Impact of Multiple Negative Charges on Blood Clearance and Biodistribution Characteristics of 99mTc-labeled Dimeric Cyclic RGD Peptides

Overview

Journal Bioconjug Chem

Publisher American Chemical Society

Specialty Biochemistry

Date 2014 Aug 22

PMID 25144854

Citations 10

Authors

Yong Yang

Shundong Ji

Shuang Liu

Affiliations

Soon will be listed here.

Abstract

This study sought to evaluate the impact of multiple negative charges on blood clearance kinetics and biodistribution properties of (99m)Tc-labeled RGD peptide dimers. Bioconjugates HYNIC-P6G-RGD2 and HYNIC-P6D-RGD2 were prepared by reacting P6G-RGD2 and P6D-RGD2, respectively, with excess HYNIC-OSu in the presence of diisopropylethylamine. Their IC50 values were determined to be 31 ± 5 and 41 ± 6 nM, respectively, against (125)I-echistatin bound to U87MG glioma cells in a whole-cell displacement assay. Complexes [(99m)Tc(HYNIC-P6G-RGD2)(tricine)(TPPTS)] ((99m)Tc-P6G-RGD2) and [(99m)Tc(HYNIC-P6D-RGD2)(tricine)(TPPTS)] ((99m)Tc-P6D-RGD2) were prepared in high radiochemical purity (RCP > 95%) and specific activity (37-110 GBq/μmol). They were evaluated in athymic nude mice bearing U87MG glioma xenografts for their biodistribution. The most significant difference between (99m)Tc-P6D-RGD2 and (99m)Tc-P6G-RGD2 was their blood radioactivity levels and tumor uptake. The initial blood radioactivity level for (99m)Tc-P6D-RGD2 (4.71 ± 1.00%ID/g) was ∼5× higher than that of (99m)Tc-P6G-RGD2 (0.88 ± 0.05%ID/g), but this difference disappeared at 60 min p.i. (99m)Tc-P6D-RGD2 had much lower tumor uptake (2.20-3.11%ID/g) than (99m)Tc-P6G-RGD2 (7.82-9.27%ID/g) over a 2 h period. Since HYNIC-P6D-RGD2 and HYNIC-P6G-RGD2 shared a similar integrin αvβ3 binding affinity (41 ± 6 nM versus 31 ± 5 nM), the difference in their blood activity and tumor uptake is most likely related to the nine negative charges and high protein binding of (99m)Tc-P6D-RGD2. Despite its low uptake in U87MG tumors, the tumor uptake of (99m)Tc-P6D-RGD2 was integrin αvβ3-specific. SPECT/CT studies were performed using (99m)Tc-P6G-RGD2 in athymic nude mice bearing U87MG glioma and MDA-MB-231 breast cancer xenografts. The SPECT/CT data demonstrated the tumor-targeting capability of (99m)Tc-P6G-RGD2, and its tumor uptake depends on the integrin αvβ3 expression levels on tumor cells and neovasculature. It was concluded that the multiple negative charges have a significant impact on the blood clearance kinetics and tumor uptake of (99m)Tc-labeled dimeric cyclic RGD peptides.

Citing Articles

Synthesis and Preclinical Evaluation of Three Novel Ga-Labeled Bispecific PSMA/FAP-Targeting Tracers for Prostate Cancer Imaging.

Verena A, Zhang Z, Kuo H, Merkens H, Zeisler J, Wilson R Molecules. 2023; 28(3).

PMID: 36770755 PMC: 9921851. DOI: 10.3390/molecules28031088.

Design and Evaluation of Rhein-Based MRI Contrast Agents for Visualization of Tumor Necrosis Induced by Combretastatin A-4 Disodium Phosphate.

Zhang L, Zhang D, Gao M, Jin Q, Jiang C, Wu T Mol Imaging Biol. 2020; 23(2):220-229.

PMID: 33048270 DOI: 10.1007/s11307-020-01551-3.

The evolving roles of radiolabeled quinones as small molecular probes in necrotic imaging.

Su C, Xu Y Br J Radiol. 2020; 93(1111):20200034.

PMID: 32374626 PMC: 7336069. DOI: 10.1259/bjr.20200034.

Updated developments on molecular imaging and therapeutic strategies directed against necrosis.

Zhang D, Gao M, Jin Q, Ni Y, Zhang J Acta Pharm Sin B. 2019; 9(3):455-468.

PMID: 31193829 PMC: 6543088. DOI: 10.1016/j.apsb.2019.02.002.

Rhenium and Technetium-oxo Complexes with Thioamide Derivatives of Pyridylhydrazine Bifunctional Chelators Conjugated to the Tumour Targeting Peptides Octreotate and Cyclic-RGDfK.

North A, Karas J, Ma M, Blower P, Ackermann U, White J Inorg Chem. 2017; 56(16):9725-9741.

PMID: 28766938 PMC: 5569669. DOI: 10.1021/acs.inorgchem.7b01247.

References

Haubner R, Wester H . Radiolabeled tracers for imaging of tumor angiogenesis and evaluation of anti-angiogenic therapies. Curr Pharm Des. 2004; 10(13):1439-55. DOI: 10.2174/1381612043384745. View

Ji S, Zhou Y, Voorbach M, Shao G, Zhang Y, Fox G . Monitoring tumor response to linifanib therapy with SPECT/CT using the integrin αvβ3-targeted radiotracer 99mTc-3P-RGD2. J Pharmacol Exp Ther. 2013; 346(2):251-8. PMC: 3716312. DOI: 10.1124/jpet.112.202622. View

Chen X, Park R, Shahinian A, Tohme M, Khankaldyyan V, Bozorgzadeh M . 18F-labeled RGD peptide: initial evaluation for imaging brain tumor angiogenesis. Nucl Med Biol. 2004; 31(2):179-89. DOI: 10.1016/j.nucmedbio.2003.10.002. View

Shi J, Zhou Y, Chakraborty S, Kim Y, Jia B, Wang F . Evaluation of In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic Stability. Theranostics. 2011; 1:322-40. PMC: 3157017. DOI: 10.7150/thno/v01p0322. View

Shi J, Wang L, Kim Y, Zhai S, Jia B, Wang F . 99mTcO(MAG2-3G3-dimer): a new integrin alpha(v)beta(3)-targeted SPECT radiotracer with high tumor uptake and favorable pharmacokinetics. Eur J Nucl Med Mol Imaging. 2009; 36(11):1874-84. DOI: 10.1007/s00259-009-1166-1. View

Tsiapa I, Loudos G, Varvarigou A, Fragogeorgi E, Psimadas D, Tsotakos T . Biological evaluation of an ornithine-modified (99m)Tc-labeled RGD peptide as an angiogenesis imaging agent. Nucl Med Biol. 2012; 40(2):262-72. DOI: 10.1016/j.nucmedbio.2012.10.015. View

Nwe K, Kim Y, Milenic D, Baidoo K, Brechbiel M . (111)In- and (203)Pb-Labeled Cyclic RGD Peptide Conjugate as an α(v)β(3) Integrin-Binding Radiotracer. J Labelled Comp Radiopharm. 2012; 55(11):423-426. PMC: 3496268. DOI: 10.1002/jlcr.2965. View

Liu Z, Niu G, Shi J, Liu S, Wang F, Liu S . (68)Ga-labeled cyclic RGD dimers with Gly3 and PEG4 linkers: promising agents for tumor integrin alphavbeta3 PET imaging. Eur J Nucl Med Mol Imaging. 2009; 36(6):947-57. DOI: 10.1007/s00259-008-1045-1. View

Chakraborty S, Shi J, Kim Y, Zhou Y, Jia B, Wang F . Evaluation of 111In-labeled cyclic RGD peptides: tetrameric not tetravalent. Bioconjug Chem. 2010; 21(5):969-78. PMC: 2874107. DOI: 10.1021/bc900555q. View

10.

Li Y, Guo J, Tang S, Lang L, Chen X, Perrin D . One-step and one-pot-two-step radiosynthesis of cyclo-RGD-(18)F-aryltrifluoroborate conjugates for functional imaging. Am J Nucl Med Mol Imaging. 2013; 3(1):44-56. PMC: 3545361. View

11.

Zhou Y, Kim Y, Chakraborty S, Shi J, Gao H, Liu S . 99mTc-labeled cyclic RGD peptides for noninvasive monitoring of tumor integrin αVβ3 expression. Mol Imaging. 2011; 10(5):386-97. DOI: 10.2310/7290.2011.00006. View

12.

Zhou Y, Kim Y, Lu X, Liu S . Evaluation of 99mTc-labeled cyclic RGD dimers: impact of cyclic RGD peptides and 99mTc chelates on biological properties. Bioconjug Chem. 2012; 23(3):586-95. PMC: 3310279. DOI: 10.1021/bc200631g. View

13.

Pierre V, Allen M, Caravan P . Contrast agents for MRI: 30+ years and where are we going?. J Biol Inorg Chem. 2014; 19(2):127-31. PMC: 4075138. DOI: 10.1007/s00775-013-1074-5. View

14.

Chen X, Sievers E, Hou Y, Park R, Tohme M, Bart R . Integrin alpha v beta 3-targeted imaging of lung cancer. Neoplasia. 2005; 7(3):271-9. PMC: 1501139. DOI: 10.1593/neo.04538. View

15.

Shi J, Kim Y, Chakraborty S, Jia B, Wang F, Liu S . 2-Mercaptoacetylglycylglycyl (MAG2) as a bifunctional chelator for 99mTc-labeling of cyclic RGD dimers: effect of technetium chelate on tumor uptake and pharmacokinetics. Bioconjug Chem. 2009; 20(8):1559-68. PMC: 2888811. DOI: 10.1021/bc9001739. View

16.

Shi J, Wang L, Kim Y, Zhai S, Liu Z, Chen X . Improving tumor uptake and excretion kinetics of 99mTc-labeled cyclic arginine-glycine-aspartic (RGD) dimers with triglycine linkers. J Med Chem. 2008; 51(24):7980-90. PMC: 2626178. DOI: 10.1021/jm801134k. View

17.

Onthank D, Liu S, Silva P, Barrett J, Harris T, Robinson S . 90Y and 111In complexes of a DOTA-conjugated integrin alpha v beta 3 receptor antagonist: different but biologically equivalent. Bioconjug Chem. 2004; 15(2):235-41. DOI: 10.1021/bc034108q. View

18.

Zhou Y, Shao G, Liu S . Monitoring Breast Tumor Lung Metastasis by U-SPECT-II/CT with an Integrin α(v)β(3)-Targeted Radiotracer( 99m)Tc-3P-RGD(2). Theranostics. 2012; 2(6):577-88. PMC: 3381346. DOI: 10.7150/thno.4443. View

19.

Wu Y, Zhang X, Xiong Z, Cheng Z, Fisher D, Liu S . microPET imaging of glioma integrin {alpha}v{beta}3 expression using (64)Cu-labeled tetrameric RGD peptide. J Nucl Med. 2005; 46(10):1707-18. View

20.

Dijkgraaf I, Liu S, Kruijtzer J, Soede A, Oyen W, Liskamp R . Effects of linker variation on the in vitro and in vivo characteristics of an 111In-labeled RGD peptide. Nucl Med Biol. 2007; 34(1):29-35. DOI: 10.1016/j.nucmedbio.2006.10.006. View