The Effect of Albumin-Binding Moiety on Tumor Targeting and Biodistribution Properties of 67Ga-Labeled Albumin Binder-Conjugated Alpha-Melanocyte-Stimulating Hormone Peptides.
The Effect of Albumin-Binding Moiety on Tumor Targeting and Biodistribution Properties of 67Ga-Labeled Albumin Binder-Conjugated Alpha-Melanocyte-Stimulating Hormone Peptides.
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白蛋白结合部分对 67Ga 标记的白蛋白结合剂缀合的 α-黑素细胞刺激激素肽的肿瘤靶向和生物分布特性的影响。
DOI：
10.1089/cbr.2021.0273
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发表时间：
2022
影响因子：
3.4
通讯作者：
Miao,Yubin
中科院分区：
文献类型：
--
作者：
Xu,Jingli;Gallazzi,Fabio;Fisher,DarrellR;Gonzalez,Rene;Miao,Yubin
背景：本研究的目的是检测4-对甲苯基丁酸作为白蛋白结合（ALB）部分对67 Ga标记的白蛋白结合剂缀合的α-促黑素细胞激素肽的肿瘤靶向和生物分布特性的影响。材料和方法：以4-对甲苯基丁酸作为ALB部分，合成DOTA-Lys（ALB）-G/GG/GGG-Nle-CycMSHhex{1，4，7，10-tetraazacyclodecane-1，4，7，10-tetraaceticacid-Lys（ALB）-Gly/GlyGly/GlyGlyGly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH 2}。在B16/F10黑素瘤细胞上测定肽的黑皮质素-1受体（MC 1 R）结合亲和力。在注射后2小时，在携带B16/F10黑素瘤的C57小鼠上检查67 Ga-DOTA-Lys（ALB）-G/GG/GGG-Nle-CycMSHhex的生物分布，以选择用于进一步评价的先导肽。67 Ga-DOTA-Lys的黑色素瘤靶向性和显像特性（ALB）-GGNle-CycMSHhex{67 Ga-ALB-G2}在携带B16/F10黑素瘤的C57小鼠上测定。DOTA-Lys的IC 50值（ALB）-G/GG/GGG-Nle-CycMSHhex{ALB-G1，ALB-G2，ALB-G3}为0.67 ± 0.07，在B16/F10细胞上为0.5 ± 0.09和0.51 ± 0.03 nM，67 Ga-ALB-G2由于其较高的肿瘤摄取而被进一步评估为先导肽注射后2小时，67 Ga-ALB-G1和67 Ga-ALB-G3的肾脏摄取率分别为30.25 ± 3.24%ID/g和7.09 ± 2.22%ID/g，低于67 Ga-ALB-G1和67 Ga-ALB-G3。B16/F10黑色素瘤对67 Ga-ALB-G2的摄取在注射后0.5、2、4和24 h分别为15.64 ± 4.55、30.25 ± 3.24、26.76 ± 3.23和10.71 ± 1.21%ID/g。B16/F10黑色素瘤病灶在2 h postinjection.Conclusions：4-p-（tolyl）butyric acid作为ALB部分的引入增加了血液潴留，并导致更高的肿瘤/肾脏比of 67 Ga-ALB-G2相比，其对应物没有白蛋白结合剂。然而，当用治疗性放射性核素标记67 Ga时，需要进一步降低血液和肝脏中67 Ga-ALB-G2的高摄取以促进其治疗应用。
Background:The purpose of this study was to examine the effect of 4-p-(tolyl)butyric acid as an albumin-binding (ALB) moiety on tumor targeting and biodistribution properties of67Ga-labeled albumin binder-conjugated alpha-melanocyte-stimulating hormone peptides.Materials and Methods:DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSHhex{1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(ALB)-Gly/GlyGly/GlyGlyGly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} were synthesized with 4-p-(tolyl)butyric acid serving as an ALB moiety. The melanocortin-1 receptor (MC1R)-binding affinities of the peptides were determined on B16/F10 melanoma cells. The biodistribution of67Ga-DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSHhexwas examined on B16/F10 melanoma-bearing C57 mice at 2 h postinjection to select a lead peptide for further evaluation. The melanoma targeting and imaging properties of67Ga-DOTA-Lys(ALB)-GGNle-CycMSHhex{67Ga-ALB-G2} were determined on B16/F10 melanoma-bearing C57 mice.Results:The IC50value of DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSHhex{ALB-G1, ALB-G2, ALB-G3} was 0.67 ± 0.07, 0.5 ± 0.09 and 0.51 ± 0.03 nM on B16/F10 cells, respectively.67Ga-ALB-G2 was further evaluated as a lead peptide because of its higher tumor uptake (30.25 ± 3.24%ID/g) and lower kidney uptake (7.09 ± 2.22%ID/g) than67Ga-ALB-G1 and67Ga-ALB-G3 at 2 h postinjection. The B16/F10 melanoma uptake of67Ga-ALB-G2 was 15.64 ± 4.55, 30.25 ± 3.24, 26.76 ± 3.23, and 10.71 ± 1.21%ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. The B16/F10 melanoma lesions were clearly visualized by SPECT/CT using67Ga-ALB-G2 as an imaging probe at 2 h postinjection.Conclusions:The introduction of 4-p-(tolyl)butyric acid as an ALB moiety increased the blood retention, and resulted in higher tumor/kidney ratio of67Ga-ALB-G2 as compared with its counterpart without an albumin binder. However, the resulting high uptake of67Ga-ALB-G2 in blood and liver need to be further reduced to facilitate its therapeutic application when replacing67Ga with therapeutic radionuclides.