title: Hydrophobically modified oligoethylenimines as highly efficient transfection agents for siRNA delivery.
abstract: RNA interference is a promising therapeutic strategy for treatment of diseases, in particular, cancer. Despite a huge number of targets identified for different cancer types, there are no effective delivery strategies available so far. Polymeric delivery vehicles are often based on large macromolecules. Such approaches often lead to accumulation of toxicity and narrow therapeutic windows. In the current paper, an alternative approach is presented. Low molecular weight oligoethylenimine (OEI) 800 Da was hydrophobically modified through the Michael addition of different alkyl acrylates. An optimal structure containing ten hexyl acrylate residues per one OEI chain (OEI-HA-10) was found to be a promising candidate for siRNA delivery. Hydrophobic modification stabilized the siRNA polyplex structure, increased the colloidal stability of the nanoparticles, and provided lytic properties to OEI required for crossing cellular membranes in the delivery process. In addition, the acrylate ester bond enables fast degradation of OEI-HA-10 into far less toxic components. Further improvement of biological properties of the OEI-HA-10 polyplexes by different formulation strategies was demonstrated. In particular, a remarkable increase of biocompatibility without loss of efficiency could be achieved by coformulation of OEI-HA-10 with lauryl acrylate modified OEI-LA-5.
authors.affiliation: Center for Drug Research, Department of Pharmacy, Pharmaceutical Biology-Biotechnology, and Center for NanoScience (CeNS), Ludwig-Maximilians-University, Butenandstr. 5-13, D-81377 Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Philipp
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Zhao
authors.forename: Peter
authors.initials: P
authors.lastname: Tarcha
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Arkadi
authors.initials: A
authors.lastname: Zintchenko
mesh_terms: D000179:Acrylates / Q000737:chemistry; D000818:Animals; D001388:Aziridines / Q000737:chemistry*; D001672:Biocompatible Materials; D002463:Cell Membrane Permeability; D004355:Drug Stability; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D053758:Nanoparticles / Q000737:chemistry; D011108:Polymers / Q000737:chemistry* / Q000493:pharmacokinetics; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014162:Transfection / Q000379:methods*
chemical_list: D000179:Acrylates; D001388:Aziridines; D001672:Biocompatible Materials; D011108:Polymers; D034741:RNA, Small Interfering; C033132:aziridine