CN108904446A - A kind of preparation method and application of the medicament-carried nano micelle of artery plaque microenvironment response - Google Patents
A kind of preparation method and application of the medicament-carried nano micelle of artery plaque microenvironment response Download PDFInfo
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- 239000000693 micelle Substances 0.000 title claims abstract description 31
- 210000001367 artery Anatomy 0.000 title claims abstract description 21
- 230000004044 response Effects 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 49
- 229940079593 drug Drugs 0.000 claims abstract description 46
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 27
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 claims abstract description 18
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 9
- -1 polypropylene Polymers 0.000 claims abstract description 9
- 239000004743 Polypropylene Substances 0.000 claims abstract description 8
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920001155 polypropylene Polymers 0.000 claims abstract description 8
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 4
- 238000001338 self-assembly Methods 0.000 claims abstract description 4
- 229920001400 block copolymer Polymers 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229920000642 polymer Polymers 0.000 claims description 12
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 150000008126 allyl sulfides Chemical class 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 210000003038 endothelium Anatomy 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000003292 glue Substances 0.000 claims description 3
- 239000003999 initiator Substances 0.000 claims description 3
- 230000007170 pathology Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims description 3
- 208000024248 Vascular System injury Diseases 0.000 claims description 2
- 208000012339 Vascular injury Diseases 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- BBDNZMUIQBRBJH-UHFFFAOYSA-N sulfurochloridic acid;toluene Chemical compound OS(Cl)(=O)=O.CC1=CC=CC=C1 BBDNZMUIQBRBJH-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- 230000003647 oxidation Effects 0.000 abstract description 7
- 238000007254 oxidation reaction Methods 0.000 abstract description 7
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 4
- 230000003902 lesion Effects 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 230000036542 oxidative stress Effects 0.000 abstract description 4
- 206010061218 Inflammation Diseases 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 239000001301 oxygen Substances 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 230000004043 responsiveness Effects 0.000 abstract description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 239000003937 drug carrier Substances 0.000 abstract 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 4
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
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- 239000007787 solid Substances 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 101000668058 Infectious salmon anemia virus (isolate Atlantic salmon/Norway/810/9/99) RNA-directed RNA polymerase catalytic subunit Proteins 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- 241000255964 Pieridae Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
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- 230000007812 deficiency Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical class CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008798 inflammatory stress Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 201000002818 limb ischemia Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229920002492 poly(sulfone) Polymers 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000008268 response to external stimulus Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
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- 230000003827 upregulation Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C08G75/00—Macromolecular compounds obtained by reactions forming a linkage containing sulfur with or without nitrogen, oxygen, or carbon in the main chain of the macromolecule
- C08G75/02—Polythioethers
- C08G75/06—Polythioethers from cyclic thioethers
- C08G75/08—Polythioethers from cyclic thioethers from thiiranes
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Vascular Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Urology & Nephrology (AREA)
- Biophysics (AREA)
- Heart & Thoracic Surgery (AREA)
- Dispersion Chemistry (AREA)
- Polymers & Plastics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of preparation method and applications of the medicament-carried nano micelle of artery plaque microenvironment response.Nano-micelle includes that hydrophilic section polyethylene glycol and hydrophobic section polypropylene sulfide are self-assembly of by bi-block copolymer.Since PEG-PPS micella can respond the active oxygen of patch（ROS）Disintegrate, itself can consume lesion component R OS and realize that its effectively inhibits, meanwhile, micella is used as the pharmaceutical carrier of stimuli responsive again, and the drug Andro of quick release load reduces lesions position inflammatory reaction, plays the effect for significantly increasing and treating patch.This oxidation responsiveness by carrier itself realizes that drug release generates anti-inflammatory effect and alleviates the method for oxidative stress simultaneously, provides a kind of promising innovative therapeutic strategy for atherosclerosis, has a extensive future.
Description
Technical field
The present invention relates to nanosecond medical science fields, and in particular, to a kind of medicament-carried nano glue of artery plaque microenvironment response
The preparation method and application of beam more particularly to a kind of nano-micelle for the artery plaque microenvironment response that can load andrographolide
Preparation method and application.
Background technique
Atherosclerosis is a kind of chronic inflammation disease, worldwide by wide influence, and is caused each
Kind serious complication, including hypertension, angina pectoris and limb ischemia etc..It is currently available that therapeutic strategy is concentrated mainly on rouge
Noninflammatory control in the adjusting of matter metabolin, in addition, the statins as current common treatment of atherosclerosis, it can
It can cause the side reaction such as myopathy and diabetes.Therefore, the treatment urgent need of atherosclerosis seeks new strategy.
It is well known that oxidative stress participates in the development of atherosclerosis.On the one hand, the low density lipoprotein being retained in inner membrance
Albumen（LDL）It is easy to by by active oxygen（ROS）It is oxidized to OxLDL ELISA（oxLDL）, it is atherosclerotic plaque
The committed step of formation.Generated oxLDL can induce and promote the expression of a variety of chemotactic factor (CF)s, and promote raising for monocyte
Collect and eventually lead to it and is divided into macrophage.On the other hand, the inner membrance that ROS can be directly resulted in is impaired, pushes Atherosclerosis
The progress and deterioration of change.Inner membrance is impaired to directly result in born of the same parents' chemoattractant protein-1（MCP-1）And interleukins（IL-6）Equal chemotactics
The excessively high expression of inflammatory factor, and then cause the migration of monocyte and leucocyte to damage location, it will lead to more inflammatories
The secretion of cell factor and the progress for promoting atherosclerotic plaque form vicious circle.Therefore, inflammation and oxidative stress are
Two key factors of Pathogenesis of Atherosclerosis, the adjusting of the two or can for patch treat new strategy be provided.
Crucial effect effect based on inflammatory reaction in atherosclerosis, there are many effective antiinflammatory drug quilts in the recent period
Application study.Andrographolide（Andro）It is a kind of diterpenes diterpenoids lactones compound, nuclear factor can be blocked（NF）- κ B access and have
There is very strong anti-inflammatory activity.However, being limited to water-soluble too poor, Andro is difficult to clinically realize application.Currently, glue
The administration nano-drug administration systems such as beam are improving the utilization rate of dewatering medicament, are reducing toxic side effect and promoted in terms of shows
Huge potentiality.On the other hand, Nano medication has the advantages that passive target, can adhere on impaired blood vessel, across function
Infull blood vessel endothelium, and be retained on atherosclerotic plaque.Therefore, nano-micelle can be used as the carrier of andrographolide
Realize effective treatment of artery plaque.
However, more rare for the nano-micelle of atherosclerosis microenvironment in the prior art, only several needles
To the nano-micelle of atherosclerosis microenvironment, there is also following defects：The first, it can not well solve in blood circulation
Avoid the problem that drug leakage and to can discharge rapidly drug after target position again, second, nano-micelle functions only as carrying medicine work
The effect of tool.
Summary of the invention
The present invention provides a kind of medicament-carried nano of artery plaque microenvironment response to overcome the above-mentioned deficiency of the prior art
Micella, the medicament-carried nano micelle are able to respond Plaque pathology position specific stimulation and discharge drug（Such as andrographolide）, in addition,
The medicament-carried nano micelle can also effectively atherosclerosis-inducing patch recession, play the role of adjuvant treatment.
It is a further object to provide the preparation sides of the medicament-carried nano micelle of above-mentioned artery plaque microenvironment response
Method.
It is also another object of the present invention to provide the medicament-carried nano micelles of above-mentioned artery plaque microenvironment response to control in preparation
Treat the application in atherosclerosis drug.
To achieve the goals above, the present invention is achieved by following scheme：
It includes hydrophilic section polyethylene glycol that a kind of medicament-carried nano micelle of artery plaque microenvironment response, which is by bi-block copolymer,
（PEG）With hydrophobic section polypropylene sulfide（PPS）It is self-assembly of nano-micelle, the molecular weight of the polyethylene glycol is 1 kDa~5
KDa, the molecular weight of polypropylene sulfide are the kDa of 2 kDa~10.
Hydrophobic segment of the polypropylene sulfide as micella can be oxidized to hydrophilic polysulfones structure in the presence of ROS, real
The disintegration of existing micella and the release of drug；Meanwhile introducing stability and biology that hydrophilic segment polyethylene glycol increases nano-micelle
Compatibility.
To obtain the nano-scale that can more preferably pass through endothelial cell injury gap（Less than 150 nm, especially 117.9 ±
23.7 nm）, while again can be with high-efficient carrier drug（Especially andrographolide）Nano-micelle, block polymer choosing
The molecular weight of polyethylene glycol is preferably 2000 Da, and the molecular weight of polypropylene sulfide is preferably 6000 Da.
A kind of preparation method of the medicament-carried nano micelle of artery plaque microenvironment response, includes the following steps：
S1. the PEG sulfonated as Material synthesis using PEG-OH；
S2. using sulfonated PEG as raw material, the PEG of thioacetic acid is synthesized with thioacetic acid nak response in methyl alcohol；
S3. initiator is made with the PEG of thioacetic acid, sodium methoxide makees catalyst, and the ring-opening polymerisation for causing allyl sulfides obtains
PEG-PPS block polymer.
Preferably, the specific steps are by PEG-OH using PEG-OH sulfonated as Material synthesis PEG by S1
After being dissolved with anhydrous chloroform, under the conditions of 0 DEG C, DMAP, triethylamine and paratoluensulfonyl chloride is added, 12 h precipitating is stirred at room temperature
In a large amount of ether, filtration drying.
By polyethylene glycol allyl sulfides（PEG-PPS）Self assembly loads in the anti-inflammatory small-molecule drug Herba Andrographitis of hydrophobicity
Ester（Andro）It is prepared.
The medicament-carried nano micelle of claimed above-mentioned artery plaque microenvironment response is athero- in preparation treatment artery
Harden the application in drug.
A kind of drug for treating atherosclerosis is prepared by above-mentioned medicament-carried nano micelle load andrographolide.
The drug consumes the ROS of artery plaque when can release the drug by nano-micelle carrier, combine the anti-inflammatory effect of andrographolide, produces
Raw enhancement treatment of atherosclerosis effect.
Preferably, the Nano medication diameter is within 150 nm, it can be achieved that the richness of vascular injury site
Collect and pass through injured endothelium and reaches Plaque pathology area.
Preferably, the Nano medication diameter is 117.9 ± 23.7 nm.
Preferably, after obtaining block polymer, assembling and drug by supersonic induced polymer, control
The feed ratio 1 of andrographolide and polymer:10 to obtain maximum drugloading rate and optimal Nano medication size.
Compared with prior art, the Nano medication has following beneficial effect：
The present invention provides a kind of nano-micelle of artery plaque microenvironment response, which can be effectively prevented from and convey
The leakage of drug in journey, while to lesions position microenvironment rapid delivery of pharmaceuticals can be responded behind target spot position.It is of particular importance that
It can cause the consumption of lesions position ROS in artery plaque drug release, the treatment for combining anti-inflammatory drug is played the role of heightening the effect of a treatment.
This carrier itself plays the role of heightening the effect of a treatment in response to environmental stimulus or provides one newly for the treatment of atherosclerosis
Thinking.
Detailed description of the invention
Fig. 1 is block polymer synthetic line figure and active oxygen（ROS）Structure change after processing.
Fig. 2A is that the TEM of Nano medication schemes；B is through hydrogen peroxide（0.3%）Nano medication TEM figure after handling 24 h；C is
The grain size distribution of Nano medication；D is to load the nano-micelle of FDA through hydrogen peroxide（0.3%）The fluorescence of different time is bent after processing
Line.
Fig. 3 is intake situation of 264.7 cell of RAW to load FDA nano-micelle different time.
Fig. 4 is Nano medication to the effect assessment for inhibiting inflammatory factor IL-6 and MCP-1 expression；* indicate that conspicuousness is poor
It is different（*P﹤ 0.05, * *P﹤ 0.01, * * *P﹤ 0.001）.
Fig. 5 is oxidation level intracellular after Nano medication processing 264.7 cell of RAW；Upper row：Control, LPS and LPS+
MC；Lower row：LPS+Adro and LPS+A-MC.
Specific embodiment
With reference to the accompanying drawings of the specification and specific embodiment, the present invention is further explained.These embodiments are merely to illustrate
The present invention rather than limit the scope of the invention.Test method without specific conditions in lower example embodiment, usually according to
This field normal condition or the condition suggested according to manufacturer.What those skilled in the art was done on the basis of the present invention
The variation and replacement of any unsubstantiality belong to scope of the present invention.
The synthesis of 1 block polymer of embodiment
The synthesis of polymer is as shown in Figure 1.Firstly, the PEG sulfonated as Material synthesis using PEG-OH.Specifically, by 7.0 g
PEG-OH first use 50 mL anhydrous chloroforms dissolve, then under the conditions of 0 DEG C, be added 43 mg DMAP, 0.73 mL triethylamine and
Reaction solution is deposited in a large amount of anhydrous ether by 1.0 g paratoluensulfonyl chlorides after 12 h of reaction are stirred at room temperature, and is obtained by filtration solid
Body obtains sulfonated PEG after vacuum drying；
Then using sulfonated PEG as raw material, thioacetic acid PEG is synthesized with thioacetic acid nak response in methyl alcohol.4.0 g sulphurs
The PEG of acidification is dissolved in the methanol of 5 mL, and the triethylamine of 12 mL and 12 h of thioacetic acid nak response of 2.28 g, rotation is added
It is evaporated off after methanol and redissolves solid with chloroform, then successively washed with the sodium bicarbonate solution of saturation and sodium chloride solution, point
From organic layer be deposited in anhydrous ether after anhydrous magnesium sulfate is dry, filter and be dried to obtain product.
Finally, making initiator with the PEG of thioacetic acid, sodium methoxide makees catalyst, causes the ring-opening polymerisation of allyl sulfides
Obtain PEG-PPS.The PEG of 1.0 g thioacetic acids is dissolved in 10 mL tetrahydrofurans, and the sodium ethoxide room temperature that 30 mg are added is stirred
Mix 1 h.Then reaction solution is cooled to 0 DEG C, the allyl sulfides of 1.95 mL is added, cooling device and room temperature are removed after 30 min
Stir 12 h.Then, reaction solution is added drop-wise in the deionized water of 100 mL under the action of ultrasound, dialyses 2 days remove in water
Freeze-drying after tetrahydrofuran is gone to obtain final product.
To obtain optimal polymer blocks ratio, being respectively synthesized PPS molecular weight is the embedding of 4000,6000 and 8000 Da
Section polymer.Filter out 6000 block.
The preparation and characterization of 2 Nano medication of embodiment
The andrographolide of polymer 20 mg and 2 mg of the block that Example 1 is prepared be dissolved in 1.5 mL DMSO and
The in the mixed solvent of 0.5 mL chloroform is added drop-wise in 20 mL water under ultrasonication.Revolving removes the chloroform of mixed solution, so
It is dialysed in water 24 h with 14 kDa bag filters afterwards, is concentrated by ultrafiltration, is washed with water three times.Droplet measurement is the results show that micella
Hydrated diameter is 117.9 ± 23.7 nm（Fig. 2 C）, the results show that Nano medication is uniform spherical structure, diameter is current potential
100 nm or so（Fig. 2A）.For prove Nano medication have oxidation responsiveness, we with 0.3% dioxygen water process Nano medication
48 h, by treated, TEM detection is done in sample sample preparation, and discovery Nano medication becomes random aggregated structure（Fig. 2 B）, can return
Because being disintegrated in micellar structure.
3 Nano medication oxidation-sensitive of embodiment discharges qualitative research
In order to which the Andro confirmed in Nano medication can be discharged in response to oxidation environment, we are by fluorescein oxalic acid（FDA）Substitution
Andro is supported on the fluorescence detection that in-vitro simulated release has been carried out in nano-micelle.As shown in Figure 2 D, 0.3% hydrogen peroxide is added
Afterwards, the fluorescence of FDA changes with time and gradually increases, this is because FDA is released from micella and the fluorescence solution that occurs
It is quenched.
The cellular uptake of 4 Nano medication of embodiment
We evaluate the ability that Nano medication enters cell using confocal experiments.The Nano medication of FDA will be loaded（FDA-
MC）It is co-cultured respectively with normal 264.7 cell of RAW and LPS 264.7 cell of RAW induced（It is generated after LPS induction similar
In the oxidation environment of artery plaque）, as shown in figure 3, fluorescence intracellular enhances with the extension of incubation time, and LPS induction group
FDA fluorescence is apparently higher than untreated fish group, also shows the ability that oxidation microenvironment triggering micella disintegrates.
Inhibition of 5 Nano medication of embodiment to inflammatory factor and the regulation to ROS
We have rated after Nano medication is treated 264.7 intracellular IL-6 and MCP-1 of RAW in transcriptional level using PCR experiment
Expression, as shown in figure 4, LPS group proves, the intracellular IL-6 of RAW 264.7 and MCP-1 of plaque site expression all can be apparent
Up-regulation, after nano-micelle is handled, which can be significantly suppressed, and especially load the Nano medication of Andro（A-MC）
Show best therapeutic effect.Similarly, which also shows inhibits artery plaque oxidative stress well
Ability（Fig. 5）.
Claims (9)
1. a kind of medicament-carried nano micelle of artery plaque microenvironment response, which is characterized in that by bi-block copolymer comprising hydrophilic
Section polyethylene glycol and hydrophobic section polypropylene sulfide are self-assembly of nano-micelle, and the molecular weight of the polyethylene glycol is 1 kDa~5
KDa, the molecular weight of polypropylene sulfide are the kDa of 2 kDa~10.
2. medicament-carried nano micelle according to claim 1, which is characterized in that the molecular weight of the polyethylene glycol is 2 kDa,
The molecular weight of polypropylene sulfide is 6 kDa.
3. the preparation method of the medicament-carried nano micelle of the response of artery plaque microenvironment described in claim 1, which is characterized in that including
Following steps：
S1. the PEG sulfonated as Material synthesis using PEG-OH；
S2. using sulfonated PEG as raw material, the PEG of thioacetic acid is synthesized with thioacetic acid nak response in methyl alcohol；
S3. initiator is made with the PEG of thioacetic acid, sodium methoxide makees catalyst, and the ring-opening polymerisation for causing allyl sulfides obtains
PEG-PPS。
4. preparation method according to claim 3, which is characterized in that PEG S1 sulfonated as Material synthesis using PEG-OH
The specific steps are PEG-OH is dissolved with anhydrous chloroform after, in low temperature（0-5 ℃）Under the conditions of, DMAP, triethylamine and right is added
8-24 h is stirred at room temperature in toluene sulfochloride, is deposited in filtration drying in a large amount of ether.
5. the medicament-carried nano micelle of artery plaque microenvironment response of any of claims 1 or 2 treats Atherosclerosis in preparation
Application in chemical drug object.
6. a kind of selectively targeted Nano medication of Aortic Plaque, which is characterized in that by medicament-carried nano glue described in claim 1
Beam loading andrographolide is prepared.
7. Nano medication according to claim 6, which is characterized in that the Nano medication diameter, can within 150 nm
It realizes the enrichment of vascular injury site and passes through injured endothelium and reach Plaque pathology area.
8. Nano medication according to claim 7, which is characterized in that the Nano medication diameter is 117.9 ± 23.7
nm。
9. Nano medication according to claim 6, which is characterized in that the feed ratio 1 of control andrographolide and polymer:
10 to obtain maximum drugloading rate and optimal Nano medication size.
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