Abstract
Background
Because of its over-expression in many human tumors, the folate receptor (FR) is a promising target for tumor-specific imaging.
Objective
To evaluate the uptake of FR-targeted gadolinium (P866) and iron-oxide (P1048) agents in an ovarian tumor model.
Materials and methods
FR-positive ovarian cancer cells (IGROV-1) were incubated with FR-targeted agents (P866 or P1048) in the absence or presence of competing free folate. Intracellular gadolinium or iron-oxide concentrations were measured. MR imaging of implanted ovarian tumors in rats was performed following injection of FR-targeted (P866 and P1048) and nontargeted (P1001 and P904) agents. Changes in longitudinal and transverse relaxation rates (ΔR1 and ΔR2), which were proportional to the contrast agent concentration in the tumors, were compared between tumors injected with FR-targeted and nontargeted agents.
Results
IGROV-1 cells showed uptake of P866 and P1048, which decreased with competing free folate. The ΔR1 values were higher at 1 h following injection of P866 than following injection of P1001 (P < 0.05), indicating a higher amount of contrast agent retained in the tumor following P866 injection. There was a trend for higher ΔR2 values at 48 h following injection of P1048 than following injection of P904, but it was not statistically significant (P = 0.09).
Conclusion
Specific accumulation of the FR-targeted gadolinium agent P866 was suggested in an FR-positive ovarian tumor model, demonstrating the possibility of combining the specificity of receptor targeting with the improved anatomic resolution of MR imaging. This could improve diagnosis and treatment of FR-positive tumors.
Similar content being viewed by others
References
Matherly LH, Goldman DI (2003) Membrane transport of folates. Vitam Horm 66:403–456
Salazar MD, Ratnam M (2007) The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer Metastasis Rev 26:141–152
Sadasivan E, Rothenberg SP, da Costa M et al (1986) Characterization of multiple forms of folate-binding protein from human leukemia cells. Biochim Biophys Acta 882:311–321
Antony AC (1996) Folate receptors. Annu Rev Nutr 16:501–521
Ross JF, Chaudhuri PK, Ratnam M (1994) Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer 73:2432–2443
Toffoli G, Cernigoi C, Russo A et al (1997) Overexpression of folate binding protein in ovarian cancers. Int J Cancer 74:193–198
Weitman SD, Lark RH, Coney LR et al (1992) Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res 52:3396–3401
Patrick TA, Kranz DM, van Dyke TA et al (1997) Folate receptors as potential therapeutic targets in choroid plexus tumors of SV40 transgenic mice. J Neurooncol 32:111–123
Yang R, Kolb EA, Qin J et al (2007) The folate receptor alpha is frequently overexpressed in osteosarcoma samples and plays a role in the uptake of the physiologic substrate 5-methyltetrahydrofolate. Clin Cancer Res 13:2557–2567
Wang H, Zheng X, Behm FG et al (2000) Differentiation-independent retinoid induction of folate receptor type beta, a potential tumor target in myeloid leukemia. Blood 96:3529–3536
Shen F, Ross JF, Wang X et al (1994) Identification of a novel folate receptor, a truncated receptor, and receptor type beta in hematopoietic cells: cDNA cloning, expression, immunoreactivity, and tissue specificity. Biochemistry 33:1209–1215
Antony AC (1992) The biological chemistry of folate receptors. Blood 79:2807–2820
Bettio A, Honer M, Muller C et al (2006) Synthesis and preclinical evaluation of a folic acid derivative labeled with 18F for PET imaging of folate receptor-positive tumors. J Nucl Med 47:1153–1160
Reddy JA, Xu LC, Parker N et al (2004) Preclinical evaluation of (99m)Tc-EC20 for imaging folate receptor-positive tumors. J Nucl Med 45:857–866
Guo W, Hinkle GH, Lee RJ (1999) 99mTc-HYNIC-folate: a novel receptor-based targeted radiopharmaceutical for tumor imaging. J Nucl Med 40:1563–1569
Mathias CJ, Wang S, Waters DJ et al (1998) Indium-111-DTPA-folate as a potential folate-receptor-targeted radiopharmaceutical. J Nucl Med 39:1579–1585
Ke CY, Mathias CJ, Green MA (2005) Targeting the tumor-associated folate receptor with an 111In-DTPA conjugate of pteroic acid. J Am Chem Soc 127:7421–7426
Leamon CP, Parker MA, Vlahov IR et al (2002) Synthesis and biological evaluation of EC20: a new folate-derived, (99 m)Tc-based radiopharmaceutical. Bioconjug Chem 13:1200–1210
Muller C, Hohn A, Schubiger PA et al (2006) Preclinical evaluation of novel organometallic 99 mTc-folate and 99 mTc-pteroate radiotracers for folate receptor-positive tumour targeting. Eur J Nucl Med Mol Imaging 33:1007–1016
Okarvi SM, Jammaz IA (2006) Preparation and in vitro and in vivo evaluation of technetium-99m-labeled folate and methotrexate conjugates as tumor imaging agents. Cancer Biother Radiopharm 21:49–60
Moon WK, Lin Y, O’Loughlin T et al (2003) Enhanced tumor detection using a folate receptor-targeted near-infrared fluorochrome conjugate. Bioconjug Chem 14:539–545
Kennedy MD, Jallad KN, Thompson DH et al (2003) Optical imaging of metastatic tumors using a folate-targeted fluorescent probe. J Biomed Opt 8:636–641
Chen WT, Khazaie K, Zhang G et al (2005) Detection of dysplastic intestinal adenomas using a fluorescent folate imaging probe. Mol Imaging 4:67–74
Konda SD, Aref M, Brechbiel M et al (2000) Development of a tumor-targeting MR contrast agent using the high-affinity folate receptor: work in progress. Invest Radiol 35:50–57
Konda SD, Aref M, Wang S et al (2001) Specific targeting of folate-dendrimer MRI contrast agents to the high affinity folate receptor expressed in ovarian tumor xenografts. MAGMA 12:104–113
Wiener EC, Konda SD, Wang S et al (2002) Imaging folate binding protein expression with MRI. Acad Radiol 9(Suppl 2):S316–S319
Choi H, Choi SR, Zhou R et al (2004) Iron oxide nanoparticles as magnetic resonance contrast agent for tumor imaging via folate receptor-targeted delivery. Acad Radiol 11:996–1004
Saborowski O, Simon GH, Raatschen HJ et al (2007) MR imaging of antigen-induced arthritis with a new, folate receptor-targeted contrast agent. Contrast Media Mol Imaging 2:72–81
Paulos CM, Reddy JA, Leamon CP et al (2004) Ligand binding and kinetics of folate receptor recycling in vivo: impact on receptor-mediated drug delivery. Mol Pharmacol 66:1406–1414
Tung CH, Lin Y, Moon WK et al (2002) A receptor-targeted near-infrared fluorescence probe for in vivo tumor imaging. Chembiochem 3:784–786
Raynal I, Prigent P, Peyramaure S et al (2004) Macrophage endocytosis of superparamagnetic iron oxide nanoparticles: mechanisms and comparison of ferumoxides and ferumoxtran-10. Invest Radiol 39:56–63
Wiener EC, Konda S, Shadron A et al (1997) Targeting dendrimer-chelates to tumors and tumor cells expressing the high-affinity folate receptor. Invest Radiol 32:748–754
Corot C, Lancelot E, Prigent P, Port M (2005) Tumor imaging using a high relaxivity gadolinium chelate targeted to the folate receptor. Proceedings of the 13th Scientific Meeting of the International Society of Magnetic Resonance in Medicine, Miami, FL, p 2601
Miotti S, Bagnoli M, Ottone F et al (1997) Simultaneous activity of two different mechanisms of folate transport in ovarian carcinoma cell lines. J Cell Biochem 65:479–491
Corot C, Guilbert I, Robert P, Raynal I, Robic C, Raynaud JS, Prigent P, Dencausse A, Idee JM (2007) Superparamagnetic contrast agents. In: Modo MM, Bulte JW (eds) Molecular and cellular MR imaging. CRC Press, Boca Raton, pp 60–83
Wu M, Gunning W, Ratnam M (1999) Expression of folate receptor type alpha in relation to cell type, malignancy, and differentiation in ovary, uterus, and cervix. Cancer EpidemiolBiomarkers Prev 8:775–782
Buist MR, Molthoff CF, Kenemans P et al (1995) Distribution of OV-TL3 and MOv18 in normal and malignant ovarian tissue. J Clin Pathol 48:631–636
Figini M, Ferri R, Mezzanzanica D et al (2003) Reversion of transformed phenotype in ovarian cancer cells by intracellular expression of anti-folate receptor antibodies. Gene Ther 10:1018–1025
Toffoli G, Russo A, Gallo A et al (1998) Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer. Int J Cancer 79:121–126
Acknowledgement
Zhen J. Wang is supported by NIBIB T32 Training Grant 1 T32 EB001631-01A1.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, Z.J., Boddington, S., Wendland, M. et al. MR imaging of ovarian tumors using folate-receptor-targeted contrast agents. Pediatr Radiol 38, 529–537 (2008). https://doi.org/10.1007/s00247-008-0764-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00247-008-0764-6