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赖氨酸连接子的结构修饰增强了 99mTc 标记的 RGD 缀合α-MSH 杂合肽的肿瘤向肾脏摄取比值。

Structural modification on the Lys linker enhanced tumor to kidney uptake ratios of 99mTc-labeled RGD-conjugated α-MSH hybrid peptides.

机构信息

College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131, United States.

出版信息

Mol Pharm. 2012 May 7;9(5):1418-24. doi: 10.1021/mp2006642. Epub 2012 Apr 4.

DOI:10.1021/mp2006642
PMID:22452443
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3348435/
Abstract

The purpose of this study was to examine whether the structural modification on the positively charged Lys linker could reduce the kidney uptake of (99m)Tc-labeled Arg-Gly-Asp (RGD)-conjugated α-melanocyte stimulating hormone (α-MSH) hybrid peptides. The RGD motif {cyclic(Arg-Gly-Asp-D-Tyr-Asp)} was coupled to [Cys(3,4,10), D-Phe(7), Arg(11)]α-MSH(3-13) {(Arg(11))CCMSH} through a neutral glycine linker to eliminate the positively charged amino side chain of the Lys linker or without a linker to delete the Lys linker. The receptor binding affinity of RGD-Gly-(Arg(11))CCMSH and RGD-(Arg(11))CCMSH was determined in B16/F1 melanoma cells. The melanoma targeting and imaging properties of (99m)Tc-RGD-Gly-(Arg(11))CCMSH and (99m)Tc-RGD-(Arg(11))CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The structural modification on the Lys linker retained a low nanomolar receptor binding affinity of RGD-Gly-(Arg(11))CCMSH and RGD-(Arg(11))CCMSH (1.5 and 1.0 nM, respectively). The structural modification on the Lys linker dramatically decreased the renal uptake of (99m)Tc-RGD-Gly-(Arg(11))CCMSH and (99m)Tc-RGD-(Arg(11))CCMSH by 79% and 77% at 4 h postinjection compared to (99m)Tc-RGD-Lys-(Arg(11))CCMSH. (99m)Tc-RGD-(Arg(11))CCMSH displayed a higher melanoma uptake (16.12 ± 3.09% ID/g) than (99m)Tc-RGD-Gly-(Arg(11))CCMSH (11.50 ± 1.01% ID/g) at 2 postinjection. The tumor uptake of (99m)Tc-RGD-(Arg(11))CCMSH was 1.4 times the tumor uptake of (99m)Tc-RGD-Gly-(Arg(11))CCMSH at 2 postinjection. A dramatically enhanced tumor-to-kidney uptake ratio of (99m)Tc-RGD-(Arg(11))CCMSH suggests that (188)Re-RGD-(Arg(11))CCMSH may behave in a similar fashion warranting future evaluation for melanoma treatment.

摘要

本研究旨在探讨正电荷赖氨酸连接子的结构修饰是否可以降低（99m）Tc 标记的 Arg-Gly-Asp（RGD）缀合的α-黑素细胞刺激素（α-MSH）杂合肽的肾脏摄取。RGD 基序{cyclic(Arg-Gly-Asp-D-Tyr-Asp)}通过中性甘氨酸连接子与[Cys(3,4,10), D-Phe(7), Arg(11)]α-MSH(3-13) {(Arg(11))CCMSH}偶联，消除赖氨酸连接子的正电荷侧链，或不使用连接子删除赖氨酸连接子。在 B16/F1 黑色素瘤细胞中测定 RGD-Gly-(Arg(11))CCMSH 和 RGD-(Arg(11))CCMSH 的受体结合亲和力。在携带 B16/F1 黑色素瘤的 C57 小鼠中测定（99m）Tc-RGD-Gly-(Arg(11))CCMSH 和（99m）Tc-RGD-(Arg(11))CCMSH 的黑色素瘤靶向和成像特性。赖氨酸连接子的结构修饰保留了 RGD-Gly-(Arg(11))CCMSH 和 RGD-(Arg(11))CCMSH 的低纳摩尔受体结合亲和力（分别为 1.5 和 1.0 nM）。赖氨酸连接子的结构修饰使（99m）Tc-RGD-Gly-(Arg(11))CCMSH 和（99m）Tc-RGD-(Arg(11))CCMSH 在注射后 4 小时的肾脏摄取分别降低了 79%和 77%，而（99m）Tc-RGD-Lys-(Arg(11))CCMSH。与（99m）Tc-RGD-Gly-(Arg(11))CCMSH（注射后 2 小时 11.50±1.01% ID/g）相比，（99m）Tc-RGD-(Arg(11))CCMSH 在注射后 2 小时的黑色素瘤摄取更高（16.12±3.09% ID/g）。（99m）Tc-RGD-(Arg(11))CCMSH 的肿瘤摄取是（99m）Tc-RGD-Gly-(Arg(11))CCMSH 的 1.4 倍，注射后 2 小时。（99m）Tc-RGD-(Arg(11))CCMSH 的肿瘤-肾脏摄取比值明显提高，提示（188）Re-RGD-(Arg(11))CCMSH 可能具有类似的行为，值得进一步评估用于黑色素瘤治疗。

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