Improving Tumor Uptake and Pharmacokinetics of 64Cu-Labeled Cyclic RGD Peptide Dimers with Gly3 and PEG4 Linkers

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• 作者：Jiyun Shi ; Young-Seung Kim ; Shizhen Zhai ; Zhaofei Liu ; Xiaoyuan Chen ; Shuang Liu
• 刊名：Bioconjugate Chemistry
• 出版年：2009
• 出版时间：April 15, 2009
• 年：2009
• 卷：20
• 期：4
• 页码：750-759
• 全文大小：345K
• 年卷期：v.20,no.4(April 15, 2009)
• ISSN：1520-4812

文摘

Radiolabeled cyclic RGD (Arg-Gly-Asp) peptides represent a new class of radiotracers with potential for early tumor detection and noninvasive monitoring of tumor metastasis and therapeutic response in cancer patients. This article describes the synthesis of two cyclic RGD peptide dimer conjugates, DOTA-PEG₄-E[PEG₄-c(RGDfK)]₂ (DOTA-3PEG₄-dimer: DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; PEG₄ = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and DOTA-G₃-E[G₃-c(RGDfK)]₂ (DOTA-3G₃-dimer: G₃ = Gly-Gly-Gly). Integrin α_vβ₃ binding affinities of cyclic RGD peptides were determined by competitive displacement of ¹²⁵I-echistatin bound to U87MG human glioma cells and follow the order of DOTA-E{E[c(RGDfK)]₂}₂ (DOTA-tetramer: IC₅₀ = 10 ± 2 nM) > DOTA-3G₃-dimer (IC₅₀ = 62 ± 6 nM) DOTA-3PEG₄-dimer (IC₅₀ = 74 ± 3 nM) > DOTA-E[c(RGDfK)]₂ (DOTA-dimer: IC₅₀ = 102 ± 5 nM). The addition of PEG₄ and G₃ linkers between two cyclic RGD motifs in DOTA-3G₃-dimer and DOTA-3PEG₄-dimer makes it possible for them to achieve the simultaneous integrin α_vβ₃ binding in a bivalent fashion. Both ⁶⁴Cu(DOTA-3PEG₄-dimer) and ⁶⁴Cu(DOTA-3G₃-dimer) were prepared in high yield with specific activity being >50 Ci/mmol. Biodistribution and imaging studies were performed in athymic nude mice bearing U87MG human glioma xenografts. The results from those studies show that PEG₄ and G₃ linkers are particularly useful for improving tumor uptake and clearance kinetics of ⁶⁴Cu radiotracers from the nontumor organs, such as kidneys, liver, and lungs. There is a linear relationship between the tumor size and %ID tumor uptake, suggesting that ⁶⁴Cu(DOTA-3PEG₄-dimer) and ⁶⁴Cu(DOTA-3PEG₄-dimer) might be useful for noninvasive monitoring of tumor growth or shrinkage during antiangiogenic therapy. MicroPET imaging data clearly demonstrate the utility of ⁶⁴Cu(DOTA-3G₃-dimer) as a new PET radiotracer for imaging integrin α_vβ₃-positive tumors.