Skip to main content

Advertisement

Log in

Protein-Based MRI Contrast Agents for Molecular Imaging of Prostate Cancer

  • Brief Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to demonstrate a novel protein-based magnetic resonance imaging (MRI) contrast agent that has the capability of targeting prostate cancer and which provides high-sensitivity MR imaging in tumor cells and mouse models.

Procedure

A fragment of gastrin-releasing peptide (GRP) was fused into a protein-based MRI contrast agent (ProCA1) at different regions. MR imaging was obtained in both tumor cells (PC3 and H441) and a tumor mouse model administrated with ProCA1.GRP.

Results

PC3 and DU145 cells treated with ProCA1.GRPs exhibited enhanced signal in MRI. Intratumoral injection of ProCA1.GRP in a PC3 tumor model displayed enhanced MRI signal. The contrast agent was retained in the PC3 tumor up to 48 h post-injection.

Conclusions

Protein-based MRI contrast agent with tumor targeting modality can specifically target GRPR-positive prostate cancer. Intratumoral injection of the ProCA1 agent in the prostate cancer mouse model verified the targeting capability of ProCA1.GRP and showed a prolonged retention time in tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

MRI:

Magnetic resonance imaging

GRP:

Gastrin-releasing peptide

GRPR:

Gastrin-releasing peptide receptor

ELISA:

Enzyme-linked immunosorbent assay

HRP:

Horseradish peroxide

TBST:

Tris-buffered saline and Tween-20

RIO:

Region of interest

References

  1. Sherry AD, Woods M (2008) Chemical exchange saturation transfer contrast agents for magnetic resonance imaging. Annu Rev Biomed Eng 10:391–411

    Article  PubMed  CAS  Google Scholar 

  2. Caravan P, Ellison JJ, McMurry TJ, Lauffer RB (1999) Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev 99:2293–2352

    Article  PubMed  CAS  Google Scholar 

  3. Tweedle MF (2009) Peptide-targeted diagnostics and radiotherapeutics. Acc Chem Res 42:958–968

    Article  PubMed  CAS  Google Scholar 

  4. Yoo B, Pagel MD (2008) An overview of responsive MRI contrast agents for molecular imaging. Front Biosci 13:1733–1752

    Article  PubMed  CAS  Google Scholar 

  5. Mulder WJ, Strijkers GJ, Griffioen AW, van Bloois L, Molema G et al (2004) A liposomal system for contrast-enhanced magnetic resonance imaging of molecular targets. Bioconjug Chem 15:799–806

    Article  PubMed  CAS  Google Scholar 

  6. Cyrus T, Lanza GM, Wickline SA (2007) Molecular imaging by cardiovascular MR. J Cardiovasc Magn Reson 9:827–843

    Article  PubMed  Google Scholar 

  7. Branca RT, Chen YM, Mouraviev V, Galiana G, Jenista ER et al (2009) iDQC anisotropy map imaging for tumor tissue characterization in vivo. Magn Reson Med 61:937–943

    Article  PubMed  Google Scholar 

  8. Collins DJ, Padhani AR (2004) Dynamic magnetic resonance imaging of tumor perfusion. Approaches and biomedical challenges. IEEE Eng Med Biol Mag 23:65–83

    Article  PubMed  Google Scholar 

  9. Stephen RM, Gillies RJ (2007) Promise and progress for functional and molecular imaging of response to targeted therapies. Pharm Res 24:1172–1185

    Article  PubMed  CAS  Google Scholar 

  10. Artemov D, Mori N, Ravi R, Bhujwalla ZM (2003) Magnetic resonance molecular imaging of the HER-2/neu receptor. Cancer Res 63:2723–2727

    PubMed  CAS  Google Scholar 

  11. Zhang X, Cai W, Cao F, Schreibmann E, Wu Y et al (2006) 18F-labeled bombesin analogs for targeting GRP receptor-expressing prostate cancer. J Nucl Med 47:492–501

    PubMed  CAS  Google Scholar 

  12. Yang JJ, Yang J, Wei L, Zurkiya O, Yang W et al (2008) Rational design of protein-based MRI contrast agents. J Am Chem Soc 130:9260–9267

    Article  PubMed  CAS  Google Scholar 

  13. Gonzalez N, Moody TW, Igarashi H, Ito T, Jensen RT (2008) Bombesin-related peptides and their receptors: recent advances in their role in physiology and disease states. Curr Opin Endocrinol Diabetes Obes 15:58–64

    Article  PubMed  CAS  Google Scholar 

  14. Sun B, Halmos G, Schally AV, Wang X, Martinez M (2000) Presence of receptors for bombesin/gastrin-releasing peptide and mRNA for three receptor subtypes in human prostate cancers. Prostate 42:295–303

    Article  PubMed  CAS  Google Scholar 

  15. Uchida K, Kojima A, Morokawa N, Tanabe O, Anzai C et al (2002) Expression of progastrin-releasing peptide and gastrin-releasing peptide receptor mRNA transcripts in tumor cells of patients with small cell lung cancer. J Cancer Res Clin Oncol 128:633–640

    Article  PubMed  CAS  Google Scholar 

  16. Grady EF, Slice LW, Brant WO, Walsh JH, Payan DG et al (1995) Direct observation of endocytosis of gastrin releasing peptide and its receptor. J Biol Chem 270:4603–4611

    Article  PubMed  CAS  Google Scholar 

  17. Shin C, Mok KH, Han JH, Ahn JH, Lim Y (2006) Conformational analysis in solution of gastrin releasing peptide. Biochem Biophys Res Commun 350:120–124

    Article  PubMed  CAS  Google Scholar 

  18. Heimbrook DC, Boyer ME, Garsky VM, Balishin NL, Kiefer DM et al (1988) Minimal ligand analysis of gastrin releasing peptide. Receptor binding and mitogenesis. J Biol Chem 263:7016–7019

    PubMed  CAS  Google Scholar 

  19. Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815

    Article  PubMed  CAS  Google Scholar 

  20. Yang W, Wilkins AL, Ye Y, Liu ZR, Li SY et al (2005) Design of a calcium-binding protein with desired structure in a cell adhesion molecule. J Am Chem Soc 127:2085–2093

    Article  PubMed  CAS  Google Scholar 

  21. Yang W, Wilkins AL, Li S, Ye Y, Yang JJ (2005) The effects of Ca2+ binding on the dynamic properties of a designed Ca2+-binding protein. Biochemistry 44:8267–8273

    Article  PubMed  CAS  Google Scholar 

  22. Ye Y, Lee HW, Yang W, Shealy SJ, Wilkins AL et al (2001) Metal binding affinity and structural properties of an isolated EF-loop in a scaffold protein. Protein Eng 14:1001–1013

    Article  PubMed  CAS  Google Scholar 

  23. Roberts HC, Roberts TP, Brasch RC, Dillon WP (2000) Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade. AJNR Am J Neuroradiol 21:891–899

    PubMed  CAS  Google Scholar 

  24. Hawnaur JM, Zhu XP, Hutchinson CE (1998) Quantitative dynamic contrast enhanced MRI of recurrent pelvic masses in patients treated for cancer. Br J Radiol 71:1136–1142

    PubMed  CAS  Google Scholar 

  25. Ye F, Wu X, Jeong EK, Jia Z, Yang T et al (2008) A peptide targeted contrast agent specific to fibrin–fibronectin complexes for cancer molecular imaging with MRI. Bioconjug Chem 19:2300–2303

    Article  PubMed  CAS  Google Scholar 

  26. Ye Y, Shealy S, Lee HW, Torshin I, Harrison R et al (2003) A grafting approach to obtain site-specific metal-binding properties of EF-hand proteins. Protein Eng 16:429–434

    Article  PubMed  CAS  Google Scholar 

  27. Jensen JA, Carroll RE, Benya RV (2001) The case for gastrin-releasing peptide acting as a morphogen when it and its receptor are aberrantly expressed in cancer. Peptides 22:689–699

    Article  PubMed  CAS  Google Scholar 

  28. Nunn AD, Linder KE, Tweedle MF (1997) Can receptors be imaged with MRI agents? Q J Nucl Med 41:155–162

    PubMed  CAS  Google Scholar 

  29. Maniccia AW, Yang W, Li SY, Johnson JA, Yang JJ (2006) Using protein design to dissect the effect of charged residues on metal binding and protein stability. Biochemistry 45:5848–5856

    Article  PubMed  CAS  Google Scholar 

  30. Liu Z, Li ZB, Cao Q, Liu S, Wang F et al (2009) Small-animal PET of tumors with (64)Cu-labeled RGD-bombesin heterodimer. J Nucl Med 50:1168–1177

    Article  PubMed  CAS  Google Scholar 

  31. Liu Z, Niu G, Wang F, Chen X (2009) (68)Ga-labeled NOTA-RGD-BBN peptide for dual integrin and GRPR-targeted tumor imaging. Eur J Nucl Med Mol Imaging 36:1483–1494

    Article  PubMed  CAS  Google Scholar 

  32. Ho CL, Chen LC, Lee WC, Chiu SP, Hsu WC et al (2009) Receptor-binding, biodistribution, dosimetry, and micro-SPECT/CT imaging of 111In-[DTPA(1), Lys(3), Tyr(4)]-bombesin analog in human prostate tumor-bearing mice. Cancer Biother Radiopharm 24:435–443

    PubMed  CAS  Google Scholar 

  33. Brennan MJ (1963) Some reflections on research. J Assoc Phys Ment Rehabil 17:171

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dan Adams, Birgit Neuhaus, Dr. Christie Cater, Jie Jiang, Dr. Leland Chung for their assistance. This work is supported in part by research grants from NIH CA118113 to Zhi-Ren Liu and NIH GM62999 and EB007268 to Jenny J Yang.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jenny J. Yang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 4247 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wei, L., Li, S., Yang, J. et al. Protein-Based MRI Contrast Agents for Molecular Imaging of Prostate Cancer. Mol Imaging Biol 13, 416–423 (2011). https://doi.org/10.1007/s11307-010-0342-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-010-0342-9

Key words

Navigation