Performance of Pyridylthiourea-Polyethylenimine Polyplex for siRNA-Mediated Liver Cancer Therapy in Cell Monolayer, Spheroid, and Tumor Xenograft Models.

Jean Baptiste Gossart,Benoît Frisch,Guy Zuber,Cendrine Seguin,Eric Robinet,Emilie Heuillard,Francine Gossé,Etienne Pascal,Mathieu Gonçalves,Florent Meyer

doi:10.1002/gch2.201700013

Jean Baptiste Gossart, Benoît Frisch + Show 8 more

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https://doi.org/10.1002/gch2.201700013

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Abstract

Medical application of siRNAs relies on methods for delivering nucleic acids into the cytosol. Synthetic carriers, which assemble with nucleic acids into delivery systems, show promises for cancer therapy but efficiency remains to be improved. In here, the effectiveness of pyridylthiourea‐polyethylenimine (πPEI), a siRNA carrier that favors both polyplex disassembly and endosome rupture upon sensing the acidic endosomal environment, in 3 experimental models of hepatocellular cancer is tested. The πPEI‐assisted delivery of a siRNA targeting the polo‐like kinase 1 into Huh‐7 monolayer produces a 90% cell death via a demonstrated RNA interference mechanism. Incubation of polyplex with Huh‐7 spheroids leads to siRNA delivery into the superficial first cell layer and a 60% reduction in spheroid growth compared to untreated controls. Administration of polyplexes into mice bearing subcutaneous implanted Huh‐7Luc tumors results in a reduced tumor progression, similar to the one observed in the spheroid model. Altogether, these results support the in vivo use of synthetic and dedicated polymers for increasing siRNA‐mediated gene knockdown, and their clinical promise in cancer therapeutics.

Highlights

Introduction into the cytosolSynthetic carriers, which assemble with nucleic acids into delivery systems, show promises for cancer therapy but efficiency remains to be improved
Kawata et al demonstrated that a polyplex of atelocollagen with siRNA targeting the polo-like kinase 1 reduced mouse liver metastatic proliferation.[25]
Judge et al describes the antitumoral efficacy of stable nucleic acid particles containing a chemically modified siRNA targeting the polo-like kinase 1 (siPLK) for treatment of mouse hepatic tumor models.[10c]. Li et al evaluated several lipidic formulations and genetic targets and suggested that one novel lipid formulation and a siRNA targeting CDCA1 are efficient for Hepatocellular cancer (HCC) treatment.[26]

Summary

Introduction

Introduction into the cytosolSynthetic carriers, which assemble with nucleic acids into delivery systems, show promises for cancer therapy but efficiency remains to be improved. Synthetic interfering RNAs (siRNAs) are double-stranded RNA duplexes able to suppress expression of a gene through a sequence-selective and enzymatic-mediated mRNA degradation mechanism rupture upon sensing the acidic endosomal environment, in 3 experimental models of hepatocellular cancer is tested. Incubation of polyplex with Huh-7 spheroids leads to siRNA delivery into the superficial occurring in the cytosol of all mammalian cells.[1] This gene silencing method is mediated by binding of siRNAs to the RNA-induced silencing complex (RISC)[2] and can be employed therapeutically in diseases with an identified genetic target. SiRNA implanted Huh-7Luc tumors results in a reduced tumor progression, similar to the one observed in the spheroid model. These results support the in vivo use of synthetic and dedicated polymers for increasing siRNAmediated gene knockdown, and their clinical promise in cancer therapeutics

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