TW201023914A

TW201023914A - Releasable polymeric lipids for nucleic acids delivery system

Releasable polymeric lipids for nucleic acids delivery system Download PDF

Info

Publication number: TW201023914A
Authority: TW; Taiwan
Prior art keywords: group; substituted; compound; alkyl; ch2ch2o
Prior art date: 2008-11-17

Application number

TW098138947A

Other languages

English (en)

Chinese (zh)

Inventor

Hong Zhao

wei-li Yan

lian-jun Shi

Dechun Wu

Original Assignee

Enzon Pharmaceuticals Inc

Priority date

2008-11-17

Filing date

2009-11-17

Publication date

2010-07-01

2009-11-17 Application filed by Enzon Pharmaceuticals Inc filed Critical Enzon Pharmaceuticals Inc

2010-07-01 Publication of TW201023914A publication Critical patent/TW201023914A/zh

Links

150000002632 lipids Chemical class 0.000 title claims abstract description 191
150000007523 nucleic acids Chemical class 0.000 title claims abstract description 106
102000039446 nucleic acids Human genes 0.000 title claims abstract description 101
108020004707 nucleic acids Proteins 0.000 title claims abstract description 101
239000002105 nanoparticle Substances 0.000 claims abstract description 296
239000000203 mixture Substances 0.000 claims abstract description 178
238000000034 method Methods 0.000 claims abstract description 75
230000014509 gene expression Effects 0.000 claims abstract description 35
229920000642 polymer Polymers 0.000 claims abstract description 33
150000002466 imines Chemical class 0.000 claims abstract description 10
DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 6
125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims abstract 2
-1 c26 dilute Chemical group 0.000 claims description 152
125000000217 alkyl group Chemical group 0.000 claims description 120
150000001875 compounds Chemical class 0.000 claims description 114
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 97
210000004027 cell Anatomy 0.000 claims description 96
108091034117 Oligonucleotide Proteins 0.000 claims description 84
229920001223 polyethylene glycol Polymers 0.000 claims description 80
239000002202 Polyethylene glycol Substances 0.000 claims description 68
230000000692 anti-sense effect Effects 0.000 claims description 59
239000002253 acid Substances 0.000 claims description 58
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 56
229910052739 hydrogen Inorganic materials 0.000 claims description 52
239000002773 nucleotide Substances 0.000 claims description 51
108090000623 proteins and genes Proteins 0.000 claims description 50
239000001257 hydrogen Substances 0.000 claims description 49
206010028980 Neoplasm Diseases 0.000 claims description 48
235000012000 cholesterol Nutrition 0.000 claims description 48
125000003729 nucleotide group Chemical group 0.000 claims description 45
125000003545 alkoxy group Chemical group 0.000 claims description 41
125000003118 aryl group Chemical group 0.000 claims description 41
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 40
201000011510 cancer Diseases 0.000 claims description 39
150000001412 amines Chemical class 0.000 claims description 36
125000000753 cycloalkyl group Chemical group 0.000 claims description 36
229920006395 saturated elastomer Polymers 0.000 claims description 35
125000004404 heteroalkyl group Chemical group 0.000 claims description 32
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230000008685 targeting Effects 0.000 claims description 27
230000004927 fusion Effects 0.000 claims description 26
125000001072 heteroaryl group Chemical group 0.000 claims description 26
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
125000003107 substituted aryl group Chemical group 0.000 claims description 23
125000000304 alkynyl group Chemical group 0.000 claims description 20
JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 19
125000003342 alkenyl group Chemical group 0.000 claims description 19
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
229910052760 oxygen Inorganic materials 0.000 claims description 19
125000003396 thiol group Chemical group [H]S* 0.000 claims description 19
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 18
239000001301 oxygen Substances 0.000 claims description 17
108020004459 Small interfering RNA Proteins 0.000 claims description 16
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 16
239000004055 small Interfering RNA Substances 0.000 claims description 16
241000124008 Mammalia Species 0.000 claims description 15
229910052757 nitrogen Inorganic materials 0.000 claims description 15
102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 claims description 14
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
230000001588 bifunctional effect Effects 0.000 claims description 13
125000004405 heteroalkoxy group Chemical group 0.000 claims description 13
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
229920001427 mPEG Polymers 0.000 claims description 12
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
125000003710 aryl alkyl group Chemical group 0.000 claims description 11
201000010099 disease Diseases 0.000 claims description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
108010002687 Survivin Proteins 0.000 claims description 10
239000002246 antineoplastic agent Substances 0.000 claims description 10
125000002704 decyl group Chemical group [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])C([H])([H])C([H])([H])* 0.000 claims description 10
238000006116 polymerization reaction Methods 0.000 claims description 10
125000006850 spacer group Chemical group 0.000 claims description 10
102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 claims description 9
230000000890 antigenic effect Effects 0.000 claims description 9
125000004104 aryloxy group Chemical group 0.000 claims description 9
229910052799 carbon Inorganic materials 0.000 claims description 9
229940125904 compound 1 Drugs 0.000 claims description 9
125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 8
230000000670 limiting effect Effects 0.000 claims description 8
125000005129 aryl carbonyl group Chemical group 0.000 claims description 7
125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 7
230000002222 downregulating effect Effects 0.000 claims description 7
230000002401 inhibitory effect Effects 0.000 claims description 7
GUCPYIYFQVTFSI-UHFFFAOYSA-N 4-methoxybenzamide Chemical compound COC1=CC=C(C(N)=O)C=C1 GUCPYIYFQVTFSI-UHFFFAOYSA-N 0.000 claims description 6
IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims description 6
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
108010045100 HSP27 Heat-Shock Proteins Proteins 0.000 claims description 6
102100039165 Heat shock protein beta-1 Human genes 0.000 claims description 6
101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 claims description 6
108010088665 Zinc Finger Protein Gli2 Proteins 0.000 claims description 6
125000001931 aliphatic group Chemical group 0.000 claims description 6
108010080146 androgen receptors Proteins 0.000 claims description 6
125000004093 cyano group Chemical class *C#N 0.000 claims description 6
125000005842 heteroatom Chemical group 0.000 claims description 6
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
125000005055 alkyl alkoxy group Chemical group 0.000 claims description 5
OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 5
125000005553 heteroaryloxy group Chemical group 0.000 claims description 5
229910052698 phosphorus Inorganic materials 0.000 claims description 5
125000000547 substituted alkyl group Chemical group 0.000 claims description 5
102100026882 Alpha-synuclein Human genes 0.000 claims description 4
108091023037 Aptamer Proteins 0.000 claims description 4
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BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 claims description 4
101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 claims description 4
108700020796 Oncogene Proteins 0.000 claims description 4
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239000000074 antisense oligonucleotide Substances 0.000 claims description 4
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108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 claims description 4
125000001589 carboacyl group Chemical group 0.000 claims description 4
229950003499 fibrin Drugs 0.000 claims description 4
235000019152 folic acid Nutrition 0.000 claims description 4
239000011724 folic acid Substances 0.000 claims description 4
229910052740 iodine Inorganic materials 0.000 claims description 4
239000002679 microRNA Substances 0.000 claims description 4
239000011734 sodium Substances 0.000 claims description 4
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125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
125000004414 alkyl thio group Chemical group 0.000 claims description 3
125000003438 dodecyl group Chemical group [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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
229940014144 folate Drugs 0.000 claims description 3
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229910052708 sodium Inorganic materials 0.000 claims description 3
125000004079 stearyl 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])([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])C([H])([H])[H] 0.000 claims description 3
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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 description 2
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125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims 2
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NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims 1
MKRUTSBGYOOLHT-UHFFFAOYSA-N OC(CCCCCCCCCOCCCCCCCCCC(O)[N+](=O)[O-])[N+](=O)[O-] Chemical compound OC(CCCCCCCCCOCCCCCCCCCC(O)[N+](=O)[O-])[N+](=O)[O-] MKRUTSBGYOOLHT-UHFFFAOYSA-N 0.000 claims 1
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