title: Differential Modulation of Cellular Bioenergetics by Poly(L-lysine)s of Different Molecular Weights.
abstract: Poly(L-lysine)s (PLLs), and related derivatives, have received considerable attention as nonviral vectors. High molecular weight PLLs (H-PLLs) are superior transfectants compared with low Mw PLLs (L-PLLs), but suggested to be more cytotoxic. Through a pan-integrated metabolomic approach using Seahorse XF technology, we studied the impact of PLL size on cellular bioenergetic processes in two human cell lines. In contrast to L-PLLs (1-5 kDa), H-PLLs (15-30 kDa) were more detrimental to both mitochondrial oxidative phosphorylation (OXPHOS) and glycolytic activity resulting in considerable intracellular ATP depletion, thereby initiating necrotic-type cell death. The cellular differences to polycation sensitivity were further related to the mitochondrial state, where the impact was substantial on cells with hyperpolarized mitochondria. These medium-throughput approaches offer better opportunities for understanding inter-related intracellular and cell type-dependent processes instigating a bioenergetics crisis, thus, aiding selection (from available libraries) and improved design of safer biodegradable polycations for nucleic acid compaction and cell type-specific delivery.
authors.affiliation: †Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Hall
authors.affiliation: †Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Lin-Ping
authors.initials: LP
authors.lastname: Wu
authors.affiliation: †Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Ladan
authors.initials: L
authors.lastname: Parhamifar
authors.affiliation: †Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.|‡NanoScience Centre, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Seyed Moein
authors.initials: SM
authors.lastname: Moghimi
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D016344:Medicare Part A; D055432:Metabolomics; D008970:Molecular Weight; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011107:Polylysine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014481:United States
chemical_list: D011107:Polylysine