title: Endosomal escape and the knockdown efficiency of liposomal-siRNA by the fusogenic peptide shGALA.
abstract: An siRNA that specifically silences the expression of mRNA is a potential therapeutic agent for dealing with many diseases including cancer. However, the poor cellular uptake and bioavailability of siRNA remains a major obstacle to clinical development. For efficient delivery to tumor tissue, the pharmacokinetics and intracellular trafficking of siRNA must be rigorously controlled. To address this issue, we developed a liposomal siRNA carrier, a multi-functional nano device (MEND). We describe herein an approach for systemic siRNA delivery to tumors by combining the MEND system with shGALA, a fusogenic peptide. In cultured cell experiments, shGALA-modification enhanced the endosomal escape of siRNA encapsulated in a polyethylene glycol modified MEND (PEG-MEND), resulting in an 82% knockdown of the target gene. In vivo systemic administration clarified that the shGALA-modified MEND (shGALA-MEND) showed 58% gene silencing in tumor tissues at a dose of 4 mg of siRNA/kg body weight. In addition, a significant inhibition of tumor growth was observed only for the shGALA-MEND and no somatic or hepatic toxicity was observed. Given the above data, this peptide-modified delivery system, a shGALA-MEND has great potential for the systemic delivery of therapeutic siRNA aimed at cancer therapy.
authors: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060 0812, Japan.
authors: Yu
authors: Y
authors: Sakurai
authors: Hiroto
authors: H
authors: Hatakeyama
authors: Yusuke
authors: Y
authors: Sato
authors: Hidetaka
authors: H
authors: Akita
authors: Kentaro
authors: K
authors: Takayama
authors: Sachiko
authors: S
authors: Kobayashi
authors: Shiroh
authors: S
authors: Futaki
authors: Hideyoshi
authors: H
authors: Harashima