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Hybrid 99mTc-magnetite tracer for dual modality sentinel lymph node mapping

  • Engineering and Nano-engineering Approaches for Medical Devices
  • Original Research
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Abstract

Accuracy of sentinel lymph node identification using radioactive tracers in non-superficial cancers can be limited by radiation shine through and low spatial resolution of detection systems such as intraoperative gamma probes. By utilising a dual radioactive/magnetic tracer, sensitive lymphoscintigraphy can be paired with high spatial resolution intraoperative magnetometer probes to improve the accuracy of sentinel node detection in cancers with complex multidirectional lymphatic drainage. Dextran-coated magnetite nanoparticles (33 nm mean hydrodynamic diameter) were labelled with 99mTc and applied as a lymphotropic tracer in small and large animal models. The dual tracer could be radiolabelled with 98 ± 2% efficiency after 10 min of incubation at room temperature. Biodistribution studies of the tracer were conducted in normal rats (subdermal and intravenous tail delivery, n = 3) and swine (subdermal hind limb delivery, n = 5). In rats the dual tracer migrated through four tiers of lymph node, 20 min after subdermal injection. Results from intravenous biodistribution test for radiocolloids demonstrated no aggregation in vivo, however indicated the presence of some lower-molecular weight radioactive impurities (99mTc-dextran). In swine, the dual tracer could be effectively used to map lymphatic drainage from hind hoof to popliteal and inguinal basins using intraoperative gamma and magnetometer probes. Of the eight primary nodes excised, eight were positively identified by gamma probe and seven by magnetometer probe. The high-purity dual tracer shows early promise for sentinel node identification in complex lymphatic environments by combining sensitive preoperative lymphoscintigraphy with a high-resolution intraoperative magnetometer probe.

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References

  1. Borgstein P, Pijpers R, Comans EF, van Diest PJ, Boom RP, Meijer S. Sentinel lymph node biopsy in breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg. 1998;186:275–83.

    Article  CAS  Google Scholar 

  2. Valdes Olmos RA, Hoefnagel CA, Nieweg OE, Jansen L, Rutgers EJ, Borger J, et al. Lymphoscintigraphy in oncology: a rediscovered challenge. Eur J Nucl Med. 1999;26:S2–S10.

    Article  CAS  Google Scholar 

  3. Van de Ven C, De Leyn P, Coosemans W, Van Raemdonck D, Lerut T. Three-field lymphadenectomy and pattern of lymph node spread in T3 adenocarcinoma of the distal esophagus and the gastro-esophageal junction. Eur J Cardio-Thorac Surg. 1999;15:769–73.

    Article  Google Scholar 

  4. Gretschel S, Bembenek A, Huenerbein M, Dresel S, Schneider W, Schlag PM. Efficacy of different technical procedures for sentinel lymph node biopsy in gastric cancer staging. Ann Surg Oncol. 2007;14:2028–35.

    Article  Google Scholar 

  5. Zanzonico P, Heller S. The intraoperative gamma probe: basic principles and choices available. Semin Nucl Med. 2000;30:33–48.

    Article  CAS  Google Scholar 

  6. Aarsvold JAN. Update on detection of sentinel lymph nodes in patients with breast cancer. Semin Nucl Med. 2005;35:116–28.

    Article  Google Scholar 

  7. Tsopelas C, Bevington E, Kollias J, Shibli S, Farshid G, Coventry B, et al. Tc-99-Evans blue dye for mapping contiguous lymph node sequences and discriminating the sentinel lymph node in an ovine model. Ann Surg Oncol. 2006;13:692–700.

    Article  Google Scholar 

  8. Van den Berg NS, Buckle T, GIJSH Kleinjan, WMC Klop, Horenblas S, Van der Poel HG, et al. Hybrid tracers for sentinel node biopsy. Q J Nucl Med Mol Imaging. 2014;58:193–206.

    Google Scholar 

  9. van der Poel HG, Buckle T, Brouwer OR, Olmos RAV, van Leeuwen FWB. Intraoperative laparoscopic fluorescence guidance to the sentinel lymph node in prostate cancer patients: clinical proof of concept of an integrated functional imaging approach using a multimodal tracer. Eur Urol. 2011;60:826–33.

    Article  Google Scholar 

  10. Nahrendorf M, Keliher E, Marinelli B, Waterman P, Feruglio PF, Fexon L, et al. Hybrid PET-optical imaging using targeted probes. Proc Natl Acad Sci USA. 2010;107:7910–5.

    Article  Google Scholar 

  11. Thorek DLJ, Ulmert D, Diop N-FM, Lupu ME, Doran MG, Huang R, et al. Non-invasive mapping of deep-tissue lymph nodes in live animals using a multimodal PET/MRI nanoparticle. Nat Commun 2014;5:3097.

  12. Glaus C, Rossin R, Welch MJ, Bao G. In vivo evaluation of (64)Cu-labeled magnetic nanoparticles as a dual-modality PET/MR imaging agent. Bioconjugate Chem. 2010;21:715–22.

    Article  CAS  Google Scholar 

  13. Madru R, Tran TA, Axelsson J, Ingvar C, Bibic A, Stahlberg F, et al. (68)Ga-labeled superparamagnetic iron oxide nanoparticles (SPIONs) for multi-modality PET/MR/Cherenkov luminescence imaging of sentinel lymph nodes. Am J Nucl Med Mol Imaging. 2013;4:60–9.

    Google Scholar 

  14. Xie J, Chen K, Huang J, Lee S, Wang J, Gao J, et al. PET/NIRF/MRI triple functional iron oxide nanoparticles. Biomaterials. 2010;31:3016–22.

    Article  CAS  Google Scholar 

  15. Lerman H, Metser U, Lievshitz G, Sperber F, Shneebaum S, Even-Sapir E. Lymphoscintigraphic sentinel node identification in patients with breast cancer: the role of SPECT-CT. Eur J Nucl Med Mol Imaging. 2006;33:329–37.

    Article  CAS  Google Scholar 

  16. Manca G, Volterrani D, Mazzarri S, Chondrogiannis S, Giammarile F, Rubello D, et al. Sentinel lymph node biopsy of oral/oropharyngeal squamous cell carcinoma techniques, indications, advantages, and accuracy. Clin Nucl Med. 2015;40:401–4.

    Article  Google Scholar 

  17. van den Berg N, Brouwer O, Klop WM, Karakullukcu B, Zuur C, Tan IB, et al. Concomitant radio- and fluorescence-guided sentinel lymph node biopsy in squamous cell carcinoma of the oral cavity using ICG-99mTc-nanocolloid. Eur Nucl Med Mol Imaging. 2012;39:1128–36.

    Article  CAS  Google Scholar 

  18. Cousins A, Balalis GL, Thompson SK, Morales DF, Mohtar A, Wedding AB, et al. Novel handheld magnetometer probe based on magnetic tunnelling junction sensors for intraoperative sentinel lymph node identification. Sci Rep 2015;5:10842.

  19. Douek M, Klaase J, Monypenny I, Kothari A, Zechmeister K, Brown D, et al. Sentinel node biopsy using a magnetic tracer versus standard technique: the SentiMAG multicentre trial. Ann Surg Oncol. 2014;21:1237–45.

    Article  Google Scholar 

  20. Minamiya Y, Ito M, Katayose Y, Saito H, Imai K, Sato Y, et al. Intraoperative sentinel lymph node mapping using a new sterilizable magnetometer in patients with nonsmall cell lung cancer. Ann Thorac Surg. 2006;81:327–30.

    Article  Google Scholar 

  21. Nakagawa T, Minamiya Y, Katayose Y, Saito H, Taguchi K, Imano H, et al. A novel method for sentinel lymph node mapping using magnetite in patients with non-small cell lung cancer. J Thorac Cardiovasc Surg. 2003;126:563–7.

    Article  Google Scholar 

  22. Shiozawa M, Lefor A, Hozumi Y, Kurihara K, Sata N, Yasuda Y, et al. Sentinel lymph node biopsy in patients with breast cancer using superparamagnetic iron oxide and a magnetometer. Ann Surg Oncol. 2010;17:S59–S.

    Google Scholar 

  23. Winter A, Woenkhaus J, Wawroschek F. A novel method for intraoperative sentinel lymph node detection in prostate cancer patients using superparamagnetic iron oxide nanoparticles and a handheld magnetometer: the initial clinical experience. Ann Surg Oncol. 2014;21:4390–6.

    Article  Google Scholar 

  24. Tsopelas C. Particle size analysis of Tc-99m-labeled and unlabeled antimony trisulfide and rhenium sulfide colloids intended for lymphoscintigraphic application. J Nucl Med. 2001;42:460–6.

    CAS  Google Scholar 

  25. Kobayashi H, Kawamoto S, Bernardo M, Brechbiel MW, Knopp MV, Choyke PL. Delivery of gadolinium-labeled nanoparticles to the sentinel lymph node: comparison of the sentinel node visualization and estimations of intra-nodal gadolinium concentration by the magnetic resonance imaging. J Control Release. 2006;111:343–51.

    Article  CAS  Google Scholar 

  26. Polom K, Murawa D, Rho YS, Nowaczyk P, Hunerbein M, Murawa P. Current trends and emerging future of indocyanine green usage in surgery and oncology: a literature review. Cancer. 2011;117:4812–22.

    Article  Google Scholar 

  27. Pouw JJ, Ahmed M, Anninga B, Schuurman K, Pinder SE, Van Hemelrijck M, et al. Comparison of three magnetic nanoparticle tracers for sentinel lymph node biopsy in an in vivo porcine model. Int J Nanomed. 2015;10:1235–43.

    Article  CAS  Google Scholar 

  28. Pinero-Madrona A, Torro-Richart JA, de Leon-Carrillo JM, de Castro-Parga G, Navarro-Cecilia J, Dominguez-Cunchillos F, et al. Superparamagnetic iron oxide as a tracer for sentinel node biopsy in breast cancer: a comparative non-inferiority study. EJSO. 2015;41:991–7.

    Article  CAS  Google Scholar 

  29. Pouw JJ, Grootendorst MR, Bezooijen R, Klazen CAH, De Bruin WI, Klaase JM, et al. Pre-operative sentinel lymph node localization in breast cancer with superparamagnetic iron oxide MRI: the SentiMAG multicentre trial imaging subprotocol. Br J Radiol 2015;88:20150634.

  30. OECD. Medical technology database (stat.), OECD; 2016.

  31. Bouziotis P, Psimadas D, Tsotakos T, Stamopoulos D, Tsoukalas C. Radiolabeled iron oxide nanoparticles as dual-modality SPECT/MRI and PET/MRI agents. Curr Top Med Chem. 2012;12:2694–702.

    Article  CAS  Google Scholar 

  32. Ferro-Flores G, Ocampo-Garcia BE, Santos-Cuevas CL, Morales-Avila E, Azorin-Vega E. Multifunctional radiolabeled nanoparticles for targeted therapy. Curr Med Chem. 2014;21:124–38.

    Article  CAS  Google Scholar 

  33. Fu CM, Wang YF, Chao YC, Hung SH, Yang MD. Directly labeling ferrite nanoparticles with Tc-99m radioisotope for diagnostic applications. IEEE Trans Magn. 2004;40:3003–5.

    Article  CAS  Google Scholar 

  34. Madru R, Kjellman P, Olsson F, Wingardh K, Ingvar C, Stahlberg F, et al. Tc-99m-labeled superparamagnetic iron oxide nanoparticles for multimodality SPECT/MRI of sentinel lymph nodes. J Nucl Med. 2012;53:459–63.

    Article  CAS  Google Scholar 

  35. Wang A-Y, Kuo C-L, Lin J-L, Fu C-M, Wang Y-F. Study of magnetic ferrite nanoparticles labeled with Tc-99m-pertechnetate. J Radioanal Nucl Chem. 2010;284:405–13.

    Article  CAS  Google Scholar 

  36. Henze E, Robinson GD, Kuhl DE, Schelbert HR. Tc-99m dextran: a new blood-pool-labeling agent for radionuclide angiocardiography. J Nucl Med. 1982;23:348–53.

    CAS  Google Scholar 

  37. Technetium (99mTc) colloidal sulphur injection. Ph Eur 5.0 ed.: Council of Europe, 2004.

  38. Saar L, Getty R. The lymph nodes and the lymph vessels of the abdominal wall, pelvic wall and the pelvic limb of swine. Iowa State Univ Vet. 1963;26:9.

    Google Scholar 

  39. Henze E, Schelbert HR, Collins JD, Najafi A, Barrio JR, Bennett LR. Lymphoscintigraphy with Tc-99m-labeled dextran. J Nucl Med. 1982;23:923–9.

    CAS  Google Scholar 

  40. Matsunaga K, Hara K, Imamura T, Fujioka T, Takata J, Karube Y. Technetium labeling of dextran incorporating cysteamine as a ligand. Nucl Med Biol. 2005;32:279–85.

    Article  CAS  Google Scholar 

  41. Shanehsazzadeh S, Lahooti A. Biodistribution of 80 nm iron oxide nanoparticles labeled with Tc-99m in Balb/c mice. Nucl Med Biol. 2014;41:625.

    Article  Google Scholar 

  42. Shanehsazzadeh S, Oghabian MA, Daha FJ, Amanlou M, Allen BJ. Biodistribution of ultra small superparamagnetic iron oxide nanoparticles in BALB mice. J Radioanal Nucl Chem. 2013;295:1517–23.

    Article  CAS  Google Scholar 

  43. Bellin MF, Beigelman C, Precetti-Morel S. Iron oxide-enhanced MR lymphography: initial experience. Eur J Radiol. 2000;34:257–64.

    Article  CAS  Google Scholar 

  44. Orsini F, Lorenzoni A, Erba PA, Mariani G. Radiopharmaceuticals for single-photon emission imaging and for therapy. In: Strauss HW, Mariani G, Volterrani D, Larson SM, editors. Nuclear oncology: pathophysiology and clinical applications. New York, NY: Springer Science & Business Media; 2012. pp. 21–34.

  45. Tsopelas C. Lymphoscintigraphy is more effective using higher specific activity Tc-99m-antimony trisulfide colloid in the rat. Hell J Nucl Med. 2014;17:19–26.

    Google Scholar 

  46. Ercan MT, Schneidereit M, Senekowitsch R, Kriegel H. Evaluation of Tc-99m-dextran as a lymphoscintigraphic agent in rabbits. Eur J Nucl Med. 1985;11:80–4.

    CAS  Google Scholar 

  47. Tsopelas C,Penglis S, Visualisation of lymphatic flow in a rabbit model using six 99 Tc m-blue dyes. ANZ Nucl Med. 2000;31:135

    Google Scholar 

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Acknowledgements

This work was supported by the NHMRC Project [grant number APP1045841]. BT is supported by a NHMRC CDF Fellowship. The authors acknowledge the support of the South Australian Health and Medical Research Institute node of the National Imaging Facility.

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Correspondence to Benjamin Thierry.

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Cousins, A., Tsopelas, C., Balalis, G. et al. Hybrid 99mTc-magnetite tracer for dual modality sentinel lymph node mapping. J Mater Sci: Mater Med 29, 76 (2018). https://doi.org/10.1007/s10856-018-6080-2

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