((BO/00381/22)) Funder: Hungarian Academy of Sciences
(ÚNKP-22-5-ELTE-1157)
(ÚNKP-23-5-ELTE-494)
Malignant melanoma is one of the most aggressive and resistant tumor types, with high
metastatic properties. Because of the lack of suitable chemotherapeutic agents for
treatment, the 5-year survival rate of melanoma patients with regional and distant
metastases is lower than 10%. Targeted tumor therapy that provides several promising
results might be a good option for the treatment of malignant melanomas. Our goal
was to develop novel melanoma-specific peptide–drug conjugates for targeted tumor
therapy. Melanocortin-1-receptor (MC1R) is a cell surface receptor responsible for
melanogenesis and it is overexpressed on the surface of melanoma cells, providing
a good target. Its native ligand, α-MSH (α-melanocyte-stimulating hormone) peptide,
or its derivatives, might be potential homing devices for this purpose. Therefore,
we prepared three α-MSH derivative–daunomycin (Dau) conjugates and their in vitro
and in vivo antitumor activities were compared. Dau has an autofluorescence property;
therefore, it is suitable for preparing conjugates for in vitro (e.g., cellular uptake)
and in vivo experiments. Dau was attached to the peptides via a non-cleavable oxime
linkage that was applied efficiently in our previous experiments, resulting in conjugates
with high tumor growth inhibition activity. The results indicated that the most promising
conjugate was the compound in which Dau was connected to the side chain of Lys (Ac-SYSNleEHFRWGK(Dau=Aoa)PV-NH2).
The highest cellular uptake by melanoma cells was demonstrated using the compound,
with the highest tumor growth inhibition detected both on mouse (38.6% on B16) and
human uveal melanoma (55% on OMC-1) cells. The effect of the compound was more pronounced
than that of the free drug.
