title: Structure-Function Correlation of Aminated Poly(α)glutamate as siRNA Nanocarriers.
abstract: It has been two decades since cationic polymers were introduced to the world of oligonucleotides delivery. However, the optimal physicochemical properties to make them a successful delivery vehicle are yet unknown. An ideal system became particularly interesting and necessary with the introduction of RNA interference as a promising therapeutic approach. Such nanocarrier should overcome challenges such as low plasma stability, poor cellular internalization and endosomal escape to induce gene silencing. To that end, we synthesized a library of biodegradable aminated poly(α)glutamate varied by amine moieties. In an attempt to elucidate the structure-function relationship, our polyplexes were physicochemically characterized and their silencing activity and cytotoxicity were evaluated. We found several structures that demonstrated improved cellular internalization. These candidates silenced gene expression to less than 50% of their initial levels, while being safe to cells and mice. Based on our research, an improved and promising tailor-designed siRNA delivery platform can be developed.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Room 607, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Adva
authors.initials: A
authors.lastname: Krivitsky
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Room 607, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Polyak
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Room 607, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Scomparin
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Room 607, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Eliyahu
authors.affiliation: QBI Enterprise, Ltd., Ness-Ziona 70400, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Ori
authors.affiliation: QBI Enterprise, Ltd., Ness-Ziona 70400, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Avkin-Nachum
authors.affiliation: School of Chemistry, the Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University , Tel Aviv 69978, Israel.
authors.forename: Vadim
authors.initials: V
authors.lastname: Krivitsky
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Room 607, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Satchi-Fainaro
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011099:Polyglutamic Acid / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D014407:Tumor Cells, Cultured; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000588:Amines; D004337:Drug Carriers; D011108:Polymers; D034741:RNA, Small Interfering; D011099:Polyglutamic Acid; D020830:rac1 GTP-Binding Protein