EP4247874A1 - Functionalised polyglycine-poly(alkylene imine)-copolymers, the preparation thereof and use thereof for preparing formulations of or for complexing anionic active ingredients and effect substances - Google Patents
Functionalised polyglycine-poly(alkylene imine)-copolymers, the preparation thereof and use thereof for preparing formulations of or for complexing anionic active ingredients and effect substancesInfo
- Publication number
- EP4247874A1 EP4247874A1 EP21815364.1A EP21815364A EP4247874A1 EP 4247874 A1 EP4247874 A1 EP 4247874A1 EP 21815364 A EP21815364 A EP 21815364A EP 4247874 A1 EP4247874 A1 EP 4247874A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- chr
- structural units
- copolymers
- mol
- Prior art date
- 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.)
- Pending
Links
- 229920001577 copolymer Polymers 0.000 title claims abstract description 107
- 239000000203 mixture Substances 0.000 title claims abstract description 14
- 125000000129 anionic group Chemical group 0.000 title claims abstract description 8
- 238000009472 formulation Methods 0.000 title claims abstract description 8
- 239000000126 substance Substances 0.000 title abstract description 18
- 239000004480 active ingredient Substances 0.000 title abstract description 11
- 230000000694 effects Effects 0.000 title abstract description 9
- 230000000536 complexating effect Effects 0.000 title abstract description 3
- 238000002360 preparation method Methods 0.000 title description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 5
- -1 guanidino, carboxyl Chemical group 0.000 claims description 86
- 239000002245 particle Substances 0.000 claims description 53
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 37
- 230000007062 hydrolysis Effects 0.000 claims description 23
- 238000006460 hydrolysis reaction Methods 0.000 claims description 23
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- 102000039446 nucleic acids Human genes 0.000 claims description 16
- 108020004707 nucleic acids Proteins 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- 150000007523 nucleic acids Chemical class 0.000 claims description 14
- 229920000765 poly(2-oxazolines) Polymers 0.000 claims description 13
- 239000002105 nanoparticle Substances 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 239000007800 oxidant agent Substances 0.000 claims description 10
- 230000036961 partial effect Effects 0.000 claims description 10
- 239000012948 isocyanate Substances 0.000 claims description 9
- 150000002513 isocyanates Chemical class 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012868 active agrochemical ingredient Substances 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 150000003459 sulfonic acid esters Chemical class 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 3
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- 150000002978 peroxides Chemical class 0.000 claims 1
- 125000000962 organic group Chemical group 0.000 abstract 1
- 229920000642 polymer Polymers 0.000 description 66
- 229920002873 Polyethylenimine Polymers 0.000 description 32
- 229920006187 aquazol Polymers 0.000 description 24
- 239000012861 aquazol Substances 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 238000007254 oxidation reaction Methods 0.000 description 18
- 230000003647 oxidation Effects 0.000 description 17
- 150000003254 radicals Chemical class 0.000 description 17
- 239000000178 monomer Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- GQWWGRUJOCIUKI-UHFFFAOYSA-N 2-[3-(2-methyl-1-oxopyrrolo[1,2-a]pyrazin-3-yl)propyl]guanidine Chemical group O=C1N(C)C(CCCN=C(N)N)=CN2C=CC=C21 GQWWGRUJOCIUKI-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 239000000654 additive Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 238000012512 characterization method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 238000004448 titration Methods 0.000 description 10
- 239000004471 Glycine Substances 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- 125000003277 amino group Chemical group 0.000 description 9
- 230000015556 catabolic process Effects 0.000 description 9
- 238000006731 degradation reaction Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 125000003368 amide group Chemical group 0.000 description 8
- 238000012656 cationic ring opening polymerization Methods 0.000 description 8
- 238000007306 functionalization reaction Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical group 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 150000002924 oxiranes Chemical class 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000001542 size-exclusion chromatography Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 229920002521 macromolecule Polymers 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 150000000376 2-oxazolines Chemical class 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 5
- 239000003999 initiator Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 238000004566 IR spectroscopy Methods 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 150000001266 acyl halides Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 229920000232 polyglycine polymer Polymers 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 108020004459 Small interfering RNA Proteins 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 229920005605 branched copolymer Polymers 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 229920003118 cationic copolymer Polymers 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000007334 copolymerization reaction Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 239000007857 degradation product Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 3
- 229920000333 poly(propyleneimine) Polymers 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000000954 titration curve Methods 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- NYEZZYQZRQDLEH-UHFFFAOYSA-N 2-ethyl-4,5-dihydro-1,3-oxazole Chemical compound CCC1=NCCO1 NYEZZYQZRQDLEH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002730 additional effect Effects 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 238000000149 argon plasma sintering Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000001541 aziridines Chemical class 0.000 description 2
- QVQLCTNNEUAWMS-UHFFFAOYSA-N barium oxide Chemical compound [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 229920005684 linear copolymer Polymers 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 150000004702 methyl esters Chemical group 0.000 description 2
- 108091070501 miRNA Proteins 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 238000006362 organocatalysis Methods 0.000 description 2
- 150000002918 oxazolines Chemical class 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000012712 reversible addition−fragmentation chain-transfer polymerization Methods 0.000 description 2
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000004055 small Interfering RNA Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- ZRCXHANDGUCXKE-UHFFFAOYSA-N 2-(2-hydroxyethyl)butanediamide Chemical compound NC(=O)CC(C(N)=O)CCO ZRCXHANDGUCXKE-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 description 1
- SPXXVGQMQJYJJO-UHFFFAOYSA-N 2-prop-2-enyloxirane Chemical compound C=CCC1CO1 SPXXVGQMQJYJJO-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 108091092742 A-DNA Proteins 0.000 description 1
- 108020004491 Antisense DNA Proteins 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 108020004513 Bacterial RNA Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- JTKXTLRAUSOBTQ-UHFFFAOYSA-N C.N=C=O Chemical compound C.N=C=O JTKXTLRAUSOBTQ-UHFFFAOYSA-N 0.000 description 1
- 238000010453 CRISPR/Cas method Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- GXBYFVGCMPJVJX-UHFFFAOYSA-N Epoxybutene Chemical compound C=CC1CO1 GXBYFVGCMPJVJX-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108020005196 Mitochondrial DNA Proteins 0.000 description 1
- 241001181114 Neta Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 108020004688 Small Nuclear RNA Proteins 0.000 description 1
- 102000039471 Small Nuclear RNA Human genes 0.000 description 1
- 108020003224 Small Nucleolar RNA Proteins 0.000 description 1
- 102000042773 Small Nucleolar RNA Human genes 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000012963 UV stabilizer Substances 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 108091027569 Z-DNA Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000005426 adeninyl group Chemical group N1=C(N=C2N=CNC2=C1N)* 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003816 antisense DNA Substances 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000001204 arachidyl 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])C([H])([H])C([H])([H])[H] 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229920000229 biodegradable polyester Polymers 0.000 description 1
- 239000004622 biodegradable polyester Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001715 carbamic acids Chemical class 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 229940039231 contrast media Drugs 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000011258 core-shell material Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=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 description 1
- 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 description 1
- 229920006237 degradable polymer Polymers 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- VCJZTATVUDMNLU-UHFFFAOYSA-N dibromomethylbenzene Chemical compound BrC(Br)C1=CC=CC=C1 VCJZTATVUDMNLU-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000004815 dispersion polymer Substances 0.000 description 1
- 125000005066 dodecenyl group Chemical group C(=CCCCCCCCCCC)* 0.000 description 1
- 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 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- CHGFQXWEMFIZRC-UHFFFAOYSA-N ethane;isocyanic acid Chemical compound CC.N=C=O CHGFQXWEMFIZRC-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical group FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- UQSQSQZYBQSBJZ-UHFFFAOYSA-M fluorosulfonate Chemical group [O-]S(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-M 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 150000002432 hydroperoxides Chemical class 0.000 description 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical class Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000002960 margaryl 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])[H] 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000007144 microwave assisted synthesis reaction Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001421 myristyl 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])[H] 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001196 nonadecyl 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])C([H])([H])[H] 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 125000001400 nonyl 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])[H] 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000005064 octadecenyl group Chemical group C(=CCCCCCCCCCCCCCCCC)* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000000913 palmityl 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])[H] 0.000 description 1
- 125000002958 pentadecyl 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])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920000773 poly(2-methyl-2-oxazoline) polymer Polymers 0.000 description 1
- 229920001279 poly(ester amides) Polymers 0.000 description 1
- 238000006068 polycondensation reaction Methods 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000011164 primary particle Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 239000002924 silencing RNA Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 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 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000003142 tertiary amide group Chemical group 0.000 description 1
- 125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 1
- 150000007970 thio esters Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- 125000002889 tridecyl 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])[H] 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- 125000002948 undecyl 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])[H] 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
- C08G69/04—Preparatory processes
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/48—Polymers modified by chemical after-treatment
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/02—Polyamines
- C08G73/0206—Polyalkylene(poly)amines
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/02—Polyamines
- C08G73/0233—Polyamines derived from (poly)oxazolines, (poly)oxazines or having pendant acyl groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
- C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
- C08G69/10—Alpha-amino-carboxylic acids
Definitions
- the invention relates to new copolymers which can be described as functionalized polyglycine-polyalkyleneimine copolymers and which are distinguished by very good degradability.
- the invention relates to the preparation and processing of these copolymers by oxidation of polyalkyleneimines followed by functionalization of NH groups in the partially oxidized polymer backbone.
- These copolymers can be used in particular to produce active substance and effect substance formulations and to complex anionic active substances and effect substances, in particular genetic material such as siRNA, mRNA, DNA and CRISPR/Cas.
- Biocompatible polymers represent highly attractive materials for biomedical applications such as drug delivery.
- Poly(ethylene glycol) (PEG) is currently the most commonly used polymer for such purposes. Due to its high hydrophilicity and so-called “cloaking behavior” it elicits little immune response in the body and thus increases the drug's blood circulation time.
- PEG has several disadvantages, namely the formation of toxic by-products, sequestration in organs, and the stimulation of anti-PEG antibodies.
- PAOx Poly(2-n-alkyl-2-oxazolines) with short side chains show similar hydrophilicity, biocompatibility and "cloaking behavior" and therefore appear to be promising candidates as a replacement for PEG, which is further demonstrated in a detailed comparison of their solution behavior was confirmed (cf. Grube, M.; Leiske, MN; Schubert, US; Nischang, I. POx as an alternative to PEG? A hydrodynamic and light scattering study. Macromolecules 2018, 51, 1905-1916). In contrast to PEG, PAOx also exhibit higher structural versatility due to their side-chain modifiability.
- PAOx with longer side chains are hydrophobic and can be used to make amphiphilic copolymers, low surface energy materials or low adhesion coatings. Thermal and crystalline properties can also be tuned by variations in the PAOx side chains (compare Hoogenboom, R.; Fijten, M.W.M.; Thijs, H.M.L.; van Lankvelt, B.
- Biodegradability would be an important property for a large number of applications in biomedicine and other fields, for example to prevent accumulation of polymers with molecular weights beyond 20,000 g mol' 1 in the body and to remove the polymer completely from the organism.
- a strategy to solve the problem could be to incorporate hydrolytically sensitive groups into the polymer backbone, such as ester or amide moieties. These can be hydrolyzed under, for example, acidic or enzymatic conditions, which could lead to degradation of the entire polymer.
- Several routes have been explored to incorporate ester groups into the PAOx backbone.
- the resulting polymers can be viewed as alternating poly(ester-co-oxazolines) and therefore as biodegradable PAOx alternatives.
- all polymers exhibited amorphous behavior and exhibited a lower T g compared to their non-degradable PAOx counterparts.
- the object of the present invention is therefore to provide new functionalized copolymers with improved degradability.
- Another object of the present invention is to provide a simple method for preparing these functionalized copolymers.
- R 1 is a radical of the formula -CO-R 2 , of the formula -CO-NH-R 2 , of the formula -CH 2 -CH(OH)-R 12 or of the formula -CH 2 -CH(NH 2 )-R 12 means,
- R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 and R 11 are independently hydrogen, methyl, ethyl, propyl or butyl,
- R 2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, -C m H 2m -X or -(C n H 2 nO)o-(CpH 2p -O)qR 6 ,
- R 6 is hydrogen or Ci-Cß-alkyl
- R 12 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl or aralkyl,
- X is selected from the group consisting of hydroxyl, alkoxy, amino, N-alkylamino, N,N-dialkylamino, heterocyclyl having at least one ring nitrogen atom, guanidino, carboxyl, carboxylic acid ester, sulfuric acid ester, sulfonic acid ester or carbamic acid ester, m is an integer from 1 to 18 is, n and p are independently integers from 2 to 4, where n is not equal to p, and o and q are independently integers from 0 to 60, where at least one of o or q is not equal to 0, the percentages refer to the Total amount of the structural units of the formula (I), (II) and (III) or of the formula (IV), (V) and (VI) are related.
- These copolymers can be prepared starting from readily available poly(alkyleneimines).
- the invention therefore also relates, in a first variant, to a process for preparing these copolymers with the measures i) reacting a polyalkyleneimine which preferably contains recurring structural units of the formula (Ia) or the formula (IVa) in an amount of at least 90 mol % an oxidizing agent, whereby a copolymer containing the structural units of the formula (Ia) and the formula (II) or containing the structural units of the formula (IVa) and the formula (V) is obtained
- the invention relates, in a second variant, to a process for preparing these copolymers with the measures iii) partial hydrolysis of a polyoxazoline containing recurring structural units of the formula (I) or of a polyoxazine containing recurring structural units of the formula (IV)
- degradable, functionalized polyglycine-polyalkyleneimine copolymers having amide bonds integrated into the polymer backbone can be prepared via a simple synthetic route.
- polyalkyleneimines can be partially oxidized and the resulting product can be reacted with an epoxide, an aziridine, an isocyanate or a activated ester or acyl halide.
- polyoxazolines or polyoxazines can be partially hydrolyzed, resulting in polyalkyleneimine units, which can be partially oxidized in a subsequent step.
- Polyalkyleneimines used in the first variant of the process according to the invention usually contain at least 90 mol % of recurring structural units of the formula (Ia) or of the formula (IVa) and are commercially available or can be obtained by hydrolysis of poly(2-oxazolines) substituted in the 2-position ( POx), in particular from PEtOx, or from poly(2-oxazines) substituted in the 2-position.
- the starting materials used for the hydrolysis are usually POx which contain at least 20 mol %, preferably at least 50 mol %, of repeating structural units derived from 2-oxazoline in the polymer. While commercially available polyalkyleneimines are branched, linear polyalkyleneimines are obtained by the hydrolysis of POx.
- hydrolysis of polyoxazolines or polyoxazines can also take place partially and leads to copolymers which contain recurring structural units of the formulas (I) and (III) or which contain recurring structural units of the formulas (IV) and (VI). These copolymers can be oxidized, leading directly to the copolymers of this invention. In this variant of the process, there is usually no reacylation.
- a preferred simple synthetic route for the post-polymerization proceeds via the consecutive hydrolysis of poly(2-ethyl-2-oxazoline) (PEtOx), a partial oxidation and reacylation.
- PEtOx poly(2-ethyl-2-oxazoline)
- CROP cationic ring opening polymerization
- PEI linear poly(ethyleneimine)
- PEI is disadvantageous because of its cytotoxicity and, like PEtOx, its non-degradability.
- Englert et al. reported on the controlled oxidation of linear PEI with hydrogen peroxide to increase the degradability by incorporating amide groups into the PEI backbone (cf. Enhancing the biocompatibility and biodegradability of linear poly(ethylene imine) through controlled oxidation; Macromolecules 2015, 48, 7420 -7427).
- the resulting structure corresponds to the repeating unit of poly(glycine) and hence the polymer can be considered poly(ethyleneimine-co-glycine) (referred to herein as oxPEI). Due to its additional hydrolytically sensitive amide groups, the polymer not only showed increased degradability, but also improved biocompatibility compared to the otherwise cytotoxic PEI.
- oxPEI was functionalized with a subsequent reacylation step or by reaction with isocyanates or with epoxides or with aziridines. Accordingly, the homologous polypropyleneimine (PPI) can also be used instead of PEI.
- PPI polypropyleneimine
- acylating reagents such as acyl halides
- poly(2-n-alkyl-2-oxazoline-stat-glycines) referred to herein as dP(AOx-co-EI)
- the amount of acyl derivative of the formula (VII) or of isocyanate of the formula (VIII) or of epoxide of the formula (IX) or of aziridine of the formula (X) should be chosen so that the proportion of structural units of the formula (III) or of formula (VI) in the resulting copolymer is between 20 and 90 mol%.
- copolymers are to be understood as meaning the abovementioned organic compounds which are characterized by the repetition of certain units (monomer units or repeating units).
- the copolymers according to the invention consist of at least three types of different repeating units. Polymers are produced through the chemical reaction of monomers with the formation of covalent bonds (polymerization) and form the so-called polymer backbone by linking the polymerized units. This can have side chains on which functional groups can be located. Copolymers according to the invention consist of at least three different monomer units, which can be arranged randomly, as a gradient, alternately or as a block.
- copolymers can form nanoscale structures (eg nanoparticles, micelles, vesicles) in an aqueous environment.
- water-soluble compounds or “water-soluble copolymers” are to be understood as meaning compounds or copolymers which dissolve in at least 1 g/L of water at 25°C.
- active substances are to be understood as meaning compounds or mixtures of compounds which exert a desired effect on a living organism. These can be, for example, active pharmaceutical ingredients or agrochemical active ingredients. Active ingredients can be low or high molecular weight organic compounds. The active ingredients are preferably pharmaceutically active substances of higher molecular weight, hydrophilic active ingredients from nucleic acids, in particular from potentially therapeutically useful nucleic acids (e.g. small interfering RNA, short hairpin RNA, micro RNA, plasmid DNA), being of particular interest.
- nucleic acids e.g. small interfering RNA, short hairpin RNA, micro RNA, plasmid DNA
- pharmaceutically active substance means any inorganic or organic molecule, substance or compound which has a pharmacological effect.
- active pharmaceutical ingredient is used herein synonymously with the term “drug”.
- effect substances are to be understood as meaning compounds or mixtures of compounds which are added to a formulation in order to impart certain additional properties to it and/or to facilitate its processing.
- effect substances and “auxiliaries and additives” are used synonymously in this description.
- auxiliaries and additives are substances that are added to a formulation in order to impart certain additional properties to it and/or to facilitate its processing.
- auxiliaries and additives are tracers, contrast media, carriers, fillers, pigments, dyes, perfumes, lubricants, UV stabilizers, antioxidants or surfactants.
- auxiliary and Additives means any pharmacologically acceptable and therapeutically useful substance that is not a pharmaceutical active substance, but can be formulated together with a pharmaceutical active substance in a pharmaceutical composition in order to influence, in particular improve, qualitative properties of the pharmaceutical composition.
- the auxiliaries and/or additives preferably have no pharmacological effect or, with regard to the intended treatment, no appreciable or at least no undesired pharmacological effect.
- polymer particles are to be understood as meaning copolymers according to the invention which are present in particle form and which may also contain other ingredients.
- the particles may be in liquid form dispersed in a hydrophilic liquid, or the particles may be in solid form, either dispersed in a hydrophilic liquid or in the form of a powder.
- the size of the particles can be determined by visual methods, for example by microscopy; for particle sizes in the nano range, light scattering or electron microscopy can be used.
- the shape of the polymer particles can be arbitrary, for example spherical, ellipsoidal or irregular.
- the polymer particles can also form aggregates of several primary particles.
- the particles of copolymers according to the invention are preferably in the form of nanoparticles.
- the particles can also contain other components, for example active ingredients or auxiliaries or additives.
- Nanoparticles are to be understood as meaning particles whose diameter is less than 1 ⁇ m and which can be composed of one or more molecules. They are generally characterized by a very high surface-to-volume ratio and thus offer very high chemical reactivity. Nanoparticles can consist of copolymers according to the invention or contain other components in addition to these copolymers, such as active ingredients or auxiliaries or additives.
- the copolymers according to the invention can be in the form of linear polymers or they can also be branched copolymers.
- Linear copolymers are formed, for example, by consecutive hydrolysis of PEtOx, followed by partial oxidation to oxPEI and reacylation to dP(AOx-co-EI).
- branched copolymers arise from partial oxidation of commercially available PEI, which is known to be branched, to oxPEI followed by re-functionalization, e.g., from reacylation to dP(AOx-co-EI).
- solubility of the copolymers according to the invention can be influenced by copolymerization with suitable monomers and/or by functionalization. Such techniques are known to those skilled in the art.
- the copolymers according to the invention can cover a wide molar mass range.
- Typical molar masses (M n ) range from 1000 to 500 000 g/mol, in particular from 1000 to 50 000 g/mol. These molar masses can be determined by 1 H NMR spectroscopy of the dissolved polymer.
- an analytical ultracentrifuge or chromatographic methods such as size exclusion chromatography, can be used to determine the molar masses.
- Preferred copolymers according to the invention have an average molar mass (number average) in the range from 1000 to 50 000 g/mol, in particular from 3000 to 20 000 g/mol, determined by 1 H-NMR spectroscopy or by using an analytical ultracentrifuge. These are preferably linear copolymers. Branched copolymers according to the invention preferably have a higher average molar mass, for example an M n in the range from 50,000 to 500,000 g/mol, in particular from 80,000 to 200,000 g/mol.
- the molar proportion of structural units of the formula (I) in the copolymers according to the invention is 5 to 75 mol %, preferably 20 to 60 mol %, based on the total amount of structural units of the formulas (I), (II) and (III).
- the molar proportion of structural units of the formula (II) in the copolymers according to the invention is 5 to 75 mol %, preferably 10 to 60 mol %, based on the total amount of structural units of the formulas (I), (II) and (III).
- the molar proportion of structural units of the formula (III) in the copolymers according to the invention is 20 to 90 mol %, preferably 21 to 90 mol %, and in particular 30 to 80 mol %, based on the total amount of structural units of the formulas (I), (II ) and (III).
- the molar proportion of structural units of the formula (IV) in the novel copolymers is 5 to 75 mol %, preferably 20 to 60 mol %, based on the total amount of structural units of the formulas (IV), (V) and (VI).
- the molar proportion of structural units of the formula (V) in the copolymers according to the invention is 5 to 75 mol %, preferably 10 to 60 mol %, based on the total amount of structural units of the formulas (IV), (V) and (VI).
- the molar proportion of structural units of the formula (VI) in the copolymers according to the invention is 20 to 90 mol%, preferably 21 to 90 mol%, and in particular 30 to 80 mol%, based on the total amount of structural units of the formulas (IV), (V ) and (VI).
- R 1 is a radical of the formula -CO-R 2 or of the formula -CO-NH-R 2 or of the formula -CH 2 -CH(OH)-R 12 or of the formula -CH 2 -CH(NH 2 )-R 12 , preferably a radical of the formula -CO-R 2 .
- R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 and R 11 independently of one another are hydrogen, methyl, ethyl, propyl or butyl, preferably hydrogen, methyl or ethyl and in particular hydrogen.
- R 2 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, -C m H 2m -X or -(C n H 2n -O)o-(CpH 2 pO) q -R 6 , preferably hydrogen, CiC-is-alkyl , Cyclohexyl or phenyl, in particular CiC-is-alkyl and very particularly preferably C4-Ci4-alkyl.
- R 6 is hydrogen or CiC 6 -alkyl, preferably hydrogen or methyl
- R 12 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or aralkyl, preferably hydrogen, Ci-Cis-alkyl, C 2 -Ci 8 -alkenyl, cyclohexyl or phenyl, in particular hydrogen, Ci-Cß-alkyl or C 2 -C3- alkenyl.
- m is an integer from 1 to 18, preferably from 2 to 12.
- X is hydroxyl, alkoxy, amino, A/-alkylamino, //,A/-dialkylamino, heterocyclyl having at least one ring nitrogen atom, guanidino, carboxyl, carboxylic acid ester, sulfuric acid ester, sulfonic acid ester or carbamic acid ester.
- a heterocyclyl group is a cyclic saturated or unsaturated monovalent radical having five to seven ring atoms, of which one to three of the ring atoms are heteroatoms other than carbon, at least one of which is a nitrogen atom, preferably heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur and wherein the remaining ring atoms are carbon atoms.
- Heterocylyl groups can also form ring systems with two or more heterocyclic rings which are linked via covalent bonds, such as bipyridyl radicals, or which are fused, such as indenyl radicals.
- heterocyclyl groups can be ring systems in which one or more heterocyclic rings which are connected to hydrocarbon rings, eg benzimidazole rings, occur.
- Heterocyclyl groups can be aromatic or non-aromatic.
- Heterocyclyl groups can consist of one ring. Examples are piperidinyl, pyridyl, morpholinyl or imidazolyl radicals.
- Heterocyclyl groups can consist of several rings. Examples are benzimidazole or indenyl radicals.
- n and p are independently integers from 2 to 4, where n is not equal to p.
- n is 2 and p is 3.
- o and q are independently integers from 0 to 60, at least one of o or q being non-zero.
- o and q are independently 1 to 40, especially 2 to 10.
- the radicals R 2 and R 12 can be alkyl. These are usually alkyl groups with one to twenty carbon atoms, which can be straight-chain or branched. Examples are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl. Methyl, ethyl and propyl are preferred.
- R 12 can be alkenyl. These are usually alkenyl groups with two to twenty carbon atoms, which can be straight-chain or branched. The double bond can be in any position in the chain, but is preferably in the alpha position.
- alkenyl radicals are vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl or eicosenyl. Vinyl and allyl are particularly preferred.
- the radicals R 2 and R 12 can mean cycloalkyl. These are usually cycloalkyl groups with five to six ring carbon atoms. Cyclohex
- the radicals R 2 and R 12 can mean aryl. These are usually aromatic hydrocarbon radicals with five to ten ring carbon atoms. Phenyl is preferred.
- the radicals R 22 and R 12 can mean aralkyl. These are usually aryl groups linked to the rest of the molecule via an alkylene group. Benzyl is preferred.
- Radical X can mean alkoxy. These are usually C-i-Ce alkoxy groups. Preference is given to ethoxy and in particular methoxy.
- Radical X can be amino, A/-alkylamino or /V,/V-dialkylamino.
- the alkyl groups are usually Ci-C 6 -alkyl groups. Ethyl and especially methyl are preferred.
- Radical X can denote heterocyclyl with at least one ring nitrogen atom.
- Piperidinyl, pyridyl, pyrimidinyl, purinyl, morpholinyl, imidazolyl, benzimidazolyl, adeninyl, guaninyl, cytosinyl, thyminyl or uracilyl are preferred.
- Radical X can be a carboxylic ester (-COOR), sulfonic ester (-SO 3 R), sulfuric ester (-SO 4 R) or carbamic ester (-NR'COOR or -OCONRR) (R and R' are each monovalent organic radicals).
- R and R' are usually esters of carboxylic, sulfonic, sulfuric or carbamic acids with aliphatic alcohols, in particular with aliphatic Ci-Cß alcohols. Ethyl and especially methyl esters are preferred.
- Copolymers are preferred which contain 15 to 60 mol % of structural units of the formula (I), 10 to 60 mol % of structural units of the formula (II) and 25 to 75 mol % of structural units of the formula (III).
- copolymers wherein R 1 is a radical of the formula -CO-R 2 .
- R 2 is CiC-is-alkyl, in particular CrCe-alkyl, and very particularly preferably CrC2-alkyl.
- copolymers in which R 2 is Cs-Cis-alkyl, in particular C7-C12-alkyl are particularly preferred.
- R 2 is Ci-Cis-alkyl and R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 and R 11 are hydrogen.
- copolymers are preferred in which R 6 is hydrogen or methyl.
- R 12 is Ci-Ci 8 - alkyl or C2-Ci8-alkenyl, in particular methyl, ethyl, vinyl or allyl.
- the copolymers according to the invention can consist of the structural units of the formulas (I), (II) and (III) or of the structural units of the formulas (IV), (V) and (VI) or also contain further structural units which are derived from monomers , which can be copolymerized with monomers used in the preparation of polyalkyleneimines or polyoxazolines.
- the proportion of such further structural units, based on the total mass of the copolymer, is generally up to 25 mol %.
- These further structural units can be randomly distributed or arranged in the form of blocks in the copolymer.
- Preferred copolymers according to the invention are characterized in that they contain at least 90 mol %, in particular at least 95 mol %, based on their total mass, of structural units of the formula (I), the formula (II) and the formula (III) or the Formula (IV), the formula (V) and the formula (VI).
- copolymers according to the invention have end groups which typically arise in the preparation of poly(oxazolines) or of poly(alkyleneimines). These end groups can be modified by functionalization. The techniques required for this are known to those skilled in the art.
- Copolymers according to the invention can be covalently linked to other active ingredients or effect substances via the end groups.
- the copolymers according to the invention can be prepared by partial oxidation of polyalkyleneimines and by re-functionalization of the oxidized product by reaction with an epoxide, aziridine, isocyanate, an activated carboxylic acid or an acyl halide.
- the oxidation is preferably carried out in solution, in particular in an aqueous or alcoholic-aqueous solution.
- Oxidizing agents known per se can be used as the oxidizing agent. Examples are per-compounds, hypochlorites, chlorine or oxygen, especially hydrogen peroxide.
- Per compounds are preferably used. Examples of this are hydrogen peroxide, peracids, organic peroxides or organic hydroperoxides, in particular hydrogen peroxide.
- the amount of oxidizing agent is chosen so that the desired proportion of oxidized structural units is formed in the polymer backbone.
- the reaction temperature is generally between 10 and 80°C, in particular in the range from 20 to 40°C.
- the oxidation reaction time is generally between 5 minutes and 5 days.
- the oxidized product is refunctionalized by reaction with an acyl derivative of the formula (VII) described above or with an isocyanate of the formula (VIII) described above. or with an epoxide of formula (IX) described above or with an aziridine of formula (X) described above.
- acyl derivatives are acyl halides, carboxylic acid anhydrides or carboxylic acids activated by known coupling agents, for example N-hydroxysuccinimide ester (NHS ester), dicyclohexylcarbodiimide ester (DCC ester) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ester (EDC ester).
- NHS ester N-hydroxysuccinimide ester
- DCC ester dicyclohexylcarbodiimide ester
- EDC ester 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ester
- isocyanates are monoalkyl isocyanates such as methane isocyanate or ethane isocyanate, cyclohexyl isocyanate or phenyl isocyanate.
- Suitable epoxides are ethylene oxide, propylene oxide, 1,2-epoxybut-3-ene or 1,2-epoxypent-4-ene.
- Suitable aziridines are azacyclopropane, 1,2-azapropane, 1,2-azabut-3-ene or 1,2-azappent-4-ene.
- the reaction temperature is generally between 10 and 80°C, in particular in the range from 20 to 40°C.
- the reaction time for the refunctionalization is generally between 5 minutes and 5 days, in particular between 12 and 48 hours.
- the poly(alkylenimines) used are preferably copolymers which have been obtained by alkaline or, in particular, by acidic hydrolysis of poly(2-oxazolines), in particular of poly(2-alkyl-2-oxazolines). These copolymers are linear and are used as well-defined starting materials derived from polymers that can be obtained by CROP of commercially available monomers.
- Poly(oxazolines) are known compounds. These are usually prepared by cationic ring-opening polymerization of 2-oxazolines in solution and in the presence of an initiator.
- initiators are electrophiles such as esters of aromatic sulfonic acids, salts or esters of aliphatic sulfonic acids or carboxylic acids, or aromatic halogen compounds. Multifunctional electrophiles can also be used as initiators.
- branched or star-shaped molecules can also form.
- Examples of preferred initiators are esters of arylsulfonic acids such as methyl tosylate, esters of alkanesulfonic acids such as methyl triflate, or mono- or dibromomethylbenzene.
- the polymerisation is usually carried out in a polar aprotic solvent, for example in acetonitrile.
- 2-oxazines can also be used to prepare homologous poly(oxazines).
- the hydrolysis of poly(oxazolines) is preferably carried out in solution, in particular in an aqueous or alcoholic-aqueous solution.
- Inorganic or organic acids can be used as acids.
- Mineral acids are preferably used.
- hydrochloric acid, sulfuric acid or nitric acid preferably hydrochloric acid.
- suitable bases are alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide.
- the reaction temperature is generally between 20 and 180°C, in particular in the range from 70 to 130°C.
- the reaction time in the acidic hydrolysis is generally between 5 minutes and 24 hours. Preference is therefore given to processes in which the polyalkyleneimine used in step i) is obtained by hydrolysis, in particular by acidic hydrolysis, of a poly(oxazoline).
- copolymers according to the invention can be used to produce formulations which contain pharmaceutical or agrochemical active substances.
- the copolymers according to the invention can be water-soluble or non-water-soluble.
- Copolymers functionalized with formyl, acetyl, propionyl or butionyl groups are generally water soluble.
- Copolymers functionalized with longer alkanoyl chains are not water-soluble.
- Water-insoluble copolymers according to the invention can be present in dispersed form in hydrophilic liquids, for example as emulsions or as suspensions.
- copolymers according to the invention are preferably in the form of particles, in particular in the form of nanoparticles.
- the invention therefore also relates to particles, in particular nanoparticles, containing the copolymers described above.
- Particles which contain one or more pharmaceutical or agrochemical active ingredients are very particularly preferred.
- particularly preferred particles contain at least one active pharmaceutical ingredient and suitable auxiliaries and additives.
- the particles can be present as a powder in solid form or they can be present in dispersed form in hydrophilic solvents, the particles being present in the dispersing medium in liquid form or, in particular, in solid form.
- the particles preferably form a disperse phase in a liquid containing water and/or water-miscible compounds.
- the proportion of particles in a dispersion can cover a wide range.
- the proportion of particles in the dispersion medium is 0.5 to 20% by weight, preferably 1 to 5% by weight.
- the particles according to the invention can be produced by precipitation, preferably by nanoprecipitation.
- the copolymers according to the invention which are little or not hydrophilic due to the presence of hydrophobic groups, are dissolved in a water-miscible solvent, such as acetone. This solution is dropped into a hydrophilic dispersing medium. This is preferably done with vigorous stirring. This can promote the production of smaller particles.
- the copolymer is deposited in the dispersing medium in finely divided form.
- the particles according to the invention can also be produced by emulsification, preferably by nanoemulsion.
- the copolymers according to the invention which are little or not hydrophilic due to the presence of hydrophobic groups, are dissolved in a water-immiscible solvent, such as dichloromethane or ethyl acetate. This solution is combined with a hydrophilic dispersing medium, preferably resulting in two liquid phases form. This mixture is then emulsified by energy input, preferably by exposure to ultrasound.
- one or more active ingredients and/or one or more auxiliaries and additives can be present when it is dispersed in the dispersing medium.
- these active substances and/or auxiliaries and additives can be added after the copolymer has been dispersed in the hydrophilic liquid.
- the polymer particles can be separated from the hydrophilic liquid in different ways. Examples are centrifugation, ultrafiltration or dialysis.
- the polymer dispersion produced according to the invention can be further purified after production. Common methods include cleaning by dialysis, by ultrafiltration, by filtration or by centrifugation.
- copolymers according to the invention can be used outstandingly for complex formation with anionic compounds.
- Such complexes can be in dissolved form, but preferably in the form of particles and especially in the form of nanoparticles.
- the invention therefore also relates to complexes of the above-described copolymers and compounds with anionic groups, for example with carboxyl groups, sulfate groups, sulfonate groups or phosphate groups.
- the invention also relates to particles, in particular nanoparticles containing complexes of the above-described copolymers and compounds with anionic groups, for example with carboxyl groups, sulfate groups, sulfonate groups or phosphate groups.
- anionic groups for example with carboxyl groups, sulfate groups, sulfonate groups or phosphate groups.
- nucleic acids or proteins can be used as compounds with anionic groups.
- the present invention particularly preferably relates to particles containing complexes formed from nucleic acids and the copolymers containing the structural units of the formulas (I), (II) and (III) or of the formulas (IV), (V) and (VI) described above.
- DNA and/or RNA and modifications thereof can be used as nucleic acids in the complexes and particles according to the invention.
- DNA Any type of DNA can be used. Examples are A-DNA, B-DNA, Z-DNA, mtDNA, antisense DNA, bacterial DNA and viral DNA.
- RNA any type of RNA can also be used. Examples are hnRNA, mRNA, tRNA, rRNA, mtRNA, snRNA, snoRNA, scRNA, siRNA, miRNA, antisense RNA, bacterial RNA and viral RNA.
- Combinations of DNA and RNA can also be used in the complexes and particles according to the invention.
- the particles according to the invention contain nucleic acid copolymer complexes which are distributed over the entire volume of the particle.
- the particles according to the invention have nucleic acid-copolymer complexes both inside and in the outer areas of the nanoparticles Find. Such particles are also referred to below as “polyplexes”.
- the complexes and particles according to the invention can be characterized by their N/P ratio. This is the molar ratio of basic nitrogen atoms in the copolymer to the phosphate groups in the nucleic acid.
- the N/P ratio in the particles according to the invention can vary within wide ranges. Typically, the N/P ratio in the particles according to the invention is between 1 and 200, preferably between 2.5 and 100, more preferably between 5 and 50, and most preferably between 10 and 30.
- Preferred particles according to the invention have diameters of up to 50 ⁇ m, determined by DLS. Nanoparticles with diameters of between 50 and 1000 nm, determined by means of DLS, are preferred.
- Particles according to the invention which contain no auxiliaries or additives, in particular no protective colloids and/or surfactants, are preferred.
- the particles containing polyplexes according to the invention can be produced by precipitation.
- the cationic copolymers used according to the invention which are hydrophilic depending on the pH due to the presence of polar groups, are dissolved in water or in an aqueous buffer solution.
- a pH of the aqueous solution is adjusted from 3 to 6.5, for example by using an acetate buffer or another suitable buffer such as citrate buffer, lactate buffer, phosphate buffer and phosphate-citrate buffer pH of the aqueous nucleic acid solution is preferably adjusted to a value between 6.5 and 8.5, particularly preferably to a value between 6.8 and 7.5.
- a buffer solution containing HEPES, TRIS, or just salts is particularly suitable for this.
- Both solutions are combined with one another, with the amounts of nucleic acids and cationic copolymer being chosen such that a desired N/P ratio is established.
- the mixture is agitated, e.g. for a short time, such as between 2 and 20 seconds. This can be done by stirring and/or by vortexing.
- the resulting particles are left for some time before further use, for example between 5 and 20 minutes to allow binding between polymer and nucleic acids.
- the particles according to the invention are precipitated in finely divided form in the dispersing medium.
- auxiliaries and additives can be present during their precipitation in the dispersing medium.
- these auxiliaries and additives can be added after the nucleic acid copolymer complex has been dispersed in the aqueous phase.
- Water is used as the dispersing medium. Buffer substances, salts, sugars or acids and bases can be added to this in order to adjust the desired pH value or the osmolarity.
- the particles according to the invention are outstandingly suitable for gene transfer from cells, ie for introducing nucleic acids into cells.
- the particles containing nucleic acids are added to individual cells, tissues or a cell culture and taken up by the cells by endocytosis.
- the invention also relates to the use of the particles described above for gene transfer into cells, ie for introducing nucleic acids into cells.
- Proton ( 1 H) nuclear magnetic resonance (NMR) spectra were measured on a Bruker AC 300 MHz and a Bruker AC 400 MHz spectrometer, respectively. Measurements were performed at room temperature using either D 2 O or d 4 -methanol as solvent. Chemical shifts ( ⁇ 5) are reported in parts per million (ppm) relative to the residual non-deuterated solvent resonance signal.
- Infrared (IR) spectroscopy was performed on a Shimadzu IRAffinity-1 CE system equipped with a Quest ATR single-reflective diamond crystal ATR cuvette for extended range measurement.
- Size exclusion chromatography was performed in N,N-dimethylacetamide (DMAc) using an Agilent 1200 series system equipped with a PSS degasser, G1310A pump, G1329A autosampler, Techlab oven, G1362A refractive index detector (RID) and a PSS GRAMguard/30/1000 A column (10 pm particle size).
- DMAc with 0.21% by weight LiCl was used as the eluent.
- the flow rate was 1 ml min'1 and the oven temperature was 40°C.
- Polystyrene (PS) standards from 400 to 1,000,000 g mol' 1 were used for the calculation of molar masses.
- PEtOx was synthesized by cationic ring-opening polymerization (CROP) of EtOx.
- CROP cationic ring-opening polymerization
- MeOTs 124 g, 0.665 mol
- EtOx 3965 g, 40.00 mol, 60.2 equiv
- MeCN dry MeCN
- PEtOx (80.0 g, 12.5 mmol) was dissolved in aqueous hydrochloric acid (6 M, 600 mL) and heated at 90 °C for 24 h. Volatiles were removed under reduced pressure and the residue was dissolved in deionized water (1600 mL). Aqueous NaOH (3 M, 300 mL) was added in portions to reach pH 10, resulting in precipitation of the polymer. The polymer was then filtered off and through Recrystallize in water (800 mL). PEI was obtained as a white solid (yield: 47.5 g)
- the degree of hydrolysis DH was calculated according to equation (1) from the integrals of the 1 H NMR spectra of PEI.
- D is the integral of the methylene groups of the ethyleneimine units and A is the integral of the methyl groups of the remaining EtOx units.
- the degree of oxidation DO was calculated from the integrals of the polymer backbone signals of the 1 H NMR spectra of oxPEI according to Equation (2).
- F is the integral of the methylene group of the glycine units
- A is the integral of the methyl groups of the remaining EtOx units
- D is the integral of the methylene groups of the ethyleneimine units.
- Titrations to determine the residual amino groups were performed using an automated Metrohm OMNIS titrator equipped with a Metrohm Ecotrode plus pH electrode. All measurements were performed in a dynamic titration mode, which adapts the titration rate to the change in adjusted the pH value during the titration.
- a typical measurement was performed as follows: The polymer was dissolved in deionized water to give a polymer solution with a concentration of 3 mg ml' 1 . The polymer solution was acidified to reach a pH of 2 by adding a half-concentrated aqueous HCl solution dropwise. The solution was then titrated to pH 12 against 0.1 M aqueous sodium hydroxide solution while stirring. The equivalence points were determined from the first derivative of the titration curve.
- the polymer (20 mg) was dissolved in 6 mol L' 1 HCl (2 mL) and stirred at 90 °C for 48 h.
- the reaction mixture was neutralized with aqueous sodium hydroxide solution and water was removed under reduced pressure.
- Production example H1 Synthesis of poly(2-methyl-2-oxazoline-co-ethyleneimine-co-glycine), dP(MeOx-co-EI)
- P(MeOx-co-EI) 6 was prepared according to the general procedure by adding 500 mg oxPEI, 614 ⁇ L (446 mg, 4.41 mmol, 1 equiv per amine unit) triethylamine and 157.2 ⁇ L (173 mg, 2, 20 mmol, 0.5 equiv per amine unit) acetyl chloride were used. The precipitated triethylammonium salt was filtered off after the reaction, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in methanol and precipitated three times in ice-cold diethyl ether (about -80°C).
- Preparation Example H2 Synthesis of Poly(2-ethyl-2-oxazoline-co-ethyleneimine-co-glycine), dP(EtOx-co-EI) P(EtOx-co-EI) was prepared according to the general procedure by adding 500 mg oxPEI, 614 ⁇ L (446 mg, 4.41 mmol, 1 equiv. per amine unit) triethylamine and 192.2 ⁇ L (204 mg, 2.20 mmol, 0.5 equiv per amine unit) propionyl chloride were used. Triethylammonium chloride formed during the reaction was filtered off and the solution was concentrated under reduced pressure.
- Example C1 Characterization of the polymers by 1 H-NMR spectroscopy
- the first step was to synthesize a significant amount of PEtOx as a well-defined starting material via CROP (see general synthetic methods, Synthesis of PEtOx).
- a synthesis protocol was developed in a 10 L Normag reactor, yielding almost 4 kg of PEtOx with a degree of polymerization (DP) of 60 and a narrow dispersity (D) of 1.14 determined by SEC in DMAc. Since the CROP was terminated by the addition of water, the resulting PEtOx contained two isomeric end groups arising from nucleophilic attack at the 2- or 5-positions of the oxazoline ring, but in both cases resulting in hydroxyl end groups upon hydrolysis to linear poly(ethyleneimine) (PEI) led.
- PEI linear poly(ethyleneimine)
- the hydrolysis was carried out under acidic conditions (cf. general synthesis methods, synthesis of PEI). To obtain complete hydrolysis, the reaction was carried out overnight with excess 6M HCl. The successful synthesis was confirmed by the 1 H NMR spectrum, which clearly showed the disappearance of the signals assigned to the ethyl substituents of PEtOx. Furthermore, a clear upfield shift of the backbone signal confirmed the formation of PEI.
- the degree of hydrolysis (DH) was determined to be 99%, calculated by the ratio of the integrals in the 1 H NMR spectrum (see General Synthetic Methods, Synthesis and Characterization of dP(AOx-co-EI), Equation (1)).
- oxPEI was prepared by oxidizing PEI with hydrogen peroxide as the oxidizing agent.
- the structure of the resulting oxPEI corresponds to the repeating unit of poly(glycine) alongside unaffected ethyleneimine units. Therefore, the polymer can also be referred to as a poly(ethyleneimine-staf-glycine) copolymer.
- the degree of oxidation (DO) which was determined by the integral ratio in the 1 H-NMR spectrum to be 54% (cf. General synthetic methods, Synthesis and characterization of dP(AOx-co-EI), Eq. (2)), confirmed the successful synthesis.
- the methylene group signals assigned to the ethyleneimine and glycine repeat units appeared in close proximity in the 1 H NMR spectrum and partially overlapped.
- the resulting oxPEI provided the platform for the synthesis of various degradable polymers.
- subsequent reacylation with the aliphatic acyl chlorides acetyl chloride and propionic acid chloride was applied to reintroduce amide moieties equivalent to the /V-acylethyleneimine -structures in PAOx were.
- the resulting polymer structures resemble PAOx with additional, randomly distributed poly(glycine) units and polyethylenimine units integrated into the polymer backbone.
- poly(2-n-alkyl-2-oxazoline-staf-ethyleneimine-stat-glycine)-copolymers or due to the degradability of the glycine unit as degradable poly(2-alkyl-2-oxazoline-stat-ethyleneimine)- analogues are considered.
- the described synthetic approach thus allowed the preparation of polymers with the same chain length and DO using only EtOx as a commercially available monomer.
- Example C2 Characterization of the polymers by IR spectroscopy
- Figure 1 shows ATR-IR spectra of dP(MeOx-co-EI) and dP(EtOx-co-EI) in the wavenumber range from 600 to 4000 cm' 1 including the assignment of the most important bands.
- the IR spectroscopy of PEtOx, PEI, poly(glycine), as well as oxPEI has been previously reported in the literature, which allowed easy assignment of vibrational bands.
- the band at 3235 and 3246 cm' 1 im can be assigned to the NH vibration of the amino group.
- the vibrational band at 1647 and 1650 cm'- 1 can be assigned to the amide I band, which is mainly due to the carbonyl stretching vibration.
- Example C4 Characterization of the polymers by titration
- Example C5 Characterization of the polymers by degradation studies using acidic hydrolysis
- dP(AOx-co-EI) Compared to PAOx is its ability to be potentially degradable due to the additional backbone amide groups.
- dP(MeOx-co-EI) and dP(EtOx-co-EI) were treated with 6 M HCl at 90°C for 2 days. These conditions are similar to those used for the hydrolysis of PEtOx to PEI where no degradation of either the PEtOx or the PEI polymer backbone occurs.
- Figures 5 and 6 show the overlays of the 1 H NMR spectra of dP(MeOx-co-EI) and dP(EtOx-co-EI) before (lower spectrum) and after (upper spectrum) treatment with HCl. For reasons of clarity, the individual spectra are superimposed vertically.
- Figures 5 and 6 show the successful degradation of the polymers under these conditions.
- the polymers Before treatment with HCl, the polymers showed broad peaks typical of polymers, while the peaks of the degraded polymer were sharp, as is commonly observed for small molecules.
- the singlet at 3.67 ppm can be assigned to the methylene unit of the glycine formed upon degradation, while the triplets in the region of 3.65 ppm and 3.21 ppm can be assigned to the remaining ethyleneimine units.
- a sharp signal appeared at 8.77 ppm, which had already been reported for oxPEI after degradation and which could be due to further degradation products.
- the broad amide signal at about 8.0 ppm disappeared, indicating hydrolysis of the associated backbone amide groups.
- the overlay of the spectra of dP(MeOx-co-El) before and after treatment with HCl showed similar behavior. Side chain cleavage as acetic acid gave a singlet at 2.17 ppm.
- the broad polymer backbone peaks split into a sharp singlet at 3.61 ppm, as above described can be assigned to glycine.
- Several triplets ranging from 3.58 to 2.95 ppm were due to degradation products of the ethyleneimine units.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102020007115.5A DE102020007115A1 (en) | 2020-11-21 | 2020-11-21 | Functionalized polyglycine-poly(alkyleneimine) copolymers, their production and use for the production of formulations or for complexing anionic active ingredients and effect substances |
PCT/EP2021/000145 WO2022106048A1 (en) | 2020-11-21 | 2021-11-19 | Functionalised polyglycine-poly(alkylene imine)-copolymers, the preparation thereof and use thereof for preparing formulations of or for complexing anionic active ingredients and effect substances |
Publications (1)
Publication Number | Publication Date |
---|---|
EP4247874A1 true EP4247874A1 (en) | 2023-09-27 |
Family
ID=78806450
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP21815364.1A Pending EP4247874A1 (en) | 2020-11-21 | 2021-11-19 | Functionalised polyglycine-poly(alkylene imine)-copolymers, the preparation thereof and use thereof for preparing formulations of or for complexing anionic active ingredients and effect substances |
Country Status (7)
Country | Link |
---|---|
US (1) | US20230416462A1 (en) |
EP (1) | EP4247874A1 (en) |
CN (1) | CN116710505A (en) |
CA (1) | CA3202541A1 (en) |
DE (1) | DE102020007115A1 (en) |
IL (1) | IL302918A (en) |
WO (1) | WO2022106048A1 (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3346527A (en) | 1963-12-23 | 1967-10-10 | Chemirad Corp | Metal complex-forming compounds and process of making and using same |
US9682100B2 (en) * | 2015-01-26 | 2017-06-20 | International Business Machines Corporation | Cationic polyamines for treatment of viruses |
-
2020
- 2020-11-21 DE DE102020007115.5A patent/DE102020007115A1/en active Pending
-
2021
- 2021-11-19 IL IL302918A patent/IL302918A/en unknown
- 2021-11-19 CN CN202180085606.8A patent/CN116710505A/en active Pending
- 2021-11-19 EP EP21815364.1A patent/EP4247874A1/en active Pending
- 2021-11-19 CA CA3202541A patent/CA3202541A1/en active Pending
- 2021-11-19 WO PCT/EP2021/000145 patent/WO2022106048A1/en active Application Filing
- 2021-11-19 US US18/253,649 patent/US20230416462A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
CA3202541A1 (en) | 2022-05-27 |
DE102020007115A1 (en) | 2022-05-25 |
CN116710505A (en) | 2023-09-05 |
WO2022106048A1 (en) | 2022-05-27 |
US20230416462A1 (en) | 2023-12-28 |
IL302918A (en) | 2023-07-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE60302784T2 (en) | CONTROLLED DERIVABLE POLYMER BIOMOLECULAR OR ACTIVE SUBSTRATE AND METHOD FOR SYNTHESIS OF THE SUBSTRATE | |
Nam et al. | New micelle-like polymer aggregates made from PEI–PLGA diblock copolymers: micellar characteristics and cellular uptake | |
DE60310695T2 (en) | AMPHIPHILES DIBLOCK, TRIBLOCK AND STARBLOCK COPOLYMERS AND THE MEDICAMENTS CONTAINING THEM | |
Zhao et al. | pH-Responsive polymeric nanocarriers for efficient killing of cariogenic bacteria in biofilms | |
EP2367865B1 (en) | Compositions comprising glycidyl ether copolymers | |
WO2004046258A2 (en) | Lcst polymers | |
DE602004007155T2 (en) | CATIONIC POLYMERS WITH REMOVABLE NETWORKS | |
EP4247875A1 (en) | Functionalized polyglycine-poly(alkylenimine) copolymers, their preparation and use for preparing active ingredient formulations and special-effect substance formulations | |
EP1226204B1 (en) | Cationic block copolymers | |
CN101218204A (en) | Modified poly(propylene-imine) dendrimers and their use as transfection agents for anionic bioactive factors | |
DE60306769T2 (en) | TRIBLOCK POLYMERS FOR MEDICINAL OR INTRODUCTION TO NANO BALL BASE | |
Chen et al. | Amphiphilic block copolymer micelles with fluorescence as nano-carriers for doxorubicin delivery | |
WO2022106048A1 (en) | Functionalised polyglycine-poly(alkylene imine)-copolymers, the preparation thereof and use thereof for preparing formulations of or for complexing anionic active ingredients and effect substances | |
Petrova et al. | Novel thermo-responsive double-hydrophilic and hydrophobic MPEO-b-PEtOx-b-PCL triblock terpolymers: Synthesis, characterization and self-assembly studies | |
WO2018166651A1 (en) | Organic polymer particles containing poly(oxazoline) stabilizers and use of poly(oxazolines) for stabilizing organic polymer particles | |
WO2023247064A1 (en) | Poly(oxazoline)- and poly(oxazine)-based lipids, process for the preparation thereof, and use thereof | |
US9801954B2 (en) | Lipid substitution on aminoglycoside based polymers: plasmid delivery, anticancer drug delivery and transgene expression | |
JP4730938B2 (en) | Graft copolymer and method for producing graft copolymer | |
KR100669161B1 (en) | Biodegradable polymeric vesicles made from amphiphilic copolymers | |
Keshtpour | Self-immolative Polymers as a Degradable and Triggerable Class of Surfactants | |
Turan | Synthesis and self assembly of poly (2-isopropyl-2-oxazoline)-b-poly (2-phenyl-2-oxazoline)-b-poly (2-isopropyl-2-oxazoline) | |
DE102014016901B4 (en) | Process for the production of new dextran derivatives as active ingredient carrier systems and their use | |
Rieger | Heterobifunctional Linear Dendritic Block Co-Polymers (LDBCS) as Multifunctional Carriers for Targeted Drug Delivery | |
임권택 | Synthesis of stimuli-responsive drug delivery systems via RAFT polymerization and Diels-Alder click reaction for doxorubicin release | |
WO2021209169A2 (en) | Nanoparticles containing complexes of nucleic acids and cationic copolymers, process for preparing them and their use for gene transfer in cells |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20230621 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: NGP POLYMERS GMBH |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) |