CN103446586A - 二氢卟吩钛合物在制备治疗肿瘤药物中的应用 - Google Patents
二氢卟吩钛合物在制备治疗肿瘤药物中的应用 Download PDFInfo
- Publication number
- CN103446586A CN103446586A CN2013103715849A CN201310371584A CN103446586A CN 103446586 A CN103446586 A CN 103446586A CN 2013103715849 A CN2013103715849 A CN 2013103715849A CN 201310371584 A CN201310371584 A CN 201310371584A CN 103446586 A CN103446586 A CN 103446586A
- Authority
- CN
- China
- Prior art keywords
- chlorin
- tumor
- photosensitizer
- porphin
- drug
- 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 32
- 239000003814 drug Substances 0.000 title claims abstract description 28
- 229940079593 drug Drugs 0.000 title abstract description 12
- RKCAIXNGYQCCAL-UHFFFAOYSA-N porphin Chemical compound N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RKCAIXNGYQCCAL-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 title abstract description 7
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000010936 titanium Substances 0.000 title abstract description 3
- 229910052719 titanium Inorganic materials 0.000 title abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title abstract 3
- -1 chlorin titanium compound Chemical class 0.000 claims description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- ICLZNGAELWYHKL-CAPFRKAQSA-N (E)-3-[5-[5-[4-(N-phenylanilino)phenyl]thiophen-2-yl]thiophen-2-yl]prop-2-enoic acid Chemical group OC(=O)\C=C\c1ccc(s1)-c1ccc(s1)-c1ccc(cc1)N(c1ccccc1)c1ccccc1 ICLZNGAELWYHKL-CAPFRKAQSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 13
- 239000003504 photosensitizing agent Substances 0.000 description 35
- SURLGNKAQXKNSP-DBLYXWCISA-N chlorin Chemical compound C\1=C/2\N/C(=C\C3=N/C(=C\C=4NC(/C=C\5/C=CC/1=N/5)=CC=4)/C=C3)/CC\2 SURLGNKAQXKNSP-DBLYXWCISA-N 0.000 description 20
- 241000699670 Mus sp. Species 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 201000007270 liver cancer Diseases 0.000 description 8
- 208000014018 liver neoplasm Diseases 0.000 description 8
- 238000002428 photodynamic therapy Methods 0.000 description 8
- 239000000178 monomer Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical group CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 description 6
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 5
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- KGHNSNSWRMJVND-UHFFFAOYSA-N Hypocrellin Natural products COC1=CC(=O)C2=C3C4C(C(C(=O)C)C(C)(O)Cc5c(OC)c(O)c6C(=O)C=C(OC)C(=C13)c6c45)C(=C2O)OC KGHNSNSWRMJVND-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- BQJKVFXDDMQLBE-UHFFFAOYSA-N shiraiachrome A Natural products COC1=C2C3=C(OC)C=C(O)C4=C3C3=C5C(CC(C)(O)C(C(C)=O)C3=C(OC)C4=O)=C(OC)C(=O)C(C(O)=C1)=C25 BQJKVFXDDMQLBE-UHFFFAOYSA-N 0.000 description 5
- OYINILBBZAQBEV-UWJYYQICSA-N (17s,18s)-18-(2-carboxyethyl)-20-(carboxymethyl)-12-ethenyl-7-ethyl-3,8,13,17-tetramethyl-17,18,22,23-tetrahydroporphyrin-2-carboxylic acid Chemical compound N1C2=C(C)C(C=C)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1C(O)=O)=NC1=C(CC(O)=O)C([C@@H](CCC(O)=O)[C@@H]1C)=NC1=C2 OYINILBBZAQBEV-UWJYYQICSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- 241001597008 Nomeidae Species 0.000 description 4
- 206010034972 Photosensitivity reaction Diseases 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 229960003569 hematoporphyrin Drugs 0.000 description 4
- VANSZAOQCMTTPB-SETSBSEESA-N hypocrellin Chemical compound C1[C@@](C)(O)[C@@H](C(C)=O)C2=C(OC)C(O)=C3C(=O)C=C(OC)C4=C3C2=C2C3=C4C(OC)=CC(=O)C3=C(O)C(OC)=C21 VANSZAOQCMTTPB-SETSBSEESA-N 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 101710161048 Phytochrome 2 Proteins 0.000 description 3
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- WIQKYZYFTAEWBF-UHFFFAOYSA-L motexafin lutetium hydrate Chemical compound O.[Lu+3].CC([O-])=O.CC([O-])=O.C1=C([N-]2)C(CC)=C(CC)C2=CC(C(=C2C)CCCO)=NC2=CN=C2C=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=NC=C2C(C)=C(CCCO)C1=N2 WIQKYZYFTAEWBF-UHFFFAOYSA-L 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 208000007578 phototoxic dermatitis Diseases 0.000 description 3
- 231100000018 phototoxicity Toxicity 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 150000003609 titanium compounds Chemical class 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 3
- 229960003895 verteporfin Drugs 0.000 description 3
- 206010003445 Ascites Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010025421 Macule Diseases 0.000 description 2
- 206010067193 Naevus flammeus Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 208000006787 Port-Wine Stain Diseases 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical class C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 201000005619 esophageal carcinoma Diseases 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- ISVXIZFUEUVXPG-UHFFFAOYSA-N etiopurpurin Chemical compound CC1C2(CC)C(C(=O)OCC)=CC(C3=NC(C(=C3C)CC)=C3)=C2N=C1C=C(N1)C(CC)=C(C)C1=CC1=C(CC)C(C)=C3N1 ISVXIZFUEUVXPG-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 208000002026 familial multiple nevi flammei Diseases 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 150000004032 porphyrins Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229950003776 protoporphyrin Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 201000008261 skin carcinoma Diseases 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- SIEXFRDYNDREBM-UHFFFAOYSA-N 2-[[2-[7-carboxy-3-(2-carboxyethyl)-17-ethenyl-12-ethyl-2,8,13,18-tetramethyl-2,3,23,24-tetrahydroporphyrin-5-yl]acetyl]amino]butanedioic acid Chemical compound N1C2=C(C)C(C=C)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1C(O)=O)=NC1=C(CC(=O)NC(CC(O)=O)C(O)=O)C(C(CCC(O)=O)C1C)=NC1=C2 SIEXFRDYNDREBM-UHFFFAOYSA-N 0.000 description 1
- MHIITNFQDPFSES-UHFFFAOYSA-N 25,26,27,28-tetrazahexacyclo[16.6.1.13,6.18,11.113,16.019,24]octacosa-1(25),2,4,6,8(27),9,11,13,15,17,19,21,23-tridecaene Chemical compound N1C(C=C2C3=CC=CC=C3C(C=C3NC(=C4)C=C3)=N2)=CC=C1C=C1C=CC4=N1 MHIITNFQDPFSES-UHFFFAOYSA-N 0.000 description 1
- PUUBADHCONCMPA-USOGPTGWSA-N 3-[(21S,22S)-11-ethyl-16-(1-hexoxyethyl)-4-hydroxy-12,17,21,26-tetramethyl-7,23,24,25-tetrazahexacyclo[18.2.1.15,8.110,13.115,18.02,6]hexacosa-1,4,6,8(26),9,11,13(25),14,16,18(24),19-undecaen-22-yl]propanoic acid Chemical compound CCCCCCOC(C)C1=C(C2=NC1=CC3=NC(=CC4=C(C5=C(CC(=C6[C@H]([C@@H](C(=C2)N6)C)CCC(=O)O)C5=N4)O)C)C(=C3C)CC)C PUUBADHCONCMPA-USOGPTGWSA-N 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- VSEIDZLLWQQJGK-CHOZPQDDSA-N CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O Chemical compound CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O VSEIDZLLWQQJGK-CHOZPQDDSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 235000009421 Myristica fragrans Nutrition 0.000 description 1
- LYPFDBRUNKHDGX-SOGSVHMOSA-N N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 Chemical compound N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 LYPFDBRUNKHDGX-SOGSVHMOSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 229910010068 TiCl2 Inorganic materials 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000004035 chlorins Chemical class 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000002468 fat body Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- PSDMOPINLDTFSZ-UHFFFAOYSA-N lutetium(3+) Chemical compound [Lu+3] PSDMOPINLDTFSZ-UHFFFAOYSA-N 0.000 description 1
- 239000001115 mace Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 208000023983 oral cavity neoplasm Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000000258 photobiological effect Effects 0.000 description 1
- 229940109328 photofrin Drugs 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 208000017983 photosensitivity disease Diseases 0.000 description 1
- 231100000434 photosensitization Toxicity 0.000 description 1
- MCTOGTBIQBEIBZ-QHWUVJKOSA-K photrex Chemical compound CCOC(=O)C([C@@]1([C@H]2C)CC)=CC3=C1N([Sn](N14)(Cl)Cl)C2=CC(C(=C2C)CC)=NC2=CC1=C(CC)C(C)=C4C=C1C(CC)=C(C)C3=N1 MCTOGTBIQBEIBZ-QHWUVJKOSA-K 0.000 description 1
- 229960004293 porfimer sodium Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- MCTOGTBIQBEIBZ-RHJKTMSGSA-K rostaporfin Chemical compound CCOC(=O)C([C@]1([C@H]2C)CC)=CC3=C1N([Sn](N14)(Cl)Cl)C2=CC(C(=C2C)CC)=NC2=CC1=C(CC)C(C)=C4C=C1C(CC)=C(C)C3=N1 MCTOGTBIQBEIBZ-RHJKTMSGSA-K 0.000 description 1
- 229950005932 rostaporfin Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000012109 statistical procedure Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 229950010924 talaporfin Drugs 0.000 description 1
- 229960002197 temoporfin Drugs 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ZWYDDDAMNQQZHD-UHFFFAOYSA-L titanium(ii) chloride Chemical compound [Cl-].[Cl-].[Ti+2] ZWYDDDAMNQQZHD-UHFFFAOYSA-L 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了二氢卟吩钛合物在制备治疗肿瘤药物中的应用，相比于二氢卟吩本身，本发明的药物具有更好的治疗效果。
Description
技术领域
本发明涉及肿瘤治疗技术领域，尤其涉及二氢卟吩钛合物在制备治疗肿瘤药物中的应用。
背景技术
光动力治疗(Photodynamic treatment，PDT)是一种兴起于20世纪新的肿瘤治疗方法，随着大功率激光发生器及光敏剂的发展，PDT已成为除手术、放射治疗、化疗之外肿瘤治疗的第4种有效疗法。PDT治疗肿瘤时需要同时包括四个要素：基质、光敏剂、氧气、激光，其中光敏剂为PDT治疗的核心因素，其光敏性能直接决定了PDT对肿瘤的治疗效果。目前，光敏剂已进入第二代光敏剂的研发。最早用于PDT的光敏剂是血卟啉衍生物。Dougherty等从HpD中分离纯化出一种较强的光生物活性物质，是目前临床上常用的光敏剂即光敏素2(Photofrin2)，光敏素2于1992年由加拿大QLT光药物公司正式投产，是国际上第一个正式注册的光敏剂。光敏素2远好于HpD对肿瘤的抑制率。经我国食品药品监督局审理通过，酞氰光敏剂已于2009年1月开始临床试验研究，临床适应症以食管癌为主，其余包括支气管癌、鼻咽癌、头颈部肿瘤、皮肤癌、膀胱癌等。目前已经进入临床试验阶段的第一代光敏剂还有：卟吩姆钠，替莫泊芬，四间-羟基苯基二氢卟酚，维替泊芬，盐酸5-氨基乙酰丙酸，以及新近批准的甲基-氨基乙酰丙酸酯。目前还有几种有潜力的光敏剂正在临床试验中，包括：HPPH(2-[1-hexyloxylethyl]-2-divinyl pyropheophorbidea，Photochlor，Roswell Park Cancer Institute)，motexafin Lutetium(MLu，Lutetium(III)texaphyrin，Lu-Tex，Antrin，Pharmacyclics，inc)，Npe6(mono-L-aspartyl chlorin e6，taporfin sodium，talaporfin，LS11，Light ScienceCorporation)，SnET2(tin ethyl etiopurpurin，Sn etiopurpurin，Rostaporfin，Photrex，Miravant MedicalTechnologies)。
第一代光敏剂对肿瘤的治疗有效率高达到95％以上，但是在治疗过程中患者服药后需要避光处理一个月，对患者的日常生活造成极大的影响，严重影响了患者的生活质量也给患者心里造成比较大的影响。同时，第一代光敏剂给药途径为介入给药，需要对患者造成微创伤口，对晚期肿瘤患者特别是放化疗后免疫系统被破坏的患者造成了很多不必要的感染因素。其次，第一代光敏剂在患者服用后需要18-24h才能到达肿瘤病灶区，延长了治疗的整个治疗时间。第一代光敏剂由于其皮肤光毒性和光穿透力弱仅仅能用于表浅肿瘤，而且患者需暗室避光1月，且仪器操作繁杂，适应症有限，故而在国内外推广有限，如国内仅有南方医院和北京302医院有推广。
第二代光敏剂
国外的第二代光敏剂
1 苯卟啉衍生物单环酸A(BPD-MA)
BPD-MA是目前国外唯一被批准应用于临床的第二代光敏剂。它是由加拿大的QLT公司开发的，于2000年被美国食品与药物管理局(FDA)批准试用于肿瘤和视网膜黄斑变性的临床治疗。BPD-MA的优点是能用于治疗人体内位置更深且更大的肿瘤组织；在靶组织处快速集中，在正常组织处快速清除，药物进入5分钟后即可进行光照，不同于HpD那样要有两天等待时间：由于吸收快，清除也快，使对皮肤的光过敏性时间缩短为一天，而HpD要持续几周。但由于BPD-MA是源自天然产物的半合成产物，合成过程也比较复杂，总体产率很低，故原料合成的成本很高，同时其成品药物Verteporfin的制剂成本也非常高，所以一支含有15毫克有效成分的Verteporfin市场售价要一千美元左右，这就极大限制了其临床应用。目前该药还未在我国注册上市。
2 5－氨基酮戊酸(5-aminolevulinic acid，5-ALA)
5-ALA是一种内源性光敏剂，可在体内合成得到原卟啉IX(Protoporphyrin IX，PpIX)，进而转化成亚铁血红素过程中的一种中间产物。Pp IX有很强的光敏活性，因为是细胞的正常成份，其毒性低，代谢快，避光时间只需1～2天，PpIX可在很多肿瘤细胞内选择性聚集，在胃肠道肿瘤内比周围组织浓度高8～15倍，在皮肤乳腺肿瘤内比周围正常组织高10倍左右。635nm波长为5-ALA的最佳激发波长。自Kennedy等人1990年将5-ALA-PDT试用于临床以来，它在临床上治疗皮肤癌、食管癌、胃肠道肿、膀胱癌及肺癌的效果越来越得到肯定。
3 间-四羟基二氢卟吩(m-THPC)
m-THPC的单态氧产率高，在652nm和514nm的光敏化杀伤作用分别是HpD及Photofrin II的100倍和10倍，m-THPC的肿瘤选择性高，经肿瘤组织选择性摄取后，浓度可达正常组织的14倍。此外，m-THPC在体内代谢快、副作用小，皮肤光敏性低，只需避光10天左右。m-THPC对胸膜瘤、弥漫性间皮瘤、口腔肿瘤、结肠及直肠癌均有良好疗效，并可以有效预防恶性肿瘤的复发。
4二氢卟吩e6(Chlorin e6)
二氢卟吩e6(Chlorin e6)属叶绿素类新光敏剂，经化学处理后可得到单天冬氨酰基二氢卟吩(monoaspartyl-chlorin e6，Npe6)，后者在体内存留时间短，清除快，在波长664nm处有一强吸收峰，几乎不引起皮肤光敏副作用，现已进入二期临床试用。
红紫素类光敏剂
红紫素亦属于叶绿素类光敏剂，它是一个家族，较有代表性的有初红紫素(ET2)、八乙基红紫素(NT2)等。在有些红紫素大环中加一个金属原子形成金属红紫素如含锡的、锡原红紫素(SnEF2)，锡八乙基红紫素(SnNT2)等。它们多在650-670nm处有一强吸收峰。红紫素不容于水，可用脂制体、油乳剂或其它包裹复合物的形式输入体内，但同时也提高了其制备成本。
(2)国内的第二代光敏剂
目前国内正在开发的具有独立知识产权的第二代光敏剂主要有血卟啉单甲醚、竹红菌素类和二苯基卟吩(Diphenyl-2，3-dihydroxychlorin，DPCOH)。
血卟啉单甲醚
上海第二军医大学研制的血卟啉单甲醚，化学纯度可达99.8％，在体内排泄快，对肿瘤细胞的体外光敏杀伤效率与国外的第二代光敏剂ALA和BPD-MA相似。解放军总医院于1996年开始将其用于鲜红斑痣的临床治疗，已治疗患者近千例。临床结果显示，血卟啉单甲醚的组织选择性好，疗效稳定，避光时间短，是一种理想的治疗鲜红斑痣和视网膜黄斑变性的光敏剂。
竹红菌素
竹红菌素是我国特产的天然光敏物质。竹红菌素类化合物分离纯化相对简单、结构明确、光毒性强而暗毒性低，结构修饰和改性相对容易。近几年，中科院化学所利用竹红菌素母体分子合成了约40种不同的衍生物，部分衍生物的理化特性和光动力效率已达到或优于国外最新光敏剂。
DPCOH
DPCOH是中科院化学所合成的一种卟吩类光敏剂，具有很高的光动力活性，能够在有氧条件下光敏产生单重态氧(1O2)和超氧负离子(O2·－)，单重态氧量子产率为ΦΔ＝0.70。在无氧条件下，DPCOH可以高效地光敏化产生自身负离子自由基(Sen·－)。体外细胞实验表明，对于肿瘤细胞有很强的光动力杀伤作用，其光毒性是血卟啉衍生物(HPD)的200倍以上，而暗毒性特性基本上与HPD相当。
二氢卟吩类光敏剂属于卟啉类化合物，是一种典型的第二代光敏剂，以吡咯环为基本骨架核心，根据其支链的不同，二氢卟吩类光敏剂包括：二氢卟吩e6(Chlorin e6)及其衍生物、二氢卟吩e4(Chlorin e4)及其衍生物、二氢卟吩f(Chlorin f)及其衍生物、meso-四(间-羟基苯基)二氢卟吩(m-THPC)、单天门冬酰基二氢卟吩e6(Npe6)、二氢卟吩e6锌合物等。这几类化合物具有明确的化学结构式、红光区λmax较卟啉类光敏剂发生明显红移具有更强的人体组织穿透能力、摩尔吸收系数ε大、肿瘤选择性摄入率高、光敏作用强及在体内清除快等优点，已成为PDT研究领域的热点。其中，苯并卟啉单酸环A(BPD-MA)已于2001年在美国获准上市，MACE和SnET2也正在进行三期临床试验。虽然第二代光敏剂已经取得了长足的进步，但仍存在以下缺陷：水溶性差、人体吸收困难、肿瘤靶向性不高、光吸收率不理想、特异吸收光波长仍不理想对人体组织穿透率有限、单态氧产率不高对肿瘤的杀伤效果不理想、易被空气中的氧气氧化发生降解不利于保存。
二氢卟吩类光敏剂中吡咯环在电解质溶液中呈现负二价电负性，很容易与过渡金属发生化学反应形成二氢卟吩金属化合物，金属离子进入卟啉环后能很好的保护内部的氮原子不与环境中的氧化物、阳离子、基质等接触，并且能有效的压缩吡咯环中大π键的反键轨道，降低分子键中电子跃迁的能级，产生显著地大环反应效应，使化合物的特异激发光波长增加发生显著地红移。
发明内容
本发明所要解决的技术问题在于如何提高二氢卟吩的作用效果。为了实现本发明的目的，拟采用如下技术方案：
本发明一方面涉及式I所示的二氢卟吩钛合物在制备治疗肿瘤药物中的应用，优选的，所述的药物为光敏剂
在本发明的一个优选实施方式中，所述的药物仅包含二氢卟吩钛合物以及生理盐水。
本发明的二氢卟吩钛合物能够有效提高光敏剂的作用效果，对治疗肿瘤具有优异的效果。
附图说明
图1：二氢卟吩钛合物HNMR鉴定结果；
图2：二氢卟吩钛合物紫外可见光谱图；
图3：药物联合激光对H22小鼠肝癌生长的抑制作用。
具体实施方式
二氢卟吩钛合物的制备方法
以二氢卟吩e6单体为合成材料，将20g二氢卟吩e6(Chlorin e6，Ce6)溶于500mL乙醇中，(待充分溶解后，在氮气气氛保护下，采用660nm波长红光照射20min，并加热到70℃，以激活二氢卟吩。
在氮气保护气氛下将分析纯TiCl2溶于去离子水中并调节溶液pH值为8.2，加入激活后的二氢卟吩，避光缓慢搅拌，合成得到二氢卟吩e6钛合物。合成完成后，二氢卟吩钛合物加入无水乙醇中，氮气保护下50℃避光缓慢搅拌24h，得到稳定的二氢卟吩e6钛合物。
二氢卟吩钛合物的H NMR检测结果如图1所示，其紫外可见光谱如图2所示，相比于二氢卟吩e6，二氢卟吩钛合物特征吸收峰从630nm处红移至680nm左右，同时在相同浓度下其吸光度增加21％，同时其半峰宽也显著增加17％，光响应性能得到大幅提高。而同样是采用Zn和Cu所制备的二氢卟吩锌合物或者是铜合物，其光特征吸收峰仅从630nm处红移至655nm，其吸光度以及半峰宽未发生明显变化。
二氢卟吩e6钛合物联合激光照射荷瘤动物模型实验
实验目的：
根据《抗肿瘤药物药效学指导原则》和《细胞毒类抗肿瘤药物非临床研究技术指导原则》的要求，测试药物联合激光以及单体联合激光对H22小鼠肝癌的生长有无抑制作用以及作用的强度。
受试样品：
配制方法：药物无需自行配制，单体称取后溶于生理盐水中。
组别及给药方案：
模型对照组：尾静脉注射生理盐水，0.2ml／10g，每天1次，持续6次；
阳性组：腹腔注射环磷酰胺20mg／kg，0.2ml／10g，每天1次，持续6次；
药物联合激光组：尾静脉注射药物，0.025ml／10g，每天1次，持续6次；注射后2.5小时，每只小鼠均照射1分钟激光，注射后8.5小时，每只小鼠均照射1分钟激光；
单体联合激光组：尾静脉注射单体，0.2ml／10g，每天1次，持续6次；注射后2.5小时，每只小鼠均照射1分钟激光，注射后8.5小时，每只小鼠均照射1分钟激光；
激光照射组：尾静脉注射生理盐水，0.2ml／10g，每天1次，持续6次；注射后2.5小时，每只小鼠均照射1分钟激光，注射后8.5小时，每只小鼠均照射1分钟激光；
受试动物：
来源、种系、品系：清洁级ICR小鼠
实验动物生产许可证：SCXK(苏)2007-0001，合格证编号：0001817
实验动物使用许可证：SYXK(军)2007-030
体重：18-22g
性别：雄性
动物数：每组6只，共30只
实验方法：
1模型的制备
将液氮中冻存的细胞37℃水浴中快速解冻；在超净工作台内，PBS清洗复苏的细胞两次，0.2mlPBS重新混匀细胞，接种于ICR小鼠腹腔内；6天后，小鼠腹部肿大，断颈处死种鼠，乙醇浸泡后于超净工作台内抽取腹水；离心抽取的腹水用PBS清洗细胞2次，PBS重悬细胞计数，调整细胞悬液浓度为1*107个／ml；每只ICR右侧腋窝接种0.1ml。
2分组与给药
接种后待动物肿瘤长至长径约为0.8cm时随机分组，每组6只，给药方案见组别与给药方案，连续给药6天后测量肿瘤长短径，处死小鼠并拍照。手术剥取瘤块，称重，拍照并固定保存。
3观测指标
抗肿瘤活性的评价指标：肿瘤生长抑制率(％)，计算公式如下：
4统计处理
均值用X±SD表示，组间分析用t检验进行统计学处理，应用SPSS(Staffstical Package for the SocialScience)17.0对结果进行统计分析。
实验结果：
实验结果见附：表1药物联合激光照射对H22小鼠肝癌的抑制作用；图3药物联合激光对H22小鼠肝癌生长的抑制作用；
表1药物联合激光照射对H22小鼠肝癌的抑制作用(X±SD，n＝6，肿瘤体积单位：cm3，肿瘤重量单位：g)
*P＜0.05，**P＜0.01
本实验建立了H22小鼠移植瘤模型，利用该模型评价了药物联合激光照射对H22小鼠肝癌的抗肿瘤活性。实验结果为：药物联合激光组的抑瘤率为54.98％，而单体联合激光组的抑瘤率为22.65％。结论为：单体联合激光组对H22小鼠肝癌无明显的抗肿瘤作用，而药物(二氢卟吩钛)联合激光组对H22小鼠肝癌有明显的抗肿瘤作用，且有显著性差异，P＜0.01。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。
Claims (3)
1.式I所示的二氢卟吩钛合物在制备治疗肿瘤药物中的应用，优选的，所述的药物为光敏剂
2.根据权利要求1所述的应用，所述的药物仅包含二氢卟吩钛合物以及生理盐水。
3.权利要求1式I所示的二氢卟吩钛合物。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310371584.9A CN103446586B (zh) | 2013-08-22 | 2013-08-22 | 二氢卟吩钛合物在制备治疗肿瘤药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310371584.9A CN103446586B (zh) | 2013-08-22 | 2013-08-22 | 二氢卟吩钛合物在制备治疗肿瘤药物中的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103446586A true CN103446586A (zh) | 2013-12-18 |
| CN103446586B CN103446586B (zh) | 2015-08-19 |
Family
ID=49729693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310371584.9A Expired - Fee Related CN103446586B (zh) | 2013-08-22 | 2013-08-22 | 二氢卟吩钛合物在制备治疗肿瘤药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103446586B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112521410A (zh) * | 2020-12-29 | 2021-03-19 | 河南大学 | 一种InCe6卟啉组装体、其制备方法及应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102503947A (zh) * | 2011-11-02 | 2012-06-20 | 文剑 | 光氧动力治疗肿瘤用光敏剂二氢卟吩e6钛合物及制备方法 |
-
2013
- 2013-08-22 CN CN201310371584.9A patent/CN103446586B/zh not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102503947A (zh) * | 2011-11-02 | 2012-06-20 | 文剑 | 光氧动力治疗肿瘤用光敏剂二氢卟吩e6钛合物及制备方法 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112521410A (zh) * | 2020-12-29 | 2021-03-19 | 河南大学 | 一种InCe6卟啉组装体、其制备方法及应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103446586B (zh) | 2015-08-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5330741A (en) | Long-wavelength water soluble chlorin photosensitizers useful for photodynamic therapy and diagnosis of tumors | |
| JP5226317B2 (ja) | 新規のポルフィリン誘導体、特にクロリン及び／又はバクテリオクロリン、並びに光線力学療法におけるその適用 | |
| Gao et al. | Synthesis and evaluation of novel chlorophyll a derivatives as potent photosensitizers for photodynamic therapy | |
| Xu | Research and development of photodynamic therapy photosensitizers in China | |
| EP2931728B1 (en) | Chlorin derivative useful in photodynamic therapy and diagnosis | |
| Swavey et al. | Porphyrin and phthalocyanine photosensitizers as PDT agents: a new modality for the treatment of melanoma | |
| CN107638568B (zh) | 一种可生物降解的黑磷基放疗增敏剂及其制备方法与应用 | |
| Gurinovich et al. | Photodynamic activity of chlorin e6 and chlorin e6 ethylenediamide in vitro and in vivo | |
| Morgan et al. | Verdins: new photosensitizers for photodynamic therapy | |
| CN103724356A (zh) | 一种富勒烯卟啉类衍生物光敏剂及其制备方法与应用 | |
| Castro et al. | The surprisingly positive effect of zinc-phthalocyanines with high photodynamic therapy efficacy of melanoma cancer | |
| Boscencu et al. | Porphyrin macrocycles: General properties and theranostic potential | |
| CN104650129B (zh) | 一种轴向酯键连接哌啶或吗啉衍生物的硅酞菁 | |
| CN103446586B (zh) | 二氢卟吩钛合物在制备治疗肿瘤药物中的应用 | |
| Xiao et al. | Phycocyanobilin from Arthrospira platensis: A potential photodynamic anticancer agent | |
| Parab et al. | Sensitizers in photodynamic therapy | |
| Abrahamse et al. | Photodynamic therapy, a potential therapy for improve cancer management | |
| Ferreira et al. | Can efficiency of the photosensitizer be predicted by its photostability in solution? | |
| Melissari et al. | Porphyrinoids for photodynamic therapy | |
| CN105837583B (zh) | 卟烯‑铱金属配合物及其制备方法和应用 | |
| Yawalkar et al. | Fundamentals of photodynamic therapy | |
| Kulsi et al. | Sub cellular organelles-targeting photo dynamic therapy (PDT) | |
| Meerovich et al. | Hydroxyaluminium tetra-3-phenylthiophthalocyanine is a new effective photosensitizer for photodynamic therapy and fluorescent diagnosis | |
| Wang et al. | Synthesis and evolution of S-Porphin sodium as a potential antitumor agent for photodynamic therapy against breast cancer | |
| CN103254223B (zh) | 一种轴向氨基乙基苯氧基和低聚乙二醇修饰的硅酞菁 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| DD01 | Delivery of document by public notice |
Addressee: Liu Hui Document name: Notification to Pay the Fees |
|
| DD01 | Delivery of document by public notice |
Addressee: Liu Hui Document name: Notification of Termination of Patent Right |
|
| DD01 | Delivery of document by public notice | ||
| DD01 | Delivery of document by public notice | ||
| DD01 | Delivery of document by public notice |
Addressee: Liu Hui Document name: Notification of Decision on Request for Restoration of Right |
|
| DD01 | Delivery of document by public notice |
Addressee: Liu Hui Document name: Notification of Decision on Request for Restoration of Right |
|
| DD01 | Delivery of document by public notice | ||
| DD01 | Delivery of document by public notice |
Addressee: Liu Hui Document name: Notification to Pay the Fees |
|
| DD01 | Delivery of document by public notice | ||
| DD01 | Delivery of document by public notice |
Addressee: Liu Hui Document name: Notification of Termination of Patent Right |
|
| DD01 | Delivery of document by public notice | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150819 Termination date: 20170822 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |