Skip to main content

Advertisement

SpringerLink
Log in

89Zr-Labeled Paramagnetic Octreotide-Liposomes for PET-MR Imaging of Cancer

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Dual-modality PET/MR platforms add a new dimension to patient diagnosis with high resolution, functional, and anatomical imaging. The full potential of this emerging hybrid modality could be realized by using a corresponding dual-modality probe. Here, we report pegylated liposome (LP) formulations, housing a MR T1 contrast agent (Gd) and the positron-emitting 89Zr (half-life: 3.27 days), for simultaneous PET and MR tumor imaging capabilities.

Methods

89Zr oxophilicity was unexpectedly found advantageous for direct radiolabeling of preformed paramagnetic LPs. LPs were conjugated with octreotide to selectively target neuroendocrine tumors via human somatostatin receptor subtype 2 (SSTr2). 89Zr-Gd-LPs and octreotide-conjugated homolog were physically, chemically and biologically characterized.

Results

89Zr-LPs showed reasonable stability over serum proteins and chelator challenges for proof-of-concept in vitro and in vivo investigations. Nuclear and paramagnetic tracking quantified superior SSTr2-recognition of octreotide-LP compared to controls.

Conclusions

This study demonstrated SSTr2-targeting specificity along with direct chelator-free 89Zr-labeling of LPs and dual PET/MR imaging properties.

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

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

CL:

control-liposome

CT:

computed tomography

LP:

liposome

MRI:

magnetic resonnance imaging

OCT:

octreotide

OL:

octreotide-liposome

PEG:

polyethylene glycol

PET:

positron emission tomography

SPECT:

single-photon emission computed tomography

SSTr2:

somatostatin receptor subtype 2

REFERENCES

  1. Cherry SR. Multimodality imaging: beyond PET/CT and SPECT/CT. Semin Nucl Med. 2009;39(5):348–53. Epub 2009/08/04.

    Article  PubMed  Google Scholar 

  2. Catana C, Procissi D, Wu Y, Judenhofer MS, Qi J, Pichler BJ, et al. Simultaneous in vivo positron emission tomography and magnetic resonance imaging. Proc Natl Acad Sci U S A. 2008;105(10):3705–10. Epub 2008/03/06.

    Article  PubMed  CAS  Google Scholar 

  3. Bellin MF. MR contrast agents, the old and the new. Eur J Radiol. 2006;60(3):314–23. Epub 2006/09/29.

    Article  PubMed  Google Scholar 

  4. Shellock FG. MR imaging in patients with intraspinal bullets. J Magn Reson Imaging. 1999;10(1):107. Epub 1999/07/10.

    Article  PubMed  CAS  Google Scholar 

  5. Terreno E, Delli Castelli D, Cabella C, Dastru W, Sanino A, Stancanello J, et al. Paramagnetic liposomes as innovative contrast agents for magnetic resonance (MR) molecular imaging applications. Chem Biodivers. 2008;5(10):1901–12. Epub 2008/10/31.

    Article  PubMed  CAS  Google Scholar 

  6. Soret M, Bacharach SL, Buvat I. Partial-volume effect in PET tumor imaging. J Nucl Med. 2007;48(6):932–45. Epub 2007/05/17.

    Article  PubMed  Google Scholar 

  7. Phillips WT, Goins BA, Bao A. Radioactive liposomes. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2009;1(1):69–83. Epub 2010/01/06.

    Article  PubMed  CAS  Google Scholar 

  8. Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS. 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. J Nucl Med. 2010;51(8):1293–300. Epub 2010/07/28.

    Article  PubMed  CAS  Google Scholar 

  9. Laverman P, Boerman OC, Oyen WJG, Corstens FHM, Storm G. In vivo applications of PEG liposomes: unexpected observations. Crit Rev Ther Drug Carrier Syst. 2001;18(6):551–66. Epub 2002/01/16.

    Article  PubMed  CAS  Google Scholar 

  10. ElBayoumi TA, Torchilin VP. Tumor-targeted nanomedicines: enhanced antitumor efficacy in vivo of doxorubicin-loaded, long-circulating liposomes modified with cancer-specific monoclonal antibody. Clin Cancer Res. 2009;15(6):1973–80. Epub 2009/03/12.

    Article  PubMed  CAS  Google Scholar 

  11. Iwase Y, Maitani Y. Octreotide-targeted liposomes loaded with CPT-11 enhanced cytotoxicity for the treatment of medullary thyroid carcinoma. Mol Pharm. 2011;8(2):330–7. Epub 2010/12/21.

    Article  PubMed  CAS  Google Scholar 

  12. Iwase Y, Maitani Y. Dual functional octreotide-modified liposomal irinotecan leads to high therapeutic efficacy for medullary thyroid carcinoma xenografts. Cancer Sci. 2012;103(2):310–6.

    Article  PubMed  CAS  Google Scholar 

  13. Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003;24(4):389–427. Epub 2003/08/16.

    Article  PubMed  CAS  Google Scholar 

  14. Sun M, Wang Y, Shen J, Xiao Y, Su Z, Ping Q. Octreotide-modification enhances the delivery and targeting of doxorubicin-loaded liposomes to somatostatin receptors expressing tumor in vitro and in vivo. Nanotechnology. 2010;21(47):475101. Epub 2010/10/30.

    Article  PubMed  Google Scholar 

  15. Holland JP, Sheh Y, Lewis JS. Standardized methods for the production of high specific-activity zirconium-89. Nucl Med Biol. 2009;36(7):729–39. Epub 2009/09/02.

    Article  PubMed  CAS  Google Scholar 

  16. Stewart JC. Colorimetric determination of phospholipids with ammonium ferrothiocyanate. Anal Biochem. 1980;104(1):10–4. Epub 1980/05/01.

    Article  PubMed  CAS  Google Scholar 

  17. Medina OP, Pillarsetty N, Glekas A, Punzalan B, Longo V, Gonen M, et al. Optimizing tumor targeting of the lipophilic EGFR-binding radiotracer SKI 243 using a liposomal nanoparticle delivery system. J Control Release. 2011;149(3):292–8. Epub 2010/11/05.

    Article  PubMed  CAS  Google Scholar 

  18. Barlow DJ, Hollinshead CM, Harvey RD, Webster JRP, Hughes AV, Weston A, et al. Effects of surface pressure on the structure of distearoylphosphatidylcholine monolayers formed at the air/water interface. Langmuir. 2009;25(7):4070–7.

    Article  PubMed  Google Scholar 

  19. Abou DS, Ku T, Smith-Jones PM. In vivo biodistribution and accumulation of 89Zr in mice. Nucl Med Biol. 2011;38(5):675–81. Epub 2011/07/02.

    Article  PubMed  CAS  Google Scholar 

  20. Enoch HG, Strittmatter P. Formation and properties of 1000-A-diameter, single-bilayer phospholipid vesicles. Proc Natl Acad Sci U S A. 1979;76(1):145–9. Epub 1979/01/01.

    Article  PubMed  CAS  Google Scholar 

  21. Zhang H, Moroz MA, Serganova I, Ku T, Huang R, Vider J, et al. Imaging expression of the human somatostatin receptor subtype-2 reporter gene with 68 Ga-DOTATOC. J Nucl Med. 2011;52(1):123–31. Epub 2010/12/15.

    Article  PubMed  CAS  Google Scholar 

  22. Euhus DM, Hudd C, LaRegina MC, Johnson FE. Tumor measurement in the nude mouse. J Surg Oncol. 1986;31(4):229–34. Epub 1986/04/01.

    Article  PubMed  CAS  Google Scholar 

  23. Beattie BJ, Forster GJ, Govantes R, Le CH, Longo VA, Zanzonico PB, et al. Multimodality registration without a dedicated multimodality scanner. Mol Imaging. 2007;6(2):108–20. Epub 2007/04/21.

    PubMed  Google Scholar 

  24. Na DH, Murty SB, Lee KC, Thanoo BC, DeLuca PP. Preparation and stability of poly(ethylene glycol) (PEG)ylated octreotide for application to microsphere delivery. AAPS PharmSciTech. 2003;4(4):E72. Epub 2004/06/17.

    Article  PubMed  Google Scholar 

  25. Strijkers GJ, Mulder WJ, van Heeswijk RB, Frederik PM, Bomans P, Magusin PC, et al. Relaxivity of liposomal paramagnetic MRI contrast agents. MAGMA. 2005;18(4):186–92. Epub 2005/09/13.

    Article  PubMed  CAS  Google Scholar 

  26. Dijkers EC, Oude Munnink TH, Kosterink JG, Brouwers AH, Jager PL, de Jong JR, et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;87(5):586–92. Epub 2010/04/02.

    Article  PubMed  CAS  Google Scholar 

  27. Fabre RM, Talham DR. Stable supported lipid bilayers on zirconium phosphonate surfaces. Langmuir. 2009;25(21):12644–52. Epub 2009/08/29.

    Article  PubMed  CAS  Google Scholar 

  28. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000;65(1–2):271–84. Epub 2000/03/04.

    Article  PubMed  CAS  Google Scholar 

  29. Beschiaschvili G, Seelig J. Peptide binding to lipid bilayers. Nonclassical hydrophobic effect and membrane-induced pK shifts. Biochemistry. 1992;31(41):10044–53. Epub 1992/10/20.

    Article  PubMed  CAS  Google Scholar 

  30. Ahrens ET, Rothbacher U, Jacobs RE, Fraser SE. A model for MRI contrast enhancement using T1 agents. Proc Natl Acad Sci U S A. 1998;95(15):8443–8. Epub 1998/07/22.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

This work was funded in part by the Geoffrey Beene Cancer Research Center of MSKCC (JSL), the Office of Science (BER) - U.S. Department of Energy (Award DE-SC0002456; JSL). We thank Drs. Grimm, Blasberg, Pillarsetty, McDevitt and Le for their insights. We also acknowledge support provided by Mr. William H., Mrs. Alice Goodwin, the Commonwealth Foundation for Cancer Research and The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center. Finally, we would like to thank technical services provided by the MSKCC Small-Animal Imaging Core Facility.

Author information

Authors and Affiliations

  1. Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 16, New York, New York, 10065, USA

    Diane S. Abou, Daniel L. J. Thorek, Nicholas N. Ramos & Jason S. Lewis

  2. Radiochemistry & Imaging Sciences Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 16, New York, New York, 10065, USA

    Sean D. Carlin & Jason S. Lewis

  3. Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 16, New York, New York, 10065, USA

    Bradley J. Beattie

  4. Radiation and Isotopes for Health, Department of Radiation Radionuclides & Reactor, TU Delft, Mekelweg 15, 2629 JB, Delft, Netherlands

    Hubert T. Wolterbeek

  5. Analytical Biotechnology, Department Biotechnology, TU Delft, Julianalaan 67, 2628 BC, Delft, Netherlands

    Martijn W. H. Pinkse

Authors
  1. Diane S. Abou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel L. J. Thorek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicholas N. Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martijn W. H. Pinkse
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hubert T. Wolterbeek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sean D. Carlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bradley J. Beattie
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jason S. Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jason S. Lewis.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Material

LP purification, labeling efficiency, in vitro experiment, maximum intensity projection PET images, histology and autoradiography of tumors, as well as 24 and 96 h p.i. radioactive tissue distribution are included in supplementary material. (DOC 216 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abou, D.S., Thorek, D.L.J., Ramos, N.N. et al. 89Zr-Labeled Paramagnetic Octreotide-Liposomes for PET-MR Imaging of Cancer. Pharm Res 30, 878–888 (2013). https://doi.org/10.1007/s11095-012-0929-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-012-0929-8

KEY WORDS

Search

Navigation