Skip to main content
SpringerLink
Log in

MR Molecular Imaging of Prostate Cancer with a Peptide-Targeted Contrast Agent in a Mouse Orthotopic Prostate Cancer Model

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

ABSTRACT

Purpose

To study the effectiveness of a peptide targeted nanoglobular Gd-DOTA complexes for MR molecular imaging of prostate cancer in a mouse orthotopic PC-3 prostate cancer model.

Methods

A CLT1 (CGLIIQKNEC) peptide-targeted generation 2 nanoglobular Gd-DOTA monoamide conjugate [CLT1-G2-(Gd-DOTA)] was used for imaging fibrin-fibronectin complexes in prostate tumor using a non-specific peptide KAREC modified conjugate, KAREC-G2-(Gd-DOTA) as a control. Cy5 conjugates of CLT1 and KAREC were synthesized for binding studies. Orthotopic PC-3 prostate tumors were established in the prostate of athymic male nude mice. MRI study was performed on a Bruker 7T small animal MRI system.

Results

CLT1 peptide showed specific binding in the prostate tumor with no binding in normal tissues. The control peptide had little binding in normal and tumor tissues. CLT1-G2-(Gd-DOTA) resulted in stronger contrast enhancement in tumor tissue than KAREC-G2-(Gd-DOTA). CLT1-G2-(Gd-DOTA) generated ~100% increase in contrast-to-noise ratio (CNR) in the tumor compared to precontrast CNR at 1 min post-injection, while KAREC-G2-(Gd-DOTA) resulted in 8% increase.

Conclusion

CLT1-G2-(Gd-DOTA) is a promising molecular MRI contrast agent for fibrin-fibronectin complexes in tumor stroma. It has potential for diagnosis and assessing prognosis of malignant tumors with MRI.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

REFERENCES

  1. Weissleder R. Molecular imaging in cancer. Science. 2006;312:1168–71.

    Article  PubMed  CAS  Google Scholar 

  2. Yallapu MM, Foy SP, Jain TK, Labhasetwar V. PEG-functionalized magnetic nanoparticles for drug delivery and magnetic resonance imaging applications. Pharm Res. 2010;27:2283–95.

    Article  PubMed  CAS  Google Scholar 

  3. Cheng Z, Thorek DL, Tsourkas A. Gadolinium-conjugated dendrimer nanoclusters as a tumor-targeted T1 magnetic resonance imaging contrast agent. Angew Chem Int Ed Engl. 2010;49:346–50.

    Article  PubMed  CAS  Google Scholar 

  4. Pan D, Caruthers SD, Chen J, Winter PM, Senpan A, Schmieder AH, Wickline SA, Lanza GM. Nanomedicine strategies for molecular targets with MRI and optical imaging. Future Med Chem. 2010;2:471–90.

    Article  PubMed  CAS  Google Scholar 

  5. Sipkins DA, Cheresh DA, Kazemi MR, Nevin LM, Bednarski MD, Li KC. Detection of tumor angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging. Nat Med. 1998;4:623–6.

    Article  PubMed  CAS  Google Scholar 

  6. Curtet C, Maton F, Havet T, Slinkin M, Mishra A, Chatal JF, Muller RN. Polylysine-Gd-DTPAn and polylysine-Gd-DOTAn coupled to anti-CEA F(ab′)2 fragments as potential immunocontrast agents. Relaxometry, biodistribution, and magnetic resonance imaging in nude mice grafted with human colorectal carcinoma. Invest Radiol. 1998;33:752–61.

    Article  PubMed  CAS  Google Scholar 

  7. Ke T, Jeong E, Wang X, Feng Y, Parker D, Lu Z. RGD targeted poly(L-glutamic acid)-cystamine-(Gd-DO3A) conjugate for detecting angiogenesis biomarker alpha(v)beta(3) integrin with MRT1 mapping. Int J Nanomed. 2007;2:191–9.

    CAS  Google Scholar 

  8. Artemov D, Mori N, Ravi R, Bhujwalla Z. Magnetic resonance molecular imaging of the HER-2/neu receptor. Cancer Res. 2003;63:2723–7.

    PubMed  CAS  Google Scholar 

  9. Caravan P, Das B, Dumas S, Epstein FH, Helm PA, Jacques V, Koerner S, Kolodziej A, Shen L, Sun WC, Zhang Z. Collagen-targeted MRI contrast agent for molecular imaging of fibrosis. Angew Chem Int Ed Engl. 2007;46:8171–3.

    Article  PubMed  CAS  Google Scholar 

  10. Boutry S, Burtea C, Laurent S, Toubeau G, Vander Elst L, Muller RN. Magnetic resonance imaging of inflammation with a specific selectin-targeted contrast agent. Magn Reson Med. 2005;53:800–7.

    Article  PubMed  CAS  Google Scholar 

  11. Sirol M, Fuster V, Badimon JJ, Fallon JT, Moreno PR, Toussaint JF, Fayad ZA. Chronic thrombus detection with in vivo magnetic resonance imaging and a fibrin-targeted contrast agent. Circulation. 2005;112:1594–600.

    Article  PubMed  Google Scholar 

  12. Santimaria M, Moscatelli G, Viale GL, Giovannoni L, Neri G, Viti F, Leprini A, Borsi L, Castellani P, Zardi L, Neri D, Riva P. Immunoscintigraphic detection of the ED-B domain of fibronectin, a marker of angiogenesis, in patients with cancer. Clin Cancer Res. 2003;9:571–9.

    PubMed  CAS  Google Scholar 

  13. Sönmez H, Süer S, Karaarslan I, Baloğlu H, Kökoğlu E. Tissue fibronectin levels of human prostatic cancer, as a tumor marker. Canc Biochem Biophys. 1995;15:107–10.

    Google Scholar 

  14. Kaspar M, Zardi L, Neri D. Fibronectin as target for tumor therapy. Int J Cancer. 2006;118:1331–9.

    Article  PubMed  CAS  Google Scholar 

  15. Pilch J, Brown D, Komatsu M, Järvinen TA, Yang M, Peters D, Hoffman RM, Ruoslahti E. Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds. Proc Natl Acad Sci U S A. 2006;103:2800–4.

    Article  PubMed  CAS  Google Scholar 

  16. Ye F, Jeong E, Jia Z, Yang T, Parker D, Lu Z. A peptide targeted contrast agent specific to fibrin-fibronectin complexes for cancer molecular imaging with MRI. Bioconjugate Chem. 2008;19:2300–3.

    Article  CAS  Google Scholar 

  17. Tan M, Wu X, Jeong E, Chen Q, Lu Z. Peptide-targeted nanoglobular Gd-DOTA monoamide conjugates for magnetic resonance cancer molecular imaging. Biomacromolecules. 2010;11:754–61.

    Article  PubMed  CAS  Google Scholar 

  18. Mahato R, Qin B, Cheng K. Blocking IKKα expression inhibits prostate cancer invasiveness. Pharm Res. 2011;28:1357–69.

    Article  PubMed  CAS  Google Scholar 

  19. Lee CM, Jeong HJ, Cheong SJ, Kim EM, Kim DW, Lim ST, Sohn MH. Prostate cancer-targeted imaging using magnetofluorescent polymeric nanoparticles functionalized with bombesin. Pharm Res. 2010;27:712–21.

    Article  PubMed  CAS  Google Scholar 

  20. Wu X, Feng Y, Jeong EK, Emerson L, Lu ZR. Tumor characterization with dynamic contrast enhanced magnetic resonance imaging and biodegradable macromolecular contrast agents in mice. Pharm Res. 2009;26:2202–8.

    Article  PubMed  CAS  Google Scholar 

  21. Işisağ A, Neşe N, Ermete M, Lekili M, Ayhan S, Kandiloğlu AR. Col IV and Fn distribution in prostatic adenocarcinoma and correlation of 67LR, MMP-9 and TIMP-1 expression with Gleason score. Anal Quant Cytol Histol. 2003;25:263–72.

    PubMed  Google Scholar 

  22. Desai B, Elatre W, Quinn DI, Jadvar H. FDG PET/CT demonstration of pancreatic metastasis from prostate cancer. Clin Nucl Med. 2011;36:961–2.

    Article  PubMed  Google Scholar 

  23. Pinkawa M, Eble MJ, Mottaghy FM. PET and PET/CT in radiation treatment planning for prostate cancer. Expert Rev Anticancer Ther. 2011;11:1035–41.

    Article  Google Scholar 

  24. Rieter WJ, Keane TE, Ahlman MA, Ellis CT, Spicer KM, Gordon LL. Diagnostic performance of In-111 capromab pendetide SPECT/CT in localized and metastatic prostate cancer. Clin Nucl Med. 2011;36:872–8.

    Article  PubMed  Google Scholar 

  25. Schuster DM, Savir-Baruch B, Nieh PT, Master VA, Halkar RK, Rossi PJ, Lewis MM, Nye JA, Yu W, Bowman FD, Goodman MM. Detection of recurrent prostate carcinoma with anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PET/CT and 111In-capromab pendetide SPECT/CT. Radiology. 2011;259:852–61.

    Article  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS & DISCLOSURES

This work is supported in part by the NIH R01 CA097465 and a J&J-CWRU Innovation Challenge grant. We greatly appreciate Drs. Xin Yu, Ya Chen and Yong Chen for their technical assistance in MRI data acquisition. In addition, Mrs. Yvonne Parker provided expert technical assistance in the production of orthotopic tumor xenografts. We thank James P. Basilion for use of the Maestro Imaging System.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Case Western Reserve University, Wickenden Building, Room 427, 10900 Euclid Avenue, Cleveland, Ohio, 44106-7207, USA

    Mingqian Tan, Wen Li, Xueming Wu & Zheng-Rong Lu

  2. Laboratory of Biomedical Material Engineering Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, People’s Republic of China

    Mingqian Tan

  3. Department of Molecular Biology and Microbiology School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

    Susan M. Burden-Gulley & Susann M. Brady-Kalnay

  4. Dept. of Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, Ohio, 44195, USA

    Daniel Lindner

  5. Department of Radiology, Case Western Reserve University, Cleveland, Ohio, 44106, USA

    Vikas Gulani & Zheng-Rong Lu

  6. Department of Urology, Case Western Reserve University, Cleveland, Ohio, 44106, USA

    Vikas Gulani

Authors
  1. Mingqian Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan M. Burden-Gulley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xueming Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Susann M. Brady-Kalnay
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vikas Gulani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zheng-Rong Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zheng-Rong Lu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tan, M., Burden-Gulley, S.M., Li, W. et al. MR Molecular Imaging of Prostate Cancer with a Peptide-Targeted Contrast Agent in a Mouse Orthotopic Prostate Cancer Model. Pharm Res 29, 953–960 (2012). https://doi.org/10.1007/s11095-011-0635-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-011-0635-y

KEY WORDS

Search

Navigation