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(44)Sc: an attractive isotope for peptide-based PET imaging.

Hernandez R, Valdovinos HF, Yang Y, Chakravarty R, Hong H, Barnhart TE, Cai W - Mol. Pharm. (2014)

Bottom Line: A dimeric cyclic-RGD peptide, (cRGD)2, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with (44)Sc in high yield (>90%) and specific activity (7.4 MBq/nmol).The integrin αvβ3 specificity of the tracer was corroborated, both in vitro and in vivo, by competitive cell binding and receptor blocking assays.Our findings, together with the advantageous radionuclidic properties of (44)Sc, capitalize on the relevance of this isotope as an attractive alternative isotope to more established radiometals for small molecule-based PET imaging, and as imaging surrogate of (47)Sc in theranostic applications.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.

ABSTRACT
The overexpression of integrin αvβ3 has been linked to tumor aggressiveness and metastasis in several cancer types. Because of its high affinity, peptides containing the arginine-glycine-aspartic acid (RGD) motif have been proven valuable vectors for noninvasive imaging of integrin αvβ3 expression and for targeted radionuclide therapy. In this study, we aim to develop a (44)Sc-labeled RGD-based peptide for in vivo positron emission tomography (PET) imaging of integrin αvβ3 expression in a preclinical cancer model. High quality (44)Sc (t1/2, 3.97 h; β(+) branching ratio, 94.3%) was produced inexpensively in a cyclotron, via proton irradiation of natural Ca metal targets, and separated by extraction chromatography. A dimeric cyclic-RGD peptide, (cRGD)2, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with (44)Sc in high yield (>90%) and specific activity (7.4 MBq/nmol). Serial PET imaging of mice bearing U87MG tumor xenografts showed elevated (44)Sc-DOTA-(cRGD)2 uptake in the tumor tissue of 3.93 ± 1.19, 3.07 ± 1.17, and 3.00 ± 1.25 %ID/g at 0.5, 2, and 4 h postinjection, respectively (n = 3), which were validated by ex vivo biodistribution experiments. The integrin αvβ3 specificity of the tracer was corroborated, both in vitro and in vivo, by competitive cell binding and receptor blocking assays. These results parallel previously reported studies showing similar tumor targeting and pharmacokinetic profiles for dimeric cRGD peptides labeled with (64)Cu or (68)Ga. Our findings, together with the advantageous radionuclidic properties of (44)Sc, capitalize on the relevance of this isotope as an attractive alternative isotope to more established radiometals for small molecule-based PET imaging, and as imaging surrogate of (47)Sc in theranostic applications.

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Inhibition of 125I-echistatin binding to integrin αvβ3 on human glioblastoma (U87MG) cells bycRGD, (cRGD)2, and DOTA-(cRGD)2. Solid circles:cRGD (IC50 of 508 ± 87 nM); solid squares (cRGD)2 (IC50 of 66 ± 10 nM); solid triangles DOTA-(cRGD)2 (IC50 of 316 ± 38 nM). All data representmean ± SD (n = 3).
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fig2: Inhibition of 125I-echistatin binding to integrin αvβ3 on human glioblastoma (U87MG) cells bycRGD, (cRGD)2, and DOTA-(cRGD)2. Solid circles:cRGD (IC50 of 508 ± 87 nM); solid squares (cRGD)2 (IC50 of 66 ± 10 nM); solid triangles DOTA-(cRGD)2 (IC50 of 316 ± 38 nM). All data representmean ± SD (n = 3).

Mentions: We determined and comparedthe binding affinities of cRGD, (cRGD)2, and DOTA-(cRGD)2 for integrin αvβ3 in acompetitive cell binding assay (Figure 2).A concentration-dependent displacement of the bound 125I-Echistain was observed upon the addition of the RGD-based competitors.The IC50 values for cRGD, (cRGD)2, and DOTA-(cRGD)2 were 508 ± 87, 66 ± 10, and 316 ± 38 nM, respectively.The 10-fold higher affinity of (cRGD)2 compared with cRGDmonomer demonstrated the polyvalency effect typical of multimericpeptides. DOTA conjugation to (cRGD)2 had a marginal impacton its binding affinity to integrin αvβ3.


(44)Sc: an attractive isotope for peptide-based PET imaging.

Hernandez R, Valdovinos HF, Yang Y, Chakravarty R, Hong H, Barnhart TE, Cai W - Mol. Pharm. (2014)

Inhibition of 125I-echistatin binding to integrin αvβ3 on human glioblastoma (U87MG) cells bycRGD, (cRGD)2, and DOTA-(cRGD)2. Solid circles:cRGD (IC50 of 508 ± 87 nM); solid squares (cRGD)2 (IC50 of 66 ± 10 nM); solid triangles DOTA-(cRGD)2 (IC50 of 316 ± 38 nM). All data representmean ± SD (n = 3).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128785&req=5

fig2: Inhibition of 125I-echistatin binding to integrin αvβ3 on human glioblastoma (U87MG) cells bycRGD, (cRGD)2, and DOTA-(cRGD)2. Solid circles:cRGD (IC50 of 508 ± 87 nM); solid squares (cRGD)2 (IC50 of 66 ± 10 nM); solid triangles DOTA-(cRGD)2 (IC50 of 316 ± 38 nM). All data representmean ± SD (n = 3).
Mentions: We determined and comparedthe binding affinities of cRGD, (cRGD)2, and DOTA-(cRGD)2 for integrin αvβ3 in acompetitive cell binding assay (Figure 2).A concentration-dependent displacement of the bound 125I-Echistain was observed upon the addition of the RGD-based competitors.The IC50 values for cRGD, (cRGD)2, and DOTA-(cRGD)2 were 508 ± 87, 66 ± 10, and 316 ± 38 nM, respectively.The 10-fold higher affinity of (cRGD)2 compared with cRGDmonomer demonstrated the polyvalency effect typical of multimericpeptides. DOTA conjugation to (cRGD)2 had a marginal impacton its binding affinity to integrin αvβ3.

Bottom Line: A dimeric cyclic-RGD peptide, (cRGD)2, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with (44)Sc in high yield (>90%) and specific activity (7.4 MBq/nmol).The integrin αvβ3 specificity of the tracer was corroborated, both in vitro and in vivo, by competitive cell binding and receptor blocking assays.Our findings, together with the advantageous radionuclidic properties of (44)Sc, capitalize on the relevance of this isotope as an attractive alternative isotope to more established radiometals for small molecule-based PET imaging, and as imaging surrogate of (47)Sc in theranostic applications.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.

ABSTRACT
The overexpression of integrin αvβ3 has been linked to tumor aggressiveness and metastasis in several cancer types. Because of its high affinity, peptides containing the arginine-glycine-aspartic acid (RGD) motif have been proven valuable vectors for noninvasive imaging of integrin αvβ3 expression and for targeted radionuclide therapy. In this study, we aim to develop a (44)Sc-labeled RGD-based peptide for in vivo positron emission tomography (PET) imaging of integrin αvβ3 expression in a preclinical cancer model. High quality (44)Sc (t1/2, 3.97 h; β(+) branching ratio, 94.3%) was produced inexpensively in a cyclotron, via proton irradiation of natural Ca metal targets, and separated by extraction chromatography. A dimeric cyclic-RGD peptide, (cRGD)2, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with (44)Sc in high yield (>90%) and specific activity (7.4 MBq/nmol). Serial PET imaging of mice bearing U87MG tumor xenografts showed elevated (44)Sc-DOTA-(cRGD)2 uptake in the tumor tissue of 3.93 ± 1.19, 3.07 ± 1.17, and 3.00 ± 1.25 %ID/g at 0.5, 2, and 4 h postinjection, respectively (n = 3), which were validated by ex vivo biodistribution experiments. The integrin αvβ3 specificity of the tracer was corroborated, both in vitro and in vivo, by competitive cell binding and receptor blocking assays. These results parallel previously reported studies showing similar tumor targeting and pharmacokinetic profiles for dimeric cRGD peptides labeled with (64)Cu or (68)Ga. Our findings, together with the advantageous radionuclidic properties of (44)Sc, capitalize on the relevance of this isotope as an attractive alternative isotope to more established radiometals for small molecule-based PET imaging, and as imaging surrogate of (47)Sc in theranostic applications.

Show MeSH
Related in: MedlinePlus