Qiao Zheng, Xu Jingli, Gonzalez Rene, Miao Yubin
Department of Radiology, University of Colorado Denver, Aurora, Colorado 80045, United States.
Department of Medical Oncology, University of Colorado Denver, Aurora, Colorado 80045, United States.
Mol Pharm. 2022 Jul 4;19(7):2535-2541. doi: 10.1021/acs.molpharmaceut.2c00211. Epub 2022 Apr 29.
The aim of this study was to evaluate the effect of linker on tumor targeting and biodistribution of Cu-NOTA-PEGNle-CycMSH {Cu-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-polyethylene glycol-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH} and Cu-NOTA-AocNle-CycMSH {Cu-NOTA-8-aminooctanoic acid-Nle-CycMSH} on melanoma-bearing mice. NOTA-PEGNle-CycMSH and NOTA-AocNle-CycMSH were synthesized and purified by HPLC. The melanocortin-1 (MC1) receptor binding affinities of the peptides were examined on B16/F10 melanoma cells. The biodistributions of Cu-NOTA-PEGNle-CycMSH and Cu-NOTA-AocNle-CycMSH were determined on B16/F10 melanoma-bearing C57 mice. The melanoma imaging property of Cu-NOTA-PEGNle-CycMSH was further examined on B16/F10 melanoma-bearing C57 mice because of its higher melanoma uptake than Cu-NOTA-AocNle-CycMSH. The IC values of NOTA-PEGNle-CycMSH and NOTA-AocNle-CycMSH were 1.24 ± 0.07 and 2.75 ± 0.48 nM on B10/F10 melanoma cells. Cu-NOTA-PEGNle-CycMSH and Cu-NOTA-AocNle-CycMSH were readily prepared with more than 90% radiolabeling yields and showed MC1R-specific binding on B16/F10 cells. Cu-NOTA-PEGNle-CycMSH exhibited higher tumor uptake than Cu-NOTA-AocNle-CycMSH at 0.5, 2, 4, and 24 h post-injection. The tumor uptake of Cu-NOTA-PEGNle-CycMSH was 16.23 ± 0.42, 19.59 ± 1.48, 12.83 ± 1.69, and 8.78 ± 2.29% ID/g at 0.5, 2, 4, and 24 h post-injection, respectively. Normal organ uptake of Cu-NOTA-PEGNle-CycMSH was lower than 2% ID/g at 2 h post-injection except for kidney uptake. The renal uptake of Cu-NOTA-PEGNle-CycMSH was 3.66 ± 0.52, 3.27 ± 0.52, and 1.47 ± 0.56 ID/g at 2, 4, and 24 h post-injection, respectively. Cu-NOTA-PEGNle-CycMSH showed high tumor to normal organ uptake ratios after 2 h post-injection. The B16/F10 melanoma lesions could be clearly visualized by positron emission tomography (PET) using Cu-NOTA-PEGNle-CycMSH as an imaging probe at 2 h post-injection. High tumor uptake and low kidney uptake of Cu-NOTA-PEGNle-CycMSH underscored its potential as an MC1R-targeted theranostic peptide for melanoma imaging and therapy.
本研究的目的是评估连接体对Cu-NOTA-PEGNle-CycMSH{Cu-1,4,7-三氮杂环壬烷-1,4,7-三乙酸-聚乙二醇-Nle-c[天冬氨酸-组氨酸-D-苯丙氨酸-精氨酸-色氨酸-赖氨酸]-CONH}和Cu-NOTA-AocNle-CycMSH{Cu-NOTA-8-氨基辛酸-Nle-CycMSH}在荷黑素瘤小鼠体内的肿瘤靶向性和生物分布的影响。NOTA-PEGNle-CycMSH和NOTA-AocNle-CycMSH通过高效液相色谱法合成并纯化。在B16/F10黑素瘤细胞上检测了这些肽与黑皮质素-1(MC1)受体的结合亲和力。在荷B16/F10黑素瘤的C57小鼠上测定了Cu-NOTA-PEGNle-CycMSH和Cu-NOTA-AocNle-CycMSH的生物分布。由于Cu-NOTA-PEGNle-CycMSH比Cu-NOTA-AocNle-CycMSH对黑素瘤的摄取更高，因此在荷B16/F10黑素瘤的C57小鼠上进一步检测了Cu-NOTA-PEGNle-CycMSH的黑素瘤成像特性。NOTA-PEGNle-CycMSH和NOTA-AocNle-CycMSH在B10/F10黑素瘤细胞上的IC值分别为1.24±0.07和2.75±0.48 nM。Cu-NOTA-PEGNle-CycMSH和Cu-NOTA-AocNle-CycMSH易于制备，放射性标记产率超过90%，并在B16/F10细胞上显示出MC1R特异性结合。在注射后0.5、2、4和24小时，Cu-NOTA-PEGNle-CycMSH的肿瘤摄取高于Cu-NOTA-AocNle-CycMSH。注射后0.5、2、4和24小时，Cu-NOTA-PEGNle-CycMSH的肿瘤摄取分别为16.23±0.42、19.59±1.48、12.83±1.69和8.78±2.29%ID/g。注射后2小时，除肾脏摄取外，Cu-NOTA-PEGNle-CycMSH在正常器官中的摄取低于2%ID/g。注射后2、4和24小时，Cu-NOTA-PEGNle-CycMSH的肾脏摄取分别为3.66±0.52、3.27±0.52和1.47±0.56 ID/g。注射后2小时，Cu-NOTA-PEGNle-CycMSH显示出高的肿瘤与正常器官摄取比。注射后2小时，使用Cu-NOTA-PEGNle-CycMSH作为成像探针，通过正电子发射断层扫描(PET)可以清晰地观察到B16/F10黑素瘤病变。Cu-NOTA-PEGNle-CycMSH的高肿瘤摄取和低肾脏摄取突出了其作为用于黑素瘤成像和治疗的MC1R靶向治疗诊断肽的潜力。
