title: Block copolymers containing a hydrophobic domain of membrane-lytic peptides form micellar structures and are effective gene delivery agents.
abstract: Endosomal release peptides have been incorporated in synthetic gene delivery formulations to increase transfection efficiencies. In this work, cationic copolymers containing sHGP, a membrane-lytic peptide derived from HIV gp41, were synthesized and evaluated. Diblock, with sHGP displayed on one block, and statistical, with sHGP randomly displayed, copolymers were prepared via RAFT polymerization. While the statistical copolymer existed as unimers in solution, amphiphilic diblock copolymers self-assembled into cationic micelles in aqueous solution as evidenced by TEM and dynamic light scattering analyses. This self-assembly sequestered the lytic domain and significantly reduced the cytotoxicity of the materials. However, when complexed with plasmid DNA, both the diblock and statistical copolymers of sHGP showed higher gene delivery efficacy compared to the copolymers without the membrane lytic motif. The ability of amphiphilic, diblock copolymers containing endosomal release motifs to self-assemble and sequester lytic domains is a promising feature for the nucleic acid delivery.
authors.affiliation: Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, 3720 15 Ave NE, Box 355061, Seattle, Washington 98195, United States.
authors.forename: Joan G
authors.initials: JG
authors.lastname: Schellinger
authors.forename: Joshuel A
authors.initials: JA
authors.lastname: Pahang
authors.forename: Julie
authors.initials: J
authors.lastname: Shi
authors.forename: Suzie H
authors.initials: SH
authors.lastname: Pun
references.citation: Biomaterials. 2013 Mar;34(9):2318-26
references.pmid: 23261217
references.citation: Bioconjug Chem. 2008 Apr;19(4):920-7
references.pmid: 18376855
references.citation: Adv Drug Deliv Rev. 1999 Aug 20;38(3):279-289
references.pmid: 10837761
references.citation: Virol J. 2007 Nov 20;4:123
references.pmid: 18028545
references.citation: J Control Release. 2007 Oct 8;122(3):252-60
references.pmid: 17643543
references.citation: J Control Release. 2011 May 10;151(3):220-8
references.pmid: 21078351
references.citation: J Control Release. 2009 Oct 1;139(1):40-7
references.pmid: 19470398
references.citation: J Biol Chem. 2003 Jan 3;278(1):585-90
references.pmid: 12411431
references.citation: Biomacromolecules. 2013 Jun 10;14(6):1961-70
references.pmid: 23641942
references.citation: Macromol Biosci. 2011 May 12;11(5):576-89
references.pmid: 21188686
references.citation: Mol Pharm. 2010 Aug 2;7(4):1260-5
references.pmid: 20476763
references.citation: Acc Chem Res. 2012 Jul 17;45(7):1089-99
references.pmid: 22242774
references.citation: Biomaterials. 2008 Dec;29(36):4838-46
references.pmid: 18829102
references.citation: Acc Chem Res. 2012 Jul 17;45(7):1048-56
references.pmid: 22455499
references.citation: Angew Chem Int Ed Engl. 2013 May 10;52(20):5377-81
references.pmid: 23592572
references.citation: Biomacromolecules. 2010 Nov 8;11(11):2904-11
references.pmid: 20886830
references.citation: Biomaterials. 2011 Jul;32(21):4936-42
references.pmid: 21459440
references.citation: Gene Ther. 1999 Apr;6(4):595-605
references.pmid: 10476219
references.citation: J Am Chem Soc. 2012 Oct 10;134(40):16554-7
references.pmid: 23013485
references.citation: Acta Biomater. 2009 Mar;5(3):817-31
references.pmid: 19010748
references.citation: Gene Ther. 2002 Mar;9(6):407-14
references.pmid: 11960317
references.citation: J Control Release. 2011 Oct 30;155(2):303-11
references.pmid: 21782863
references.citation: Gene Ther. 1998 Mar;5(3):409-14
references.pmid: 9614562