Cationic liquid crystalline nanoparticles for the delivery of synthetic RNAi-based therapeutics.

Emanuela Gentile,Dong Cai,Lin Ji,Xiaobo Cao,Jack A Roth,Jing Lin,Majidi Mourad,Apar Pataer,Veerabhadran Baladandayuthapani,Feng Meng,Taro Oba,Ruping Shao,Heather Y Lin

doi:10.18632/oncotarget.18421

Emanuela Gentile, Dong Cai + Show 11 more

Open Access

https://doi.org/10.18632/oncotarget.18421

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Abstract

RNA interference (RNAi)-based therapeutics have been used to silence the expression of targeted pathological genes. Small interfering RNA (siRNAs) and microRNA (miRNAs) inhibitor have performed this function. However, short half-life, poor cellular uptake, and nonspecific distribution of small RNAs call for the development of novel delivery systems to facilitate the use of RNAi. We developed a novel cationic liquid crystalline nanoparticle (CLCN) to efficiently deliver synthetic siRNAs and miRNAs. CLCNs were prepared by using high-speed homogenization and assembled with synthetic siRNA or miRNA molecules in nuclease-free water to create CLCN/siRNA or miRNA complexes. The homogeneous and stable CLCNs and CLCN-siRNA complexes were about 100 nm in diameter, with positively charged surfaces. CLCNs are nontoxic and are taken up by human cells though endocytosis. Significant inhibition of gene expression was detected in transiently transfected lung cancer H1299 cells treated with CLCNs/anti-GFP complexes 24 hours after transfection. Biodistribution analysis showed that the CLCNs and CLCNs-RNAi complexes were successfully delivered to various organs and into the subcutaneous human lung cancer H1299 tumor xenografts in mice 24 hours after systemic administration. These results suggest that CLCNs are a unique and advanced delivery system capable of protecting RNAi from degradation and of efficiently delivering RNAi in vitro and in vivo.

Highlights

RNA interference (RNAi) is a potential new class of drugs that can selectively silence disease-causing genes, including those causing genetic disorders, viral infections, autoimmune diseases, and cancer [1,2,3,4]
After the homogenization and the purification, cationic liquid crystalline nanoparticle (CLCN) were conjugated with nucleic acids, such as siRNA or miRNA therapeutics dissolved in UltraPure DNase/RNase-Free Distilled Water
In order for synthetic RNAi-based therapeutics to be applied in a broad range of diseases, a number of challenges must be overcome [24]

Summary

Introduction

RNA interference (RNAi) is a potential new class of drugs that can selectively silence disease-causing genes, including those causing genetic disorders, viral infections, autoimmune diseases, and cancer [1,2,3,4]. Based on the natural process of cell infection and the transfer of genetic materials into host, viruses have been evaluated as possible gene carriers, but toxicity, immunogenicity, and the inadequate size of the inserted genetic materials, impair their efficacy in vivo [10, 11] To overcome these challenges, nonviral vectors such as lipid-based delivery systems, cationic liposomes, lipid nanoparticles, and a variety of cationic and biodegradable polymers [12, 13] have been used to mask the negative charges of the siRNA or miRNA www.impactjournals.com/oncotarget backbone and facilitate cellular uptake, partially mediating the efficient delivery of siRNA in vitro and in vivo [14, 15]. The fabrication method provides an efficient, cost-effective process for producing RNAi delivery systems

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