Targeted Herceptin–dextran iron oxide nanoparticles for noninvasive imaging of HER2/neu receptors using MRI

  • Ting-Jung Chen
  • Tsan-Hwang Cheng
  • Chiao-Yun Chen
  • Sodio C. N. Hsu
  • Tian-Lu Cheng
  • Gin-Chung Liu
  • Yun-Ming Wang
Original Paper


A novel magnetic resonance imaging (MRI) contrast agent containing Herceptin is reported. The surfaces of superparamagnetic iron oxide nanoparticles were modified with dextran and conjugated with Herceptin (Herceptin–nanoparticles) to improve their dispersion, magnetization, and targeting of the specific receptors on cells. From analytical results, we found that Herceptin–nanoparticles were well dispersed in solutions of various pH range, and had no hysteresis, high saturation magnetization (80 emu/g), and low cytotoxicity to a variety of cells. Notably, the magnetic resonance enhancements for the different breast cancer cell lines (BT-474, SKBR-3, MDA-MB-231, and MCF-7) are proportional to the HER2/neu expression level in vitro. When Herceptin–nanoparticles were administered to mice bearing breast tumor allograft by intravenous injection, the tumor site was detected in T2-weighted magnetic resonance images as a 45% enhancement drop, indicating a high level of accumulation of the contrast agent within the tumor sites. Therefore, targeting of cancer cells was observed by in vitro and in vivo MRI studies using Herceptin–nanoparticles contrast agent. In addition, Herceptin–nanoparticles enhancing the magnetic resonance signal intensity were sufficient to detect the cell lines with a low level of HER2/neu expression.


Superparamagnetic iron oxide Herceptin HER2/neu receptor Magnetic resonance imaging 



We are grateful to the National Science Council of the Republic of China for financial support under contracts no. NSC 96-2627-M-037-001 and NSC 97-2623-7-037-001-NU. This research was also supported in part by grants from National Health Research Institutes under contract no. NHRI-EX-95-9424EI.

Supplementary material

775_2008_445_MOESM1_ESM.pdf (116 kb)
Supporting information (PDF 116 kb)


  1. 1.
    Sun C, Veiseh O, Gunn J, Fang C, Hansen S, Lee D, Sze R, Ellenbogen RG, Olson J, Zhang M (2008) Small 4:240–249CrossRefGoogle Scholar
  2. 2.
    Schellenberger E, Schnorr J, Reutelingsperger C, Ungethüm L, Meyer W, Taupitz M, Hamm B (2008) Small 4:225–230PubMedCrossRefGoogle Scholar
  3. 3.
    Li Z, Tan B, Allix M, Cooper AI, Rosseinsky MJ (2008) Small 4:231–239PubMedCrossRefGoogle Scholar
  4. 4.
    Kalambur VS, Longmire EK, Bischof JC (2007) Langmuir 23:12329–12336PubMedCrossRefGoogle Scholar
  5. 5.
    Gupta AK, Gupta M (2005) Biomaterials 26:3995–4021PubMedCrossRefGoogle Scholar
  6. 6.
    Yigit MV, Mazumdar D, Kim H-K, Lee JH, Odintsov B, Lu Y (2007) Chembiochem 8:1675–1678PubMedCrossRefGoogle Scholar
  7. 7.
    Paul KG, Frigo TB, Groman JY, Groman EV (2004) Bioconjug Chem 15:194–401CrossRefGoogle Scholar
  8. 8.
    Koch AM, Reynolds F, Kircher MF, Merkle HP, Weissleder R, Josephson L (2003) Bioconjug Chem 14:1115–1121PubMedCrossRefGoogle Scholar
  9. 9.
    Josephson L, Kircher MF, Mahmood U, Tang Y, Weissleder R (2002) Bioconjug Chem 13:554–560PubMedCrossRefGoogle Scholar
  10. 10.
    Högemann D, Josephson L, Weissleder R, Basilion JP (2000) Bioconjug Chem 11:941–946PubMedCrossRefGoogle Scholar
  11. 11.
    Lee H, Yu MK, Park S, Moon S, Min JJ, Jeong YY, Kang H-W, Jon S (2007) J. Am Chem Soc 129:12739–12745CrossRefGoogle Scholar
  12. 12.
    Choi H, Choi SR, Zhou R, Kung HF, Chen IW (2004) Acad Radiol 11:996–1004PubMedCrossRefGoogle Scholar
  13. 13.
    Tran T, Engfeldt T, Orlova A, Sandström M, Feldwisch J, Abrahmsén L, Wennborg A, Tolmachev V, Karlström AE (2007) Bioconjug Chem 18:1956–1964PubMedCrossRefGoogle Scholar
  14. 14.
    Germershaus O, Merdan T, Bakowsky U, Behe M, Kissel T (2006) Bioconjug Chem 17:1190–1199PubMedCrossRefGoogle Scholar
  15. 15.
    Shukla R, Thomas TP, Peters JL, Desai AM, Kukowska-Latallo J, Patri AK, Kotlyar A, Baker JR (2006) Bioconjug Chem 17:1109–1115PubMedCrossRefGoogle Scholar
  16. 16.
    Hilger I, Leistner Y, Berndt A, Fritsche C, Haas KM, Kosmehl H, Kaiser WA (2004) Eur Radiol 14:1124–1129PubMedCrossRefGoogle Scholar
  17. 17.
    Pan M-H, Lin C-C, Lin J-K, Chen W-J (2007) J Agric Food Chem 55:5030–5037PubMedCrossRefGoogle Scholar
  18. 18.
    Suna B, Ranganathana B, Feng S-S (2008) Biomaterials 29:475–486CrossRefGoogle Scholar
  19. 19.
    Bergman I, Whitaker-Dowling P, Gao Y, Griffin JA, Watkinse SC (2003) Virology 316:337–347PubMedCrossRefGoogle Scholar
  20. 20.
    Colbern GT, Hiller AJ, Musterer RS, Working PK, Henderson IC (1999) J Inorg Biochem 77:117–120PubMedCrossRefGoogle Scholar
  21. 21.
    Meares CF, Chmura AJ, Orton MS, Corneillie TM, Awhetstone P (2003) J Mol Recognit 16:255–259PubMedCrossRefGoogle Scholar
  22. 22.
    Garmestania K, Milenica DE, Plascjakb PS, Brechbiel MW (2002) Nucl Med Biol 29:599–606CrossRefGoogle Scholar
  23. 23.
    Chen T-J, Cheng T-H, Hung Y-C, Lin K-T, Liuc G-C, Wang Y-M (2008) J Biomed Mater Res A 87:165–175PubMedGoogle Scholar
  24. 24.
    Taktak S, Sosnovik D, Cima MJ, Weissleder R, Josephson L (2007) Anal Chem 79:8863–8869PubMedCrossRefGoogle Scholar
  25. 25.
    Casula MF, Y-w Jun, Zaziski DJ, Chan EM, Corrias A, Alivisatos AP (2006) J Am Chem Soc 128:1675–1682PubMedCrossRefGoogle Scholar
  26. 26.
    Park J, Lee E, Hwang N-M, Kang M, Kim SC, Hwang Y, Park J-G, Noh H-J, Kim J-Y, Park J-H, Hyeon T (2005) Angew Chem Int Ed 44:2872–2877CrossRefGoogle Scholar
  27. 27.
    Sun S, Zeng H (2002) J Am Chem Soc 124:8204–8205PubMedCrossRefGoogle Scholar
  28. 28.
    Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele HH, Josephson L (1990) Radiology 175:485–493Google Scholar
  29. 29.
    Lee H, Lee E, Kim DK, Jang NK, Jeong YY, Jon S (2006) J Am Chem Soc 128:7383–7389PubMedCrossRefGoogle Scholar
  30. 30.
    Cheng F-Y, Su C-H, Yang Y-S, Yeh C-S, Tsai C-Y, Wu C-L, Wu M-T, Shieh D-B (2005) Biomaterials 26:729–738PubMedCrossRefGoogle Scholar
  31. 31.
    Shieh D-B, Cheng F-Y, Su C-H, Yeh C-S, Wu M-T, Wu Y-N, Tsai C-Y, Wu C-L, Chen D-H, Chou C-H (2005) Biomaterials 26:7183–7191PubMedCrossRefGoogle Scholar
  32. 32.
    Varanda LC, Jafelicci M, Tartaj P, O’Grady K, González-Carreño T, Morales MP, Muñoz T, Serna CJ (2002) J Appl Phys 92:2079–2085CrossRefGoogle Scholar
  33. 33.
    Jun Y-W, Huh Y-M, Choi J-S, Lee J-H, Song H-T, Kim S, Yoon S, Kim K-S, Shin J-S, Suh J-S, Cheon J (2005) J Am Chem Soc 127:5732–5733PubMedCrossRefGoogle Scholar
  34. 34.
    Huh Y-M, Jun Y-W, Song H-T, Kim S, Choi J-S, Lee J-H, Yoon S, Kim K-S, Shin J-S, Suh J-S, Cheon J (2005) J Am Chem Soc 127:12387–12391PubMedCrossRefGoogle Scholar
  35. 35.
    Horák D, Babič M, Jendelová P, Herynek V, Trchova M, Pientka Z, Pollert E, Hájek M, Syková E (2007) Bioconjug Chem 8:635–644CrossRefGoogle Scholar
  36. 36.
    Sturla SJ, Irwin JJ, Loeppky RN, Mulvihill MJ, Searcey M (2007) ACS Chem Biol 2:286–292PubMedCrossRefGoogle Scholar
  37. 37.
    Lee J-H, Huh Y-M, Jun Y-W, Seo J-W, Jang J-T, Song H-T, Kim S, Cho E-J, Yoon H-G, Suh J-S, Cheon J (2006) Nat Med 13:95–99PubMedCrossRefGoogle Scholar

Copyright information

© SBIC 2008

Authors and Affiliations

  • Ting-Jung Chen
    • 1
  • Tsan-Hwang Cheng
    • 2
  • Chiao-Yun Chen
    • 3
    • 4
  • Sodio C. N. Hsu
    • 5
  • Tian-Lu Cheng
    • 6
  • Gin-Chung Liu
    • 3
    • 4
  • Yun-Ming Wang
    • 1
    • 5
  1. 1.Department of Biological Science and TechnologyNational Chiao Tung UniversityHsinchuTaiwan
  2. 2.Department of Biological Science and TechnologyChung Hwa University of Medical TechnologyTainan CountyTaiwan
  3. 3.Department of Medical ImagingKaohsiung Medical University HospitalKaohsiungTaiwan
  4. 4.Department of RadiologyKaohsiung Medical UniversityKaohsiungTaiwan
  5. 5.Faculty of Medicinal and Applied ChemistryKaohsiung Medical UniversityKaohsiungTaiwan
  6. 6.Faculty of Biomedical Science and Environmental BiologyKaohsiung Medical UniversityKaohsiungTaiwan

Personalised recommendations