title: Polymers for nucleic acid transfer-an overview.
abstract: For the last five decades cationic polymers have been used for nucleic acids transfection. Our understanding of polymer-nucleic acid interactions and their rational use in delivery has continuously increased. The great improvements in macromolecular chemistry and the recognition of distinct biological extra- and intracellular delivery hurdles triggered several breakthrough developments, including the discovery of natural and synthetic polycations for compaction of nucleic acids into stable nanoparticles termed polyplexes; the incorporation of targeting ligands and surface-shielding of polyplexes to enable receptor-mediated gene delivery into defined target tissues; and strongly improved intracellular transfer efficacy by better endosomal escape of vesicle-trapped polyplexes into the cytosol. These experiences triggered the development of second-generation polymers with more dynamic properties, such as endosomal pH-responsive release mechanisms, or biodegradable units for improved biocompatibility and intracellular release of the nucleic acid pay load. Despite a better biological understanding, significant challenges such as efficient nuclear delivery and persistence of gene expression persist. The therapeutic perspectives widened from pDNA-based gene therapy to application of novel therapeutic nucleic acids including mRNA, siRNA, and microRNA. The finding that different therapeutic pay loads require different tailor-made carriers complicates preclinical developments. Convincing evidence of medical efficacy still remains to be demonstrated. Bioinspired multifunctional polyplexes resembling "synthetic viruses" appear as attractive opportunity, but provide additional challenges: how to identify optimum combinations of functional delivery units, and how to prepare such polyplexes reproducibly in precise form? Design of sequence-defined polymers, screening of combinatorial polymer and polyplex libraries are tools for further chemical evolution of polyplexes.
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-University Munich, and Nanosystems Initiative Munich (NIM), Munich, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D001682:Biological Availability; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry; D011073:Polyamines; D000071228:Polyelectrolytes; D011108:Polymers / Q000737:chemistry* / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D001672:Biocompatible Materials; D004247:DNA; D011073:Polyamines; D000071228:Polyelectrolytes; D011108:Polymers; D012333:RNA, Messenger; D034741:RNA, Small Interfering
keywords: Cationic polymers; Gene transfer; Receptor targeting; pDNA; siRNA