CN106075471A - A kind of have lympha targeted fluorocarbon emulsion and preparation method thereof - Google Patents
A kind of have lympha targeted fluorocarbon emulsion and preparation method thereof Download PDFInfo
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- CN106075471A CN106075471A CN201610544518.0A CN201610544518A CN106075471A CN 106075471 A CN106075471 A CN 106075471A CN 201610544518 A CN201610544518 A CN 201610544518A CN 106075471 A CN106075471 A CN 106075471A
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- chitosan
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- fluorocarbon emulsion
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- 239000000839 emulsion Substances 0.000 title claims abstract description 40
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000004945 emulsification Methods 0.000 title claims description 4
- 229920001661 Chitosan Polymers 0.000 claims abstract description 40
- 238000003756 stirring Methods 0.000 claims abstract description 30
- 235000019832 sodium triphosphate Nutrition 0.000 claims abstract description 20
- 230000000694 effects Effects 0.000 claims abstract description 14
- 210000002751 lymph Anatomy 0.000 claims abstract description 13
- 229920002101 Chitin Polymers 0.000 claims abstract description 12
- -1 perfluorocarbon compound Chemical class 0.000 claims abstract description 12
- 230000008685 targeting Effects 0.000 claims abstract description 12
- 239000008367 deionised water Substances 0.000 claims abstract description 7
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003643 water by type Substances 0.000 claims abstract description 7
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 6
- WTWWXOGTJWMJHI-UHFFFAOYSA-N perflubron Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br WTWWXOGTJWMJHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000002105 nanoparticle Substances 0.000 claims description 5
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 4
- 229920004890 Triton X-100 Polymers 0.000 claims description 4
- 239000013504 Triton X-100 Substances 0.000 claims description 4
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229920001451 polypropylene glycol Polymers 0.000 claims description 3
- GGHDAUPFEBTORZ-UHFFFAOYSA-N propane-1,1-diamine Chemical compound CCC(N)N GGHDAUPFEBTORZ-UHFFFAOYSA-N 0.000 claims description 3
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 claims description 2
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 claims description 2
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical compound OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 claims description 2
- GNSFRPWPOGYVLO-UHFFFAOYSA-N 3-hydroxypropyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCO GNSFRPWPOGYVLO-UHFFFAOYSA-N 0.000 claims description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 2
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 2
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical compound CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 claims description 2
- XYLMUPLGERFSHI-UHFFFAOYSA-N alpha-Methylstyrene Chemical compound CC(=C)C1=CC=CC=C1 XYLMUPLGERFSHI-UHFFFAOYSA-N 0.000 claims description 2
- 235000019864 coconut oil Nutrition 0.000 claims description 2
- 239000003240 coconut oil Substances 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 238000009826 distribution Methods 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical group O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 2
- VLCAYQIMSMPEBW-UHFFFAOYSA-N methyl 3-hydroxy-2-methylidenebutanoate Chemical compound COC(=O)C(=C)C(C)O VLCAYQIMSMPEBW-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229960001217 perflubron Drugs 0.000 claims description 2
- 229950011087 perflunafene Drugs 0.000 claims description 2
- UWEYRJFJVCLAGH-IJWZVTFUSA-N perfluorodecalin Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)[C@@]2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[C@@]21F UWEYRJFJVCLAGH-IJWZVTFUSA-N 0.000 claims description 2
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 claims description 2
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000001593 sorbitan monooleate Substances 0.000 claims description 2
- 229940035049 sorbitan monooleate Drugs 0.000 claims description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims 2
- DBCAQXHNJOFNGC-UHFFFAOYSA-N 4-bromo-1,1,1-trifluorobutane Chemical compound FC(F)(F)CCCBr DBCAQXHNJOFNGC-UHFFFAOYSA-N 0.000 claims 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 claims 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Substances CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 claims 1
- 235000019197 fats Nutrition 0.000 claims 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
- 229910000077 silane Inorganic materials 0.000 claims 1
- LFQCEHFDDXELDD-UHFFFAOYSA-N tetramethyl orthosilicate Chemical compound CO[Si](OC)(OC)OC LFQCEHFDDXELDD-UHFFFAOYSA-N 0.000 claims 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 18
- 206010028980 Neoplasm Diseases 0.000 description 12
- 238000003384 imaging method Methods 0.000 description 7
- 206010027476 Metastases Diseases 0.000 description 6
- 230000009401 metastasis Effects 0.000 description 5
- 238000013170 computed tomography imaging Methods 0.000 description 4
- 229920002674 hyaluronan Polymers 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 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
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(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-MNSSHETKSA-N 0.000 description 2
- 229940099552 hyaluronan Drugs 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 230000001926 lymphatic effect Effects 0.000 description 2
- 210000001365 lymphatic vessel Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QZPSOSOOLFHYRR-UHFFFAOYSA-N 3-hydroxypropyl prop-2-enoate Chemical compound OCCCOC(=O)C=C QZPSOSOOLFHYRR-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102100026849 Lymphatic vessel endothelial hyaluronic acid receptor 1 Human genes 0.000 description 1
- 101710178181 Lymphatic vessel endothelial hyaluronic acid receptor 1 Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 150000004816 dichlorobenzenes Chemical class 0.000 description 1
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical compound C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004880 lymph fluid Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000005073 lymphatic endothelial cell Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 description 1
- ZPIRTVJRHUMMOI-UHFFFAOYSA-N octoxybenzene Chemical compound CCCCCCCCOC1=CC=CC=C1 ZPIRTVJRHUMMOI-UHFFFAOYSA-N 0.000 description 1
- 229950008618 perfluamine Drugs 0.000 description 1
- JAJLKEVKNDUJBG-UHFFFAOYSA-N perfluorotripropylamine Chemical compound FC(F)(F)C(F)(F)C(F)(F)N(C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F JAJLKEVKNDUJBG-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229940051841 polyoxyethylene ether Drugs 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
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
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
Abstract
The present invention discloses a kind of preparation method with lympha targeted fluorocarbon emulsion, 8 ~ 10 parts of chitosans are joined in 1% acetum of 4 ~ 5 parts, 4 ~ 5 parts of sodium tripolyphosphates are joined in the deionized water of 4 ~ 5 parts, 1 ~ 2 part of sodium tripolyphosphate solution is slowly dropped in the chitosan solution of 4 ~ 5 parts, 8 ~ 10 parts of chitin nanometers are dispersed in 4 ~ 5 parts of deionized waters, add 1 ~ 2 part of cross-linking agent, 0.5 ~ 1 part of hyaluronate sodium, after stirring at least 12 hours, obtain the chitosan emulsion that lymph is had targeting；In gained chitosan emulsion, add 0.5～10 part of perfluorocarbon compound, 05 parts of solubilizing agents, i.e. obtain the fluorocarbon emulsion with lympha targeted effect.This product preparation method is simple, can be prepared on a large scale.
Description
Technical field
The present invention relates to the preparation method of a kind of fluorocarbons Emulsion, a kind of have lympha targeted effect
Fluorocarbons Emulsion and preparation method thereof.
Background technology
Lymph metastasis is the main transfer form of solid tumor, is also to cause tumor patient main causes of death.Lymph turns
Shifting typically occurs in tumor early stage or mid-term, if can not control in time it is possible to tumor cell can be caused to blood with lymphatic return
Liquid spreads, and causes widely neoplasm metastasis.Additionally, along with engineering in medicine and the development of computer technology, molecular imaging is
Clinical tumor diagnosis provides the most fast, basis for estimation intuitively.Among these, nuclear magnetic resonance divides owing to it has soft tissue
Resolution is high, imaging parameters is many, amount of image information is big and without advantages such as ionization infringements, the most extensively applies.And current,
Conventional nano-medicament carrier is easily collected on the internal organs such as liver, spleen after carrying out intravenous injection, it is difficult to arrive lymph metastasis stove.Cause
This, can prepare a kind of magnetic resonance contrast agent for lymph metastasis stove and make great sense the diagnosis of tumor.
Hyaluronic acid (hyaluronan, HA) and lymphatic vasculature have the HA in substantial connection tissue to need to enter
Intralymphatic the circulation with lymph fluid are degraded in arriving lymph node, and have HA's on the surface of lymphatic endothelial cells
Specific receptor LYVE-1(lymphatic endothelial hyaluronan receptor-1).And LyP-1 small peptide is one
Planting nine cyclic peptide obtained by display technique of bacteriophage, it not only has targeting, and also has lymph metastasis tumor tumor
There is targeting ability.The two is combined, it is possible to reach the effect that lymph metastasis tumor is accurately positioned.
Perfluorocarbon compound is the extended familys compound that a class has biomedical applications widely, and fluoro substituents gives fluorine
The character that carbon molecule is special, such as calorifics, chemistry and biology inertia, ray impermeability, good diffusibility, low surface is opened
Power, low-viscosity, high density and high gas solubility etc..Therefore, perfluorocarbon compound can serve as ultra sonic imaging, CT imaging
(CT technology) etc..But perfluorocarbon compound is inert, it is impossible to be dissolved in blood plasma, therefore its table
Face just can input body vein after needing activated dose of emulsifying.Therefore, the preparation of research perfluorocarbon compound has become study hotspot.
Summary of the invention
Present invention aim at for the deficiencies in the prior art, it is provided that with chitosan as medium, hyaluronic acid is that targeting divides
Son, obtains having lympha targeted fluorocarbon emulsion.This fluorocarbon emulsion stable performance, it is possible to keep its physical and chemical performance for a long time
Stable, there is not agglomeration.Can stop for a long time at tumor locus, lymphatic vessel and the imaging effect of blood vessel to intra-tumor
Well.
A kind of preparation method with lympha targeted fluorocarbon emulsion, it is characterised in that the method includes walking as follows
Suddenly, in following steps, number refers to mass fraction:
A, 8 ~ 10 parts of chitosans are joined in 1% acetum of 4 ~ 5 parts, stir at least 1 hour, treat that chitosan is the most molten
Xie Hou, passes sequentially through 0.45 μm and the filter paper of 0.22 μm by solution；
B, 4 ~ 5 parts of sodium tripolyphosphates are joined in the deionized water of 4 ~ 5 parts, stir at least 30 minutes, treat that sodium tripolyphosphate is complete
After CL, solution is passed sequentially through 0.45 μm and the filter paper of 0.22 μm；
C, 1 ~ 2 part of sodium tripolyphosphate solution is slowly dropped in the chitosan solution of 4 ~ 5 parts, stirs at least 30 minutes and form shell
Polysaccharide nanoparticle；Subsequently more than 10000 turns rotating speed be centrifuged, separate out thing again in freeze dryer lyophilizing obtain chitosan nano
Sub-powder；
D, 8 ~ 10 parts of chitin nanometers are dispersed in 4 ~ 5 parts of deionized waters, add 1 ~ 2 part of cross-linking agent, 0.5 ~ 1 part transparent
Matter acid sodium, after stirring at least 12 hours, obtains the chitosan emulsion to lymph with targeting；
E, in gained chitosan emulsion add 0.5～10 part of perfluorocarbon compound, 0-5 part solubilizing agent, at 60 DEG C and indifferent gas
Under atmosphere, to stir 30 minutes under the rotating speeds of 10000 revs/min, it is cooled to 25 DEG C, stands 24 hours；It is then centrifuged for separating；Take
Clear liquid, i.e. obtains the fluorocarbon emulsion with lympha targeted effect.
Described cross-linking agent be tetraisocyanate, propane diamine, Polyethylene Glycol, polypropylene glycol, trimethylolpropane, poly-the third two
Alcohol glycidyl ether, a-methyl styrene, acrylonitrile, acrylic acid, methacrylic acid, Biformyl, tetraethyl orthosilicate, positive silicic acid first
Ester, trimethoxy silane, p-methyl benzenesulfonic acid, paratoluensulfonyl chloride, diacrylate-BDO ester, dimethacrylate second
Diol ester, butyl acrylate, cumyl peroxide, double 2,4 one dichloro-benzoyls of peroxidating, acrylic acid, 2-(Acryloyloxy)ethanol,
Hydroxypropyl acrylate, methacrylic acid, hydroxyethyl methylacrylate, Hydroxypropyl methacrylate, divinylbenzene, N-methylol
At least one in acrylamide, N-[2-(2-methyl-4-oxopentyl).
Described fluorocarbons is FC-77(perfluoro-cyclicether), PFOB(PERFLUBRON), PFD(perfluorodecalin) or FC-
3283(perfluamine) one or more mixture.
Described solubilizing agent is Tu-80(polyoxyethylenesorbitan sorbitan monooleate), 6501(fatty acid distribution of coconut oil diethanol acyl
Amine), AEO-9(fatty alcohol-polyoxyethylene ether), Brij-35(polyoxyethylene lauryl ether) or Triton X-100(Polyethylene Glycol
Octyl phenyl ether) at least one.
A kind of have lympha targeted fluorocarbon emulsion, it is characterised in for preparing according to any of the above-described described method.
Compared with prior art, present invention have the advantage that
This product preparation method is simple, can be prepared on a large scale.The fluorocarbon emulsion prepared, has ultrasonic and CT imaging function, and
Lymphsystem had targeting, it is possible to keep its physical and chemical performance stable for a long time, agglomeration does not occur.In tumor
Position can stop for a long time, good to the lymphatic vessel of intra-tumor and the imaging effect of blood vessel.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in detail.Following example will assist in the technology of this area
Personnel are further appreciated by the present invention, but limit the present invention the most in any form.It should be pointed out that, the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, it is also possible to make some deformation and improvement.These broadly fall into the present invention
Protection domain.
Embodiment 1:
A, 8 parts of chitosans are joined in 1% acetum of 5 parts, stir 1 hour, after chitosan is completely dissolved, by molten
Liquid passes sequentially through 0.45 μm and the filter paper of 0.22 μm.
B, 5 parts of sodium tripolyphosphates are joined in the deionized water of 4 parts, stir 45 minutes, treat that sodium tripolyphosphate is the most molten
Xie Hou, passes sequentially through 0.45 μm and the filter paper of 0.22 μm by solution.
C, 2 parts of sodium tripolyphosphate solutions are slowly dropped in the chitosan solution of 4 parts, stir 30 minutes and form chitosan
Nanoparticle.Centrifugal in 12000 speed of walking around subsequently, separate out thing again in freeze dryer lyophilizing obtain chitin nanometer powder.
D, 10 parts of chitin nanometers are dispersed in 4 parts of deionized waters, add 2 parts of propane diamine, 0.5 part of hyaluronic acid
Sodium, after stirring 12 hours, obtains the chitosan emulsion to lymph with targeting.
E, in gained chitosan emulsion add 10 parts of PFOB, 1 part of Tu-80, under 60 DEG C and inert atmosphere, with 10000
Rev/min rotating speed under stir 30 minutes, be cooled to 25 DEG C, stand 24 hours；It is then centrifuged for separating；Take supernatant, i.e. obtain
There is the fluorocarbon emulsion of lympha targeted effect.
The particle diameter of the fluorocarbon emulsion prepared by the method is 426nm, has good ultra sonic imaging effect.
Embodiment 2:
A, 9 parts of chitosans are joined in 1% acetum of 5 parts, stir 1.5 hours, after chitosan is completely dissolved, will
Solution passes sequentially through 0.45 μm and the filter paper of 0.22 μm.
B, 5 parts of sodium tripolyphosphates are joined in the deionized water of 5 parts, stir 30 minutes, treat that sodium tripolyphosphate is the most molten
Xie Hou, passes sequentially through 0.45 μm and the filter paper of 0.22 μm by solution.
C, 2 parts of sodium tripolyphosphate solutions are slowly dropped in the chitosan solution of 5 parts, stir 30 minutes and form chitosan
Nanoparticle.Centrifugal in 12000 speed of walking around subsequently, separate out thing again in freeze dryer lyophilizing obtain chitin nanometer powder.
D, 10 parts of chitin nanometers are dispersed in 5 parts of deionized waters, add 2 parts of Biformyls, 0.7 part of hyaluronic acid
Sodium, after stirring 12 hours, obtains the chitosan emulsion to lymph with targeting.
E, in gained chitosan emulsion add 5 parts of PFOB, 5 parts of Triton X-100, under 60 DEG C and inert atmosphere, with
Stir 30 minutes under the rotating speed of 10000 revs/min, be cooled to 25 DEG C, stand 24 hours；It is then centrifuged for separating；Take supernatant,
I.e. obtain the fluorocarbon emulsion with lympha targeted effect.
The particle diameter of the fluorocarbon emulsion prepared by the method is 583nm, has good ultra sonic imaging effect.
Embodiment 3:
A, 10 parts of chitosans are joined in 1% acetum of 4 parts, stir 2 hours, after chitosan is completely dissolved, by molten
Liquid passes sequentially through 0.45 μm and the filter paper of 0.22 μm.
B, 5 parts of sodium tripolyphosphates are joined in the deionized water of 4 parts, stir 30 minutes, treat that sodium tripolyphosphate is the most molten
Xie Hou, passes sequentially through 0.45 μm and the filter paper of 0.22 μm by solution.
C, 1.5 parts of sodium tripolyphosphate solutions are slowly dropped in the chitosan solution of 5 parts, stir formation at least 30 minutes
Chitin nanometer.Centrifugal in 11000 speed of walking around subsequently, separate out thing again in freeze dryer lyophilizing obtain chitin nanometer
Powder.
D, 10 parts of chitin nanometers are dispersed in 5 parts of deionized waters, add double 2,4 one dichloro-benzenes of 1 part of peroxidating
Formyl, 1 part of hyaluronate sodium, obtain the chitosan emulsion to lymph with targeting.
E, in gained chitosan emulsion add 0.5 part of FC-77,1 part of Brij-35, under 60 DEG C and inert atmosphere, with
Stir 30 minutes under the rotating speed of 10000 revs/min, be cooled to 25 DEG C, stand 24 hours；It is then centrifuged for separating；Take supernatant,
I.e. obtain the fluorocarbon emulsion with lympha targeted effect.
The particle diameter of the fluorocarbon emulsion prepared by the method is 256nm, has good CT imaging effect.
Embodiment 4:
A, 8 parts of chitosans are joined in the acetum of 5 parts, stir 1 hour, after chitosan is completely dissolved, by solution
Pass sequentially through 0.45 μm and the filter paper of 0.22 μm.
B, 4 parts of sodium tripolyphosphates are joined in the deionized water of 5 parts, stir 30 minutes, treat that sodium tripolyphosphate is the most molten
Xie Hou, passes sequentially through 0.45 μm and the filter paper of 0.22 μm by solution.
C, 2 parts of sodium tripolyphosphate solutions are slowly dropped in the chitosan solution of 4 parts, stir 45 minutes and form chitosan
Nanoparticle.Centrifugal in 10000 speed of walking around subsequently, separate out thing again in freeze dryer lyophilizing obtain chitin nanometer powder.
D, 9 parts of chitin nanometers are dispersed in 5 parts of deionized waters, add 1 part of acrylic acid, 0.5 part of hyaluronic acid
Sodium, after stirring 12 hours, obtains the chitosan emulsion to lymph with targeting.
E, in gained chitosan emulsion add 1 part of FC-3283, under 60 DEG C and inert atmosphere, with 10000 revs/min
Rotating speed under stir 30 minutes, be cooled to 25 DEG C, stand 24 hours；It is then centrifuged for separating；Take supernatant, i.e. obtain that there is pouring
The fluorocarbon emulsion of bar targeting.
The particle diameter of the fluorocarbon emulsion prepared by the method is 321nm, has good CT imaging effect.
Claims (5)
1. a preparation method with lympha targeted fluorocarbon emulsion, it is characterised in that the method comprises the steps,
In following steps, number refers to mass fraction:
A, 8 ~ 10 parts of chitosans are joined in 1% acetum of 4 ~ 5 parts, stir at least 1 hour, treat that chitosan is the most molten
Xie Hou, passes sequentially through 0.45 μm and the filter paper of 0.22 μm by solution；
B, 4 ~ 5 parts of sodium tripolyphosphates are joined in the deionized water of 4 ~ 5 parts, stir at least 30 minutes, treat that sodium tripolyphosphate is complete
After CL, solution is passed sequentially through 0.45 μm and the filter paper of 0.22 μm；
C, 1 ~ 2 part of sodium tripolyphosphate solution is slowly dropped in the chitosan solution of 4 ~ 5 parts, stirs at least 30 minutes and form shell
Polysaccharide nanoparticle；Subsequently more than 10000 turns rotating speed be centrifuged, separate out thing again in freeze dryer lyophilizing obtain chitosan nano
Sub-powder；
D, 8 ~ 10 parts of chitin nanometers are dispersed in 4 ~ 5 parts of deionized waters, add 1 ~ 2 part of cross-linking agent, 0.5 ~ 1 part transparent
Matter acid sodium, after stirring at least 12 hours, obtains the chitosan emulsion to lymph with targeting；
E, in gained chitosan emulsion add 0.5～10 part of perfluorocarbon compound, 0-5 part solubilizing agent, at 60 DEG C and indifferent gas
Under atmosphere, to stir 30 minutes under the rotating speeds of 10000 revs/min, it is cooled to 25 DEG C, stands 24 hours；It is then centrifuged for separating；Take
Clear liquid, i.e. obtains the fluorocarbon emulsion with lympha targeted effect.
A kind of preparation method with lympha targeted fluorocarbon emulsion the most according to claim 1, it is characterised in that described
Cross-linking agent be tetraisocyanate, propane diamine, Polyethylene Glycol, polypropylene glycol, trimethylolpropane, polypropylene glycol (+)-2,3-Epoxy-1-propanol
Ether, a-methyl styrene, acrylonitrile, acrylic acid, methacrylic acid, Biformyl, tetraethyl orthosilicate, methyl silicate, trimethoxy
Base silane, p-methyl benzenesulfonic acid, paratoluensulfonyl chloride, diacrylate-BDO ester, Ethylene glycol dimethacrylate, third
Olefin(e) acid butyl ester, cumyl peroxide, peroxidating double 2,4 one dichloro-benzoyls, acrylic acid, 2-(Acryloyloxy)ethanol, acrylic acid hydroxyl
Propyl ester, methacrylic acid, hydroxyethyl methylacrylate, Hydroxypropyl methacrylate, divinylbenzene, N-methylol acryloyl
At least one in amine, N-[2-(2-methyl-4-oxopentyl).
A kind of preparation method with lympha targeted fluorocarbon emulsion the most according to claim 1, it is characterised in that described
Fluorocarbons be FC-77(perfluoro-cyclicether), PFOB(PERFLUBRON), PFD(perfluorodecalin) or FC-3283(perfluor three
Propylamine) one or more mixture.
The most according to claim 1 have lympha targeted fluorocarbon emulsion and preparation method thereof, it is characterised in that described
Solubilizing agent is Tu-80(polyoxyethylenesorbitan sorbitan monooleate), 6501(fatty acid distribution of coconut oil diglycollic amide), AEO-9(fat
Polyoxyethylenated alcohol), Brij-35(polyoxyethylene lauryl ether) or Triton X-100(Triton X-100) in
At least one.
5. one kind has lympha targeted fluorocarbon emulsion, it is characterised in that prepare according to method described in any of the above-described claim
Obtain.
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