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Targeted delivery of siRNAs against hepatocellular carcinoma-related genes by a galactosylated polyaspartamide copolymerPerrone, Francesca ...Given the lack of effective treatments for Hepatocellular carcinoma (HCC), the development of novel therapeutic approaches is very urgent. Here, siRNAs were delivered to HCC cells by a synthetic ... polymer containing %,%-poly-(N-2-hydroxyethyl)-D,L-aspartamide-(PHEA) derivatized with diethylene triamine (DETA) and bearing in the side chain galactose (GAL) linked via a polyethylene glycol (PEG) to obtain (PHEA-DETA-PEG-GAL, PDPG). The GAL residue allows the targeting to the asialo-glycoprotein receptor (ASGPR), overexpressed in HCC cells compared to normal hepatocytes. Uptake studies performed using a model siRNA or a siRNA targeted against the enhanced green fluorescence protein, demonstrated the PDPG specific delivery of siRNA to HuH7 cells, a human cellular model of HCC. GAL-free copolymer (PHEA-DETA-PEG-NH2, PDP) or the chemical block of ASGPR, impaired PDPG targeting effectiveness in vitro. The specificity of PDPG delivery was confirmed in vivo in a mouse dorsal skinfold window chamber assay. Functional studies using siRNAs targeting the mRNAs of HCC-related genes (eEF1A1, eEF1A2 and E2F1) delivered by PDPG, significantly decreased HuH7 vitality/number and down regulated the expression of the target genes. Only minor effectiveness was in contrast observed for PDP. In IHH, a human model of normal hepatocytes with reduced ASGPR expression, PDPG barely reduced cell vitality. In a subcutaneous xenograft mouse model of HCC, PDPG-siRNAs reduced HCC tumor growth compared to controls without significant toxic effects. In conclusion, our study demonstrates the valuable potentials of PDPG for the specific delivery of siRNAs targeting HCC-related genes.Source: Journal of controlled release. - ISSN 0168-3659 (Vol. 330, 2021, str. 1132-1151)Type of material - article, component partPublish date - 2021Language - englishCOBISS.SI-ID - 38630403
Author
Perrone, Francesca |
Čemažar, Maja |
Kamenšek, Urška |
Dapas, Barbara |
Zanconati, Fabrizio |
Bonazza, Deborah |
Grassi, Mario |
Pozzato, Gabriele |
Farra, Rossella |
Cavallaro, Gennara
Topics
hepatocelularni karcinom |
siRNA |
E2F1 |
usmerjena delitev ASGPR |
hepatocellular carcinoma |
siRNA |
E2F1 |
ASGPR targeted delivery
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Perrone, Francesca | |
Čemažar, Maja | 14575 |
Kamenšek, Urška | 28387 |
Dapas, Barbara | |
Zanconati, Fabrizio | |
Bonazza, Deborah | |
Grassi, Mario | |
Pozzato, Gabriele | |
Farra, Rossella | |
Cavallaro, Gennara |
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