EP3568401A1 - Lanthanide complexes comprising dendrimers - Google Patents
Lanthanide complexes comprising dendrimersInfo
- Publication number
- EP3568401A1 EP3568401A1 EP18700278.7A EP18700278A EP3568401A1 EP 3568401 A1 EP3568401 A1 EP 3568401A1 EP 18700278 A EP18700278 A EP 18700278A EP 3568401 A1 EP3568401 A1 EP 3568401A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- group
- brs
- groups
- solution
- 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.)
- Withdrawn
Links
- 239000000412 dendrimer Substances 0.000 title claims abstract description 91
- 229920000736 dendritic polymer Polymers 0.000 title claims abstract description 90
- 229910052747 lanthanoid Inorganic materials 0.000 title claims abstract description 34
- 150000002602 lanthanoids Chemical class 0.000 title claims abstract description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 48
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 12
- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 claims description 10
- 150000004032 porphyrins Chemical class 0.000 claims description 10
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 8
- -1 oxyme Chemical class 0.000 claims description 7
- 229910052779 Neodymium Inorganic materials 0.000 claims description 6
- 229910052769 Ytterbium Inorganic materials 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- 230000008685 targeting Effects 0.000 claims description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 150000001409 amidines Chemical class 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 150000004056 anthraquinones Chemical class 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 150000007857 hydrazones Chemical class 0.000 claims description 4
- 150000002466 imines Chemical class 0.000 claims description 4
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 150000003456 sulfonamides Chemical class 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 150000003568 thioethers Chemical class 0.000 claims description 4
- 150000003852 triazoles Chemical class 0.000 claims description 4
- 229910052692 Dysprosium Inorganic materials 0.000 claims description 3
- 229910052691 Erbium Inorganic materials 0.000 claims description 3
- 229910052693 Europium Inorganic materials 0.000 claims description 3
- 229910052689 Holmium Inorganic materials 0.000 claims description 3
- 108091034117 Oligonucleotide Proteins 0.000 claims description 3
- 229910052777 Praseodymium Inorganic materials 0.000 claims description 3
- 229910052772 Samarium Inorganic materials 0.000 claims description 3
- 229910052775 Thulium Inorganic materials 0.000 claims description 3
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 3
- 150000004676 glycans Chemical class 0.000 claims description 3
- 239000005017 polysaccharide Substances 0.000 claims description 3
- 229920001282 polysaccharide Polymers 0.000 claims description 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- 150000008163 sugars Chemical group 0.000 claims description 3
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 125000002355 alkine group Chemical group 0.000 claims description 2
- 125000002228 disulfide group Chemical group 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical group 0.000 claims description 2
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 2
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims 2
- 125000001484 phenothiazinyl group Chemical class C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims 2
- 229960002685 biotin Drugs 0.000 claims 1
- 235000020958 biotin Nutrition 0.000 claims 1
- 239000011616 biotin Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 102
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 96
- 239000000243 solution Substances 0.000 description 89
- 238000005481 NMR spectroscopy Methods 0.000 description 59
- 150000001875 compounds Chemical class 0.000 description 48
- 210000004027 cell Anatomy 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- 238000003786 synthesis reaction Methods 0.000 description 26
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 22
- 230000005284 excitation Effects 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000000843 powder Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 150000001345 alkine derivatives Chemical class 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- UMYGQXLPGOSJLB-UQQUJRAVSA-N 2-[4-[(2Z)-2-[1-difluoroboranyl-3-(4-methoxyphenyl)-5-phenylpyrrol-2-yl]imino-5-phenylpyrrol-3-yl]phenoxy]acetic acid Chemical compound FB(N1C(=C(C=C1C1=CC=CC=C1)C1=CC=C(C=C1)OC)\N=C\1/N=C(C=C/1C1=CC=C(OCC(=O)O)C=C1)C1=CC=CC=C1)F UMYGQXLPGOSJLB-UQQUJRAVSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 12
- 238000000502 dialysis Methods 0.000 description 12
- 238000000862 absorption spectrum Methods 0.000 description 11
- 239000012298 atmosphere Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000001317 epifluorescence microscopy Methods 0.000 description 10
- 238000011534 incubation Methods 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 230000007246 mechanism Effects 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 238000004020 luminiscence type Methods 0.000 description 8
- 238000006862 quantum yield reaction Methods 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- RZRMGSKFTDVBSY-UHFFFAOYSA-N 3-(4-methoxyphenyl)-2-nitroso-5-phenyl-1h-pyrrole Chemical compound C1=CC(OC)=CC=C1C1=C(N=O)NC(C=2C=CC=CC=2)=C1 RZRMGSKFTDVBSY-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 230000001413 cellular effect Effects 0.000 description 7
- 238000003384 imaging method Methods 0.000 description 7
- 230000037361 pathway Effects 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000009056 active transport Effects 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000004624 confocal microscopy Methods 0.000 description 6
- 238000000684 flow cytometry Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000005286 illumination Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- CSHWQDPOILHKBI-UHFFFAOYSA-N peryrene Natural products C1=CC(C2=CC=CC=3C2=C2C=CC=3)=C3C2=CC=CC3=C1 CSHWQDPOILHKBI-UHFFFAOYSA-N 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- JKEHCFWDVMZLOF-FNQDKCGUSA-N tert-butyl N-[2-[[2-[4-[(2Z)-2-[1-difluoroboranyl-3-(4-methoxyphenyl)-5-phenylpyrrol-2-yl]imino-5-phenylpyrrol-3-yl]phenoxy]acetyl]amino]ethyl]carbamate Chemical compound FB(N1C(=C(C=C1C1=CC=CC=C1)C1=CC=C(C=C1)OC)\N=C\1/N=C(C=C/1C1=CC=C(OCC(=O)NCCNC(OC(C)(C)C)=O)C=C1)C1=CC=CC=C1)F JKEHCFWDVMZLOF-FNQDKCGUSA-N 0.000 description 5
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 4
- CRJUQMZGGKYCDK-UHFFFAOYSA-N 3-(4-methoxyphenyl)-4-nitro-1-phenylbutan-1-one Chemical compound C1=CC(OC)=CC=C1C(C[N+]([O-])=O)CC(=O)C1=CC=CC=C1 CRJUQMZGGKYCDK-UHFFFAOYSA-N 0.000 description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 4
- KNKIAJCZNZNYJO-UHFFFAOYSA-N 4-(4-methoxyphenyl)-2-phenyl-1h-pyrrole Chemical compound C1=CC(OC)=CC=C1C1=CNC(C=2C=CC=CC=2)=C1 KNKIAJCZNZNYJO-UHFFFAOYSA-N 0.000 description 4
- 101100207328 Arabidopsis thaliana TPPH gene Proteins 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 4
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 229940125846 compound 25 Drugs 0.000 description 4
- 229940125851 compound 27 Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000000295 emission spectrum Methods 0.000 description 4
- 238000000695 excitation spectrum Methods 0.000 description 4
- 239000012216 imaging agent Substances 0.000 description 4
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- 230000009057 passive transport Effects 0.000 description 4
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- 230000003595 spectral effect Effects 0.000 description 4
- YNHJECZULSZAQK-UHFFFAOYSA-N tetraphenylporphyrin Chemical compound C1=CC(C(=C2C=CC(N2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3N2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 YNHJECZULSZAQK-UHFFFAOYSA-N 0.000 description 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 239000012124 Opti-MEM Substances 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 229940127204 compound 29 Drugs 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 230000012202 endocytosis Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- CHJJSSJFRARSRD-UHFFFAOYSA-N methyl 2-[4-(5-phenyl-1H-pyrrol-3-yl)phenoxy]acetate Chemical compound COC(=O)COc1ccc(cc1)-c1c[nH]c(c1)-c1ccccc1 CHJJSSJFRARSRD-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 238000002428 photodynamic therapy Methods 0.000 description 3
- 235000010378 sodium ascorbate Nutrition 0.000 description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 3
- 229960005055 sodium ascorbate Drugs 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
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- AKYAUBWOTZJUBI-UHFFFAOYSA-N hex-2-ynoic acid Chemical compound CCCC#CC(O)=O AKYAUBWOTZJUBI-UHFFFAOYSA-N 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000012188 high-throughput screening assay Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- XQBXQQNSKADUDV-UHFFFAOYSA-N lanthanum;nitric acid Chemical compound [La].O[N+]([O-])=O XQBXQQNSKADUDV-UHFFFAOYSA-N 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 230000034778 micropinocytosis Effects 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000009126 molecular therapy Methods 0.000 description 1
- MLEBFEHOJICQQS-UHFFFAOYSA-N monodansylcadaverine Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)NCCCCCN MLEBFEHOJICQQS-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000012634 optical imaging Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- KJOLVZJFMDVPGB-UHFFFAOYSA-N perylenediimide Chemical compound C=12C3=CC=C(C(NC4=O)=O)C2=C4C=CC=1C1=CC=C2C(=O)NC(=O)C4=CC=C3C1=C42 KJOLVZJFMDVPGB-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 150000004033 porphyrin derivatives Chemical class 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 239000004054 semiconductor nanocrystal Substances 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000006557 surface reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229910052714 tellurium Inorganic materials 0.000 description 1
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000031998 transcytosis Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- JLGLQAWTXXGVEM-UHFFFAOYSA-N triethylene glycol monomethyl ether Chemical compound COCCOCCOCCO JLGLQAWTXXGVEM-UHFFFAOYSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 230000007332 vesicle formation Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C09B69/00—Dyes not provided for by a single group of this subclass
- C09B69/10—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds
- C09B69/107—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds containing an azomethine dye
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
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- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0028—Oxazine dyes
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- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
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- 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
- C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
- C08G83/002—Dendritic macromolecules
- C08G83/003—Dendrimers
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- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
- C09B23/0016—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being a halogen atom
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- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
- C09B23/0033—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being bound through a sulfur atom
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
- C09B23/0041—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain the substituent being bound through a nitrogen atom
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- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0066—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09B5/00—Dyes with an anthracene nucleus condensed with one or more heterocyclic rings with or without carbocyclic rings
- C09B5/62—Cyclic imides or amidines of peri-dicarboxylic acids of the anthracene, benzanthrene, or perylene series
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- C09B69/00—Dyes not provided for by a single group of this subclass
- C09B69/10—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds
- C09B69/101—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds containing an anthracene dye
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- C09B69/00—Dyes not provided for by a single group of this subclass
- C09B69/10—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds
- C09B69/105—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds containing a methine or polymethine dye
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- C09B69/00—Dyes not provided for by a single group of this subclass
- C09B69/10—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds
- C09B69/109—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds containing other specific dyes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Optical investigation techniques, e.g. flow cytometry
- G01N15/1429—Signal processing
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/6456—Spatial resolved fluorescence measurements; Imaging
- G01N21/6458—Fluorescence microscopy
Definitions
- the present invention relates to lanthanide complexes based on dendrimers.
- the subject of the present invention is dendrimeric compounds, grafted to an antenna, capable of complexing with lanthanides.
- the methods related to fluorescence have the advantages of being very sensitive, to allow real-time measurements, which are not very dangerous for biological media (because of the small quantity of imaging agents required for condition to use suitable excitation wavelengths) and very accessible (in terms of manufacturing and use costs), experimental time, mobility and level of specialization of users.
- Fluorescent reporters based on semiconductor nanocrystals are another range of optical imaging agent choices. Another limiting factor is the high toxicity of the metals that make up these nanoparticles (cadmium, tellurium and selenium) in the case where the latter dissociate.
- the family of lanthanides includes 14 elements with extremely interesting and unique optical properties, characterized by narrow and precise emission bands, ranging from visible to near infrared (> 1,200 nm). Each lanthanide has distinct and identifiable spectral properties. It is thus possible to decline, on the basis of the same technology, a whole range of different wavelengths by simply choosing the nature of the lanthanide to be incorporated in the molecule. These emission bands are much narrower than organic fluorophores and fluorescent nanoparticles (quantum dots), which allows for better spectral discrimination and multiplexed assays.
- the position (in nm) of these emission bands does not vary according to the environment (cell, pH, temperatures, hydrophilic / hydrophobic sites, etc.) which facilitates their detections and minimizes the adaptation of the equipment (single filter for a given lanthanide).
- the environment cell, pH, temperatures, hydrophilic / hydrophobic sites, etc.
- fluorescent probes compatible with biological applications and operating in lower energy conversion based on lanthanides which are ideally excitable and emitters above 600 nm, corresponding to the biological window.
- the current infrared near-infrared probes are of an organic nature, the commercial ones are few and suffer from limitations such as the tendency towards photobleaching and restricted Stokes displacements.
- the object of the present invention is therefore to provide a polymetallic lanthanide dendrimeric complex emitting in the near infrared and capable of being excited in the near infrared.
- Another object of the invention is to provide an absorbing and emitting light emitting system in the near infrared and to observe various biological systems without destroying them or interfere with their operation.
- Another object of the invention is to provide a luminescent system for limiting spurious fluorescence / luminescence signals generated by biological materials (autofluorescence).
- the present invention relates to a complex comprising at least one dendrimer (D) and at least one lanthanide (Ln), in which the dendrimer (D) comprises a unit of formula (I) below:
- Ci is a valence group 4 of formula> N-CH 2 -CH 2 -N ⁇ ;
- a 2 and A 3 are groups of formula - (CH 2 ) 2 -C (O) -NH- (CH 2 ) 2-;
- Luminescent compounds containing lanthanides have, among other advantages, a spectral specificity in the visible and near-infrared spectral discrimination by their narrow emission bands specific to the nature of each lanthanide. In order to obtain a good luminescence intensity, it is important to introduce functional groups on the molecule that make it capable of absorbing a large amount of light radiation and to transfer the resulting energy onto the luminescent lanthanide to obtain the light. emission of luminescence radiation by return of the lanthanide to the ground state.
- Near infrared offers a lot of unique advantages. It makes it possible to dispense with the auto-fluorescence of the tissues, and thus makes it possible to improve the signal-to-noise ratio and thus the detection sensitivity. Moreover, the biological tissues do not absorb or slightly between 640 nm and 1100 nm (window of biological transparency), which allows an excitation of the probes in depth and a non-invasive biological observation (diagnosis and research).
- the lanthanide complexes are photostable. This photostability property is crucial in allowing the imaging agent to be excited i) over long experimental times and / or ii) during successive experiments and / or iii) by powerful excitation sources (lasers for confocal microscopy for example). A larger amount of photons can thus be collected without disturbing or damaging the functioning of the biological system to be studied (it is important to remember here that the excitation wavelength (> 650 nm) interacts extremely weakly with fluids and tissues. and increase the intensity and quality of the signal collected.
- the structure of the dendrimers makes it possible to group on the same molecule a large density of lanthanides and antennas making it possible to increase the quantity of photons emitted per unit volume, which increases the intensity of the signal per molecule and therefore the sensitivity of the detection.
- the present invention thus relates to an entity obtained by complexation between a dendrimer (D) as defined above and at least one lanthanide.
- the complexes thus obtained are luminescent molecules.
- the lanthanides are encapsulated within the dendrimer due to the presence of oxygen and nitrogen atoms.
- the arrangement of the branches of the dendrimer around lanthanides partially protects them from direct interactions with solvent and water molecules in particular.
- the complexes according to the invention are obtained by placing a dendrimer (D) in contact with a solution of lanthanides.
- the dendrimer (D) is dissolved for example in a solution of DMSO and a solution of lanthanide salt is added to the solution containing the compound (D) in particular in an eight to one ratio.
- the reaction mixture was mixed and the resulting dendrimer-lanthanide conjugate was isolated by dialysis.
- the unit of formula (I) is connected via at least one arm to at least one antenna as defined above.
- At least one is covalently connected to at least one antenna, via an arm.
- the term "antenna” designates an entity capable of absorbing a large amount of excitation light to transfer the energy corresponding to the lanthanides and / or to emit directly by fluorescence.
- the antenna is selected from the group consisting of anthraquinones, cyanines, especially cyanines 5, cyanines 5.5 and cyanines 7, aza-BODIPY, perylenediimides, porphyrins, phenothiazine salts and their salts. derivatives.
- antennas it is also possible to use compounds of the "IR dyes" type well known to those skilled in the art.
- these antennas there may be mentioned for example the following compounds:
- These antennas are fixed on the dendrimers via chlorine by substitution and thus in the final form there is no chlorine but is a C, N, S and O.
- arm refers to an entity for covalently connecting the pattern of formula (I) and the antenna.
- the antenna is connected to the unit of formula (I) in a covalent manner via at least one arm corresponding to the following formula (II):
- a 4 is a group of formula - (CH 2 ) 2 -X '- (CH 2 ) 2-, X' representing a group - C (O) -NH- or a group -NH-C (O) -, and preferably being a group of formula - (CH 2 ) 2 -C (O) -NH- (CH 2 ) 2 -;
- X is a group of formula -NH-C (O) -; - i is an integer between 1 and 3;
- k 0 or 1
- a 5 and A 6 are selected, independently of each other, from the radicals (cyclo) alkylene, linear or branched, comprising from 1 to 12 carbon atoms;
- Z is selected from -O-, -NH-, -S-, amide, ester, triazole, amine, ether, thioether, urea, thiourea, imine, oxyme, hydrazone, sulfonamide, carbamate, amidine, phosphoramidate, disulfide groups; and sulfonyl; and
- Y is selected from -O-, -NH-, -S-, alkylene, amide, ester, triazole, amine, ether, thioether, urea, thiourea, imine, oxyme, hydrazone, sulfonamide, carbamate, amidine, phosphoramidate , disulfide and sulfonyl.
- the dendrimer has the following formula:
- Ci is a valence group 4 of formula> N-CH 2 -CH 2 -N ⁇ ;
- a 2 - A 2 , A 3 and A 4 are groups of formula - (CH 2 ) 2 -C (O) -NH- (CH 2 ) 2 -;
- radicals R ' are chosen, independently of one another, from the group consisting of:
- L representing an antenna selected from the group consisting of anthraquinones, cyanines, aza-BODIPY, perylenediimides, porphyrins, phenothiazine salts and their derivatives; . groups of formula (2) below:
- L representing a function that can be involved in a bioconjugation reaction, and preferably being an alkyne group, at least one of R 'groups having the formula (1).
- water-solubilising group designates a chemical entity making it possible to increase the solubility of the probe in aqueous media.
- water-solubilising groups there may be mentioned, for example, phosphates, sulphonates, sugars and PEG chains.
- targeting group refers to a molecule, biological or not, capable of recognizing and / or binding a specific biological site.
- Targeting groups include, for example, antibodies, proteins, peptides, carbohydrates, lipids, polysaccharides, fatty acids, amino acids, deoxyribonucleic acids, ribonucleic acids, oligonucleotides, medicaments and the like. ligands.
- Formula (II) above contains 32 peripheral groups R ', of which at least one comprises an antenna connected to the dendrimer via an arm.
- the dendrimers according to the invention may comprise at least one arm through which at least one antenna is linked.
- at least one of the groups R ' has the formula (1) above.
- the dendrimer is a generation 4 dendrimer of the following formula ( ⁇ ):
- R ' being as defined above.
- k 0.
- At least one of the groups R ' corresponds to the following formula (1'):
- a 5 and Z are as defined in formula (II), and
- a 5 is chosen from alkylene radicals, linear or branched, comprising from 1 to 4 carbon atoms.
- a 5 and L are as defined above.
- a 5 is chosen from alkylene radicals, linear or branched, comprising from 1 to 4 carbon atoms.
- a 5 and L are as defined above.
- a 5 is chosen from alkylene radicals, linear or branched, comprising from 1 to 4 carbon atoms.
- the antenna responds to one of the following formulas:
- this may contain a metal, chosen in particular from Ag, Al, As, Au, Cd, Co, Cu, Fe, Ir, Mg, Mn, Ni, Os, Pd, Pt, Rh, Ru, Sb, Sn, V , Zn, La, Ce, Pr, Nd, Sm,
- a metal chosen in particular from Ag, Al, As, Au, Cd, Co, Cu, Fe, Ir, Mg, Mn, Ni, Os, Pd, Pt, Rh, Ru, Sb, Sn, V , Zn, La, Ce, Pr, Nd, Sm,
- the dendrimer (D) according to the invention has the following formula:
- the dendrimer (D) according to the invention has the following formula:
- L 2 is one of the following antennas:
- the dendrimer (D) according to the invention corresponds to the formula
- R2 responds to one of the following formulas:
- the lanthanide is chosen from the group consisting of Yb, Nd, Ho, Tm, Sm, Dy, Eu, Pr and Er.
- the present invention also relates to a conjugate comprising a biological molecule and a complex as defined above, wherein said complex is linked to the biological molecule via a linker, said biological molecule being chosen from the group consisting of antibodies, proteins, peptides, carbohydrates, lipids, polysaccharides, fatty acids, amino acids, deoxyribonucleic acids, ribonucleic acids, oligonucleotides, drugs and ligands.
- the present invention also relates to the use of a complex as defined above as a fluorescent chromophore.
- fluorescent chromophore refers to a molecule that can re-emit light after excitation with a quantum yield greater than 10 -6 (10 -4 %).
- the complexes according to the invention may especially be used in the field of cell imaging, veterinary imaging, blood tests, biopsies, histological sectional analyzes, high throughput screening assays, bioanalytical assays. plates 96, 396 and 1536 wells or assisted surgery (guided) by imaging.
- the present invention also relates to the use of a complex as defined above as a photodynamic therapy agent (PDT).
- PDT photodynamic therapy agent
- Figure 1 shows the 1 H NMR spectrum (DMSO, TFA, 40 ° C) of the G3P- (TPP) 32 dendrimer.
- Figure 2 shows the 1 H NMR spectrum (DMSO, room temperature, suspension in water) of the G3P- (TPP) 32 dendrimer.
- the absorption spectrum of the compound 9 is multiplied by a factor corresponding to the number of chromophores attached to the branches of the dendrimer, for example, by 16 for (Ln 8 -) G3P- (Bodipy1) 16 and by 32 for (Ln 8 -) G3P- (Bodipy1) 32 .
- the experiments were carried out for a 10 ⁇ solution in DMSO and under uninterrupted illumination at 670 nm, the emission being collected at 735 nm.
- Figure 7 shows the confocal microscopy imaging results.
- the emission of aza-BODIPY (A ex : 633 nm; A em : 650-800 nm) was observed under excitation at 633 nm (6% laser power).
- Figure 8 represents the results of the study of cellular internalisation by flow cytometry.
- the HeLa cells were treated with NaN 3 (active internalization inhibitor) or preincubated at 4 ° C for 30 minutes (inhibition of active and passive pathways) before incubation. with the dendrimers.
- the signal emitted by the aza-Bodipy chromophore was collected ( eg 655 nm ⁇ 40 nm, A em : long pass filter 785 nm, 8 s exposure).
- Figure 12 shows the results of epifluorescence microscopy imaging on HeLa cells.
- B luminescence image (A eg 655 bandwidth of 40nm; A em: 750 bandwidth 50 nm; exposure time of (seconds).
- C Image resulting from the merger of A and B.
- Figure 13 shows the absorption spectrum of Yb 8 -G3P- (TPP) 32 (1.0 ⁇ ) in DMSO and in the DMSO / (Opti-MEM: FCS) mixture (2.2 ⁇ ) at 298 K .
- Figure 14 shows the visible emission spectrum of Yb 8 -G3- (TPP) 32 (37 ⁇ ) in DMSO under excitation at 520 nm, 298K.
- Figure 15 shows the near-infrared emission spectra of Yb 8 -G3- (TPP) 32 (37 ⁇ ) and G3- (TPP) 32 (37 ⁇ ) in DMSO under excitation at 520 nm, 298K .
- Figure 17 shows the images obtained by epifluorescence microscopy of HeLa cells.
- A After 1 hr and 30 min of incubation with a 1 ⁇ l solution of Yb-G3P-TPP dendrimer complex.
- B The same cells after 2 min of selected light exposure with a bandpass filter centered at 417 nm: vesicle formation.
- C cells not incubated with Yb 8 -G3- (TPP) 32 .
- This antenna (10) is obtained according to the reaction scheme below
- nitrobutanone 2 (1.16 mmol, 1 eq.) And 5 eq are dissolved in a flask. of KOH in 100 mL of MeOH / THF (1: 2). The solution is stirred at room temperature for one hour and then added dropwise to a solution of concentrated H 2 SO 4 (2 mL / mmol) dissolved in 100 mL of MeOH at 0 ° C. After the addition is complete, the ice bath is removed and the solution stirred at room temperature for 1 hour. The mixture is then poured into an Erlenmeyer flask containing water and ice and the solution is neutralized by adding a 4M sodium hydroxide solution.
- the mixture is extracted with dichloromethane and the organic phase is dried over MgSO 4 , filtered and the solvent evaporated under reduced pressure.
- the residue is dissolved in 100 mL glacial acetic acid and 5 eq. ammonium acetate are added.
- the solution is heated at reflux for one hour during which the color of the solution changes from yellow to deep blue.
- the solution is cooled to room temperature and the acetic acid evaporated under reduced pressure.
- the black solid is then dissolved in dichloromethane and the solution is washed several times with a saturated solution of sodium bicarbonate and brine.
- the organic phase is dried over MgSO 4 , filtered and concentrated under reduced pressure.
- the organic phase is dried, filtered and concentrated under reduced pressure.
- the residue is dissolved in a minimum volume of ethanol and excess aqueous solution of sodium acetate and ice are added and the mixture is stirred for one hour.
- the solution is then extracted with dichloromethane and washed with brine.
- the organic phase is dried over MgSO 4 , filtered and concentrated in vacuo.
- the residue is then dissolved in a minimum volume of dichloromethane and the product is precipitated by addition. slow of petroleum ether.
- the solid is filtered on Buchner and washed with petroleum ether. 0.503 g of nitrosopyrrole 6 (1.81 mmol, 76%) are obtained in the form of a green powder.
- aqueous phase is then reextracted three times with dichloromethane and the combined organic phases are dried over MgSO 4 , filtered and concentrated in vacuo.
- the residue is purified by chromatography on silica with a gradient of PE / DCM. Azabodipy 8 is obtained as an iridescent dark blue powder (0.196 g, 0.318 mmol, 99%).
- azabodipy 8 (0.5 mmol, 1 eq) in a THF / water / H 3 PO 4 mixture (50 mL: 25 mL: 10 mL) is dissolved in a flask. The solution is stirred under reflux for 20 hours until no trace of the ester is visible by TLC. After cooling, the solution is extracted with dichloromethane. The organic phase is washed with brine and then the aqueous phases are re-extracted with dichloromethane until no blue color is observed in the aqueous phase. The organic phase is dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue can optionally be purified by chromatography with DCM / MeOH if the ester is still present in the crude. Azabodipy 9 is obtained as a dark blue solid (0.294 g, 0.49 mmol, 98%).
- This antenna (19) is obtained according to the reaction scheme below:
- IR (cm 1 ): u 3394, 2948, 2875, 2080, 1496, 1246, 831, 752, 692.
- This compound (ocher-golden powder) is synthesized by applying the procedure described for the preparation of compound 6.
- IR (cm 1 ): u 3280, 2918, 2850, 2092, 1603, 1360, 1258, 1,164, 1038, 828, 768, 695, 668.
- IR (cm 1 ): u 2094, 1759, 1600, 1496, 1241, 1166, 903, 806, 764, 694, 675.
- the mixture 1,7- and 1,6-dibromoperylene-3,4,9,10-tetracarboxylic dianhydride (1.03 g, 1.8 mmol, 1.0 eq) is solubilized under argon in 20 ml of NMP.
- hexylamine 0.546 g, 5.4 mmol, 700 ⁇ , 7.3 eq
- acetic acid 0.32 g, 7.2 mmol, 412 ⁇ , 4.0 eq
- the reaction mixture is stirred at 85 ° C. under an inert atmosphere for 2 hours. After returning to ambient temperature, the reaction mixture is poured into ethanol. The red precipitate is filtered under vacuum and washed several times with ethanol.
- the desired mixture P1a and P1b is obtained in the form of a red powder which is used directly in the next reaction.
- the mixture obtained above (20a, 20b) is solubilized in pyrrolidine.
- the solution is stirred under an inert atmosphere at 85 ° C. for 16 hours.
- the aqueous phase is extracted three times with dichloromethane.
- the organic phases are combined, dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- the crude reaction product is purified on a chromatographic column on silica gel (eluent: Hexane / ethyl acetate (7/3)) to give the isomer 1, 7 (P2) as a green powder.
- the organic crude is then dried over Na 2 S0 4 , filtered and evaporated under reduced pressure
- the crude product is purified on a chromatographic column (eluent: hexane / ethyl acetate (6/4)) to give the compound P3 in the form of a green powder.
- the compound 23 (135 mg, 1, 9.10 4 mol, 1, 0eq) is solubilized in dry dichloromethane (20 mL). To this solution are added triethylamine (256 ⁇ l, 1.9 mmol, 10.0 eq) and 4-toluenesulfonyl chloride (366 mg, 1.9 mmol, 10.0 eq). The reaction mixture is stirred at ambient temperature under an inert atmosphere for 16 hours. At the end of the reaction, water is added and the organic phase is washed three times with water. The organic phase is then dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude reaction product is purified on a chromatographic column (Eluent: Hexane / ethyl acetate (8/2)) to give the compound P5 in the form of a green powder.
- a chromatographic column Eluent: Hexane / ethyl acetate (8/2)
- Triethylene glycol mono methyl ether (2.0 g, 1.22 ⁇ 10 2 mol, 1.0 eq) is solubilized in 120 ml of dry CH 2 Cl 2 .
- To this solution are added under argon 4-toluenesulfonyl chloride (4.64 g, 2.43 ⁇ 10 -2 mol, 2.0 eq) and triethylamine (2.68 g, 2.43 ⁇ 10 -2 mol, 2.0 g). eq).
- the reaction mixture is stirred under an inert atmosphere at ambient temperature for 16 hours.
- water is added to the reaction mixture and the organic phase is washed three times with water, dried over Na 2 SO 4 , filtered and evaporated under vacuum.
- the crude reaction product is purified by chromatography column on silica gel (eluent: CH 2 Cl 2 / MeOH (0.5%)) to give the desired product in the form of a colorless oil.
- Tetraphenylporphyrin (TPPH, compound 28) was synthesized following the Alder-Rothemund method from a mixture of benzaldehyde and pyrrole in propionic acid, heated at 130 ° C for two hours. The crystalline product was isolated by filtration in 6% yield. The low yield is in agreement with the literature and the synthetic route used.
- the next step is an electrophilic aromatic substitution, also called aromatic nitration.
- aromatic nitration is controllable regioselectively in the para position of the phenyl, by varying the amount of sodium nitrite and the reaction time in the TFA. Indeed, after concentrating TPPH in TFA, the latter was treated with 1 .8 equivalents of sodium nitrite for exactly 3 minutes.
- the reaction mixture was re-engaged without intermediate purification in order to reduce the nitro group to an amino group in the presence of excess of tin chloride and hydrochloric acid.
- the mono-amino unsymmetric porphyrin (compound 29) was isolated by column chromatography (silica, DCM / Hexane, 9: 1).
- TPPH TPPH (906 mg, 1.5 mmol, 1.0 equiv) was dissolved in 70 mL of TFA, then sodium nitrite (181 mg, 2.6 mmol, 1.8 equiv) was added. . The solution was stirred at room temperature for exactly 3 minutes. The reaction mixture was then quenched with 200 mL of water. The aqueous solution was extracted with DCM. The organic layer was washed with saturated aqueous NaHCO 3 solution , dried over anhydrous Na 2 SO 4 , filtered and evaporated in vacuo to give a purple solid. The latter was dissolved without purification in 50 ml of concentrated HCl.
- n equivalents of 9 (4 eq./NH 2 for a total functionalization is 128 eq or 0.5 eq./NH 2 for a hemifunctionalization or 16 eq.), N eq. HBTU and n eq. of DIPEA in 10 mL of dry, degassed DMF.
- the solution is stirred at room temperature for 15 minutes.
- 1 eq. of G3P- (NH 2 ) 32 (typically, 0.100 mL of a 12.44% solution of G3P- (NH 2 ) 32 in MeOH, ie 1 .8 ⁇ of dendrimer) are dissolved in 10 mL of anhydrous DMF.
- argon was bubbled in the dendrimer solution for 5 minutes before adding it to the activated azabodipy solution.
- the reaction is allowed to stir overnight at room temperature in the dark.
- the solution is concentrated under reduced pressure to evaporate the maximum of DMF and DIPEA.
- the pasty blue residue is then dissolved in quality DMSO for analysis, and placed in a bag of dialysis membrane (10 kDa) sealed with tongs.
- the dialysis rod is immersed in DMSO 3a in a 500 mL Erlenmeyer flask and gently stirred in the dark.
- the dialysis DMSO is changed every hour on the first day, then every half day on the following days.
- the functionalized dendrimer solution is recovered inside the flange and the maximum of DMSO evaporated by evaporation under vacuum.
- Hexynoic acid (428 mg, 3.8 ⁇ 10 -4 mol, 40.0 eq), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloric acid (592 mg, 3.8 ⁇ 10 -4 mol, 40.0 eq), HOBT (516 mg, 3.8 10 -4 mol, 40.0 eq) and DIPEA are dissolved in 40 mL distilled DMF. The solution is stirred under an inert atmosphere for 30 min. To this solution is added a solution of G3P- (NH 2) 3 2 (660 mg, 9.5 10 -5 mol, 1 .0 eq). The reaction mixture is stirred under an inert atmosphere at 25 ° C.
- G3P- (Alkyne) 32 (20 mg, 2.0 ⁇ 10 -6 mol, 1.0 eq) and the chromophore bearing an azide function (compound Perylene) (8.0 ⁇ 10 -5 mol, 40 eq) are solubilized in 1 ml of distilled DMF.
- the solution is degassed under argon for 20min.
- To this solution is then added a solution of CuSO 4 5H 2 O and sodium ascorbate in H 2 O / DMF (1 ml, 1/1, v / v).
- the reaction mixture is stirred under an inert atmosphere at room temperature for 24 hours. At the end of the reaction, the solvents are evaporated under reduced pressure and an EDTA solution is added to the reaction crude.
- G3P- (Alkyne) 32 (20 mg, 2.0 10 -6 mol, 1 0 eq) and the chromophore azide (1, 6.10 "5 mol, 8.0 eq) are solubilized in 1 mL DMF.
- the solution is degassed under argon for 20 min
- a solution of CuSO 4 .5H 2 O ( 7 ⁇ 10 -6 mol, 3.5 eq) and sodium ascorbate (7 ⁇ 10 6 mol, 3.5 eq) (1 mL, DMF / H 2 O (1 / 1, v / v)) is then added.
- the reaction mixture is stirred under argon at 25 ° C for 12 h.
- the solvents are evaporated under reduced pressure.
- the reaction crude is triturated in an aqueous solution of EDTA for 5 h and then dialyzed in water (MW 2 kDa).
- the compound 27 the nitrogenous hydrosolubilizing group (4.0 ⁇ 10 -5 mol, 20.0 eq)
- the solution is degassed under argon for 20 minutes
- a solution of CuSO 4 .5H 2 O (2.0.10 "5 mol, 10.0 eq) and sodium ascorbate (2.0 ⁇ 10 -5 mol, 10.0 eq) (1 mL, DMF / H 2 O (1/1, v / v)) is then added
- the reaction mixture is stirred under argon at 25 ° C.
- a dendrimer solution in DMSO was treated with 8 eq. of lanthanide nitrate for 7 days at room temperature.
- the forms of the excitation spectra measured under observation of the emission at 760 nm correspond to those of the absorption spectra ( Figure 4 vs. 3).
- the characteristic luminescence in the form of narrow bands of Yb 3+ or Nd 3+ ions could not be observed in the near infrared under excitation of the chromophore. This result can be explained by an insufficient capacity of the Bodipy chromophore to sensitize the lanthanides tested or an unbalanced ratio between the number of chromophoric groups and the number of Ln 3+ which could induce the masking of the characteristic signals of the Nd 3+ or Yb 3 + under a broad emission band from organic groups.
- the fully functionalized dendrimers and their complexes formed with Yb 3+ and Nd 3+ have a very similar photostability with a decrease of only 28-34% of the initial luminescence intensity after 3h of illumination.
- the partially functionalized dendrimer, the G3P- (Bodipy1) i 6 completely loses its emission signal ( Figure 5, right).
- the photostability of G3P- (Bodipy1) 16 could be improved by the incorporation of Ln 3+ .
- the intensity of Nd 8 -G3P- (Bodipy1) 16 is decreased by 40% after 3h of illumination while the emission signal of Yb 8 -G3P- (Bodipy1) 16 after a slight increase of the signal of emission returns to its initial intensity value after 200 min of treatment.
- compound 9 (FIG. 5) loses 75% of its luminescence intensity after 3 hours of illumination. Therefore, in general, the attachment of the chromophore moieties to the dendrimer structure and the presence of Ln 3+ can be used to advantage to ensure and improve the photostability of the probe. Cytotoxicity of aza-Bodipy-based molecules
- HeLa cells incubated with aza-BODIPY-COOH show a signal of lower intensity than that observed for Yb 8 -G3P- (aza-BODIPY) 16 (FIG. 7, top: (A) vs. (D)), despite a quantum yield of aza-BODIPY-COOH 3.4 times higher than that of Yb 8 -G3P- (aza-BODIPY) 16 (Table 2).
- Flow cytometry has been used to quantify cell internalization of dendrimers and to better understand signal intensity differences observed in confocal microscopy.
- the mechanisms of passive (non-dependent energy) and active (energy dependent) internalisation of cells have been studied. Active transport was inhibited with sodium azide (NaN 3 ), while incubation at 4 ° C inhibited active and passive transport pathways by increasing the plasma membrane stiffness of HeLa cells (S. Vranic, N. Boggetto, V. Contremoulins, S. Mornet, N. Reinhardt, Marano F., A. Baeza-Squiban, S. Boland, Deciphering the mechanisms of cellular uptake of nanoparticles by accurate evaluation of internalization imaging flow cytometry, Particle and Fiber Toxicology, 10 (2013) 1-16).
- Endocytosis is the main active mechanism allowing entry into the cell (BD Grant, JG Donaldson, Pathways and Mechanisms of Endocytic Recycling, Nature Reviews Molecular Cell Biology, 1 (2009) 597-608, L. Kou, J. Sun, Y. Zhai, Z. He, The endocytosis and intracellular fate of nanomedicines: implications for rational design, Asian Journal of Pharmaceutical Sciences, 8 (201 3) 1-10, D. Vercauteren, RE Vandenbroucke, AT Jones, J Rejman, J. Demeester, SC De Smedt, NN Sanders, K.
- the excitation on the bands centered on the ligand results in an intense broadband emission centered at 725 nm. No narrow emission bands characteristic of Nd or Yb could be observed in the near infrared.
- Yb 8 -G3P- (TPP) 32 shows a typical porphyrin emission: two bands in the visible region: centered at 664 nm and 717 nm, Figure 14. A narrow band corresponding to transition 2 F 5/2 ⁇ 2 F 7/2 of the Yb 3+ in the near infrared has been observed, Figure 15. However, the signal seems to be superimposed on the residual emission of the tetraphenylporphyrin chromophore. This result can be explained by a low capacity of the chromophore to sensitize Yb 3+ or an unbalanced ratio between the number of chromophore groups and that of lanthanide cations.
- the excitation spectrum of Yb 8 -G3- (TPP) 32 shows bands comparable to those observed on the absorption spectrum, thus indicating that the sensitization of Yb 3+ occurs by the transfer of energy from the tetraphenylporphyrin chromophore to the lanthanide cation, Figure 16.
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