Abstract
In this study, we reported the preparation and evaluation of 177Lu-DOTA-RGD2, 177Lu-DOTA-Bz-RGD2 and 177Lu-DTPA-Bz-RGD2 (RGD2 = E[c(RGDfK)]2) as a potential therapeutic radiotracers for the treatment of integrin αvβ3-positive tumors. The BALB/c nude mice bearing the U87MG human glioma xenografts were used to evaluate the biodistribution characteristics and excretion kinetics of 177Lu-DOTA-RGD2, 177Lu-DOTA-Bz-RGD2 and 177Lu-DTPA-Bz-RGD2. It was found that there were no major differences in their lipophilicity and biodistribution characteristics, particularly at latter time points. A major advantage of using DTPA-Bz as the bifunctional chelator (BFC) was its high radiolabeling efficiency (fast and high yield radiolabeling) at room temperature. Using DOTA and DOTA-Bz as BFCs, the radiolabeling kinetics was slow, and heating at 100°C and higher DOTA-conjugate concentration were needed for successful 177Lu-labeling. Therefore, DTPA-Bz is an optimal BFC for routine preparation of 177Lu-labeled cyclic RGDfK peptides, and 177Lu-DTPA-Bz-RGD2 is worthy of further investigation for targeted radiotherapy of integrin αvβ3-positive tumors.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- DOTA:
-
1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid
- DOTA-Bz:
-
2-(p-Isothiocyanobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
- DTPA-Bz:
-
2-(p-Isothiocyanobenzyl)diethylenetriaminepentaacetic acid
References
Abdollahi A, Griggs DW, Zieher H, Roth A, Lipson KE, Saffrich R, Gröne H-J, Hallahan DE, Reisfeld RA, Debus J et al (2005) Inhibition of alpha(v)beta3 integrin survival signaling enhances antiangiogenic and antitumor effects of radiotherapy. Clin Cancer Res 11(17):6270–6279
Alghisi GC, Rüegg C (2006) Vascular integrins in tumor angiogenesis: mediators and therapeutic targets. Endothelium 13(2):113–135
Beer AJ, Haubner R, Sarbia M, Goebel M, Luderschmidt S, Grosu AL, Schnell O, Niemeyer M, Kessler H, Wester HJ et al (2006) Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man. Clin Cancer Res 12(13):3942–3949
Beer AJ, Grosu AL, Carlsen J, Kolk A, Sarbia M, Stangier I, Watzlowik P, Wester HJ, Haubner R, Schwaiger M (2007) [18F]galacto-RGD positron emission tomography for imaging of alphavbeta3 expression on the neovasculature in patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 13(22 Pt 1):6610–6616
Blower PJ, Lewis JS, Zweit J (1996) Copper radionuclides and radiopharmaceuticals in nuclear medicine. Nucl Med Biol 23(8):957–980
Brooks PC, Clark RA, Cheresh DA (1994) Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264(5158):569
Cai W, Niu G, Chen X (2008) Imaging of integrins as biomarkers for tumor angiogenesis. Curr Pharm Des 14(28):2943–2973
Chen X, Liu S, Hou Y, Tohme M, Park R, Bading JR, Conti PS (2004) MicroPET imaging of breast cancer alphav-integrin expression with 64Cu-labeled dimeric RGD peptides. Mol Imaging Biol 6(5):350–359
de Jong M, Bakker WH, Krenning EP, Breeman WA, van der Pluijm ME, Bernard BF, Visser TJ, Jermann E, Behe M, Powell P et al (1997) Yttrium-90 and indium-111 labelling, receptor binding and biodistribution of [DOTA0, d-Phe1, Tyr3]octreotide, a promising somatostatin analogue for radionuclide therapy. Eur J Nucl Med 24(4):368–371
de Keizer B, van Aken MO, Feelders RA, de Herder WW, Kam BL, van Essen M, Krenning EP, Kwekkeboom DJ (2008) Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0, Tyr3]octreotate. Eur J Nucl Med Mol Imaging 35(4):749–755
Deshpande SV, DeNardo SJ, Kukis DL, Moi MK, McCall MJ, DeNardo GL, Meares CF (1990) Yttrium-90-labeled monoclonal antibody for therapy: labeling by a new macrocyclic bifunctional chelating agent. J Nucl Med 31(4):473–479
Folkman J (2003) Fundamental concepts of the angiogenic process. Curr Mol Med 3(7):643–651
Haubner RH, Wester HJ, Weber WA, Schwaiger M (2003) Radiotracer-based strategies to image angiogenesis. Q J Nucl Med 47(3):189–199
Jia B, Shi J, Yang Z, Xu B, Liu Z, Zhao H, Liu S, Wang F (2006) 99mTc-labeled cyclic RGDfK dimer: initial evaluation for SPECT imaging of glioma integrin alphavbeta3 expression. Bioconjug Chem 17(4):1069–1076
Jia B, Liu Z, Shi J, Yu Z, Yang Z, Zhao H, He Z, Liu S, Wang F (2008) Linker effects on biological properties of 111In-labeled DTPA conjugates of a cyclic RGDfK dimer. Bioconjug Chem 19(1):201–210
Jin H, Varner J (2004) Integrins: roles in cancer development and as treatment targets. Br J Cancer 90(3):561–565
Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, McParland B, Cohen PS, Hui AM, Palmieri C et al (2008) Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med 49(6):879–886
Liu S (2004) The role of coordination chemistry in the development of target-specific radiopharmaceuticals. Chem Soc Rev 33(7):445–461
Liu S (2006) Radiolabeled multimeric cyclic RGD peptides as integrin alphavbeta3 targeted radiotracers for tumor imaging. Mol Pharm 3(5):472–487
Liu S, Edwards DS (2001a) Bifunctional chelators for therapeutic lanthanide radiopharmaceuticals. Bioconjug Chem 12(1):7–34
Liu S, Edwards DS (2001b) Synthesis and characterization of two (111)In-labeled DTPA-peptide conjugates. Bioconjug Chem 12(4):630–634
Liu S, Cheung E, Rajopadhye M, Williams NE, Overoye KL, Edwards DS (2001a) Isomerism and solution dynamics of (90)Y-labeled DTPA–biomolecule conjugates. Bioconjug Chem 12(1):84–91
Liu S, Cheung E, Ziegler MC, Rajopadhye M, Edwards DS (2001b) (90)Y and (177)Lu labeling of a DOTA-conjugated vitronectin receptor antagonist useful for tumor therapy. Bioconjug Chem 12(4):559–568
Liu Z, Wang F, Chen X (2008) Integrin alpha v beta 3-targeted cancer therapy. Drug Dev Res 69(6):329–339
Liu Z, Li Z, Cao Q, Liu S, Wang F, Chen X (2009a) Small-animal PET of tumors with 64Cu-labeled RGD-bombesin heterodimer. J Nucl Med 50(7):1168–1177
Liu Z, Liu S, Wang F, Liu S, Chen X (2009b) Noninvasive imaging of tumor integrin expression using (18)F-labeled RGD dimer peptide with PEG (4) linkers. Eur J Nucl Med Mol Imaging 36(8):1296–1307
Liu Z, Niu G, Shi J, Liu S, Wang F, Liu S, Chen X (2009c) (68)Ga-labeled cyclic RGD dimers with Gly(3) and PEG (4) linkers: promising agents for tumor integrin alpha (v)beta (3) PET imaging. Eur J Nucl Med Mol Imaging 36(6):947–957
Liu Z, Yan Y, Chin FT, Wang F, Chen X (2009d) Dual integrin and gastrin-releasing peptide receptor targeted tumor imaging using 18F-labeled PEGylated RGD-bombesin heterodimer 18F-FB-PEG3-Glu-RGD-BBN. J Med Chem 52(2):425–432
Moi MK, Meares CF, McCall MJ, Cole WC, DeNardo SJ (1985) Copper chelates as probes of biological systems: stable copper complexes with a macrocyclic bifunctional chelating agent. Anal Biochem 148(1):249–253
Peterson JJ, Meares CF (1999) Enzymatic cleavage of peptide-linked radiolabels from immunoconjugates. Bioconjug Chem 10(4):553–557
Shi J, Wang L, Kim YS, Zhai S, Liu Z, Chen X, Liu S (2008) Improving tumor uptake and excretion kinetics of 99mTc-labeled cyclic arginine-glycine-aspartic (RGD) dimers with triglycine linkers. J Med Chem 51(24):7980–7990
Shi J, Kim YS, Zhai S, Liu Z, Chen X, Liu S (2009) Improving tumor uptake and pharmacokinetics of (64)Cu-labeled cyclic RGD peptide dimers with Gly(3) and PEG(4) linkers. Bioconjug Chem 20(4):750–759
Stimmel JB, Kull FC Jr (1998) Samarium-153 and lutetium-177 chelation properties of selected macrocyclic and acyclic ligands. Nucl Med Biol 25(2):117–125
Stimmel JB, Stockstill ME, Kull FC Jr (1995) Yttrium-90 chelation properties of tetraazatetraacetic acid macrocycles, diethylenetriaminepentaacetic acid analogues, and a novel terpyridine acyclic chelator. Bioconjug Chem 6(2):219–225
Temming K, Schiffelers RM, Molema G, Kok RJ (2005) RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature. Drug Resist Updat 8(6):381–402
Veeravagu A, Liu Z, Niu G, Chen K, Jia B, Cai W, Jin C, Hsu AR, Connolly AJ, Tse V et al (2008) Integrin alphavbeta3-targeted radioimmunotherapy of glioblastoma multiforme. Clin Cancer Res 14(22):7330–7339
Wang L, Shi J, Kim YS, Zhai S, Jia B, Zhao H, Liu Z, Wang F, Chen X, Liu S (2009) Improving tumor-targeting capability and pharmacokinetics of (99m)Tc-labeled cyclic RGD dimers with PEG(4) linkers. Mol Pharm 6(1):231–245
Acknowledgments
We thank Dr. Shuang Liu at School of Health Sciences, Purdue University, for providing radiolabeling precursors. We also thank Dr. Zhi Yang at Department of Nuclear Medicine, Peking University School of Oncology, for the friendly assistance on the animal imaging. This work is supported, in part, by NSFC projects (30640067, 30870728, 30930030 and 30900373), an 863 project (2007AA02Z467) and a Grant from the Ministry of Science and Technology of China (2009ZX09103-733).
Author information
Authors and Affiliations
Corresponding author
Additional information
Jiyun Shi and Zhaofei Liu have contributed equally to this work
Rights and permissions
About this article
Cite this article
Shi, J., Liu, Z., Jia, B. et al. Potential therapeutic radiotracers: preparation, biodistribution and metabolic characteristics of 177Lu-labeled cyclic RGDfK dimer. Amino Acids 39, 111–120 (2010). https://doi.org/10.1007/s00726-009-0382-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-009-0382-0