title: Thyroid hormone (T3)-modification of polyethyleneglycol (PEG)-polyethyleneimine (PEI) graft copolymers for improved gene delivery to hepatocytes.
abstract: Targeting of gene vectors to liver hepatocytes could offer the opportunity to cure various acquired and inherited diseases. Efficient gene delivery to the liver parenchyma has been obscured from efficient targeting of hepatocytes. Here we show that the thyroid hormone, triiodothyronine (T3), can be used to improve the gene transfer efficiency of nonviral gene vectors to hepatocytes in vitro and to the liver of mice in vivo. T3 conjugated to the distal ends of fluorescent labeled PEG-g-dextran resulted in T3-specific cellular endosomal uptake into the hepatocellular cell line HepG2. PEG-g-PEI graft copolymers with increasing molar PEG-ratios were synthesized, complexed with plasmid DNA, and transfected into HepG2 or HeLa cells. Gene transfer efficiency decreased as the number of PEG blocks increased. T3 conjugation to PEI and the distal ends of PEG blocks resulted in T3 specific gene transfer in HepG2 cells as evidenced by reduction of gene transfer efficiency after pre-incubation of cells with excess of T3. In vivo application of T3-PEG-g-PEI based gene vectors in mice after tail vein injection resulted in a significantly 7-fold increase of gene expression in the liver compared with PEG-g-PEI based gene vectors.
authors.affiliation: Department of Pediatrics, Ludwig-Maximilians University, 80337 Munich, Germany. carsten.rudolph@med.uni-muenchen.de
authors.forename: Carsten
authors.initials: C
authors.lastname: Rudolph
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sieverling
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schillinger
authors.forename: Eugenia
authors.initials: E
authors.lastname: Lesina
authors.forename: Christian
authors.initials: C
authors.lastname: Plank
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Thünemann
authors.forename: Hubert
authors.initials: H
authors.lastname: Schönberger
authors.forename: Joseph
authors.initials: J
authors.lastname: Rosenecker
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008422:Materials Testing; D051379:Mice; D008810:Mice, Inbred C57BL; D011073:Polyamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D014018:Tissue Distribution; D014162:Transfection / Q000379:methods*; D014284:Triiodothyronine / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D011073:Polyamines; D014284:Triiodothyronine; D011092:Polyethylene Glycols; D004247:DNA