Cu-Labeled Phosphonate Cross-Bridged Chelator Conjugates of C(RGDyK) for PET/CT Imaging of Osteolytic Bone Metastases

Overview

Journal Cancer Biother Radiopharm

Specialties Oncology
Pharmacology
Radiology

Date 2018 Apr 11

PMID 29634417

Citations 4

Authors

Meltem Ocak

Wissam Beaino

Alexander White

Dexing Zeng

Zhengxin Cai

Carolyn J Anderson

Affiliations

Soon will be listed here.

Abstract

Objective: The goal of this research was to evaluate c(RGDyK) conjugated to phosphonate-based cross-bridged chelators using Cu-free click chemistry in the 4T1 mouse mammary tumor bone metastasis model in comparison with Cu-CB-TE2A-c(RGDyK), which previously showed selective binding to integrin αvβ3 on osteoclasts.

Experimental: Two phosphonate-based cross-bridged chelators (CB-TE1A1P and CB-TE1K1P) were conjugated to c(RGDyK) through bio-orthogonal strain-promoted alkyne-azide cycloaddition. In vitro and in vivo evaluation of the Cu-labeled TE1A1P-DBCO-c(RGDyK) (AP-c(RGDyK)), TE1K1P-PEG4-DBCO-c(RGDyK) (KP-c(RGDyK)), and CB-TE2A-c(RGDyK) were compared in the 4T1 mouse model of bone metastasis. The affinities of the unconjugated and chelator-c(RGDyK) analogs for αvβ3 integrin were determined using a competitive-binding assay. For in vivo evaluation, BALB/c mice were injected with 1 × 10 4T1/Luc cells in the left ventricle. Formation of metastases was monitored by bioluminescence imaging (BLI) followed by small-animal PET/CT 2 h postinjection of radiotracers.

Results: The chelator-peptide conjugates showed similar affinity to integrin αvβ3, in the low nM range. PET imaging demonstrated a higher uptake in bones having metastases for all Cu-labeled c(RGDyK) analogs compared with bones in nontumor-bearing mice. The correlation between uptake of Cu-AP-c(RGDyK) and Cu-KP-c(RGDyK) in bones with metastases based on PET/CT imaging, and osteoclast number based on histomorphometry, was improved over the previously investigated Cu-CB-TE2A-c(RGDyK).

Conclusion: These data suggest that the phosphonate chelator conjugates of c(RDGyK) peptides are promising PET tracers suitable for imaging tumor-associated osteoclasts in bone metastases.

Citing Articles

Theragnostic Cu/Cu Radioisotopes Production With RFT-30 Cyclotron.

Lee J, Chae J, Hur M, Yang S, Kong Y, Lee J Front Med (Lausanne). 2022; 9:889640.

PMID: 35665337 PMC: 9158440. DOI: 10.3389/fmed.2022.889640.

Mutual Prodrugs of 5-Fluorouracil: From a Classic Chemotherapeutic Agent to Novel Potential Anticancer Drugs.

Ciaffaglione V, Modica M, Pittala V, Romeo G, Salerno L, Intagliata S ChemMedChem. 2021; 16(23):3496-3512.

PMID: 34415107 PMC: 9290623. DOI: 10.1002/cmdc.202100473.

A Novel Sulforaphane-Regulated Gene Network in Suppression of Breast Cancer-Induced Osteolytic Bone Resorption.

Pore S, Hahm E, Kim S, Singh K, Nyiranshuti L, Latoche J Mol Cancer Ther. 2019; 19(2):420-431.

PMID: 31784454 PMC: 7007818. DOI: 10.1158/1535-7163.MCT-19-0611.

Cu-based Radiopharmaceuticals in Molecular Imaging.

Zhou Y, Li J, Xu X, Zhao M, Zhang B, Deng S Technol Cancer Res Treat. 2019; 18:1533033819830758.

PMID: 30764737 PMC: 6378420. DOI: 10.1177/1533033819830758.

References

Haubner R, Wester H, Reuning U, Senekowitsch-Schmidtke R, Diefenbach B, Kessler H . Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting. J Nucl Med. 1999; 40(6):1061-71. View

Davies J, Warwick J, Totty N, Philp R, Helfrich M, Horton M . The osteoclast functional antigen, implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor. J Cell Biol. 1989; 109(4 Pt 1):1817-26. PMC: 2115816. DOI: 10.1083/jcb.109.4.1817. View

Anderson C, Wadas T, Wong E, Weisman G . Cross-bridged macrocyclic chelators for stable complexation of copper radionuclides for PET imaging. Q J Nucl Med Mol Imaging. 2007; 52(2):185-92. PMC: 4286870. View

Withofs N, Charlier E, Simoni P, Alvarez-Miezentseva V, Mievis F, Giacomelli F . ¹⁸F-FPRGD₂ PET/CT imaging of musculoskeletal disorders. Ann Nucl Med. 2015; 29(10):839-47. DOI: 10.1007/s12149-015-1011-5. View

Nakamura I, Pilkington M, Lakkakorpi P, Lipfert L, Sims S, Dixon S . Role of alpha(v)beta(3) integrin in osteoclast migration and formation of the sealing zone. J Cell Sci. 1999; 112 ( Pt 22):3985-93. DOI: 10.1242/jcs.112.22.3985. View

Zheleznyak A, Wadas T, Sherman C, Wilson J, Kostenuik P, Weilbaecher K . Integrin α(v)β₃ as a PET imaging biomarker for osteoclast number in mouse models of negative and positive osteoclast regulation. Mol Imaging Biol. 2011; 14(4):500-8. PMC: 4277818. DOI: 10.1007/s11307-011-0512-4. View

Guo Y, Ferdani R, Anderson C . Preparation and biological evaluation of (64)Cu labeled Tyr(3)-octreotate using a phosphonic acid-based cross-bridged macrocyclic chelator. Bioconjug Chem. 2012; 23(7):1470-7. PMC: 4263031. DOI: 10.1021/bc300092n. View

Horton M, Taylor M, Arnett T, Helfrich M . Arg-Gly-Asp (RGD) peptides and the anti-vitronectin receptor antibody 23C6 inhibit dentine resorption and cell spreading by osteoclasts. Exp Cell Res. 1991; 195(2):368-75. DOI: 10.1016/0014-4827(91)90386-9. View

Jiang M, Ferdani R, Shokeen M, Anderson C . Comparison of two cross-bridged macrocyclic chelators for the evaluation of 64Cu-labeled-LLP2A, a peptidomimetic ligand targeting VLA-4-positive tumors. Nucl Med Biol. 2012; 40(2):245-51. PMC: 3563241. DOI: 10.1016/j.nucmedbio.2012.10.010. View

10.

Takayama S, Ishii S, Ikeda T, Masamura S, Doi M, Kitajima M . The relationship between bone metastasis from human breast cancer and integrin alpha(v)beta3 expression. Anticancer Res. 2005; 25(1A):79-83. View

11.

Chambers T, Fuller K, Darby J, PRINGLE J, Horton M . Monoclonal antibodies against osteoclasts inhibit bone resorption in vitro. Bone Miner. 1986; 1(2):127-35. View

12.

Guise T, Mohammad K, Clines G, Stebbins E, Wong D, Higgins L . Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res. 2006; 12(20 Pt 2):6213s-6216s. DOI: 10.1158/1078-0432.CCR-06-1007. View

13.

Nakamura I, Gailit J, Sasaki T . Osteoclast integrin alphaVbeta3 is present in the clear zone and contributes to cellular polarization. Cell Tissue Res. 1996; 286(3):507-15. DOI: 10.1007/s004410050720. View

14.

Gaertner F, Kessler H, Wester H, Schwaiger M, Beer A . Radiolabelled RGD peptides for imaging and therapy. Eur J Nucl Med Mol Imaging. 2012; 39 Suppl 1:S126-38. DOI: 10.1007/s00259-011-2028-1. View

15.

Cai Z, OuYang Q, Zeng D, Nguyen K, Modi J, Wang L . 64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging: in silico through in vivo studies. J Med Chem. 2014; 57(14):6019-29. PMC: 4261236. DOI: 10.1021/jm500416f. View

16.

Sato M, Sardana M, Grasser W, Garsky V, Murray J, Gould R . Echistatin is a potent inhibitor of bone resorption in culture. J Cell Biol. 1990; 111(4):1713-23. PMC: 2116239. DOI: 10.1083/jcb.111.4.1713. View

17.

Ruoslahti E . Integrins as signaling molecules and targets for tumor therapy. Kidney Int. 1997; 51(5):1413-7. DOI: 10.1038/ki.1997.193. View

18.

Kumar R, Basu S, Torigian D, Anand V, Zhuang H, Alavi A . Role of modern imaging techniques for diagnosis of infection in the era of 18F-fluorodeoxyglucose positron emission tomography. Clin Microbiol Rev. 2008; 21(1):209-24. PMC: 2223836. DOI: 10.1128/CMR.00025-07. View

19.

Sprague J, Peng Y, Sun X, Weisman G, Wong E, Achilefu S . Preparation and biological evaluation of copper-64-labeled tyr3-octreotate using a cross-bridged macrocyclic chelator. Clin Cancer Res. 2004; 10(24):8674-82. DOI: 10.1158/1078-0432.CCR-04-1084. View

20.

Ferdani R, Stigers D, Fiamengo A, Wei L, Li B, Golen J . Synthesis, Cu(II) complexation, 64Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms. Dalton Trans. 2011; 41(7):1938-50. PMC: 3462348. DOI: 10.1039/c1dt11743b. View