title: Subcellular trafficking and transfection efficacy of polyethylenimine-polyethylene glycol polyplex nanoparticles with a ligand to melanocortin receptor-1.
abstract: We have synthesized and investigated properties of new PEI-PEG-based polyplexes containing MC1SP-peptide, a ligand specific for melanocortin receptor-1 (targeted polyplexes), and control polyplexes without this ligand peptide (non-targeted polyplexes). The targeted polyplexes demonstrated receptor-mediated transfection of Cloudman S91 (clone M-3) murine melanoma cells that was more efficient than with the non-targeted ones. Transfection with the targeted polyplexes was inhibited by chlorpromazine, an inhibitor of the clathrin-mediated endocytosis pathway, and, to a lesser extent, by filipin III or nystatin, inhibitors of the lipid-raft endocytosis pathway, whereas transfection with the non-targeted polyplexes was inhibited mainly by nystatin or filipin III. The targeted polyplexes caused significantly higher in vivo transfection of melanoma tumor cells after intratumoral administration compared to the non-targeted control. The targeted polyplexes carrying the HSVtk gene, after ganciclovir administration, more efficiently inhibited melanoma tumor growth and prolonged the lifespan of DBA/2 tumor-bearing mice compared to the non-targeted ones. Packed targeted polyplexes appeared and accumulated in the melanoma cells 6h earlier than the non-targeted ones. The targeted polyplexes enter into the nuclei of the melanoma cells more rapidly than the non-targeted control, and this difference may also be attributed to processes of receptor-mediated endocytosis. We believe that these data may be useful for the optimization of polyplex systems.
authors.affiliation: Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5, Vavilov St., 119334, Moscow, Russia. mdurymanov@gmail.com
authors.forename: Mikhail O
authors.initials: MO
authors.lastname: Durymanov
authors.forename: Elena A
authors.initials: EA
authors.lastname: Beletkaia
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Ulasov
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Khramtsov
authors.forename: Georgiy A
authors.initials: GA
authors.lastname: Trusov
authors.forename: Nikita S
authors.initials: NS
authors.lastname: Rodichenko
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Slastnikova
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Vinogradova
authors.forename: Natalia Y
authors.initials: NY
authors.lastname: Uspenskaya
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Kopantsev
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Rosenkranz
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Sverdlov
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Sobolev
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry; D004705:Endocytosis; D018773:Genes, erbB-1; D015316:Genetic Therapy; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D049409:Luciferases, Firefly / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism*; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D008024:Ligands; D009842:Oligopeptides; D044102:Receptor, Melanocortin, Type 1; C544016:poly(ethylene glycol)-co-poly(ethyleneimine); D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D004247:DNA; D049409:Luciferases, Firefly