Synthesis and Biological Evaluation of an iso DGR‐Paclitaxel Conjugate Containing a Cell‐Penetrating Peptide to Promote Cellular Uptake

Two new Drug Delivery Systems (DDS) c yclo [DKP‐ iso DGR]‐PEG‐4‐Val‐Ala‐PTX ( 2 ) and cyclo [DKP‐ iso DGR]‐PEG‐4‐sC18‐Val‐Ala‐PTX ( 3 ), containing the c yclo [DKP‐ iso DGR] integrin ligand and the cytotoxic agent Paclitaxel (PTX), were synthesized to investigate the influence of a PEG‐4 chain and of the sC18 cell‐penetrating peptide (CPP) on the cellular uptake and the cytotoxicity of the constructs. A “double click‐reaction strategy” was planned, to realize the connection of c yclo [DKP‐ iso DGR] and PTX to the CPP moiety. Anti‐proliferative bioassays were performed on the α V β 3 ‐positive U87 human glioblastoma cell line using a short contact time (15 min) followed by draining, washing of the cells, and re‐incubation for 72 h. Compound 3 was significantly more potent (IC 50 =27.6 μM) than compound 2 (IC 50 >100 μM), and showed a reduced potency loss with respect to PTX (IC 50 =71 nM).