Evaluation of 111In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic Stability

Evaluation of 111In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic Stability

<p><b>Purpose: </b>The purpose of this study was to demonstrate the valence of cyclic RGD peptides, P-RGD (PEG<sub>4</sub>-c(RGDfK): PEG<sub>4</sub> = 15-amino-4,710,13-tetraoxapentadecanoic acid), P-RGD<sub>2</sub> (PEG<sub>4</sub>-E...

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Main Author: Jiyun Shi, Yang Zhou, Sudipta Chakraborty, Young-Seung Kim, Bing Jia, Fan Wang, Shuang Liu
Format: Article
Language:English
Published: Ivyspring International Publisher 2011-01-01
Series:Theranostics
Online Access:http://www.thno.org/v01p0322.htm
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record_format Article
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language English
format Article
sources DOAJ
author Jiyun Shi, Yang Zhou, Sudipta Chakraborty, Young-Seung Kim, Bing Jia, Fan Wang, Shuang Liu
spellingShingle Jiyun Shi, Yang Zhou, Sudipta Chakraborty, Young-Seung Kim, Bing Jia, Fan Wang, Shuang Liu
Evaluation of 111In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic Stability
Theranostics
author_facet Jiyun Shi, Yang Zhou, Sudipta Chakraborty, Young-Seung Kim, Bing Jia, Fan Wang, Shuang Liu
author_sort Jiyun Shi, Yang Zhou, Sudipta Chakraborty, Young-Seung Kim, Bing Jia, Fan Wang, Shuang Liu
title Evaluation of 111In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic Stability
title_short Evaluation of 111In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic Stability
title_full Evaluation of 111In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic Stability
title_fullStr Evaluation of 111In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic Stability
title_full_unstemmed Evaluation of 111In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic Stability
title_sort evaluation of 111in-labeled cyclic rgd peptides: effects of peptide and linker multiplicity on their tumor uptake, excretion kinetics and metabolic stability
publisher Ivyspring International Publisher
series Theranostics
issn 1838-7640
publishDate 2011-01-01
description <p><b>Purpose: </b>The purpose of this study was to demonstrate the valence of cyclic RGD peptides, P-RGD (PEG<sub>4</sub>-c(RGDfK): PEG<sub>4</sub> = 15-amino-4,710,13-tetraoxapentadecanoic acid), P-RGD<sub>2</sub> (PEG<sub>4</sub>-E[c(RGDfK)]<sub>2</sub>, 2P-RGD<sub>4</sub> (E{PEG<sub>4</sub>-E[c(RGDfK)]<sub>2</sub>}<sub>2</sub>, 2P4G-RGD<sub>4</sub> (E{PEG<sub>4</sub>-E[G<sub>3</sub>-c(RGDfK)]<sub>2</sub>}<sub>2</sub>: G<sub>3</sub> = Gly-Gly-Gly) and 6P-RGD<sub>4</sub> (E{PEG<sub>4</sub>-E[PEG<sub>4</sub>-c(RGDfK)]<sub>2</sub>}<sub>2</sub>) in binding to integrin &#945;<sub>v</sub>&#946;<sub>3</sub>, and to assess the impact of peptide and linker multiplicity on biodistribution properties, excretion kinetics and metabolic stability of their corresponding <sup>111</sup>In radiotracers.</p><p><b>Methods: </b>Five new RGD peptide conjugates (DOTA-P-RGD (DOTA =1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid), DOTA-P-RGD<sub>2</sub>, DOTA-2P-RGD<sub>4</sub>, DOTA-2P4G-RGD<sub>4</sub>, DOTA-6P-RGD<sub>4</sub>), and their <sup>111</sup>In complexes were prepared. The integrin &#945;<sub>v</sub>&#946;<sub>3</sub> binding affinity of cyclic RGD conjugates were determined by a competitive displacement assay against <sup>125</sup>I-c(RGDyK) bound to U87MG human glioma cells. Biodistribution, planar imaging and metabolism studies were performed in athymic nude mice bearing U87MG human glioma xenografts.</p><p><b>Results:</b> The integrin &#945;<sub>v</sub>&#946;<sub>3</sub> binding affinity of RGD conjugates follows the order of: DOTA-6P-RGD<sub>4</sub> (IC<sub>50</sub> = 0.3 &#177; 0.1 nM) <b>&#126; </b>DOTA-2P4G-RGD<sub>4</sub> (IC<sub>50</sub> = 0.2 &#177; 0.1 nM) &#126; DOTA-2P-RGD<sub>4</sub> (IC<sub>50</sub> = 0.5 &#177; 0.1 nM) &#62; DOTA-3P-RGD<sub>2</sub> (DOTA-PEG<sub>4</sub>-E[PEG<sub>4</sub>-c(RGDfK)]<sub>2</sub>: IC<sub>50</sub> = 1.5 &#177; 0.2 nM) <b>&#62; </b>DOTA-P-RGD<sub>2</sub> (IC<sub>50</sub> = 5.0 &#177; 1.0 nM) &#62;&#62; DOTA-P-RGD (IC<sub>50</sub> = 44.3 &#177; 3.5 nM) &#126; c(RGDfK) (IC<sub>50</sub> = 49.9 &#177; 5.5 nM) &#62;&#62; DOTA-6P-RGK<sub>4</sub> (IC<sub>50</sub> = 437 &#177; 35 nM). The fact that DOTA-6P-RGK<sub>4</sub> had much lower integrin &#945;<sub>v</sub>&#946;<sub>3</sub> binding affinity than DOTA-6P-RGD<sub>4</sub> suggests that the binding of DOTA-6P-RGD<sub>4</sub> to integrin &#945;<sub>v</sub>&#946;<sub>3</sub> is RGD-specific. This conclusion is consistent with the lower tumor uptake for <sup>111</sup>In(DOTA-6P-RGK<sub>4</sub>) than that for <sup>111</sup>In(DOTA-6P-RGD<sub>4</sub>). It was also found that the G<sub>3</sub> and PEG<sub>4</sub> linkers between RGD motifs have a significant impact on the integrin &#945;<sub>v</sub>&#946;<sub>3</sub>-targeting capability, biodistribution characteristics, excretion kinetics and metabolic stability of <sup>111</sup>In-labeled cyclic RGD peptides.</p><p><b>Conclusion: </b>On the basis of their integrin &#945;<sub>v</sub>&#946;<sub>3</sub> binding affinity and tumor uptake of their corresponding <sup>111</sup>In radiotracers, it was conclude that 2P-RGD<sub>4</sub>, 2P4G-RGD<sub>4</sub> and 6P-RGD<sub>4</sub> are most likely bivalent in binding to integrin &#945;<sub>v</sub>&#946;<sub>3</sub>, and extra RGD motifs might contribute to the long tumor retention times of <sup>111</sup>In(DOTA-2P-RGD<sub>4</sub>),<sup> 111</sup>In(DOTA-2P4G-RGD<sub>4</sub>) and <sup>111</sup>In(DOTA-6P-RGD<sub>4</sub>) than that of <sup>111</sup>In(DOTA-3P-RGD<sub>3</sub>) at 72 h p.i. Among the <sup>111</sup>In-labeled cyclic RGD tetramers evaluated in the glioma model, <sup>111</sup>In(DOTA-2P4G-RGD<sub>4</sub>) has very high tumor uptake with the best tumor/kidney and tumor/liver ratios, suggesting that <sup>90</sup>Y(DOTA-2P4G-RGD<sub>4</sub>) and <sup>177</sup>Lu(DOTA-2P4G-RGD<sub>4</sub>) might have the potential for targeted radiotherapy of integrin &#945;<sub>v</sub>&#946;<sub>3</sub>-positive tumors.</p>
url http://www.thno.org/v01p0322.htm
work_keys_str_mv AT jiyunshiyangzhousudiptachakrabortyyoungseungkimbingjiafanwangshuangliu evaluationof111inlabeledcyclicrgdpeptideseffectsofpeptideandlinkermultiplicityontheirtumoruptakeexcretionkineticsandmetabolicstability
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spelling doaj-7fc077efdf81459394158f5ac83cabf82020-11-24T20:46:33ZengIvyspring International PublisherTheranostics1838-76402011-01-0111322340Evaluation of 111In-Labeled Cyclic RGD Peptides: Effects of Peptide and Linker Multiplicity on Their Tumor Uptake, Excretion Kinetics and Metabolic StabilityJiyun Shi, Yang Zhou, Sudipta Chakraborty, Young-Seung Kim, Bing Jia, Fan Wang, Shuang Liu<p><b>Purpose: </b>The purpose of this study was to demonstrate the valence of cyclic RGD peptides, P-RGD (PEG<sub>4</sub>-c(RGDfK): PEG<sub>4</sub> = 15-amino-4,710,13-tetraoxapentadecanoic acid), P-RGD<sub>2</sub> (PEG<sub>4</sub>-E[c(RGDfK)]<sub>2</sub>, 2P-RGD<sub>4</sub> (E{PEG<sub>4</sub>-E[c(RGDfK)]<sub>2</sub>}<sub>2</sub>, 2P4G-RGD<sub>4</sub> (E{PEG<sub>4</sub>-E[G<sub>3</sub>-c(RGDfK)]<sub>2</sub>}<sub>2</sub>: G<sub>3</sub> = Gly-Gly-Gly) and 6P-RGD<sub>4</sub> (E{PEG<sub>4</sub>-E[PEG<sub>4</sub>-c(RGDfK)]<sub>2</sub>}<sub>2</sub>) in binding to integrin &#945;<sub>v</sub>&#946;<sub>3</sub>, and to assess the impact of peptide and linker multiplicity on biodistribution properties, excretion kinetics and metabolic stability of their corresponding <sup>111</sup>In radiotracers.</p><p><b>Methods: </b>Five new RGD peptide conjugates (DOTA-P-RGD (DOTA =1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid), DOTA-P-RGD<sub>2</sub>, DOTA-2P-RGD<sub>4</sub>, DOTA-2P4G-RGD<sub>4</sub>, DOTA-6P-RGD<sub>4</sub>), and their <sup>111</sup>In complexes were prepared. The integrin &#945;<sub>v</sub>&#946;<sub>3</sub> binding affinity of cyclic RGD conjugates were determined by a competitive displacement assay against <sup>125</sup>I-c(RGDyK) bound to U87MG human glioma cells. Biodistribution, planar imaging and metabolism studies were performed in athymic nude mice bearing U87MG human glioma xenografts.</p><p><b>Results:</b> The integrin &#945;<sub>v</sub>&#946;<sub>3</sub> binding affinity of RGD conjugates follows the order of: DOTA-6P-RGD<sub>4</sub> (IC<sub>50</sub> = 0.3 &#177; 0.1 nM) <b>&#126; </b>DOTA-2P4G-RGD<sub>4</sub> (IC<sub>50</sub> = 0.2 &#177; 0.1 nM) &#126; DOTA-2P-RGD<sub>4</sub> (IC<sub>50</sub> = 0.5 &#177; 0.1 nM) &#62; DOTA-3P-RGD<sub>2</sub> (DOTA-PEG<sub>4</sub>-E[PEG<sub>4</sub>-c(RGDfK)]<sub>2</sub>: IC<sub>50</sub> = 1.5 &#177; 0.2 nM) <b>&#62; </b>DOTA-P-RGD<sub>2</sub> (IC<sub>50</sub> = 5.0 &#177; 1.0 nM) &#62;&#62; DOTA-P-RGD (IC<sub>50</sub> = 44.3 &#177; 3.5 nM) &#126; c(RGDfK) (IC<sub>50</sub> = 49.9 &#177; 5.5 nM) &#62;&#62; DOTA-6P-RGK<sub>4</sub> (IC<sub>50</sub> = 437 &#177; 35 nM). The fact that DOTA-6P-RGK<sub>4</sub> had much lower integrin &#945;<sub>v</sub>&#946;<sub>3</sub> binding affinity than DOTA-6P-RGD<sub>4</sub> suggests that the binding of DOTA-6P-RGD<sub>4</sub> to integrin &#945;<sub>v</sub>&#946;<sub>3</sub> is RGD-specific. This conclusion is consistent with the lower tumor uptake for <sup>111</sup>In(DOTA-6P-RGK<sub>4</sub>) than that for <sup>111</sup>In(DOTA-6P-RGD<sub>4</sub>). It was also found that the G<sub>3</sub> and PEG<sub>4</sub> linkers between RGD motifs have a significant impact on the integrin &#945;<sub>v</sub>&#946;<sub>3</sub>-targeting capability, biodistribution characteristics, excretion kinetics and metabolic stability of <sup>111</sup>In-labeled cyclic RGD peptides.</p><p><b>Conclusion: </b>On the basis of their integrin &#945;<sub>v</sub>&#946;<sub>3</sub> binding affinity and tumor uptake of their corresponding <sup>111</sup>In radiotracers, it was conclude that 2P-RGD<sub>4</sub>, 2P4G-RGD<sub>4</sub> and 6P-RGD<sub>4</sub> are most likely bivalent in binding to integrin &#945;<sub>v</sub>&#946;<sub>3</sub>, and extra RGD motifs might contribute to the long tumor retention times of <sup>111</sup>In(DOTA-2P-RGD<sub>4</sub>),<sup> 111</sup>In(DOTA-2P4G-RGD<sub>4</sub>) and <sup>111</sup>In(DOTA-6P-RGD<sub>4</sub>) than that of <sup>111</sup>In(DOTA-3P-RGD<sub>3</sub>) at 72 h p.i. Among the <sup>111</sup>In-labeled cyclic RGD tetramers evaluated in the glioma model, <sup>111</sup>In(DOTA-2P4G-RGD<sub>4</sub>) has very high tumor uptake with the best tumor/kidney and tumor/liver ratios, suggesting that <sup>90</sup>Y(DOTA-2P4G-RGD<sub>4</sub>) and <sup>177</sup>Lu(DOTA-2P4G-RGD<sub>4</sub>) might have the potential for targeted radiotherapy of integrin &#945;<sub>v</sub>&#946;<sub>3</sub>-positive tumors.</p>http://www.thno.org/v01p0322.htm

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