CN106750252A - DSPE polyethylene glycol 2000 double leaf acid and its preparation method and application - Google Patents
DSPE polyethylene glycol 2000 double leaf acid and its preparation method and application Download PDFInfo
- Publication number
- CN106750252A CN106750252A CN201611101776.8A CN201611101776A CN106750252A CN 106750252 A CN106750252 A CN 106750252A CN 201611101776 A CN201611101776 A CN 201611101776A CN 106750252 A CN106750252 A CN 106750252A
- Authority
- CN
- China
- Prior art keywords
- acid
- polyethylene glycol
- double
- dspe
- double leaf
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002253 acid Substances 0.000 title claims abstract description 66
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 50
- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 title abstract description 6
- 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 73
- 239000011724 folic acid Substances 0.000 claims abstract description 49
- 235000019152 folic acid Nutrition 0.000 claims abstract description 48
- 229960000304 folic acid Drugs 0.000 claims abstract description 26
- 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 25
- 239000002961 echo contrast media Substances 0.000 claims abstract description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000011187 glycerol Nutrition 0.000 claims abstract description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 150000002632 lipids Chemical class 0.000 claims abstract description 12
- OYIFNHCXNCRBQI-UHFFFAOYSA-N 2-aminoadipic acid Chemical compound OC(=O)C(N)CCCC(O)=O OYIFNHCXNCRBQI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229920003266 Leaf® Polymers 0.000 claims description 58
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- 238000003786 synthesis reaction Methods 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000004698 Polyethylene Substances 0.000 claims description 10
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 claims description 10
- 229960004065 perflutren Drugs 0.000 claims description 10
- 229920000573 polyethylene Polymers 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical class C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000005119 centrifugation Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 230000010358 mechanical oscillation Effects 0.000 claims description 5
- 229920000136 polysorbate Polymers 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 3
- 238000006073 displacement reaction Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 239000002872 contrast media Substances 0.000 abstract description 19
- 206010006187 Breast cancer Diseases 0.000 abstract description 10
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 10
- 230000008685 targeting Effects 0.000 abstract description 4
- 230000004913 activation Effects 0.000 abstract description 2
- JDXQWYKOKYUQDN-UHFFFAOYSA-N 3-hydroxypyrrolidine-2,5-dione Chemical class OC1CC(=O)NC1=O JDXQWYKOKYUQDN-UHFFFAOYSA-N 0.000 abstract 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 abstract 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 abstract 1
- 229940014144 folate Drugs 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 12
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 12
- 239000002245 particle Substances 0.000 description 11
- 238000011161 development Methods 0.000 description 10
- 125000003929 folic acid group Chemical group 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 7
- 229940064302 folacin Drugs 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 238000002604 ultrasonography Methods 0.000 description 7
- 239000007789 gas Substances 0.000 description 6
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- -1 monoethanolamine-polyethylene Chemical group 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 239000001361 adipic acid Substances 0.000 description 2
- 235000011037 adipic acid Nutrition 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 239000006059 cover glass Substances 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PKEXHDRGMPOQQN-WCCKRBBISA-N N[C@@H](CCCC(=O)O)C(=O)O.NC(C(=O)O)CCCC(=O)O Chemical class N[C@@H](CCCC(=O)O)C(=O)O.NC(C(=O)O)CCCC(=O)O PKEXHDRGMPOQQN-WCCKRBBISA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000002607 contrast-enhanced ultrasound Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011645 metastatic carcinoma Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
-
- 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
- A61K49/227—Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G2650/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterized by the type of post-polymerisation functionalisation
- C08G2650/04—End-capping
Abstract
The invention discloses a kind of DSPE polyethylene glycol 2000 double leaf acid and preparation method thereof；The present invention synthesizes the phosphatidyl ethanolamine polyethylene glycol N hydroxysuccinimides of 1,2 distearoyl SN glycerine 3 first, is connected with the Amino End Group folic acid of activation by aminoadipic acid, that is, synthesized the lipid of double leaf acid molecule.The present invention also provides application of the DSPE polyethylene glycol 2000 double leaf acid in double leaf acid targeted ultrasound contrast agent is prepared.The acid of DSPE polyethylene glycol 2000 double leaf can significantly improve the targeting binding ability of acoustic contrast agent breast cancer MCF 7.
Description
Technical field
The invention belongs to chemistry and the crossing domain of medical science, more particularly to a kind of DSPE-poly-
Ethylene glycol 2000- double leaf acid and preparation method thereof and the application in acoustic contrast agent is prepared.
Background technology
Morbidity and mortality of the breast cancer in women are higher, the whole world annual about 500, and 000 people dies from breast cancer.Mammary gland
The early detection of cancer and making a definite diagnosis is conducive to the corresponding treatment of selection in time, reduces the death rate, is the research mesh that everybody strongly pursues
Mark.
With the fast development of ultrasound molecular imaging technique and bio-nanotechnology, nanoscale ultrasound contrast agents development is fast
Speed, with scattering properties higher, can significantly increase the material of ultrasound detection signal.With conventional ultrasound contrast agent (blood pool imaging agent)
Difference, nanoscale ultrasound contrast agents have very strong penetration power, can pass through vascular wall, and its development and application is also helped further
Development targeting, high efficiency, miniaturization and the new contrast-enhanced ultrasound agent with auxiliary therapeutic action.And targeted nano level ultrasound is micro-
Appearances for steeping contrast agent makes it possible the targeted imaging of lesion, is the important symbol that ultrasound molecular iconography develops.
Recent study shows：Tumor tissues more normal more folic acid of organization need, folacin receptor in growth course
Hardly expressed in most normal structures, and abnormal expression is raised on most of cancer cell.Report display：Ovary
Folacin receptor in cancer, carcinoma of endometrium, breast cancer, colon cancer, nasopharyngeal carcinoma is all in notable high level expression；And it is highly undifferentiated
Metastatic carcinoma expression folacin receptor level it is more taller than non-metastatic cancer.Folate-targeted Na Pao (NB) can significantly improve Na Pao
With the passive binding ability of the tumour cell of folacin receptor expression high.Folic acid and the specific combination energy of tumor surface folacin receptor
Power is relevant with following two factors：1) amount of different tumor tissue cells surface folacin receptor；2) folic acid of connection on carrier
Content.Report has two kinds for the targeted approach for folacin receptor at present：A kind of is using the monoclonal such as mAb Mov18
Antibody, but because mAb Mov18 possess stronger immunogenicity, and the microvesicle composite molecular weight of antibody one is greatly, tissue penetration
Power is weak to wait limitation, limits its development；Another kind be with folic acid in itself, folic acid relatively stablizes, cheap and be not likely to produce pair
Effect, therefore application is than wide.PEG2000 possesses good biocompatibility, hydrophilic, is to connect most normal as group
One of high molecular polymer seen.
Do not find L-2-Aminoadipic acid aminoadipic acids in the prior art as intermediate linking group, make more
Many folic acid is connected with lipid DSPE surfaces, so as to realize enrichments of the Na Pao in tumour target site.
The content of the invention
In view of the shortcomings of the prior art, the invention provides a kind of DSPE-PEG
2000- double leafs acid (DSPE-PEG2000-AD- (FOL)2) and preparation method thereof；The present invention also provides distearyl acyl group phosphatidyl
Application of the monoethanolamine-polyethylene glycol 2000-double leaf acid in double leaf acid targeted ultrasound contrast agent is prepared.
The technical scheme is that：
First, DSPE-PEG 2000- double leafs acid
DSPE-PEG 2000- double leafs acid, with structure shown below：
2nd, the preparation of DSPE-PEG 2000- double leafs acid
The preparation method of DSPE-PEG 2000- double leafs acid, syntheti c route is as follows：
(1) synthesis 1,2- distearoyl-SN- glycerine-3- phosphatidyl ethanolamines-polyethylene glycol 2000-N- maloyls are sub-
Amine；
(2) synthesis 1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol-aminoadipic acid；
(3) Amino End Group folic acid is synthesized；
(4) synthesis DSPE-PEG 2000- double leafs acid；
According to the system of currently preferred, described DSPE-PEG 2000- double leafs acid
Preparation Method, preparation process is as follows：
(1) synthesis 1,2- distearoyl-SN- glycerine-3- phosphatidyl ethanolamines-polyethylene glycol 2000-N- maloyls are sub-
Amine
280mg1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol 2000 (c-terminus) is dissolved in anhydrous
In dichloromethane 8mL, 17.5mg N- hydroxysuccinimides and 62mg dicyclohexylcarbodiimides are sequentially added.Mixture is normal
The lower lucifuge reaction 3h of temperature；It is filtered to remove the N of generation, N- dichloro urethanes；Filtrate pours into the ether 200mL for pre-cooling
In, ether mixtures are placed in -20 DEG C of 4h；Filtering, is dried to obtain required product；
(2) synthesis 1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol-aminoadipic acid
49mgL-2 aminoadipic acids are dissolved in the 0.1M borate buffers 10mL that pH is 8,300mg bis- is subsequently adding hard
Acyl phosphatidyl-ethanolamine-polyethylene glycol 2000-N- hydroxysuccinimides, lucifuge reaction 30min；By reaction solution 0.2N salt
Acid for adjusting pH value is 4-4.5, is extracted 3 times with chloroform, each 80mL, merges organic phase, and with anhydrous sodium sulfate drying, filtering is dense
Contracting, is subsequently poured into the ether that 200mL is pre-cooled, and 4h is stirred at -20 DEG C, is filtered, and is dried to obtain required product；
(3) Amino End Group folic acid is synthesized
441mg folic acid is dissolved in 20mL anhydrous dimethyl sulphoxides, 428mgN- tertbutyloxycarbonyl -1,3- third is sequentially added
Diamines and 572mg dicyclohexylcarbodiimides, react 4h at room temperature.Reaction solution is poured into the ether that 300mL is pre-cooled,
4h is stirred at -20 DEG C, filtering, filter cake is washed with tetrahydrofuran, is dried, and obtains folic acid-N- tertbutyloxycarbonyl (yields：90%)；Will
654mg Amino End Group folic acid is dissolved in anhydrous methylene chloride, and 50mL trifluoroacetic acids are added under ice bath；2h is reacted at room temperature；Decompression rotation
Evaporation removes dichloromethane and trifluoroacetic acid；Gained residue is poured into the ether for pre-cooling, is filtered, be dried to obtain institute
Need product；
(4) synthesis DSPE-PEG 2000- double leafs acid
By the 1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol-amino of synthesis in 300mg steps (2)
Adipic acid is dissolved in the dry DMFs of 5mL, and the Amino End Group folic acid of synthesis is dissolved in 1mL bis- in 55mg steps (3)
In methyl sulfoxide, it is subsequently adding into system；Reacting at normal temperature without light is overnight；Be subsequently adding 8mL water, the hydrochloric acid of 6mL 0.1N and
2mL saturated aqueous common salts, are extracted 4 times, each 80mL with chloroform；Merge organic phase, anhydrous sodium sulfate drying, filtering, concentration；Gained
Residue is poured into the ether that 200mL is pre-cooled, and 3h is stirred at -20 DEG C, filtering, is dried to obtain required product.
3rd, the application of DSPE-PEG 2000- double leafs acid
The application of DSPE-PEG 2000- double leafs acid of the present invention, its feature exists
In for preparing double leaf acid targeted ultrasound contrast agent.
According to the present invention, the preparation method of the sour targeted ultrasound contrast agent of described double leaf, step is as follows：
0.5mg sorbester p18s are weighed, 0.5ml Tween 80s are placed in 1.5mLEP pipes, add 1mg DPPCs,
1mg DSPE-PEG 2000- double leafs acid, PBS is settled to 1mL, is passed through perfluoropropane gas and puts
Swap out air, and heating 50min is completely dissolved to lipid during centrifuge tube is positioned over into thermostat water bath, and lucifuge adds DiI dyestuffs, then
The secondary perfluoropropane gas that are filled with replace air therein, are taken out after mechanical oscillation 90s, 300rpm centrifugation 3min, remove a layer liquid,
As prepared double leaf acid targeted ultrasound contrast agent.
The present invention also provides a kind of double leaf acid targeted ultrasound contrast agent, it is characterised in that by distearyl of the present invention
Acylphosphatidyl ethanolamine-polyethylene glycol 2000-double leaf acid is prepared from.
It is not specified according to prior art in above preparation method of the present invention.
Present invention synthesis 1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol-N- maloyls first
Imines, is connected by aminoadipic acid with the Amino End Group folic acid of activation, that is, synthesized the lipid of double leaf acid molecule.The present invention is also carried
Supplied DSPE-PEG 2000- double leafs acid prepare double leaf acid targeted ultrasound contrast agent in
Using.Double leaf acid targeted ultrasound is further prepared into by DSPE-PEG 2000- double leaf acid to make
Shadow agent.
Beneficial effects of the present invention are as follows：
(1) DSPE-PEG 2000- double leaf acid prepared by the present invention is not apparent from increasing super
Sound contrast agent particle diameter；
(2) the external development capability of acoustic contrast agent is not influenceed；
(3) acid of DSPE-PEG 2000- double leafs can show under the premise of above-mentioned (1), (2)
Write the targeting binding ability for improving acoustic contrast agent breast cancer MCF-7.
Brief description of the drawings
Fig. 1 is to point out the DSPE-PEG 2000- double leafs nuclear-magnetism spectrum that acid success synthesizes
Figure；
Fig. 2 is three groups of light microscopic figures of the acoustic contrast agent of different folate contents；
Fig. 3 is three groups of acoustic contrast agent grain-size graphs of different folate contents；
Fig. 4 is three groups of acoustic contrast agents of different folate contents development figure in vitro；
Fig. 5 is that CCK-8 methods detect three groups of different lipid concentrations of the acoustic contrast agent of different folate contents to breast cancer
MCF-7 cytotoxicity figures；
Fig. 6 is fluorogram of three groups of acoustic contrast agents of different folate contents to breast cancer MCF-7 binding abilities；
Fig. 7 is flow cytometry of three groups of acoustic contrast agents of different folate contents to breast cancer MCF-7 binding abilities
Figure.
Specific embodiment
With reference to embodiment, the present invention is described further, but not limited to this.
Embodiment 1：The preparation of DSPE-PEG 2000- double leafs acid
The preparation method of DSPE-PEG 2000- double leafs acid, comprises the following steps：
(1) synthesis 1,2- distearoyl-SN- glycerine-3- phosphatidyl ethanolamines-polyethylene glycol 2000-N- maloyls are sub-
Amine
280mg1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol 2000 (c-terminus) is dissolved in anhydrous
In dichloromethane (8mL), 17.5mg N- hydroxysuccinimides and 62mg dicyclohexylcarbodiimides are sequentially added.Mixture
Lucifuge reaction 3h under normal temperature.It is filtered to remove the N of generation, N- dichloro urethanes；Filtrate pours into the ether for pre-cooling
In (200mL), ether mixtures are placed in -20 DEG C of 4h.Filtering, is dried to obtain required product.
(2) synthesis 1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol-aminoadipic acid
49mgL-2 aminoadipic acids are dissolved in 0.1M borate buffers (10mL) that pH is 8,300mg bis- is subsequently adding
Stearyl phosphatidyl monoethanolamine-polyethylene glycol 2000-N- hydroxysuccinimides, lucifuge reaction 30min.By reaction solution 0.2N
Salt acid for adjusting pH value is 4-4.5, and (3*80mL) is extracted with chloroform, merges organic phase, and with anhydrous sodium sulfate drying, filtering is concentrated,
It is subsequently poured into the ether that 200mL is pre-cooled, 4h is stirred at -20 DEG C, filter, is dried to obtain required product.
(3) Amino End Group folic acid is synthesized
441mg folic acid is dissolved in 20mL anhydrous dimethyl sulphoxides, 428mgN- tertbutyloxycarbonyl -1,3- third is sequentially added
Diamines and 572mg dicyclohexylcarbodiimides, react 4h at room temperature.Reaction solution is poured into the ether that 300mL is pre-cooled,
4h is stirred at -20 DEG C, filtering, filter cake is washed with tetrahydrofuran, is dried, and obtains folic acid-N- tertbutyloxycarbonyl (yields：90%)；Will
654mg Amino End Group folic acid is dissolved in anhydrous methylene chloride, and 50mL trifluoroacetic acids are added under ice bath.2h is reacted at room temperature.Decompression rotation
Evaporation removes dichloromethane and trifluoroacetic acid.Gained residue is poured into the ether for pre-cooling, is filtered, be dried to obtain institute
Need product.
(4) synthesis DSPE-PEG 2000- double leafs acid
By the synthesis 1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol-amino of synthesis in 300mg (2)
Adipic acid is dissolved in the dry DMFs of 5mL, and the Amino End Group folic acid of synthesis is dissolved in 1mL dimethyl in 55mg (3)
In sulfoxide, it is subsequently adding into system.Reacting at normal temperature without light is overnight.8mL water is subsequently adding, the hydrochloric acid and 2mL of 6mL 0.1N are satisfied
And saline solution, extract (4*80mL) with chloroform.Merge organic phase, anhydrous sodium sulfate drying, filtering, concentration.Gained residue falls
Enter in the ether that 200mL is pre-cooled, 3h is stirred at -20 DEG C, filter, be dried to obtain required product.
In the present embodiment, the yield of gained DSPE-PEG 2000- double leafs acid is
70%, purity is 90%.
The nuclear magnetic spectrogram that the acid success of DSPE-PEG 2000- double leafs synthesizes is shown in Fig. 1.
Chemical shift is 0.8 hydrogen of position six, and each DSPE molecule has two methyl, has eight between chemical shift 6~8 in the position
Individual hydrogen, is folic acid benzene ring hydrogen, and each folate molecule contains 4 hydrogen, so two folate molecules of correspondence.
Embodiment 2：The preparation of double leaf acid targeted ultrasound contrast agent
0.5mg sorbester p18s are weighed, 0.5ml Tween 80s are placed in 1.5mLEP pipes, add 1mg DPPCs,
1mg DSPE-PEG 2000- double leafs acid, PBS is settled to 1mL, is passed through perfluoropropane gas and puts
Swap out air, and heating 50min is completely dissolved to lipid during centrifuge tube is positioned over into thermostat water bath, and lucifuge adds DiI dyestuffs, then
The secondary perfluoropropane gas that are filled with replace air therein, are taken out after mechanical oscillation 90s, 300rpm centrifugation 3min, remove a layer liquid,
As prepared double leaf acid targeted ultrasound contrast agent.
With reference to experimental example, the present invention is described further, but not limited to this.
Three kinds of preparations of the acoustic contrast agent of different folate contents：
0.5mg sorbester p18s are weighed, 0.5ml Tween 80s are placed in 1.5mLEP pipes, add 1mg DPPCs,
Be separately added into 1mg1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol (A groups), 1mg1,2- distearoyls -
SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol-folic acid (B groups), 1mg DSPE-PEGs
2000- double leafs acid (C groups), PBS is settled to 1mL, is passed through perfluoropropane gas and displaces air, and centrifuge tube is positioned over into thermostatted water
50min is heated in bath to be completely dissolved to lipid, lucifuge adds DiI dyestuffs, perfluoropropane gas displacement is filled with again therein
Air, takes out after mechanical oscillation 90s, 300rpm centrifugation 3min, removes a layer liquid, as prepared acoustic contrast agent.
A groups are blank liposomes group, and B groups are single folic acid group, and C groups are many folic acid groups.
Experimental example 1：Three kinds of sign experiments of the acoustic contrast agent of different folate contents
Light Microscopic observation nanoscale UCAs sizes, form, the Na Pao of visible different folate contents is under 1000 × light microscopic
Spherical, uniform particle diameter is uniformly dispersed without aggregation, sees Fig. 2.Detect that ultrasound is made using nanometer laser granularity and Zeta potential analyzer
The particle diameter of shadow agent, all indexs are measured in triplicate is averaged, and particle diameter distribution difference, A, B, C are steeped in receiving for different folate contents
Three groups of particle diameters are respectively 129.43 ± 12.33nm, 244.1 ± 35.09nm, 286.87 ± 22.96nm, see Fig. 2.Single folic acid group,
Double leaf acid group receive bubble particle diameter compared with blank group significant difference (P is equal<0.05), single folic acid group organizes particle diameter without obvious with double leaf acid
Difference (P>0.05), three groups of acoustic contrast agent particle diameters are respectively less than 400nm, see Fig. 3.
Experimental example 2：Three kinds of external development capability determination experiments of acoustic contrast agent of different folate contents
Three groups of NBs are placed in the circular hole that agar gel is made, using the imaging mode of GElogiq E9 diasonographs,
Frequency 9.0MHz, mechanical index (M I) 0.12, two dimension is set with the observation of ultrasonic contrast pattern synchronization, regulation parameter so that tube sealing
There is uniform enhancing in pin inside, and parameter keeps constant, with Ultrasound Instrument inter workstation storage image data, Image J softwares point
Analysis noise ratio, the external development capability development capabilities of NBs of different folate contents are different, see Fig. 4, are consistent with particle diameter difference.
The gray value that tri- groups of A, B, C is respectively 205.28 ± 2.10,216.13 ± 1.16,218.17 ± 2.09, wherein, single folic acid group,
Double leaf acid group receive bubble particle diameter compared with blank group significant difference (P is equal<0.01), single folic acid group organizes particle diameter without obvious with double leaf acid
Difference (P>0.05) Fig. 4, is seen.
Experimental example 3：Three kinds of acoustic contrast agents of different folate contents are to MCF-7 Breast Cancer Cell cytotoxicity test experience
MCF-7 cells are inoculated in 96 orifice plates with 10000/hole, add culture medium, 37 DEG C, in 5%CO2 incubators
Culture 24h, is separately added into 10ul concentration for 0 μ g/mL, 100 μ g/mL, 120 μ g/mL, 150 μ g/mL, 200 μ g/mL, 300 μ g/
The lipid of mL, 600 μ g/mL, after overnight incubation, changes culture medium into fresh culture containing 10ulCCK-8, continues to be incubated 1-
4h, its absorbance value is detected with ELIASA at 450nm wavelength.Result shows lipid concentration non-table when less than 50 μ g/mL
Reveal obvious cytotoxicity, it is 50 μ g/mL to point out to carry out suitable lipid concentration during cell experiment, sees Fig. 5.
Experimental example 4：External binding ability reality of three kinds of acoustic contrast agents of different folate contents to MCF-7 Breast Cancer Cell
Test
6 × 105 cells, plus nutrient solution 5mL are inoculated with blake bottle, 37 DEG C, adherent 24h are trained in 5%CO2 incubators,
Equivalent list folic acid is separately added into experimental group and control group, double leaf acid NBs, control group adds blank NBs, is placed in incubator altogether
Taken out after culture 1h, rinsed cell 3 times with PBS, be centrifuged after 0.25% Trypsin Induced, add 200 μ LPBS to mix thin
Born of the same parents, ratio is sticked with flow cytomery nanoparticles on tumor cells.Flow cytometry tests find double leaf acid group MCF-7
Ratio 96.76% of the cell with fluorescence, single folic acid group and be respectively 33.33% without ratio of the targeting group cell with fluorescence,
0.52%, show that the double leaf acid group more mono- folic acid groups of Na Pao and blank group and tumour cell have combination effect higher, see Fig. 6.
Take the logarithm the MCF-7 cells in growth period, with 0.25% Trypsin Induced, take the counting of 10 μ L cell suspensions, with containing
The DMEM nutrient solutions of 10% hyclone adjust cell concentration to 5 × 104/mL, are inoculated in per hole 1mL and have inserted cover glass
Creep plate in 12 orifice plates, 37 DEG C, 5%CO2Adherent 24h in incubator, is separately added into 100 μ L blank liposomes, and single folic acid, double leaf acid is received
Bubble, is placed in and 1h is co-cultured in incubator.Cover glass is taken out, PBS is rinsed 3 times, acetone/methanol mixed liquor fixes 10min, PBS
Rinse 2 times, Hoechst dyeing 10min, PBS flushing 3 times, magazine is preserved after mounting, in fluorescence microscopy Microscopic observation.Fluorescence shows
Nucleus in micro- visible control group of Microscopic observation is in blue-fluorescence, visible in blueness in single folic acid group without other fluorescence phenomenons
Around red fluorogen around the nucleus of fluorescence, and major part is attached on cell membrane, and double leaf acid group is also shown in blueness
Around red fluorogen around the nucleus of fluorescence, and major part is attached on cell membrane, compared to single folic acid group fluorescence intensity
It is relatively strong, see Fig. 7.
Claims (7)
1. DSPE-PEG 2000- double leafs acid, it is characterised in that with knot as follows
Structure：
2. the preparation method of compound as claimed in claim 1, it is characterised in that syntheti c route is as follows：
(1) synthesis 1,2- distearoyl-SN- glycerine-3- phosphatidyl ethanolamines-polyethylene glycol 2000-N- hydroxysuccinimides；
(2) synthesis 1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol-aminoadipic acid；
(3) Amino End Group folic acid is synthesized；
(4) synthesis DSPE-PEG 2000- double leafs acid；
3. the preparation method of compound as claimed in claim 2, it is characterised in that preparation process is as follows：
(1) synthesis 1,2- distearoyl-SN- glycerine-3- phosphatidyl ethanolamines-polyethylene glycol 2000-N- hydroxysuccinimides
280mg1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol 2000 (c-terminus) is dissolved in anhydrous dichloro
In methane 8mL, 17.5mg N- hydroxysuccinimides and 62mg dicyclohexylcarbodiimides are sequentially added；Under mixture normal temperature
Lucifuge reacts 3h；It is filtered to remove the N of generation, N- dichloro urethanes；Filtrate is poured into the ether 200mL for pre-cooling,
Ether mixtures are placed in -20 DEG C of 4h；Filtering, is dried to obtain required product；
(2) synthesis 1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol-aminoadipic acid
49mgL-2 aminoadipic acids are dissolved in the 0.1M borate buffers 10mL that pH is 8,300mg distearyls are subsequently adding
Phosphatidyl-ethanolamine-polyethylene glycol 2000-N- hydroxysuccinimides, lucifuge reaction 30min；Reaction solution is adjusted with 0.2N hydrochloric acid
Section pH value is 4-4.5, is extracted 3 times with chloroform, each 80mL, merges organic phase, and with anhydrous sodium sulfate drying, filtering is concentrated, so
Pour into afterwards in the ether that 200mL is pre-cooled, 4h is stirred at -20 DEG C, filter, be dried to obtain required product；
(3) Amino End Group folic acid is synthesized
441mg folic acid is dissolved in 20mL anhydrous dimethyl sulphoxides, 428mgN- tertbutyloxycarbonyl -1,3- propane diamine is sequentially added
With 572mg dicyclohexylcarbodiimides, 4h is reacted at room temperature；Reaction solution is poured into the ether that 300mL is pre-cooled, -20
DEG C stirring 4h, filtering, filter cake washed with tetrahydrofuran, is dried, and obtains folic acid-N- tertbutyloxycarbonyl (yields：90%)；By 654mg
Amino End Group folic acid is dissolved in anhydrous methylene chloride, and 50mL trifluoroacetic acids are added under ice bath；2h is reacted at room temperature；Vacuum rotary steam evaporates
Remove dichloromethane and trifluoroacetic acid；Gained residue is poured into the ether for pre-cooling, is filtered, be dried to obtain required product
Thing；
(4) synthesis DSPE-PEG 2000- double leafs acid
Will in 300mg steps (2) synthesis 1,2- distearoyl-SN- glycerine -3- phosphatidyl ethanolamines-polyethylene glycol-amino oneself two
Acid is dissolved in the dry DMFs of 5mL, and the Amino End Group folic acid of synthesis is dissolved in 1mL dimethyl in 55mg steps (3)
In sulfoxide, it is subsequently adding into system；Reacting at normal temperature without light is overnight；8mL water is subsequently adding, the hydrochloric acid and 2mL of 6mL 0.1N are satisfied
And saline solution, extracted 4 times with chloroform, each 80mL；Merge organic phase, anhydrous sodium sulfate drying, filtering, concentration；Gained is remained
Thing is poured into the ether that 200mL is pre-cooled, and 3h is stirred at -20 DEG C, filtering, is dried to obtain required product.
4. the application of compound as claimed in claim 1, it is characterised in that for preparing double leaf acid targeted ultrasound contrast agent.
5. the application of compound as claimed in claim 4, it is characterised in that the system of described double leaf acid targeted ultrasound contrast agent
Preparation Method, step is as follows：
0.5mg sorbester p18s are weighed, 0.5ml Tween 80s are placed in 1.5mLEP pipes, add 1mg DPPCs, 1mg
DSPE-PEG 2000- double leafs acid, PBS is settled to 1mL, is passed through perfluoropropane gas displacement
Go out air, heating 50min is completely dissolved to lipid during centrifuge tube is positioned over into thermostat water bath, and lucifuge adds DiI dyestuffs, again
It is filled with perfluoropropane gas and replaces air therein, taken out after mechanical oscillation 90s, 300rpm centrifugation 3min removes a layer liquid, i.e.,
It is prepared double leaf acid targeted ultrasound contrast agent.
6. a kind of double leaf acid targeted ultrasound contrast agent, it is characterised in that as the distearyl acyl group phosphatidyl second described in claim 1
Hydramine-polyethylene glycol 2000-double leaf acid is prepared from.
7. the preparation method of double leaf as claimed in claim 6 acid targeted ultrasound contrast agent, it is characterised in that step is as follows：
0.5mg sorbester p18s are weighed, 0.5ml Tween 80s are placed in 1.5mLEP pipes, add 1mg DPPCs, 1mg
DSPE-PEG 2000- double leafs acid, PBS is settled to 1mL, is passed through perfluoropropane gas displacement
Go out air, heating 50min is completely dissolved to lipid during centrifuge tube is positioned over into thermostat water bath, and lucifuge adds DiI dyestuffs, again
It is filled with perfluoropropane gas and replaces air therein, taken out after mechanical oscillation 90s, 300rpm centrifugation 3min removes a layer liquid, i.e.,
It is prepared double leaf acid targeted ultrasound contrast agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611101776.8A CN106750252B (en) | 2016-12-05 | 2016-12-05 | Distearoylphosphatidylethanolamine-polyethylene glycol 2000- double leaf acid and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611101776.8A CN106750252B (en) | 2016-12-05 | 2016-12-05 | Distearoylphosphatidylethanolamine-polyethylene glycol 2000- double leaf acid and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106750252A true CN106750252A (en) | 2017-05-31 |
| CN106750252B CN106750252B (en) | 2018-11-30 |
Family
ID=58884518
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611101776.8A Active CN106750252B (en) | 2016-12-05 | 2016-12-05 | Distearoylphosphatidylethanolamine-polyethylene glycol 2000- double leaf acid and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106750252B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016014337A1 (en) * | 2014-07-25 | 2016-01-28 | Nemucore Medical Innovations, Inc. | Drug delivery nanoemulsion systems |
| CN105535996A (en) * | 2016-01-08 | 2016-05-04 | 贵州医科大学 | Novel fluorescence lipidosome nano probe and preparing method thereof |
| CN106794164A (en) * | 2014-08-14 | 2017-05-31 | L.E.A.F.控股集团公司 | Liposomal encapsulated compatibility medicine |
-
2016
- 2016-12-05 CN CN201611101776.8A patent/CN106750252B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016014337A1 (en) * | 2014-07-25 | 2016-01-28 | Nemucore Medical Innovations, Inc. | Drug delivery nanoemulsion systems |
| CN106794164A (en) * | 2014-08-14 | 2017-05-31 | L.E.A.F.控股集团公司 | Liposomal encapsulated compatibility medicine |
| CN105535996A (en) * | 2016-01-08 | 2016-05-04 | 贵州医科大学 | Novel fluorescence lipidosome nano probe and preparing method thereof |
Non-Patent Citations (1)
| Title |
|---|
| FABIANA CANAL ET. AL.: ""Relevance of folic acid/polymer ratio in targeted PEG–epirubicin conjugates"", 《JOURNAL OF CONTROLLED RELEASE》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106750252B (en) | 2018-11-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Feng et al. | Self-assembly of AIEgens | |
| Huang et al. | A facile surface modification strategy for fabrication of fluorescent silica nanoparticles with the aggregation-induced emission dye through surface-initiated cationic ring opening polymerization | |
| CN108653236A (en) | A kind of biomembrane contains the preparation method and its usage of medicament nano crystal | |
| CN109260480B (en) | A kind of preparation method for the chitosan nano meter level acoustic contrast agent carrying adriamycin | |
| CN106075440B (en) | A kind of hepatoma-targeting photo-thermal therapy agent and the preparation method and application thereof | |
| CN105273055A (en) | RGD tetrapeptide-modified beta-carboline, preparation, activity and application thereof | |
| CN105315338A (en) | LDV-modified [beta]-carboline, and preparation, nano structure, activity and application thereof | |
| CN107629089A (en) | Tacrine platinum (II) complex of high activity and its synthetic method and application | |
| Tang et al. | Nanoscale vesicles assembled from non-planar cyclic molecules for efficient cell penetration | |
| Hu et al. | Superfluorinated copper sulfide nanoprobes for simultaneous 19 F magnetic resonance imaging and photothermal ablation | |
| CN107519501A (en) | A kind of ferromagnetic nano material and preparation method and application | |
| CN104591105B (en) | Cobalt selenide nano material and application thereof | |
| CN106432647B (en) | PH response block polymers and its mixed micelle based on tertiary amino and application | |
| Liu et al. | Capture and separation of circulating tumor cells using functionalized magnetic nanocomposites with simultaneous in situ chemotherapy | |
| Feng et al. | Poly (amino acid) s-based star AIEgens for cell uptake with pH-response and chiral difference | |
| CN104815341A (en) | Targeted polymer micelle magnetic nanoparticle, and preparation method and application thereof | |
| CN106750252B (en) | Distearoylphosphatidylethanolamine-polyethylene glycol 2000- double leaf acid and its preparation method and application | |
| CN113081965B (en) | Sensitivity and H based on ROS 2 S-responsive multifunctional liposome and preparation method and application thereof | |
| CN106749518A (en) | A kind of polypeptide nano material containing double pyrenyl groups and its preparation method and application | |
| CN107349434A (en) | A kind of dissaving polymer and its preparation method and application | |
| CN104857502A (en) | Vascular endothelial growth factor loaded nano controlled-release compound and a preparation method thereof | |
| CN107375952A (en) | The double relaxation platinum oxidation iron gold nano grains of T1/T2 and preparation method | |
| CN106806906A (en) | A kind of preparation method for collecting the fluorescence imaging rare earth upconversion nano pharmaceutical carrier integrated with medicine is carried | |
| CN109620972A (en) | A kind of T1-T2 bimodal targeted imaging contrast agent and preparation method for pulmonary cancer diagnosis | |
| CN109705129A (en) | A kind of gold nano cell fluorescence probe and its preparation method and application with promotion cell activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |