Synthesis of multimeric integrin ligands for the selective tumor-targeted delivery of cytotoxic drugs
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Data di Pubblicazione:
2016
Citazione:
Synthesis of multimeric integrin ligands for the selective tumor-targeted delivery of cytotoxic drugs / A. Dias, A.F. Raposo Moreira Dias, A. Dal Corso, A. Pina, M. Caruso, L. Belvisi, D. Arosio, L. Pignataro, C. Gennari, P. Lopez Rivas. ((Intervento presentato al convegno Synthesis and Biomedical Applications of Tumor-Targeting Peptidomimetics tenutosi a Bologna nel 2016.
Abstract:
Conjugation of cytotoxic agents to targeting carriers (e.g. antibodies or small molecules) capable of selectively binding to tumor-specific antigens, is emerging as a successful strategy to overcome the lack of selectivity typical of traditional chemotherapeutics. αVβ3 integrin has been widely investigated as receptor for tumor-targeting strategies, as it is over-expressed on the blood vessels of several human cancers[1]. Extracellular matrix proteins are recognized by this receptor through the Arg-Gly-Asp (RGD) sequence, which has been incorporated in numerous peptide- and peptidomimetic ligands[2]. Among them, our research group developed the new integrin ligand DKP3-RGD[3], in which the RGD sequence is constrained into a cycle by a bifunctional 2,5-diketopiperazine (DKP) scaffold.
Our research group has recently developed the RGD-PTX conjugate 1, containing a dipeptide linker that can be selectively cleaved by the proteases present inside the target cell [4]. Compound 1 displayed a fairly effective integrin-targeting, inhibiting cell proliferation with increased selectivity towards αVβ3-expressing cells compared to the free PTX. In order to increase the binding affinity towards the cells overexpressing integrin αVβ3, the dimeric conjugate 2 has been synthesized. The ability of compound 2 to compete with biotinylated vitronectin for the binding to the purified αVβ3 integrin has been tested in vitro. As expected, the dimeric compound 2 showed higher binding affinity than the monomeric analog 1 (IC50 = 4 nM vs. 13 nM). Remarkably, the IC50 obtained for the dimeric compound 2 is identical to the one reported for the free ligand DKP3-RGD.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
A. Dias, A.F. Raposo Moreira Dias, A. Dal Corso, A. Pina, M. Caruso, L. Belvisi, D. Arosio, L. Pignataro, C. Gennari, P. Lopez Rivas
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