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Tumor Targeting with an iso DGR–Drug Conjugate
Author(s) -
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
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201701844
Subject(s) - conjugate , paclitaxel , integrin , peptidomimetic , linker , in vitro , dipeptide , chemistry , pharmacology , cancer research , microbiology and biotechnology , medicine , biology , biochemistry , receptor , cancer , amino acid , peptide , computer science , mathematical analysis , mathematics , operating system
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).