title: Galactosylated polyaspartamide copolymers for siRNA targeted delivery to hepatocellular carcinoma cells.
abstract: 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 α,β-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, PHEA-DETA-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.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), Lab of Biocompatible Polymers, University of Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Gennara
authors.initials: G
authors.lastname: Cavallaro
authors.affiliation: Department of Industrial Engineering and Information Technology, University of Trieste, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Farra
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), Lab of Biocompatible Polymers, University of Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Emanuela Fabiola
authors.initials: EF
authors.lastname: Craparo
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), Lab of Biocompatible Polymers, University of Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Sardo
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), Lab of Biocompatible Polymers, University of Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Porsio
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche, Chimiche, Farmaceutiche (STEBICEF), Lab of Biocompatible Polymers, University of Palermo, via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Giammona
authors.affiliation: Department of Life Sciences, University of Trieste, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Perrone
authors.affiliation: Department of Industrial Engineering and Information Technology, University of Trieste, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Grassi
authors.affiliation: Department of 'Medical, Surgery and Health Sciences, University of Trieste, Cattinara Hospital, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pozzato
authors.affiliation: Department of Life Sciences, University of Trieste, Italy. Electronic address: ggrassi@units.it.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Grassi
authors.affiliation: Department of Life Sciences, University of Trieste, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dapas
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000628:therapy; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000628:therapy; D010455:Peptides / Q000737:chemistry*; D011108:Polymers; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D010455:Peptides; D011108:Polymers; D034741:RNA, Small Interfering; C008965:alpha,beta-poly((2-hydroxyethyl)-aspartamide)
keywords: E2F1; HCC; PHEA-DETA-PEG-GAL; Polyplexes; siRNA