Folate-mediated targeted PLK1 inhibition therapy for ovarian cancer: A comparative study of molecular inhibitors and siRNA therapeutics

PLK1 is a promising target for clinical treatment of diverse malignancies including ovarian cancer (OC), in which PLK1 over-expression is often correlated with poor prognosis and short survival. PLK1 can be blocked with small molecular inhibitors like volasertib (Vol) or silenced with PLK1-specific siRNA (siPLK1), hence effectively suppressing tumor growth. Surprisingly, despite intensive work on molecu[1]lar inhibitor and siRNA therapeutics, there is no direct comparison between them reported for targeted tumor therapy. Herein, we employing folate as a ligand and polymersomes as a nanovehicle performed a comparative study on Vol and siPLK1 in inhibiting OC in vitro and in vivo. Folate-targeted polymersomal Vol and siPLK1 (termed as FA-Ps-Vol and FA-Ps-siPLK1, respectively) were both nano-sized and stable, and displayed an optimal FA density of 20% for SKOV-3 cells. Notably, FA-Ps-Vol and FA-Ps-siPLK1 exhibited an IC50 of 193 and 770 nM, respectively, to SKOV-3 cells, indicating a greater potency of Vol than siPLK1. The markedly increased uptake for FA-Ps-Vol and FA-Ps-siPLK1 compared with respective non-targeted controls by SKOV-3 tumor xenografts in mice confirmed that FA mediates strong OC-targeting in vivo. Intriguingly, FA-Ps-Vol while greatly lessening toxic effects of Vol potently repressed tumor growth with a remarkable tumor inhibition rate (TIR) of 97% at 20 mg (i.e. 32.4 μmol) Vol equiv./kg. FA-Ps-siPLK1 achieved effective tumor inhibition (TIR = ca. 87% or 90%) at 2 or 4 mg (i.e. 0.15 or 0.3 μmol) siPLK1 equiv./kg without causing adverse effects. This comparative study highlights that molecular inhibitor has the advantage of easy dose escalation and potent protein inhibition at the expense of certain adverse effects while siRNA therapeutics has low toxicity with moderate protein inhibition in vivo.

Z. Wang, S.S. Zhao, F.H. Meng*, J.D. Yuan, and Z.Y. Zhong*, Folate-mediated targeted PLK1 inhibition therapy for ovarian cancer: A comparative study of molecular inhibitors and siRNA therapeutics, Acta Biomaterialia 2022, 138, 443-452.