Skip to main content
SpringerLink
Log in

99mTc Stearyl 6-(benzylidenehydrazinyl) nicotinamide Liposomes as Tumor Permeability Evaluation Tracer

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Nanomedicine is a highly demanded discipline. Liposomes have seen an increased attention due to their physicochemical properties that allow them to act as nanocarriers of drugs and also of radioisotopes that can be used to diagnose and treat cancer. In order to obtain a novel permeability cancer imaging agent based on 99mTc-labeled liposomes, we describe microwave-assisted synthesis of stearyl 6-(benzylidenehydrazinyl) nicotinamide lipid, which was included in two formulations: nanometric hydrazinonicotinic acid (HYNIC) liposome and its PEGylated coated analogue, HYNIC-PEG liposome. Radiolabeling with 99mTc via stearyl 6-(benzylidenehydrazinyl) nicotinamide was found to be easy, reproducible, and stable, revealing high radiochemical purity (94 ± 1.7%) for both liposomal formulations. Biodistribution at 4 h and 24 h and scintigraphic images at 4 h were performed in normal and melanoma-bearing C57BL/6 mice. Biodistribution studies at 4 h showed tumor uptake of 99mTc-HYNIC liposome and 99mTc-HYNIC-PEG liposome (1.1 ± 0.6 and 2.5 ± 0.4, respectively) and also at 24 h p.i. (1.8 ± 0.5 and 3.0 ± 1.1, respectively). Scintigraphic images showed appreciable tumor uptake in melanoma tumor–bearing mice with both liposomal formulations. Our results show that 99mTc stearyl 6-(benzylidenehydrazinyl) nicotinamide liposomes can be used as diagnostic noninvasive in vivo tumor-targeting agents capable of evaluating tumor permeability and development who can be used in personalized chemotherapy planning.

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
Fig. 7

Similar content being viewed by others

References

  1. American Cancer Society. Cancer facts & figures 2020. 2020. Available from: http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-048738.pdf. (Accessed 16 June 2020).

  2. Sharma R, Aboagye E. Development of radiotracers for oncology--the interface with pharmacology. Br J Pharmacol. 2011;163(8):1565–85. https://doi.org/10.1111/j.1476-5381.2010.01160.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chen-Yang Z, Rui C, Zhe Y, Zhong-Min T. Nanotechnology for cancer therapy based on chemotherapy. Molecules. 2018;23(4):826. https://doi.org/10.3390/molecules23040826.

    Article  CAS  Google Scholar 

  4. Van der Geest T, Laverman P, Metselaar JM, Storm G, Boerman, Otto C. Radionuclide imaging of liposomal drug delivery. Expert Opin Drug Deliv. 2016;13(9):1231–42. https://doi.org/10.1080/17425247.2016.1205584.

    Article  CAS  PubMed  Google Scholar 

  5. Deshpande PP, Biswas S, Torchilin VP. Current trends in the use of liposomes for tumor targeting. Nanomedicine (London). 2013;8(9). https://doi.org/10.2217/nnm.13.118.

  6. Boerman OC, Leverman P, Yen WJ, Corstens FH, Storm G. Radiolabeled liposomes for scintigraphic imaging. Prog Lipid Res. 2000;39(5):461–75. https://doi.org/10.1016/s0163-7827(00)00013-8.

    Article  CAS  PubMed  Google Scholar 

  7. Jensen ATI, Rasmussen P, Andresen TL. PET imaging of liposomes labeled with an [18F]-fluorocholesteryl ether probe prepared by automated radiosynthesis. J Liposome Res. 2012:295–305. https://doi.org/10.3109/08982104.2012.698418.

  8. Helbok AB, Decristoforo C, Dobrozemsky G, Rangger C, Diederen E, Stark B, et al. Radiolabeling of lipid-based nanoparticles for diagnostics and therapeutic applications: a comparison using different radiometals. J Liposome Res. 2010;20(3):219–27. https://doi.org/10.3109/08982100903311812.

    Article  CAS  PubMed  Google Scholar 

  9. Laverman P, Storm G, Boerman OC. In: Bulte JWM, Modo M, editors. Nanoparticles in biomedical imaging: emerging technologies and applications. New York: Springer; 2008. https://doi.org/10.1007/978-0-387-72027-2.

    Chapter  Google Scholar 

  10. Allen TM, Cullis PR. Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev. 2013;65(1):36–48. https://doi.org/10.1016/j.addr.2012.09.037.

    Article  CAS  PubMed  Google Scholar 

  11. Khoshbakht S, Kobarfard F, Beiki D, Sabzevari O, Amini M, Mehrnejad F, et al. HYNIC a bifunctional prosthetic group for the labeling of peptides with 99mTc and 18FDG. J Radioanal Nucl Chem. 2016;307:1125–34. https://doi.org/10.1007/s10967-015-4259-2.

    Article  CAS  Google Scholar 

  12. Surfraz MBU, King R, Mather SJ, Biagini SCG, Blower PJ. Trifluoroacetyl as a protecting group for HYNIC: stability in the presence of electrophiles and application in the synthesis of Tc-99m-radiolabelled peptides. Tetrahedron. 2010;66(11):2037–43. https://doi.org/10.1016/j.tet.2010.01.038.

    Article  CAS  Google Scholar 

  13. Surfraz MBU, Biagini SCG, Blower PJ. A technetium intermediate specifically promotes deprotection of trifluoroacetyl HYNIC during radiolabelling under mild conditions. Dalton Trans. 2008:2920–2. https://doi.org/10.1039/B805110K.

  14. Greenland WE, Howland K, Hardy J, Fogelman I, Blower. Solid-phase synthesis of peptide radiopharmaceuticals using Fmoc-N-epsilon-(hynic-Boc)-lysine, a technetium-binding amino acid: application to Tc-99m-labeled salmon calcitonin. J Med Chem. 2003;46(9):1751–7. https://doi.org/10.1021/jm030761n.

    Article  CAS  PubMed  Google Scholar 

  15. García MF, Calzada V, Camacho X, Goicochea E, Gambini JP, Quinn TP, et al. Microwave-assisted synthesis of HYNIC protected analogue for 99mTc labeled antibody. Curr Radiopharm. 2014;7:84–90. https://doi.org/10.2174/1874471007666141128160449.

    Article  CAS  PubMed  Google Scholar 

  16. Harris TD, Sworin M, Williams N, Rajopadhye M, Damphousse PR, Glowacka D, et al. Synthesis of stable hydrazones of a hydrazinonicotinyl-modified peptide for the preparation of 99mTc-labeled radiopharmaceuticals. Bioconjug Chem. 1999;10:808–14. https://doi.org/10.1021/bc9900237.

    Article  CAS  PubMed  Google Scholar 

  17. Teixeira V, Cabral P, Porcal W. Microwave-assisted solid-phase synthesis of nicotinylhydrazones for use in radiochemistry of technetium-99m, ARKIVOC: archive for organic chemistry. 2018.

  18. Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Woo Joo S, Zarghami N, Hanifehpour Y, et al. Liposome: classification, preparation, and applications. Nanoscale Res Lett. 2013;8(1):102.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cabrera M, Madrano A, Lecot N, Fernandez M, Moreno M, Chabalgoity JA, et al. A novel method to radiolabel stealth liposome through 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-DTPA with 99mTc and biological evaluation. J Anal Oncol. 2013;2(1).

  20. Stalteri MA, Bansal S, Hider R, Mather SJ. Comparison of the stability of technetium-labeled peptides to challenge with cysteine. Bioconjug Chem. 1999;10(1):130–6. https://doi.org/10.1021/bc9800466.

    Article  CAS  PubMed  Google Scholar 

  21. Hnatowich DJ, Virzi F, Fogarasi M, Rusckowski P, Winnard J. Can a cysteine challenge assay predict the in vivo behavior of 99mTc-labeled antibodies? Nucl Med Biol. 1994;21(8):1035–44. https://doi.org/10.1016/0969-8051(94)90175-9.

    Article  CAS  PubMed  Google Scholar 

  22. Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm. 2008;5(4):505–15. https://doi.org/10.1021/mp800051m.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stewart BW, Wild CP, editors. World cancer report 2014. Lyon: International Agency for Research on Cancer; 2014. ISBN: 978-92-832-0429-9

    Google Scholar 

  24. Kan P, Tsao CW, Wang AJ, Su WC, Liang HF. A liposomal formulation able to incorporate a high content of paclitaxel and exert promising anticancer effect. J Drug Deliv. 2011;629234:1–9. https://doi.org/10.1155/2011/629234.

    Article  CAS  Google Scholar 

  25. Dawidczyk CM, Russell LM, Hultz M, Searson PC. Tumor accumulation of liposomal doxorubicin in three murine models: optimizing delivery efficiency. Nanomedicine. 2017;13(5):1637–44. https://doi.org/10.1016/j.nano.2017.02.008.

    Article  CAS  PubMed  Google Scholar 

  26. Suk JS, Xu Q, Kim N, Hanes J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2016;99(Pt A):28–51. https://doi.org/10.1016/j.addr.2015.09.012.

    Article  CAS  PubMed  Google Scholar 

  27. Najlah M, Suliman AS, Tolaymat I, Kurusamy S, Kannappan V, Elhissi AMA, et al. Development of injectable PEGylated liposome encapsulating disulfiram for colorectal cancer treatment. Pharmaceutics. 2019;11:610. https://doi.org/10.3390/pharmaceutics11110610.

    Article  CAS  PubMed Central  Google Scholar 

  28. Vali AM, Toliyat T, Shafaghi B, Dadashzadeh S. Preparation, optimization, and characterization of topotecan loaded PEGylated liposomes using factorial design. Drug Dev Ind Pharm. 2008;34(1):10–23. https://doi.org/10.1080/03639040701385055.

    Article  CAS  PubMed  Google Scholar 

  29. Nakamura K, Yamashita K, Itoh Y, Yoshino K, Nozawa S, Kasukawa H. Comparative studies of polyethylene glycol-modified liposomes prepared using different PEG-modification methods. Biochim Biophys Acta Biomembr. 2012;1818(11):2801–7. https://doi.org/10.1016/j.bbamem.2012.06.019.

    Article  CAS  Google Scholar 

  30. Hnatowich DJ, Friedman B, Clancy B, Novak M. Labeling of preformed liposomes with Ga-67 and Tc-99m by chelation. J Nucl Med. 1981;22:810–4.

    CAS  PubMed  Google Scholar 

  31. Decristoforo C, Mather S. Technetium-99m somatostatin analogues: effect of labelling methods and peptide sequence. Eur J Nucl Med. 1999;26:869–76. https://doi.org/10.1007/s002590050461.

    Article  CAS  PubMed  Google Scholar 

  32. Greenwald RB, Zhao H, Peng P, Longley CB, Dai QH, Xia J, et al. An unexpected amide bond cleavage: poly (ethylene glycol) transport forms of vancomycin. Eur J Med Chem. 2005;40:798–804. https://doi.org/10.1016/j.ejmech.2005.01.011.

    Article  CAS  PubMed  Google Scholar 

  33. Özcan İ, Segura-Sánchez F, Bouchemal K, Sezak M, Özer O, Güneri T, et al. Pegylation of poly(γ-benzyl-L-glutamate) nanoparticles is efficient for avoiding mononuclear phagocyte system capture in rats. Int J Nanomedicine. 2010;5:1103–11. https://doi.org/10.2147/IJN.S15493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jokerst JV, Lobovkina T, Zare RN, Gambhir SS. Nanoparticle PEGylation for imaging and therapy. Nanomedicine. 2011;6(4). https://doi.org/10.2217/nnm.11.19.

  35. Hayashi Y, Takamiya M, Jensen PB, Ojea-Jiménez I, Claude H, Antony C, et al. Differential nanoparticle sequestration by macrophages and scavenger endothelial cells visualized in vivo in real-time and at ultrastructural resolution. ACS Nano. 2020;14(2):1665–81. https://doi.org/10.1021/acsnano.9b07233.

    Article  CAS  PubMed  Google Scholar 

  36. Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and challenges of liposome assisted drug delivery. Front Pharmacol. 2015;6:286. https://doi.org/10.3389/fphar.2015.00286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Golombek SK, May JN, Theek B, Appold A, Drude N, Kiessling F, et al. Tumor targeting via EPR: strategies to enhance patient responses. Adv Drug Deliv Rev. 2018;130:17–38. https://doi.org/10.1016/j.addr.2018.07.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen Y, Zhang W, Huang Y, Gao F, Fang X. In vivo biodistribution and anti-tumor efficacy evaluation of doxorubicin and paclitaxel-loaded pluronic micelles decorated with c(RGDyK) peptide. PLoS ONE. 2016;11(3):e0149952. https://doi.org/10.1371/journal.pone.014995240.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Perche, Torchilin. Recent trends in multifunctional liposomal nanocarriers for enhanced tumor targeting. Nanotechnologies in Cancer. 2013; Article ID 705265. https://doi.org/10.1155/2013/705265.

  40. Nunes SS, Fernandes RS, Cavalcante CH, da Costa CI, Leite EA, Lopes SCA, et al. Influence of PEG coating on the biodistribution and tumor accumulation of pH-sensitive liposomes. Drug Deliv Transl Res. 2019 Feb;9(1):123–30. https://doi.org/10.1007/s13346-018-0583-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Souhami RL, Patel HM, Ryman BE. The effect of reticuloendothelial blockade on the blood clearance and tissue distribution of liposomes. Biochim Biophys Acta. 1981;674:354–71.

    Article  CAS  PubMed  Google Scholar 

  42. Dams ETM, Laverman P, Oyen WJG, Storm G, Scherphof GL, van Der Meer JWM, et al. Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J Pharmacol Exp Ther. 2000;292(3):1071–9.

    CAS  PubMed  Google Scholar 

Download references

Funding

This research was supported by Agencia Nacional de Investigación e Innovación (ANII), Uruguay.

Author information

Authors and Affiliations

  1. Laboratorio de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, 11400, Montevideo, Uruguay

    Mirel Cabrera & Pablo Cabral

  2. Laboratorio de ATN en Bioquímica y Biotecnología, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, 11400, Montevideo, Uruguay

    Nicole Lecot

  3. Laboratorio de Experimentación Animal, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Mataojo 2055, 11400, Montevideo, Uruguay

    Marcelo Fernández

  4. Centro de Medicina Nuclear, Hospital de Clínicas, Facultad de Medicina, Universidad de la Republica, Av Italia s/n, 11600, Montevideo, Uruguay

    J. P. Gambini

  5. Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Av. General Flores 2124, 11800, Montevideo, Uruguay

    Williams Porcal

Authors
  1. Mirel Cabrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicole Lecot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcelo Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. P. Gambini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Williams Porcal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pablo Cabral
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mirel Cabrera.

Ethics declarations

Competing Interests

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

Cabrera, M., Lecot, N., Fernández, M. et al. 99mTc Stearyl 6-(benzylidenehydrazinyl) nicotinamide Liposomes as Tumor Permeability Evaluation Tracer. AAPS PharmSciTech 22, 115 (2021). https://doi.org/10.1208/s12249-021-01984-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-021-01984-1

KEY WORDS

Search

Navigation