CN108721618A - Fe3O4@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA and its preparation method and application - Google Patents
Fe3O4@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA and its preparation method and application Download PDFInfo
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- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 150000001875 compounds Chemical class 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 210000003743 erythrocyte Anatomy 0.000 claims abstract description 15
- 239000002105 nanoparticle Substances 0.000 claims abstract description 13
- 239000000243 solution Substances 0.000 claims abstract description 11
- 238000010521 absorption reaction Methods 0.000 claims abstract description 8
- 238000005119 centrifugation Methods 0.000 claims abstract description 8
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 5
- GJKGAPPUXSSCFI-UHFFFAOYSA-N 2-Hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone Chemical compound CC(C)(O)C(=O)C1=CC=C(OCCO)C=C1 GJKGAPPUXSSCFI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 238000005406 washing Methods 0.000 claims abstract description 4
- 239000002131 composite material Substances 0.000 claims abstract description 3
- 238000010253 intravenous injection Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 7
- -1 hydroxybenzene amine Chemical class 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 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 claims description 5
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 3
- 150000001448 anilines Chemical class 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 229960003742 phenol Drugs 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 230000001681 protective effect Effects 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000004246 zinc acetate Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 239000003999 initiator Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 239000002245 particle Substances 0.000 claims 1
- 239000001509 sodium citrate Substances 0.000 claims 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims 1
- 229940038773 trisodium citrate Drugs 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 36
- 229910052760 oxygen Inorganic materials 0.000 abstract description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 26
- 239000001301 oxygen Substances 0.000 abstract description 26
- 206010021143 Hypoxia Diseases 0.000 abstract description 11
- 238000011282 treatment Methods 0.000 abstract description 9
- 201000011510 cancer Diseases 0.000 abstract description 7
- 230000007954 hypoxia Effects 0.000 abstract description 4
- 238000002428 photodynamic therapy Methods 0.000 description 16
- 238000003384 imaging method Methods 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000001146 hypoxic effect Effects 0.000 description 6
- 108010003272 Hyaluronate lyase Proteins 0.000 description 5
- 102000001974 Hyaluronidases Human genes 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 229960002773 hyaluronidase Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000001179 sorption measurement Methods 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- INGWEZCOABYORO-UHFFFAOYSA-N 2-(furan-2-yl)-7-methyl-1h-1,8-naphthyridin-4-one Chemical compound N=1C2=NC(C)=CC=C2C(O)=CC=1C1=CC=CO1 INGWEZCOABYORO-UHFFFAOYSA-N 0.000 description 2
- 102100032912 CD44 antigen Human genes 0.000 description 2
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108010064719 Oxyhemoglobins Proteins 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 108010002255 deoxyhemoglobin Proteins 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000002114 nanocomposite Substances 0.000 description 2
- 239000003504 photosensitizing agent Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
- 239000005751 Copper oxide Substances 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 101001054921 Homo sapiens Lymphatic vessel endothelial hyaluronic acid receptor 1 Proteins 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
- 102100026849 Lymphatic vessel endothelial hyaluronic acid receptor 1 Human genes 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910000431 copper oxide Inorganic materials 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229940014041 hyaluronate Drugs 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000009940 knitting Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005395 methacrylic acid group Chemical class 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 229920003168 pharmaceutical polymer Polymers 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/41—Porphyrin- or corrin-ring-containing peptides
- A61K38/42—Haemoglobins; Myoglobins
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
- A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a kind of bionical red blood cell Fe3O4@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA and its preparation method and application, system preparation include the following steps：To Fe3O4After@CuO solution adds OxyHb to react, centrifugation or magnetic field separation remove unadsorbed OxyHb, absorption is completed after ZnPc reactions are added in the aqueous solution of sample, centrifugation or magnetic field separation remove unadsorbed ZnPc, m-HA mixings are added in product, after photoinitiator Irgacure2959 is added, ultraviolet light, after product centrifuge washing, Fe is obtained3O4@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA.Five yuan of compound systems prepared by the present invention are to be suitble to intravenous injection Organic-inorganic composite nano-particle, can simulate red blood cell and carry out cancer target biography oxygen, realize effective PDT treatments in tumor hypoxia area, effectively apply in preparing photosensitive drug.
Description
Technical field
The invention belongs to the photosensitive system technical fields with photodynamic activity, are related to a kind of with similar erythrocytic function
, tie up to the application in photosensitive treatment hypoxic tumor from the nano complex of oxygen carrying.
Background technology
Cancer is to endanger a big disease of human life and health.Photodynamic therapy (Photodynamic therapy, PDT)
Because of the anticancer effect of its unique cure mechanism and wide spectrum, there is unique curative effect and wide development in treating malignant tumor
Potentiality.The mechanism of PDT is that photochemical reaction occurs using the photosensitizer of light source sensitization tumor locus, in O2Participation under generate work
Property oxygen induce neoplastic lesion.Wherein photosensitizer, light source and O2It is that it plays active three elements.O2It is transported to by blood circulation
Whole body is respectively organized, and is then absorbed and utilized by cell.O residing for each cell in normal structure2Environment is more balanced, and entity tumor group
The blood vessel structure integrality for knitting position is poor, and supply of blood flow is discontinuously indefinite, leads to the O residing for tumour cell2Environment is different：Close to base
The tumour cell of counterdie and blood vessel is in oxygen-rich area because of sufficient blood flow, most of tumour far from basilar memebrane and vascular tissue
Then anoxia state is presented because of blood supply insufficiency in cell.And oxygen is one of PDT three elements, weary oxygen must reduce the activity of PDT.
Therefore, seek the oxygen content that effective ways increase hypoxic tumor tissue, to realizing that the effectively treatment of efficient PDT entity tumors has
Important meaning.ZnPc (Zinc phthalocyanine, ZnPc) is that the metal combination species of a kind of great application prospect are photosensitive
Agent has very high biological safety (low dark toxicity) and photosensitive antitumor activity.However, under hypoxic condition PDT activity
It is undesirable, become and restricts the main bottleneck that ZnPc is applied in treatment of solid tumor in vivo.
Oxyhemoglobin (OxyHemoglobin, Hb) is a kind of protein of delivery oxygen in higher organism body, it exists
It is most important oxygen transfer medium in organism in red blood cell in blood.As can simulation red blood cell, Hb is effectively transmitted
To tumor tissue cell, so that it may effectively solve the problems, such as the weary oxygen of tumor microenvironment, realize that the areas Fa Yang are oxygen-enriched, realize hypoxic tumor
PDT is effectively treated.
In recent years, nanotechnology is widely used in drug delivery system.Wherein, magnetic nano ferroferric oxide (Fe3O4)
The magnetic targeted and NMR imaging diagnostic function having by it are by therapeutic field of tumor extensive concern.Hyaluronic acid
(Hyaluronate, HA) is a kind of common medical pharmaceutical polymers, but HA is easily degraded in blood-transmitted.m-HA
It is a kind of HA methacrylic acids modified outcome, there is excellent photoinduction polymerizing power and good biological safety.Because of its energy
Effectively avoid degrading in blood and being widely used (Adv.Funct.Mater.2014,24,2295- as HA substitutes
2304).And make its nano material wrapped up that there is day since tumour cell film surface height expresses hyaluronic acid receptor CD44
Right cancer target ability.In addition, tumor tissues position height expression hyaluronidase (HAase), it can be by m-HA in tumor tissues
Effectively degradation release lapping.
Invention content
Goal of the invention：In view of the problems of the existing technology, the present invention provides a kind of bionical red blood cell Fe3O4@CuO@
OxyHb@ZnPc@five yuan of compound systems of m-HA, the system can simulate red blood cell and carry out cancer target biography oxygen, realize tumor hypoxia area
Effective PDT treatment.
The present invention also provides the Fe3O4It the preparation method of@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA and its is making
Application in standby photosensitive drug.
Technical solution：To achieve the goals above, a kind of bionical red blood cell Fe as described herein3O4@CuO@OxyHb@
The preparation method of ZnPc@five yuan of compound systems of m-HA, includes the following steps：
To Fe3O4After@CuO solution adds OxyHb to react, centrifugation or magnetic field separation remove unadsorbed OxyHb, and absorption is completed
After ZnPc reactions are added in the aqueous solution of sample, centrifugation or magnetic field separation remove unadsorbed ZnPc, and product is added m-HA mixings, adds
After entering photoinitiator Irgacure 2959, ultraviolet light after product centrifuge washing, obtains Fe3O4@CuO@OxyHb@ZnPc@
Five yuan of compound systems of m-HA.
Wherein, the Fe3O4@CuO are by FeCl3·6H2After O is uniformly dissolved in ethylene glycol, sodium acetate and citric acid is added
Trisodium, mixture are transferred to reaction kettle after stirring evenly, reaction obtains Fe3O4Nano-particle, by dry Fe3O4Nano-particle is molten
Solution is stirring evenly and then adding into Cu (NO in the mixed solution of ethyl alcohol and acetonitrile3)2·3H2O and NH3·H2After 90 DEG C of reactions of O, production
After 60 DEG C of drying of object 1000rpm centrifugations, it is transferred to the reaction of magnetic boat and obtains Fe3O4@CuO nano-particles.
Wherein, the ZnPc is first dissolved in N`-N- dimethylformamides, carbonic acid by para hydroxybenzene amine and triphenylchloromethane
Potassium, dichloromethane in the mixed solvent, N2Under protective condition, reaction generates compound 1；By 4,5- dichloros phthalic nitrile and compound
1 is dissolved in addition K2CO3N`-N- dimethylformamides reaction generate compound 2；It is urged again through DBU with zinc acetate by compound 2
Change, the reaction generation compound 3 in n-pentanol solution；Compound 3 is reacted in methyl alcohol with iodomethane to be ultimately generated side chain eight and takes
For aniline quaternary ammonium salt phthalocyanine derivates ZnPc.
Bionical red blood cell Fe made by preparation method of the present invention3O4Five yuan of@CuO@OxyHb@ZnPc@m-HA are compound
System.
Preferably, the Fe3O4@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA are that one kind is suitble to intravenous injection to have
Machine-inorganic composite nanoparticles.
Five yuan of bionical red blood cell Fe3O4@CuO@OxyHb@ZnPc@m-HA made by preparation method of the present invention are multiple
Zoarium ties up to the application prepared in photosensitive drug.
PDT significant effects decline this problem caused by the present invention is directed to the weary oxygen microenvironment of entity tumor, utilize Fe3O4@
CuO simulates red blood cell to the efficient absorption ability of OxyHb, builds Fe3O4@CuO@OxyHb@ZnPc@m-HA systems, which can
It simulates red blood cell and carries out cancer target biography oxygen, realize effective PDT treatments in tumor hypoxia area.
Mechanism：The present invention is in magnetic nano ferroferric oxide surface modification copper oxide (Fe3O4@CuO) after, it can specificity suction
Attached hemoglobin.By passing through condition optimizing, synthesize the star-like Fe for having very strong adsorption capacity to OxyHb3O4@CuO；It is used
ZnPc be eight substituted aniline quaternary ammonium salt of side chain modify ZnPc derivative.
The present invention utilizes layer assembly principle, synthesizes Fe3O4@CuO@OxyHb@ZnPc@m-HA compound systems.The system is noted
After entering in organism, through under magnetic targeted and the receptor-mediated active targeting inductions of CD44, being enriched in tumor tissues, in tumor tissues
Hyaluronidase (HAase) degrade system hyaluronic acid derivatives layer, discharge Fe3O4@CuO@OxyHb@ZnPc, weary oxygen environment thorn
Swash OxyHb release oxygen and realize that the areas Fa Yang are oxygen-enriched, efficient PDT can be realized in ZnPc under excess oxygen；In addition, also available
Fe3O4NMR imaging function realize diagnosis and treatment integration.
Advantageous effect：Compared with prior art, the invention has the advantages that：
Fe obtained by the present invention3O4@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA have the following advantages：
1, Fe in Fe3O4@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA obtained by the present invention3O4@CuO have pole
High OxyHb adsorption capacities, every gram of Fe3O4The OxyHb of the adsorbable nearly 1g of@CuO, high OxyHb load capacity can ensure that system height carries
Oxygen ability, in addition, Fe3O4@CuO have magnetic targeted and NMR imaging diagnostic function.
2, five yuan of nano composite systems of the invention are coated by m-HA gel layers, it can be ensured that during blood-transmitted,
OxyHb keeps stable and O2It is not discharged from OxyHb, and after reaching tumor tissues position, m-HA is degraded by HAase and triggers O2It releases
Put the PDT processes of supply ZnPc.
3, it is of the invention can simulate red blood cell from oxygen carrier nanometer system and carry out cancer target pass oxygen, realize tumor hypoxia area
Effective PDT treatments, are effectively applied in the application in preparing photosensitive drug.
4, preparation method of the invention is simple and effective, and raw material sources are extensive, and bioavilability is high, can mass produce profit
With.
Description of the drawings
Fig. 1 is that eight substituted aniline quaternary ammonium salt of side chain modifies ZnPc derivative synthetic route charts；
Fig. 2 is Fe3O4The adsorption curve schematic diagram of@CuO absorption OxyHb；
Fig. 3 is Fe3O4@CuO@OxyHb@ZnPc@five yuan of compound system transmission electron microscope pictures of m-HA (scale=200nm)；
Fig. 4 is (5%O under weary oxygen environment2)Fe3O4@CuO@OxyHb@ZnPc@m-HA and Fe3O4(deoxidation is blood red by@CuO Hb
Albumen) the photosensitive antitumor activity comparison schematic diagrams of@ZnPc@m-HA；
Fig. 5 is Fe3O4Tumor tissues NMR imaging diagnosis of the@CuO@OxyHb@ZnPc@m-HA in transplantable tumor tumor-bearing mice
Functional schematic.
Specific implementation mode
Below in conjunction with drawings and examples, the invention will be further described.
Embodiment 1
ZnPc is synthesized
Step carries out as shown in Figure 1 for the synthesis of eight substituted aniline quaternary ammonium salt phthalocyanine derivates of side chain.Para hydroxybenzene amine
(436mg, 4.00mmol) is dissolved in N`-N- dimethylformamides (8mL), carbon with triphenylchloromethane (1.67g, 6.00mmol)
Sour potassium (561.2mg, 4.06mmol), dichloromethane (25mL) in the mixed solvent, N2Under protective condition, reaction generates compound 1；
4,5- dichloros phthalic nitrile (250mg, 1.27mmol) is dissolved in compound 1 (1.11g, 3.16mmol) and K is added2CO3
The N`-N- dimethylformamides (8mL) of (561.2mg, 4.06mmol) react generation compound 2 for 24 hours under the conditions of 75 DEG C；Chemical combination
Object 2 (410mg, 0.50mmol) is catalyzed with zinc acetate (55.2mg, 0.30mmol) through DBU (0.38mL, 2.82mmol), positive penta
140 DEG C of reaction 12h, generate compound 3 in alcohol (8mL) solution；Compound 3 (300mg, 0.20mmol) is with iodomethane in methanol
Reaction ultimately generates eight substituted aniline quaternary ammonium salt phthalocyanine derivates (ZnPc) of side chain for 24 hours in (25mL).
Embodiment 2
Fe3O4It is prepared by@CuO
1.35g FeCl3·6H2After O is uniformly dissolved in 70mL ethylene glycol, sodium acetate (3.85g) and citric acid three is added
Sodium (0.4g), is transferred to reaction kettle after stirring evenly under the conditions of 80 DEG C of mixture, 200 DEG C of reaction 16h obtain Fe3O4Nano-particle.
The Fe of 50mg dryings3O4Nanoparticle dissolution is stirring evenly and then adding into the mixed solution of ethyl alcohol (90mL) and acetonitrile (30mL)
Cu(NO3)2·3H2O (100mg) and NH3·H2O (1mL) reacts 2h at 90 DEG C.Product is transferred to 280 DEG C of reaction 2h of magnetic boat and obtains
Fe3O4@CuO nano-particles, Fe3O4@CuO nano-particles are evenly dispersed with water, and 10mg mL are made-1Fe3O4@CuO solution.
Embodiment 3
Fe3O4(all steps of the reaction are saturated in oxygen molten five yuan of compound system structures of@CuO@OxyHb@ZnPc@m-HA
It is carried out in liquid)
Take 100 μ L Fe3O4@CuO solution (10mg mL-1) in 5.0mL OxyHb (2mg mL are added-1) reaction 1.5h centrifugations
Or magnetic field separation removes unadsorbed OxyHb.Absorption complete to be added in the aqueous solution of sample ZnPc (20 μ L, 10-3mol L-1) reaction
20min is centrifuged or magnetic field separation removes unadsorbed ZnPc.2mg m-HA vortex mixings 10min is added in product.Photoinitiator is added
Irgacure 2959 (0.1%, w:V) after, ultraviolet light 10min.After product centrifuge washing, Fe is obtained3O4@CuO@OxyHb@
Five yuan of compound systems of ZnPc@m-HA.
Test example 1
(1) by Fe in embodiment 23O4@CuO absorption OxyHb abilities are evaluated using uv-vis spectra：
Fe3O4The adsorption curve detection of@CuO absorption OxyHb, as shown in Fig. 2, with Fe3O4When@CuO are mixed with OxyHb
Between extension, the absorbance of OxyHb constantly reduces and is finally reached balance in solution centrifuged supernatant, illustrates that OxyHb exists
Fe3O4The adsorption equilibrium of@CuO material surfaces.
(2) Fe prepared by embodiment 33O4The pattern of@CuO@OxyHb@ZnPc@five yuan of nano composite systems of m-HA is to transmit
Electron microscope observation：
As shown in figure 3, transmission electron microscope observing nanoparticle size and pattern, as a result show that nano particle is hub-and-spoke configuration, point
It dissipates good.
(3) mtt assay is used to detect external photosensitive antitumor activity：
(the 5%O under weary oxygen environment2) compare Fe3O4@CuO@OxyHb@ZnPc@m-HA and Fe3O4(deoxidation is blood red by@CuO Hb
Albumen) the photosensitive antitumor activities of@ZnPc@m-HA, deoxyhemoglobin does not have oxygen carrying capability, as shown in figure 4, experimental result table
Bright, after OxyHb is replaced with deoxyhemoglobin, photosensitive antitumor activity is remarkably decreased under hypoxic condition, is illustrated of the invention real
Five yuan of compound systems for applying the preparation of example 3 have from oxygen carrying capacity, it can be achieved that effective PDT treatments under hypoxic condition.
(4) Fe prepared by embodiment 33O4@CuO OxyHb ZnPc five yuan of nano complexes of m-HA tie up to transplantable tumor lotus knurl
Tumor tissues NMR imaging in mouse is observed using toy NMR imaging instrument：
Fe prepared by embodiment 33O4Cores of the@CuO@OxyHb@ZnPc@m-HA in transplantable tumor tumor-bearing mice tumor tissues
Magnetic imaging diagnostic analysis, the results are shown in Figure 5, and NMR imaging shows that five yuan of compound system tail vein injections enter mouse for a period of time
Afterwards, T2 reduction of contrast signal is remarkably decreased.Illustrate enrichment of the compound system at tumour, it was demonstrated that system has magnetic targeted and nuclear-magnetism
Imaging function.
Claims (6)
1. a kind of bionical red blood cell Fe3O4The preparation method of@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA, feature exist
In including the following steps：
To Fe3O4After@CuO solution adds OxyHb to react, centrifugation or magnetic field separation remove unadsorbed OxyHb, and sample is completed in absorption
Aqueous solution in ZnPc reactions are added after, centrifugation or magnetic field separation remove unadsorbed ZnPc, and m-HA mixings are added in product, and light is added
After initiator Irgacure 2959, ultraviolet light after product centrifuge washing, obtains Fe3O4@CuO@OxyHb@ZnPc@m-HA
Five yuan of compound systems.
2. wanting the preparation method described in 1 according to right, which is characterized in that the Fe3O4@CuO are by FeCl3·6H2O is in ethylene glycol
After being uniformly dissolved, sodium acetate and trisodium citrate is added, mixture is transferred to reaction kettle after stirring evenly, reaction obtains Fe3O4Nanometer
Particle, by dry Fe3O4Nanoparticle dissolution is stirring evenly and then adding into Cu in the mixed solution of ethyl alcohol and acetonitrile
(NO3)2·3H2O and NH3·H2O is obtained by the reaction.
3. wanting the preparation method described in 1 according to right, which is characterized in that the ZnPc is first by para hydroxybenzene amine and triphenyl chloromethane
Alkane is dissolved in N`-N- dimethylformamides, potassium carbonate, dichloromethane in the mixed solvent, N2Under protective condition, reaction generates chemical combination
Object 1；It is dissolved in by 4,5- dichloros phthalic nitrile and compound 1 and K is added2CO3N`-N- dimethylformamides reaction generate chemical combination
Object 2；It is catalyzed again through DBU with zinc acetate by compound 2, the reaction generation compound 3 in n-pentanol solution；Compound 3 and iodine first
Alkane reacts in methyl alcohol ultimately generates eight substituted aniline quaternary ammonium salt phthalocyanine derivates ZnPc of side chain.
4. the bionical red blood cell Fe made by a kind of any preparation methods of claim 1-33O4@CuO@OxyHb@ZnPc@
Five yuan of compound systems of m-HA.
5. Fe according to claim 43O4@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA, which is characterized in that described
Fe3O4@CuO@OxyHb@ZnPc@five yuan of compound systems of m-HA are preferably a kind of intravenous injection Organic-inorganic composite nano-particle.
6. the bionical red blood cell Fe made by a kind of any preparation methods of claim 1-33O4@CuO@OxyHb@ZnPc@
Application of the five yuan of compound systems of m-HA in preparing photosensitive drug.
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