CN110960686A - Phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy - Google Patents
Phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy Download PDFInfo
- Publication number
- CN110960686A CN110960686A CN201911369436.7A CN201911369436A CN110960686A CN 110960686 A CN110960686 A CN 110960686A CN 201911369436 A CN201911369436 A CN 201911369436A CN 110960686 A CN110960686 A CN 110960686A
- Authority
- CN
- China
- Prior art keywords
- polyethylene glycol
- phthalocyanine compound
- monomethyl ether
- tumor
- modified
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 Phthalocyanine compound Chemical class 0.000 title claims abstract description 87
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 52
- 238000002428 photodynamic therapy Methods 0.000 title abstract description 15
- 238000000799 fluorescence microscopy Methods 0.000 title abstract description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 87
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 86
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 42
- 230000008685 targeting Effects 0.000 claims abstract description 21
- 239000000126 substance Substances 0.000 claims abstract description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 239000007850 fluorescent dye Substances 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000009825 accumulation Methods 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 239000012634 fragment Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 66
- 239000000047 product Substances 0.000 description 44
- 238000010898 silica gel chromatography Methods 0.000 description 43
- 238000003786 synthesis reaction Methods 0.000 description 36
- 230000015572 biosynthetic process Effects 0.000 description 35
- 229910052725 zinc Inorganic materials 0.000 description 35
- 239000011701 zinc Substances 0.000 description 35
- XQZYPMVTSDWCCE-UHFFFAOYSA-N phthalonitrile Chemical compound N#CC1=CC=CC=C1C#N XQZYPMVTSDWCCE-UHFFFAOYSA-N 0.000 description 34
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 33
- 229910052786 argon Inorganic materials 0.000 description 33
- 239000004246 zinc acetate Substances 0.000 description 33
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 31
- CKFGINPQOCXMAZ-UHFFFAOYSA-N methanediol Chemical group OCO CKFGINPQOCXMAZ-UHFFFAOYSA-N 0.000 description 28
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Substances OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 27
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 239000003921 oil Substances 0.000 description 21
- 238000000746 purification Methods 0.000 description 17
- 238000012512 characterization method Methods 0.000 description 16
- 235000019256 formaldehyde Nutrition 0.000 description 14
- 229920006391 phthalonitrile polymer Polymers 0.000 description 14
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 13
- 239000012043 crude product Substances 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 239000012972 dimethylethanolamine Substances 0.000 description 11
- 238000001819 mass spectrum Methods 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 239000002504 physiological saline solution Substances 0.000 description 8
- 210000003462 vein Anatomy 0.000 description 8
- 239000003814 drug Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002189 fluorescence spectrum Methods 0.000 description 6
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000002211 ultraviolet spectrum Methods 0.000 description 6
- 201000007270 liver cancer Diseases 0.000 description 5
- 208000014018 liver neoplasm Diseases 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OQHXZZGZASQSOB-UHFFFAOYSA-N 3,4,5,6-tetrachlorobenzene-1,2-dicarbonitrile Chemical compound ClC1=C(Cl)C(Cl)=C(C#N)C(C#N)=C1Cl OQHXZZGZASQSOB-UHFFFAOYSA-N 0.000 description 4
- SRIJSZQFAMLVQV-UHFFFAOYSA-N 4,5-dichlorobenzene-1,2-dicarbonitrile Chemical compound ClC1=CC(C#N)=C(C#N)C=C1Cl SRIJSZQFAMLVQV-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000013399 early diagnosis Methods 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003504 photosensitizing agent Substances 0.000 description 4
- 229920000573 polyethylene Polymers 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- GODZNYBQGNSJJN-UHFFFAOYSA-N 1-aminoethane-1,2-diol Chemical compound NC(O)CO GODZNYBQGNSJJN-UHFFFAOYSA-N 0.000 description 2
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 2
- RSKSHEHZUXLZHF-UHFFFAOYSA-N 3,6-dichlorobenzene-1,2-dicarbonitrile Chemical compound ClC1=CC=C(Cl)C(C#N)=C1C#N RSKSHEHZUXLZHF-UHFFFAOYSA-N 0.000 description 2
- MPAIWVOBMLSHQA-UHFFFAOYSA-N 3,6-dihydroxybenzene-1,2-dicarbonitrile Chemical compound OC1=CC=C(O)C(C#N)=C1C#N MPAIWVOBMLSHQA-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 108091023037 Aptamer Proteins 0.000 description 2
- 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 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000002059 diagnostic imaging Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229960004293 porfimer sodium Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229940014800 succinic anhydride Drugs 0.000 description 2
- 229950010924 talaporfin Drugs 0.000 description 2
- 229960002197 temoporfin Drugs 0.000 description 2
- JLGLQAWTXXGVEM-UHFFFAOYSA-N triethylene glycol monomethyl ether Chemical compound COCCOCCOCCO JLGLQAWTXXGVEM-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-O N-dimethylethanolamine Chemical compound C[NH+](C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-O 0.000 description 1
- 0 NC*CCCCCCCC*CC1CC1 Chemical compound NC*CCCCCCCC*CC1CC1 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 239000000562 conjugate Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000012634 optical imaging Methods 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000002165 photosensitisation Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- 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
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
-
- 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
- A61K49/0036—Porphyrins
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33303—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group
- C08G65/33306—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group acyclic
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33365—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing cyano group
- C08G65/33375—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing cyano group cyclic
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G2650/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterized by the type of post-polymerisation functionalisation
- C08G2650/04—End-capping
Abstract
The invention discloses a polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy and application thereof. The polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound has the following structure:
Description
Technical Field
The invention belongs to the field of organic synthesis and medicines, particularly relates to a phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy and application thereof, and particularly relates to application of a polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound in preparation of a tumor targeted fluorescence probe and a photodynamic antitumor drug.
Background
2011 WHO suggested that 40% of cancer patients can be cured by early discovery, early diagnosis and early treatment, which fully explains the necessity and importance of early discovery and early diagnosis of cancer[1]. The medical imaging technology can carry out early diagnosis and prognosis evaluation on diseases, provides information such as the position, the size, whether metastasis occurs and the like of a tumor, and has unique advantages in the aspects of early diagnosis and treatment of the tumor. Wherein the optical imaging technique has many advantages compared with the traditional imaging modes such as Ultrasound (US), electronic Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET) and the like, such as high sensitivity, non-ionic low-energy radiation, non-invasive or minimally invasive, continuous real-time monitoring, low equipment price and the like[2]. Wherein, near infrared Fluorescence (NIRF) has stronger tissue penetration depth due to the wavelength range of 650-900nm, and meanwhile, the tissue autofluorescence is weaker, so that the near infrared Fluorescence (NIRF) has a superior in vivo Fluorescence imaging effect. The near-infrared fluorescence imaging can help doctors to accurately obtain tumor boundary information in the operation, and compared with the method that doctors rely on subjective vision and palpation in the operation, the near-infrared fluorescence imaging can effectively and objectively evaluate tumors and residual tissues thereof, and realize accurate diagnosis and treatment of the tumors. Fluorescence imaging has been used for intraoperative localization of primary tumors in clinical studies[3]Surgical navigation[4,5]Identification of normal and diseased parathyroid glands[6]And other biomedical imaging[7-10]。
The tumor targeting probe can realize selective accumulation in tumor tissues, so that the construction of the high-selectivity targeting probe is the key point and difficulty of medical imaging research. The most reported tumor targeting probes are mainly based on antibody[11-14]Polypeptide, and a process for producing the same[15-17]Aptamer and aptamer[18]And small molecule receptor-ligand, the probe has the defects of high cost, low immunogenicity, low affinity, short half-life and the like, and limits the clinical application to a certain extentBed conversion[19]。
Photodynamic Therapy (PDT) is to utilize photosensitizer to convert oxygen molecules into high-activity singlet oxygen under the irradiation of laser with specific wavelength, and the singlet oxygen reacts with macromolecules in tumor cells to generate oxidation reaction, thereby damaging tumor tissues and playing an anti-tumor role[20]. The core of photodynamic therapy is photosensitizer, and various photosensitizing drugs such as Temoporfin (Temoporfin), Porfimer Sodium (Porfimer Sodium), Talaporfin Sodium (Talaporfin Sodium) and the like are approved to be applied to photodynamic therapy of malignant tumors such as head and neck cancer, gastric cancer, cervical cancer and the like at present.
The phthalocyanine is a planar macrocyclic molecule with 18 conjugated electrons, has excellent physical and chemical stability, has fluorescence emission wavelength near 690nm, belongs to a near-infrared I-region fluorescent agent, has high fluorescence quantum yield and singlet oxygen yield, can be used for fluorescence imaging and photodynamic therapy, and is a representative of a second-generation photosensitizer. However, the poor water solubility and easy aggregation of phthalocyanine compounds limit the application of the phthalocyanine compounds[21]. The modified compound can enhance water solubility, reduce toxicity, and change the circulation time and the pharmacokinetic characteristic of the medicine in vivo. Chinese patent CN 102675625B reports a synthesis method of octacarboxyl metal phthalocyanine polyethylene glycol modifier, and the compound has good water solubility. Chinese patent CN 103254223B reports that an axial oligo-ethylene glycol modified silicon phthalocyanine has good amphipathy and photodynamic activity. Chinese patent CN 103626781B, CN 103554116B, CN 104447769B reports that metal phthalocyanine is connected with tumor targeting drugs through an oligoethylene glycol chain to construct phthalocyanine-gefitinib, phthalocyanine-tamoxifen and phthalocyanine-erlotinib conjugates so as to enhance tumor targeting property and anti-tumor activity.
The invention synthesizes mono-substituted, di-substituted, tetra-substituted, eight-substituted and sixteen-substituted polyethylene glycol monomethyl ether (or polyethylene glycol) modified phthalocyanine compounds with different chain lengths, researches the accumulation characteristics and photodynamic treatment effect of the phthalocyanine compounds in tumor tissues and explores the structure-activity relationship.
Reference to the literature
[1]Siegel R L,Miller K D,Jemal A.Cancer statistics,2017[J].CA:acancer journal for clinicians,2017,67(1):7-30.
[2]Hong G S,Antaris A L,Dai H J.Near-infrared fluorophores forbiomedical imaging[J].Nature Biomedical Engineering,2017,1(1):0010.
[3]Nguyen Q T,Tsien R Y.Fluorescence-guided surgery with livemolecular navigation--a new cutting edge[J].Nat Rev Cancer,2013,13(9):653-662.
[4]Tummers Q R,Verbeek F P,Prevoo H A,et al.First experience onlaparoscopic near-infrared fluorescence imaging of hepatic uveal melanomametastases using indocyanine green[J].Surg Innov,2015,22(1):20-25.
[5]Tummers Q R,Schepers A,Hamming J F,et al.Intraoperative guidancein parathyroid surgery using near-infrared fluorescence imaging and low-dosemethylene blue[J].Surgery,2015,158(5):1323-1330.
[6]Yeung T M,Wang L M,Colling R,et al.Intraoperative identificationand analysis of lymph nodes at laparoscopic colorectal cancer surgery usingfluorescence imaging combined with rapid OSNA pathological assessment[J].SurgEndosc,2018,32(2):1073-1076.
[7]Backes F J,Cohen D,Salani R,et al.Prospective clinical trial ofrobotic sentinel lymph node assessment with isosulfane blue(ISB)andindocyanine green(ICG)in endometrial cancer and the impact of ultrastaging(NCT01818739)[J].Gynecol Oncol,2019,153(3):496-499.
[8]Verbeek F P,Schaafsma B E,Tummers Q R,et al.Optimization of near-infrared fluorescence cholangiography for open and laparoscopic surgery[J].Surg Endosc,2014,28(4):1076-1082.
[9]Verbeek F P,van der Vorst J R,Schaafsma B E,et al.Intraoperativenear infrared fluorescence guided identification of the ureters using lowdose methylene blue:a first in human experience[J].J Urol,2013,190(2):574-579.
[10]van Dongen G A,Visser G W,Vrouenraets M B.Photosensitizer-antibody conjugates for detection and therapy of cancer[J].Adv Drug DelivRev,2004,56(1):31-52.
[11]Urano Y,Asanuma D,Hama Y,et al.Selective molecular imaging ofviable cancer cells with pH-activatable fluorescence probes[J].Nat Med,2009,15(1):104-109.
[12]Zettlitz K A,Waldmann C M,Tsai W K,et al.A dual-modality linkerenables site-specific conjugation of antibody fragments for18F-Immuno-PET andfluorescence imaging[J].JNucl Med,2019,60(10):1467-1473.
[13]El-Sayed A,Bernhard W,Barreto K,et al.Evaluation of antibodyfragment properties for near-infrared fluorescence imaging of HER3-positivecancer xenografts[J].Theranostics,2018,8(17):4856-4869.
[14]Ranyuk E,Cauchon N,Klarskov K,et al.Phthalocyanine-peptideconjugates:receptor-targeting bifunctional agents for imaging andphotodynamic therapy[J].J Med Chem,2013,56(4):1520-1534.
[15]Wang W,Hu Z.Targeting peptide-based probes for molecular imagingand diagnosis[J].Adv Mater,2019,31(45):e1804827.
[16]Wang W,Ma Z,Zhu S,et al.Molecular cancer imaging in the secondnear-infrared window using a renal-excreted NIR-II fluorophore-peptide probe[J].Adv Mater,2018,30(22):e1800106.
[17]Hwang D W,Ko H Y,Lee J H,et al.A nucleolin-targeted multimodalnanoparticle imaging probe for tracking cancer cells usingan aptamer[J].JNucl Med,2010,51(1):98-105.
[18]Zhao M,Liu Z,Dong L,et al.A GPC3-specificaptamer-mediatedmagnetic resonance probe for hepatocellular carcinoma[J].Int J Nanomedicine,2018,13:4433-4443.
[19]Ahmed S,Strand S,Weinmann-Menke J,et al.Molecular endoscopicimaging in cancer[J].Dig Endosc,2018,30(6):719-729.
[20]Benov L.Photodynamic therapy:current status and future directions[J].Med Princ Pract,2015,24(Suppl 1):14-28.
[21]Michael T M Choi,Pearl P S Li,Dennis K P Ng.A direct comparisonof the aggregation behavior of phthalocyanines and 2,3-naphthalocyanines[J].Tetrahedron 2000,56(24):3881-3887.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound with tumor targeting.
The second purpose of the invention is to provide the application of the polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound with tumor targeting as a tumor targeting fluorescent probe.
The third purpose of the invention is to provide the application of the polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound with tumor targeting as the photodynamic anti-tumor medicament.
The purpose of the invention is realized by the following technical scheme:
a polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound with tumor targeting has the following structure:
wherein the content of the first and second substances,
n＝25-125，X1either O or NH, X2OH or OCH3；
n＝4-30，X1Either O or NH, X2OH or OCH3；R3/R4H or
R3，R4Not simultaneously being H, when R3＝H，
When n is 25-75, X1Either O or NH, X2OH or OCH3When R is4＝H，
When n is 25-75, X1Either O or NH, X2OH or OCH3When is coming into contact with
When n is 5-38, X1Either O or NH, X2OH or OCH3；R5/R6H or
R5，R6Not simultaneously H, n-2-25, X1Either O or NH, X2OH or OCH3。
An application of polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound with tumor targeting in preparing a tumor targeting fluorescent probe.
An application of polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound with tumor targeting in preparing photodynamic antitumor drugs.
The polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound can selectively accumulate in tumor tissues within a specific molecular weight range, and has tumor targeting without connecting a tumor targeting segment. The polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound provided by the invention has the advantages of good chemical stability, low toxicity and appropriate half-life, and can be independently or simultaneously applied to tumor targeted fluorescence imaging and tumor photodynamic therapy.
Drawings
FIG. 1 is a mass spectrum of a PEGylated monomethyl ether-modified zinc phthalocyanine compound in example 1 of the present invention.
FIG. 2 is a mass spectrum of a PEGylated monomethyl ether-modified zinc phthalocyanine compound in example 2 of the present invention.
FIG. 3 is a mass spectrum of a PEGylated monomethyl ether-modified zinc phthalocyanine compound in example 3 of the present invention.
FIG. 4 is a mass spectrum of a PEGylated monomethyl ether-modified zinc phthalocyanine compound of example 4 of the present invention.
FIG. 5 is a mass spectrum of a PEGylated monomethyl ether-modified zinc phthalocyanine compound of example 5 of the present invention.
FIG. 6 is a mass spectrum of a PEGylated monomethyl ether-modified zinc phthalocyanine compound of example 11 in accordance with the present invention.
FIG. 7 is a mass spectrum of a PEGylated monomethyl ether-modified zinc phthalocyanine compound of example 13 of the present invention.
FIG. 8 is a mass spectrum of a PEGylated monomethyl ether-modified zinc phthalocyanine compound of example 14 of the present invention.
FIG. 9 is a mass spectrum of a polyethylene glycol-modified zinc phthalocyanine compound according to example 18 of the present invention.
FIG. 10 is a mass spectrum of a polyethylene glycol-modified zinc phthalocyanine compound according to example 20 of the present invention.
FIG. 11 shows an ultraviolet spectrum and a fluorescence spectrum of a polyethylene glycol monomethyl ether-modified zinc phthalocyanine compound according to example 24 of the present invention.
FIG. 12 shows an ultraviolet spectrum and a fluorescence spectrum of a polyethylene glycol monomethyl ether-modified zinc phthalocyanine compound according to example 25 of the present invention.
FIG. 13 shows an ultraviolet spectrum and a fluorescence spectrum of a polyethylene glycol monomethyl ether-modified zinc phthalocyanine compound according to example 26 of the present invention.
FIG. 14 shows an ultraviolet spectrum and a fluorescence spectrum of a polyethylene glycol monomethyl ether-modified zinc phthalocyanine compound according to example 27 of the present invention.
FIG. 15 shows an ultraviolet spectrum and a fluorescence spectrum of a polyethylene glycol monomethyl ether-modified zinc phthalocyanine compound according to example 28 of the present invention.
FIG. 16 shows an ultraviolet spectrum and a fluorescence spectrum of a polyethylene glycol monomethyl ether-modified zinc phthalocyanine compound according to example 29 of the present invention.
FIG. 17 is a photograph of living body/tissue near-infrared fluorescence images of PEGylated monomethylether zinc phthalocyanine compounds of examples 3, 4,5, 6 and 11 of the present invention.
FIG. 18 shows the PEGylated monomethyl ether-modified zinc phthalocyanine compounds in examples 5 and 11 of the present invention for photodynamic therapy of liver cancer H22The results of the in vivo experiments of the mice are shown.
Detailed Description
The invention is further illustrated by the following examples, which are intended only for a better understanding of the invention and do not limit the scope of the invention:
example 1 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
1.99g of phthalonitrile, 5.0g of polyethylene glycol monomethyl ether (average molecular weight 500) -modified phthalonitrile and 1.43g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine under protection of argon and reacted at 135 ℃ for 24 h. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-20/1 provided the desired product in 23.0% yield (see figure 1 for characterization). The structural formula is as follows:
example 2 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
1.99g of phthalonitrile, 9.0g of polyethylene glycol monomethyl ether (average molecular weight 1000) modified phthalonitrile and 1.43g of zinc acetate were dissolved in 40mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-20/1 provided the desired product in 22.1% yield (see figure 2 for characterization). The structural formula is as follows:
example 3 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
1.99g of phthalonitrile, 17.0g of polyethylene glycol monomethyl ether (average molecular weight 2000) -modified phthalonitrile and 1.43g of zinc acetate were dissolved in 40mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-20/1 provided the desired product in 20.3% yield (see figure 3 for characterization). The structural formula is as follows:
example 4 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
1.0g of phthalonitrile, 12.5g of polyethylene glycol monomethyl ether (average molecular weight 3000) modified phthalonitrile and 0.7g of zinc acetate were dissolved in 40mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-20/1 provided the desired product in 19.5% yield (see figure 4 for characterization). The structural formula is as follows:
example 5 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
1.0g of phthalonitrile, 16.5g of polyethylene glycol monomethyl ether (average molecular weight 4000) -modified phthalonitrile and 0.7g of zinc acetate were dissolved in 40mL of N, N-dimethylethanolamine under protection of argon and reacted at 135 ℃ for 24 h. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-20/1 provided the desired product in 17.2% yield (see figure 5 for characterization). The structural formula is as follows:
example 6 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
0.5g of phthalonitrile, 10.0g of polyethylene glycol monomethyl ether (average molecular weight 5000) -modified phthalonitrile and 0.35g of zinc acetate are dissolved in 40mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-20/1 gave the desired product in 5.1% yield. The structural formula is as follows:
example 7 Synthesis of Zinc Phthalocyanine Compound modified with polyethylene glycol
2.83g of phthalonitrile, 10.0g of polyethylene glycol (average molecular weight 1000) modified phthalonitrile and 1.5g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 40/1-20/1 gave the desired product in 15.1% yield.
The structural formula is as follows:
EXAMPLE 8 Synthesis of Zinc Phthalocyanine Compound modified with polyethylene glycol
0.4g of phthalonitrile, 10.0g of polyethylene glycol (average molecular weight 5000) -modified phthalonitrile and 0.3g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 30/1-10/1 gave the desired product in 3.6% yield.
The structural formula is as follows:
example 9 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
0.2g of ZnPc-NH2Dissolved in 10mL of dry pyridine, added with 40mg of succinic anhydride, and reacted at 60 ℃ for 4 hours. And (5) evaporating the solvent under reduced pressure, washing with water, and drying to obtain a bluish purple product. Dissolving 50mg of the bluish purple product in 10mL of DMF, adding 290mg of methoxypolyethylene glycol amine (average molecular weight 4000), 28mg of EDCI and 1mg of DMAP, reacting at room temperature for 24h, and separating by silica gel column chromatography to obtain the target product with the yield of 71.3 percent. The structural formula is as follows:
example 10 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
5.0g of polyethylene glycol monomethyl ether (average molecular weight 200) modified phthalonitrile and 0.6g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24 hours under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-10/1 gave the desired product in 65.1% yield. The structural formula is as follows:
example 11 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
5.0g of polyethylene glycol monomethyl ether (average molecular weight of 350) modified phthalonitrile and 0.5g of zinc acetate are dissolved in 30mL of N, N-dimethylethanolamine and reacted for 24h at 135 ℃ under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-10/1 provided the desired product in 68.3% yield (see figure 6 for characterization). The structural formula is as follows:
example 12 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
5.0g of polyethylene glycol monomethyl ether (average molecular weight 500) modified phthalonitrile and 0.4g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-10/1 gave the desired product in 66.0% yield. The structural formula is as follows:
example 13 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
5.0g of polyethylene glycol monomethyl ether (average molecular weight of 750) modified phthalonitrile and 0.32g of zinc acetate are dissolved in 30mL of N, N-dimethylethanolamine and reacted for 24h at 135 ℃ under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-10/1 provided the desired product in 56.2% yield (see figure 7 for characterization). The structural formula is as follows:
example 14 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
5.0g of polyethylene glycol monomethyl ether (average molecular weight is 1000) modified phthalonitrile and 0.22g of zinc acetate are dissolved in 30mL of N, N-dimethylethanolamine and reacted for 24h at 135 ℃ under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-10/1 provided the desired product in 43.3% yield (see figure 8 for characterization). The structural formula is as follows:
example 15 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
6.6g of polyethylene glycol monomethyl ether (average molecular weight 1200) modified phthalonitrile and 0.23g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-10/1 gave the desired product in 36.8% yield. The structural formula is as follows:
example 16 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
8.2g of polyethylene glycol monomethyl ether (average molecular weight 2000) modified phthalonitrile and 0.23g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24 hours under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-10/1 gave the desired product in 9.8% yield. The structural formula is as follows:
example 17 Synthesis of Zinc Phthalocyanine Compound modified with polyethylene glycol
5.0g of polyethylene glycol (average molecular weight 200) -modified phthalonitrile and 0.7g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under the protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-10/1 gave the desired product in 66.2% yield. The structural formula is as follows:
EXAMPLE 18 Synthesis of Zinc Phthalocyanine Compound modified with polyethylene glycol
5.0g of polyethylene glycol (average molecular weight 300) -modified phthalonitrile and 0.56g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under protection of argon. Concentration under reduced pressure gave a dark green oil. Purification by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-10/1 provided the desired product in 60.2% yield (see figure 9 for characterization).
The structural formula is as follows:
EXAMPLE 19 Synthesis of Zinc Phthalocyanine Compound modified with polyethylene glycol
5.0g of polyethylene glycol (average molecular weight 400) modified phthalonitrile and 0.5g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under the protection of argon. Concentration under reduced pressure gave a dark green oil which was purified by column chromatography on silica gel with a gradient elution of dichloromethane/methanol 50/1-10/1 to give the desired product in 45.7% yield. The structural formula is as follows:
EXAMPLE 20 Synthesis of Zinc Phthalocyanine Compound modified with polyethylene glycol
5.0g of polyethylene glycol (average molecular weight 600) modified phthalonitrile and 0.35g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under the protection of argon. Concentration under reduced pressure gave a dark green oil which was purified by column chromatography on silica gel with a dichloromethane/methanol gradient 50/1-10/1 to give the desired product in 30.7% yield (see figure 10 for characterization).
The structural formula is as follows:
example 21 Synthesis of Zinc Phthalocyanine Compound modified with polyethylene glycol
5.0g of polyethylene glycol (average molecular weight 800) modified phthalonitrile and 0.27g of zinc acetate were dissolved in 30mL of N, N-dimethylethanolamine and reacted at 135 ℃ for 24h under protection of argon. Concentration under reduced pressure gave a dark green oil which was purified by column chromatography on silica gel with a gradient elution of dichloromethane/methanol 50/1-10/1 to give the desired product in 26.7% yield. The structural formula is as follows:
EXAMPLE 22 Synthesis of Zinc Phthalocyanine Compound modified with polyethylene glycol
6.0g of phthalonitrile modified with polyethylene glycol (average molecular weight 1500) and 0.22g of zinc acetate were dissolved in 30ml of N-dimethylethanolamine and reacted at 135 ℃ for 24 hours under the protection of argon. Concentration under reduced pressure gave a dark green oil which was purified by column chromatography on silica gel with a gradient elution of dichloromethane/methanol 50/1-10/1 to give the desired product in 20.4% yield. The structural formula is as follows:
example 23 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
0.2g of ZnPc- (NH)2)4Dissolved in 10mL of dry pyridine, added with 160mg of succinic anhydride, and reacted at 60 ℃ for 4 hours. And (5) evaporating the solvent under reduced pressure, washing with water, and drying to obtain a bluish purple product. Dissolving 200mg of the bluish purple product in 10mL of DMF, adding 260mg of methoxypolyethylene glycol amine (average molecular weight 350), 115mg of EDCI and 4mg of DMAP, reacting at room temperature for 24h, and separating by silica gel column chromatography to obtain the target product with the yield of 81.6%. The structural formula is as follows:
example 24 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
Dissolving 1.0g of 3, 6-dihydroxy phthalonitrile in 30mL of DMF, adding 1.9g of potassium carbonate and 12.5g of polyethylene glycol monomethyl ether mesylate (M.W.1000), reacting at 60 ℃ for 24h, and separating a crude product by silica gel column chromatography to obtain a light yellow semisolid. Dissolving the obtained pale yellow semisolid 2.0g and 20mL of DMEA, adding 232mg of phthalonitrile, 120mg of zinc acetate and argon protection, and reacting at 135 ℃ for 24 h. The product was isolated by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-20/1 to give 11.2% yield (see figure 11 for characterization). The structural formula is as follows:
example 25 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
Dissolving 1.0g of 3, 6-dihydroxy phthalonitrile in 50mL of DMF, adding 1.9g of potassium carbonate and 40g of polyethylene glycol monomethyl ether mesylate (M.W.3000), reacting at 60 ℃ for 24h, and separating a crude product by silica gel column chromatography to obtain a light yellow semisolid. Dissolving the obtained pale yellow semisolid 2.0g and 20mL of DMEA, adding 85mg of phthalonitrile, 30mg of zinc acetate and argon protection, and reacting at 135 ℃ for 24 h. The product was isolated by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-20/1 to give the desired product in 6.1% yield (see figure 12 for characterization). The structural formula is as follows:
example 26 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
Dissolving 1.0g of 4, 5-dichloro phthalonitrile in 10mL of DMF, adding 1.6g of potassium carbonate and 12g of polyethylene glycol monomethyl ether (M.W.1000), reacting at 60 ℃ for 24h, and separating a crude product by silica gel column chromatography to obtain a light yellow semisolid. 2.0g of the obtained pale yellow semisolid and 20mL of DMEA are dissolved, and 230mg of phthalonitrile, 125mg of zinc acetate and argon protection are added to react for 24 hours at 135 ℃. The product was isolated by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-20/1 to give the desired product in 10.6% yield (see figure 13 for characterization). The structural formula is as follows:
example 27 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
Dissolving 1.0g of 4, 5-dichloro phthalonitrile in 10mL of DMF, adding 1.9g of potassium carbonate and 36g of polyethylene glycol monomethyl ether (M.W.3000), reacting at 60 ℃ for 24h, and separating a crude product by silica gel column chromatography to obtain a light yellow semisolid. Dissolving the obtained pale yellow semisolid 2.0g and 20mL of DMEA, adding 85mg of phthalonitrile, 36mg of zinc acetate and argon protection, and reacting at 135 ℃ for 24 h. The product was isolated by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-20/1 to give the desired product in 5.8% yield (see figure 14 for characterization). The structural formula is as follows:
example 28 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
Dissolving tetrachlorophthalonitrile 1.0g in DMF 30mL, adding diethylene glycol monomethyl ether 2g and potassium carbonate 2.3g, reacting at 60 ℃ for 24h, and separating the crude product by silica gel column chromatography to obtain a light yellow oily substance. 1.0g of the obtained pale yellow oily substance is taken, 20ml of MEA is dissolved, 300mg of zinc acetate is added, and the mixture reacts for 24 hours at 135 ℃ under the protection of argon. The product was isolated by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 60/1-30/1 to give the desired product in 24.0% yield (see figure 15 for characterization). The structural formula is as follows:
example 29 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
1.0g of tetrachlorophthalonitrile is dissolved in 30mL of DMF, 332g of polyethylene glycol monomethyl ether (M.W.1500) and 2.3g of potassium carbonate are added, the mixture reacts for 24 hours at the temperature of 60 ℃, and a crude product is separated by silica gel column chromatography to obtain a light yellow oily substance. 1.0g of the obtained light yellow oily substance is taken and dissolved with 20mL of DMEA, and 30mg of phthalonitrile, 30mg of zinc acetate and argon protection are added for reaction at 135 ℃ for 24 h. The product was isolated by silica gel column chromatography eluting with a dichloromethane/methanol gradient 50/1-20/1 to give the desired product in 13.2% yield (see figure 16 for characterization). The structural formula is as follows:
example 30 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
Dissolving tetrachlorophthalonitrile 1.0g in DMF 30mL, adding diethylene glycol monomethyl ether 2.0g and potassium carbonate 2.3g, reacting at 60 ℃ for 24h, and separating the crude product by silica gel column chromatography to obtain light yellow oily matter. 1.0g of the obtained pale yellow oily substance is taken and dissolved with 20mL of DMEA, and 110mg of zinc acetate is added to react for 24h at 135 ℃ under the protection of argon. Separation by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-20/1 gave the desired product in 56.6% yield. The structural formula is as follows:
example 31 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
Dissolving tetrachlorophthalonitrile 1.0g in DMF 30mL, adding polyethylene glycol monomethyl ether (M.W.1000)18.0g and potassium carbonate 2.3g, reacting at 60 deg.C for 24h, and separating the crude product by silica gel column chromatography to obtain pale yellow oily substance. 1.0g of the obtained pale yellow oily substance is taken and dissolved with 20mL of DMEA, and 50mg of zinc acetate is added to react for 24h at 135 ℃ under the protection of argon. Separation by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-20/1 gave the desired product in 21.9% yield. The structural formula is as follows:
example 32 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
Dissolving 1.0g of 4, 5-dichloro phthalonitrile in 30mL of DMF, adding 3.1g of triethylene glycol monomethyl ether and 2.3g of potassium carbonate, reacting at 60 ℃ for 24 hours, and separating a crude product by silica gel column chromatography to obtain a light yellow oily substance. 1.0g of the obtained pale yellow oily substance is taken and dissolved with 20mL of DMEA, and 110mg of zinc acetate is added to react for 24h at 135 ℃ under the protection of argon. Separation by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-20/1 gave the desired product in 65.2% yield. The structural formula is as follows:
example 33 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
1.0g of 4, 5-dichloro phthalonitrile is dissolved in 30mL of DMF, 18g of polyethylene glycol monomethyl ether (averageMw1000) and 2.3g of potassium carbonate are added, the mixture reacts for 24 hours at the temperature of 60 ℃, and a crude product is separated by silica gel column chromatography to obtain a light yellow oily substance. 1.0g of the obtained pale yellow oily substance is taken and dissolved with 20mL of DMEA, and 30mg of zinc acetate is added to react for 24h at 135 ℃ under the protection of argon. Separation by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-20/1 gave the desired product in 22.7% yield. The structural formula is as follows:
example 34 Synthesis of Zinc Phthalocyanine Compound modified with Methyleneglycol
Dissolving 1.0g of 3, 6-dichloro phthalonitrile in 30mL of DMF, adding 3.1g of triethylene glycol monomethyl ether and 2.3g of potassium carbonate, reacting at 60 ℃ for 24 hours, and separating a crude product by silica gel column chromatography to obtain a light yellow oily substance. 1.0g of the obtained pale yellow oily substance is taken and dissolved with 20mL of DMEA, and 110mg of zinc acetate is added to react for 24h at 135 ℃ under the protection of argon. Separation by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-20/1 gave the desired product in 49.3% yield. The structural formula is as follows:
example 35 Synthesis of Zinc Phthalocyanine Compound modified with Methylpolyethylene glycol
Dissolving 1.0g of 3, 6-dichloro phthalonitrile in 30mL of DMF, adding 18g of polyethylene glycol monomethyl ether (averageMw1000) and 2.3g of potassium carbonate, reacting at 60 ℃ for 24 hours, and separating a crude product by silica gel column chromatography to obtain a light yellow oily substance. 1.0g of the obtained pale yellow oily substance is taken and dissolved with 20mL of DMEA, and 30mg of zinc acetate is added to react for 24h at 135 ℃ under the protection of argon. Separation by silica gel column chromatography eluting with a gradient of dichloromethane/methanol 50/1-20/1 gave the desired product in 39.9% yield. The structural formula is as follows:
example 36 the experimental procedure of near-infrared fluorescence imaging of living bodies and tissues, using polyethylene glycol monomethyl ether or polyethylene glycol-modified zinc phthalocyanine compounds prepared in examples 1 to 35 of the present invention as fluorescent probes, includes the following steps:
(1) preparing 2X 10 of polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound by using 0.9 percent of normal saline-4mol/L, as a fluorescent probe solution (the compound of example 1 dissolved in 5% ethanol physiological saline).
(2) To transplant liver cancer H22The mice are experimental animal models, 3 mice are used in each group, 0.2mL of fluorescent probe solution is injected into the tail vein, and 0.9% of physiological saline is injected into the tail vein of a blank control group, wherein 0.2mL of physiological saline is injected into the tail vein of the blank control group. The mice were anesthetized by intraperitoneal injection of 4% chloral hydrate physiological saline solution at 0h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h and 48h at 0.165mL/20g, the experimental animals were placed in a small animal in vivo imaging system (Maestroex), the emission wavelength range was set to 670-.
(3) Transplanted liver cancer H22 mice are used as experimental animal models, 3 mice are injected into each group, 0.2mL of fluorescent probe solution is injected into tail vein, and 0.9% of physiological saline is injected into tail vein of blank control group, wherein 0.2mL of physiological saline is injected into tail vein of blank control group. After 3-4h, sacrifice, dissect tumor, heart, liver, spleen, lung, kidney, intestine, muscle, and place in small animal living body imaging system (Maestro EX) for fluorescence imaging (see table 1/fig. 17).
TABLE 1 average fluorescence intensity ratio of PEG monomethyl ether or PEG-modified Zinc phthalocyanine compound tissue imaging (liver average fluorescence intensity is 1)
Example 37 evaluation of the photodynamic anti-tumor activity of the polyethylene glycol monomethyl ether or polyethylene glycol-modified zinc phthalocyanine compound prepared in examples 1 to 35 of the present invention in vitro, comprises the steps of:
(1) cells were collected in logarithmic growth phase and cultured in a medium containing 10% fetal calf serum at 1X 104The density of each cell/well was plated in 96-well plates at 37 ℃ with 5% CO2Incubate in incubator for 24h to allow cells to adhere.
(2) Removing culture medium, sequentially adding 100 μ L of a series of medicinal solutions with increasing concentrations prepared according to multiple relation into each well, standing at 37 deg.C and 5% CO2An incubator for incubation for 48h in a dark group; after 24h incubation, the light group was irradiated with a laser at 670nm for 20min (40 mW/cm)2) Incubation was continued for 24 h.
(3) mu.L of MTT solution (1mg/mL) was added to each well, and the mixture was incubated at 37 ℃ with 5% CO2Culturing in an incubator for 4 h. The supernatant was discarded, 150. mu.L of DMSO was added to each well, and the wells were shaken well.
(4) And (3) detecting the absorbance value of each hole at the wavelength of 490nm by using a microplate reader, and calculating the cell growth inhibition rate according to the following formula: the growth inhibition ratio (%) × (1-dose group OD value/control group OD value) × 100%. IC was calculated by SPSS software based on the relationship between concentration and inhibition50Values (results are shown in table 2).
TABLE 2 in vitro antitumor Activity of polyethylene glycol monomethyl ether or polyethylene glycol modified Zinc phthalocyanine Compounds (IC)50，nM)
The cell survival rate of the light-resistant group is more than 80% when the drug concentration is 10 mu M.
Example 38 treatment of transplanted liver cancer H with PEGylated monomethyl ether-modified Zinc Phthalocyanine Compounds prepared in inventive examples 5 and 1122The in vivo experimental process of the mouse comprises the following steps:
(1) extracting liver cancer H of mice 7 days after inoculation under aseptic condition22Ascites of the breeding rats were treated with sterile physiological saline at a ratio of 1: 10 dilutionPreparing tumor cell suspension, inoculating 0.2mL of the suspension to right forelimb armpit subcutaneous of a healthy Kunming mouse with the weight of 18-22g, and preparing a solid tumor animal model.
(2) After 1 week of inoculation, the tumor growth was 0.5X 0.5cm2The mice were randomly divided into a blank control group and a polyethylene glycol monomethyl ether-modified zinc phthalocyanine compound photodynamic treatment group, 5 mice in each group were weighed. 0.2 mL/blank control group of physiological saline is injected into tail vein, and the polyethylene glycol monomethyl ether modified zinc phthalocyanine compound is prepared into 2 multiplied by 10 by the physiological saline-4M solution, photodynamic therapy group according to 2.4 μ M/kg tail vein injection dosing. Irradiating with laser with wavelength of 670nm for 10min after administration for 2h and 4h respectively, wherein the irradiation intensity is as follows: 100J/cm2After 2 weeks, the animals were sacrificed, and tumor inhibition rates were calculated by weighing the tumors (see table 3 for results), and the tumor inhibition effect was evaluated (see fig. 18 for results). Tumor inhibition (%) (average tumor weight in control blank-average tumor weight in administration group)/average tumor weight in control blank × 100.
Table 3 photodynamic therapy effect of methoxypolyethylene glycols-modified zinc phthalocyanine compounds prepared in example 5 and example 11
Claims (3)
1. A polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound with tumor targeting is characterized by having the following structure:
wherein the content of the first and second substances,
n＝25-125，X1either O or NH, X2OH or OCH3；
R3/R4H or
R3，R4Not simultaneously being H, when R3＝H，
When n is 25-75, X1Either O or NH, X2OH or OCH3When R is4＝H，
When n is 25-75, X1Either O or NH, X2OH or OCH3When is coming into contact with
When n is 5-38, X1Either O or NH, X2OH or OCH3；R5/R6H or
R5，R6Not simultaneously H, n-2-25, X1Either O or NH, X2OH or OCH3。
2. The application of the tumor targeting polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound in the preparation of a tumor targeting fluorescent probe in claim 1.
3. The application of the tumor targeting polyethylene glycol monomethyl ether or polyethylene glycol modified zinc phthalocyanine compound in preparing photodynamic anti-tumor drugs in claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911369436.7A CN110960686A (en) | 2019-12-26 | 2019-12-26 | Phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911369436.7A CN110960686A (en) | 2019-12-26 | 2019-12-26 | Phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110960686A true CN110960686A (en) | 2020-04-07 |
Family
ID=70036788
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911369436.7A Pending CN110960686A (en) | 2019-12-26 | 2019-12-26 | Phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110960686A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539799A (en) * | 2013-08-29 | 2014-01-29 | 中国医学科学院生物医学工程研究所 | Preparation method and application of water-soluble aminopolycarboxylic acid modified phthalocyanine compound |
| CN106620698A (en) * | 2016-11-22 | 2017-05-10 | 福州大学 | Preparation method for ZnPc-UCNP-PEG-G nano-compound |
| CN108456298A (en) * | 2018-05-15 | 2018-08-28 | 长春理工大学 | A kind of amphipathic nature polyalcohol and synthetic method of the modification of solubility unsymmetrical phthalocyanine |
| CN108658995A (en) * | 2018-05-29 | 2018-10-16 | 南京师范大学 | One kind two sulphur bipyridyls modification ZnPc and its preparation method and application |
-
2019
- 2019-12-26 CN CN201911369436.7A patent/CN110960686A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539799A (en) * | 2013-08-29 | 2014-01-29 | 中国医学科学院生物医学工程研究所 | Preparation method and application of water-soluble aminopolycarboxylic acid modified phthalocyanine compound |
| CN106620698A (en) * | 2016-11-22 | 2017-05-10 | 福州大学 | Preparation method for ZnPc-UCNP-PEG-G nano-compound |
| CN108456298A (en) * | 2018-05-15 | 2018-08-28 | 长春理工大学 | A kind of amphipathic nature polyalcohol and synthetic method of the modification of solubility unsymmetrical phthalocyanine |
| CN108658995A (en) * | 2018-05-29 | 2018-10-16 | 南京师范大学 | One kind two sulphur bipyridyls modification ZnPc and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| FENG LV等: "《Zinc Phthalocyanine Labelled Polyethylene Glycol: Preparation, Characterization, Interaction with Bovine Serum Albumin and Near Infrared Fluorescence Imaging in Vivo》", 《MOLECULES》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109010826B (en) | Targeting material based on indole squarylium cyanine dye and preparation method thereof, and fluorescent nanoparticles and preparation method thereof | |
| Lv et al. | Lactose substituted zinc phthalocyanine: A near infrared fluorescence imaging probe for liver cancer targeting | |
| CN110684017B (en) | High-stability near-infrared two-region small-molecule fluorescent probe and preparation method and application thereof | |
| EP4015518B1 (en) | Active-targeting near-infrared fluorescent molecule for targeting folate receptor and preparation method therefor | |
| CN111518545B (en) | High-stability near-infrared two-region nano fluorescent probe and preparation method and application thereof | |
| CN110003461B (en) | Polyiodide-modified BODIPY derivative and preparation method and application thereof | |
| CN111362971B (en) | PSMA (patterned beam mosaic Virus inhibitor) -targeted bis-benzothiadiazole compound as well as preparation method and application thereof | |
| Zhu et al. | Cascade-responsive nano-assembly for efficient photothermal-chemo synergistic inhibition of tumor metastasis by targeting cancer stem cells | |
| JP2011518890A (en) | Novel chlorin e6-folate binding compound, process for producing the same, and pharmaceutical composition for cancer treatment containing the same | |
| CN107057398A (en) | The application that a kind of seven methines cyanine dye and its tumour are precisely diagnosed and treated | |
| CN108658995B (en) | Zinc phthalocyanine modified by dipyridyl disulfide and preparation method and application thereof | |
| CN108727353B (en) | IR820-PTX amphiphilic small molecule prodrug combining photothermal therapy and chemotherapy and nanoparticle preparation method and application thereof | |
| Zhang et al. | Surfactant-stripped J-aggregates of azaBODIPY derivatives: All-in-one phototheranostics in the second near infrared window | |
| CN113292541B (en) | Nitroreductase responsive diagnosis and treatment integrated probe and preparation method and application thereof | |
| CN110898222A (en) | Preparation method and application of A-D-A type organic molecule/amphiphilic polymer composite nanoparticles | |
| CN113683602B (en) | Heptamethine cyanine micromolecule for multi-modal treatment of hypoxic tumors, and preparation method and application thereof | |
| US8609837B2 (en) | Metallation enhancements in tumor-imaging and PDT therapy | |
| CN109010827A (en) | Chlorambucil-poly-dopamine prodrug nanoparticle antitumor application thereof | |
| CN110003086A (en) | A kind of amphipathic small molecules IR820-1MT and its preparation with and its preparation method and application | |
| CN110960686A (en) | Phthalocyanine compound for tumor targeted fluorescence imaging and photodynamic therapy | |
| CN111420053B (en) | Multifunctional magnetic nanoparticle compound capable of intracellular aggregation and preparation method thereof | |
| CN113999156A (en) | Near-infrared fluorescent small molecule probe and synthetic method and application thereof | |
| CN111943954A (en) | Dihydroporphin derivative and corresponding preparation method and application thereof | |
| CN111569069A (en) | Tumor double-targeting diagnosis and treatment photosensitizer and preparation method and application thereof | |
| KR100918811B1 (en) | A pharmaceutical composition for treating cancer comprising chlorin e6-folic acid conjugate compound and chitosan |
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 | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20220607 Address after: 300385 6-726, floor 6, block C, Saida emerging industrial park, Xiqing Economic and Technological Development Zone, Xiqing District, Tianjin Applicant after: Tianjin hairunjiahe innovative pharmaceutical research Co.,Ltd. Address before: 300192, 236 Bai Causeway Road, Tianjin, Nankai District Applicant before: CHINESE ACADEMY OF MEDICAL SCIENCES INSTITUTE OF BIOMEDICAL ENGINEERING |
|
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200407 |