Novel Cu-64-Labeled NOTA-Conjugated Lactam-Cyclized Alpha-Melanocyte-Stimulating Hormone Peptides with Enhanced Tumor to Kidney Uptake Ratios
Molecular pharmaceutics(2022)
摘要
The aim of this study was to evaluate the effect of linker on tumor targeting and biodistribution of Cu-64-NOTA-PEG(2)Nle-CycMSH(hex) {Cu-64-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-polyethylene glycol-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} and Cu-64-NOTA-AocNle-CycMSH(hex) {Cu-64-NOTA-8-aminooctanoic acid-Nle-CycMSH(hex)} on melanoma-bearing mice. NOTA-PEG(2)Nle-CycMSH(hex) and NOTA-AocNle-CycMSH(hex) 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-64-NOTA-PEG(2)Nle-CycMSH(hex) and Cu-64-NOTA-AocNle-CycMSH(hex) were determined on B16/F10 melanoma-bearing C57 mice. The melanoma imaging property of Cu-64-NOTA-PEG(2)Nle-CycMSH(hex) was further examined on B16/F10 melanoma-bearing C57 mice because of its higher melanoma uptake than Cu-64-NOTA-AocNle-CycMSH(hex). The IC50 values of NOTA-PEG(2)Nle-CycMSH(hex) and NOTA-AocNle-CycMSH(hex) were 1.24 ?? 0.07 and 2.75 +/- 0.48 nM on B10/F10 melanoma cells. Cu-64-NOTA-PEG(2)Nle-CycMSH(hex) and Cu-64-NOTA-AocNle-CycMSH(hex) were readily prepared with more than 90% radiolabeling yields and showed MC1R-specific binding on B16/F10 cells. Cu-64-NOTA-PEG(2)Nle-CycMSH(hex) exhibited higher tumor uptake than Cu-64-NOTA-AocNle-CycMSH(hex) at 0.5, 2, 4, and 24 h post-injection. The tumor uptake of Cu-64-NOTA-PEG(2)Nle-CycMSH(hex) 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-64-NOTA-PEG(2)Nle-CycMSH(hex) was lower than 2% ID/g at 2 h post-injection except for kidney uptake. The renal uptake of Cu-64-NOTA-PEG(2)Nle-CycMSH(hex) 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-64-NOTA-PEG(2)Nle-CycMSH(hex) 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-64-NOTA-PEG(2)Nle-CycMSH(hex) as an imaging probe at 2 h post-injection. High tumor uptake and low kidney uptake of Cu-64-NOTA-PEG(2)Nle-CycMSH(hex) underscored its potential as an MC1R-theranostic peptide for melanoma and therapy.
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关键词
Cu-64-NOTA, lactam-cyclized, alpha-melanocyte-stimulating hormone, melanocortin-1 receptor, melanoma imaging and therapy
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