title: Fatty acid modified octa-arginine for delivery of siRNA.
abstract: Therapeutic delivery of small interfering RNA (siRNA) is a major challenge that limits its potential clinical application. Four fatty acids derivatives of octa-arginine (R8) were synthesized and evaluated for the delivery of siRNA into hepatocellular carcinoma Hep G2 and human lung adenocarcinoma A549 cells. The results showed that the long chain acid oleic acid or stearic acid derivatives of R8, OA-R8 and StA-R8, were more efficient in siRNA complexation and form nanoparticles with greater stability compared to the native R8. Cellular uptake of fluorescence-labeled siRNA delivered by OA-R8 and StA-R8 in Hep G2 and A549 cells was substantially 40-50 times higher than unmodified R8. A significant reduction in siRNA cellular uptake was observed in the presence of sucrose and cytochalasin D, indicating endocytosis as a primary mechanism of cellular entry. A survivin siRNA was used to prepare nanoparticles with OA-R8 or StA-R8 and evaluated for silencing of survivin mRNA and protein in A549 cells, and the inhibition efficiencies of survivin protein reached to 50.3% and 54.6%, respectively. The results showed greater effectiveness with the derivatized R8. Taken together, these findings showed that long chain fatty acid derivatives of R8 are efficient delivery agents for siRNA and may facilitate its therapeutic application.
authors.affiliation: School of Life Sciences, Jilin University, Changchun 130012, China.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Life Sciences, Jilin University, Changchun 130012, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Jilin University, Changchun 130012, China; Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Jilin University, Changchun 130012, China. Electronic address: tenglesheng@jlu.edu.cn.
authors.forename: Lesheng
authors.initials: L
authors.lastname: Teng
mesh_terms: D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D001120:Arginine / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides; D015638:Cytochalasin D / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D005227:Fatty Acids / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D008175:Lung Neoplasms; D053758:Nanoparticles / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology*; D013395:Sucrose / Q000494:pharmacology
chemical_list: D057846:Cell-Penetrating Peptides; D005227:Fatty Acids; D034741:RNA, Small Interfering; D015638:Cytochalasin D; D013395:Sucrose; D001120:Arginine
keywords: Cell penetrating peptide; Fatty acids; Octa-arginine; siRNA delivery