CN107266929B - 一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其制备方法与应用 - Google Patents
一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其制备方法与应用 Download PDFInfo
- Publication number
- CN107266929B CN107266929B CN201710472496.6A CN201710472496A CN107266929B CN 107266929 B CN107266929 B CN 107266929B CN 201710472496 A CN201710472496 A CN 201710472496A CN 107266929 B CN107266929 B CN 107266929B
- Authority
- CN
- China
- Prior art keywords
- matrix material
- fluorescent dye
- near infrared
- infrared fluorescent
- switch function
- 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.)
- Active
Links
- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 34
- 239000000975 dye Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 239000002243 precursor Substances 0.000 title abstract description 13
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 title abstract 3
- 239000011159 matrix material Substances 0.000 claims abstract description 32
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 14
- 239000002502 liposome Substances 0.000 claims abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 12
- 238000001338 self-assembly Methods 0.000 claims abstract description 12
- 150000002433 hydrophilic molecules Chemical class 0.000 claims abstract description 7
- 238000003745 diagnosis Methods 0.000 claims abstract description 6
- 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 17
- 238000003384 imaging method Methods 0.000 claims description 14
- 230000035945 sensitivity Effects 0.000 claims description 11
- 239000000412 dendrimer Substances 0.000 claims description 8
- 229920000736 dendritic polymer Polymers 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- -1 Z NH Inorganic materials 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002923 oximes Chemical class 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- 230000003252 repetitive effect Effects 0.000 claims description 4
- 229910052711 selenium Inorganic materials 0.000 claims description 4
- 239000011669 selenium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000002262 Schiff base Substances 0.000 claims description 3
- 150000004753 Schiff bases Chemical class 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000009977 dual effect Effects 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims 1
- 239000002131 composite material Substances 0.000 claims 1
- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 230000010354 integration Effects 0.000 abstract description 3
- 238000006862 quantum yield reaction Methods 0.000 abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 abstract description 2
- 238000010791 quenching Methods 0.000 abstract description 2
- 230000000171 quenching effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
- 150000001875 compounds Chemical class 0.000 description 40
- 239000000243 solution Substances 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 230000007613 environmental effect Effects 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 238000001890 transfection Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000011580 nude mouse model Methods 0.000 description 5
- 238000001959 radiotherapy Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000013603 viral vector Substances 0.000 description 5
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 239000013598 vector Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 208000019065 cervical carcinoma Diseases 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000005311 nuclear magnetism Effects 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- YUFRRMZSSPQMOS-UHFFFAOYSA-N 2-(2-aminoethyldisulfanyl)ethanamine;hydron;dichloride Chemical compound Cl.Cl.NCCSSCCN YUFRRMZSSPQMOS-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000001815 biotherapy Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 238000012637 gene transfection Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 2
- 229960004657 indocyanine green Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- RWFHJEVTRVSDNX-UHFFFAOYSA-N phenol;propanoic acid Chemical compound CCC(O)=O.OC1=CC=CC=C1 RWFHJEVTRVSDNX-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical class [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- CVFXPOKENLGCID-KRWDZBQOSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC1=C(S(=O)(=O)NC(N)=NCCC[C@H](NC(=O)OC(C)(C)C)C(O)=O)C(C)=C2CC(C)(C)OC2=C1C CVFXPOKENLGCID-KRWDZBQOSA-N 0.000 description 1
- FLHJIAFUWHPJRT-UHFFFAOYSA-N 2,3,3-trimethylindole Chemical compound C1=CC=C2C(C)(C)C(C)=NC2=C1 FLHJIAFUWHPJRT-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
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- NPBGTPKLVJEOBE-IUCAKERBSA-N Lys-Arg Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=N NPBGTPKLVJEOBE-IUCAKERBSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 206010058046 Post procedural complication Diseases 0.000 description 1
- 208000035965 Postoperative Complications Diseases 0.000 description 1
- 208000007660 Residual Neoplasm Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 239000011246 composite particle Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 239000002122 magnetic nanoparticle Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- FORVAIDSGSLRPX-RGMNGODLSA-N methyl (2s)-2,6-diaminohexanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CCCCN FORVAIDSGSLRPX-RGMNGODLSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000003017 phosphorus Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005316 response function Methods 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/10—The polymethine chain containing an even number of >CH- groups
- C09B23/107—The polymethine chain containing an even number of >CH- groups four >CH- groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- 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
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
- A61K49/0082—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion micelle, e.g. phospholipidic micelle and polymeric micelle
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
- A61K49/0084—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion liposome, i.e. bilayered vesicular structure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
- A61K49/0084—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion liposome, i.e. bilayered vesicular structure
- A61K49/0086—Polymersome, i.e. liposome with polymerisable or polymerized bilayered-forming substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Materials Engineering (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明公开了一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其制备方法与应用,属于生物医用材料领域。所述近红外荧光染料通过在长甲川链中插入环烃基团,使其光稳定性更好,荧光量子产率高。所述近红外荧光染料可作为疏水端与生物相容性好的亲水分子通过环境敏感键相结合并自组装形成纳米尺寸的脂质体或胶束或囊泡。所得脂质材料可与药物和\或基因混合后自组装形成脂质体或胶束或囊泡,药物和\或基因被包裹在内部形成载体系统。呈荧光淬灭状态的载体系统进入靶点细胞,处于特定环境中时,材料上的环境敏感键断裂,发生解组装,释放出药物和\或基因,发挥治疗作用,同时聚集在内部的菁染料也被释放出来,使得荧光恢复,从而实现荧光开关功能,进而实现诊疗一体化。
Description
技术领域
本发明属于生物医用材料领域,涉及一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其制备方法与应用。
技术背景
随着成像技术的发展,近红外荧光成像由于其对生物体损伤小,组织穿透能力强,生物背景干扰低等优点已广泛应用于生物成像领域。作为近红外荧光探测的有机染料主要包括菁染料类(如Cy系列)、BODIPY类、罗丹明类、方酸类和卟啉类等。菁染料具有光谱范围广、摩尔吸光系数高、荧光量子产率高、灵敏度高以及细胞毒性低等特点,其中吲哚菁绿(ICG)作为FDA唯一批准的近红外荧光染料已广泛应用于临床诊断。但是菁染料存在光稳定性较差的缺陷。
近年来,恶性肿瘤严重威胁着人类的健康。目前,常用的治疗手段主要包括手术切除、放射治疗、化学药物治疗和生物治疗。手术切除的方法适用于肿瘤早期,效果明显,但对患者损伤较大,易产生手术并发症,而且对于重要的组织或器官,即使被肿瘤侵及也不能切除。放射治疗是一种重要的辅助性治疗手段,术前放疗可缩小肿瘤,有利于切除,术后放疗可抑制残存肿瘤细胞的生长。但放疗只能用于局部治疗而且会对周围正常组织造成不可逆的损伤。化学药物治疗能有效杀死肿瘤细胞,是一种全身性治疗手段。但是化疗药物存在选择性低,体内半衰期短,溶解性差等问题。生物治疗尤其是基因治疗作为一种新兴的治疗手段倍受关注。基因治疗是将外源基因引入病变细胞,通过外源基因的表达,抑制或沉默致病基因的表达,从根本上控制肿瘤细胞的增值或转移,通过纠正或补偿的方式,使病变细胞恢复正常细胞的功能。常用的基因载体主要包括病毒类载体和非病毒类载体。病毒类载体转染效率高,但同时也具有较高的免疫原性和致癌性并且易引发炎症。考虑到安全性,病毒类载体在临床应用中受到很大限制。非病毒类载体,如聚合物胶束、脂质体以及树枝状大分子等,存在转染效率相比病毒类载体低的缺陷。另一方面,目前能够很好的实现诊疗一体化的载体尚不多见。
发明内容
本发明的目的是针对现有技术的不足,在已有工作的基础上,提供一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其制备方法与应用。
本发明通过以下技术方案来实现:
一类以菁染料荧光基团为母体骨架结构的近红外荧光染料,其结构通式如下:
(I)
其中,X为C(CH3)2、O、S或Se,Y为F、Cl、Br或I,Z为NH、O或S,R0为H、Na或K,R1为氢、卤素、甲基、芳香基、硝基、磺酸基、醛基、羧基或苄基,R2为甲基、羧基、磺酸基或苄基,m和n均为0-18。
作为可选方式,在上述近红外荧光染料中,所述X为C(CH3)2,所述Y为Br,所述Z为O,所述R0为Na,所述R1为H,所述m=0,所述R2为甲基,所述n=2。
本发明还提供了一种上述以菁染料荧光基团为母体骨架结构的近红外荧光染料的制备方法,包括以下步骤:
(1)以甲苯为溶剂,130℃下回流,制备化合物II
(II)
(2)以二氯甲烷为溶剂,60℃下回流,制备化合物III
(III)
(3)以醋酸酐为溶剂,65℃下回流,避光,制备化合物IV
(IV)
(4)室温下,制备化合物V
(V)
(5)以DMSO作溶剂,65℃下回流,避光,制备化合物I
作为可选方式,在上述制备方法中,反应在保护气氛下进行。进一步的,保护气体为氮气、氩气或氦气。
作为可选方式,在上述制备方法中,后处理方法为反应结束后,旋蒸除去溶剂,用二氯甲烷重新溶解,分别用饱和碳酸氢钠洗,饱和磷酸二氢钠或饱和稀盐酸洗,饱和食盐水洗,用无水硫酸镁或无水硫酸钠干燥,用硅胶柱提纯,用二氯甲烷和甲醇的混合溶液进行梯度洗脱,得到目标产物。
本发明还提供了上述以菁染料荧光基团为母体骨架结构的近红外荧光染料的一种应用,其特征在于,将其用于制作体内外生物成像试剂。进一步的,所述体内外生物成像为干细胞成像、组织成像以及活体成像等。
本发明还提供了上述以菁染料荧光基团为母体骨架结构的近红外荧光染料的另一种应用,其特征在于,将其用于制备药物和\或基因的载体。进一步的,所述应用具体为以所述的近红外荧光染料作为疏水端与生物相容性好的亲水分子通过环境敏感键相结合并自组装形成纳米尺寸的脂质体或胶束或囊泡。
本发明还提供了一种脂质材料,其是以上述的近红外荧光染料作为疏水端与生物相容性好的亲水分子通过环境敏感键相结合并自组装形成纳米尺寸的脂质体或胶束或囊泡。所述脂质材料作为药物和\或基因的载体。所述脂质材料可具有荧光开关功能,还可具有治疗和成像双重功能,可实现诊疗一体化。所述脂质材料与传统的脂质体或胶束或囊泡包载染料的方式相比,染料担载量更大,从而使得荧光强度更高,而且在亲水外壳的保护下,进一步降低了光漂白的风险。
作为可选方式,在上述脂质材料中,所述亲水端与疏水端通过含有还原敏感的二硫键或二硒键的分子连接,或含有pH敏感的酰腙键或肟键或希夫碱键等分子连接,或含有酶敏感的酯键分子或短肽连接。
作为可选方式,所述脂质材料可与基因复合并自组装形成脂质体或胶束或囊泡,使荧光发生淬灭,在特定环境中释放出基因后荧光恢复,从而实现荧光开关功能。
作为可选方式,所述脂质材料的结构通式如下:
其中,K为树状分子的重复单元,G1和Gn分别表示一代和n代树状分子,n为2或3或4或5,X为具有微环境敏感响应功能的连接分子,X为二硫键或二硒键或酰腙键或肟键或希夫碱键或酶敏感的酯键或短肽,R1为本发明所述的以菁染料荧光基团为母体骨架结构的近红外荧光染料,R2为亲水性基团。
作为可选方式,在上述脂质材料中,所述亲水端为二代以上的胺类树状分子,其重复单元为氨基酸(如赖氨酸、精氨酸)。
本发明还提供了一种载体系统,其特征在于,包括上述的脂质材料以及复合在其中的药物和\或基因。在特定环境中材料上的微环境敏感键断裂,发生解组装释放出药物和\或基因从而达到治疗目的。作为可选,所述药物和\或基因在自组装过程中被包裹在所述脂质体或胶束或囊泡中。
本说明书中公开的所有特征,或公开的所有方法或过程中的步骤,除了互相排斥的特征和/或步骤以外,均可以以任何方式组合。
本发明的有益效果:
1、本发明所述一类以菁染料荧光基团为母体骨架结构的近红外荧光染料,通过在其长甲川链中插入环烃基团,使其光稳定性大大提高。
2、本发明所述的近红外荧光染料荧光量子产率高,可用于干细胞成像、组织成像以及活体成像等体内外生物成像。
3、本发明所述的近红外荧光染料可作为疏水端与生物相容性好的亲水分子通过环境敏感键相结合并自组装形成纳米尺寸的脂质体或胶束或囊泡,与传统的脂质体或胶束或囊泡包载染料的方式相比,染料担载量更大,从而使得荧光强度更高,而且在亲水外壳的保护下,进一步降低了光漂白的风险。
4、本发明所述脂质材料可与基因复合并自组装形成脂质体或胶束或囊泡,使荧光发生淬灭,在特定环境中释放出基因后荧光恢复,从而实现荧光开关功能。近红外荧光染料作为疏水端位于载体系统内部,导致染料局部浓度升高,同时由于菁染料分子间强的范德瓦尔斯力使其产生自聚集,结果使光谱带发生迁移,呈荧光淬灭状态。而当载体系统进入靶点细胞,处于特定环境中时,材料上的微环境敏感键断裂,发生解组装,释放出药物和\或基因,发挥治疗作用,同时聚集在内部的菁染料也被释放出来,使得荧光恢复,从而实现荧光开关功能,进而实现诊疗一体化。
5、本发明所述脂质材料可作为药物和\或基因的载体,在特定环境中,材料上的微环境敏感键断裂,发生解组装释放出药物和\或基因从而达到治疗目的,实现诊疗一体化。
6、本发明所述一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其脂质材料制备方法简单,原料易得,细胞毒性低,基因转染效率高。
附图说明:
图1为本发明实施例1中所制备的化合物5的紫外吸收光谱图。
图2 为本发明实施例4中所制备的化合物9的MS质谱图。
图3为本发明实施例4中所制备的化合物9的1H NMR 400M核磁图。
图4为本发明实施例3中所制备的化合物8的MS质谱图。
图5为本发明实施例3中所制备的化合物8的1H NMR 400M核磁图。
图6为本发明实施例4中所制备的化合物11的MS质谱图。
图7为本发明实施例4中所制备的化合物11的1H NMR 400M核磁图。
图8为本发明实施例4中所制备的化合物12的电泳图。
图9为本发明实施例4中所制备的化合物12的DLS图。
图10为本发明实施例4中所制备的化合物12荷载pEGFP质粒对Hela细胞的转染效果图。
图11为本发明实施例4中所制备的化合物12的体内荧光成像图。
具体实施方式:
以下通过实施例的具体实施方式再对本发明所述内容作进一步详细说明。下面实例选用本发明的优选实施方式,本领域技术人员很容易将其推广到其他材料。此处所描述的具体实例仅用于解释本发明,并不用于限定本发明的内容。在不脱离本发明的精神和原则之内做的任何修改,以及根据本领域普通技术知识和惯用手段做出的等同替换或者改进,均应包括在本发明的保护范围内。
实施例1
以菁染料荧光基团为母体骨架结构的近红外荧光染料的制备
(1)化合物1合成路线如下:
具体步骤:在100 mL封管中,将2,3,3-三甲基吲哚10 g (63 mmol, 1 eq)溶于30mL甲苯,再加入7.72 g (63 mmol, 1 eq)1-溴丙烷。130℃下反应72 h,冷却后,静置一段时间,倒掉上层溶液。下层红色固体用乙醚洗两次,旋干,称重得15 g化合物1,产率84.7 %,密封后于-20℃冰箱保存。
(2)化合物2合成路线如下:
具体步骤:在250 mL圆底烧瓶中,将40 mL DMF与20 mL二氯甲烷混合,冰水浴下,再将20 mL二氯甲烷与37 mL三氯氧磷的混合液滴加入上述溶液中。然后滴加入10 g(0.10mol, 1 eq)环己酮,加热至60℃回流反应3 h。待反应液冷却至室温后,缓慢倒入200 mL冰水中,分层后收集水相。加入100 mL冷冻的饱和NaCl溶液,析出沉淀,抽滤得到14.6黄色固体即为化合物2,产率84.8 %。
(3)化合物3合成路线如下:
具体步骤:在100 mL圆底烧瓶中,将2.45 g (8.72 mmol, 3 eq)化合物1,0.50 g(2.91 mmol, 1 eq)化合物2以及0.48 g (5.82 mmol, 2 eq)无水乙酸钠分散于20 mL醋酸酐中。加热至65℃,N2保护下避光反应5 h。减压浓缩醋酸酐后,加乙醚沉淀,抽滤后,得1.75g绿色固体即为化合物3,产率97.2 %。
(4)化合物4合成路线如下:
具体步骤:在100 mL圆底烧瓶中,将对羟基苯丙酸10 g(60.24 mmol, 1 eq)溶于20 mL水,将4.8g(0.12 mol, 2 eq)氢氧化钠溶于20 mL水后滴加入对羟基苯丙酸溶液中。室温下反应6 h后,将反应液分别用乙酸乙酯和二氯甲烷洗一次,收集水相,减压浓缩后得12 g黄色固体即为化合物4,产率94.8 %。
(5)化合物5合成路线如下:
具体步骤:在100 mL圆底烧瓶中,将1 g (1.60 mmol, 1 eq)化合物3和0.67 g(3.20 mmol, 2 eq)化合物4溶于20 mL二甲基压砜(DMSO),65℃下,N2保护避光反应6 h。待反应液冷却至室温后,加入大量甲基叔丁基醚,搅拌数分钟后,倒掉上层溶液。用甲基叔丁基醚重复洗三次,抽干,得到1.13 g绿色固体即为化合物5,产率92.2 %。
实施例2
含有还原敏感键的连接分子的制备
化合物6合成路线如下:
具体步骤:在1 L的圆底烧瓶中,将胱胺二盐酸盐8 g (35 mmol, 1 eq)溶于300mL甲醇,再加入三乙胺7.07 g(70 mmol, 2 eq)。然后将二碳酸二叔丁酯6.7 g (31 mmol,0.88 eq)溶于200 mL甲醇,搅拌下,冰水浴中,用滴液漏斗将二碳酸二叔丁酯的甲醇溶液缓慢滴加入胱胺二盐酸盐的甲醇溶液中。30℃反应过夜,然后用旋转蒸发仪旋掉甲醇,加100mL二氯甲烷重新溶解。用50 mL饱和NaCl溶液洗两次,用无水硫酸钠干燥,抽滤后,旋干。称重得到7.2 g粗产品,粗产率为92.3 %。用硅胶柱提纯,以二氯甲烷/甲醇体系作为洗脱液,分离得到3.6 g化合物6纯产品。
实施例3
二代赖氨酸-精氨酸树状分子的制备
(1)化合物7合成路线如下:
具体步骤:将Boc-Arg(Pbf)-OH 11.3 g (21.45mmol, 2.5 eq)和苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU) 9.76 g (25.74mmol, 3eq)分别溶于20 mL N,N-二甲基甲酰胺(DMF)中,在250 mL圆底烧瓶中混合后,加入N,N-二异丙基乙胺(DIEA) 3.33 g(25.74mmol, 3eq)反应一段时间。将L-赖氨酸甲酯盐酸盐2 g (8.58mmol, 1eq)溶于20 mLDMF中,搅拌下滴加入上述反应液中。30℃,N2保护下反应48 h。反应结束后用旋转蒸发仪旋掉DMF,加200 mL二氯甲烷重新溶解。分别用100 mL饱和碳酸氢钠(NaHCO3),100 mL饱和磷酸二氢钠(NaH2PO4)和100 mL饱和氯化钠溶液(NaCl)各洗两遍。收集有机相,用无水硫酸镁干燥,抽滤后,旋干。通过重结晶的方法提纯,将粗产品溶于少量DCM后,加入大量石油醚中,析出白色晶体,抽滤后得到纯产品7.12 g即为化合物7,产率71.2 %。
(2)化合物8合成路线如下:
具体步骤:将5.2 g (4.42 mmol)化合物7溶于10 mL甲醇中,然后取0.6 g氢氧化钠溶于5 mL水中。搅拌下,将氢氧化钠水溶液滴加入化合物7的甲醇溶液中,使氢氧化钠的终浓度为1 M。30℃下反应过夜,用旋转蒸发仪旋掉甲醇后,加入20 mL水溶解。搅拌下,用1M的盐酸调pH至2-3,析出大量白色沉淀,加入200 mL乙酸乙酯溶解。收集有机相,分别用100mL饱和NaHCO3,100 mL饱和NaH2PO4和100 mL饱和NaCl溶液各洗两遍。然后用无水硫酸镁干燥,抽滤后旋干。称重得到5.06 g化合物8,产率98.4 %。
实施例4
以所述近红外荧光染料为疏水端的环境响应型脂质材料的制备
(1)化合物9合成路线如下:
具体步骤:将100 mg (0.14 mmol, 1 eq)化合物5溶于10 mL二氯甲烷,将69.36mg (0.22 mmol, 1.5 eq) O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)溶于10mL DMF,将上述两种溶液置于100 mL圆底烧瓶中,再加入27.92 mg (0.22 mmol, 1.5 eq)DIEA搅拌一段时间。取27.47 mg (0.14 mmol, 1 eq)化合物6溶液10 mL二氯甲烷后,滴加入上述反应液中。30℃,N2保护下避光反应过夜。减压旋掉有机相,再加50 mL二氯甲烷重新溶解,分别用20 mL饱和NaH2PO4和饱和NaCl溶液洗一次。无水硫酸镁干燥,抽滤后旋干,得到114 mg绿色固体即为化合物9,产率82.4 %。用硅胶柱提纯,以二氯甲烷\甲醇体系作为洗脱液。
(2)化合物10合成路线如下:
具体步骤:在50 mL圆底烧瓶中,取70 mg (0.07 mmol)化合物9溶液2 mL二氯甲烷,再加入2 mL三氟乙酸,室温下避光反应4 h。减压旋掉有机相,再加50 mL二氯甲烷重新溶解,分别用20 mL饱和NaHCO3和饱和NaCl溶液洗一次,无水硫酸钠干燥,抽滤后旋干,得50mg绿色固体即化合物10,产率80.9 %。
(3)化合物11合成路线如下:
具体步骤:将48.2 mg (0.04 mmol, 1 eq)化合物8溶于10 mL二氯甲烷,将25.7mg (0.08 mmol, 2 eq) TBTU溶液5 mL DMF,将上述两种溶液置于100 mL圆底烧瓶中,再加入16.07 mg (0.12 mmol, 3 eq) DIEA反应一段时间。取50 mg (0.06 mmol, 1.5 eq)化合物10溶于10 mL二氯甲烷,滴加入上述溶液中。30℃,N2保护下避光反应48 h。减压旋掉有机相,再加50 mL二氯甲烷重新溶解,分别用20 mL饱和NaHCO3,20 mL饱和NaH2PO4和20 mL饱和NaCl溶液洗一次。用无水硫酸镁干燥,抽滤后旋干,得到66 mg绿色固体即为化合物11,产率82.2 %。
(4)化合物12合成路线如下:
具体步骤:在50 mL圆底烧瓶中,取60 mg (0.029 mmol)化合物11溶于2 mL二氯甲烷,再加入2 mL三氟乙酸,室温下避光反应4 h。减压旋掉有机相,加20 mL乙醚沉淀,3000rpm离心3 min收集沉淀,得到35 mg绿色固体,即为化合物12,产率89.4 %。本实施例中制得的环境响应型脂质材料与传统的脂质体或胶束或囊泡包载染料的方式相比,染料担载量更大,从而使得荧光强度更高,而且在亲水外壳的保护下,进一步降低了光漂白的风险。本发明是所述纸质材料与传统包载方式的染料担载量对比见表1。
实施例5
取1 mg化合物5溶于10 mL甲醇,稀释10倍后测紫外吸收(UV-1800, Shimadzu,Japan),得最大紫外吸收波长为766 nm。
实施例6
基因载体的制备
方案一
(1)将质粒DNA或RNA溶于无菌的HBG缓冲溶液(4-羟乙基哌嗪乙磺酸 20 毫摩尔,5% 葡萄糖)中,配制成0.1 mg/mL的基因溶液(记为溶液A);将实施例4中制备的以所述近红外荧光染料为疏水端的环境响应型脂质材料(优选如化合物12所示的脂质材料)用乙醇注入法加入HBG缓冲溶液中,配制成0.1~10 mg/mL的自组装体溶液,溶液B;
(2)将上述步骤中得到的溶液B与基因溶液混合,在室温下孵育20分钟后,得到二元复合物,其中基因通过静电吸附作用结合在自组装体外围。所述自组装体作为压缩基因的阳离子载体,进一步的,在上述二元复合物外围还可通过电荷吸附作用引入遮蔽体系,形成三元复合物。
方案二
将质粒DNA溶于无菌的HBG缓冲溶液中,配制成0.1 mg/mL的DNA溶液(溶液A);将实施例4中制备的以所述近红外荧光染料为疏水端的环境响应型脂质材料用乙醇注入法或者薄膜超声法加入溶液A中,自组装得到高效装配基因的载体系统。
作为可选,在上述两种方案中,所述脂质材料与基因的质量比例为0.1:1~50:1。
作为可选,还可在上述步骤(2)中加入药物或磁性纳米粒子制得三元或四元化合物。
实施例7
体外基因转染实验
(1)取实施例4中制备的以所述近红外荧光染料为疏水端的环境响应型脂质材料按照实施例6中所述方法制成基因载体系统。
制备得到转pEGFP质粒的基因载体系统,并取聚乙烯亚胺压缩的pEGFP质粒作为对比。
(2)Hela细胞的培养:取人宫颈癌细胞Hela细胞,在含有10 %(质量/体积百分数)的胎牛血清的DMEM培养基中,在含5 %(体积分数)CO2,温度为37℃的培养箱中培养24 h。
转染前24 h内,取对数生长期的Hela细胞,胰酶消化后用DMEM稀释,按每孔4×105细胞的密度接种于6孔培养板,置于含5 %(体积百分数)的CO2,温度为37℃的孵箱中继续培养至 80-90 %融合,转染时,吸弃前一天加注的细胞培养板中的培养液,用PBS洗涤两次后,将荷载pEGFP质粒的复合物颗粒用无血清或者含有10 %(质量/体积百分数)的小牛血清的DMEM培养基(pH用1 M HCl调至6.8)至终体积2 mL,继续培养48 h。
(3)体外转染效率的测定:取出培养板,用倒置荧光显微镜照相,结果如图10所示,图中亮点为转染成功的带绿色荧光的细胞。
有益结果:本发明所述含有近红外荧光染料结构的环境响应型脂质材料制成的基因载体系统,具有优异的转染效率,其转染效率超过商品化PEI25k,在有血清条件下转染优势更为突出。
实施例8
体内成像实验
建立肿瘤模型:雄性近交系裸小鼠,4~5周龄,体重15 g~17 g,在无特定病原体SPF级动物合格环境下饲养,自由摄取水分和食物,各实验均在无菌超净工作台中进行,无菌条件下,取对数生长期人宫颈癌细胞Hela细胞,制备细胞悬液,浓度为2×106个/mL,裸鼠右腋下接种0.1 mL/只,建立人宫颈癌细胞Hela细胞裸鼠移植瘤模型 。
待裸鼠皮下包块长至约100 mm3时,通过尾静脉注射的方式将50 μg以所述近红外荧光染料为疏水端的环境响应型脂质材料制成的基因载体系统注射入裸鼠体内(对照组注射PEI25k/DNA和Lip2000/DNA)。
静脉注射8小时后,于小鼠腹腔注射100 μL, 5 %水合氯醛进行麻醉,利用小动物成像系统中进行图像采集。采用卤素灯进行荧光照片采集,激发光滤光片波长为730 nm,发射光滤光片波长为760 nm。活体图像采集完毕后,小鼠立即被断颈处死,摘除肿瘤和主要脏器(心、肝、脾、肺、肾),进行各组织的图像采集。
有益结果:本发明所述一类以所述近红外荧光染料为疏水端的环境响应型脂质材料制成的基因载体系统在小鼠体内转染8 h后,在肿瘤部位发现了明显的高于对照组的近红外荧光信号,离体组织的结果相似。
以上所述仅为本发明的优选实施例,对本发明而言仅是说明性的并不用于限制本发明。对于本领域普通技术人员来说,在本发明权利要求所限定的精神和范围内还可对其进行许多改进和变型,甚至等效变更,但都应视为本发明的保护范围。
Claims (9)
1.一种具有荧光开关功能的脂质材料,其特征在于,包括一类以菁染料荧光基团为母体骨架结构的近红外荧光染料和具有良好生物相容性的亲水分子,所述近红外荧光染料作为疏水端与所述亲水分子通过环境敏感键相连接即通过含有还原敏感的二硫键或二硒键的分子连接,或含有pH敏感的酰腙键或肟键或希夫碱键连接,或含有酶敏感的酯键分子或短肽连接,并自组装形成纳米尺寸的脂质体或胶束或囊泡;
所述近红外荧光染料的结构通式如下:
其中,X为C(CH3)2、O、S或Se,Y为F、Cl、Br或I,Z为NH、O或S,R0为H、Na或K,R1为氢、卤素、甲基、芳香基、硝基、磺酸基、醛基、羧基或苄基,R2为甲基、羧基、磺酸基或苄基,m和n均为0-18。
2.根据权利要求1所述具有荧光开关功能的脂质材料,所述疏水端与亲水分子通过具有以下结构的分子连接:
3.根据权利要求1所述具有荧光开关功能的脂质材料,其特征在于:所述近红外荧光染料的结构通式中X为C(CH3)2,所述Y为Br,所述Z为O,所述R0为Na,所述R1为H,所述m=0,所述R2为甲基,所述n=2。
4.根据权利要求1所述具有荧光开关功能的脂质材料,其特征在于,所述脂质材料的结构通式如下:
其中,K为树状分子的重复单元,G1和Gn分别表示一代和n代树状分子,n为2或3或4或5,X为二硫键或二硒键或酰腙键或肟键或希夫碱键或酶敏感的酯键或短肽,R1为权利要求1所述的近红外荧光染料,R2为亲水性基团。
5.根据权利要求1所述具有荧光开关功能的脂质材料,其特征在于,所述亲水端为二代以上的胺类树状分子,其重复单元为氨基酸。
6.根据权利要求5所述具有荧光开关功能的脂质材料,其特征在于,所述亲水端为二代以上的胺类树状分子,其重复单元为赖氨酸、精氨酸。
7.根据权利要求1所述具有荧光开关功能的脂质材料,其特征在于,所述脂质材料的结构式如下:
8.一种如权利要求1所述的具有荧光开关功能的脂质材料的应用,其特征在于,将其用于制作具有治疗和成像双重功能的诊疗一体化的药物和\或基因复合物。
9.一种载体系统,其特征在于,包括权利要求1所述的具有荧光开关功能的脂质材料以及复合在其中的药物和\或基因。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710472496.6A CN107266929B (zh) | 2017-06-21 | 2017-06-21 | 一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710472496.6A CN107266929B (zh) | 2017-06-21 | 2017-06-21 | 一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其制备方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107266929A CN107266929A (zh) | 2017-10-20 |
CN107266929B true CN107266929B (zh) | 2019-10-29 |
Family
ID=60067910
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710472496.6A Active CN107266929B (zh) | 2017-06-21 | 2017-06-21 | 一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107266929B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110305111B (zh) * | 2019-08-07 | 2021-06-15 | 四川大学华西医院 | 一种亚铜离子近红外探针及其制备方法和应用 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2289563A1 (en) * | 2009-08-28 | 2011-03-02 | Fujifilm Corporation | Near infrared fluorescent imaging agent |
WO2015064786A1 (ko) * | 2013-10-31 | 2015-05-07 | 주식회사 디케이씨코포레이션 | 생체 분자 표지를 위한 시아닌 염료 및 그 제조방법 |
KR20150049824A (ko) * | 2013-10-31 | 2015-05-08 | 주식회사 디케이씨코포레이션 | 생체 분자 표지를 위한 시아닌 염료 및 그 제조방법 |
CN104910252A (zh) * | 2015-06-16 | 2015-09-16 | 四川大学 | 一种基于树状分子的pH响应型脂质及其制备方法与应用 |
EP2944326A1 (en) * | 2014-05-16 | 2015-11-18 | Cyanagen Srl | Novel tricarbocyanine-cyclodextrin(s) conjugates and use thereof |
WO2016189007A1 (fr) * | 2015-05-25 | 2016-12-01 | Fluoptics | Traceur fluorescent ciblant multivalent optimise |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG10201706428XA (en) * | 2009-02-06 | 2017-09-28 | Beth Israel Deaconess Medical Ct Inc | Charge-balanced imaging agents |
US9808538B2 (en) * | 2015-09-09 | 2017-11-07 | On Target Laboratories, LLC | PSMA-targeted NIR dyes and their uses |
-
2017
- 2017-06-21 CN CN201710472496.6A patent/CN107266929B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2289563A1 (en) * | 2009-08-28 | 2011-03-02 | Fujifilm Corporation | Near infrared fluorescent imaging agent |
WO2015064786A1 (ko) * | 2013-10-31 | 2015-05-07 | 주식회사 디케이씨코포레이션 | 생체 분자 표지를 위한 시아닌 염료 및 그 제조방법 |
KR20150049824A (ko) * | 2013-10-31 | 2015-05-08 | 주식회사 디케이씨코포레이션 | 생체 분자 표지를 위한 시아닌 염료 및 그 제조방법 |
EP2944326A1 (en) * | 2014-05-16 | 2015-11-18 | Cyanagen Srl | Novel tricarbocyanine-cyclodextrin(s) conjugates and use thereof |
WO2016189007A1 (fr) * | 2015-05-25 | 2016-12-01 | Fluoptics | Traceur fluorescent ciblant multivalent optimise |
CN104910252A (zh) * | 2015-06-16 | 2015-09-16 | 四川大学 | 一种基于树状分子的pH响应型脂质及其制备方法与应用 |
Non-Patent Citations (1)
Title |
---|
《近红外荧光脂质体的设计合成及其应用》;李元;《中国优秀硕士学位论文全文数据库 工程科技I辑》;20160831(第8期);14-18、20 * |
Also Published As
Publication number | Publication date |
---|---|
CN107266929A (zh) | 2017-10-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Liu et al. | Recent advances of AIE light-up probes for photodynamic therapy | |
CN101440282B (zh) | 近红外荧光分子探针及其合成方法和用途 | |
CN109096170B (zh) | 近红外染料、其靶向成像剂、纳米载体和抗癌药物及应用 | |
CN102406949B (zh) | 一种靶向示踪的多模式诊断纳米影像药物 | |
CN109336909B (zh) | 具有聚集诱导发光性质的近红外二区荧光化合物及制备方法、纳米粒胶束及其应用 | |
CN103402547B (zh) | 开关型荧光纳米颗粒探针以及使用其的荧光分子成像法 | |
CN109010826B (zh) | 一种基于吲哚方酸菁染料的靶向材料及其制备方法和荧光纳米粒子及其制备方法 | |
CN106432203B (zh) | 基于四苯乙烯基的Gemini型两亲性化合物及其制备方法和用途 | |
Wu et al. | Nanobody modified high-performance AIE photosensitizer nanoparticles for precise photodynamic oral cancer therapy of patient-derived tumor xenograft | |
CN115006553B (zh) | 用于制备肿瘤诊断显像剂的多肽及其应用 | |
CN111004307B (zh) | 一种治疗早期脑胶质瘤的吲哚菁绿类化合物及其制备方法和应用 | |
CN104910252B (zh) | 一种基于树状分子的pH响应型脂质及其制备方法与应用 | |
WO2023001317A1 (zh) | 基于切伦科夫效应的酸响应纳米胶束及其制备方法和应用 | |
CN104800855A (zh) | 用于光学成像和光动力治疗的肿瘤靶向融合蛋白药物载体 | |
CN107266929B (zh) | 一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其制备方法与应用 | |
Xia et al. | PM1-loaded recombinant human H-ferritin nanocages: A novel pH-responsive sensing platform for the identification of cancer cells | |
CN105111773A (zh) | 一类氨基菁类荧光染料及其制备方法和应用 | |
CN115006527B (zh) | 一种线粒体靶向光敏剂及其制备方法和应用 | |
JP2011173859A (ja) | 新規インドシアニン化合物を用いた診断用組成物及び分析方法 | |
CN111135298B (zh) | 一种双亲性氟硼二吡咯类化合物及其制备方法和用途 | |
CN111420053B (zh) | 一种可胞内聚集的多功能磁性纳米粒复合物及其制备方法 | |
CN104069492B (zh) | 靶向表达尿激酶受体的肿瘤的光敏剂及其制备方法和用途 | |
CN109602920B (zh) | 一类树枝状分子影像探针及其制备方法 | |
CN113952467A (zh) | 一种子宫内膜异位症分子诊疗制剂及其制备方法和应用 | |
CN107586321B (zh) | F-18标记修饰Dimer-San A探针的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |