Effect of DOTA Position on Melanoma Targeting and Pharmacokinetic Properties of 111In-Labeled Lactam Bridge-Cyclized α-Melanocyte Stimulating Hormone Peptide

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• 作者：Haixun Guo ; Jianquan Yang ; Fabio Gallazzi ; Eric R. Prossnitz ; Larry A. Sklar ; Yubin Miao
• 刊名：Bioconjugate Chemistry
• 出版年：2009
• 出版时间：November 18, 2009
• 年：2009
• 卷：20
• 期：11
• 页码：2162-2168
• 全文大小：240K
• 年卷期：v.20,no.11(November 18, 2009)
• ISSN：1520-4812

文摘

The purpose of this study was to examine the effect of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) position on melanoma targeting and pharmacokinetics of radiolabeled lactam bridge-cyclized α-melanocyte stimulating hormone (α-MSH) peptide. Method: A novel lactam bridge-cyclized α-MSH peptide, Ac-GluGlu-CycMSH[DOTA] {Ac-Glu-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Lys(DOTA)]}, was synthesized using standard 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry. DOTA was directly attached to the α-amino group of Lys in the cyclic ring, while the N-terminus of the peptide was acetylated to generate Ac-GluGlu-CycMSH[DOTA]. The MC1 receptor binding affinity of Ac-GluGlu-CycMSH[DOTA] was determined in B16/F1 melanoma cells. Melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-¹¹¹In were determined in B16/F1 melanoma-bearing C57 mice and compared to that of ¹¹¹In-DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp] (¹¹¹In-DOTA-GlyGlu-CycMSH; DOTA was coupled to the N-terminus of the peptide). Results: Ac-GluGlu-CycMSH[DOTA] displayed 0.6 nM MC1 receptor binding affinity in B16/F1 cells. Ac-GluGlu-CycMSH[DOTA]-¹¹¹In was readily prepared with greater than 95% radiolabeling yield. Ac-GluGlu-CycMSH[DOTA]-¹¹¹In exhibited high tumor uptake (11.42 ± 2.20% ID/g 2 h postinjection) and prolonged tumor retention (9.42 ± 2.41% ID/g 4 h postinjection) in B16/F1 melanoma-bearing C57 mice. The uptake values for nontarget organs were generally low (<1.3% ID/g) except for the kidneys 2, 4, and 24 h postinjection. Conclusions: DOTA position exhibited profound effect on melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-¹¹¹In, providing a new insight into the design of lactam bridge-cyclized peptide for melanoma imaging and therapy.