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Cancer Lett. 2019 Apr 1;446:25-37. doi: 10.1016/j.canlet.2018.12.021. Epub 2019 Jan 11.

Cell-targeted c(AmpRGD)-sunitinib molecular conjugates impair tumor growth of melanoma.

Author information

1
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134, Florence, Italy. Electronic address: francesca.bianchini@unifi.it.
2
Food and Drug Department, University of Parma, Parco Area delle Scienze 27A, 43124, Parma, Italy.
3
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
4
Food and Drug Department, University of Parma, Parco Area delle Scienze 27A, 43124, Parma, Italy. Electronic address: andrea.sartori@unipr.it.

Abstract

Drug resistance and off-organ toxicity remain unsolved issues in chemotherapy of advanced-stage melanoma patients. Thus, the creation of new molecular conjugates able to combine a selective accumulation, high ability of internalization and signaling pathway inhibition, are highly requested. Recently, we reported a new class of molecular conjugates, compounds 1-3, where the anti-αVβ3 integrin peptidomimetic c(AmpRGD), which is a selective ligand for αVβ3 integrin, was covalently bound to the tyrosine kinase inhibitor sunitinib. Here, we report that these c(AmpRGD)-sunitinib conjugates and, in particular, compound 3, are selectively internalized by human melanoma cells through αVβ3 receptor-mediated endocytosis. Compound 3 is more effective than sunitinib in reducing in vitro melanoma cells proliferation, cloning efficiency, migration, and invasion. More interestingly, compound 3 is able to significantly reduce the growth of xenografted melanoma tumor developed in immune-compromised mice, more efficiently than an equimolar dose of sunitinib. Indeed, its targeting ability was demonstrated by the selective localization at the tumor level with respect to healthy tissues. Thus, c(AmpRGD)-sunitinib conjugates such as compound 3 could serve as intriguing multiple-target agents to selectively reach melanoma cells and interfere with the progression of the disease.

KEYWORDS:

Integrin ligands; Multi-targeting drugs; RTK inhibitors; Selective cell-internalization

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