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) 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 cytotoxic agent Paclitaxel (PTX), were synthesized to investigate influence of a PEG-4 chain sC18 cell-penetrating peptide (CPP) on cellular uptake cytotoxicity constructs. A “double click-reaction strategy” was planned, realize connection PTX CPP moiety. Anti-proliferative bioassays performed αVβ3-positive U87 human glioblastoma cell line using short contact time (15 min) followed by draining, washing cells, re-incubation for 72 h. Compound 3 significantly more potent (IC50=27.6 μM) than compound 2 (IC50>100 μM), showed reduced potency loss with respect (IC50=71 nM).