adv Powder Technol. 2021;32(12):4711–22.

  29. Targhi AA, et al. Synergistic effect of curcumin-Cu and curcumin-Ag nanoparticle loaded niosome: enhanced antibacterial and anti-biofilm activities. Bioorg Chem. 2021;115:105116.

    Article  CAS  PubMed  Google Scholar 

  30. Moghtaderi M, et al. Enhanced antibacterial activity of Echinacea angustifolia extract against multidrug-resistant Klebsiella pneumoniae through niosome encapsulation. Nanomaterials (Basel). 2021;11(4):1573.

    Article  CAS  Google Scholar 

  31. Jamshidifar E, et al. Super magnetic niosomal nanocarrier as a new approach for treatment of breast cancer: a case study on SK-BR-3 and MDA-MB-231 cell lines. Int J Mol Sci. 2021;22(15):7948.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mirzaie A, Peirovi N, Akbarzadeh I, Moghtaderi M, Heidari F, Yeganeh FE, Noorbazargan H, Mirzazadeh S, Bakhtiari R. Preparation and optimization of ciprofloxacin encapsulated niosomes: a new approach for enhanced antibacterial activity, biofilm inhibition and reduced antibiotic resistance in ciprofloxacin-resistant methicillin-resistance Staphylococcus aureus. Bioorg Chem. 2020;103:104231.

    Article  CAS  PubMed  Google Scholar 

  33. Ghafelehbashi R, Akbarzadeh I, Tavakkoli Yaraki M, Lajevardi A, Fatemizadeh M, Heidarpoor Saremi L. Preparation, physicochemical properties, in vitro evaluation and release behavior of cephalexin-loaded niosomes. Int J Pharm. 2019;569:118580.

    Article  CAS  PubMed  Google Scholar 

  34. Barani M, et al. Lawsone-loaded niosome and its antitumor activity in MCF-7 breast cancer cell line: a nano-herbal treatment for cancer. Daru. 2018;26(1):11–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hajizadeh MR, et al. In vitro cytotoxicity assay of D-limonene niosomes: an efficient nano-carrier for enhancing solubility of plant-extracted agents. Res Pharm Sci. 2019;14(5):448.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ch MH, et al. Niosome-encapsulated tobramycin reduced antibiotic resistance and enhanced antibacterial activity against multidrug-resistant clinical strains of Pseudomonas aeruginosa. J Biomed Mater Res A. 2021;109(6):966–80.

  37. Rasul A, et al. In vitro characterization and release studies of combined nonionic surfactant-based vesicles for the prolonged delivery of an immunosuppressant model drug. Int J Nanomedicine. 2020;15:7937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tila D, et al. pH-sensitive, polymer modified, plasma stable niosomes: promising carriers for anti-cancer drugs. EXCLI J. 2015;14:21.

    PubMed  PubMed Central  Google Scholar 

  39. Khannazer N, Paylakhi SH, Mirshafiey A, Azizi G, Motamed N. Silibinin, up-regulates chemokine receptor expression in MDA-MB-231 breast cancer cell line. Bangladesh J Medical Sci. 2015;14(2):190–5.

    Article  Google Scholar 

  40. Khan R, Irchhaiya R. An overview on niosomes as efficient drug carriers. Int J Pharm Biosci. 2017;8:106–16.

    CAS  Google Scholar 

  41. Muzzalupo R, Tavano L. Niosomal drug delivery for transdermal targeting: recent advances. Res Rep Transdermal Drug Deliv. 2015;4:23.

    CAS  Google Scholar 

  42. Khindri S, Aggarwal G. Role of niosomes and proniosomes for enhancing bioavailability of drugs. J Drug Deliv Ther. 2015;5(1):28–33.

    Google Scholar 

  43. Akbarzadeh I, et al. Niosomal formulation for co-administration of hydrophobic anticancer drugs into MCF-7 cancer cells. Arch Adv Biosci. 2020;11(2) https://doi.org/10.22037/aab.v11i2.28906.

  44. Rochdy Haj-Ahmad R, Elkordy AA, Chaw CS. In vitro characterisation of Span™ 65 niosomal formulations containing proteins. Curr Drug Deliv. 2015;12(5):628–39.

    Article  PubMed  Google Scholar 

  45. Li Q, Li Z, Zeng W, Ge S, Lu H, Wu C, Ge L, Liang D, Xu Y. Proniosome-derived niosomes for tacrolimus topical ocular delivery: in vitro cornea permeation, ocular irritation, and in vivo anti-allograft rejection. Eur J Pharm Sci. 2014;62:115–23.

    Article  CAS  PubMed  Google Scholar 

  46. Basiri L, Rajabzadeh G, Bostan A. α-Tocopherol-loaded niosome prepared by heating method and its release behavior. Food Chem. 2017;221:620–8.

    Article  CAS  PubMed  Google Scholar 

  47. Kassem MA, el-Sawy HS, Abd-Allah FI, Abdelghany TM, el-Say KM. Maximizing the therapeutic efficacy of imatinib mesylate–loaded niosomes on human colon adenocarcinoma using Box-Behnken design. J Pharm Sci. 2017;106(1):111–22.

    Article  CAS  PubMed  Google Scholar 

  48. Patel J, Ketkar S, Patil S, Fearnley J, Mahadik KR, Paradkar AR. Potentiating antimicrobial efficacy of propolis through niosomal-based system for administration. Integr Med Res. 2015;4(2):94–101.

    Article  PubMed  Google Scholar 

  49. Bragagni M, Mennini N, Furlanetto S, Orlandini S, Ghelardini C, Mura P. Development and characterization of functionalized niosomes for brain targeting of dynorphin-B. Eur J Pharm Biopharm. 2014;87(1):73–9.

    Article  CAS  PubMed  Google Scholar 

  50. Moghassemi S, Hadjizadeh A. Nano-niosomes as nanoscale drug delivery systems: an illustrated review. J Control Release. 2014;185:22–36.

    Article  CAS  PubMed  Google Scholar 

  51. Sadeghi S, Bakhshandeh H, Ahangari Cohan R, Peirovi A, Ehsani P, Norouzian D. Synergistic anti-staphylococcal activity of niosomal recombinant lysostaphin-LL-37. Int J Nanomedicine. 2019;14:9777–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Barani M, Mirzaei M, Torkzadeh-Mahani M, Nematollahi MH. Lawsone-loaded niosome and its antitumor activity in MCF-7 breast cancer cell line: a nano-herbal treatment for cancer. DARU J Pharm Sci. 2018;26(1):11–7.

    Article  CAS  Google Scholar 

  53. Hajizadeh MR, Maleki H, Barani M, Fahmidehkar MA, Mahmoodi M, Torkzadeh-Mahani M. In vitro cytotoxicity assay of D-limonene niosomes: an efficient nano-carrier for enhancing solubility of plant-extracted agents. Res Pharm Sci. 2019;14(5):448–58.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Alemi A, Zavar Reza J, Haghiralsadat F, Zarei Jaliani H, Haghi Karamallah M, Hosseini SA, Haghi Karamallah S. Paclitaxel and curcumin coadministration in novel cationic PEGylated niosomal formulations exhibit enhanced synergistic antitumor efficacy. J Nanobiotechnology. 2018;16(1):28.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Sadeghi S, Ehsani P, Cohan RA, Sardari S, Akbarzadeh I, Bakhshandeh H, Norouzian D. Design and physicochemical characterization of lysozyme loaded niosomal formulations as a new controlled delivery system. Pharm Chem J. 2020;53:1–10.

    Article  Google Scholar 

  56. Salem HF, et al. Evaluation and optimization of pH-responsive niosomes as a carrier for efficient treatment of breast cancer. Drug Deliv Transl Res. 2018;8(3):633–44.

    Article  CAS  PubMed  Google Scholar 

  57. Manosroi A, Bauer K. The entrapment of a human insulin-DEAE dextran complex in different compound liposomes. Drug Dev Ind Pharm. 1989;15(14-16):2531–46.

    Article  CAS  Google Scholar 

  58. Ag Seleci D, Seleci M, Walter JG, Stahl F, Scheper T. Niosomes as nanoparticular drug carriers: fundamentals and recent applications. J Nanomater. 2016;2016:1–13.

    Article  Google Scholar 

  59. Kanaani L. Effects of cisplatin-loaded niosomal nanoparticleson BT-20 human breast carcinoma cells. Asian Pac J Cancer Prev: APJCP. 2017;18(2):365–8.

    PubMed  PubMed Central  Google Scholar 

  60. Yazdi Rouholamini SE, Moghassemi S, Maharat Z, Hakamivala A, Kashanian S, Omidfar K. Effect of silibinin-loaded nano-niosomal coated with trimethyl chitosan on miRNAs expression in 2D and 3D models of T47D breast cancer cell line. Artif Cells Nanomed Biotechnol. 2018;46(3):524–35.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was partly supported by the Bahar Tashkhis Teb, (BTT9903) and the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers “Digital biodesign and personalized healthcare” (N. 075-15-2020-917).

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Authors and Affiliations

  1. Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Iman Akbarzadeh, Bahare Shokoohian & Massoud Vosough

  2. Gastroenterology and Liver Diseases Research Center, Research, Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mahsa Farid, Mandana Kazem Arki, Hamid Asadzadeh Aghdaei & Nikoo Hossein-khannazer

  3. Department of Genetic, Islamic Azad University, North Tehran Branch, Tehran, Iran

    Mehrnoosh Javidfar

  4. Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Negar Zabet

  5. World-Class Research Center “Digital biodesign and personalized healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia

    Anastasia Shpichka & Peter Timashev

  6. Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, Moscow, Russia

    Anastasia Shpichka & Peter Timashev

  7. Yaroslav-the-Wise Novgorod State University, Veliky Novgorod, Russia

    Anastasia Shpichka

  8. Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Hassan Noorbazargan

  9. Chemistry Department, Lomonosov Moscow State University, Moscow, Russia

    Peter Timashev

  10. Istituto Italiano di Tecnologia, Centre for Materials Interface, viale Rinaldo Piaggio 34, Pontedera, 56025, Pisa, Italy

    Pooyan Makvandi

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  1. Iman Akbarzadeh
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  2. Mahsa Farid
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  3. Mehrnoosh Javidfar
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  4. Negar Zabet
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  7. Anastasia Shpichka
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  8. Hassan Noorbazargan
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  10. Nikoo Hossein-khannazer
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  11. Peter Timashev
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  12. Pooyan Makvandi
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  13. Massoud Vosough
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Contributions

I.A. and M.F. performed the experiments and data collection and drafted the manuscript. M.J., N.Z., B.S., M.K.A, P.T., N.H., and P.M. and contributed to the development of the concept, study design, and critically reviewed the manuscript. A.S., H.N., and H.A.A. contributed to study design, data collection, and data analysis and drafting the results. M.V. developed the concept, contributed to data analysis, critical reviewing and approval of the manuscript, and financially supported the project.

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Correspondence to Nikoo Hossein-khannazer, Peter Timashev or Massoud Vosough.

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Akbarzadeh, I., Farid, M., Javidfar, M. et al. The Optimized Formulation of Tamoxifen-Loaded Niosomes Efficiently Induced Apoptosis and Cell Cycle Arrest in Breast Cancer Cells. AAPS PharmSciTech 23, 57 (2022). https://doi.org/10.1208/s12249-022-02212-0

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