Tumor Targeting with an iso DGR–Drug Conjugate

• Published in: Chemistry : a European journal Vol. 23; no. 33; pp. 7910 - 7914
• Main Authors: Zanella, Simone, Angerani, Simona, Pina, Arianna, López Rivas, Paula, Giannini, Clelia, Panzeri, Silvia, Arosio, Daniela, Caruso, Michele, Gasparri, Fabio, Fraietta, Ivan, Albanese, Clara, Marsiglio, Aurelio, Pignataro, Luca, Belvisi, Laura, Piarulli, Umberto, Gennari, Cesare
• Format: Journal Article
• Language: English
• Published: 12.06.2017
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201701844

Abstract Herein we report the first example of an iso DGR–drug conjugate ( 2 ), designed to release paclitaxel selectively within cancer cells expressing integrin α V β 3 . Conjugate 2 was synthesized by connecting the iso DGR peptidomimetic 5 with paclitaxel via the lysosomally cleavable Val–Ala dipeptide linker. Conjugate 2 displayed a low nanomolar affinity for the purified integrin α V β 3 receptor (IC 50 =11.0 n m ). The tumor targeting ability of conjugate 2 was assessed in vitro in anti‐proliferative assays on two isogenic cancer cell lines characterized by different integrin α V β 3 expression: human glioblastoma U87 (α V β 3 +) and U87 β 3 ‐KO (α V β 3 −). The iso DGR‐PTX conjugate 2 displayed a remarkable targeting index (TI=9.9), especially when compared to the strictly related RGD‐PTX conjugate 4 (TI=2.4).