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

// Emanuela Gentile 1 , Taro Oba 1 , Jing Lin 1 , Ruping Shao 1 , Feng Meng 1 , Xiaobo Cao 1 , Heather Y. Lin 2 , Majidi Mourad 1 , Apar Pataer 1 , Veerabhadran Baladandayuthapani 2 , Dong Cai 3 , Jack A. Roth 1 and Lin Ji 1 1 Section of Thoracic Molecular Oncology, Department of Thoracic & Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States 2 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States 3 Department of Physics, The University of Houston, Houston, TX 77004, United States Correspondence to: Emanuela Gentile, email: egentile@mdanderson.org Keywords: delivery systems, cationic nanoparticles, RNAi, lung cancer, gene silencing Received: December 28, 2016      Accepted: May 05, 2017      Published: June 09, 2017 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 .