title: Correlation of length of linear oligo(ethanamino) amides with gene transfer and cytotoxicity.
abstract: The optimization of synthetic carriers for gene transfer remains a major challenge. Cationic polymers such as polyethylenimine (PEI) often show increasing gene transfer activity with increasing molecular weight, but this favorable effect is accompanied by an undesired increase in cytotoxicity. Moreover, the polydispersity of polymers prevents accurate determination of optimum size. Herein we describe the step-by-step elongation of precise linear oligo(ethanamino) amides by making use of the artificial amino acid succinoyl-tetraethylene pentamine (Stp) for solid-phase-assisted synthesis. This procedure enabled us to identify the optimal oligomer Stp30-W (8.4 kDa) with a length of 30 Stp units, with which effective gene transfer occurs in the absence of cytotoxicity. The transfection efficiency of Stp30-W exceeded that of standard linear PEI (22 kDa) by sixfold; nevertheless, Stp30-W exhibited tenfold lower cytotoxicity. In addition to the lower molecular weight, the succinate spacer between the oligoamine units may also contribute to the favorable biocompatibility. The cytotoxicity of the cationic polymer PEI is a major concern for use as a carrier for gene delivery, so this comparison between linear PEI and the new Stp oligomers is particularly relevant.
authors: Pharmaceutical Biotechnology, Center for System-Based Drug Research & Center for NanoScience (CeNS), Ludwig Maximilians University, Butenandtstraße 5-13, 81377 Munich (Germany); Nanosystems Initiative Munich (NIM), Schellingstraße 4, 80799 Munich (Germany).
authors: Claudia
authors: C
authors: Scholz
authors: Petra
authors: P
authors: Kos
authors: Laurent
authors: L
authors: Leclercq
authors: Xiaoyun
authors: X
authors: Jin
authors: Hervé
authors: H
authors: Cottet
authors: Ernst
authors: E
authors: Wagner
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001672:Biocompatible Materials; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005029:Ethylenediamines / Q000138:chemical synthesis / Q000494:pharmacology; D018014:Gene Transfer Techniques; D051379:Mice; D009757:Nylons / Q000138:chemical synthesis* / Q000494:pharmacology*; D010316:Particle Size; D011073:Polyamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011094:Polyethyleneimine / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D005029:Ethylenediamines; D009757:Nylons; D011073:Polyamines; D011094:Polyethyleneimine; D004247:DNA; C034269:tetraethylenepentamine
keywords: DNA; cytotoxicity; gene transfer; polymers; solid-phase synthesis; transfection