title: Polyplex Evolution: Understanding Biology, Optimizing Performance.
abstract: Polyethylenimine (PEI) is a gold standard polycationic transfectant. However, the highly efficient transfecting activity of PEI and many of its derivatives is accompanied by serious cytotoxic complications and safety concerns at innate immune levels, which impedes the development of therapeutic polycationic nucleic acid carriers in general and their clinical applications. In recent years, the dilemma between transfection efficacy and adverse PEI activities has been addressed from in-depth investigations of cellular processes during transfection and elucidation of molecular mechanisms of PEI-mediated toxicity and translation of these integrated events to chemical engineering of novel PEI derivatives with an improved benefit-to-risk ratio. This review addresses these perspectives and discusses molecular events pertaining to dynamic and multifaceted PEI-mediated cytotoxicity, including membrane destabilization, mitochondrial dysfunction, and perturbations of glycolytic flux and redox homeostasis as well as chemical strategies for the generation of better tolerated polycations. We further examine the effect of PEI and its derivatives on complement activation and interaction with Toll-like receptors. These perspectives are intended to lay the foundation for an improved understanding of interlinked mechanisms controlling transfection and toxicity and their translation for improved engineering of polycation-based transfectants.
authors.affiliation: Genome Integrity Unit, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Hall
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität, 81377 Munich, Germany; Nanosystems Initiative Munich, 80799 Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lächelt
authors.affiliation: Genome Integrity Unit, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, 171 65 Solna, Sweden.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität, 81377 Munich, Germany; Nanosystems Initiative Munich, 80799 Munich, Germany. Electronic address: ernst.wagner@cup.uni-muenchen.de.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.affiliation: School of Medicine, Pharmacy and Health, Durham University, Queen's Campus, Stockton-on-Tees TS17 6BH, UK. Electronic address: moein.moghimi@gmail.com.
authors.forename: Seyed Moein
authors.initials: SM
authors.lastname: Moghimi
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D003167:Complement Activation / Q000187:drug effects; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006019:Glycolysis; D006801:Humans; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D011094:Polyethyleneimine / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology
chemical_list: D051193:Toll-Like Receptors; D011094:Polyethyleneimine; D003165:Complement System Proteins
keywords: complement system; cytotoxicity; mitochondrion; polyethylenimine; polyplex