The limited efficacy of available treatments for hepatocellular carcinoma (HCC) requires the development
of novel therapeutic approaches. We synthesized a novel cationic polymer based on a,b-poly-(N-2-
hydroxyethyl)-D,L-aspartamide (PHEA) for drug delivery to HCC cells. The copolymer was synthesized by
subsequent derivatization of PHEA with diethylene triamine (DETA) and with a polyethylene glycol (PEG)
derivative bearing galactose (GAL) molecules, obtaining the cationic derivative PHEA-DETA-PEG-GAL.
PHEA-DETA-PEG-GAL has suitable chemical-physical characteristics for a potential systemic use and can
effectively deliver a siRNA (siE2F1) targeted against the transcription factor E2F1, a gene product involved
in HCC. The presence of GAL residues in the polyplexes allows the targeting of HCC cells that express the
asialo-glycoprotein receptor (ASGP-R). In these cells, but not in ASGP-R non-expressing cells, PHEADETA-PEG-GAL/siE2F1 polyplexes induce the reduction of the mRNA and protein levels of E2F1 and of
E2F1-regulated genes, all involved in the promotion of the G1/S phase transition. This results in a
decrease of cell proliferation with a G1/G0 phase cells accumulation. Notably, removal of GAL residue
almost completely abrogates the targeting capacity of the developed polyplexes.
In conclusion, the generated polyplexes demonstrate the potential to effectively contributing to the
development of novel anti-HCC therapeutic approaches via a siRNA-targeted delivery.
