CN113880917A - 几种肿瘤高亲和肽及其应用 - Google Patents
几种肿瘤高亲和肽及其应用 Download PDFInfo
- Publication number
- CN113880917A CN113880917A CN202111233746.3A CN202111233746A CN113880917A CN 113880917 A CN113880917 A CN 113880917A CN 202111233746 A CN202111233746 A CN 202111233746A CN 113880917 A CN113880917 A CN 113880917A
- Authority
- CN
- China
- Prior art keywords
- tumor
- radionuclide
- yqp
- tyr
- targeting peptide
- 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.)
- Granted
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 115
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 95
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 58
- 229920001184 polypeptide Polymers 0.000 claims abstract description 51
- 230000008685 targeting Effects 0.000 claims abstract description 40
- 238000003384 imaging method Methods 0.000 claims abstract description 33
- 239000007850 fluorescent dye Substances 0.000 claims abstract description 13
- 239000000539 dimer Substances 0.000 claims abstract description 7
- 239000000523 sample Substances 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 42
- 238000002360 preparation method Methods 0.000 claims description 16
- 238000003745 diagnosis Methods 0.000 claims description 12
- 239000003446 ligand Substances 0.000 claims description 7
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 6
- 230000001588 bifunctional effect Effects 0.000 claims description 6
- 239000002738 chelating agent Substances 0.000 claims description 6
- 239000012216 imaging agent Substances 0.000 claims description 6
- 125000005647 linker group Chemical group 0.000 claims description 6
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims description 4
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000002372 labelling Methods 0.000 claims description 3
- VYFPSYVVFFFYBF-UHFFFAOYSA-N sodium;triphenylphosphane Chemical compound [Na].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VYFPSYVVFFFYBF-UHFFFAOYSA-N 0.000 claims description 3
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 claims description 2
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 claims description 2
- 238000000149 argon plasma sintering Methods 0.000 claims description 2
- 229940044683 chemotherapy drug Drugs 0.000 claims description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims description 2
- 238000001415 gene therapy Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229960002591 hydroxyproline Drugs 0.000 claims description 2
- 230000004807 localization Effects 0.000 claims description 2
- ZLVYMPOQNJTFSG-QMMMGPOBSA-N monoiodotyrosine Chemical compound OC(=O)[C@@H](NI)CC1=CC=C(O)C=C1 ZLVYMPOQNJTFSG-QMMMGPOBSA-N 0.000 claims description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 2
- GBHSCKFAHCEEAZ-UHFFFAOYSA-N 2-[hydroxymethyl(methyl)amino]acetic acid Chemical compound OCN(C)CC(O)=O GBHSCKFAHCEEAZ-UHFFFAOYSA-N 0.000 claims 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000000032 diagnostic agent Substances 0.000 claims 1
- 229940039227 diagnostic agent Drugs 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 229940126585 therapeutic drug Drugs 0.000 claims 1
- 206010006187 Breast cancer Diseases 0.000 abstract description 19
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 19
- 238000012634 optical imaging Methods 0.000 abstract description 11
- 206010009944 Colon cancer Diseases 0.000 abstract description 9
- 208000001333 Colorectal Neoplasms Diseases 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 201000011510 cancer Diseases 0.000 abstract description 5
- 201000007270 liver cancer Diseases 0.000 abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 238000009206 nuclear medicine Methods 0.000 abstract description 3
- 229920000642 polymer Polymers 0.000 abstract description 2
- 239000003068 molecular probe Substances 0.000 abstract 1
- 239000000178 monomer Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 30
- 241000699670 Mus sp. Species 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 14
- 239000011347 resin Substances 0.000 description 14
- 229920005989 resin Polymers 0.000 description 14
- 241000699660 Mus musculus Species 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000011580 nude mouse model Methods 0.000 description 12
- 230000003287 optical effect Effects 0.000 description 12
- 238000013170 computed tomography imaging Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 210000003462 vein Anatomy 0.000 description 10
- 102000000905 Cadherin Human genes 0.000 description 9
- 108050007957 Cadherin Proteins 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000009826 distribution Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 210000003734 kidney Anatomy 0.000 description 8
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 7
- 239000007997 Tricine buffer Substances 0.000 description 7
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 7
- 239000000975 dye Substances 0.000 description 7
- 239000007791 liquid phase Substances 0.000 description 7
- 239000002504 physiological saline solution Substances 0.000 description 7
- 238000002603 single-photon emission computed tomography Methods 0.000 description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- -1 tetrafluoroborate Chemical compound 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000008362 succinate buffer Substances 0.000 description 5
- KLBPUVPNPAJWHZ-UMSFTDKQSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KLBPUVPNPAJWHZ-UMSFTDKQSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000012317 TBTU Substances 0.000 description 4
- 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 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 230000009089 cytolysis Effects 0.000 description 4
- SILCDLWESNHZKB-UHFFFAOYSA-L disodium 4-hydroxy-4-oxobutanoate Chemical compound [Na+].[Na+].OC(=O)CCC([O-])=O.OC(=O)CCC([O-])=O SILCDLWESNHZKB-UHFFFAOYSA-L 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 230000002285 radioactive effect Effects 0.000 description 4
- 239000012217 radiopharmaceutical Substances 0.000 description 4
- 229940121896 radiopharmaceutical Drugs 0.000 description 4
- 230000002799 radiopharmaceutical effect Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- HBBSDZXXUIHKJE-UHFFFAOYSA-N 6-hydrazinylpyridine-3-carboxylic acid Chemical compound NNC1=CC=C(C(O)=O)C=N1 HBBSDZXXUIHKJE-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000013399 early diagnosis Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229940074404 sodium succinate Drugs 0.000 description 3
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 3
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 3
- JARBLLDDSTVWSM-IJAHGLKVSA-N (2s,3r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-trityloxybutanoic acid Chemical compound O([C@H](C)[C@H](NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(O)=O)C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 JARBLLDDSTVWSM-IJAHGLKVSA-N 0.000 description 2
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- FJQZXCPWAGYPSD-UHFFFAOYSA-N 1,3,4,6-tetrachloro-3a,6a-diphenylimidazo[4,5-d]imidazole-2,5-dione Chemical compound ClN1C(=O)N(Cl)C2(C=3C=CC=CC=3)N(Cl)C(=O)N(Cl)C12C1=CC=CC=C1 FJQZXCPWAGYPSD-UHFFFAOYSA-N 0.000 description 2
- FVIIUVNKCOEULE-UHFFFAOYSA-N 2,2,3-trimethyl-1,3-dihydroindole-5-sulfonic acid Chemical compound CC1C2=C(C=CC(=C2)S(=O)(=O)O)NC1(C)C FVIIUVNKCOEULE-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 239000000298 carbocyanine Substances 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- VATYWCRQDJIRAI-UHFFFAOYSA-N p-aminobenzaldehyde Chemical compound NC1=CC=C(C=O)C=C1 VATYWCRQDJIRAI-UHFFFAOYSA-N 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- GOUUPUICWUFXPM-XIKOKIGWSA-N (2s,4r)-1-(9h-fluoren-9-ylmethoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid Chemical compound C1[C@H](O)C[C@@H](C(O)=O)N1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 GOUUPUICWUFXPM-XIKOKIGWSA-N 0.000 description 1
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 1
- IOMZCWUHFGMSEJ-UHFFFAOYSA-N 4-(azaniumylamino)benzenesulfonate Chemical compound NNC1=CC=C(S(O)(=O)=O)C=C1 IOMZCWUHFGMSEJ-UHFFFAOYSA-N 0.000 description 1
- UAWMVMPAYRWUFX-UHFFFAOYSA-N 6-Chloronicotinic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1 UAWMVMPAYRWUFX-UHFFFAOYSA-N 0.000 description 1
- JDDWRLPTKIOUOF-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-[[4-[2-[bis(4-methylphenyl)methylamino]-2-oxoethoxy]phenyl]-(2,4-dimethoxyphenyl)methyl]carbamate Chemical compound COC1=CC(OC)=CC=C1C(C=1C=CC(OCC(=O)NC(C=2C=CC(C)=CC=2)C=2C=CC(C)=CC=2)=CC=1)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JDDWRLPTKIOUOF-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000016362 Catenins Human genes 0.000 description 1
- 108010067316 Catenins Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005859 cell recognition Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003748 differential diagnosis Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000008558 metabolic pathway by substance Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- 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
-
- 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
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- 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
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
-
- 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
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
- A61K51/048—DTPA (diethylenetriamine tetraacetic acid)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
- A61K51/065—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules conjugates with carriers being macromolecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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"
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
- G01N23/02—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by transmitting the radiation through the material
- G01N23/04—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by transmitting the radiation through the material and forming images of the material
- G01N23/046—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by transmitting the radiation through the material and forming images of the material using tomography, e.g. computed tomography [CT]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Optics & Photonics (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pathology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Cell Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Hospice & Palliative Care (AREA)
- Food Science & Technology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Pulmonology (AREA)
- Radiology & Medical Imaging (AREA)
- Theoretical Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明公开了几种肿瘤高亲和肽及其应用,这些高亲和多肽能和多种肿瘤细胞特异性结合,优选乳腺癌,肝癌和结直肠癌。利用靶向肽高亲和力特性可用于恶性肿瘤的光学成像和核医学显像。这些高亲和力多肽单体,多肽二聚体或者多肽的多聚体直接或间接的偶联荧光染料可作为肿瘤特异性靶向分子探针,预期能达到对肿瘤边界精准定位的效果,可为术前和术中影像导航带来实时性,具有提高手术精确度的优点。
Description
技术领域
本发明属于生物工程制药技术领域和蛋白质多肽类药物及生物医学工程领域,具体涉及肿瘤靶向肽及其应用,例如可用于肿瘤诊断、术中导航以及肿瘤治疗中。
背景技术
肿瘤己经成为威胁人类健康和生命的罪魁祸首,因此,肿瘤的早期诊断以及肿瘤的有效治疗显得尤为重要并且迫切。对于肿瘤,常规影像诊断技术主要为B超、CT和MRI,这些影像诊断技术是通过显示组织的功能变化来达到诊断的结果,有较好的应用价值,但在鉴别诊断、全身分期和早期疗效评价上仍存在一定的不足。不可否认,筛选和优化靶向肿瘤的多肽是一种新的途径,可以为肿瘤的诊断、分期以及手术指导开发新型的分子显像药物,可以发现更微小病灶,达到早期诊断的目的。
钙粘素家族是一类介导钙依赖性细胞粘附的跨膜糖蛋白。在功能上,钙粘素介导的粘附作用调节细胞的生长与分化。钙粘素通过与连环蛋白形成复合物,来介导细胞与细胞之间的粘附,维持组织结构的稳定。由于钙粘素在细胞识别、粘附、和信号传递中的重要作用,所以探究钙粘素在癌症发生过程中的表达变化和功能作用具有重要的意义。在多种人类恶性肿瘤组织中能检测到P-钙粘素表达的改变,可见的表达与恶性肿瘤的发生发展息息相关。P-钙粘素在不同类型肿瘤组织中,其对肿瘤的作用也不尽相同。如膀胱、癌结肠癌、乳腺癌和胰腺癌等,P-钙粘素促进肿瘤的发展与转移
花菁类染料具有分子量小、毒性低、波长可调范围广、以及摩尔消光系数大等优点,使其广泛地用于荧光标记领域。通过对花菁类染料结构的修饰,使其连接上具有活性的反应基团,然后与特异性靶分子如抗体、蛋白质、短肽、小分子等的氨基或羧基发生反应形成稳定的共价键,形成具有特异性靶向分子探针进行荧光分子活体成像是近红外荧光染料的一个重要用途。单光子发射计算机断层/计算机断层扫描(Single-Photon emissiontomography/computerized tomography,SPECT/CT)是近20年来发展起来并在临床上推广的一种新型的核医学显像技术,主要是利用短半衰期放射性核素来标记具有特异性靶向的配体进行示踪显像,可显示活体内物质代谢、细胞增殖、受体分布等信息,用于疾病的诊断和人体生命活动的研究。所以,特异性靶向的配体是荧光成像以及放射性核素显像的关键。
基于以上考虑,申请人设计出了一类新型的肿瘤靶向多肽,这类多肽能特异性的靶向肿瘤组织中的P-钙粘素,偶联荧光染料可进行光学成像来协助医生在利用分子影像手术导航设备时可以在术中精确定位肿瘤边界,来达到对肿瘤精准切除的目的,从而减少对病人创伤,降低术后复发的风险。除此之外,该靶向多肽还可偶联放射性核素进行核素成像,来达到肿瘤早期诊断和治疗的目的。
发明内容
本发明的首要目的在于提供几种结构新颖,肿瘤特异性靶向的多肽及其序列;
本发明的另一目的在于提供几种肿瘤特异性靶向的荧光探针的制备方法;
本发明的另一目的在于提供几种肿瘤特异性靶向的放射性探针的制备方法;
本发明的再一目的是提供几种所述的探针在光学及SPECT显像中的应用。
本发明的上述目的可通过以下技术方案实现:
肿瘤特异性靶向肽,选自以下任意一种:
肿瘤靶向肽YQP-1,序列为Hyp-Ser-Asp-Asn-Tyr-Thr-NH2;
肿瘤靶向肽YQP-2,序列为Glu-Nle-Gly-Hyp-Ser-Asp-Asn-Tyr(3-I)-Thr-NH2;
肿瘤靶向肽YQP-3,序列为Hyp-Ser-Asp-Asn-Tyr(3-I)-Thr-NH2;
肿瘤靶向肽YQP-4,序列为Glu-Ile-Asp-Pro-Ser-Asp-Asn-Tyr-Thr-Tyr-Tyr-Asn-Gln-Asn-Phe-Lys-Gly;
肿瘤靶向肽YQP-5,序列为Cys-Pro-Ser-Asp-Asn-Tyr-Thr-Cys 1-7,二硫键环;
肿瘤靶向肽YQP-6,序列为Phe-Thr-Ala-Tyr-Asn-Gly-Tyr-Tyr-Asp-Gly-Gly-Phe-NH2。
其中:Hyp为羟脯氨酸,Tyr(3-I)为碘代酪氨酸,Nle为正亮氨酸。
本发明所述的肿瘤靶向肽YQP-X(X=1-6)可以委托生物公司合成,也可以通过本领域常规技术手段制备。
多肽YQP-1的固相合成方法如下:
1)树脂溶胀
称取Rink Amide MBHA树脂,放入反应柱,加入适量的二氯甲烷(DCM),微微鼓吹氮气10-30 分钟,使树脂充分膨胀开来。抽掉DCM溶液,用DMF洗涤3遍,抽干。
2)脱除Fmoc
反应柱中加入20%的六氢吡啶DMF溶液,去保护5分钟一次,8分钟一次。反应结束后用DMF 洗涤6遍。
3)偶联
准确称取投料树脂摩尔数3倍的Fmoc-Thr(trt)-OH与O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU),完全溶于DMF中,加入N,N-二异丙基乙胺(DIPEA)使羧基活化,然后将溶液加入反应柱进行反应,1h后检测,检测结构呈阳性即可。依次按照顺序从C端向N端偶联脱除Fmoc,直至偶联完最后一个氨基酸Fmoc-Hyp-OH,然后脱除Fmoc后,再将目标树脂肽收缩,称重。
4)裂解
配制87.5%TFA+5%苯甲硫醚+2.5%乙二硫醇+2.5%苯酚+2.5%水的裂解液,在低温条件下,将裂解液缓慢加入树脂肽中,切割液体积按照粗肽树脂重量的7-8倍,缓慢搅拌2h后,抽滤得液体,加入冰乙醚搅拌,然后离心得固体,用乙醚洗涤三遍,抽干称重并且测定质荷比,确定分子量。
5)纯化分离
采用高效液相色谱法进行纯化,纯化用色谱填料为10μm的反相C18,流动相系统为0.1%TFA/ 水溶液-0.1%TFA/乙腈溶液,采用梯度系统洗脱,循环进样纯化,取粗品溶液上样于色谱柱中,启动流动相洗脱,收集主峰蒸去乙腈后,得目的肽浓缩液,然后冻干得目的多肽。
环状多肽YQP-5的制备方法如下:
1)树脂溶胀
称取Fmoc-Cys(trt)-2chlorotrityl Resin树脂,放入反应柱,加入适量的二氯甲烷(DCM),微微鼓吹氮气10-30分钟,使树脂充分膨胀开来。抽掉DCM溶液,用DMF洗涤3遍,抽干。
2)脱除Fmoc
反应柱中加入20%的六氢吡啶DMF溶液,去保护5分钟一次,8分钟一次。反应结束后用DMF 洗涤6遍。
3)偶联
准确称取投料树脂摩尔数3倍的Fmoc-Cys(trt)-OH与O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU),完全溶于DMF中,加入DIEA使羧基活化,然后将溶液加入反应柱进行反应,1h 后检测,检测结构呈阳性即可。依次按照顺序从C端向N端偶联脱除Fmoc,直至偶联完最后一个氨基酸Fmoc-Cys(trt)-OH,然后脱除Fmoc后,再将目标树脂肽收缩,称重。
4)裂解
配制87.5%TFA+5%苯甲硫醚+2.5%乙二硫醇+2.5%苯酚+2.5%水的裂解液,在低温条件下,将裂解液缓慢加入树脂肽中,切割液体积按照粗肽树脂重量的7-8倍,缓慢搅拌2h后,抽滤得液体,加入冰乙醚搅拌,然后离心得固体,用乙醚洗涤三遍,抽干称重并且测定质荷比,确定分子量为。
5)二硫键成环
将样品溶于纯水中进行搅拌,调节PH,使多肽水溶液呈弱碱性,加入双氧水,反应0.5h后进行检测,检测结果呈阳性即可,调节多肽溶液PH,使之呈酸性。
6)纯化分离
采用高效液相色谱法进行纯化,纯化用色谱填料为10μm的反相C18,流动相系统为0.1%TFA/ 水溶液-0.1%TFA/乙腈溶液,采用梯度系统洗脱,循环进样纯化,取环化好后的溶液上样于色谱柱中,启动流动相洗脱,收集主峰蒸去乙腈后,得目的肽浓缩液,然后冻干得目的多肽。
本发明所述的肿瘤特异性靶向肽或其二聚体、多聚体在制备肿瘤诊断试剂或肿瘤治疗药物中的应用;优选在制备肿瘤诊断显像剂中的应用;进一步优选在制备肿瘤边界的精准定位和术中影像导航显像试剂或制备放射性核素显像试剂中的应用。
一种荧光分子影像探针,具备以下通式:
M-L-R,
其中,M表示光标记,所述的光标记选自近红外荧光染料、有机发色团、有机荧光团、光吸收化合物、光反射化合物、光散射化合物和生物发光分子;
L为连接基团,L优选Aca、PEG4、PEG6、G6中的任意一种;
R为权利要求1所述的任意一个肿瘤特异性靶向肽或其二聚体、多聚体。
所述的荧光分子影像探针优选其结构通式如下式所示:
其结构中含有用于靶向肿瘤的多肽R和用于光学成像的近红外荧光染料结构MPA(上述左侧结构) 以及起到增加靶向多肽与近红外荧光染料之间的距离并调节体内药代动力学特性的连接基团L。
本发明还提供了制备所述多肽荧光探针的方法,包括:
1)近红外荧光染料MPA的合成
将冰醋酸、对肼基苯磺酸、甲基异丙基酮和醋酸钠混合反应,纯化后得产物2,2,3-三甲基[3H]- 吲哚-5-磺酸;再将邻二氯苯加入到2,2,3-三甲基[3H]-吲哚-5-磺酸与1,3-丙磺酸内脂的混合物中,制得2,2,3-三甲基-5-磺酸-1-(3-磺酸-丙基)-[3H]-吲哚;再将该产物与N-[(3-(anilinomethylene)-2-chl oro-1-cyclohexen-1-yl)methylene]-anilinemonohydrochloride反应得到绿色碳菁染料,最后将碳菁染料与巯基丙酸及三乙胺反应,制备液相分离纯化得水溶性近红外染料MPA。
2)MPA-L-YQP-X(X=1-6)的合成
将分离纯化得到的近红外染料MPA与L-YQP-X(X=1-6)多肽溶于二甲基亚砜中,加入适量的N,N- 二异丙基乙胺(DIPEA),室温反应过夜,反应完成后经制备液相纯化分离得到目标荧光化合物。其中,L-YQP-X可以委托生物公司固相合成。
一种放射性核素探针,其特征在于为放射性核素标记的权利要求1所述的肿瘤特异性靶向肽或其二聚体多肽;所述的放射性核素优选自125I、131I、18F、99mTc、68Ga,64Cu,67Ga,90Y,111In或177Lu。
作为本发明的一种优选,本发明进一步提供一种放射性核素探针,它是放射性核素标记的多肽配合物,多肽YQP-X(X=1-6)结构中,包含有酪氨酸,其中酚羟基的邻位可以通过亲电取代反应进行放射性碘标记(125I/131I),此外,选用18F对多肽进行多肽YQP-X(X=1-6)标记,选用不同的核素多分子进行标记,用于疾病的诊断或治疗。结构式如(Ⅱ)所示
作为本发明的另一种优选,本发明进一步提供另一种放射性核素探针,它是放射性核素锝标记的多肽或二聚体多肽,结构式如(IV)所示,此外,
其结构中含有用于靶向肿瘤的多肽YQP-X(X=1-6)或二聚体多肽、用于放射性标记的双功能螯合剂6-肼基吡啶-3-甲酸(HYNIC),放射性核素配体N-三(羟甲基)甲基甘氨酸(Tricine)和三苯基膦三间磺酸钠盐(TPPTS)、以及放射性核素及连接基团。连接基团可以选自谷氨酸两个羧基连接两分子连接基团L所组成的连接支架(L2E)或赖氨酸的羧基和氨基连接两分子连接基团L所组成的连接支架 (L2K),或者起到增加靶向多肽与放射性核素配体N-三(羟甲基)甲基甘氨酸(Tricine)和三苯基膦三间磺酸钠盐(TPPTS)之间距离并调节体内药代动力学特性的连接基团L,L选自Aca、PEG4、PEG6、 G6。
其中,通过对双功能螯合剂的改变,比如替换成双功能螯合剂DOTA,NOTA或DTPA,放射性核素可选除99mTc之外的其他放射性核素,比如68Ga,64Cu,67Ga,90Y,111In或177Lu用于疾病的诊断或治疗,结构式如(Ⅷ)所示。M代表核素,L选自Aca、PEG4、PEG6、G6。
本发明还提供了制备所述放射性核素探针制备的方法,包括:
1)HYNIC-NHS的合成
将6-氯烟酸和80%水合肼加入到乙醇中,加热回流反应,反应完成后减压旋蒸溶剂,得到的粘稠物加入到蒸馏水中,调PH=5.5左右,析出固体,抽滤烘干得到黄色固体,产品经ESI-MS质谱和核磁氢谱确定为6-联肼烟酸。得到的6-联肼烟酸和对氨基苯甲醛加入到二甲基亚砜(DMSO)中,加热反应5-6小时,反应完成后加入到水中析出,抽滤得固体,此固体烘干后与1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)以及N-羟基琥珀酰亚胺(NHS)一起加入到DMSO中室温反应,反应完成后加入水中析出固体,此固体通过硅胶柱纯化后经ESI-MS质谱和核磁氢谱确定为目标产物。
2)HYNIC-Aca-YQP-1的合成
将纯化的中间体HYNIC-NHS溶于DMSO中,然后加入2摩尔量的EDCI和2摩尔量的NHS,室温反应5小时,用分析型高效液相检测反应进程,反应完成后加入2摩尔量的靶向肽YQP-X,然后再加入4摩尔量的DIPEA,室温反应3小时,反应完成后通过制备液相进行分离纯化并通过质谱确证。
3)放射性探针99mTc-HYNIC-Aca-YQP-1的合成
分别配制浓度为100.0mg/mL的TPPTS(三苯基磷三间磺酸钠)溶液,浓度为130.0mg/mL的 Tricine(三甲基甘氨酸),浓度为102.4mg/mL丁二酸-丁二酸钠缓冲液(其中丁二酸77.0mg,丁二酸钠25.4mg),分别取10.0uL TPPTS溶液,10.0uL Tricine溶液,10.0uL丁二酸-丁二酸钠缓冲液分别和10.0uL(1.0mg/mL)所述(YQP-X)2-L2E-HYNIC混合于西林瓶中,然后加入10mCi Na 99mTcO4于 100℃金属浴加热20分钟,待反应结束后冷却至室温,分别制成多肽放射性药物,产品经Agilent ZORBAX SB-Aq分析柱分析鉴定。
本发明所述的荧光分子影像探针、本发明所述的放射性核素探针在制备肿瘤诊断、治疗或示踪的试剂、靶向型基因治疗或化疗药物中的应用。
本发明所述的多肽化合物可特异性靶向至肿瘤部位,并且在肿瘤部位有很好的摄取和滞留,具有较高的靶/非靶比值,适合用作荧光肿瘤显像剂以及放射性核素显像剂及治疗剂,并可用于制备肿瘤术中影像导航及肿瘤边界精准定位的光学显像药物。
本发明所述的新型多肽及以此系列多肽构建的荧光以及放射性核素探针与现有技术相比的有益效果为:
1、本发明发现的YQP-X系列多肽是低分子量多肽,合成成本低廉,并且此系列短肽有三个氨基酸是经修饰的非天然氨基酸,非天然氨基酸的引入可极大地提高此系列多肽在活体内的稳定性,不易在体内被降解,靶向活性不易被破坏,有更强的潜力靶向至靶部位,体内外实验结果表明了此系列探针在体内外具有优异的稳定性以及靶向性,稳定性的增强会促进此系列的影像探针在肿瘤部位的浓聚和滞留,进而达到更好的肿瘤显像效果,使得更加有利于在临床上推广应用。
2、YQP-X系列多肽经体内光学和放射性核素显像结果证实对多种肿瘤具有优异的显像效果,包括前列腺癌、乳腺癌、胰腺癌、结直肠癌、肺癌以及肝癌,能特异性靶向肿瘤部位的性质将有可能实现对恶性肿瘤的核医学诊断、治疗以及光学成像指导外科医生进行手术导航,达到对病灶的精准切除。
3、本发明中使用了稳定性以及水溶性更理想的近红外荧光染料MPA作为光学显像基团,改善了药物在体内的药代动力学。
4、本发明中引入了多个水溶性的PEG4或PEG6分子,以进一步改善药代动力学特性,特别是从非肿瘤组织的清除动力学。
5、本发明中使用HYNIC作为双功能螯合剂,同时使用Tricine和TPPTS作为协同配体从而使“99mTc-HYNIC核”具有更好的体内外稳定性。
以下结合附图及实施例对本发明作进一步说明。
附图说明
图1制备的近红外染料MPA的结构(A),多肽YQP-1的结构(B)制备的MPA-Aca-YQP-1质谱图(C)
图2为实施例2合成125I-YQP-1结构(A),放射性HPLC分析图谱(B)。
图3多肽YQP-1的结构(A),HYNIC的结构(B)以及HYNIC-Aca-YQP-1质谱(C)
图4为实施例3制备的靶向放射性药物99mTc-HYNIC-Aca-YQP-1结构图(A),放射性HPLC分析图谱(B)
图5为实施例1制备的化合物MPA-Aca-YQP-1在乳腺癌MCF-7荷瘤鼠体内的光学成像图。
图6为实施例1制备的化合物MPA-Aca-YQP-1在结直肠癌HCT116荷瘤鼠体内的光学成像图。
图7实施例2制备的化合物125I-YQP-1在结直肠癌HCT116荷瘤鼠体内的SPECT-CT成像图。
图8为实施例3制备的化合物99mTc-HYNIC-Aca-YQP-1在肝癌Bel-7404荷瘤鼠体内的SPECT-CT 成像图。
图9为实施例3制备的化合物99mTc-HYNIC-Aca-YQP-1在肝癌HepG2荷瘤鼠体内的SPECT-CT 成像图。
图10为实施例3制备的化合物99mTc-HYNIC-Aca-YQP-1在乳腺癌MCF-7荷瘤鼠体内的SPECT-CT 成像图。
图11为实施例3制备的化合物99mTc-HYNIC-Aca-YQP-1在结直肠癌HCT116荷瘤鼠体内的 SPECT-CT成像图。
图12为实施例7制备的化合物MPA-Aca-YQP-2在乳腺癌MCF-7荷瘤鼠体内的光学成像图。
图13为实施例8制备的化合物99mTc-HYNIC-Aca-YQP-3在乳腺癌MCF-7荷瘤鼠体内的SPECT-CT 成像图。
图14为实施例9制备的化合物99mTc-HYNIC-Aca-YQP-4在乳腺癌MCF-7荷瘤鼠体内的SPECT-CT 成像图。
图15为实施例10制备的化合物MPA-Aca-YQP-5在乳腺癌MCF-7荷瘤鼠体内的光学成像图。
图16为实施例11制备的化合物MPA-Aca-YQP-6在肝癌Bel-7404荷瘤鼠体内的光学成像图。
具体实施方式
以下通过具体的实施例和应用例来进一步说明本发明:其中合成步骤中所使用的化学物质均为现有物质或市售商品。本发明多肽的合成为现有技术,既可以按照发明内容部分的方法合成,也可以按照本领域的其他现有技术合成,或者委托具有蛋白合成业务的生物公司合成。
实施例1荧光靶向化合物MPA-Aca-YQP-1的合成
合成步骤参考我们课题组前期申请的一篇发明专利,授权专利号:CN101440282,主要合成步骤如下:
称取固相合成的Aca-YQG-1化合物10mg,制备的染料MPA纯品12.38mg加入到200μL二甲基亚砜(DMSO)中,然后加入2.3mg 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)偶联剂以及3.82mg N-羟基丁二酰亚胺(NHS),混匀后再加入4.1mg N,N-二异丙基乙胺(DIPEA),室温反应过夜,反应完成后用制备液相进行分离纯化,制备液相条件如下所示:使用了Agilent 1220Infinity II 系列HPLC系统配备Agilent ZORBAX SB-C18半制备柱(9.4×250mm,5um),梯度淋洗60分钟,流速2mL/min,其中流动相A为超纯水(0.01%TFA),B为乙腈(0.01%TFA)。淋洗梯度设定为: 0-5分钟时95%A和5%B,15分钟时80%A和20%B,45分钟时50%A和50%B,60分钟时5%A和 95%B。最后制得的绿色产物经分析型HPLC和ESI-MS质谱分析确认为预期产物MPA-Aca-YQG-1,参见图2。在上述制备过程中,以固相合成的L-YQG-X多肽替代步骤中使用的Aca-YQG-1多肽,即得到本发明其他5种具有肿瘤靶向光学成像功能的多肽化合物。
实施例2 125I-YQP-1的合成
1.首先精准称量Iodogen氧化剂固体(5μg),溶解到无水二氯甲烷中(20μL),利用移液枪将Iodogen的二氯甲烷溶液转移到1.5ml EP管中,在底部微微加热,并辅以氮吹仪,将低沸点的二氯甲烷充分挥发。二氯甲烷溶剂挥发后的Iodogen会在EP管底部形成一层薄薄的Iodogen氧化剂薄膜。
2.取事先配置好的YQP-1多肽的磷酸缓冲液(pH=7.4,20μL,0.5mg/ml)加入到有氧化剂薄膜的EP管中。然后再吸取总放射活度为300μCi的Na125I溶液。最后将混合溶液在室温条件下,置于振荡器上震荡反应5min。
3.吸取反应后的反应液,放射活度为15μCi,体积为1μL。稀释到磷酸缓冲液(pH=7.4,20μ) 进高效液相色谱观察反应情况。HPLC配置有放射性检测器。设置检测核素类型为125I。
实施例3制备的靶向放射性药物99mTc-HYNIC-Aca-YQP-1
将合成好并纯化的5mg中间体(PEG4)2E-HYNIC溶于0.3mL DMSO中,然后加入2.1mgEDCI和 1.25mg NHS,室温反应5小时,用分析型高效液相检测反应进程,反应完成后加入靶向肽7.8mg YQG-1,然后再加5.6mg DIPEA,室温反应3小时,反应完成后通过制备液相进行分离纯化,最后得到黄色固体6.5mg,通过质谱确证为目标产物。
分别配制浓度为100.0mg/mL的TPPTS(三苯基磷三间磺酸钠)溶液,浓度为130.0mg/mL的 Tricine(三甲基甘氨酸),浓度为102.4mg/mL丁二酸-丁二酸钠缓冲液(其中丁二酸77.0mg,丁二酸钠25.4mg),分别取10.0uL TPPTS溶液,10.0uL Tricine溶液,10.0uL丁二酸-丁二酸钠缓冲液分别和10.0uL(1.0mg/mL)所述(YQP-1)2-(PEG4)2E-HYNIC混合于西林瓶中,然后加入10mCi Na 99mTcO4 于100℃金属浴加热20分钟,待反应结束后冷却至室温,制得多肽放射性药物 (YQP-1)2-(PEG4)2E-HYNIC-99mTc,产品经Agilent ZORBAX SB-Aq分析柱分析鉴定。使用的HPLC法为配备了放射性在线检测器(Flow-RAM)和Agilent ZORBAXSB-Aq分析柱(4.6×250mm,5um)的 Agilent 1220Infinity II系列HPLC系统。梯度淋洗45分钟,流速1mL/min,其中流动相A为超纯水 (0.01%TFA),B为乙腈(0.01%TFA)。淋洗梯度设定为:0-5分钟时95%A和5%B,15分钟时 70%A和30%B,20分钟时65%A和35%B,25分钟时45%A和55%B,45分钟时5%A和95%B。
实施例4化合物MPA-Aca-YQP-1在荷瘤鼠体内的光学成像
按实施例4制备好化合物MPA-Aca-YQP-1并配制成生理盐水溶液,取0.1mL(约10nmol)通过尾静脉,分别注射2种荷瘤裸鼠尾静脉(MCF-7,HCT116),每种荷瘤鼠三只。,并于给药后1h、2h、 4h、8h、10h和12h进行光学信号采集。观察探针在小鼠体内的分布以及在肿瘤区域的富集。1h显像结果图如图5和6所示,化合物MPA-Aca-YQP-1在3只荷瘤裸鼠中的成像结果基本一致,从1h的成像图中可以看出探针已经在肿瘤中有明显摄取,直至10h探针依然在肿瘤中有滞留,其中,4h时探针在肿瘤部位富集最多,而在其它背景器官的摄取清除较快,从膀胱的信号可以推断出此探针主要通过肾脏代谢。
实施例5制备的化合物125I-YQP-1在结直肠癌HCT116荷瘤鼠体内的SPECT-CT成像
按实施例2方法制备好化合物125I-YQP-1并配制成生理盐水溶液,取0.1mL(约10nmol)分别注射于3只结直肠癌HCT116荷瘤裸鼠尾静脉,并于给药后0.5h、1h、2h、3h、4h进行SPECT信号采集。观察放射性核素探针在小鼠体内的分布以及在肿瘤区域的富集。1h显像结果图如图7所示,探针125I-YQP-1在肿瘤部位有明显的摄取,说明此探针可靶向结直肠癌HCT116肿瘤细胞,并且主要通过肾脏代谢出体外。
实施例6制备的化合物99mTc-HYNIC-Aca-YQP-1在荷瘤鼠体内的SPECT-CT成像
按实施例3方法制备好化合物99mTc-HYNIC-Aca-YQP-1并配制成生理盐水溶液,取0.1mL(约10 nmol)通过尾静脉,分别注射4种荷瘤裸鼠尾静脉(HepG2,Bel-7404,MCF-7,HCT116),每种荷瘤鼠三只。并于给药后0.5h、1h、2h、3h、4h进行SPECT信号采集。观察放射性核素探针在小鼠体内的分布以及在肿瘤区域的富集。1h显像结果图如图8,9,10和11所示,探针99mTc-HYNIC-Aca-YQP-1在肿瘤部位有明显的摄取,说明此探针可靶向结肿瘤细胞,并且主要通过肾脏代谢出体外。
实施例7化合物MPA-Aca-YQP-2在乳腺癌MCF-7荷瘤鼠体内的光学成像
按实施例1方法制备好化合物MPA-Aca-YQP-2并配制成生理盐水溶液,取0.1mL(约10nmol) 分别注射于3只乳腺癌MCF-7荷瘤裸鼠(体重约22克)尾静脉,并于给药后1h、2h、4h、8h、10h 和12h进行光学信号采集。观察探针在小鼠体内的分布以及在肿瘤区域的富集。显像结果图如图12所示,化合物MPA-Aca-YQP-2在3只荷瘤裸鼠中的成像结果基本一致,从2h的成像图中可以看出探针已经在肿瘤中有明显摄取,直至10h探针依然在肿瘤中有滞留,其中,4h时探针在肿瘤部位富集最多,而在其它背景器官的摄取清除较快,从膀胱的信号可以推断出此探针主要通过肾脏代谢。
实施例8制备的化合物99mTc-HYNIC-Aca-YQP-3在乳腺癌MCF-7荷瘤鼠体内的SPECT-CT成像
按实施例3方法制备好化合物99mTc-HYNIC-Aca-YQP-3并配制成生理盐水溶液,取0.1mL(约10 nmol)分别注射于3只乳腺癌MCF-7荷瘤裸鼠尾静脉,并于给药后0.5h、1h、2h、3h、4h进行SPECT 信号采集。观察放射性核素探针在小鼠体内的分布以及在肿瘤区域的富集。1h显像结果图如图13所示,探针99mTc-HYNIC-Aca-YQP-2在肿瘤部位有明显的摄取,说明此探针可靶向乳腺癌MCF-7肿瘤细胞,并且主要通过肾脏代谢出体外。
实施例9制备的化合物99mTc-HYNIC-Aca-YQP-4在乳腺癌MCF-7荷瘤鼠体内的SPECT-CT成像
按实施例3方法制备好化合物99mTc-HYNIC-Aca-YQP-4并配制成生理盐水溶液,取0.1mL(约10 nmol)分别注射于3只乳腺癌MCF-7荷瘤裸鼠尾静脉,并于给药后0.5h、1h、2h、3h、4h进行SPECT 信号采集。观察放射性核素探针在小鼠体内的分布以及在肿瘤区域的富集。1h显像结果图如图14所示,探针99mTc-HYNIC-Aca-YQP-2在肿瘤部位有明显的摄取,说明此探针可靶向乳腺癌MCF-7肿瘤细胞,并且主要通过肾脏代谢出体外。
实施例10化合物MPA-Aca-YQP-5在肝癌Bel-7404荷瘤鼠体内的光学成像
参考实施例1方法制备好化合物MPA-Aca-YQP-5并配制成生理盐水溶液,取0.1mL(约10nmol) 分别注射于3只肝癌Bel-7404荷瘤裸鼠(体重约22克)尾静脉,并于给药后1h、2h、4h、8h、10h 和12h进行光学信号采集。观察探针在小鼠体内的分布以及在肿瘤区域的富集。注射后1h显像结果图如图15所示,化合物MPA-Aca-YQP-5在3只荷瘤裸鼠中的成像结果基本一致,从1h的成像图中可以看出探针已经在肿瘤中有明显摄取,而在其它背景器官的摄取清除较快,从膀胱的信号可以推断出此探针主要通过肾脏代谢。
实施例11化合物MPA-Aca-YQP-6在乳腺癌MCF-7荷瘤鼠体内的光学成像
参考实施例1制备好化合物MPA-Aca-YQP-6并配制成生理盐水溶液,取0.1mL(约10nmol)分别注射于3只乳腺癌MCF-7荷瘤裸鼠(体重约22克)尾静脉,并于给药后1h、2h、4h、8h、10h和 12h进行光学信号采集。观察探针在小鼠体内的分布以及在肿瘤区域的富集。注射后1h显像结果图如图16所示,化合物MPA-Aca-YQP-6在3只荷瘤裸鼠中的成像结果基本一致,从1h的成像图中可以看出探针已经在肿瘤中有明显摄取,而在其它背景器官的摄取清除较快,从膀胱的信号可以推断出此探针主要通过肾脏代谢。
Claims (10)
1.肿瘤特异性靶向肽,其特征在于选自以下任意一种:
肿瘤靶向肽YQP-1,序列为Hyp-Ser-Asp-Asn-Tyr-Thr-NH2;
肿瘤靶向肽YQP-2,序列为Glu-Nle-Gly-Hyp-Ser-Asp-Asn-Tyr(3-I)-Thr-NH2;
肿瘤靶向肽YQP-3,序列为Hyp-Ser-Asp-Asn-Tyr(3-I)-Thr-NH2;
肿瘤靶向肽YQP-4,序列为Glu-Ile-Asp-Pro-Ser-Asp-Asn-Tyr-Thr-Tyr-Tyr-Asn-Gln-Asn-Phe-Lys-Gly;
肿瘤靶向肽YQP-5,序列为Cys-Pro-Ser-Asp-Asn-Tyr-Thr-Cys 1-7,二硫键环;
肿瘤靶向肽YQP-6,序列为Phe-Thr-Ala-Tyr-Asn-Gly-Tyr-Tyr-Asp-Gly-Gly-Phe-NH2;
其中:Hyp为羟脯氨酸,Tyr(3-I)为碘代酪氨酸,Nle为正亮氨酸。
2.权利要求1所述的肿瘤特异性靶向肽或其二聚体、多聚体在制备肿瘤诊断试剂或肿瘤治疗药物中的应用。
3.根据权利要求2所述的应用,其特征在于权利要求1所述的肿瘤特异性靶向肽或其二聚体、多聚体在制备肿瘤诊断显像剂中的应用;优选在制备肿瘤边界的精准定位和术中影像导航显像试剂或制备放射性核素显像试剂中的应用。
4.一种荧光分子影像探针,其特征在于具备以下通式:
M-L-R,
其中,M表示光标记,所述的光标记选自红外荧光染料、含有机发色团、有机荧光团的化合物、光吸收化合物、光反射化合物、光散射化合物或生物发光分子;
L为连接基团,L优选Aca、PEG4、PEG6、G6;
R为权利要求1所述的任意一个肿瘤特异性靶向肽或其二聚体、多聚体。
6.一种放射性核素探针,其特征在于为放射性核素标记的权利要求1所述的肿瘤特异性靶向肽或其二聚体多肽;所述的放射性核素优选自125I、131I、18F、99mTc、68Ga,64Cu,67Ga,90Y,111In或177Lu。
7.根据权利要求6所述的放射性核素探针,其特征在于所述的放射性核素探针为放射性碘或氟标记权利要求1所述的肿瘤特异性靶向肽中酪氨酸的酚羟基邻位上的氢。
8.根据权利要求6所述的放射性核素探针,其特征在于所述的放射性核素探针包括权利要求1所述的肿瘤特异性靶向肽或其二聚体多肽、连接基团、放射性核素配体、用于放射性核素标记的双功能螯合剂以及放射性核素。
9.根据权利要求6所述的放射性核素探针,其特征在于所述的连接基团选自Aca、PEG4、PEG6、G6,所述的双功能螯合剂HYNIC、DOTA,NOTA或DTPA,所述的放射性核素选自99mTc,68Ga,64Cu,67Ga,90Y,111In或177Lu,所述的放射性核素配体为N-三(羟甲基)甲基甘氨酸和三苯基膦三间磺酸钠盐。
10.权利要求4或5所述的荧光分子影像探针、权利要求6-9中任一项所述的放射性核素探针在制备肿瘤诊断、治疗或示踪的试剂、靶向型基因治疗或化疗药物中的应用。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111233746.3A CN113880917B (zh) | 2021-10-22 | 2021-10-22 | 几种肿瘤高亲和肽及其应用 |
CN202310302441.6A CN116731104A (zh) | 2021-10-22 | 2021-10-22 | 肿瘤高亲和肽yqp-3及其应用 |
CN202310302442.0A CN116375804A (zh) | 2021-10-22 | 2021-10-22 | 肿瘤高亲和肽yqp-4及其应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111233746.3A CN113880917B (zh) | 2021-10-22 | 2021-10-22 | 几种肿瘤高亲和肽及其应用 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310302441.6A Division CN116731104A (zh) | 2021-10-22 | 2021-10-22 | 肿瘤高亲和肽yqp-3及其应用 |
CN202310302442.0A Division CN116375804A (zh) | 2021-10-22 | 2021-10-22 | 肿瘤高亲和肽yqp-4及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113880917A true CN113880917A (zh) | 2022-01-04 |
CN113880917B CN113880917B (zh) | 2023-04-28 |
Family
ID=79004349
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310302441.6A Pending CN116731104A (zh) | 2021-10-22 | 2021-10-22 | 肿瘤高亲和肽yqp-3及其应用 |
CN202310302442.0A Pending CN116375804A (zh) | 2021-10-22 | 2021-10-22 | 肿瘤高亲和肽yqp-4及其应用 |
CN202111233746.3A Active CN113880917B (zh) | 2021-10-22 | 2021-10-22 | 几种肿瘤高亲和肽及其应用 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310302441.6A Pending CN116731104A (zh) | 2021-10-22 | 2021-10-22 | 肿瘤高亲和肽yqp-3及其应用 |
CN202310302442.0A Pending CN116375804A (zh) | 2021-10-22 | 2021-10-22 | 肿瘤高亲和肽yqp-4及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (3) | CN116731104A (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114288426A (zh) * | 2022-01-07 | 2022-04-08 | 江西中医药大学 | 艾替班特及其衍生物在制备肿瘤诊断和/或治疗试剂中的应用 |
CN116813704A (zh) * | 2023-05-26 | 2023-09-29 | 豫章师范学院 | 一种肿瘤靶向荧光分子探针及其应用 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060263368A1 (en) * | 2005-01-10 | 2006-11-23 | Research Development Foundation | Targeted chimeric molecules for cancer therapy |
US20090061422A1 (en) * | 2005-04-19 | 2009-03-05 | Linke Steven P | Diagnostic markers of breast cancer treatment and progression and methods of use thereof |
CN101440282A (zh) * | 2008-12-18 | 2009-05-27 | 中国药科大学 | 近红外荧光分子探针及其合成方法和用途 |
US20150301058A1 (en) * | 2012-11-26 | 2015-10-22 | Caris Science, Inc. | Biomarker compositions and methods |
CN110845572A (zh) * | 2019-11-28 | 2020-02-28 | 中国药科大学 | 肿瘤靶向的grp类似物及其应用 |
CN111675750A (zh) * | 2020-06-11 | 2020-09-18 | 中国药科大学 | 针对癌胚抗原相关黏附分子ceacam的肿瘤靶向肽及其应用 |
-
2021
- 2021-10-22 CN CN202310302441.6A patent/CN116731104A/zh active Pending
- 2021-10-22 CN CN202310302442.0A patent/CN116375804A/zh active Pending
- 2021-10-22 CN CN202111233746.3A patent/CN113880917B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060263368A1 (en) * | 2005-01-10 | 2006-11-23 | Research Development Foundation | Targeted chimeric molecules for cancer therapy |
US20090061422A1 (en) * | 2005-04-19 | 2009-03-05 | Linke Steven P | Diagnostic markers of breast cancer treatment and progression and methods of use thereof |
CN101440282A (zh) * | 2008-12-18 | 2009-05-27 | 中国药科大学 | 近红外荧光分子探针及其合成方法和用途 |
US20150301058A1 (en) * | 2012-11-26 | 2015-10-22 | Caris Science, Inc. | Biomarker compositions and methods |
CN110845572A (zh) * | 2019-11-28 | 2020-02-28 | 中国药科大学 | 肿瘤靶向的grp类似物及其应用 |
CN111675750A (zh) * | 2020-06-11 | 2020-09-18 | 中国药科大学 | 针对癌胚抗原相关黏附分子ceacam的肿瘤靶向肽及其应用 |
Non-Patent Citations (3)
Title |
---|
DEAN, MF等: "Link peptide cartilage growth factor is degraded by membrane proteinases", 《BIOCHEMICAL JOURNAL》 * |
KUMARA, H M C SHANTHA等: "P-Cadherin (CDH3) is overexpressed in colorectal tumors and has potential as a serum marker for colorectal cancer monitoring.", 《ONCOSCIENCE》 * |
苗婕等: "肿瘤导向肽的研究进展", 《生命的化学》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114288426A (zh) * | 2022-01-07 | 2022-04-08 | 江西中医药大学 | 艾替班特及其衍生物在制备肿瘤诊断和/或治疗试剂中的应用 |
CN116813704A (zh) * | 2023-05-26 | 2023-09-29 | 豫章师范学院 | 一种肿瘤靶向荧光分子探针及其应用 |
CN116813704B (zh) * | 2023-05-26 | 2024-01-23 | 豫章师范学院 | 一种肿瘤靶向荧光分子探针及其应用 |
Also Published As
Publication number | Publication date |
---|---|
CN116375804A (zh) | 2023-07-04 |
CN116731104A (zh) | 2023-09-12 |
CN113880917B (zh) | 2023-04-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110845572B (zh) | 肿瘤靶向的grp类似物及其应用 | |
CN114796528B (zh) | 肿瘤特异性靶向的多肽及其应用 | |
EP3613441A1 (en) | Dual-target imaging molecular probe, preparation method therefor, and application thereof | |
CN114933633B (zh) | 一种特异性识别fgfr4的天然肽探针及其应用 | |
CN113880917B (zh) | 几种肿瘤高亲和肽及其应用 | |
CN111675750B (zh) | 针对癌胚抗原相关黏附分子ceacam的肿瘤靶向肽及其应用 | |
CZ20013562A3 (cs) | Konjugáty barviv s peptidy s krátkým řetězcem a jejich pouľití jako optických diagnostik | |
CN112933249A (zh) | 一种pd-l1靶向双模态分子探针及其制备方法和应用 | |
CN112961215B (zh) | 一种多肽及其肿瘤靶向肽、肿瘤检测试剂、肿瘤手术导航造影剂和肿瘤靶向药 | |
CN107629016B (zh) | 伊文氏蓝配合物及其制备方法和应用 | |
CN113817023B (zh) | 一种靶向fgfr4的亲和肽及其应用 | |
CN116063379A (zh) | EphA2靶向多肽及其应用 | |
CN116023438A (zh) | 一种cxcr4靶向多肽及其应用 | |
CN112480212A (zh) | 靶向肝细胞生长因子的高亲和肽及其应用 | |
CN115286693A (zh) | 针对癌胚抗原相关细胞黏附分子ceacam6的肿瘤靶向肽及其应用 | |
CN115677833A (zh) | 一种针对人表皮细胞生长因子受体2(her2)的肿瘤亲和肽 | |
CN114177314B (zh) | 胸腺五肽及其衍生物在制备肿瘤诊断和/或治疗试剂中的应用 | |
CN116813704B (zh) | 一种肿瘤靶向荧光分子探针及其应用 | |
CN115819525A (zh) | 一种靶向肿瘤的伤寒毒素b亚基模拟肽及其应用 | |
WO2024017317A1 (zh) | 一种her2靶向肽分子及其应用 | |
CN116023432A (zh) | 双唾液酸神经节苷脂gd2亲和肽及其应用 | |
CN117924419A (zh) | 一种靶向表皮生长因子受体2的亲和肽及其应用 | |
CN116410262A (zh) | 一种肿瘤亲和肽及其应用 | |
CN116462750A (zh) | 一种基于蛋白fgf19的仿生多肽及其应用 | |
CN114288426A (zh) | 艾替班特及其衍生物在制备肿瘤诊断和/或治疗试剂中的应用 |
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 |