Skip to main content
SpringerLink
Log in

mTOR inhibitors from a diagnostic perspective: radiolabeling of everolimus and its nanoformulation, in vitro incorporation assays against cervix and ovarian cancer cells

  • Published:
Journal of Radioanalytical and Nuclear Chemistry Aims and scope Submit manuscript

Abstract

mTOR inhibitors are recently important tools for cancer treatment. They act on cell growth regulation, proliferation, and survival. Pharmacological therapy with mTOR inhibitors such as everolimus is emerging as an alternate approach. Meanwhile, early diagnosis is a hot target in cancer research. Conversely, it can be a novel diagnosis approach to monitor mTOR inhibitors during their pathway. From this point of view, radiolabeling of everolimus and its nanoformulation (EVE-PLGA nanoparticles) in high yields (95%) with an important diagnostic radionuclide (technetium-99m) is described. Besides, in vitro incorporation assays of radiolabeled everolimus and its nanoformulation against the cervix and ovarian cancer cells were demonstrated 8- and 12-times high values than control group. In conclusion, radiolabeled everolimus and its nanoformulation have a promise to improve on monitoring mTOR inhibitors.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Faes S, Demartines N, Dormond O (2017) Resistance to MTORC1 inhibitors in cancer therapy: From kinase mutations to intratumoral heterogeneity of kinase activity. Oxid Med Cell Longev. https://doi.org/10.1155/2017/1726078

    Article  PubMed  PubMed Central  Google Scholar 

  2. Estimated Cancer Prevalence Worldwide in 2020 http://globocan.iarc.fr (accessed Jul 10, 2021).

  3. de Melo AC, Paulino E, Garces ÁHI (2017) A review of MTOR pathway inhibitors in gynecologic cancer. Oxid Med Cell Longev 2017:4809751. https://doi.org/10.1155/2017/4809751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Assad DX, Elias ST, Melo AC, Ferreira CG, De Luca Canto G, Guerra ENS (2016) Potential impact of MTOR inhibitors on cervical squamous cell carcinoma: A systematic review. Oncol Lett 12(5):4107–4116. https://doi.org/10.3892/ol.2016.5157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zou Z, Tao T, Li H, Zhu X (2020) MTOR signaling pathway and MTOR inhibitors in cancer: progress and challenges. Cell Biosci 10(1):1–11. https://doi.org/10.1186/S13578-020-00396-1

    Article  CAS  Google Scholar 

  6. Feng Y, Chen X, Cassady K, Zou Z, Yang S, Wang Z, Zhang X (2021) The role of MTOR inhibitors in hematologic disease: from bench to bedside. Front Oncol 10:3043. https://doi.org/10.3389/FONC.2020.611690

    Article  Google Scholar 

  7. de Melo AC, Grazziotin-Reisner R, Erlich F, Fontes Dias MS, Moralez G, Carneiro M, Ingles Garces ÁH, Guerra Alves FV, Novaes Neto B, Fuchshuber-Moraes M et al (2016) A phase i study of MTOR inhibitor everolimus in association with cisplatin and radiotherapy for the treatment of locally advanced cervix cancer: PHOENIX I. Cancer Chemother Pharmacol. https://doi.org/10.1007/s00280-016-3064-0

    Article  PubMed  Google Scholar 

  8. Wang M, Gao M, Miller KD, Sledge GW, Zheng QH (2012) [11C]GSK2126458 and [18F]GSK2126458, the first radiosynthesis of new potential PET agents for imaging of PI3K and MTOR in cancers. Bioorg Med Chem Lett 22(4):1569–1574. https://doi.org/10.1016/J.BMCL.2011.12.136

    Article  CAS  PubMed  Google Scholar 

  9. Kinross KM, Brown DV, Kleinschmidt M, Jackson S, Christensen J, Cullinane C, Hicks RJ, Johnstone RW, McArthur GA (2011) In Vivo activity of combined PI3K/MTOR and MEK inhibition in a KrasG12D;Pten deletion mouse model of ovarian cancer. Mol Cancer Ther 10(8):1440–1449. https://doi.org/10.1158/1535-7163.MCT-11-0240

    Article  CAS  PubMed  Google Scholar 

  10. Majo VJ, Simpson NR, Prabhakaran J, Mann JJ, Kumar JSD (2014) Radiosynthesis of [18F]ATPFU: A potential PET Ligand for MTOR. J. Labelled Comp. Radiopharm. 57(13):705. https://doi.org/10.1002/JLCR.3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Han N, Jiang Y, Gai Y, Liu Q, Yuan L, Wang Y, Lan X (2019) 11 C-labeled pictilisib (GDC-0941) as a molecular tracer targeting Phosphatidylinositol 3-Kinase (PI3K) for breast cancer imaging. Contrast Media Mol Imaging. https://doi.org/10.1155/2019/1760184

    Article  PubMed  PubMed Central  Google Scholar 

  12. Altine B, Gai Y, Han N, Jiang Y, Ji H, Fang H, Niyonkuru A, Bakari KH, Arnous MMR, Liu Q et al (2019) Preclinical evaluation of a Fluorine-18 (18F)-Labeled phosphatidylinositol 3-Kinase inhibitor for Breast cancer imaging. Mol Pharm 16(11):4563–4571. https://doi.org/10.1021/ACS.MOLPHARMACEUT.9B00690

    Article  CAS  PubMed  Google Scholar 

  13. Rashidi S, Mansouri R, Ali-Hassanzadeh M, Mojtahedi Z, Shafiei R, Savardashtaki A, Hamidizadeh N, Karimazar M, Nguewa P, Manzano-Román R (2021) The host MTOR pathway and parasitic diseases pathogenesis. Parasitol Res. https://doi.org/10.1007/s00436-021-07070-6

    Article  PubMed  PubMed Central  Google Scholar 

  14. Santulli G, Totary-Jain H (2013) Tailoring MTOR-based therapy: Molecular evidence and clinical challenges. Pharmacogenomics 14(12):1517–1526. https://doi.org/10.2217/pgs.13.143

    Article  CAS  PubMed  Google Scholar 

  15. André F, O’Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C et al (2014) Everolimus for women with trastuzumab-resistant, HER2-positive, advanced Breast cancer (BOLERO-3): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15(6):580–591. https://doi.org/10.1016/S1470-2045(14)70138-X

    Article  CAS  PubMed  Google Scholar 

  16. Ge J, Zhang Q, Zeng J, Gu Z, Gao M (2020) Radiolabeling nanomaterials for multimodality imaging: New insights into nuclear medicine and cancer diagnosis. Biomaterials. https://doi.org/10.1016/j.biomaterials.2019.119553

    Article  PubMed  Google Scholar 

  17. Yurt Kilcar A, Tekin V, Biber Muftuler FZ, Medine EI (2016) 99mTc labeled plumbagin: Estrogen receptor dependent examination against Breast cancer cells and comparison with PLGA encapsulated form. J Radioanal Nucl Chem 308(1):13–22. https://doi.org/10.1007/s10967-015-4284-1

    Article  CAS  Google Scholar 

  18. Yurt Kilcar A, Biber Muftuler FZ, Medine EI, Tekin V (2016) PLGA encapsulation effect on Bioquin-HMPAO: Radiolabeling and in Vitro behaviour on Brain and Lung cancer cells. J Radioanal Nucl Chem 310(1):155–164. https://doi.org/10.1007/s10967-016-4746-0

    Article  CAS  Google Scholar 

  19. Brannon-Peppas L (1995) Recent advances on the use of biodegradable microparticles and nanoparticles in controlled drug delivery. Int J Pharm 116(1):1–9. https://doi.org/10.1016/0378-5173(94)00324-X

    Article  CAS  Google Scholar 

  20. Peltonen L, Koistinen P, Karjalainen M, Häkkinen A, Hirvonen J (2002) The effect of cosolvents on the formulation of nanoparticles from low-molecular-weight Poly(l)Lactide. AAPS PharmSciTech 3(4):E32. https://doi.org/10.1208/pt030432

    Article  PubMed  Google Scholar 

  21. Yildiz G, Yurt Kilcar A, Medine EI, Tekin V, Kozgus Guldu O, Biber Muftuler FZ (2017) PLGA encapsulation and radioiodination of Indole-3-Carbinol: Investigation of anticancerogenic effects against MCF7, Caco2 and PC3 cells by in Vitro assays. J Radioanal Nucl Chem 311(2):1043–1052. https://doi.org/10.1007/s10967-016-4929-8

    Article  CAS  Google Scholar 

  22. Zolle I (2007) Technetium-99m pharmaceuticals preparation and quality control in nuclear medicine

  23. Meek WH, Fuchsman CH (1969) Carboxylation of substituted phenols in N, N-Dimethylamide solvents at atmospheric pressure. J Chem Eng Data 14:388–391

    Article  CAS  Google Scholar 

  24. Houdaihed L, Evans JC, Allen C (2019) In Vivo evaluation of dual-targeted nanoparticles encapsulating paclitaxel and everolimus. Cancers (Basel). https://doi.org/10.3390/CANCERS11060752

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bonizzi A, Truffi M, Sevieri M, Allevi R, Sitia L, Ottria R, Sorrentino L, Sottani C, Negri S, Grignani E et al (2019) Everolimus nanoformulation in biological nanoparticles increases drug responsiveness in resistant and low-responsive breast cancer cell lines. Pharm 11(8):384. https://doi.org/10.3390/PHARMACEUTICS11080384

    Article  CAS  Google Scholar 

  26. Theobald A (1989) Radiopharmaceuticals using radioactive compounds in pharmaceutics and medicine.

  27. Schwochau K (2000) Technetium chemistry and radiopharmaceutical applications. Wiley-VCH, Winheim

    Book  Google Scholar 

  28. Pusapati RV, Daemen A, Wilson C, Sandoval W, Gao M, Haley B, Baudy AR, Hatzivassiliou G, Evangelista M, Settleman J (2016) MTORC1-Dependent metabolic reprogramming underlies escape from glycolysis addiction in cancer cells. Cancer Cell 29(4):548–562. https://doi.org/10.1016/j.ccell.2016.02.018

    Article  CAS  PubMed  Google Scholar 

  29. Assad DX, Borges GA, Avelino SR, Guerra ENS (2018) Additive cytotoxic effects of radiation and MTOR inhibitors in a cervical cancer cell line. Pathol Res Pract 214(2):259–262. https://doi.org/10.1016/j.prp.2017.10.019

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Current work is supported by Ege University Scientific Research Projects Coordination Unit (Project No. 17-TIP-046 (ID:109)). The authors thank to Fatmagül Gedik, Neşe Kavcar and Öykü Madenci for the technical assistance during the assays. A limited part of the synthesis and radiolabeling part was presented as a poster presentation at 44th FEBS Congress, From Molecules to Living Systems, Krakow, Poland, July 6-11, 2019.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, Faculty of Medicine, Selçuk University, Konya, Turkey

    Ahmet Bilgi

  2. Department of Nuclear Applications, Institute of Nuclear Sciences, Ege University, 35100, Izmir, Turkey

    Ayfer Yurt Kilcar, Cansu Kayas, Kadriye Busra Karatay & Fazilet Zumrut Biber Muftuler

  3. Department of Gynaecologic Oncology, Medical Faculty Hospital, Mersin University, Mersin, Turkey

    Sevki Goksun Gokulu

  4. Department of Obstetrics and Gynaecology, Faculty of Medicine, Ege University, Izmir, Turkey

    Nuri Yildirim, Levent Akman & Ahmet Aydin Ozsaran

Authors
  1. Ahmet Bilgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayfer Yurt Kilcar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sevki Goksun Gokulu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cansu Kayas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nuri Yildirim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kadriye Busra Karatay
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Levent Akman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fazilet Zumrut Biber Muftuler
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ahmet Aydin Ozsaran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fazilet Zumrut Biber Muftuler.

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

Bilgi, A., Yurt Kilcar, A., Gokulu, S.G. et al. mTOR inhibitors from a diagnostic perspective: radiolabeling of everolimus and its nanoformulation, in vitro incorporation assays against cervix and ovarian cancer cells. J Radioanal Nucl Chem 331, 171–178 (2022). https://doi.org/10.1007/s10967-021-08066-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10967-021-08066-3

Keywords

Search

Navigation