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Issue 5, 2018
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Development of a peptide-based bifunctional chelator conjugated to a cytotoxic drug for the treatment of melanotic melanoma

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Abstract

The cytotoxic drug gemcitabine (GEM) has been conjugated to receptor-binding peptides to target melanoma tumors. A hexapeptide having a Lys–Gly–His–Lys sequence (pep-1), an octapeptide with an Arg–Gly–Asp–Lys–Gly–His–Lys sequence (pep-2), a GEM-conjugated Lys–Gly–His–Lys peptide (GEM–pep-3) and a GEM-conjugated Asp–Gly–Arg peptide (GEM–pep-4) were synthesized and characterized. In vitro uptake of fluorescently labeled GEM–pep-3 and GEM–pep-4 on B16F10 cells was investigated. Fluorescence microscopy studies demonstrated significant uptake of GEM–pep-3 in the B16F10 mouse melanoma cell line. The peptides and GEM-coupled peptides were radiolabeled with [99mTc(CO)3(H2O)3]+ and examined for in vitro cell binding in the B16F10 melanoma cell line and in vivo biodistribution and scintigraphic studies in a B16F10 melanoma tumor-bearing mice model. In vitro cellular uptake studies and biological evaluation confirmed significant deposition of GEM–pep-3 at the melanoma tumor site. The MTT assay depicted higher cytotoxic behaviour of GEM–pep-3 than free GEM. A considerable amount of cell apoptosis was also observed in B16F10 cells. Finally, the in vivo therapeutic efficacy study revealed a significant decrease in tumor growth in the GEM–pep-3-treated animal model. These studies reveal enough potentiality of GEM–pep-3 to treat melanoma and underline the need for further evaluation.

Graphical abstract: Development of a peptide-based bifunctional chelator conjugated to a cytotoxic drug for the treatment of melanotic melanoma

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Publication details

The article was received on 18 Dec 2017, accepted on 28 Feb 2018 and first published on 06 Mar 2018


Article type: Research Article
DOI: 10.1039/C7MD00638A
Citation: Med. Chem. Commun., 2018,9, 812-826
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    Development of a peptide-based bifunctional chelator conjugated to a cytotoxic drug for the treatment of melanotic melanoma

    R. H. Gaonkar, R. Baishya, B. Paul, S. Dewanjee, S. Ganguly, M. C. Debnath and S. Ganguly, Med. Chem. Commun., 2018, 9, 812
    DOI: 10.1039/C7MD00638A

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