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WIREs Nanomed Nanobiotechnol
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Ionic α‐helical polypeptides toward nonviral gene delivery

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The advent of polymeric materials has significantly promoted the development and rapid growth of various technologies in biomedical applications, such as tissue engineering and controlled drug and gene delivery. Water‐soluble polypeptides bearing functional side chains and adopting stable secondary structures are a new class of functional polymeric materials of potentially broad applications in medicine and biotechnology. In this article, we summarize our recent effort on the design and synthesis of the water‐soluble α‐helical ionic polypeptides originally developed in our laboratory and highlight their applications in cell membrane penetration and nonviral gene/small interfering RNA (siRNA) delivery. WIREs Nanomed Nanobiotechnol 2015, 7:98–110. doi: 10.1002/wnan.1307 This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Biology-Inspired Nanomaterials > Peptide-Based Structures
(a) Proposed mechanism of hexamethyldisilazane (HMDS)‐initiated controlled ring‐opening polymerization (ROP) of N‐Carboxyanhydride (NCA). (Reprinted with permission from Ref Copyright 2007 American Chemical Society) (b) Synthesis of C‐termini functionalized polypeptides initiated by NTMS amines. (Reprinted with permission from Ref Copyright 2008 American Chemical Society) (c) Synthesis of water‐soluble α‐helical polypeptides PVBLG‐X. (Reprinted with permission from Ref Copyright 2011 Nature Publishing Group)
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(a) Structures of P14, a helical poly(arginine) mimic. (Reprinted with permission from Ref Copyright 2013 The Royal Society of Chemistry) (b) Uptake level of RhB‐P14 (20 µg/mL) in HeLa, 3T3‐L1 and Raw 264.7 cells following incubation at 37°C for 2 h. Commercial CPPs, Arg9 and TAT were included as controls. (Reprinted with permission from Ref Copyright 2013 The Royal Society of Chemistry) (c) Transfection efficiencies of P14/DNA polyplexes (N/P ratio = 15) in HeLa, 3T3‐L1, and Raw 264.7 cells. Arg9, TAT, poly(l‐arginine) (PLR), and LPF 2000 served as controls. (Reprinted with permission from Ref Copyright 2013 The Royal Society of Chemistry)
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(a) Schematic representation showing the charge and conformational transformation of PDMNBLGrPVBLG‐8 upon external light triggers. (Reprinted with permission from Ref Copyright 2013 Wiley‐VCH Verlag GmbH & Co. KGaA) (b) Confocal laser scanning microscopy (CLSM) images of HeLa cells incubated with RhB‐PDMNBLGrPVBLG‐8 (red)/YOYO‐1‐DNA (green) complexes with/without UV irradiation (bar = 20 µm). The orange color indicated colocalization of polymer and DNA, while the separation of green and red fluorescence signals suggested efficient DNA unpacking. (Reprinted with permission from Ref Copyright 2013 Wiley‐VCH Verlag GmbH & Co. KGaA)
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(a) Schematic representation of PEG‐PVBLG‐8 copolymers with different architectures. (Reprinted with permission from Ref Copyright 2013 Elsevier B.V.) (b) Cytotoxicity of polyplexes (N/P ratio = 20) toward HeLa cells as determined by the MTT assay. (Reprinted with permission from Ref Copyright 2013 Elsevier B.V.) (c) Transfection efficiencies of polyplexes in HeLa cells at various N/P ratios. (Reprinted with permission from Ref Copyright 2013 Elsevier B.V.)
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(a) Schematic illustration of supramolecular self‐assembled nanoparticles (SSNPs) developed for oral delivery of tumor necrosis factor (TNF)‐α siRNA (oleyl trimethyl chitosan = OTMC; oleyl‐PEG‐mannose = OPM; oleyl‐PEG‐cysteine = OPC; tripolyphosphate = TPP). SSNPs were constructed through electrostatic and hydrophobic self‐assembly of each component, which had a particle size of about 120 nm. (Reprinted with permission from Ref Copyright 2013 Wiley‐VCH Verlag GmbH & Co. KGaA) (b) Intestinal absorption of Cy3‐siRNA‐containing SSNPs in the in vitro follicle‐associated epithelial (FAE) and non‐FAE models. Results were represented as apparent permeability coefficient (Papp). (Reprinted with permission from Ref Copyright 2013 Wiley‐VCH Verlag GmbH & Co. KGaA) (c) Relative TNF‐α mRNA levels in mouse liver, spleen, and lung 24 h after oral gavage of SSNPs at 200 µg/kg. (Reprinted with permission from Ref Copyright 2013 Wiley‐VCH Verlag GmbH & Co. KGaA)
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(a) Schematic illustration of the internalization pathways of supramolecular self‐assembled nanocomplexes (SSANs) containing PVBLG‐8. (Reprinted with permission from Ref Copyright 2013 Wiley‐VCH Verlag GmbH & Co. KGaA) (b) Mechanistic probes of the intracellular kinetics of SSANs with and without PVBLG‐8 (genistein, methyl‐β‐cyclodextrin (mβCD) = caveolae inhibitor; chlorpromazine = clathrin‐mediated endocytosis inhibitor; dynasore = clathrin‐mediated endocytosis and caveolae inhibitor; wortmannin = macropinocytotic inhibitor). (Reprinted with permission from Ref Copyright 2013 Wiley‐VCH Verlag GmbH & Co. KGaA)
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(a) Schematic illustration showing the random coil to helix transformation of cationic polypeptides upon elongation of side‐chain length. (Reprinted with permission from Ref . Copyright 2012 Wiley‐VCH Verlag GmbH & Co. KGaA) (b) Chemical structures of PAHG, poly‐l‐lysine (PLL), and PVBLG‐1. (c) Circular dichroism (CD) spectra of PAHG, PVBLG‐1, and PLL in aqueous solution at pH 3. Both PAHG and PVBLG‐1 adopted helical conformation while PLL adopted random coil conformation. (Reprinted with permission from Ref . Copyright 2011 Nature Publishing Group) (d) The pH‐dependence of the residue molar ellipticity at 222 nm for PAHG, PVBLG‐1, and PLL. (Reprinted with permission from Ref Copyright 2011 Nature Publishing Group) (e) Temperature‐dependence of residue molar ellipticity at 222 nm for PAHG and PVBLG‐1 at pH 3. (Reprinted with permission from Ref Copyright 2011 Nature Publishing Group)
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(a) Calcein uptake in COS‐7 cells treated with PVBLG‐8 at various concentrations. In the absence of an agent capable of pore formation, calcein, a fluorescent dye, is unable to permeate intact cell membranes and thus taken up by cells in a pinocytic fashion, resulting in the appearance of small punctate intracellular fluorescent spots. As the concentration of PVBLG‐8 in the extracellular medium was increased, the intracellular fluorescence of calcein became more diffuse, which indicated membrane permeation and non‐endosomal uptake. (Reprinted with permission from Ref Copyright 2012 Wiley‐VCH Verlag GmbH & Co. KGaA) (b) Schematic presentation of a proposed model for the cellular internalization of PVBLG‐8/siRNA complexes. (Reprinted with permission from Ref Copyright 2012 The American Society of Gene & Cell Therapy)
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(a) Chemical structure of helical PVBLG‐8 and nonhelical PVBDLG‐8. (b) In vitro transfection efficiency of PVBLG‐8/pCMV‐Luc and PVBDLG‐8/pCMV‐Luc polyplexes in COS‐7 cells at various polymer/DNA weight ratios. Polyethylenimine (PEI) (25 kDa) at a 7.5:1 polymer/DNA weight ratio was included as a control. (Reprinted with permission from Ref Copyright 2012 Wiley‐VCH Verlag GmbH & Co. KGaA)
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