6-hydrazinopyridine-3-carboxylic-acid and Melanoma

Topics: Adult; Aged; Animals; Breast Neoplasms; Chemistry Techniques, Synthetic; Female; Half-Life; Humans; Hydrazines; Melanoma; Mice; Middle Aged; Nicotinic Acids; Organotechnetium Compounds; Peptides, Cyclic; Radiochemistry; Single Photon Emission Computed Tomography Computed Tomography; Tissue Distribution

Melanocortin-1 (MC1) receptor is an attractive melanoma-specific target which has been used for melanoma imaging and therapy. In this work, a new lactam bridge α-MSH analog was labeled with (99m)Tc via HYNIC and EDDA/tricine as coligands including gamma aminobutyric acid (GABA) as a three carbon chain spacer between HYNIC and the N-terminus of the cyclic peptide. Also, stability in human serum, receptor bound internalization, in vivo tumor uptake, and tissue biodistribution were thoroughly investigated.. HYNIC-GABA-Nle-CycMSHhept was synthesized using a standard Fmoc strategy. Labeling was performed at 95 °C and analysis involved instant thin layer chromatography and high performance liquid chromatography methods. The receptor bound internalization rate was studied in MC1 receptor expressing B16/F10 cells. Biodistribution of radiopeptide was studied in nude mice bearing B16/F10 tumor.. Labeling yield of >98 % (n = 3) was obtained corresponding to a specific activity of 81 MBq/nmol. Peptide conjugate showed efficient stability in the presence of human serum. The radioligand showed specific internalization into B16/F10 cells (12.45 ± 1.1 % at 4 h). In biodistribution studies, a receptor-specific uptake was observed in MC1 receptor-positive organs so that after 2 h the uptake in mouse tumor was 5.10 ± 0.08 % ID/g, while low accumulation in the kidney uptake was observed (4.58 ± 0.68 % ID/g at 2 h after injection).. The obtained results show that the presented new designed labeled peptide conjugate may be a suitable candidate for diagnosis of malignant tumors.

Topics: alpha-MSH; Amino Acid Sequence; Animals; Biological Transport; Cell Line, Tumor; Drug Stability; gamma-Aminobutyric Acid; Hydrazines; Hydrophobic and Hydrophilic Interactions; Lactams; Melanoma; Mice; Nicotinic Acids; Peptides, Cyclic; Photons; Radionuclide Imaging; Technetium; Tissue Distribution

The incidence of melanoma is rising, and therapeutic options for metastatic melanoma are limited. We report the results of experimental melanoma therapy with 188-Rhenium-labeled melanin-binding decapeptide ((188)RE-HYNIC-4B4) and a comprehensive safety evaluation of this treatment. (188)RE-HYNIC- 4B4 bound only to nonviable eumelanotic MNT1 and pheomelanotic SK-28-MEL human melanoma cells in vitro, as determined by immunofluorescence, which is consistent with the inaccessibility of intracellular melanin in live cells, and suggests specificity for tumors with a significant amount of extracellular melanin. Administration of 1 mCi (188)RE-HYNIC-4B4 to MNT1 tumor-bearing mice significantly slowed tumor growth, with the therapeutic effect being a result of specific binding to tumor melanin, as irrelevant (188)RE-labeled decapeptide did not produce therapeutic gain. Repeated doses of (188)RE-HYNIC-4B4 had a more profound effect on tumor growth than a single dose. Treatment of tumors with 0.3-0.4 cm diameter was more effective than of larger ones (0.5-0.7 cm). There was no difference in uptake of (188)REHYNIC- 4B4 in melanized tissues of black C57BL6 mice and no histologically apparent damage to these tissues in comparison with white BALB/C mice. Treatment of C57BL6 mice with (188)RE-HYNIC-4B4 did not change their behavior, as established by SHIRPA protocol, and did not cause damage to neurons and glial cells. These results indicate that radiolabeled melanin-binding peptides are efficient and safe in treatment of melanoma and could be potentially useful against this tumor.

Topics: Animals; Brain Diseases; Cell Line, Tumor; Chromatography, High Pressure Liquid; Female; Fluorescent Antibody Technique; Humans; Hydrazines; Immunotoxins; Kidney Diseases; Male; Melanins; Melanoma; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Nicotinic Acids; Peptides; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals; Rhenium; Tissue Distribution; Xenograft Model Antitumor Assays