Olaparib-Cediranib Hybrid as Dual PARP-VEGFR3 Inhibitor Elicits Antitumor Efficacy: Rational Design, Synthesis,...

Tempted by the clinical outcomes attained with the combination of poly(ADP-ribose) polymerase (PARP) and vascular endothelial growth factor receptor (VEGFR) inhibitors, a compendium of dual PARP-VEGFR inhibitory assemblages based on structural commonalities of Olaparib (PARP inhibitor) and Cediranib (VEGFR inhibitor) was furnished. The aforementioned efforts culminated into a strikingly potent antitumor agent 18 exerting remarkable cell growth inhibitory effects [IC₅₀ = 0.37 μM (HL60); 0.56 μM (A549); 0.80 μM (MDA-MB-231)] through a balanced inhibition of PARP and VEGFR. Specifically, 18 displayed magnificent PARP1, PARP2, and VEGFR3 inhibitory profiles with an IC₅₀ value of 0.0763 nM, 0.0366 nM, and 4.25 nM, respectively. Further, a charge-convertible polymer-based nanoformulation (18-PEG-PLL/DMMA nanoparticles) for targeted drug delivery of 18 was developed. Encouragingly, the nanoformulation demonstrated a cytotoxicity-devoid profile towards normal cells owing to its pH-sensitive behavior and manifested selective cell growth inhibition against solid tumor cells, possibly due to the EPR effect.