CA2742846A1

CA2742846A1 - Releasable fusogenic lipids for nucleic acids delivery systems

Releasable fusogenic lipids for nucleic acids delivery systems Download PDF

Info

Publication number: CA2742846A1
Authority: CA; Canada
Prior art keywords: substituted; ch2ch2o; 2nhc; ch2ch2; nanoparticle
Prior art date: 2008-11-17
Legal status : Abandoned

Application number

CA2742846A

Other languages

English (en)

French (fr)

Inventor

Hong Zhao

Weili Yan

Lianjun Shi

Dechun Wu

Maksim Royzen

Current Assignee

Belrose Pharma Inc

Original Assignee

Enzon Pharmaceuticals Inc

Priority date

2008-11-17

Filing date

2009-11-17

Publication date

2010-05-20

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

2010-05-20 Publication of CA2742846A1 publication Critical patent/CA2742846A1/en

Status Abandoned legal-status Critical Current

Links

150000002632 lipids Chemical class 0.000 title claims abstract description 138
230000000799 fusogenic effect Effects 0.000 title claims abstract description 51
150000007523 nucleic acids Chemical class 0.000 title claims description 101
102000039446 nucleic acids Human genes 0.000 title claims description 96
108020004707 nucleic acids Proteins 0.000 title claims description 96
239000002105 nanoparticle Substances 0.000 claims abstract description 255
239000000203 mixture Substances 0.000 claims abstract description 142
108091034117 Oligonucleotide Proteins 0.000 claims abstract description 106
238000000034 method Methods 0.000 claims abstract description 73
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 abstract description 56
230000014509 gene expression Effects 0.000 claims abstract description 28
-1 cationic lipid Chemical class 0.000 claims description 96
150000001875 compounds Chemical class 0.000 claims description 83
125000000217 alkyl group Chemical group 0.000 claims description 82
210000004027 cell Anatomy 0.000 claims description 68
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 51
206010028980 Neoplasm Diseases 0.000 claims description 49
108090000623 proteins and genes Proteins 0.000 claims description 45
229910052739 hydrogen Inorganic materials 0.000 claims description 44
239000001257 hydrogen Substances 0.000 claims description 42
201000011510 cancer Diseases 0.000 claims description 37
229920006395 saturated elastomer Polymers 0.000 claims description 35
230000000692 anti-sense effect Effects 0.000 claims description 34
125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 33
125000005647 linker group Chemical group 0.000 claims description 33
239000002773 nucleotide Substances 0.000 claims description 32
125000003118 aryl group Chemical group 0.000 claims description 30
229940106189 ceramide Drugs 0.000 claims description 29
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 29
235000012000 cholesterol Nutrition 0.000 claims description 26
150000001412 amines Chemical class 0.000 claims description 24
125000003729 nucleotide group Chemical group 0.000 claims description 24
125000003545 alkoxy group Chemical group 0.000 claims description 23
125000000547 substituted alkyl group Chemical group 0.000 claims description 22
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 20
230000001588 bifunctional effect Effects 0.000 claims description 20
125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 20
125000001072 heteroaryl group Chemical group 0.000 claims description 19
241000124008 Mammalia Species 0.000 claims description 18
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
229910052760 oxygen Inorganic materials 0.000 claims description 18
125000003107 substituted aryl group Chemical group 0.000 claims description 16
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
229910052757 nitrogen Inorganic materials 0.000 claims description 14
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 13
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
201000010099 disease Diseases 0.000 claims description 12
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
239000002253 acid Substances 0.000 claims description 11
125000003342 alkenyl group Chemical group 0.000 claims description 11
239000002246 antineoplastic agent Substances 0.000 claims description 11
230000007935 neutral effect Effects 0.000 claims description 11
125000003710 aryl alkyl group Chemical group 0.000 claims description 10
150000002466 imines Chemical class 0.000 claims description 10
125000006850 spacer group Chemical group 0.000 claims description 9
230000002401 inhibitory effect Effects 0.000 claims description 8
RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 8
108020004459 Small interfering RNA Proteins 0.000 claims description 7
150000001413 amino acids Chemical class 0.000 claims description 7
125000004405 heteroalkoxy group Chemical group 0.000 claims description 7
125000002811 oleoyl group Chemical group O=C([*])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 7
239000004055 small Interfering RNA Substances 0.000 claims description 7
229910052717 sulfur Inorganic materials 0.000 claims description 7
102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 claims description 6
101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 claims description 6
150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 6
239000000074 antisense oligonucleotide Substances 0.000 claims description 6
238000012230 antisense oligonucleotides Methods 0.000 claims description 6
229910052799 carbon Inorganic materials 0.000 claims description 6
230000002222 downregulating effect Effects 0.000 claims description 6
230000037361 pathway Effects 0.000 claims description 6
125000005017 substituted alkenyl group Chemical group 0.000 claims description 6
125000004426 substituted alkynyl group Chemical group 0.000 claims description 6
108060000903 Beta-catenin Proteins 0.000 claims description 5
102000015735 Beta-catenin Human genes 0.000 claims description 5
125000000882 C2-C6 alkenyl group Chemical class 0.000 claims description 5
125000003601 C2-C6 alkynyl group Chemical class 0.000 claims description 5
230000002378 acidificating effect Effects 0.000 claims description 5
125000004429 atom Chemical group 0.000 claims description 5
108700011259 MicroRNAs Proteins 0.000 claims description 4
108700020796 Oncogene Proteins 0.000 claims description 4
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
239000002679 microRNA Substances 0.000 claims description 4
125000001419 myristoyl group Chemical group O=C([*])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 4
125000001312 palmitoyl group Chemical group O=C([*])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 4
108091023037 Aptamer Proteins 0.000 claims description 3
102000053642 Catalytic RNA Human genes 0.000 claims description 3
108090000994 Catalytic RNA Proteins 0.000 claims description 3
102000043276 Oncogene Human genes 0.000 claims description 3
108700005077 Viral Genes Proteins 0.000 claims description 3
230000004663 cell proliferation Effects 0.000 claims description 3
230000012010 growth Effects 0.000 claims description 3
210000005260 human cell Anatomy 0.000 claims description 3
239000012678 infectious agent Substances 0.000 claims description 3
229910052698 phosphorus Inorganic materials 0.000 claims description 3
230000004647 pro-inflammatory pathway Effects 0.000 claims description 3
230000009443 proangiogenesis Effects 0.000 claims description 3
108091092562 ribozyme Proteins 0.000 claims description 3
125000003696 stearoyl group Chemical group O=C([*])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
LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
108091030071 RNAI Proteins 0.000 claims description 2
229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
150000001735 carboxylic acids Chemical class 0.000 claims description 2
125000001901 erucoyl group Chemical group O=C([*])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])=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
230000009368 gene silencing by RNA Effects 0.000 claims description 2
230000035755 proliferation Effects 0.000 claims description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 10
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 9
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 6
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 3
125000006539 C12 alkyl 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 1
102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 claims 1
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