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Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab-Modified Gold Nanoparticles Labeled with 177Lu

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ABSTRACT

Purpose

To compare the effectiveness of trastuzumab-modified gold nanoparticles (AuNP) labeled with 177Lu (trastuzumab-AuNP-177Lu) targeted to HER2 with non-targeted AuNP-177Lu for killing HER2-overexpressing breast cancer (BC) cells in vitro and inhibiting tumor growth in vivo following intratumoral (i.t.) injection.

Methods

AuNP (30 nm) were modified with polyethylene glycol (PEG) polymers linked to trastuzumab or to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex 177Lu. The binding and internalization of trastuzumab-AuNP-177Lu in HER2-positive SK-BR-3, BT-474 and MDA-MB-361 human BC cells were studied. Clonogenic survival and DNA double-strand breaks (DSBs) were measured after exposure of SK-BR-3 or MDA-MB-361 cells to trastuzumab-AuNP-177Lu or AuNP-177Lu. NOD/SCID mice with s.c. MDA-MB-361 tumor xenografts were treated by i.t. injection of 3 MBq (0.15 mg) of trastuzumab-AuNP-177Lu, AuNP-177Lu or normal saline. Tumor growth was measured over 16 days and normal tissue toxicity evaluated.

Results

Trastuzumab-AuNP-177Lu was bound and internalized by HER2 positive BC cells (KD = 7.6 ± 2.0 nM). Trastuzumab-AuNP-177Lu was 42.9 and 2.6-fold more effective than AuNP-177Lu at decreasing the clonogenic survival of SK-BR-3 (1.3 × 106 HER2/cell) and MDA-MB-361 (5.1 × 105 HER2/cell) cells, respectively, exposed overnight to these agents (1.5 nM; 20 MBq/mg Au). Under the same treatment conditions, 10-fold and 2.8-fold more DNA DSBs were observed in SK-BR-3 and MDA-MB-361 cells, respectively, exposed to trastuzumab-AuNP-177Lu than AuNP-177Lu. Trastuzumab-AuNP-177Lu was 1.8-fold more effective at inhibiting tumor growth than AuNP-177Lu. No or minimal normal tissue toxicity was observed for trastuzumab-AuNP-177Lu or AuNP-177Lu treatments.

Conclusion

Trastuzumab-AuNP-177Lu enables an efficient local radiation treatment of HER2-positive BC.

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Abbreviations

ALT:

Alanine aminotransferase

AuNP:

Gold nanoparticles

BC:

Breast cancer

Bmax :

Maximum number of binding sites

BSA:

Bovine serum albumin

BWI:

Body weight index

Cr:

Creatinine

DAPI:

4’, 6-diamidino-2-phenylindole

DOTA:

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

DSBs:

Double-strand breaks

EGFR:

Epidermal growth factor receptors

Hb:

Hemoglobin

Hct:

Hematocrit

HER2:

Human epidermal growth factor receptor 2

KD :

Dissociation constant

LABC:

Locally-advanced breast cancer

NOD/SCID:

Non-obese diabetic/severe combined immunodeficient

NSB:

Non-specific binding

OPSS:

Orthopyridyldisulfide-polyethylene glycol-N-hydroxysuccinimide

PBS:

Phosphate Buffered Saline

pCR:

Pathology complete response

PE:

Plating efficiency

PEG:

Polyethylene glycol

RBC:

Red blood cell

s.c.:

Subcutaneous

SB:

Specific binding

SEM:

Standard error of mean

SF:

Surviving fraction

SVA:

Succinimidyl valerate

t1/2 :

Half life

TB:

Total binding

TEM:

Transmission electron microscopy

TGI:

Tumor growth index

WBC:

White blood cell

References

  1. Nystrom L, Andersson I, Bjurstam N, Frisell J, Nordenskjold B, Rutqvist LE. Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet. 2002;359(9310):909–19.

    Article  PubMed  Google Scholar 

  2. Early Breast Cancer Trialists’ Collaborative G, Darby S, McGale P, Correa C, Taylor C, Arriagada R, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804):1707–16.

    Article  Google Scholar 

  3. Yalcin B. Overview on locally advanced breast cancer: defining, epidemiology, and overview on neoadjuvant therapy. Exp Oncol. 2013;35(4):250–2.

    CAS  PubMed  Google Scholar 

  4. Simos D, Clemons M, Ginsburg OM, Jacobs C. Definition and consequences of locally advanced breast cancer. Curr Opin Support Pallliat Care. 2014;8(1):33–8.

    Article  Google Scholar 

  5. Giordano SH. Update on locally advanced breast cancer. Oncologist. 2003;8(6):521–30.

    Article  PubMed  Google Scholar 

  6. Ferriere JP, Assier I, Cure H, Charrier S, Kwiatkowski F, Achard JL, et al. Primary chemotherapy in breast cancer: correlation between tumor response and patient outcome. Am J Clin Oncol. 1998;21(2):117–20.

    Article  CAS  PubMed  Google Scholar 

  7. Semiglazov V, Eiermann W, Zambetti M, Manikhas A, Bozhok A, Lluch A, et al. Surgery following neoadjuvant therapy in patients with HER2-positive locally advanced or inflammatory breast cancer participating in the NeOAdjuvant Herceptin (NOAH) study. Eur J Surg Oncol. 2011;37(10):856–63.

    Article  CAS  PubMed  Google Scholar 

  8. Adams S, Chakravarthy AB, Donach M, Spicer D, Lymberis S, Singh B, et al. Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival. Breast Cancer Res Treat. 2010;124(3):723–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Roddiger SJ, Kolotas C, Filipowicz I, Kurek R, Kuner RP, Martin T, et al. Neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with systemic chemotherapy in patients with breast cancer. Strahlenther Onkol. 2006;182(1):22–9.

    Article  PubMed  Google Scholar 

  10. Yook S, Cai Z, Lu Y, Winnik MA, Pignol JP, Reilly RM. Intratumorally injected 177Lu-labeled gold nanoparticles: gold nanoseed brachytherapy with application for neoadjuvant treatment of locally advanced breast cancer. J Nucl Med. 2016;57(6):936–42.

    Article  PubMed  Google Scholar 

  11. Meyers MO, Klauber-Demore N, Ollila DW, Amos KD, Moore DT, Drobish AA, et al. Impact of breast cancer molecular subtypes on locoregional recurrence in patients treated with neoadjuvant chemotherapy for locally advanced breast cancer. Ann Surg Oncol. 2011;18(10):2851–7.

    Article  PubMed  Google Scholar 

  12. Burness ML, Grushko TA, Olopade O. Epidermal growth factor receptor in triple-negative and basal-like breast cancer: promising clinical target or only a marker? Cancer J. 2010;16:23–32.

    Article  CAS  PubMed  Google Scholar 

  13. Yook S, Cai Z, Lu Y, Winnik MA, Pignol JP, Reilly RM. Radiation nanomedicine for EGFR-positive breast cancer: panitumumab-modified gold nanoparticles complexed to the β-particle-emitter, 177Lu. Mol Pharm. 2015;12:3963–72.

    Article  CAS  PubMed  Google Scholar 

  14. Zell JA, Tsang WY, Taylor TH, Mehta RS, Anton-Culver H. Prognostic impact of human epidermal growth factor-like receptor 2 and hormone receptor status in inflammatory breast cancer (IBC): analysis of 2,014 IBC patient cases from the California Cancer Registry. Breast Cancer Res. 2009;11(1):R9.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Miglietta L, Vanella P, Canobbio L, Parodi MA, Guglielmini P, Boccardo F. Clinical and pathological response to primary chemotherapy in patients with locally advanced breast cancer grouped according to hormonal receptors, Her2 status, grading and Ki-67 proliferation index. Anticancer Res. 2009;29(5):1621–5.

    PubMed  Google Scholar 

  16. Onitilo AA, Engel JM, Greenlee RT, Mukesh BN. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res. 2009;7(1–2):4–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McLarty K, Cornelissen B, Scollard DA, Done SJ, Chun K, Reilly RM. Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts. Eur J Nucl Med Mol Imaging. 2009;36(1):81–93.

    Article  CAS  PubMed  Google Scholar 

  18. Cai Z, Chattopadhyay N, Liu WJ, Chan C, Pignol JP, Reilly RM. Optimized digital counting colonies of clonogenic assays using image J software and customized macros: comparison with manual counting. Int J Radiat Biol. 2011;87(11):1135–46.

    Article  CAS  PubMed  Google Scholar 

  19. Mah LJ, Orlowski C, Ververis K, El-Osta A, Karagiannis TC. Utility of gammaH2AX as a molecular marker of DNA double-strand breaks in nuclear medicine: applications to radionuclide therapy employing auger electron-emitting isotopes. Curr Radiopharm. 2011;4(1):59–67.

    Article  CAS  PubMed  Google Scholar 

  20. Cai Z, Vallis KA, Reilly RM. Computational analysis of the number, area and density of gamma-H2AX foci in breast cancer cells exposed to 111In-DTPA-hEGF or gamma-rays using Image-J software. Int J Radiat Biol. 2009;85(3):262–71.

    Article  CAS  PubMed  Google Scholar 

  21. Zhu W, Okollie B, Artemov D. Controlled internalization of Her-2/neu receptors by cross-linking for targeted delivery. Cancer Biol Ther. 2007;6(12):1960–6.

    Article  CAS  PubMed  Google Scholar 

  22. Hapuarachchige S, Zhu W, Kato Y, Artemov D. Bioorthogonal, two-component delivery systems based on antibody and drug-loaded nanocarriers for enhanced internalization of nanotherapeutics. Biomaterials. 2014;35(7):2346–54.

    Article  CAS  PubMed  Google Scholar 

  23. Jiang W, Kim BY, Rutka JT, Chan WC. Nanoparticle-mediated cellular response is size-dependent. Nat Nanotechnol. 2008;3(3):145–50.

    Article  CAS  PubMed  Google Scholar 

  24. Chattopadhyay N, Cai Z, Kwon YL, Lechtman E, Pignol JP, Reilly RM. Molecularly targeted gold nanoparticles enhance the radiation response of breast cancer cells and tumor xenografts to X-radiation. Breast Cancer Res Treat. 2013;137(1):81–91.

    Article  CAS  PubMed  Google Scholar 

  25. Chattopadhyay N, Fonge H, Cai Z, Scollard D, Lechtman E, Done SJ, et al. Role of antibody-mediated tumor targeting and route of administration in nanoparticle tumor accumulation in vivo. Mol Pharm. 2012;9:2168–79.

    CAS  PubMed  Google Scholar 

  26. Shukla R, Chanda N, Zambre A, Upendran A, Katti K, Kulkarni RR, et al. Laminin receptor specific therapeutic gold nanoparticles (198AuNP-EGCg) show efficacy in treating prostate cancer. Proc Natl Acad Sci U S A. 2012;109(31):12426–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vilchis-Juarez A, Ferro-Flores G, Santos-Cuevas C, Morales-Avila E, Ocampo-Garcia B, Diaz-Nieto L, et al. Molecular targeting radiotherapy with cyclo-RGDFK (C) peptides conjugated to 177Lu-labeled gold nanoparticles in tumor-bearing mice. J Biomed Nanotechnol. 2014;10(3):393–404.

    Article  CAS  PubMed  Google Scholar 

  28. Pignol JP, Keller BM, Ravi A. Doses to internal organs for various breast radiation techniques--implications on the risk of secondary cancers and cardiomyopathy. Radiat Oncol. 2011;6:5.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lai P, Lechtman E, Mashouf S, Pignol JP, Reilly RM. Depot system for controlled release of gold nanoparticles with precise intratumoral placement by permanent brachytherapy seed implantation (PSI) techniques. Int J Pharm. 2016;515(1–2):729–39.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by a grant from the Canadian Breast Cancer Foundation (CBCF) to R.M. Reilly. S. Yook received an Ontario Graduate Scholarship (OGS), a scholarship from the Terry Fox Foundation Strategic Initiative for Excellence in Radiation Research for the 21st Century (EIRR21) and a Pharmaceutical Sciences Graduate Student Association Fellowship (GSEF). This research was presented in part at the European Association of Nuclear Medicine (EANM) Congress in Gothenburg, Sweden, October 18–22, 2014.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 3M2, Canada

    Zhongli Cai, Simmyung Yook, Dane Bergstrom & Raymond M. Reilly

  2. College of Pharmacy, Keimyung University, Daegu, South Korea

    Simmyung Yook

  3. Department of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6, Canada

    Yijie Lu & Mitchell A. Winnik

  4. Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands

    Jean-Philippe Pignol

  5. Department of Medical Imaging, University of Toronto, Toronto, Ontario, M5T 1W7, Canada

    Raymond M. Reilly

  6. Toronto General Research Institute and Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, M5G 1L7, Canada

    Raymond M. Reilly

  7. Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St, Toronto, Ontario, M5S 3M2, Canada

    Raymond M. Reilly

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  1. Zhongli Cai
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  2. Simmyung Yook
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  6. Jean-Philippe Pignol
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  7. Raymond M. Reilly
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Correspondence to Raymond M. Reilly.

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Cai, Z., Yook, S., Lu, Y. et al. Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab-Modified Gold Nanoparticles Labeled with 177Lu. Pharm Res 34, 579–590 (2017). https://doi.org/10.1007/s11095-016-2082-2

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  • DOI: https://doi.org/10.1007/s11095-016-2082-2

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