Polycationic nanocomplexes are a robust means for achieving nucleic acid condensation and efficient intracellular gene deliveries. To enhance delivery, a multilayered nanoparticle consisting of a core of electrostatically bound elements was used. These included a histone-mimetic peptides, poly-l-arginine and poly-d-glutamic acid was coated with silicate before surface functionalization with poly-l-arginine. Transfection efficiencies and duration of expression were similar when using green fluorescent protein (GFP) plasmid DNA (pDNA) or GFP mRNA. These nanoparticles demonstrated significantly higher (>100%) and significantly longer (15 vs. 4 days) transfection efficiencies in comparison to a commercial transfection agent (Lipofectamine 2000). Reprogramming of human foreskin fibroblasts using mRNA to the Sox2 transcription factor resulted in three-fold higher neurosphere formation in comparison to the commercial reagent. These results demonstrate the potential of these nanoparticles as ideal vectors for gene delivery.
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References
1.
MusickM.A., McConnellK.I., LueJ.K., WeiF., ChenC., and SuhJ.Reprogramming virus nanoparticles to bind metal ions upon activation with heat. Biomacromolecules, 12, 2153, 2011.
2.
LiH., ParkS.H., ReifJ.H., LaBeanT.H., and YanH.DNA-templated self-assembly of protein and nanoparticle linear arrays. J Am Chem Soc, 126, 418, 2004.
3.
SeoE.J., JangI.H., DoE.K., CheonH.C., HeoS.C., KwonY.W., JeongG.O., KimB.R., and KimJ.H.Efficient production of retroviruses using PLGA/bPEI-DNA nanoparticles and application for reprogramming somatic cells. PLoS One, 8, e76875, 2013.
4.
RingK.L., TongL.M., BalestraM.E., JavierR., Andrews-ZwillingY., LiG., WalkerD., ZhangW.R., KreitzerA.C., and HuangY.Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell, 11, 100, 2012.
5.
HuangfuD., OsafuneK., MaehrR., GuoW., EijkelenboomA., ChenS., MuhlesteinW., and MeltonD.A.Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol, 26, 1269, 2008.
6.
Al-DosariM.S., and GaoX.Nonviral gene delivery: principle, limitations, and recent progress. AAPS J, 11, 671, 2009.
DittoA.J., ShahP.N., and YunY.H.Non-viral gene delivery using nanoparticles. Expert Opin Drug Deliv, 6, 1149, 2009.
9.
De SmedtS.C., DemeesterJ., and HenninkW.E.Cationic polymer based gene delivery systems. Pharm Res, 17, 113, 2000.
10.
DuJ.-Z., DuX.-J., MaoC.-Q., and WangJ.Tailor-made dual pH-sensitive polymer–doxorubicin nanoparticles for efficient anticancer drug delivery. J Am Chem Soc, 133, 17560, 2011.
11.
EliyahuH., BarenholzY., and DombA.Polymers for DNA delivery. Molecules, 10, 34, 2005.
12.
GodbeyW., WuK.K., and MikosA.G.Tracking the intracellular path of poly (ethylenimine)/DNA complexes for gene delivery. Proc Natl Acad Sci U S A, 96, 5177, 1999.
13.
ShiJ., ChouB., ChoiJ.L., TaA.L., and PunS.H.Investigation of polyethylenimine/DNA polyplex transfection to cultured cells using radiolabeling and subcellular fractionation methods. Mol Pharm, 10, 2145, 2013.
14.
RungsardthongU., EhtezaziT., BaileyL., ArmesS.P., GarnettM.C., and StolnikS.Effect of polymer ionization on the interaction with DNA in nonviral gene delivery systems. Biomacromolecules, 4, 683, 2003.
WongS.Y., PeletJ.M., and PutnamD.Polymer systems for gene delivery—past, present, and future. Prog Polym Sci, 32, 799, 2007.
17.
JeongJ.H., KimS.W., and ParkT.G.Molecular design of functional polymers for gene therapy. Prog Polym Sci, 32, 1239, 2007.
18.
LakardS., HerlemG., LakardB., and FahysB.Theoretical study of the vibrational spectra of polyethylenimine and polypropylenimine. J Mol Struct Theochem, 685, 83, 2004.
19.
BeganskienėA., SirutkaitisV., KurtinaitienėM., JuškėnasR., and KareivaA.FTIR, TEM and NMR investigations of Stöber silica nanoparticles. Mater Sci (Medžiagotyra), 10, 287, 2004.
20.
ReillyM.J., LarsenJ.D., and SullivanM.O.Polyplexes traffic through caveolae to the Golgi and endoplasmic reticulum en route to the nucleus. Mol Pharm, 9, 1280, 2012.
21.
MilliliP.G., SelekmanJ.A., BlockerK.M., JohnsonD.A., NaikU.P., and SullivanM.O.Structural and functional consequences of poly (ethylene glycol) inclusion on DNA condensation for gene delivery. Microsc Res Tech, 73, 866, 2010.
22.
HuY., LitwinT., NagarajaA.R., KwongB., KatzJ., WatsonN., and IrvineD.J.Cytosolic delivery of membrane-impermeable molecules in dendritic cells using pH-responsive core-shell nanoparticles. Nano Lett, 7, 3056, 2007.
23.
YauW.W.Y., RujitanarojP.-o., LamL., and ChewS.Y.Directing stem cell fate by controlled RNA interference. Biomaterials, 33, 2608, 2012.
24.
RoperS., and HembergerM.Defining pathways that enforce cell lineage specification in early development and stem cells. Cell Cycle, 8, 1515, 2009.
25.
BakerA., SaltikM., LehrmannH., KillischI., MautnerV., LammG., ChristoforiG., and CottenM.Polyethylenimine (PEI) is a simple, inexpensive and effective reagent for condensing and linking plasmid DNA to adenovirus for gene delivery. Gene Ther, 4, 773, 1997.
26.
XiaT., KovochichM., LiongM., MengH., KabehieS., GeorgeS., ZinkJ.I., and NelA.E.Polyethyleneimine coating enhances the cellular uptake of mesoporous silica nanoparticles and allows safe delivery of siRNA and DNA constructs. ACS Nano, 3, 3273, 2009.
27.
CorsoT.D., TorresG., GoulahC., RoyI., GambinoA.S., NaydaJ., BuckleyT., StachowiakE.K., BergeyE.J., and PudavarH.Assessment of viral and non-viral gene transfer into adult rat brains using HSV-1, calcium phosphate and PEI-based methods. Folia Morphol (Warsz), 64, 130, 2005.
28.
KneuerC., SametiM., HaltnerE.G., SchiestelT., SchirraH., SchmidtH., and LehrC.-M.Silica nanoparticles modified with aminosilanes as carriers for plasmid DNA. Int J Pharm, 196, 257, 2000.
29.
HessG.T., Humphries IVW.H., FayN.C., and PayneC.K.Cellular binding, motion, and internalization of synthetic gene delivery polymers. Biochim Biophys Acta, 1773, 1583, 2007.
30.
LiaoZ.-X., HoY.-C., ChenH.-L., PengS.-F., HsiaoC.-W., and SungH.-W.Enhancement of efficiencies of the cellular uptake and gene silencing of chitosan/siRNA complexes via the inclusion of a negatively charged poly (γ-glutamic acid). Biomaterials, 31, 8780, 2010.
31.
PengS.-F., YangM.-J., SuC.-J., ChenH.-L., LeeP.-W., WeiM.-C., and SungH.-W.Effects of incorporation of poly (γ-glutamic acid) in chitosan/DNA complex nanoparticles on cellular uptake and transfection efficiency. Biomaterials, 30, 1797, 2009.
32.
DouglasK.L., PiccirilloC.A., and TabrizianM.Effects of alginate inclusion on the vector properties of chitosan-based nanoparticles. J Control Release, 115, 354, 2006.
33.
DouglasK.L., and TabrizianM.Effect of experimental parameters on the formation of alginate–chitosan nanoparticles and evaluation of their potential application as DNA carrier. J Biomater Sci Polym Ed, 16, 43, 2005.
34.
FritzJ.D., HerweijerH., ZhangG., and WolffJ.A.Gene transfer into mammalian cells using histone-condensed plasmid DNA. Hum Gene Ther, 7, 1395, 1996.
35.
WagstaffK.M., GloverD.J., TremethickD.J., and JansD.A.Histone-mediated transduction as an efficient means for gene delivery. Mol Ther, 15, 721, 2007.
36.
LiH., LuoT., ShengR., SunJ., WangZ., and CaoA.Endoplasmic reticulum localization of poly (ω-aminohexyl methacrylamide) s conjugated with (l-)-arginines in plasmid DNA delivery. Biomaterials, 34, 7923, 2013.
37.
ReillyM.J., LarsenJ.D., and SullivanM.O.Histone H3 tail peptides and poly (ethylenimine) have synergistic effects for gene delivery. Mol Pharm, 9, 1031, 2012.
38.
MosammaparastN., JacksonK.R., GuoY., BrameC.J., ShabanowitzJ., HuntD.F., and PembertonL.F.Nuclear import of histone H2A and H2B is mediated by a network of karyopherins. J Cell Biol, 153, 251, 2001.
39.
MosammaparastN., GuoY., ShabanowitzJ., HuntD.F., and PembertonL.F.Pathways mediating the nuclear import of histones H3 and H4 in yeast. J Biol Chem, 277, 862, 2002.
40.
MühlhäusserP., MüllerE.C., OttoA., and KutayU.Multiple pathways contribute to nuclear import of core histones. EMBO Rep, 2, 690, 2001.
41.
PalmeriD., and MalimM.H.Importin β can mediate the nuclear import of an arginine-rich nuclear localization signal in the absence of importin α. Mol Cell Biol, 19, 1218, 1999.
42.
FagerlundR., MelenK., KinnunenL., and JulkunenI.Arginine/lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin α5. J Biol Chem, 277, 30072, 2002.
43.
SmithB.C., and DenuJ.M.Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta, 1789, 45, 2009.
44.
FrankelA., YadavN., LeeJ., BranscombeT.L., ClarkeS., and BedfordM.T.The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity. J Biol Chem, 277, 3537, 2002.
45.
OnozatoM.L., TojoA., LeiperJ., FujitaT., PalmF., and WilcoxC.S.Expression of NG, NG-dimethylarginine dimethylaminohydrolase and protein arginine N-methyltransferase isoforms in diabetic rat kidney effects of angiotensin II receptor blockers. Diabetes, 57, 172, 2008.
46.
ShiJ., ChouB., ChoiJ.L., TaA.L., and PunS.H.Investigation of polyethylenimine/DNA polyplex transfection to cultured cells using radiolabeling and subcellular fractionation methods. Mol Pharm, 10, 2145, 2013.
47.
GoudaN., MiyataK., ChristieR.J., SumaT., KishimuraA., FukushimaS., NomotoT., LiuX., NishiyamaN., and KataokaK.Silica nanogelling of environment-responsive PEGylated polyplexes for enhanced stability and intracellular delivery of siRNA. Biomaterials, 34, 562, 2013.
48.
BehrJ.-P.The proton sponge: a trick to enter cells the viruses did not exploit. CHIMIA Int J Chem, 51, 1, 1997.
49.
FreemanE.C., WeilandL.M., and MengW.S.Modeling the proton sponge hypothesis: examining proton sponge effectiveness for enhancing intracellular gene delivery through multiscale modeling. J Biomater Sci Polym Ed, 24, 398, 2013.
50.
TugyiR., UrayK., IvánD., FellingerE., PerkinsA., and HudeczF.Partial D-amino acid substitution: Improved enzymatic stability and preserved Ab recognition of a MUC2 epitope peptide. Proc Natl Acad Sci U S A, 102, 413, 2005.
51.
ChuD.S., JohnsonR.N., and PunS.H.Cathepsin B-sensitive polymers for compartment-specific degradation and nucleic acid release. J Control Release, 157, 445, 2012.
52.
WelchB.D., VanDemarkA.P., HerouxA., HillC.P., and KayM.S.Potent D-peptide inhibitors of HIV-1 entry. Proc Natl Acad Sci U S A, 104, 16828, 2007.
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