title: Biocompatibility and efficacy of oligomaltose-grafted poly(ethylene imine)s (OM-PEIs) for in vivo gene delivery.
abstract: Polycationic polymers like poly(ethylene imine)s (PEIs) are extensively explored for the nonviral transfer of DNA or small RNAs (siRNAs). To enhance biocompatibility and alter pharmacokinetic properties, hyperbranched PEI was recently grafted with the nonligand oligosaccharides maltose or maltotriose at various degrees in a systematic study to yield (oligo-)maltose PEIs (OM-PEIs). In this paper, we investigate the in vivo biocompatibility and efficacy of a whole set of (OM-)PEIs and the corresponding (OM-)PEI-based DNA or siRNA complexes upon systemic (intravenous, i.v.) administration in mice. We determine the overall survival and animal welfare, hepatotoxicity, immune stimulation, erythrocyte aggregation, and the efficacy of DNA delivery in vivo. Higher-degree oligomaltose-grafting of PEI substantially decreases weight loss, abolishes lethality upon repeated treatment with the free polymers or with complexes, and abrogates hepatotoxicity, as determined by serum levels of liver enzymes. Immunostimulatory effects (TNF-α, IFN-γ) and erythrocyte aggregation are mainly observed upon treatment with partially maltotriose-grafted PEI or PEI-based complexes and are largely abolished upon higher-degree grafting. In vivo transfection experiments in mice bearing subcutaneous (s.c.) tumor xenografts reveal a strong dependence of reporter gene expression in a given organ on the mode of complex administration (i.v. vs intraperitoneal injection) and the OM-PEI architecture, with high-level maltose-grafted PEI (PEI-(2-Mal)) being most efficient for DNA delivery. We conclude that distinct differences between different patterns of maltose- or maltotriose-grafting are observed with regard to both biocompatibility and in vivo efficacy and identify optimal oligomaltose-PEIs for therapeutic applications.
authors.affiliation: Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig , Härtelstrasse 16-18, 04107 Leipzig, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gutsch
authors.forename: Dietmar
authors.initials: D
authors.lastname: Appelhans
authors.forename: Sabrina
authors.initials: S
authors.lastname: Höbel
authors.forename: Brigitte
authors.initials: B
authors.lastname: Voit
authors.forename: Achim
authors.initials: A
authors.lastname: Aigner
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage* / Q000737:chemistry*; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics*; D018014:Gene Transfer Techniques; D007097:Imines / Q000008:administration & dosage* / Q000737:chemistry*; D008320:Maltose / Q000008:administration & dosage* / Q000737:chemistry*; D008546:Melanoma, Experimental; D051379:Mice; D011095:Polyethylenes / Q000008:administration & dosage* / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics; D015996:Survival Rate; D014162:Transfection / Q000379:methods; D014312:Trisaccharides / Q000737:chemistry; D015431:Weight Loss
chemical_list: D001672:Biocompatible Materials; D007097:Imines; D011095:Polyethylenes; D011108:Polymers; D034741:RNA, Small Interfering; D014312:Trisaccharides; C505405:poly(ethylene imine); C008317:maltotriose; D008320:Maltose; D004247:DNA