title: Combinatorial Optimization of Sequence-Defined Oligo(ethanamino)amides for Folate Receptor-Targeted pDNA and siRNA Delivery.
abstract: Cationic polymers present a versatile platform for the nonviral delivery of therapeutic nucleic acids. In order to achieve effective nucleic acid transfer, polymeric carriers ought to comprise multiple functionalities. Precise chemistries for site-specific placements of the different delivery modules within the carriers present the basis for uncovering structure-activity relationships required for further optimization. Here we present the design and systematic evaluation of a library of 42 sequence-defined oligo(ethanamino)amides generated by solid-phase assisted syntheses. The carriers contained two- or four-arm topologies of different artificial oligoamino acid domains for nucleic acid complexation, terminated by cysteines for disulfide-triggered polyplex stabilization, linked with monodisperse polyethylene glycol (PEG) for surface shielding and terminal folic acid for receptor specific cellular uptake. Additional functional elements included histidines for endosomal escape and/or tyrosine trimers for enhanced hydrophobic polyplex stabilization. In vitro screening of the oligomer library identified a folate-PEG-linked two-arm oligocation structure comprising histidines and tyrosine trimers as the most effective class of carriers for the delivery of pDNA and siRNA.
authors.affiliation: Pharmaceutical Biotechnology, Center for System-based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-University , 81377 Munich, Germany.|Nanosystems Initiative Munich , Schellingstrasse 4, 80799 Munich, Germany.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: He
authors.affiliation: Pharmaceutical Biotechnology, Center for System-based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-University , 81377 Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Müller
authors.affiliation: Pharmaceutical Biotechnology, Center for System-based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-University , 81377 Munich, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Krhac Levacic
authors.affiliation: Pharmaceutical Biotechnology, Center for System-based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-University , 81377 Munich, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Kos
authors.affiliation: Pharmaceutical Biotechnology, Center for System-based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-University , 81377 Munich, Germany.|Nanosystems Initiative Munich , Schellingstrasse 4, 80799 Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lächelt
authors.affiliation: Pharmaceutical Biotechnology, Center for System-based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-University , 81377 Munich, Germany.|Nanosystems Initiative Munich , Schellingstrasse 4, 80799 Munich, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
mesh_terms: D000577:Amides / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000737:chemistry*; D005492:Folic Acid / Q000737:chemistry*; D010957:Plasmids; D034741:RNA, Small Interfering / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000737:chemistry*
chemical_list: D000577:Amides; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D004247:DNA; D005492:Folic Acid