CN108743948A - Ultrasonic one kettle way prepares carbon dots-hydroxyapatite nano compound and its method of modifying and application - Google Patents
Ultrasonic one kettle way prepares carbon dots-hydroxyapatite nano compound and its method of modifying and application Download PDFInfo
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- CN108743948A CN108743948A CN201810432907.3A CN201810432907A CN108743948A CN 108743948 A CN108743948 A CN 108743948A CN 201810432907 A CN201810432907 A CN 201810432907A CN 108743948 A CN108743948 A CN 108743948A
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- carbon dots
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- hydroxyapatite nano
- hydroxyapatite
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- 229910052588 hydroxylapatite Inorganic materials 0.000 title claims abstract description 78
- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 68
- 150000001875 compounds Chemical class 0.000 title claims abstract description 62
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims abstract description 16
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 46
- 235000019152 folic acid Nutrition 0.000 claims abstract description 24
- 239000011724 folic acid Substances 0.000 claims abstract description 24
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229960000304 folic acid Drugs 0.000 claims abstract description 22
- 238000012986 modification Methods 0.000 claims abstract description 19
- 230000004048 modification Effects 0.000 claims abstract description 19
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 201000011510 cancer Diseases 0.000 claims abstract description 12
- 159000000007 calcium salts Chemical class 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 229920000642 polymer Polymers 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 238000005406 washing Methods 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 12
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 12
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims description 9
- 238000004090 dissolution Methods 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 239000006228 supernatant Substances 0.000 claims description 6
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 5
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 3
- 235000019838 diammonium phosphate Nutrition 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- -1 phosphoric acid hydrogen Chemical class 0.000 claims 1
- 239000006185 dispersion Substances 0.000 abstract description 7
- 238000002604 ultrasonography Methods 0.000 abstract description 5
- 238000003745 diagnosis Methods 0.000 abstract description 2
- 238000003384 imaging method Methods 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 239000000523 sample Substances 0.000 abstract description 2
- 238000012377 drug delivery Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- CUXQLKLUPGTTKL-UHFFFAOYSA-M microcosmic salt Chemical compound [NH4+].[Na+].OP([O-])([O-])=O CUXQLKLUPGTTKL-UHFFFAOYSA-M 0.000 abstract 1
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 54
- 229940009456 adriamycin Drugs 0.000 description 25
- 229920002557 polyglycidol polymer Polymers 0.000 description 17
- 239000008367 deionised water Substances 0.000 description 15
- 229910021641 deionized water Inorganic materials 0.000 description 15
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 10
- 238000013019 agitation Methods 0.000 description 9
- 229910000474 mercury oxide Inorganic materials 0.000 description 8
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 8
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- 239000000908 ammonium hydroxide Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- MWKXCSMICWVRGW-UHFFFAOYSA-N calcium;phosphane Chemical compound P.[Ca] MWKXCSMICWVRGW-UHFFFAOYSA-N 0.000 description 4
- 238000004043 dyeing Methods 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000004700 cellular uptake Effects 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 231100000956 nontoxicity Toxicity 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 150000008537 L-aspartic acids Chemical class 0.000 description 1
- 235000019738 Limestone Nutrition 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WLQXPAUZYVXSNE-UHFFFAOYSA-N [Ca].O[N+]([O-])=O Chemical compound [Ca].O[N+]([O-])=O WLQXPAUZYVXSNE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910052586 apatite Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000003519 biomedical and dental material Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 229940064302 folacin Drugs 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 229940106305 folic acid 20 mg Drugs 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000001027 hydrothermal synthesis Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000006028 limestone Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- VWDWKYIASSYTQR-YTBWXGASSA-N sodium;dioxido(oxo)azanium Chemical compound [Na+].[O-][15N+]([O-])=O VWDWKYIASSYTQR-YTBWXGASSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention discloses ultrasonic one kettle ways to prepare carbon dots-hydroxyapatite nano compound and its method of modifying and application.Carbon dots-hydroxyapatite nano compound is one pot of preparation under alkalinity and ultrasound condition using calcium salt, microcosmic salt, folic acid as reaction initial feed, it is subject to dissaving polymer modification, it synthesizes anti-method simplicity, quick, reaction process Observable, good biocompatibility, can mass production the advantages that, also there is good hydrophilic dispersion performance, contain fluorescence property, cancer target performance simultaneously.Cancer cell targeted imaging probe is can be used as, targeted drug delivery carrier plays a significant role in the fields such as cancer diagnosis and treatment.
Description
Technical field
The present invention relates to ultrasonic one kettle ways to prepare carbon dots-hydroxyapatite nano compound and its method of modifying and application,
Belong to bio-medical material scientific domain.
Background technology
Biological nano fluorescent material plays an important role in diagnosing and treating application, is the surface because their sizes are small
Long-pending big and Color tunable.In general, fluorescent nano material includes fluorescent nano particle, the carbon of semiconductor-quantum-point and luminescence generated by light
Point etc..Compared with semiconductor-quantum-point and fluorescent nano particle, carbon dots have apparent advantage in biologic applications, such as good
Water solubility, excellent biocompatibility, unique optical property and nontoxicity.It is interesting that using certain special carbon sources and conjunction
The carbon dots prepared at method can show the Targeting Performance to specific cells.Such as：It is starting with D-Glucose and l- aspartic acids
Raw material is successfully prepared for a kind of novel carbon dots to glioma with target function by simple hydrothermal method；With
Folic acid is the carbon dots prepared by carbon source also has Targeting Performance to the cell that folacin receptor is overexpressed.
Hydroxyapatite is the main inorganic composition of human body and animal skeleton.Due to its outstanding biocompatibility, biology
Activity and nontoxicity are widely used in biomedicine field, can be used as osseous tissue renovating material, pharmaceutical carrier etc..However hydroxyl
Apatite itself do not have target function and photoluminescent property, thus cannot achieve in the cell with biological in-vivo imaging " tracking ",
Also specific tumor tissues can not be targeted.Therefore, a kind of multifunctional C with fluorescence and cancer target is quickly and easily prepared
Point-hydroxyapatite nano compound is of great significance in current field of pharmaceutical biology.
Invention content
The purpose of the present invention is to provide a kind of preparation of carbon dots-hydroxyapatite nano compound and its method of modifying.
Another object of the present invention is to provide a kind of Hyperbranched Polyglycidol-carbon dots-hydroxyl phosphorus of load adriamycin
The application of lime stone nano-complex.
The technical solution used in the present invention is：
A kind of ultrasonic one kettle way preparing carbon dots-hydroxyapatite nano compound, which is characterized in that including following step
Suddenly：
1) folic acid is dissolved in phosphate solution, adjusting reagent with pH adjusts pH to 9~12；Stirring, is added drop-wise to dropwise
In calcium salt soln, gained mixed liquor pH is adjusted reagent and adjusts pH to 9~12, and stirred by mixing, ultrasonic in stirring, quiet
It sets；The calcium salt is (1.66~1.68) with phosphatic molal weight ratio:1；
2) precipitation and supernatant are detached to obtain after standing, it is dry after precipitation centrifuge washing, it obtains carbon dots-hydroxyapatite and receives
Rice compound.
Further, after the step 1) folic acid is dissolved in phosphate solution, a concentration of 0.3~2.6mg/ of folic acid
ML, phosphatic a concentration of 0.3~1mol/L.
Further, the phosphate solution described in step 1) be selected from ammonium hydrogen phosphate, diammonium hydrogen phosphate, disodium hydrogen phosphate,
At least one of dipotassium hydrogen phosphate.
Further, the pH described in step 1) adjusts reagent and is selected from least one of ammonium hydroxide, ethylenediamine.
Further, the calcium salt soln described in step 1) is in calcium nitrate, four water-calcium nitrate, calcium chloride, calcium carbonate
At least one.
Further, the calcium salt described in step 1) and phosphatic molal weight ratio are (1.66~1.68):1.
Further, the ultrasonic temperature described in step 1) be 25~60 DEG C, the time be 3~5 hours, power be 100W~
500W。
Further, washing described in step 2) carries out alternately washing using water and/or absolute ethyl alcohol.
A kind of preparation method for dissaving polymer-carbon dots-hydroxyapatite nano compound that medicine carries, feature exist
In including the following steps：
1) carbon dots-hydroxyapatite nano compound of above-mentioned preparation is added to mixing in glycidol, heating stirring
After reaction, water ultrasonic dissolution is added to obtain carbon dots-hydroxyapatite nano compound of dissaving polymer modification；
2) antineoplastic is added in carbon dots-hydroxyapatite nano compound of dissaving polymer modification, stirring is anti-
Should be complete, precipitation obtained by centrifuge washing is dissaving polymer-carbon dots-hydroxyapatite nano compound that medicine carries.
Further, the amount ratio of the step 1) carbon dots-hydroxyapatite nano compound and glycidol is (3mg
~10mg)：1mL.
Further, magnetic agitation 36~48 hours under the conditions of the stirring condition described in step 1) is room temperature and is protected from light.
Further, carbon dots-hydroxyapatite nano of antineoplastic described in step 2) and dissaving polymer modification
The amount ratio of compound is (1mg~2.5mg)：1mL.
Further, the dissaving polymer is Hyperbranched Polyglycidol.
Dissaving polymer-carbon dots-hydroxyapatite nano compound that medicine prepared by any of the above-described method carries.
Dissaving polymer-carbon dots-hydroxyapatite nano compound that above-mentioned medicine carries is preparing targets identification or/and suppression
The application of the reagent of cancer cell processed.
Further, the cancer cell is the cancer cell that folic acid is overexpressed.
The beneficial effects of the invention are as follows：
Carbon dots-hydroxyapatite nano compound is prepared for one pot using ultrasonic wave added under mechanical stirring in the present invention.It should
Simple synthetic method, quickly, and synthesis material is cheap, products therefrom fluorescence property and good biocompatibility.Using hyperbranched
Poly epihydric alcohol carries out water-soluble sex modification to prepared carbon dots-hydroxyapatite, and products therefrom not only has good hydrophilic
Dispersion performance, stability, nontoxic performance, Targeting Performance；And still there is preferable fluorescence property.The over-expense that medicine obtained carries
Fluidized polymer-carbon dots-hydroxyapatite nano compound is alternatively arranged as target cancer cell image probe, and targeted drug, which transmits, to be carried
Body；For set diagnosis, treats and open up a new road in integrated multi-functional fluorescence targeting composite biological material.
Description of the drawings
Fig. 1 is the transmission electron microscope image of carbon dots-hydroxyapatite nano compound, the wherein length of hydroxyapatite
Degree is 20~150nm, a diameter of 4~8nm；A diameter of 1~3nm of carbon dots.
Fig. 2 is the XRD spectrum of carbon dots-hydroxyapatite nano compound and the comparison of hydroxyapatite standard card, JCDPS
NO.009-0432 is hydroxyapatite standard card.
Fig. 3 is fluorescence emission spectrum of the carbon dots-hydroxyapatite nano compound under 360nm excitations.
Fig. 4 is carbon dots-hydroxyapatite nano compound after Hyperbranched Polyglycidol modification under 360nm excitations
Fluorescence emission spectrum.
Fig. 5 is laser confocal microscope fluorescence imaging figure；Wherein HeLa represents the HeLa cells of folic acid overexpression, MCF-
7 represent people's MCF-7 cells of folic acid low expression；Specific each figure is respectively the light field figure (A) of HeLa cells, HeLa cells
Nucleus DAPI fluorescent stainings figure (B), HAp-CDs-PG are in the green fluorescence figures (C) of HeLa cells, adriamycin in HeLa cells
Red fluorescence figure (D) and HeLa cells light field figure, DAPI dyeing nucleus, HAp-CDs-PG, adriamycin close
And overlay chart (E)；The figure of Fig. 5 second rows from left to right respectively represents the light field figure (F) of MCF-7 cells, MCF-7 cell cores
DAPI fluorescent stainings figure (G), HAp-CDs-PG the fluorograms (H) of MCF-7 cells, adriamycin MCF-7 cells fluorogram
(I) and the light field figure of MCF-7 cells, the nucleus of DAPI dyeing, HAp-CDs-PG, adriamycin merge overlay chart (J).
Fig. 6 is that (HAp-CDs-PG-Dox is dissaving polymer-carbon dots-hydroxy-apatite that medicine carries to HAp-CDs-PG-Dox
Stone nano-complex, wherein HAp represent hydroxyapatite；CDs represents carbon dots；PG represents Hyperbranched Polyglycidol；Dox is represented
Antitumor drug adriamycin) co-cultured 24 hours with different Dox concentration and HeLa cells after cell viability.
Specific implementation mode
With reference to embodiment, the invention will be further described.
The ultrasonic one kettle way of 1 carbon dots of embodiment-hydroxyapatite nano compound
(1) by folic acid 20mg ultrasonic dissolutions in the ammonium dibasic phosphate aqueous solution of 30ml, 0.3mol/l, pH is adjusted with ammonium hydroxide
To 10；
(2) into step (1) acquired solution, (rotating speed is 400 revs/min) is added dropwise to the four water nitre of 30ml under stiring
In sour calcium, wherein calcium phosphorus molal weight ratio is 1.67：1, it is used in combination ammonium hydroxide to adjust pH to 10.After stirring 30min, mixed liquor is at 40 DEG C
Lower progress ultrasonic (300W) processing, and stir always, ultrasonic time is 3 hours, is stood overnight later；
(3) sediment after standing overnight is detached with supernatant, the condition for being 4000 revs/min in rotating speed by yellow mercury oxide
Lower centrifugation is used in combination water to replace washing with absolute ethyl alcohol, after washing 6 times, by yellow mercury oxide at 60 DEG C dry 12 hours to get
Carbon dots-hydroxyapatite nano compound.
The synthesis of 2 HAp-CDs-PG-Dox of embodiment
(1) the 50mg carbon dots-hydroxyapatite nano compound for weighing 1 gained of embodiment, by its ultrasonic disperse in 10ml
Glycidol in, at 140 DEG C heating and magnetic agitation, reaction 24 hours postcoolings to room temperature, add 5ml deionized waters
Ultrasonic dissolution obtains dispersion liquid.It is free to remove with deionized water by dispersion liquid centrifuge washing 6 times in the super filter tube of 100KD
Hyperbranched Polyglycidol.It is eventually adding deionized water and is diluted to 5ml, obtain the carbon dots-after Hyperbranched Polyglycidol modification
Hydroxyapatite nano compound is placed in 4 DEG C of refrigerators and preserves, to use in next step.
(2) after weighing the Hyperbranched Polyglycidol modification prepared by 2mg adriamycins ultrasonic disperse to (1) the step of 2ml
Carbon dots-hydroxyapatite nano compound in.In the environment of room temperature is with being protected from light, magnetic agitation 48 hours.It is subsequently poured into
In the super filter tube of 10KD, using deionized water centrifuge washing 4 times, to remove the adriamycin not carried, load adriamycin is obtained
(HAp-CDs-PG-Dox, wherein HAp represent hydroxy-apatite to Hyperbranched Polyglycidol-carbon dots-hydroxyapatite nano compound
Stone；CDs represents carbon dots；PG represents Hyperbranched Polyglycidol；Dox represents antitumor drug adriamycin).Deducting carrier extinction
Under the premise of degree, the concentration of adriamycin is calculated using ultraviolet specrophotometer.
The ultrasonic one kettle way of 3 carbon dots of embodiment-hydroxyapatite nano compound
(1) by folic acid 80mg ultrasonic dissolutions in the disodium hydrogen phosphate aqueous solution of 30ml, 1mol/l, pH is adjusted with ethylenediamine
To 12；
(2) into step (1) acquired solution, the calcium chloride of 30ml is added dropwise in (rotating speed is 500 revs/min) under stiring,
Wherein calcium phosphorus molal weight ratio is 1.66：1, it is used in combination ethylenediamine to adjust pH to 12.Stir 10min after, mixed liquor at 60 DEG C into
Row ultrasound (400W) processing, and maintain to stir, ultrasonic time is 5 hours.After having reacted, stand overnight；
(3) yellow mercury oxide after standing overnight is detached with supernatant, in rotating speed is 8000 revs/min by yellow mercury oxide
Centrifuge washing under centrifuge replaces washing with absolute ethyl alcohol using water.After washing 8 times, light-yellow precipitate object is dry at 80 DEG C
12 hours.Up to carbon dots-hydroxyapatite nano compound；
The synthesis of 4 HAp-CDs-PG-Dox of embodiment
(1) 100mg carbon dots-hydroxyapatite nano compound of 3 gained of embodiment is weighed, ultrasonic disperse is in the contracting of 10ml
In water glycerine.Heating and magnetic agitation at 120 DEG C.After reaction 24 hours, it is cooled to room temperature, adds 10ml deionized water ultrasounds molten
Solution.With 7 Hyperbranched Polyglycidols to be dissociated with removal of deionized water centrifuge washing in the super filter tube of 100KD.Last institute
Surplus dispersion liquid adds deionized water to be diluted to 5ml, and the carbon dots-hydroxyapatite nano obtained after Hyperbranched Polyglycidol modification is multiple
Object is closed, puts and saves as use in next step in 4 DEG C of refrigerators.
(2) after weighing Hyperbranched Polyglycidol modification of the 5mg adriamycins ultrasonic disperse in the 2ml the step of prepared by (1)
Carbon dots-hydroxyapatite nano it is compound in.At room temperature under light protected environment, magnetic agitation 36 hours.It is subsequently poured into
In the super filter tube of 10KD, using deionized water centrifuge washing 7 times, the adriamycin not carried is removed, obtains the super of load adriamycin
Branched poly epihydric alcohol-carbon dots-hydroxyapatite nano compound (HAp-CDs-PG-Dox).Before deducting carrier absorbance
It puts, the concentration of adriamycin is calculated using ultraviolet specrophotometer.
The ultrasonic one kettle way of 5 carbon dots of embodiment-hydroxyapatite nano compound
(1) folic acid 10mg ultrasonic dissolutions are adjusted in two aqueous solutions of potassium of 30ml, 0.05mol/l phosphoric acid hydrogen with ammonium hydroxide
PH to 9；
(2) into step (1) acquired solution, the calcium carbonate of 30ml is added dropwise in (rotating speed is 100 revs/min) under stiring
In, wherein calcium phosphorus molal weight ratio is 1.68：1, it is used in combination ammonium hydroxide to adjust pH to 9.Stir 30min after, mixed liquor at 25 DEG C into
Row ultrasound (100W) processing, and maintain to stir, ultrasonic time 5 hours.After having reacted, stand overnight.
(3) yellow mercury oxide after standing overnight is detached with supernatant, in rotating speed is 4000 revs/min by yellow mercury oxide
Centrifuge washing under centrifuge replaces washing with absolute ethyl alcohol using water.After washing 8 times, light-yellow precipitate object is dry at 50 DEG C
12 hours to get carbon dots-hydroxyapatite nano compound.
The synthesis of 6 HAp-CDs-PG-Dox of embodiment
(1) 30mg carbon dots-hydroxyapatite nano compound of embodiment 5 is weighed, ultrasonic disperse is sweet in the shrink of 10ml
In oil, heating and magnetic agitation at 90 DEG C.After reaction 24 hours, it is cooled to room temperature, adds 5ml deionized water ultrasonic dissolution scores
Dispersion liquid.With 8 Hyperbranched Polyglycidols to be dissociated with removal of deionized water centrifuge washing in the super filter tube of 100KD.Finally
Add deionized water to be diluted to 5ml, obtain Hyperbranched Polyglycidol modification after carbon dots-hydroxyapatite nano compound, 4 DEG C
It saves as in refrigerator and uses in next step.
(2) after weighing Hyperbranched Polyglycidol modification of the 5mg adriamycins ultrasonic disperse in the 2ml the step of prepared by (1)
Carbon dots-hydroxyapatite nano compound in.At room temperature under light protected environment, magnetic agitation 46 hours.It is subsequently poured into
In the super filter tube of 10KD, using deionized water centrifuge washing 5 times, the adriamycin not carried is removed, obtains the super of load adriamycin
Branched poly epihydric alcohol-carbon dots-hydroxyapatite nano compound (HAp-CDs-PG-Dox).Before deducting carrier absorbance
It puts, the concentration of adriamycin is calculated using ultraviolet specrophotometer.
The ultrasonic one kettle way of 7 carbon dots of embodiment-hydroxyapatite nano compound
(1) by folic acid 10mg ultrasonic dissolutions in 30ml, 0.05mol/l phosphoric acid hydrogen aqueous ammonium, pH is adjusted with ammonium hydroxide
To 9；
(2) into step (1) acquired solution, the calcium nitrate of 30ml is added dropwise in (rotating speed is 100 revs/min) under stiring
In, wherein calcium phosphorus molal weight ratio is 1.68：1, it is used in combination ammonium hydroxide to adjust pH to 9.Stir 30min after, mixed liquor at 25 DEG C into
Row ultrasound (500W) processing, and maintain to stir, ultrasonic time 5 hours.After having reacted, stand overnight.
(3) yellow mercury oxide after standing overnight is detached with supernatant, in rotating speed is 4000 revs/min by yellow mercury oxide
Centrifuge washing under centrifuge replaces washing with absolute ethyl alcohol using water.After washing 8 times, light-yellow precipitate object is dry at 50 DEG C
12 hours to get carbon dots-hydroxyapatite nano compound.
The synthesis of 8 HAp-CDs-PG-Dox of embodiment
(1) 30mg carbon dots-hydroxyapatite nano compound of embodiment 7 is weighed, ultrasonic disperse is sweet in the shrink of 10ml
In oil, heating and magnetic agitation at 90 DEG C.After reaction 24 hours, it is cooled to room temperature, adds 5ml deionized water ultrasonic dissolution scores
Dispersion liquid.With 8 Hyperbranched Polyglycidols to be dissociated with removal of deionized water centrifuge washing in the super filter tube of 100KD.Finally
Add deionized water to be diluted to 5ml, obtain Hyperbranched Polyglycidol modification after carbon dots-hydroxyapatite nano compound, 4 DEG C
It saves as in refrigerator and uses in next step.
(2) after weighing Hyperbranched Polyglycidol modification of the 5mg adriamycins ultrasonic disperse in the 2ml the step of prepared by (1)
Carbon dots-hydroxyapatite nano compound in.At room temperature under light protected environment, magnetic agitation 46 hours.It is subsequently poured into
In the super filter tube of 10KD, using deionized water centrifuge washing 5 times, the adriamycin not carried is removed, obtains the super of load adriamycin
Branched poly epihydric alcohol-carbon dots-hydroxyapatite nano compound (HAp-CDs-PG-Dox).Before deducting carrier absorbance
It puts, the concentration of adriamycin is calculated using ultraviolet specrophotometer.
Hyperbranched Polyglycidol-carbon dots-hydroxyapatite nano of the load adriamycin prepared below to embodiment is multiple
Object (HAp-CDs-PG-Dox) is closed further to be verified.
The characterization and fluorescence property of 9 HAp-CDs nano-complexes of embodiment
A kind of carbon dots-hydroxyapatite nano compound, and hyperbranched water-soluble sex modification and drug load are carried out to it,
Expression formula is：HAp-CDs-PG-Dox.Wherein HAp represents hydroxyapatite；CDs represents carbon dots；PG represents hyperbranched poly shrink
Glycerine；Dox represents antitumor drug adriamycin.HAp-CDs-PG-Dox also has targets identification to the cancer cell that folic acid is overexpressed
Function and fluorescence imaging function.
It takes experimental intermediate products carbon dots-hydroxyapatite nano compound to carry out Electronic Speculum imaging, is found to be rodlike, length is big
About in 20-150nm, diameter is in 4-8nm；Carbon dots on its surface are spherical shape, and diameter is about in 1~3nm.It is with four water nitric acid
Calcium is calcium source, and diammonium hydrogen phosphate is phosphorus source, and folate molecule is as carbon source.See Fig. 1, shows carbon dots successfully in images of transmissive electron microscope
It is incorporated in hydroxyapatite surface.It is found in the XRD spectrum of Fig. 2, prepared carbon dots-hydroxyapatite nano compound and hydroxyl
Base apatite standard card matches, and has preferable crystallinity, in addition the peak crystallization strong compared to hydroxyapatite, carbon dots
Absorption peak is blanked.Carbon dots-hydroxyapatite nano compound of Fig. 3 has good fluorescence property, and maximum excitation wavelength is
360nm, maximum emission wavelength 452nm.Carbon dots-hydroxyapatite nano after the modification of Fig. 4 Hyperbranched Polyglycidols is compound
Object still has preferable fluorescence property；Maximum excitation wavelength is 360nm, maximum emission wavelength red shift to 460nm.
The cellular uptake and image checking of 10 HAp-CDs-PG-Dox of embodiment
Method：The MCF-7 cell inoculations of HeLa cells and folic acid low expression that folic acid is overexpressed are in 6 orifice plates, culture
After overnight, by Hyperbranched Polyglycidol-carbon dots-hydroxyapatite nano compound (HAp- of the load adriamycin of preparation
CDs-PG-Dox it) is separately added into orifice plate for the amount of 3mg/ml with forming final doxorubicin concentration in cultivating system；It is total with cell
After culture 3 hours, cell is cleaned 3 times with PBS, the PBS solution liquid of 4% paraformaldehyde is then used to fix cell 10min.Most
Afterwards, then with PBS it cleans cell twice, and nucleus is marked using DAPI, cell is observed under confocal fluorescent microscopic.Wherein
Blue-fluorescence belongs to the nucleus of DAPI dyeing, and green fluorescence belongs to HAp-CDs-PG, and red fluorescence belongs to Dox.
As a result it shows：HAp-CDs-PG-Dox sends out the strong green fluorescence for belonging to HAp-CDs-PG in HeLa cells
((C) of Fig. 5), with the strong red fluorescence ((D) of Fig. 5) for belonging to Dox.However it is glimmering in MCF-7 cells Green and red
Light is all very weak ((H) (I) of Fig. 5).Therefore, HAp-CDs-PG-Dox is shown stronger in the HeLa cells that folic acid is overexpressed
Cellular uptake ability.(A) (F) of Fig. 5 is light field, and (B) (G) is the nucleus of DAPI dyeing, and (E) (J) is to merge to scheme.As a result
Show that the HeLa cells being overexpressed to folic acid that HAp-CDs-PG can be selective are imaged, it is anti-that targeted delivery can be carried out
Cancer drug is treating tumour.
Cell viability after 11 HAp-CDs-PG-Dox of embodiment is co-cultured with HeLa cells detects
Method：The HeLa cell inoculations that the folic acid that inoculum concentration is 7000/hole is overexpressed are in 96 orifice plates, overnight incubation
Afterwards, Hyperbranched Polyglycidol-carbon dots-hydroxyapatite nano compound (HAp- of different amounts of load adriamycin is added
CDs-PG-Dox), with a concentration of 0.25 μ g/ml, 0.5 μ g/ml, 1 μ g/ml, 2.5 μ g/ml, 5 μ of adriamycin in cultivating system
G/ml is to calculate；Control group is containing only cell and culture medium；After cell culture 24 hours, its vigor is detected.
As a result it shows：As doxorubicin concentration increases in Fig. 6, the vigor of HeLa cells declines, and shows HAp-CDs-
PG-Dox has preferable fragmentation effect to the HeLa cells that folic acid is overexpressed；Under the adriamycin (5 μ g/ml) of low concentration,
The cell viability of HeLa drops to 46%, this illustrates that HAp-CDs-PG is successfully used for loading and transmitting antitumor drug, and
Realize targeted therapy.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, it is other it is any without departing from the spirit and principles of the present invention made by changes, modifications, substitutions, combinations, simplifications,
Equivalent substitute mode is should be, is included within the scope of the present invention.
Claims (10)
1. a kind of ultrasonic one kettle way preparing carbon dots-hydroxyapatite nano compound, which is characterized in that include the following steps：
1) folic acid is dissolved in phosphate solution, adjusting reagent with pH adjusts pH to 9~12；Stirring, is added drop-wise to calcium salt dropwise
In solution, gained mixed liquor pH is adjusted reagent and adjusts pH to 9~12, and stirred by mixing, ultrasonic in stirring, is stood；Institute
The calcium salt stated is (1.66~1.68) with phosphatic molal weight ratio:1；
2) precipitation and supernatant are detached to obtain after standing, it is dry after precipitation centrifuge washing, it is multiple to obtain carbon dots-hydroxyapatite nano
Close object.
2. according to the method described in claim 1, it is characterized in that, after the step 1) folic acid is dissolved in phosphate solution,
A concentration of 0.3~2.6mg/mL of folic acid, phosphatic a concentration of 0.3~1mol/L.
3. according to the method described in claim 1, it is characterized in that, the phosphate solution described in step 1) is selected from phosphoric acid hydrogen
Ammonium, diammonium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate at least one of.
4. according to the method described in claim 1, it is characterized in that, the calcium salt soln described in step 1) is calcium nitrate, four water
At least one of calcium nitrate, calcium chloride, calcium carbonate.
5. according to the method described in claim 1, it is characterized in that, ultrasonic temperature described in step 1) is 25~60 DEG C, the time
It it is 3~5 hours, power is 100W~500W.
6. a kind of preparation method for dissaving polymer-carbon dots-hydroxyapatite nano compound that medicine carries, which is characterized in that
Include the following steps：
1) carbon dots-hydroxyapatite nano compound prepared by claim 1 is added to mixing in glycidol, heating stirring
After reaction, water ultrasonic dissolution is added to obtain carbon dots-hydroxyapatite nano compound of dissaving polymer modification；
2) antineoplastic is added in carbon dots-hydroxyapatite nano compound of dissaving polymer modification, has been stirred to react
Entirely, precipitation obtained by centrifuge washing is dissaving polymer-carbon dots-hydroxyapatite nano compound that medicine carries.
7. according to the method described in claim 6, it is characterized in that, the step 1) carbon dots-hydroxyapatite nano compound
Amount ratio with glycidol is (3mg~10mg)：1mL.
8. dissaving polymer-carbon dots-the hydroxyapatite carried according to medicine prepared by any one of claim 1~7 the method
Nano-complex.
9. dissaving polymer-carbon dots-hydroxyapatite nano compound that claim 1~8 any one of them medicine carries exists
It prepares targets identification or/and inhibits the application of the reagent of cancer cell.
10. application according to claim 9, which is characterized in that the cancer cell is the cancer cell that folic acid is overexpressed.
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