Abstract
The purpose of this study was to examine how the introduction of ibuprofen (IBU) affected tumor-targeting and biodistribution properties of (177)Lu-labeled IBU-conjugated alpha-melanocyte-stimulating hormone peptides. The IBU was used as an albumin binder and conjugated to the DOTA-Lys moiety without or with a linker to yield DOTA-Lys(IBU)-GG-Nle-CycMSH(hex) {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(IBU)-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH(2)}, DOTA-Lys(Asp-IBU)-GGNle-CycMSH(hex), DOTA-Lys(Asn-IBU)-GGNle-CycMSH(hex), and DOTA-Lys(Dab-IBU)-GGNle-CycMSH(hex) peptides. Their melanocortin-receptor 1 (MC1R) binding affinities were determined on B16/F10 melanoma cells first. Then the biodistribution of (177)Lu-labeled peptides was determined on B16/F10 melanoma-bearing C57 mice at 2 h postinjection to choose the lead peptide for further examination. The full biodistribution and melanoma imaging properties of (177)Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH(hex) were further evaluated using B16/F10 melanoma-bearing C57 mice. DOTA-Lys(IBU)-GG-Nle-CycMSH(hex), DOTA-Lys(Asp-IBU)-GGNle-CycMSH(hex), DOTA-Lys(Asn-IBU)-GGNle-CycMSH(hex), and DOTA-Lys(Dab-IBU)-GGNle-CycMSH(hex) displayed the IC(50) values of 1.41 ± 0.37, 1.52 ± 0.08, 0.03 ± 0.01, and 0.58 ± 0.06 nM on B16/F10 melanoma cells, respectively. (177)Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH(hex) exhibited the lowest liver and kidney uptake among all four designed (177)Lu peptides. Therefore, (177)Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH(hex) was further evaluated for its full biodistribution and melanoma imaging properties. The B16/F10 melanoma uptake of (177)Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH(hex) was 19.5 ± 3.12, 24.12 ± 3.35, 23.85 ± 2.08, and 10.80 ± 2.89% ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. Moreover, (177)Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH(hex) could clearly visualize the B16/F10 melanoma lesions at 2 h postinjection. The conjugation of IBU with or without a linker to GGNle-CycMSH(hex) affected the MC1R binding affinities of the designed peptides. The charge of the linker played a key role in the liver and kidney uptake of (177)Lu-Asp-IBU, (177)Lu-Asn-IBU, and (177)Lu-Dab-IBU. (177)Lu-Asp-IBU exhibited higher tumor/liver and tumor/kidney uptake ratios than those of (177)Lu-Asn-IBU and (177)Lu-Dab-IBU, underscoring its potential evaluation for melanoma therapy in the future.