氨基酸连接子对 111In 标记的酰胺桥环化α-MSH 肽的黑色素瘤靶向和药代动力学性质的影响。
Effects of the amino acid linkers on the melanoma-targeting and pharmacokinetic properties of 111In-labeled lactam bridge-cyclized alpha-MSH peptides.
机构信息
College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131, USA.
出版信息
J Nucl Med. 2011 Apr;52(4):608-16. doi: 10.2967/jnumed.110.086009. Epub 2011 Mar 18.
UNLABELLED
The purpose of this study was to examine the profound effects of the amino acid linkers on the melanoma-targeting and pharmacokinetic properties of (111)In-labeled lactam bridge-cyclized DOTA-[X]-CycMSH(hex) {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[X]-c[Asp-His-dPhe-Arg-Trp-Lys]-CONH(2); X = GGNle, GENle, or NleGE; GG = -Gly-Gly- and GE = -Gly-Glu-} peptides.
METHODS
Three novel peptides (DOTA-GGNle-CycMSH(hex), DOTA-GENle-CycMSH(hex), and DOTA-NleGE-CycMSH(hex)) were designed and synthesized. The melanocortin-1 (MC1) receptor-binding affinities of the peptides were determined in B16/F1 melanoma cells. The melanoma-targeting and pharmacokinetic properties of (111)In-DOTA-GGNle-CycMSH(hex) and (111)In-DOTA-GENle-CycMSH(hex) were determined in B16/F1 melanoma-bearing C57 mice.
RESULTS
DOTA-GGNle-CycMSH(hex) and DOTA-GENle-CycMSH(hex) displayed 2.1 and 11.5 nM MC1 receptor-binding affinities, whereas DOTA-NleGE-CycMSH(hex) showed 873.4 nM MC1 receptor-binding affinity. The introduction of the -GG- linker maintained high melanoma uptake while decreasing kidney and liver uptake of (111)In-DOTA-GGNle-CycMSH(hex). The tumor uptake of (111)In-DOTA-GGNle-CycMSH(hex) was 19.05 ± 5.04 and 18.6 ± 3.56 percentage injected dose per gram at 2 and 4 h after injection, respectively. (111)In-DOTA-GGNle-CycMSH(hex) exhibited 28%, 32%, and 42% less kidney uptake than (111)In-DOTA-Nle-CycMSH(hex) we reported previously, and 61%, 65%, and 68% less liver uptake than (111)In-DOTA-Nle-CycMSH(hex) at 2, 4, and 24 h after injection, respectively.
CONCLUSION
The amino acid linkers exhibited profound effects on the melanoma-targeting and pharmacokinetic properties of the (111)In-labeled lactam bridge-cyclized α-melanocyte-stimulating hormone peptides. Introduction of the -GG- linker maintained high melanoma uptake while reducing kidney and liver uptake of (111)In-DOTA-GGNle-CycMSH(hex), highlighting its potential as an effective imaging probe for melanoma detection, as well as a therapeutic peptide for melanoma treatment when labeled with a therapeutic radionuclide.
目的
本研究旨在探讨氨基酸连接子对（111）In 标记的酰胺桥环合 DOTA-[X]-CycMSH（hex）[1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-[X]-c[天冬氨酸-组氨酸-二苯丙氨酸-精氨酸-色氨酸-赖氨酸]-CONH2；X=GGNle、GENle 或 NleGE；GG=-甘氨酰-甘氨酰-和 GE=-甘氨酰-谷氨酸-]肽的黑素细胞 1（MC1）受体靶向和药代动力学特性的深远影响。
方法
设计并合成了三种新型肽（DOTA-GGNle-CycMSH（hex）、DOTA-GENle-CycMSH（hex）和 DOTA-NleGE-CycMSH（hex））。在 B16/F1 黑素瘤细胞中测定肽的黑素细胞 1（MC1）受体结合亲和力。在 B16/F1 黑素瘤荷瘤 C57 小鼠中测定（111）In-DOTA-GGNle-CycMSH（hex）和（111）In-DOTA-GENle-CycMSH（hex）的黑素瘤靶向和药代动力学特性。
结果
DOTA-GGNle-CycMSH（hex）和 DOTA-GENle-CycMSH（hex）分别显示 2.1 和 11.5 nM MC1 受体结合亲和力，而 DOTA-NleGE-CycMSH（hex）显示 873.4 nM MC1 受体结合亲和力。-GG-接头的引入保持了高黑素瘤摄取率，同时降低了（111）In-DOTA-GGNle-CycMSH（hex）的肾脏和肝脏摄取率。（111）In-DOTA-GGNle-CycMSH（hex）的肿瘤摄取率分别为 2 和 4 小时后每克 19.05±5.04%和 18.6±3.56%注入剂量。与我们之前报道的（111）In-DOTA-Nle-CycMSH（hex）相比，（111）In-DOTA-GGNle-CycMSH（hex）的肾脏摄取量分别减少 28%、32%和 42%，而与（111）In-DOTA-Nle-CycMSH（hex）相比，肝脏摄取量分别减少 61%、65%和 68%在 2、4 和 24 小时后。
结论
氨基酸接头对（111）In 标记的酰胺桥环合α-促黑素细胞激素肽的黑素细胞靶向和药代动力学特性有深远影响。-GG-接头的引入保持了（111）In-DOTA-GGNle-CycMSH（hex）的高黑素瘤摄取率，同时降低了肾脏和肝脏摄取率，这突出了它作为一种有效的黑素瘤检测成像探针的潜力，以及当用治疗放射性核素标记时作为黑素瘤治疗的治疗性肽。
Zotero 插件