Galactosylated polyaspartamide copolymers for siRNA targeted delivery to hepatocellular carcinoma cells

Barbara Porsio, Gaetano Giammona, Emanuela Fabiola Craparo, Gennara Cavallaro, Carla Sardo, Mario Grassi, Francesca Perrone, Barbara Dapas, Gabriele Pozzato, Gabriele Grassi, Rossella Farra

Risultato della ricerca: Article

13 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)397-406
Numero di pagine10
RivistaInternational Journal of Pharmaceutics
Volume525
Stato di pubblicazionePublished - 2017

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Galactose
Small Interfering RNA
Hepatocellular Carcinoma
G1 Phase
Glycoproteins
E2F1 Transcription Factor
Cell Cycle Resting Phase
Phase Transition
S Phase
Genes
Polymers
Cell Proliferation
poly(2-hydroxyethyl acrylate)
Messenger RNA
diethylenetriamine
Therapeutics
Pharmaceutical Preparations
Proteins

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cita questo

Galactosylated polyaspartamide copolymers for siRNA targeted delivery to hepatocellular carcinoma cells. / Porsio, Barbara; Giammona, Gaetano; Craparo, Emanuela Fabiola; Cavallaro, Gennara; Sardo, Carla; Grassi, Mario; Perrone, Francesca; Dapas, Barbara; Pozzato, Gabriele; Grassi, Gabriele; Farra, Rossella.

In: International Journal of Pharmaceutics, Vol. 525, 2017, pag. 397-406.

Risultato della ricerca: Article

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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 {\^I}±,{\^I}²-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.",
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author = "Barbara Porsio and Gaetano Giammona and Craparo, {Emanuela Fabiola} and Gennara Cavallaro and Carla Sardo and Mario Grassi and Francesca Perrone and Barbara Dapas and Gabriele Pozzato and Gabriele Grassi and Rossella Farra",
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T1 - Galactosylated polyaspartamide copolymers for siRNA targeted delivery to hepatocellular carcinoma cells

AU - Porsio, Barbara

AU - Giammona, Gaetano

AU - Craparo, Emanuela Fabiola

AU - Cavallaro, Gennara

AU - Sardo, Carla

AU - Grassi, Mario

AU - Perrone, Francesca

AU - Dapas, Barbara

AU - Pozzato, Gabriele

AU - Grassi, Gabriele

AU - Farra, Rossella

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - E2F1

KW - HCC

KW - PHEA-DETA-PEG-GAL

KW - Polyplexes

KW - siRNA.

UR - http://hdl.handle.net/10447/248395

UR - http://www.elsevier.com/locate/ijpharm

M3 - Article

VL - 525

SP - 397

EP - 406

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

ER -