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Bioconjugate Chem. 2003, 14, 274
CORRESPONDENCE Comment on “In Vitro and in Vivo Evaluation of a Technetium-99m-Labeled Cyclic RGD Peptide as a Specific Marker of rVβ3 Integrin for Tumor Imaging” Sir: In the article by Zi-Fen Su et al. recently published in Bioconjugate Chemistry (1), a technetium-99mlabeled RGD-4C peptide was introduced as a radioactive tracer for imaging RVβ3 expression. However, in two tumor models this compound showed only marginal accumulation in tumor bearing nude mice. We have recently developed two radiolabeled RGD-peptides (2, 3) that demonstrated a markedly higher and receptorspecific accumulation in tumor-bearing animals (tumor/ blood ratio greater 8 compared to less than 2 in the study by Su et al.). These tracers have been successfully used to image noninvasively RVβ3-positive tumors in vivo. Therefore, our findings differ significantly from the data reported by Su et al. Thus, the statement of the authors (page 568) that their work confirms and explains our previous findings is obviously not correct. Su et al. determined an association constant of 7 × 10-6 M-1 for binding of Tc-99m-RGD to the RVβ3 integrin. Because of this low affinity it is not surprising that uptake of Tc99m-RGD by RVβ3-positive tumors was only marginal in vivo. However, it is important to note that other radiolabeled RVβ3-specific ligands have shown markedly higher affinity. For example the association constant of an iodine-labeled DTPA RGD has been reported as 10 × 10-9 M-1 (4). The IC50 values of GalactoRGD and Gluco-RGD developed by our group are 5 × 10-9 M and 40 × 10-9 M, respectively. Therefore, the conclusion of the authors (abstract, last sentence) that RGD peptides generally bind with low affinity to RVβ3 is not correct. The in vitro data of the study by Su et al. only indicate that labeling of RDG-4C with technetium-99m using HYNIC as a chelator results in peptides with only modest affinity that appear not suitable for in vivo imaging. In addition, the results of the in vivo experiments are difficult to interpret because the expression of RVβ3 by
the tumor or endothelial cells was not evaluated by immunohistochemistry or Western blotting. Thus, it is unclear whether the low accumulation in the tumor is due to the low affinity of the tracer or due to low expression of RVβ3 in the tumor tissue. LITERATURE CITED (1) Su, Z.-F., Liu, G., Gupta, S., Zhu, Z., Rusckowski, M., and Hnatowich, D. J. (2002) In Vitro and in Vivo Evaluation of a Technetium-99m-Labeled Cyclic RGD Peptide as a Specific Marker of RVβ3 Integrin for Tumor Imaging. Bioconjugate Chem. 13, 561-570. (2) Haubner, R., Wester, H., Weber, W., Ziegler, S., SenekowitschSchmidtke, R., Kessler, H., et al. (2001) Noninvasive imaging of Rvβ3 integrin expression using a 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res. 61, 1781-1785. (3) Haubner, R., Wester, H. J., Burkhart, F., SenekowitschSchmidtke, R., Weber, W., Goodman, S. L., et al. (2001) Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics. J. Nucl. Med. 42, 326-336. (4) van Hagen, P. M., Breeman, W. A., Bernard, H. F., Schaar, M., Mooij, C. M., Srinivasan, A., et al. (2000) Evaluation of a radiolabeled cyclic DTPA-RGD analogue for tumour imaging and radionuclide therapy. Int. J. Cancer 90, 186-198.
Roland Haubner* and Wolfgang Weber Nuklearmedizinische Klinik und Poliklinik Technische Universita¨ t Mu¨ nchen Ismaninger Strasse 22, 81675 Mu¨ nchen, Germany E-mail:
[email protected] BC020084W
10.1021/bc020084w CCC: $25.00 © 2003 American Chemical Society Published on Web 02/28/2003
