Poly(1-vinylimidazole) Prospects in Gene Delivery
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摘要
Polymeric amines are being studied intensively as components of systems for gene delivery in genetic engineering and gene therapy of genetic disorders, including cancer. Despite remarkable achievements in the field, polymeric amines, such as polyethyleneimine, show some disadvantages. Strong interaction between the amine-containing polymer and nucleic acid hampers the release of nucleic acid in the cell cytoplasm. Amine groups can interact with the cell membrane which results in cell death. These limitations of polymeric amines stimulated an investigation of new structures for gene delivery. Imidazole-containing polymers have attracted attention as lesser basic substances, while they are able to interact with polymeric acids. Further development of imidazole-based gene delivery agents requires knowledge about some fundamental aspects of interaction between nucleic acids, and polymeric imidazoles. In this work,we studied the complexation of poly(1-vinylimidazole) and oligomeric DNA. We found that the number of active sites capable of binding with negatively charged phosphate groups is comparable with the number of protonated imidazole units in the case of high molecular weight polymer. The increase in polymer charge by 1-bromopropane quaternizating 1%-5% imidazole units or by decreasing the pH to6.5-7 considerably increased the ability of poly(1-vinylimidazole) to interact with oligonucleotides. The pH sensitivity of this interaction is interesting for cancer gene therapy because the tumours have a lowered intercellular pH(stable oligonucleotide complex) and a higher extracellular pH which can lead to complex dissociation. Minimal critical length for complexation of quaternized poly(1-vinylimidazole)and DNA is below eight units which corresponds to polymers with amine groups. Fluorescence-tagged poly(1-vinylimidazole) samples were obtained and their potential for monitoring the polymer and polymer-oligonucleotide complex internalization into living cells was demonstrated.
Polymeric amines are being studied intensively as components of systems for gene delivery in genetic engineering and gene therapy of genetic disorders, including cancer. Despite remarkable achievements in the field, polymeric amines, such as polyethyleneimine, show some disadvantages. Strong interaction between the amine-containing polymer and nucleic acid hampers the release of nucleic acid in the cell cytoplasm. Amine groups can interact with the cell membrane which results in cell death. These limitations of polymeric amines stimulated an investigation of new structures for gene delivery. Imidazole-containing polymers have attracted attention as lesser basic substances, while they are able to interact with polymeric acids. Further development of imidazole-based gene delivery agents requires knowledge about some fundamental aspects of interaction between nucleic acids, and polymeric imidazoles. In this work,we studied the complexation of poly(1-vinylimidazole) and oligomeric DNA. We found that the number of active sites capable of binding with negatively charged phosphate groups is comparable with the number of protonated imidazole units in the case of high molecular weight polymer. The increase in polymer charge by 1-bromopropane quaternizating 1%-5% imidazole units or by decreasing the pH to6.5-7 considerably increased the ability of poly(1-vinylimidazole) to interact with oligonucleotides. The pH sensitivity of this interaction is interesting for cancer gene therapy because the tumours have a lowered intercellular pH(stable oligonucleotide complex) and a higher extracellular pH which can lead to complex dissociation. Minimal critical length for complexation of quaternized poly(1-vinylimidazole)and DNA is below eight units which corresponds to polymers with amine groups. Fluorescence-tagged poly(1-vinylimidazole) samples were obtained and their potential for monitoring the polymer and polymer-oligonucleotide complex internalization into living cells was demonstrated.
Polymeric amines are being studied intensively as components of systems for gene delivery in genetic engineering and gene therapy of genetic disorders, including cancer. Despite remarkable achievements in the field, polymeric amines, such as polyethyleneimine, show some disadvantages. Strong interaction between the amine-containing polymer and nucleic acid hampers the release of nucleic acid in the cell cytoplasm. Amine groups can interact with the cell membrane which results in cell death. These limitations of polymeric amines stimulated an investigation of new structures for gene delivery. Imidazole-containing polymers have attracted attention as lesser basic substances, while they are able to interact with polymeric acids. Further development of imidazole-based gene delivery agents requires knowledge about some fundamental aspects of interaction between nucleic acids, and polymeric imidazoles. In this work,we studied the complexation of poly(1-vinylimidazole) and oligomeric DNA. We found that the number of active sites capable of binding with negatively charged phosphate groups is comparable with the number of protonated imidazole units in the case of high molecular weight polymer. The increase in polymer charge by 1-bromopropane quaternizating 1%-5% imidazole units or by decreasing the pH to6.5-7 considerably increased the ability of poly(1-vinylimidazole) to interact with oligonucleotides. The pH sensitivity of this interaction is interesting for cancer gene therapy because the tumours have a lowered intercellular pH(stable oligonucleotide complex) and a higher extracellular pH which can lead to complex dissociation. Minimal critical length for complexation of quaternized poly(1-vinylimidazole)and DNA is below eight units which corresponds to polymers with amine groups. Fluorescence-tagged poly(1-vinylimidazole) samples were obtained and their potential for monitoring the polymer and polymer-oligonucleotide complex internalization into living cells was demonstrated.
引文
1 Boussif,O.; Lezoualc'h,F.; Zanta,M.A.; Mergny,M.D.;Scherman,D.A.;Demeneix,B.;Behr, J.P.A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo:Polyethylenimine.Proc.Natl.Acad.Sci.1995,92,7297-730.
2 Fischera,D.; Lib,Y.;Ahlemeyerc,B.; Krieglsteinc,J.;Kissel,T.In vitro cytotoxicity testing of poly cations:Influence of polymer structure on cell viability and hemolysis.Biomaterials2003,24,1121-1131.
3 Miao,H.;Wang,Y.F.;Dong,H.Y.; Chen,D.Y.Complexation induced by weak interaction between DNA and PEO-bP4VP below the CMC of the polymer.Chinese J.Polym.Sci.2017,35,46-53.
4 Annenkov,V.V.;Danilovtseva,E.N.; Saraev,V.V.;Mikhaleva, A.I.Complexation of copper(Ⅱ)ions with imidazolecarboxylic polymeric systems.J.Polym.Sci., Part A:Polym.Chem.2003,41,2256-2263.
5 Asayama,S.;Sekine,T.;Kawakami,H.;Nagaoka,S.Design of aminated poly(1-vinylimidazole)for a new pH-sensitive polycation to enhance cell-specific gene delivery.BioconjugateChem.2007,18,1662-1667.
6 Dulea,M.;Biswasa,M.;Biswasa,Y.;Mandal,K.;Jana,N.R.;Mandal,T.K.Cysteine-based amphiphilic peptide-polymer conjugates via thiol-mediated radical polymerization:Synthesis,self-assembly,RNA polyplexation and N-terminus fluorescent labeling for cell imaging.Polymer 2017,112,125-135.
7 Ihm,J.E.;Han,K.O.;Han,I.K.;Ahn,K.D.;Han,D.K.;Cho,C.S.High transfection efficiency of poly(4-vinylimidazole)as a new gene carrier.Bioconjugate Chem.2003,14,707-708.
8 Ihm,J.E.;Han,K.O.;Hwang,C.S.;Kang,J.H.;Ahn,K.D.;Han,I.K.; Han,D.K.; Hubbell,J.A.; Cho,C.S.Poly(4-vinylimidazole)as nonviral gene carrier:In vitro and in vivo transfection..Acta Biomater.2005,1,165-172.
9 Asayama,S.;Nishinohara,S.;Kawakami,H.Zinc-chelated imidazole groups for DNA polyion complex formation.Metallomics 2011,680-682.
10 Asayama,S.;Matsuda,K.;Negishiband,Y.;Kawakami,H.Intracellular co-delivery of zinc ions and plasmid DNA for enhancing gene transfection activity.Metallomics 2014,6,82-87.
11 Asayama,S.; Hakamatani,T.; Kawakami,H.Synthesis and characterization of alkylated poly(1-vinylimidazole)to control the stability of its DNA polyion complexes for gene delivery.Bioconjugate Chem.2010,21,646-652.
12 Shuai,X.; Merdan,T.; Unger,F.; Kissel,T.Supramolecular gene delivery vectors showing enhanced transgene expression and good biocompatibility.Bioconjugate Chem.2005,16,322-329.
13 Pouton,C.W.; Lucas,P.; Thomas,B.J.; Uduehi,A.N.; Milroy,D.A.; Moss,S.H.Polycation-DNA complexes for gene delivery:A comparison of the biopharmaceutical properties of cationic polypeptides and cationic lipids.J.Control.Release1998,53,289-299.
14 Asayama,S.; Seno,K.; Kawakami,H.Synthesis of carboxymethyl poly(1-vinylimidazole)as a polyampholyte for biocompatibility.Chem.Lett. 2013,42,358-360.
15 Allen,M.H.;Day,K.N.;Hemp,S.T.;Long,T.E.Synthesis of folic acid-containing imidazolium copolymers for potential gene delivery applications.Macromol. Chem.Phys.2013,214,797-805.
16 Asayama,S.; Nishinohara,S.; Kawakami,H.Zinc-chelated poly(1-vinylimidazole)and a carbohydrate ligand polycation form DNA ternary complexes for gene delivery.Bioconjugate Chem.2011,22,1864-1868.
17 Drean,M.; Debuigne,A.;Jerome,C.;Goncalves,C.;Midoux,P.;Rieger,J.;Guegan,P.Poly(N-methylvinylamine)-based copolymers for improved gene transfection.Macromol Biosci.2018,1700353.
18 Pack,D.W.;Putnam,D.;Langer,R.Design of imidazole-containing endosomolytic biopolymers for gene delivery.Biotechnol.Bioeng.2000,67,217-23.
19 Sakurai,M.; Imai,T.; Yamashita,F.Temperature dependence of viscosities and potentiometric titration behavior of poly(nvinylimidazole)in aqueous salt solutions.Polym.J.1994,26,658-664.
20 Annenkov,V.V.;Danilovtseva,E.N.;Likhoshway,Y.V.;Pat-wardhanand,S.V.;Perry,C.C.Controlled stabilisation of silicic acid below pH 9 using poly(1-vinylimidazole).J.Mater.Chem.2008,18,553-559.
21 Eskin,V.E.;Magarik,S.Y.;Zhuraev,U.B.;Rudkovskaya,G.D.Light-scattering,viscosity and dynamic birefringence of poly-normal-vinylimidazole solutions.Vysokomol. Soedin.,Ser.A 1978,20,2219-2223.
22 Du,X.L.; Zhang,H.S.; Deng,Y.H.; Wang,H.Design and synthesis of a novel fluorescent reagent,6-oxy-(ethylpiperazine)-9-(2-methoxycarbonyl)fluorescein,for carboxylic acids and its application in food samples using high-performance liquid chromatography.J.Chromatogr.A 2008,1178,92-100.
23 Zelinskiy,S.N.;Danilovtseva,E.N.;Pal'shin,V.A.;Krishnan,U.M.; Annenkov,V.V.Reagents for labeling with pH-independent fluorescein-based tags.Arkivoc 2018, vii.
24 Mazyar,N.L.;Annenkov,V.V.;Kruglova,V.A.;Ananiev,S.M.;Danilotseva,E.N.;Rokhin,A.V.;Zinchenko,S.V.Acidbase properties of poly(1-vinylazoles)in aqueous solution.Russ.Chem.Bull. 2000,4912,2013-2017.
25 Sandeli,E.B.; West,T.S.Recommended nomenclature for titrimetric analysis.Pure Appl. Chem.1969,18,427-436.
26 Henrichs,P.M.;Whitlock,L.R.;Sochor,A.R.;Tan,J.S.Conformational behavior of poly(n-vinylimidazole)-potentiometric titration,viscosity,and proton nuclear magnetic resonance studies.Macromolecules 1980,13,1375-138 1.
27 Annenkov,V.V.;Danilovtseva,E.N.;Tenhu,H.;Aseyev,V.;Hirvonen,S.P.; Mikhaleva,A.I.Copolymers of 1-vinylimidazole and(meth)acrylic acid:Synthesis and polyelectrolyte properties.Eur.Polym.J.2004,40,1027-1032.
28 Annenkov,V.V.;Krishnan,U.M.;Pal'shin,V.A.;Zelinskiy,S.N.;Kandasamy,G.;Danilovtseva,E.N.Design of the oligonucleotide carriers:Importance of polyamine chain length.Polymers 2018,10,1297.
29 Basche,T.;Mullen,K.; Schmidt,M.From single molecules to nanoscopically structured materials.Adv.Polym.Sci. 2014,260,1-288.
30 Yoshikawa,K.Controlling the higher-order structure of giant DNA molecules.Adv.Drug Deliv.Rev.2001,52,235-244.
31 Tsuchida,E.;Abe,K.Interactions between macromolecules in solution and intermacromolecular complexes.Adv.Polym.Sci.1982,45,15-130.
32 Shirmanova,M.V.; Druzhkova,I.N.; Lukina,M.M.; Matlashov,M.E.;Belousov,V.V.;Snopova,L.B.;Prodanetz,N.;Dudenkova,V.V.;Lukyanov,S.A.;Zagaynova,E.V.Intracellular pH imaging in cancer cells in vitro and tumors in vivo using the new genetically encoded sensor SypHer2.Biochim.Biophys.Acta 2015,1850,1905-191 1.
33 Heiden,M.G.V.; Cantley,L.C.; Thompson,C.B.Understanding the Warburg effect:The metabolic requirements of cell proliferation.Science 2009,324,1029-1033.
34 Lu,Z.N.;Tian,B.;Guo,X.L.Repositioning of proton pump inhibitors in cancer therapy.Cancer Chemother.Pharmacol.2017,80,925-937.
2 Fischera,D.; Lib,Y.;Ahlemeyerc,B.; Krieglsteinc,J.;Kissel,T.In vitro cytotoxicity testing of poly cations:Influence of polymer structure on cell viability and hemolysis.Biomaterials2003,24,1121-1131.
3 Miao,H.;Wang,Y.F.;Dong,H.Y.; Chen,D.Y.Complexation induced by weak interaction between DNA and PEO-bP4VP below the CMC of the polymer.Chinese J.Polym.Sci.2017,35,46-53.
4 Annenkov,V.V.;Danilovtseva,E.N.; Saraev,V.V.;Mikhaleva, A.I.Complexation of copper(Ⅱ)ions with imidazolecarboxylic polymeric systems.J.Polym.Sci., Part A:Polym.Chem.2003,41,2256-2263.
5 Asayama,S.;Sekine,T.;Kawakami,H.;Nagaoka,S.Design of aminated poly(1-vinylimidazole)for a new pH-sensitive polycation to enhance cell-specific gene delivery.BioconjugateChem.2007,18,1662-1667.
6 Dulea,M.;Biswasa,M.;Biswasa,Y.;Mandal,K.;Jana,N.R.;Mandal,T.K.Cysteine-based amphiphilic peptide-polymer conjugates via thiol-mediated radical polymerization:Synthesis,self-assembly,RNA polyplexation and N-terminus fluorescent labeling for cell imaging.Polymer 2017,112,125-135.
7 Ihm,J.E.;Han,K.O.;Han,I.K.;Ahn,K.D.;Han,D.K.;Cho,C.S.High transfection efficiency of poly(4-vinylimidazole)as a new gene carrier.Bioconjugate Chem.2003,14,707-708.
8 Ihm,J.E.;Han,K.O.;Hwang,C.S.;Kang,J.H.;Ahn,K.D.;Han,I.K.; Han,D.K.; Hubbell,J.A.; Cho,C.S.Poly(4-vinylimidazole)as nonviral gene carrier:In vitro and in vivo transfection..Acta Biomater.2005,1,165-172.
9 Asayama,S.;Nishinohara,S.;Kawakami,H.Zinc-chelated imidazole groups for DNA polyion complex formation.Metallomics 2011,680-682.
10 Asayama,S.;Matsuda,K.;Negishiband,Y.;Kawakami,H.Intracellular co-delivery of zinc ions and plasmid DNA for enhancing gene transfection activity.Metallomics 2014,6,82-87.
11 Asayama,S.; Hakamatani,T.; Kawakami,H.Synthesis and characterization of alkylated poly(1-vinylimidazole)to control the stability of its DNA polyion complexes for gene delivery.Bioconjugate Chem.2010,21,646-652.
12 Shuai,X.; Merdan,T.; Unger,F.; Kissel,T.Supramolecular gene delivery vectors showing enhanced transgene expression and good biocompatibility.Bioconjugate Chem.2005,16,322-329.
13 Pouton,C.W.; Lucas,P.; Thomas,B.J.; Uduehi,A.N.; Milroy,D.A.; Moss,S.H.Polycation-DNA complexes for gene delivery:A comparison of the biopharmaceutical properties of cationic polypeptides and cationic lipids.J.Control.Release1998,53,289-299.
14 Asayama,S.; Seno,K.; Kawakami,H.Synthesis of carboxymethyl poly(1-vinylimidazole)as a polyampholyte for biocompatibility.Chem.Lett. 2013,42,358-360.
15 Allen,M.H.;Day,K.N.;Hemp,S.T.;Long,T.E.Synthesis of folic acid-containing imidazolium copolymers for potential gene delivery applications.Macromol. Chem.Phys.2013,214,797-805.
16 Asayama,S.; Nishinohara,S.; Kawakami,H.Zinc-chelated poly(1-vinylimidazole)and a carbohydrate ligand polycation form DNA ternary complexes for gene delivery.Bioconjugate Chem.2011,22,1864-1868.
17 Drean,M.; Debuigne,A.;Jerome,C.;Goncalves,C.;Midoux,P.;Rieger,J.;Guegan,P.Poly(N-methylvinylamine)-based copolymers for improved gene transfection.Macromol Biosci.2018,1700353.
18 Pack,D.W.;Putnam,D.;Langer,R.Design of imidazole-containing endosomolytic biopolymers for gene delivery.Biotechnol.Bioeng.2000,67,217-23.
19 Sakurai,M.; Imai,T.; Yamashita,F.Temperature dependence of viscosities and potentiometric titration behavior of poly(nvinylimidazole)in aqueous salt solutions.Polym.J.1994,26,658-664.
20 Annenkov,V.V.;Danilovtseva,E.N.;Likhoshway,Y.V.;Pat-wardhanand,S.V.;Perry,C.C.Controlled stabilisation of silicic acid below pH 9 using poly(1-vinylimidazole).J.Mater.Chem.2008,18,553-559.
21 Eskin,V.E.;Magarik,S.Y.;Zhuraev,U.B.;Rudkovskaya,G.D.Light-scattering,viscosity and dynamic birefringence of poly-normal-vinylimidazole solutions.Vysokomol. Soedin.,Ser.A 1978,20,2219-2223.
22 Du,X.L.; Zhang,H.S.; Deng,Y.H.; Wang,H.Design and synthesis of a novel fluorescent reagent,6-oxy-(ethylpiperazine)-9-(2-methoxycarbonyl)fluorescein,for carboxylic acids and its application in food samples using high-performance liquid chromatography.J.Chromatogr.A 2008,1178,92-100.
23 Zelinskiy,S.N.;Danilovtseva,E.N.;Pal'shin,V.A.;Krishnan,U.M.; Annenkov,V.V.Reagents for labeling with pH-independent fluorescein-based tags.Arkivoc 2018, vii.
24 Mazyar,N.L.;Annenkov,V.V.;Kruglova,V.A.;Ananiev,S.M.;Danilotseva,E.N.;Rokhin,A.V.;Zinchenko,S.V.Acidbase properties of poly(1-vinylazoles)in aqueous solution.Russ.Chem.Bull. 2000,4912,2013-2017.
25 Sandeli,E.B.; West,T.S.Recommended nomenclature for titrimetric analysis.Pure Appl. Chem.1969,18,427-436.
26 Henrichs,P.M.;Whitlock,L.R.;Sochor,A.R.;Tan,J.S.Conformational behavior of poly(n-vinylimidazole)-potentiometric titration,viscosity,and proton nuclear magnetic resonance studies.Macromolecules 1980,13,1375-138 1.
27 Annenkov,V.V.;Danilovtseva,E.N.;Tenhu,H.;Aseyev,V.;Hirvonen,S.P.; Mikhaleva,A.I.Copolymers of 1-vinylimidazole and(meth)acrylic acid:Synthesis and polyelectrolyte properties.Eur.Polym.J.2004,40,1027-1032.
28 Annenkov,V.V.;Krishnan,U.M.;Pal'shin,V.A.;Zelinskiy,S.N.;Kandasamy,G.;Danilovtseva,E.N.Design of the oligonucleotide carriers:Importance of polyamine chain length.Polymers 2018,10,1297.
29 Basche,T.;Mullen,K.; Schmidt,M.From single molecules to nanoscopically structured materials.Adv.Polym.Sci. 2014,260,1-288.
30 Yoshikawa,K.Controlling the higher-order structure of giant DNA molecules.Adv.Drug Deliv.Rev.2001,52,235-244.
31 Tsuchida,E.;Abe,K.Interactions between macromolecules in solution and intermacromolecular complexes.Adv.Polym.Sci.1982,45,15-130.
32 Shirmanova,M.V.; Druzhkova,I.N.; Lukina,M.M.; Matlashov,M.E.;Belousov,V.V.;Snopova,L.B.;Prodanetz,N.;Dudenkova,V.V.;Lukyanov,S.A.;Zagaynova,E.V.Intracellular pH imaging in cancer cells in vitro and tumors in vivo using the new genetically encoded sensor SypHer2.Biochim.Biophys.Acta 2015,1850,1905-191 1.
33 Heiden,M.G.V.; Cantley,L.C.; Thompson,C.B.Understanding the Warburg effect:The metabolic requirements of cell proliferation.Science 2009,324,1029-1033.
34 Lu,Z.N.;Tian,B.;Guo,X.L.Repositioning of proton pump inhibitors in cancer therapy.Cancer Chemother.Pharmacol.2017,80,925-937.
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