Synthesis and Biological Evaluation of an isoDGR-Paclitaxel Conjugate Containing a Cell-Penetrating Peptide to Promote Cellular Uptake

Two new Drug Delivery Systems (DDS) cyclo[DKP-isoDGR]-PEG-4-Val-Ala-PTX (2) and cyclo[DKP-isoDGR]-PEG-4-sC18-Val-Ala-PTX(3), containing the cyclo[DKP-isoDGR] integrin ligand and the cytotoxic agent Paclitaxel (PTX), were synthesized to investigate the influence of a PEG-4 chain and of the sC18 cell-penetratingpeptide (CPP) on the cellular uptake and the cytotoxicity of the constructs. A “double click-reaction strategy” was planned, to realize the connection of cyclo[DKP-isoDGR] and PTX to the CPP moiety. Anti-proliferative bioassays were performed on the aVb3-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 (IC50=27.6 M) than compound 2 (IC50>100 microM), and showed a reduced potency loss with respect to PTX (IC50=71 nM).