Therapeutic efficacy and toxicity of 225Ac-labelled vs. 213Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis

  • Markus Essler
  • Florian C. Gärtner
  • Frauke Neff
  • Birgit Blechert
  • Reingard Senekowitsch-Schmidtke
  • Frank Bruchertseifer
  • Alfred Morgenstern
  • Christof Seidl
Original Article

Abstract

Purpose

Targeted delivery of alpha-particle-emitting radionuclides is a promising novel option in cancer therapy. We generated stable conjugates of the vascular tumour-homing peptide F3 both with 225Ac and 213Bi that specifically bind to nucleolin on the surface of proliferating tumour cells. The aim of our study was to determine the therapeutic efficacy of 225Ac-DOTA-F3 in comparison with that of 213Bi-DTPA-F3.

Methods

ID50 values of 213Bi-DTPA-F3 and 225Ac-DOTA-F3 were determined via clonogenic assays. The therapeutic efficacy of both constructs was assayed by repeated treatment of mice bearing intraperitoneal MDA-MB-435 xenograft tumours. Therapy was monitored by bioluminescence imaging. Nephrotoxic effects were analysed by histology.

Results

ID50 values of 213Bi-DTPA-F3 and 225Ac-DOTA-F3 were 53 kBq/ml and 67 Bq/ml, respectively. The median survival of control mice treated with phosphate-buffered saline was 60 days after intraperitoneal inoculation of 1 × 107 MDA-MB-435 cells. Therapy with 6 × 1.85 kBq of 225Ac-DOTA-F3 or 6 × 1.85 MBq of 213Bi-DTPA-F3 prolonged median survival to 95 days and 97 days, respectively. While F3 labelled with short-lived 213Bi (t1/2 46 min) reduced the tumour mass at early time-points up to 30 days after treatment, the antitumour effect of 225Ac-DOTA-F3 (t1/2 10 days) increased at later time-points. The difference in the fraction of necrotic cells after treatment with 225Ac-DOTA-F3 (43%) and with 213Bi-DTPA-F3 (36%) was not significant. Though histological analysis of kidney samples revealed acute tubular necrosis and tubular oedema in 10–30% of animals after treatment with 225Ac-DOTA-F3 or 213Bi-DTPA-F3, protein casts were negligible (2%), indicating only minor damage to the kidney.

Conclusion

Therapy with both 225Ac-DOTA-F3 and 213Bi-DTPA-F3 increased survival of mice with peritoneal carcinomatosis. Mild renal toxicity of both constructs favours future therapeutic application.

Keywords

Targeted radionuclide therapy Phage display Tumour-homing peptide F3 Peritoneal carcinomatosis α-emitters 225Ac and 213Bi 

References

  1. 1.
    Li Y, Song E, Abbas Rizvi SM, Power CA, Beretov J, Raja C, et al. Inhibition of micrometastatic prostate cancer cell spread in animal models by 213Bi-labeled multiple targeted alpha radioimmunoconjugates. Clin Cancer Res. 2009;15:865–75.PubMedCrossRefGoogle Scholar
  2. 2.
    Wild D, Frischknecht M, Zhang H, Morgenstern A, Bruchertseifer F, Boisclair J, et al. Alpha- versus beta-particle radiopeptide therapy in a human prostate cancer model (213Bi-DOTA-PESIN and 213Bi-AMBA versus 177Lu-DOTA-PESIN). Cancer Res. 2011;71:1009–18.PubMedCrossRefGoogle Scholar
  3. 3.
    Knör S, Sato S, Huber T, Morgenstern A, Bruchertseifer F, Schmitt M, et al. Development and evaluation of peptidic ligands targeting tumour-associated urokinase plasminogen activator receptor (uPAR) for use in alpha-emitter therapy for disseminated ovarian cancer. Eur J Nucl Med Mol Imaging. 2008;35:53–64.PubMedCrossRefGoogle Scholar
  4. 4.
    Elgqvist J, Andersson H, Jensen H, Kahu H, Lindegren S, Warnhammar E, et al. Repeated intraperitoneal alpha-radioimmunotherapy of ovarian cancer in mice. J Oncol. 2010;2010:394913.PubMedGoogle Scholar
  5. 5.
    Drecoll E, Gaertner FC, Miederer M, Blechert B, Vallon M, Müller JM, et al. Treatment of peritoneal carcinomatosis by targeted delivery of the radio-labeled tumor homing peptide 213Bi-DTPA-[F3]2 into the nucleus of tumor cells. PLoS One. 2009;4:e5715.PubMedCrossRefGoogle Scholar
  6. 6.
    Song H, Hobbs RF, Vajravelu R, Huso DL, Esaias C, Apostolidis C, et al. Radioimmunotherapy of breast cancer metastases with alpha-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y. Cancer Res. 2009;69:8941–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Lingappa M, Song H, Thompson S, Bruchertseifer F, Morgenstern A, Sgouros G. Immunoliposomal delivery of 213Bi for alpha-emitter targeting of metastatic breast cancer. Cancer Res. 2010;70:6815–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Pfost B, Seidl C, Autenrieth M, Saur D, Bruchertseifer F, Morgenstern A, et al. Intravesical alpha-radioimmunotherapy with 213Bi-anti-EGFR-mAb defeats human bladder carcinoma in xenografted nude mice. J Nucl Med. 2009;50:1700–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Milenic DE, Brady ED, Garmestani K, Albert PS, Abdulla A, Brechbiel MW. Improved efficacy of alpha-particle-targeted radiation therapy: dual targeting of human epidermal growth factor receptor-2 and tumor-associated glycoprotein 72. Cancer. 2010;116(4 Suppl):1059–66.PubMedCrossRefGoogle Scholar
  10. 10.
    Bloechl S, Beck R, Seidl C, Morgenstern A, Schwaiger M, Senekowitsch-Schmidtke R. Fractionated locoregional low-dose radioimmunotherapy improves survival in a mouse model of diffuse-type gastric cancer using a 213Bi-conjugated monoclonal antibody. Clin Cancer Res. 2005;11(19 Pt 2):7070s–4s.PubMedCrossRefGoogle Scholar
  11. 11.
    Beck R, Seidl C, Pfost B, Morgenstern A, Bruchertseifer F, Baum H, et al. 213Bi-radioimmunotherapy defeats early-stage disseminated gastric cancer in nude mice. Cancer Sci. 2007;98:1215–22.PubMedCrossRefGoogle Scholar
  12. 12.
    Dahle J, Jonasdottir TJ, Heyerdahl H, Nesland JM, Borrebaek J, Hjelmerud AK, et al. Assessment of long-term radiotoxicity after treatment with the low-dose-rate alpha-particle-emitting radioimmunoconjugate (227)Th-rituximab. Eur J Nucl Med Mol Imaging. 2010;37:93–102.PubMedCrossRefGoogle Scholar
  13. 13.
    Park SI, Shenoi J, Pagel JM, Hamlin DK, Wilbur DS, Orgun N, et al. Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease. Blood. 2010;116:4231–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Norenberg JP, Krenning BJ, Konings IR, Kusewitt DF, Nayak TK, Anderson TL, et al. 213Bi-[DOTA0,Tyr3]octreotide peptide receptor radionuclide therapy of pancreatic tumors in a preclinical animal model. Clin Cancer Res. 2006;12(3 Pt 1):897–903.PubMedCrossRefGoogle Scholar
  15. 15.
    Miederer M, Henriksen G, Alke A, Mossbrugger I, Quintanilla-Martinez L, Senekowitsch-Schmidtke R, et al. Preclinical evaluation of the alpha-particle generator nuclide 225Ac for somatostatin receptor radiotherapy of neuroendocrine tumors. Clin Cancer Res. 2008;14:3555–61.PubMedCrossRefGoogle Scholar
  16. 16.
    Escorcia FE, Henke E, McDevitt MR, Villa CH, Smith-Jones P, Blasberg RG, et al. Selective killing of tumor neovasculature paradoxically improves chemotherapy delivery to tumors. Cancer Res. 2010;70:9277–86.PubMedCrossRefGoogle Scholar
  17. 17.
    Nakamae H, Wilbur DS, Hamlin DK, Thakar MS, Santos EB, Fisher DR, et al. Biodistributions, myelosuppression, and toxicities in mice treated with an anti-CD45 antibody labeled with the alpha-emitting radionuclides bismuth-213 or astatine-211. Cancer Res. 2009;69:2408–15.PubMedCrossRefGoogle Scholar
  18. 18.
    Raja C, Graham P, Abbas Rizvi SM, Song E, Goldsmith H, Thompson J, et al. Interim analysis of toxicity and response in phase 1 trial of systemic targeted alpha therapy for metastatic melanoma. Cancer Biol Ther. 2007;6:846–52.PubMedCrossRefGoogle Scholar
  19. 19.
    Zalutsky MR, Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, et al. Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81 C6. J Nucl Med. 2008;49:30–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Cordier D, Forrer F, Bruchertseifer F, Morgenstern A, Apostolidis C, Good S, et al. Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8, Met(O2)11]-substance P: a pilot trial. Eur J Nucl Med Mol Imaging. 2010;37:1335–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Rosenblat TL, McDevitt MR, Mulford DA, Pandit-Taskar N, Divgi CR, Panageas KS, et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res. 2010;16:5303–11.PubMedCrossRefGoogle Scholar
  22. 22.
    Andersson H, Cederkrantz E, Bäck T, Divgi C, Elgqvist J, Himmelman J, et al. Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(ab')2 – a phase I study. J Nucl Med. 2009;50:1153–60.PubMedCrossRefGoogle Scholar
  23. 23.
    Schwartz J, Jaggi JS, O’Donoghue JA, Ruan S, McDevitt M, Larson SM, et al. Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody. Phys Med Biol. 2011;56:721–33.PubMedCrossRefGoogle Scholar
  24. 24.
    McDevitt MR, Ma D, Lai LT, Simon J, Borchardt P, Frank RK, et al. Tumor therapy with targeted atomic nanogenerators. Science. 2001;294:1537–40.PubMedCrossRefGoogle Scholar
  25. 25.
    Apostolidis C, Molinet R, Rasmussen G, Morgenstern A. Production of Ac-225 from Th-229 for targeted alpha therapy. Anal Chem. 2005;77:6288–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Apostolidis C, Molinet R, McGinley J, Abbas K, Möllenbeck J, Morgenstern A. Cyclotron production of Ac-225 for targeted alpha therapy. Appl Radiat Isot. 2005;62:383–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Christian S, Pilch J, Akerman ME, Porkka K, Laakkonen P, Ruoslahti E. Nucleolin expressed at the cell surface is a marker of endothelial cells in angiogenic blood vessels. J Cell Biol. 2003;163:871–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Chouin N, Bernardeau K, Davodeau F, Cherel M, Faivre-Chauvet A, Bourgeois M, et al. Evidence of extranuclear cell sensitivity to alpha-particle radiation using a microdosimetric model. I. Presentation and validation of a microdosimetric model. Radiat Res. 2009;171:657–63.PubMedCrossRefGoogle Scholar
  29. 29.
    Nicolas G, Giovacchini G, Müller-Brand J, Forrer F. Targeted radiotherapy with radiolabeled somatostatin analogs. Endocrinol Metab Clin North Am. 2011;40:187–204.PubMedCrossRefGoogle Scholar
  30. 30.
    Kwekkeboom DJ, de Herder WW, Krenning EP. Somatostatin receptor-targeted radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40:173–85.PubMedCrossRefGoogle Scholar
  31. 31.
    Correia JD, Paulo A, Raposinho PD, Santos I. Radiometallated peptides for molecular imaging and targeted therapy. Dalton Trans. 2011;40:6144–67.PubMedCrossRefGoogle Scholar
  32. 32.
    Lin FI, Iagaru A. Current concepts and future directions in radioimmunotherapy. Curr Drug Discov Technol. 2010;7:253–62.PubMedCrossRefGoogle Scholar
  33. 33.
    Sharkey RM, Goldenberg DM. Cancer radioimmunotherapy. Immunotherapy. 2011;3:349–70.PubMedCrossRefGoogle Scholar
  34. 34.
    Song H, Sgouros G. Radioimmunotherapy of solid tumors: searching for the right target. Curr Drug Deliv. 2011;8:26–44.PubMedCrossRefGoogle Scholar
  35. 35.
    Seidl C, Zöckler C, Beck R, Quintanilla-Martinez L, Bruchertseifer F, Senekowitsch-Schmidtke R. 177Lu-immunotherapy of experimental peritoneal carcinomatosis shows comparable effectiveness to 213Bi-immunotherapy, but causes toxicity not observed with 213Bi. Eur J Nucl Med Mol Imaging. 2011;38:312–22.PubMedCrossRefGoogle Scholar
  36. 36.
    Jaggi JS, Seshan SV, McDevitt MR, LaPerle K, Sgouros G, Scheinberg DA. Renal tubulointerstitial changes after internal irradiation with alpha-particle-emitting actinium daughters. J Am Soc Nephrol. 2005;16:2677–89.PubMedCrossRefGoogle Scholar
  37. 37.
    Jaggi JS, Seshan SV, McDevitt MR, Sgouros G, Hyjek E, Scheinberg DA. Mitigation of radiation nephropathy after internal alpha-particle irradiation of kidneys. Int J Radiat Oncol Biol Phys. 2006;64:1503–12.PubMedCrossRefGoogle Scholar
  38. 38.
    Jaggi JS, Kappel BJ, McDevitt MR, Sgouros G, Flombaum CD, Cabassa C, et al. Efforts to control the errant products of a targeted in vivo generator. Cancer Res. 2005;65:4888–95.PubMedCrossRefGoogle Scholar
  39. 39.
    Woodward J, Kennel SJ, Stuckey A, Osborne D, Wall J, Rondinone AJ, et al. LaPO4 nanoparticles doped with actinium-225 that partially sequester daughter radionuclides. Bioconjug Chem. 2011;22:766–76.PubMedCrossRefGoogle Scholar
  40. 40.
    Seidl C, Schröck H, Seidenschwang S, Beck R, Schmid E, Abend M, et al. Cell death triggered by alpha-emitting 213Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death. Eur J Nucl Med Mol Imaging. 2005;32:274–85.PubMedCrossRefGoogle Scholar
  41. 41.
    Seidl C, Port M, Gilbertz KP, Morgenstern A, Bruchertseifer F, Schwaiger M, et al. 213Bi-induced death of HSC45-M2 gastric cancer cells is characterized by G2 arrest and up-regulation of genes known to prevent apoptosis but induce necrosis and mitotic catastrophe. Mol Cancer Ther. 2007;6:2346–59.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Markus Essler
    • 1
  • Florian C. Gärtner
    • 1
  • Frauke Neff
    • 2
  • Birgit Blechert
    • 1
  • Reingard Senekowitsch-Schmidtke
    • 1
  • Frank Bruchertseifer
    • 3
  • Alfred Morgenstern
    • 3
  • Christof Seidl
    • 1
  1. 1.Department of Nuclear MedicineTechnische Universität MünchenMunichGermany
  2. 2.Institute of PathologyHelmholtz Zentrum MünchenNeuherbergGermany
  3. 3.European Commission, Joint Research CentreInstitute for Transuranium ElementsKarlsruheGermany

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