引入8-氨基辛酸连接体可增强99mTc标记的内酰胺桥环化α-促黑素细胞激素肽在黑色素瘤中的摄取。
Introduction of an 8-aminooctanoic acid linker enhances uptake of 99mTc-labeled lactam bridge-cyclized α-MSH peptide in melanoma.
作者信息
Guo Haixun, Miao Yubin
机构信息
College of Pharmacy, University of New Mexico, Albuquerque, New Mexico.
College of Pharmacy, University of New Mexico, Albuquerque, New Mexico Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico; and Department of Dermatology, University of New Mexico, Albuquerque, New Mexico
出版信息
J Nucl Med. 2014 Dec;55(12):2057-63. doi: 10.2967/jnumed.114.145896. Epub 2014 Nov 7.
UNLABELLED
The purpose of this study was to examine the effects of amino acid, hydrocarbon, and polyethylene glycol (PEG) linkers on the melanoma targeting and imaging properties of (99m)Tc-labeled lactam bridge-cyclized HYNIC-linker-Nle-CycMSHhex (hydrazinonicotinamide-linker-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2) peptides.
METHODS
Four novel peptides (HYNIC-GGGNle-CycMSHhex, HYNIC-GSGNle-CycMSHhex, HYNIC-PEG2Nle-CycMSHhex, and HYNIC-AocNle-CycMSHhex) were designed and synthesized. The melanocortin-1 receptor binding affinities of the peptides were determined in B16/F1 melanoma cells. The biodistribution of (99m)Tc(ethylenediaminediacetic acid [EDDA])-HYNIC-GGGNle-CycMSHhex, (99m)Tc(EDDA)-HYNIC-GSGNle-CycMSHhex, (99m)Tc(EDDA)-HYNIC-PEG2Nle-CycMSHhex, and (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex were determined in B16/F1 melanoma-bearing C57 mice at 2 h after injection to select a lead peptide for further evaluation. The melanoma targeting and imaging properties of (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex were further examined because of its high melanoma uptake.
RESULTS
The inhibitory concentrations of 50% (IC50) for HYNIC-GGGNle-CycMSHhex, HYNIC-GSGNle-CycMSHhex, HYNIC-PEG2Nle-CycMSHhex, and HYNIC-AocNle-CycMSHhex were 0.7 ± 0.1, 0.8 ± 0.09, 0.4 ± 0.08, and 0.3 ± 0.06 nM, respectively, in B16/F1 melanoma cells. Among these four (99m)Tc-labeled peptides, (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex displayed the highest melanoma uptake (22.3 ± 1.72 percentage injected dose/g) at 2 h after injection. (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex exhibited high tumor-to-normal-organ uptake ratios except for the kidneys. The tumor-to-kidney uptake ratios of (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex were 3.29, 3.63, and 6.78 at 2, 4, and 24 h, respectively, after injection. The melanoma lesions were clearly visualized by SPECT/CT using (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex as an imaging probe at 2 h after injection.
CONCLUSION
High melanoma uptake and fast urinary clearance of (99m)Tc(EDDA)-HYNIC-AocNle-CycMSHhex highlighted its potential for metastatic melanoma detection in the future.
未标记
本研究的目的是考察氨基酸、烃类和聚乙二醇（PEG）连接体对（99m）Tc标记的内酰胺桥环化的联肼尼克酰胺连接体-Nle-环化促黑素六肽（hydrazinonicotinamide-linker-Nle-c[天冬氨酸-组氨酸-二苯丙氨酸-精氨酸-色氨酸-赖氨酸]-CONH2）肽的黑色素瘤靶向性和成像特性的影响。
方法
设计并合成了四种新型肽（HYNIC-GGGNle-环化促黑素六肽、HYNIC-GSGNle-环化促黑素六肽、HYNIC-PEG2Nle-环化促黑素六肽和HYNIC-AocNle-环化促黑素六肽）。在B16/F1黑色素瘤细胞中测定这些肽与黑皮质素-1受体的结合亲和力。在注射后2小时，测定（99m）Tc（乙二胺二乙酸[EDDA]）-HYNIC-GGGNle-环化促黑素六肽、（99m）Tc（EDDA）-HYNIC-GSGNle-环化促黑素六肽、（99m）Tc（EDDA）-HYNIC-PEG2Nle-环化促黑素六肽和（99m）Tc（EDDA）-HYNIC-AocNle-环化促黑素六肽在荷B16/F1黑色素瘤的C57小鼠体内的生物分布，以选择一种先导肽进行进一步评估。由于（99m）Tc（EDDA）-HYNIC-AocNle-环化促黑素六肽对黑色素瘤的摄取率高，因此进一步考察了其黑色素瘤靶向性和成像特性。
结果
在B16/F1黑色素瘤细胞中，HYNIC-GGGNle-环化促黑素六肽、HYNIC-GSGNle-环化促黑素六肽、HYNIC-PEG2Nle-环化促黑素六肽和HYNIC-AocNle-环化促黑素六肽的半数抑制浓度（IC50）分别为0.7±0.1、0.8±0.09、0.4±0.08和0.3±0.06 nM。在这四种（99m）Tc标记的肽中，（99m）Tc（EDDA）-HYNIC-AocNle-环化促黑素六肽在注射后2小时显示出最高的黑色素瘤摄取率（22.3±1.72%注射剂量/克）。（99m）Tc（EDDA）-HYNIC-AocNle-环化促黑素六肽除肾脏外，肿瘤与正常器官的摄取率比值较高。注射后2、4和24小时，（99m）Tc（EDDA）-HYNIC-AocNle-环化促黑素六肽的肿瘤与肾脏摄取率比值分别为3.29、3.63和6.78。注射后2小时，以（99m）Tc（EDDA）-HYNIC-AocNle-环化促黑素六肽为成像探针，通过SPECT/CT可清晰显示黑色素瘤病灶。
结论
（99m）Tc（EDDA）-HYNIC-AocNle-环化促黑素六肽对黑色素瘤的高摄取率和快速经尿清除突出了其在未来检测转移性黑色素瘤方面的潜力。
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