In recent years, targeted therapies that selectively address receptors and pathways involved in tumor genesis and progression have attracted growing interest. Some integrin subfamilies (e.g. αVβ3, αVβ5 and α5β1) have shown to be involved, even by close cooperation with other cell receptors (e.g. vascular endothelial growth factor receptors, VEGFRs) in tumor angiogenesis, which plays crucial role in tumor development and dissemination. Recent studies clearly demonstrated a complex in vivo regulation of tumor angiogenesis events; in particular, the αVβ3 integrin receptor is physically and functionally correlated with the VEGFR2 receptor within endothelial cells (ECs), suggesting that dual specific agents capable of inhibiting them would have a great anti-angiogenesis potential. Our research group has recently introduced a new class of cyclic semipeptide ligands, cycloAmpRGD, containing the Arg-Gly-Asp (RGD) sequence and 4-aminoproline scaffolds. These ligands demonstrated to efficiently and selectively bind to the αVβ3 integrin and their binding capability is preserved even in the presence of covalently conjugated “bulky loads” (cytotoxic and chelating agents). Here we report the synthesis, characterization and biological evaluation of a series of dual conjugates of type I, wherein the ligand cycloAmpRGD is covalently associated to a Sunitinib-derived moiety, a clinically approved anti-angiogenic multikinase inhibitor. The binding competence of these candidates toward the αVβ3 integrin in EC lines, their kinase inhibitory activity toward VEGFR2, and their ability to block endothelial cell capillary formation in vitro are described, in comparison with the single agents and related combinations. Encouraging results point to the notion that the covalent conjugation of cycloAmpRGD and Sunitinib may be of high therapeutic potential for tumor angiogenesis inhibition.

Novel cycloAmpRGD-Sunitinib Dual Conjugates as Potent Targeted Anti-angiogenic Tools / Sartori, Andrea; Portioli, Elisabetta; Zanardi, Franca; Vacondio, Federica; Bianchini, Francesca; Battistini, Lucia. - ELETTRONICO. - (2016), pp. PC04-PC04. (Intervento presentato al convegno XXXVII Convegno Nazionale della Divisione di Chimica Organica tenutosi a Mestre (VE) nel 18-22 Settembre 2016).

Novel cycloAmpRGD-Sunitinib Dual Conjugates as Potent Targeted Anti-angiogenic Tools

SARTORI, Andrea;PORTIOLI, ELISABETTA;ZANARDI, Franca;VACONDIO, Federica;BATTISTINI, Lucia
2016-01-01

Abstract

In recent years, targeted therapies that selectively address receptors and pathways involved in tumor genesis and progression have attracted growing interest. Some integrin subfamilies (e.g. αVβ3, αVβ5 and α5β1) have shown to be involved, even by close cooperation with other cell receptors (e.g. vascular endothelial growth factor receptors, VEGFRs) in tumor angiogenesis, which plays crucial role in tumor development and dissemination. Recent studies clearly demonstrated a complex in vivo regulation of tumor angiogenesis events; in particular, the αVβ3 integrin receptor is physically and functionally correlated with the VEGFR2 receptor within endothelial cells (ECs), suggesting that dual specific agents capable of inhibiting them would have a great anti-angiogenesis potential. Our research group has recently introduced a new class of cyclic semipeptide ligands, cycloAmpRGD, containing the Arg-Gly-Asp (RGD) sequence and 4-aminoproline scaffolds. These ligands demonstrated to efficiently and selectively bind to the αVβ3 integrin and their binding capability is preserved even in the presence of covalently conjugated “bulky loads” (cytotoxic and chelating agents). Here we report the synthesis, characterization and biological evaluation of a series of dual conjugates of type I, wherein the ligand cycloAmpRGD is covalently associated to a Sunitinib-derived moiety, a clinically approved anti-angiogenic multikinase inhibitor. The binding competence of these candidates toward the αVβ3 integrin in EC lines, their kinase inhibitory activity toward VEGFR2, and their ability to block endothelial cell capillary formation in vitro are described, in comparison with the single agents and related combinations. Encouraging results point to the notion that the covalent conjugation of cycloAmpRGD and Sunitinib may be of high therapeutic potential for tumor angiogenesis inhibition.
2016
Novel cycloAmpRGD-Sunitinib Dual Conjugates as Potent Targeted Anti-angiogenic Tools / Sartori, Andrea; Portioli, Elisabetta; Zanardi, Franca; Vacondio, Federica; Bianchini, Francesca; Battistini, Lucia. - ELETTRONICO. - (2016), pp. PC04-PC04. (Intervento presentato al convegno XXXVII Convegno Nazionale della Divisione di Chimica Organica tenutosi a Mestre (VE) nel 18-22 Settembre 2016).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2825203
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