Copper chelates as probes of biological systems: Stable copper complexes with a macrocyclic bifunctional chelating agent

Moi, Min K.; Meares, Claude F.; McCall, Michael; Cole, William C.; DeNardo, Sally J.

doi:10.1016/0003-2697(85)90653-0

Cited by 180 publications

(149 citation statements)

References 11 publications

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“…67Cu is very promising for radioimmunotherapy because of its half-life of 61.5 hr, abundant 3 particles, and y emissions suitable for imaging. DTPA-and EDTA-conjugated mAbs form unstable complexes with 67Cu (10), although stable complexes have been obtained using 6-p-bromoacetamidobenzyl-1 ,4,8,11-tetraazacyclotetradecane-N,N' ,N" ,N "-tetraacetate, a macrocyclic aminocarboxylate bifunctional reagent (10,32,33). The rigidity of the bifunctional VFC ligand described here prevents the formation of the "slipped" structure characteristic of Cu3+ bisdicarbollide clusters (12); however, this structure can most likely be achieved by introducing greater flexibility into the VFC ligand through the use of 3-or 4-atom bridges, rather than the 2-atom bridge provided by pyrazole.…”

Section: Resultsmentioning

confidence: 99%

A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy.

Paxton

Beatty

Hawthorne

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy ( ABSTRACTA novel transition metal complex, Venus flytrap cluster (VFC), is described for the preparation of radiolabeled antibodies. VFC contained "Co, which was held tightly between the faces of two covalently bridged carborane ligands by cluster bonding of the metal with appropriate ligand orbitals. Anti-carcinoembryonic antigen monoclonal antibody T84.66 was conjugated to 57Co-VFC with full retention of immunological activity. Biodistribution studies in nude mice bearing carcinoembryonic antigen-producing tumors showed excellent tumor localization of 57Co-VFC-T84.66. The accumulation of radionuclide in normal liver was low and independent of dose, which may reflect the stability of the radionuclide complex. These results presage the use of VFC systems for binding transition metals that are clinically useful for radioimmunodiagnosis and radioimmunotherapy.The use of monoclonal and engineered antibodies for the selective delivery of diagnostic and therapeutic radiometals to tumors requires suitable bifunctional reagents that efficiently form covalent bonds with antibody and stable radionuclide chelate complexes. With few exceptions, monoclonal antibody (mAb)-chelator conjugates have been prepared with bifunctional reagents that are members of the aminocarboxylate chelator family, with derivatives of diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) being most popular (1-5). These conjugates form stable radiopharmaceuticals with 1"'In that have been used for radioimmunodiagnosis of human tumors (6-8), although there is some concern about their uptake by normal tissues and possible metal release in vivo. Conjugates of this type, however, form less stable radiopharmaceuticals with 90Y and 67Cu (9, 10), which can be used for radioimmunotherapy. There is therefore considerable interest in the development of new bifunctional reagents that will form more stable chelate complexes with these and other clinically relevant radionuclides.Radionuclides such as 67Cu, 991Tc, 105Rh, and '86Re are transition metals. Thus, very efficient ir-bonding ligands would be expected to form complexes of great stability with these radionuclides. Hawthorne and coworkers (11, 12) first described commo-bisdicarbollide transition metal complexes in which the metal ion is held between two ir-bonding[C2B9H11]2-dicarbollide ligands. With d6 metal ions these complexes conform to both the 18-electron and cluster electron-counting rules and display extraordinary stability due to the cluster bonding of the transition metal with ligand orbitals of appropriate symmetry. Metal ions having other than six d electrons, such as d3Cr3+ and d8Cu3+, also form stable bis-dicarbollide clusters, although in the case of electron-rich (d7, d8, etc.) species, the dicarbollide ligands undergo a "slip" distortion (12). The ability to produce these complexes in high yield in aqueous media, their expected stability to physiological co...

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Section: Resultsmentioning

confidence: 99%

A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy.

Paxton

Beatty

Hawthorne

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…42 The use of the 64 Cu-DO3A chelation system can result in release of uncoordinated 64 Cu by decomposition in the blood or transchelation in the liver, resulting in elevated uptake in liver tissue. 23,41 On the other hand, CB-TE2A and NO2A chelator-peptides demonstrated less tranchelation of the bound metal. Boswell et al observed that the 64 Cu-labeled chelator CB-TE2A during biodistribution studies in normal rats underwent significantly less transchelation in liver.…”

mentioning

confidence: 99%

“…The delayed tumor tissue disappearance pattern of the 64 Cu-DO3A-radioconjugate could be due to a trapping mechanism, such as transchelation of the radiometal from the chelator to intracellular protein(s). 22,26,40 Moreover, significant transchelation of the 64 Cu-DO3A-peptide to serum proteins occurs in blood, 23,41 and the protein-bound 64 Cu form may be transported back into the blood, which over time decreases target tissue:blood ratios.…”

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confidence: 99%

In VitroandIn VivoEvaluation of⁶⁴Cu-Radiolabeled KCCYSL Peptides for Targeting Epidermal Growth Factor Receptor-2 in Breast Carcinomas

Kumar

Gallazzi

Ferdani

et al. 2010

Cancer Biotherapy and Radiopharmaceuticals

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Epidermal growth factor receptor-2 (EGFR-2) has been implicated in the pathogenesis of breast and other carcinomas. In this report, we tested the ability of a bacteriophage selected peptide KCCYSL, radiolabeled with 64 Cu, to image EGFR-2 expressing breast tumors in vivo by positron emission tomography (PET). We evaluated and compared the in vivo tissue distribution and imaging properties of 64 Cu-X-(Gly-Ser-Gly)-KCCYSL peptide (X ¼ 1,4,7,10, tetraazacyclododecane-N,N',N'',N'''-tetracetic acid, [DOTA] 1,4,8, hexadecane-4,11-diacetic acid [CB-TE2A], and 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA] chelators) in a human breast cancer xenograft mouse model using dual modality PET and computed tomography (CT). The synthesized peptides DO3A-GSG-KCCYSL, CB-TE2A-GSG-KCCYSL, and NO2A-GSG-KCCYSL were purified, radiolabeled with 64 Cu, and evaluated for human breast cancer cell (MDA-MB-435) binding, 50% inhibitory concentration, and serum stability. In vivo pharmacokinetic and small animal PET/CT imaging studies were performed using SCID mice bearing MDA-MB-435 xenografts. The radiolabeled peptides bound with an 50% inhibitory concentration of 42.0 AE 10.2 nM (DO3A), 31 AE 7.9 nM (CB-TE2A), and 44.2 AE 6.6 nM (NO2A) to cultured MDA-MB-435 cells. All of the radiolabeled peptides were stable in vitro. The tumor uptake of DO3A, CB-TE2A, and NO2A peptides were 0.73 AE 0.15 percent injected dose per gram (%ID/g), 0.64 AE 0.08%ID/g, and 0.52 AE 0.04%ID/g, respectively at 1 hour. Liver uptake for the 64 Cu-DO3A-peptide (1.68 AE 0.42%ID/g) was more than that of the 64 Cu-CB-TE2A-peptide (0.52 AE 0.02% ID/g) and 64 Cu-NO2A-peptide (0.48 AE 0.05%ID/g) at 2 hours. PET/CT studies revealed successful tumor uptake of 64 Cu-peptides at 2 hours postinjection. In vivo kidney retention was observed with all of the radiolabeled peptides. The optimization of bifunctional chelators improves the pharmacokinetic properties of the 64 Cu-labeled GSG-KCCYSL peptide, which enables the selection of a suitable peptide homolog as a PET imaging agent for EGFR-2 expressing breast carcinomas.

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“…In addition, there has been a great deal of progress in the basic chemistry of immunoconjugates providing increased stability and retention of immunoreactivity in antibody-drug conjugates (Kanellos et al, 1985), immunotoxins (Thorpe et al, 1987), antibody-isotopes (Moi et al, 1985;Gansow et al, 1989;Eaton et al, 1989;Abrams et al, 1989) and site specific radiolabelling (Rodwell et al, 1986 …”

Section: Human Milk Fat Globule Membranementioning

confidence: 99%

Monoclonal antibodies for imaging and therapy

Epenetos

Kosmas²

1989

Br J Cancer

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Copper chelates as probes of biological systems: Stable copper complexes with a macrocyclic bifunctional chelating agent

Cited by 180 publications

References 11 publications

A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy.

A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy.

In VitroandIn VivoEvaluation of⁶⁴Cu-Radiolabeled KCCYSL Peptides for Targeting Epidermal Growth Factor Receptor-2 in Breast Carcinomas

Monoclonal antibodies for imaging and therapy

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Copper chelates as probes of biological systems: Stable copper complexes with a macrocyclic bifunctional chelating agent

Cited by 180 publications

References 11 publications

A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy.

A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy.

In VitroandIn VivoEvaluation of64Cu-Radiolabeled KCCYSL Peptides for Targeting Epidermal Growth Factor Receptor-2 in Breast Carcinomas

Monoclonal antibodies for imaging and therapy

Contact Info

Product

Resources

About

In VitroandIn VivoEvaluation of⁶⁴Cu-Radiolabeled KCCYSL Peptides for Targeting Epidermal Growth Factor Receptor-2 in Breast Carcinomas