CN108114288A - It is a kind of for fluorescent specific nano-sized iron oxide hybrid dispersion liquid of metastasis of cancer Lymph nodes trace and its preparation method and application - Google Patents
It is a kind of for fluorescent specific nano-sized iron oxide hybrid dispersion liquid of metastasis of cancer Lymph nodes trace and its preparation method and application Download PDFInfo
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- CN108114288A CN108114288A CN201810014925.XA CN201810014925A CN108114288A CN 108114288 A CN108114288 A CN 108114288A CN 201810014925 A CN201810014925 A CN 201810014925A CN 108114288 A CN108114288 A CN 108114288A
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 title claims abstract description 124
- 210000001165 lymph node Anatomy 0.000 title claims abstract description 89
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 57
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 57
- 201000011510 cancer Diseases 0.000 title claims abstract description 54
- 239000007788 liquid Substances 0.000 title claims abstract description 49
- 206010027476 Metastases Diseases 0.000 title claims abstract description 47
- 230000009401 metastasis Effects 0.000 title claims abstract description 46
- 239000006185 dispersion Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229920001503 Glucan Polymers 0.000 claims abstract description 36
- 229920002307 Dextran Polymers 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims abstract description 14
- 239000002245 particle Substances 0.000 claims abstract description 10
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims abstract description 6
- 238000000975 co-precipitation Methods 0.000 claims abstract description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 24
- 238000002347 injection Methods 0.000 claims description 17
- 239000007924 injection Substances 0.000 claims description 17
- 150000002505 iron Chemical class 0.000 claims description 12
- 229910052742 iron Inorganic materials 0.000 claims description 12
- 210000001519 tissue Anatomy 0.000 claims description 11
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 230000003211 malignant effect Effects 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 238000000502 dialysis Methods 0.000 claims description 7
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 7
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 201000002510 thyroid cancer Diseases 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 210000004400 mucous membrane Anatomy 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- 229910021577 Iron(II) chloride Inorganic materials 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- 239000000908 ammonium hydroxide Substances 0.000 claims description 3
- 239000008367 deionised water Substances 0.000 claims description 3
- 229910021641 deionized water Inorganic materials 0.000 claims description 3
- 230000036571 hydration Effects 0.000 claims description 3
- 238000006703 hydration reaction Methods 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 238000000108 ultra-filtration Methods 0.000 claims description 3
- -1 Acyl propionate Chemical compound 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical group Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 230000001394 metastastic effect Effects 0.000 abstract description 6
- 206010061289 metastatic neoplasm Diseases 0.000 abstract description 6
- 239000002262 Schiff base Substances 0.000 abstract description 3
- 150000004753 Schiff bases Chemical class 0.000 abstract description 3
- 238000003745 diagnosis Methods 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
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- 239000002253 acid Substances 0.000 abstract 1
- 150000007513 acids Chemical class 0.000 abstract 1
- 238000011580 nude mouse model Methods 0.000 description 25
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- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 4
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- DCYOBGZUOMKFPA-UHFFFAOYSA-N iron(2+);iron(3+);octadecacyanide Chemical compound [Fe+2].[Fe+2].[Fe+2].[Fe+3].[Fe+3].[Fe+3].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] DCYOBGZUOMKFPA-UHFFFAOYSA-N 0.000 description 2
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- 238000010176 18-FDG-positron emission tomography Methods 0.000 description 1
- ZCXUVYAZINUVJD-AHXZWLDOSA-N 2-deoxy-2-((18)F)fluoro-alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H]([18F])[C@@H](O)[C@@H]1O ZCXUVYAZINUVJD-AHXZWLDOSA-N 0.000 description 1
- NCAJWYASAWUEBY-UHFFFAOYSA-N 3-[20-(2-carboxyethyl)-9,14-diethyl-5,10,15,19-tetramethyl-21,22,23,24-tetraazapentacyclo[16.2.1.1^{3,6}.1^{8,11}.1^{13,16}]tetracosa-1(21),2,4,6(24),7,9,11,13,15,17,19-undecaen-4-yl]propanoic acid Chemical compound N1C2=C(C)C(CC)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1CCC(O)=O)=NC1=CC(C(CCC(O)=O)=C1C)=NC1=C2 NCAJWYASAWUEBY-UHFFFAOYSA-N 0.000 description 1
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- 229920004518 DION® Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
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- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 241000399119 Spio Species 0.000 description 1
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 1
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- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 1
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- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 229910021392 nanocarbon Inorganic materials 0.000 description 1
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- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- GOPBSKKOGHDCEH-UHFFFAOYSA-N periodic acid;sodium Chemical compound [Na].OI(=O)(=O)=O GOPBSKKOGHDCEH-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000001054 red pigment Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
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- 210000005005 sentinel lymph node Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- NLUFDZBOHMOBOE-UHFFFAOYSA-M sodium;2-[[4-(diethylamino)phenyl]-(4-diethylazaniumylidenecyclohexa-2,5-dien-1-ylidene)methyl]benzene-1,4-disulfonate Chemical compound [Na+].C1=CC(N(CC)CC)=CC=C1C(C=1C(=CC=C(C=1)S([O-])(=O)=O)S([O-])(=O)=O)=C1C=CC(=[N+](CC)CC)C=C1 NLUFDZBOHMOBOE-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- 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
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Dispersion Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Biodiversity & Conservation Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Optics & Photonics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to medical preparation fields, more particularly relate to a kind of for fluorescent specific nano-sized iron oxide hybrid dispersion liquid of metastasis of cancer Lymph nodes trace and its preparation method and application；A kind of fluorescent specific nano-sized iron oxide hybrid dispersion liquid for metastasis of cancer Lymph nodes trace, including glucan derivative, ferric oxide particles and water, the glucan derivative is combined to form nano-sized iron oxide hybrid with ferric oxide particles, and the nano-sized iron oxide hybrid uniformly disperses in water；The nano-sized iron oxide hybrid is made by glucan derivative with molysite by coprecipitation；The glucan derivative is made by 5 amino-laevulic acids with oxidized dextran by schiff base reaction.The fluorescent specific nano-sized iron oxide hybrid dispersion liquid that the present invention prepares is expected to be applied to the assessment of human primary gastrointestinal cancers metastatic lymph node, and can be derived by the function of glucan, is coupled antitumor drug, reaches the integrated purpose of diagnosis and treatment.
Description
Technical field
The present invention relates to medical tracer diagnostic reagent fields, and metastasis of cancer Lymph nodes trace is used for more particularly, to one kind
Fluorescent specific nano-sized iron oxide hybrid dispersion liquid and its preparation method and application.
Background technology
Human primary gastrointestinal cancers are one of highest tumours of lethality in the range of our times.China belongs to stomach and intestine high cancer incidence area, stomach cancer
Occupy third and fourth position of all kinds of cancer causes of the death respectively with colorectal cancer, the death rate is respectively up to 17.96/10 ten thousand, 12.59/10 ten thousand.Leaching
It is the main branch mode of human primary gastrointestinal cancers to fawn on transfer, and the assessment of transfer case is to determine modus operandi, accurate pathological staging, system
Determine the main foundation of supplemental treatment regimens.Preoperative doctor's over-borrowing helps Imaging Method to assess metastasis of cancer lymph node.Such as B
Super, CT and the methods of magnetic resonance, but these Imaging Methods all can only be by size and the form of lymph node to determine whether depositing
In metastasis of cancer, accuracy rate only reaches 69-77%, and smaller lymph node is more difficult to accurate judgement.In recent years, FDG-PET extensively should
For clinic, but to human primary gastrointestinal cancers lymphatic metastasis assessment accuracy rate also only 46-85%, and due to equipment limit, can not carrying out in art
Positioning in real time and detection.In addition, clinically there are some dyestuffs such as methylene blue, patent blue, isosulfan blue, nucleic such as technetium 99 and external source
The property Lymph nodes traces agent such as fluorescer such as indocyanine green and Nano carbon suspension applies to clinic in succession.Although above-mentioned tracer
It realizes and lymph node is visualized in art, but still can not realize identification metastasis of cancer lymph node in art.
In order to understand the transfer case of regional lymph nodes in art, surgeon attempts to find out by Lymph nodes trace suspicious
Sentinel lymph node, then frozen section in art is carried out to it and is detected, the transfer case of regional lymph nodes is judged with this, region is instructed to drench
Fawn on cleaning range.This technology achieves preferable effect in the tumours such as melanoma and breast cancer.But extend to stomach and intestine
But because there are the factors such as check frequency and Skip metastasis during cancer so that the peering human primary gastrointestinal cancers lymph node status of sentinel
Prediction sensibility is simultaneously not fully up to expectations.
Therefore, it is clinical at present still to lack a kind of high specific, hypersensitivity, and can in art real-time tracer metastasis of cancer lymph
The tracer of knot.
2nd, domestic and international present Research
Recent study proves, gives exogenous 5-ALA（5-aminolevulinic acid, ALA）It can make to swell
Protoporphyrin gathers and generates the autofluorescence far above normal cell in oncocyte, and fluorescence intensity difference maximum can reach more than 30
Times, autofluorescence difference can be used for distinguishing tumour cell and normal cell in art.But clinical trial is shown, oral or intravenous note
It penetrates ALA induction porphyrin fluorescences and isolated preparation is also stayed in human intestines and stomach's metastasis of cancer lymph node diagnosis, although specificity is higher,
Sensibility is not fully up to expectations, is susceptible to the result of false positive and false negative.Inventor analyzes reason and is：（1）Due to ALA
The autofluorescence of induction does not have the effect of visualization tracer under white light, is examined in intraperitoneal living tissue with fluorescence detector
Survey can not be accomplished to shoot the arrow at the target, and in order to avoid lymph node is omitted, can only select to carry out fluoroscopic examination to isolated preparation.（2）Although
It is oral or intravenous to give exogenous ALA and accumulate in lymph node protoporphyrin, it is self higher than 10 times of normal cell to generate intensity
Fluorescence, but lymph node peripheral adipose or connective tissue are as ALA concentration increases simultaneously, and and protoporphyrin continues metabolism and forms blood
Free iron relative deficiency necessary to red pigment, causes protoporphyrin to be accumulated, and generates autofluorescence, influences metastases lymph node
There is the result of false positive or false negative in the observation of mesoporphyrin fluorescence.（3）It is passed through after giving exogenous ALA due to oral and vein
General blood circulation enters the limitation of ALA concentration in lymph node, and 200 μm of the hardly possible production of transfer stove is less than in small lymph node
Go out the self porphyrin fluorescence for being enough to detect, false negative result occur.
The deficiency that above-mentioned oral and vein uses exogenous ALA is solved, two approach can be passed through：（1）Using ALA
Regional lymph nodes are subjected to visualization dyeing on the basis of induction metastasis of cancer lymph node autofluorescence, for macroscopic lymph
Knot carries out fluoroscopic examination with a definite target in view, can not only avoid omitting to the full extent small lymph node detection but also can be with desmopyknosis
The middle time for carrying out fluoroscopic examination makes it possible that the real-time of live body lymph node is assessed.（2）Select the nano material of controlled diameter
As pharmaceutical carrier by being injected under tumour surrounding mucosa, exogenous ALA targetings are transported in lymph node, it both can be further
Increase the concentration of ALA in lymph node, improve the intensity of autofluorescence in metastasis of cancer lymph node particularly minimum cancer metastatic lymph node,
ALA in lymph node surrounding tissue can be reduced again to accumulate, and reduced the intensity of interference autofluorescence, made metastasis of cancer lymph node fluorescence contrast
Degree increases, and improves the sensibility of detection.
For this purpose, we are co-precipitated skill in previous work, using glucan and its derivative with magnetic iron oxide (SPIO)
Art has synthesized the nano-sized iron oxide hybrid dispersion liquid of a diameter of 100-150nm（DIONs）（Number of patent application：
CN201610078979.3）, the effect of visualization of black dye lymph node is realized, is provided to carry ALA specificity tracer lymph nodes
Good carrier.
The content of the invention
The present invention is at least one defect overcome described in the above-mentioned prior art（Deficiency）, provide a kind of for metastasis of cancer leaching
The fluorescent specific nano-sized iron oxide hybrid dispersion liquid of tracer is fawned on, and further provides for one kind and shows for metastasis of cancer lymph node
The preparation method and purposes of the fluorescent specific nano-sized iron oxide hybrid dispersion liquid of track.
In order to solve the above technical problems, technical scheme is as follows：
A kind of fluorescent specific nano-sized iron oxide hybrid dispersion liquid for metastasis of cancer Lymph nodes trace derives including glucan
Object, ferric oxide particles and water, the glucan derivative is combined to form nano-sized iron oxide hybrid with ferric oxide particles, described
Nano-sized iron oxide hybrid uniformly disperses in water；The nano-sized iron oxide hybrid is passed through altogether by glucan derivative and molysite
The precipitation method are made；The glucan derivative is made by 5-ALA with oxidized dextran by schiff base reaction.
Further, between a diameter of 100-180nm of the nano-sized iron oxide hybrid.
Disperse invention additionally discloses a kind of for the fluorescent specific nano-sized iron oxide hybrid of metastasis of cancer Lymph nodes trace
The purposes of liquid, the fluorescent specific nano-sized iron oxide hybrid dispersion liquid for metastasis of cancer Lymph nodes trace are used for stomach and intestine
Local injection carries out metastasis of cancer Lymph nodes trace in the preoperative of the solid malignants such as cancer, breast cancer, thyroid cancer, art, uses
When local injection uses under human primary gastrointestinal cancers mucous membrane or serous coat, around the solid malignants tissue such as breast cancer, thyroid cancer.
Disperse invention additionally discloses a kind of for the fluorescent specific nano-sized iron oxide hybrid of metastasis of cancer Lymph nodes trace
The preparation method of liquid, comprises the steps of：
The synthesis of S1, oxidized dextran：Glucan is taken to be dissolved in deionized water, sodium metaperiodate is added in, 20- is protected from light in room temperature
28h；Ethylene glycol or glycerine is added dropwise, stirring, dialysis is lyophilized to obtain oxidized dextran；
The synthesis of S2, glucan derivative：Oxidized dextran is taken to be dissolved in the phosphate buffer of pH8.0, adds in 5- amino second
Acyl propionate hydrochlorate, is protected from light after 20-28h to dialyse and lyophilized obtains glucan derivative；
The preparation of S3, fluorescent specific nano-sized iron oxide hybrid dispersion liquid：Glucan derivative is taken to be dissolved in water with trivalent iron salt
Solution is cooled to 0 DEG C or so by middle formation solution, is uniformly mixed under low temperature for use；Take divalent iron salt soluble in water, after filtering with
After above-mentioned solution stirs fully under nitrogen atmosphere, a hydration ammonia solution is added in, fully reacts 1-3h at 0-4 DEG C；Rise temperature
Degree persistently stirs 1-3h, stir speed (S.S.) 500-20000rpm under nitrogen atmosphere to 70-100 degrees Celsius；It is cooled to room temperature,
Ultrafiltration removes unreacted glucan and ammonium hydroxide, and nano-sized iron oxide hybrid dispersion liquid is obtained after dialysis is lyophilized.
Further, the trivalent iron salt is FeCl3, the divalent iron salt is FeCl2。
Further, the nonstoichiometric molar ratio of divalent iron salt and trivalent iron salt is 1:1-2.
Further, the dextran molecule amount is 30 ~ 50KDa.
Further, the dextran molecule amount is 10 ~ 100KDa.
Compared with prior art, the advantageous effect of technical solution of the present invention is：
（1）The present invention uses glucan and its Derivatives Modified, has abundant functional group on polysaccharide, can be with other drugs, core
Element, dyestuff equimolecular reaction, carries out functionalization derivative.
（2）The present invention directly prepares nano hybrid dispersion liquid with glucan and its Derivatives Modified nano-sized iron oxide, real
The specific tracer of existing human primary gastrointestinal cancers metastatic lymph node, is accurately positioned metastasis of cancer lymph node, is provided newly for accurate operation cleaning range
Thinking, experiment is simple, eliminates a series of troublesome operations, while utilizes the hydroxyl on polysaccharide, stably dispersing nano hybrid point
It is water-soluble to improve it for dispersion liquid.
（3）The fluorescent specific nano hybrid dispersion liquid that the present invention prepares can be used for human primary gastrointestinal cancers, breast cancer, thyroid gland
Local injection carries out metastasis of cancer Lymph nodes trace in the preoperative of the solid malignants such as cancer, art, during use in human primary gastrointestinal cancers mucous membrane or
Under serous coat, local injection around the solid malignants tissue such as breast cancer, thyroid cancer.
（4）The nano hybrid dispersion liquid that the present invention prepares is expected to be applied to the assessment of human primary gastrointestinal cancers metastatic lymph node, and can
Derived by the function of glucan, be coupled antitumor drug, reach the integrated purpose of diagnosis and treatment.
Description of the drawings
Fig. 1 is a kind of fluorescent specific nano-sized iron oxide hybrid for metastasis of cancer Lymph nodes trace in the present embodiment 1
Dispersion liquid synthesizes schematic diagram；
Fig. 2 disperses to be a kind of in the present embodiment 3 for the fluorescent specific nano-sized iron oxide hybrid of metastasis of cancer Lymph nodes trace
The particle diameter distribution of liquid（Dynamic light scattering determination）；
Fig. 3 disperses to be a kind of in the present embodiment 3 for the fluorescent specific nano-sized iron oxide hybrid of metastasis of cancer Lymph nodes trace
The component analysis of liquid；
Fig. 4 be the present embodiment 3 in local injection 60mg/mL fluorescent specific nano-sized iron oxide hybrid dispersion liquids 2h, 6h, 12h,
For 24 hours, 36h rear regions cancer Lymph nodes trace situation；
Fig. 5 be the present embodiment 3 in local injection 60mg/mL fluorescent specific nano-sized iron oxide hybrid dispersion liquids 2h, 6h, 12h,
For 24 hours, serum hepatic and renal function detects after 36h, 48h；
Fig. 6 is lymph in the present embodiment 3 after local injection 60mg/mL fluorescent specific nano-sized iron oxide hybrid dispersion liquids 48h
Iron content detects in the histoorgans such as knot, liver, kidney, heart, lung, spleen；
Fig. 7 is liver in the present embodiment 3 after local injection 60mg/mL fluorescent specific nano-sized iron oxide hybrid dispersion liquids 48h
The histoorgans such as dirty, kidney, heart, lung, spleen Prussia and H＆E staining conditions；
The embodiments will be further described with reference to the accompanying drawings for the realization, the function and the advantages of the object of the present invention.
Specific embodiment
Presently preferred embodiments of the present invention is described in detail below in conjunction with the accompanying drawings so that advantages and features of the invention be more easy to by
It will be appreciated by those skilled in the art that so as to make apparent define to protection scope of the present invention.
Embodiment 1
Such as Fig. 1, a kind of fluorescent specific nano-sized iron oxide hybrid dispersion liquid for metastasis of cancer Lymph nodes trace（5ALA-
Dex-SPIO）, including glucan derivative, ferric oxide particles and water, the glucan derivative is combined with ferric oxide particles
Nano-sized iron oxide hybrid is formed, the nano-sized iron oxide hybrid uniformly disperses in water；The nano-sized iron oxide hybrid
It is made by glucan derivative with molysite by coprecipitation；The glucan derivative by 5-ALA (5ALA) with
Oxidized dextran is made by schiff base reaction；Between a diameter of 100-180nm of the nano-sized iron oxide hybrid.
Embodiment 2
A kind of purposes of fluorescent specific nano-sized iron oxide hybrid dispersion liquid for metastasis of cancer Lymph nodes trace, the present embodiment
It is described using the fluorescent specific nano-sized iron oxide hybrid dispersion liquid for metastasis of cancer Lymph nodes trace described in embodiment 1
Human primary gastrointestinal cancers, breast cancer, first shape are used for for the fluorescent specific nano-sized iron oxide hybrid dispersion liquid of metastasis of cancer Lymph nodes trace
Local injection carries out metastasis of cancer Lymph nodes trace in the preoperative of the solid malignants such as gland cancer, art, in human primary gastrointestinal cancers mucous membrane during use
Or local injection uses under serous coat, around the solid malignants tissue such as breast cancer, thyroid cancer.
Embodiment 3
A kind of preparation method of fluorescent specific nano-sized iron oxide hybrid dispersion liquid for metastasis of cancer Lymph nodes trace, including
Following steps,
S1：The synthesis of oxidized dextran：
Weigh the glucan of 5.0g（Molecular weight 10KDa）（Dextran）It is dissolved in 400 mL deionized waters, then adds in periodic acid
Sodium (1.25g is dissolved in 100 mL deionized waters) (NaIO4), 24 h are protected from light in room temperature, 2mL ethylene glycol, which is added dropwise, makes unreacted
Sodium metaperiodate inactivation, continue stir 1 h after, reaction product be placed in molecular cut off be 10000 cellulose dialysis bag in,
It is dialysed 3 days with deionized water, freezes to obtain oxidized dextran.
S2：The synthesis of glucan derivative：
The oxidized dextran for weighing 0.1g is dissolved in the phosphate buffer of pH8.0, adds in 0.01g 5-ALAs
Hydrochloride, is protected from light for 24 hours that dialysis is lyophilized afterwards, obtains glucan derivative, passes through nuclear-magnetism IR Characterization.
S3：The preparation of fluorescent specific nano-sized iron oxide hybrid dispersion liquid
Weigh 3.0g glucan derivatives and 0.32g（1.2mmol）FeCl3It is dissolved in 10mL water, with 0.22 μm of filter membrane mistake
Filter, is cooled to 0 DEG C, by 0.13g by solution（0.63mmol）FeCl2It is dissolved in 0.45ml ice water, with 0.22 μm of membrane filtration
After add in above-mentioned solution, be sufficiently stirred under nitrogen atmosphere, be added dropwise ice one hydration ammonia solution 0.4ml, at 0 DEG C fully
80 DEG C are warming up to after mixing, 1h is persistently stirred under nitrogen atmosphere, solution is cooled to room temperature, excessive glucan is removed with ultrafiltration
And ammonium hydroxide, it after reaction dialysis, freezes, prepares the nano-sized iron oxide hybrid dispersion liquid of 75 mg/mL.
Above-mentioned dispersion liquid 3mL is taken, utilizes BI-200SM type light scattering apparatus（BrookhavenInstruments, USA）To it
Grain size and particle diameter distribution are characterized, and excitation light source wavelength is 532nm, and angle of scattering is 90 degree.It is all test under 25 °C into
Row, and repeat five times.Grain size distribution is obtained, as shown in Fig. 2, average grain diameter is 150nm or so.
Finally, the fluorescent specific nano-sized iron oxide hybrid dispersion liquid that can will be configured to, passes through 220nm filter mistakes
Filter out bacterium, disinfection vial, which is protected from light, seals 4 DEG C of refrigerators saves backup.
Experimental result：
Pharmacodynamics, research are carried out to above-mentioned fluorescent specific nano-sized iron oxide hybrid dispersion liquid（The tracer of rat lymph nodes）,
It is specific as follows：
Animal：Nude mouse（CAnN.Cg-Foxn1nu/Crl mice）, 4~6 week old, 14~16g of weight are cured purchased from south
University of section Experimental Animal Center.
Cell：Stomach cancer HGC-27 cell lines, purchased from Cellbio (Chinese Shanghai).
Drug：Fluorescent specific nano-sized iron oxide hybrid dispersion liquid（60mg/mL）.
Method：Stomach cancer cell suspension is inoculated into nude mice armpit week subcutaneously first, establishes armpit week metastatic lymph node nude mice model.
Again by certain density sample, in different time points subcutaneous injection around lymph node, shown with small animal living body fluorescent and stereo
Micro mirror imaging analysis nude mice model armpit week lymph node fluorescent effect, while take blood examination survey hepatic and renal function.In vitro lymph node, liver afterwards
The histoorgans such as dirty, kidney, heart, lungs, spleen, send pathology to do prussian blue staining（Perls）With H＆E dyeing, immune group
Change analysis and iron content analysis.
It is specific as follows：
（1）Stomach cancer armpit week metastatic lymph node nude mice model foundation
A, 1 × 10 will be contained7A stomach cancer cell（HGC-27）Suspension be inoculated into that armpit on the right side of nude mice is subcutaneous, and conventional muroid is complete at random
Valency forage feed.SPF grades of feeding environment, free water, feeding room temperature are 21 ± 20 DEG C, and humidity 30% ~ 50%, light application time is put down
It is daily 12 it is small when.
B, after raising 6 ~ 8 weeks, knurl situation is observed into, in vitro armpit week lymph node prepares frozen section and carries out immunohistochemistry dye
Color, it is clear and definite whether to have cancer metastasis.
（2）Drug changes the time dynamics that gastric cancer in nude mice Model transfer lymph node protoporphysin Ⅸ gathers
Prepare the fluorescent specific nano-sized iron oxide hybrid dispersion liquid of 60mg/mL concentration.5 groups will be randomly divided into knurl nude mice,
Every group 6.By 1mL sample subcutaneous injections around lymph node, tested respectively after raising 2,6,12,24,36h.
（3）The processing of gastric cancer in nude mice model sample
A, extract 1% pentobarbital sodium injection and be injected in nude mice abdominal cavity anesthesia, be imaged with small animal living body fluorescence stereo microscope
Analyze nude mice model armpit week lymph node fluorescent effect.
B, blood is taken to check and examine liver function（AST、ALT、TBIL、DBIL）, renal function（BUN、Cr）；Core dirty, liver, kidney,
The tissues such as spleen, lungs, lymph node, a part of in vitro tissue are fixed immediately with 10% formalin, and sealing is kept in dark place, and send work
Prussian blue staining and H＆E dyeing are done in inspection；Another part in vitro tissue row frozen section is cooked Ki-67 immunohistochemical analysis and iron member
Cellulose content is analyzed.
The fluorometric result of live body, in vitro tissue, pathological section is carried out to the comparative analysis of qualitative, quantitative c,
As a result：
Compare normal nude mice and into after knurl nude mice injected sample, it is seen that into knurl nude mice lymph node fluorescence intensity higher than normal nude mice
Lymph node fluorescence intensity, and after injected sample 2h, reach the visible most bright fluorescence intensity of naked eyes（Fig. 4-A）.Corresponding lymph node
Interior iron content determination experiment（Perls decoration methods）The ferro element average content in knurl nude mice lymph node is shown as higher than normal
Iron content (Fig. 4-B) in nude mice lymph node.It is shown in corresponding lymph node by the immunohistochemistry that antibody marks of Ki-67
There are a large amount of cancer metastasis (Fig. 4-C) in into knurl nude mice lymph node.Illustrate that metastasis of cancer lymph node can make sample largely assemble and stay
The longer time is put, and the sample largely assembled further enhances the autofluorescence of cancer cell and normal lymphocytes, finally
Reach discrimination transfer and non-diverting lymph node.
Into knurl nude mice postoperative 48 it is small when interior hepatic and renal function the dynamic monitor result show：The liver kidney function after sample injection 2-12h
Index rising can be surveyed, drops to normal level after 12h（Fig. 5）.Illustrate that sample influences little, tool to the hepatic and renal function of nude mice
There is reliable biological safety.
After comparing nude mice injection drug 48h, ferro element contains in the tissues such as liver, kidney, heart, spleen, lungs, lymph node
Amount display：Iron content is significantly more than other organs in lymph node（Fig. 6）.Illustrate that sample after local injection, there is height
It is thermophilic lymphocytic.
Test after nude mice injection drug 48h with the liver of normal nude mice, kidney, heart, spleen, lungs H＆E pathology knots
Fruit shows：Without apparent pathological change（Fig. 7-A）.Illustrate that sample without pathology damage, has reliable raw the main organs of nude mice
Object security.
Dynamic monitoring experiment nude mice liver in 60h, iron content in spleen（Perls decoration methods）Display：It is opened from 12h
Begin, iron content gradually increases in spleen, and 48h is reduced afterwards up to maximum；Just occurs a small amount of ferro element during liver 60h（Fig. 7-B）.
Illustrate that drug is introduced into spleen metabolism through Lymphatic Circulation, enter back into liver metabolism, further clear and definite phase metabolic pathway.
It these are only the preferred embodiment of the present invention, be not intended to limit the scope of the invention, it is every to utilize this hair
The equivalent structure or equivalent flow shift that bright specification and accompanying drawing content are made directly or indirectly is used in other relevant skills
Art field, is included within the scope of the present invention.
Claims (8)
1. a kind of fluorescent specific nano-sized iron oxide hybrid dispersion liquid for metastasis of cancer Lymph nodes trace, it is characterised in that：
Including glucan derivative, ferric oxide particles and water, the glucan derivative is combined to form nano oxygen with ferric oxide particles
Change iron hybrid, the nano-sized iron oxide hybrid uniformly disperses in water；The nano-sized iron oxide hybrid is spread out by glucan
Biology is made with molysite by coprecipitation；The glucan derivative passes through seat by 5-ALA and oxidized dextran
The reaction of husband's alkali is made.
2. a kind of fluorescent specific nano-sized iron oxide hybrid for metastasis of cancer Lymph nodes trace according to claim 1
Dispersion liquid, it is characterised in that：Between a diameter of 100-180nm of the nano-sized iron oxide hybrid.
It is 3. nano oxidized according to a kind of fluorescent specific for metastasis of cancer Lymph nodes trace of claim 1-2 any one of them
The purposes of iron hybrid dispersion liquid, it is characterised in that：The fluorescent specific for metastasis of cancer Lymph nodes trace is nano oxidized
Iron hybrid dispersion liquid, available for local injection in human primary gastrointestinal cancers, breast cancer, the preoperative of thyroid cancer solid malignant, art into
The black dye of row metastasis of cancer lymph node and fluorescent tracing, so as to distinguish Normal Lymph Nodes and metastasis of cancer lymph node, in human primary gastrointestinal cancers during use
Local injection uses under mucous membrane or serous coat, around breast cancer, thyroid cancer solid malignant tissue.
4. a kind of preparation method of fluorescent specific nano-sized iron oxide hybrid dispersion liquid for metastasis of cancer Lymph nodes trace,
It is characterized in that, comprises the steps of：
The synthesis of S1, oxidized dextran：Glucan is taken to be dissolved in deionized water, sodium metaperiodate is added in, 20- is protected from light in room temperature
28h；Ethylene glycol or glycerine is added dropwise, stirring, dialysis is lyophilized to obtain oxidized dextran；
The synthesis of S2, glucan derivative：Oxidized dextran is taken to be dissolved in the phosphate buffer of pH8.0, adds in 5- amino second
Acyl propionate hydrochlorate, is protected from light after 20-28h to dialyse and lyophilized obtains glucan derivative；
The preparation of S3, fluorescent specific nano-sized iron oxide hybrid dispersion liquid：Glucan derivative is taken to be dissolved in water with trivalent iron salt
Solution is cooled to 0 DEG C or so by middle formation solution, is uniformly mixed under low temperature for use；Take divalent iron salt soluble in water, after filtering with
After above-mentioned solution stirs fully under nitrogen atmosphere, a hydration ammonia solution is added in, fully reacts 1-3h at 0-4 DEG C；Rise temperature
Degree persistently stirs 1-3h, stir speed (S.S.) 500-20000rpm under nitrogen atmosphere to 70-100 degrees Celsius；It is cooled to room temperature,
Ultrafiltration removes unreacted glucan and ammonium hydroxide, and fluorescent specific nano-sized iron oxide hybrid dispersion liquid is obtained after dialysis is lyophilized.
5. a kind of fluorescent specific nano-sized iron oxide hybrid for metastasis of cancer Lymph nodes trace according to claim 4
The preparation method of dispersion liquid, it is characterised in that：The trivalent iron salt is FeCl3, the divalent iron salt is FeCl2。
6. a kind of fluorescent specific nano-sized iron oxide hybrid for metastasis of cancer Lymph nodes trace according to claim 4
The preparation method of dispersion liquid, it is characterised in that：The nonstoichiometric molar ratio of divalent iron salt and trivalent iron salt is 1:1-2.
7. a kind of fluorescent specific nano-sized iron oxide hybrid for metastasis of cancer Lymph nodes trace according to claim 4
The preparation method of dispersion liquid, it is characterised in that：The dextran molecule amount is 30 ~ 50KDa.
8. a kind of fluorescent specific nano-sized iron oxide hybrid for metastasis of cancer Lymph nodes trace according to claim 4
The preparation method of dispersion liquid, it is characterised in that：The dextran molecule amount is 10 ~ 100KDa.
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