Introduction of a Polyethylene Glycol Linker Improves Uptake of Cu-NOTA-Conjugated Lactam-Cyclized Alpha-Melanocyte-Stimulating Hormone Peptide in Melanoma.

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-GGNle-CycMSH {Cu-NOTA-GlyGlyNle-CycMSH} on melanoma-bearing mice. NOTA-PEGNle-CycMSH and NOTA-GGNle-CycMSH were synthesized and purified by HPLC. The biodistribution of Cu-NOTA-PEGNle-CycMSH and Cu-NOTA-GGNle-CycMSH was determined in B16/F10 melanoma-bearing C57 mice. The melanoma imaging property of Cu-NOTA-PEGNle-CycMSH was further examined in B16/F10 melanoma-bearing C57 mice. Cu-NOTA-PEGNle-CycMSH exhibited higher tumor uptake than Cu-NOTA-GGNle-CycMSH at 2, 4, and 24 h post-injection. The tumor uptake of Cu-NOTA-PEGNle-CycMSH was 27.97 ± 1.98, 24.10 ± 1.83, and 9.13 ± 1.66% ID/g at 2, 4, and 24 h post-injection, respectively. Normal organ uptake of Cu-NOTA-PEGNle-CycMSH was lower than 2.6% ID/g at 4 h post-injection, except for kidney uptake. The renal uptake of Cu-NOTA-PEGNle-CycMSH was 6.43 ± 1.31, 2.60 ± 0.79, and 0.90 ± 0.18% 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 single photon emission computed tomography (SPECT) using Cu-NOTA-PEGNle-CycMSH as an imaging probe at 4 h post-injection. The favorable tumor targeting and biodistribution properties of Cu-NOTA-PEGNle-CycMSH underscored its potential as an MC1R-targeted therapeutic peptide for melanoma treatment.