KR20010101116A - 신규 핵산 전달제, 이를 함유하는 조성물 및 용도 - Google Patents

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Publication number

KR20010101116A

KR20010101116A KR1020017006897A KR20017006897A KR20010101116A KR 20010101116 A KR20010101116 A KR 20010101116A KR 1020017006897 A KR1020017006897 A KR 1020017006897A KR 20017006897 A KR20017006897 A KR 20017006897A KR 20010101116 A KR20010101116 A KR 20010101116A

Authority

KR

South Korea

Prior art keywords

nucleic acid

delivery agent

formula

sugar

composition

Prior art date

1998-12-03

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Withdrawn

Links

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• 102000039446 nucleic acids Human genes 0.000 title claims abstract description 94
• 108020004707 nucleic acids Proteins 0.000 title claims abstract description 94
• 150000007523 nucleic acids Chemical class 0.000 title claims abstract description 94
• 239000000203 mixture Substances 0.000 title claims abstract description 84
• 239000003795 chemical substances by application Substances 0.000 title description 17
• 229940124447 delivery agent Drugs 0.000 claims abstract description 59
• 125000001424 substituent group Chemical group 0.000 claims abstract description 17
• 230000002209 hydrophobic effect Effects 0.000 claims abstract description 13
• 125000006850 spacer group Chemical group 0.000 claims abstract description 11
• 108090000623 proteins and genes Proteins 0.000 claims description 55
• 210000004027 cell Anatomy 0.000 claims description 51
• 238000000034 method Methods 0.000 claims description 46
• 108020004414 DNA Proteins 0.000 claims description 43
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 35
• 235000000346 sugar Nutrition 0.000 claims description 35
• -1 deoxynucleotides Chemical group 0.000 claims description 30
• 150000001875 compounds Chemical class 0.000 claims description 26
• 150000002632 lipids Chemical class 0.000 claims description 26
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
• 108091034117 Oligonucleotide Proteins 0.000 claims description 18
• 102000004196 processed proteins & peptides Human genes 0.000 claims description 17
• 230000001225 therapeutic effect Effects 0.000 claims description 15
• 239000002671 adjuvant Substances 0.000 claims description 14
• 125000004432 carbon atom Chemical group C* 0.000 claims description 12
• MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 claims description 12
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
• PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 claims description 12
• 238000002347 injection Methods 0.000 claims description 11
• 239000007924 injection Substances 0.000 claims description 11
• 229920005862 polyol Polymers 0.000 claims description 11
• 150000003077 polyols Chemical class 0.000 claims description 11
• 150000008163 sugars Chemical class 0.000 claims description 10
• 125000000217 alkyl group Chemical group 0.000 claims description 9
• 125000003277 amino group Chemical group 0.000 claims description 9
• 230000007935 neutral effect Effects 0.000 claims description 9
• 150000001413 amino acids Chemical class 0.000 claims description 8
• 238000009833 condensation Methods 0.000 claims description 8
• 230000005494 condensation Effects 0.000 claims description 8
• SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims description 7
• 238000009472 formulation Methods 0.000 claims description 7
• 229920000768 polyamine Polymers 0.000 claims description 7
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
• 201000010099 disease Diseases 0.000 claims description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
• VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 150000003839 salts Chemical class 0.000 claims description 6
• ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 claims description 6
• 229940063675 spermine Drugs 0.000 claims description 6
• 239000000126 substance Substances 0.000 claims description 6
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
• 229930006000 Sucrose Natural products 0.000 claims description 5
• 230000001105 regulatory effect Effects 0.000 claims description 5
• 229920006395 saturated elastomer Polymers 0.000 claims description 5
• 229960004793 sucrose Drugs 0.000 claims description 5
• 239000004215 Carbon black (E152) Substances 0.000 claims description 4
• WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 4
• 102000053602 DNA Human genes 0.000 claims description 4
• SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 claims description 4
• PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims description 4
• VHRGRCVQAFMJIZ-UHFFFAOYSA-N cadaverine Chemical compound NCCCCCN VHRGRCVQAFMJIZ-UHFFFAOYSA-N 0.000 claims description 4
• 125000004122 cyclic group Chemical group 0.000 claims description 4
• 239000003814 drug Substances 0.000 claims description 4
• 239000004312 hexamethylene tetramine Substances 0.000 claims description 4
• 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 4
• 229930195733 hydrocarbon Natural products 0.000 claims description 4
• 150000002430 hydrocarbons Chemical class 0.000 claims description 4
• KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 claims description 4
• 241000894007 species Species 0.000 claims description 4
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
• GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 claims description 3
• 229930091371 Fructose Natural products 0.000 claims description 3
• 239000005715 Fructose Substances 0.000 claims description 3
• RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 3
• PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 claims description 3
• SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 claims description 3
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
• WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 3
• 230000000692 anti-sense effect Effects 0.000 claims description 3
• 235000013681 dietary sucrose Nutrition 0.000 claims description 3
• 229930182830 galactose Natural products 0.000 claims description 3
• 239000008103 glucose Substances 0.000 claims description 3
• 239000008101 lactose Substances 0.000 claims description 3
• 239000002773 nucleotide Substances 0.000 claims description 3
• 125000003729 nucleotide group Chemical group 0.000 claims description 3
• 229940063673 spermidine Drugs 0.000 claims description 3
• OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
• 229920000945 Amylopectin Polymers 0.000 claims description 2
• 229920000856 Amylose Polymers 0.000 claims description 2
• WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 claims description 2
• 229920002307 Dextran Polymers 0.000 claims description 2
• 229920002670 Fructan Polymers 0.000 claims description 2
• 102000006947 Histones Human genes 0.000 claims description 2
• 108010033040 Histones Proteins 0.000 claims description 2
• GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
• 229920000057 Mannan Polymers 0.000 claims description 2
• 229920002873 Polyethylenimine Polymers 0.000 claims description 2
• 102000007327 Protamines Human genes 0.000 claims description 2
• 108010007568 Protamines Proteins 0.000 claims description 2
• 239000005700 Putrescine Substances 0.000 claims description 2
• HIWPGCMGAMJNRG-ACCAVRKYSA-N Sophorose Natural products O([C@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HIWPGCMGAMJNRG-ACCAVRKYSA-N 0.000 claims description 2
• 125000001931 aliphatic group Chemical group 0.000 claims description 2
• 210000004102 animal cell Anatomy 0.000 claims description 2
• GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
• DLRVVLDZNNYCBX-ZZFZYMBESA-N beta-melibiose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1 DLRVVLDZNNYCBX-ZZFZYMBESA-N 0.000 claims description 2
• HIWPGCMGAMJNRG-UHFFFAOYSA-N beta-sophorose Natural products OC1C(O)C(CO)OC(O)C1OC1C(O)C(O)C(O)C(CO)O1 HIWPGCMGAMJNRG-UHFFFAOYSA-N 0.000 claims description 2
• 229930183167 cerebroside Natural products 0.000 claims description 2
• 239000005547 deoxyribonucleotide Substances 0.000 claims description 2
• 125000002637 deoxyribonucleotide group Chemical group 0.000 claims description 2
• 150000001982 diacylglycerols Chemical class 0.000 claims description 2
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
• 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 2
• 210000005260 human cell Anatomy 0.000 claims description 2
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
• 150000002772 monosaccharides Chemical group 0.000 claims description 2
• 230000004962 physiological condition Effects 0.000 claims description 2
• 229920001282 polysaccharide Polymers 0.000 claims description 2
• 239000005017 polysaccharide Substances 0.000 claims description 2
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• 229940048914 protamine Drugs 0.000 claims description 2
• 229920002477 rna polymer Polymers 0.000 claims description 2
• PZDOWFGHCNHPQD-VNNZMYODSA-N sophorose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O PZDOWFGHCNHPQD-VNNZMYODSA-N 0.000 claims description 2
• 150000003408 sphingolipids Chemical class 0.000 claims description 2
• 239000005720 sucrose Substances 0.000 claims description 2
• UZNHKBFIBYXPDV-UHFFFAOYSA-N trimethyl-[3-(2-methylprop-2-enoylamino)propyl]azanium;chloride Chemical compound [Cl-].CC(=C)C(=O)NCCC[N+](C)(C)C UZNHKBFIBYXPDV-UHFFFAOYSA-N 0.000 claims description 2
• GHVWODLSARFZKM-UHFFFAOYSA-N trimethyl-[3-methyl-3-(prop-2-enoylamino)butyl]azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CCC(C)(C)NC(=O)C=C GHVWODLSARFZKM-UHFFFAOYSA-N 0.000 claims description 2
• 229920001221 xylan Polymers 0.000 claims description 2
• 150000004823 xylans Chemical class 0.000 claims description 2
• LTMQZVLXCLQPCT-UHFFFAOYSA-N 1,1,6-trimethyltetralin Chemical compound C1CCC(C)(C)C=2C1=CC(C)=CC=2 LTMQZVLXCLQPCT-UHFFFAOYSA-N 0.000 claims 2
• 108010029485 Protein Isoforms Proteins 0.000 claims 2
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• JSPNNZKWADNWHI-PNANGNLXSA-N (2r)-2-hydroxy-n-[(2s,3r,4e,8e)-3-hydroxy-9-methyl-1-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoctadeca-4,8-dien-2-yl]heptadecanamide Chemical compound CCCCCCCCCCCCCCC[C@@H](O)C(=O)N[C@H]([C@H](O)\C=C\CC\C=C(/C)CCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JSPNNZKWADNWHI-PNANGNLXSA-N 0.000 claims 1
• JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims 1
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• LEBBDRXHHNYZIA-LDUWYPJVSA-N [(2s,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] n-[(z)-1,3-dihydroxyoctadec-4-en-2-yl]carbamate Chemical compound CCCCCCCCCCCCC\C=C/C(O)C(CO)NC(=O)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O LEBBDRXHHNYZIA-LDUWYPJVSA-N 0.000 claims 1
• ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims 1
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• RIZIAUKTHDLMQX-UHFFFAOYSA-N cerebroside D Natural products CCCCCCCCCCCCCCCCC(O)C(=O)NC(C(O)C=CCCC=C(C)CCCCCCCCC)COC1OC(CO)C(O)C(O)C1O RIZIAUKTHDLMQX-UHFFFAOYSA-N 0.000 claims 1
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• 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
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• 238000001727 in vivo Methods 0.000 abstract description 17
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