CN110041475A - A kind of amphipathic nature block polymer, its shell crosslinking micella and preparation method and application - Google Patents
A kind of amphipathic nature block polymer, its shell crosslinking micella and preparation method and application Download PDFInfo
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- CN110041475A CN110041475A CN201910291982.7A CN201910291982A CN110041475A CN 110041475 A CN110041475 A CN 110041475A CN 201910291982 A CN201910291982 A CN 201910291982A CN 110041475 A CN110041475 A CN 110041475A
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- block polymer
- amphipathic nature
- formula
- nature block
- micella
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Links
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- 238000004132 cross linking Methods 0.000 title claims abstract description 41
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- 239000003814 drug Substances 0.000 claims abstract description 42
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 38
- 229940079593 drug Drugs 0.000 claims abstract description 21
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 21
- 239000002114 nanocomposite Substances 0.000 claims abstract description 19
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 12
- -1 methyl acrylic ester compound Chemical class 0.000 claims abstract description 12
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- 238000000034 method Methods 0.000 claims description 23
- 239000000693 micelle Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000003431 cross linking reagent Substances 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 15
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- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000005286 illumination Methods 0.000 claims description 13
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- 229950003776 protoporphyrin Drugs 0.000 description 21
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 17
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- 229940126680 traditional chinese medicines Drugs 0.000 description 11
- 229920001400 block copolymer Polymers 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 8
- 239000000178 monomer Substances 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 7
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- 229910021641 deionized water Inorganic materials 0.000 description 5
- 239000002105 nanoparticle Substances 0.000 description 5
- 239000008055 phosphate buffer solution Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 3
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- 239000013049 sediment Substances 0.000 description 3
- 238000001338 self-assembly Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- SOIJWBIPWKSGET-UHFFFAOYSA-N anthracene;dihydrochloride Chemical compound Cl.Cl.C1=CC=CC2=CC3=CC=CC=C3C=C21 SOIJWBIPWKSGET-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000000429 assembly Methods 0.000 description 2
- 230000000712 assembly Effects 0.000 description 2
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- 238000012512 characterization method Methods 0.000 description 2
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- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- SHXOKQKTZJXHHR-UHFFFAOYSA-N n,n-diethyl-5-iminobenzo[a]phenoxazin-9-amine;hydrochloride Chemical compound [Cl-].C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=[NH2+])C2=C1 SHXOKQKTZJXHHR-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 150000007970 thio esters Chemical class 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- CVEPFOUZABPRMK-UHFFFAOYSA-N 2-methylprop-2-enoic acid;styrene Chemical compound CC(=C)C(O)=O.C=CC1=CC=CC=C1 CVEPFOUZABPRMK-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- WXQDFOGZIYLEGP-UHFFFAOYSA-N C(C(C)C)#N.C(C(C)C)#N.[N] Chemical compound C(C(C)C)#N.C(C(C)C)#N.[N] WXQDFOGZIYLEGP-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001454 anthracenes Chemical class 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000005253 cladding Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 239000012792 core layer Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- KXRNYDKIPJKLTD-UHFFFAOYSA-N cyanoboron Chemical compound [B]C#N KXRNYDKIPJKLTD-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 244000144992 flock Species 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000003760 hair shine Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
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- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 238000012712 reversible addition−fragmentation chain-transfer polymerization Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002522 swelling effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/46—Polymerisation initiated by wave energy or particle radiation
- C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
- C08F2/50—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light with sensitising agents
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
- C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2438/00—Living radical polymerisation
- C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dispersion Chemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The polymer nanocomposite shell crosslinking micella and their preparation method and application that the present invention provides a kind of amphipathic nature block polymer, is made from it.The hydrophobic segment that hydrophobic property is presented by hydrophilic segment and in neutral and alkaline environment for the amphipathic nature block polymer is obtained by reversible addion-fragmentation chain transfer (RAFT) polymerization, wherein the hydrophilic segment is that oligomeric ethylene glycol methacrylate is copolymerized to obtain with the methyl acrylic ester compound with the aldehyde radical functional group for shell crosslinking, and molecular weight is 5000~10000Da.The present invention realizes the controlled release of the carrier loaded dewatering medicament of polymer nanocomposite shell crosslinking micella, the photosensitizer with red emission of Covalent bonding together and the hydrophobic segment of aldehyde radical functional group cooperation presentation hydrophobic property in neutral and alkaline environment for shell crosslinking in amphipathic nature block polymer simultaneously, can be accurately realized the controlled release of drug in the microenvironment of weak acid and under the excitation of red light irradiation.
Description
Technical field
The invention belongs to high molecular material and its preparation and application fields.In particular it relates to the two of a kind of stimulating responsive
Parent's property block copolymer, the polymer nano micelle being made of the amphipathic nature block polymer, and its preparation method and application.
Background technique
It is bionical always all by people come the height for realizing all kinds of structure functions using super-molecule assembling body simulation eucaryotic cell structure
Concern, realized especially with the Nanoscale assemblies of amphipathic nature block polymer body foci position drug conveying.
However, although the assembly that block copolymer is formed has lower the critical micelle concentration compared to Small molecular surfactant
(CMC) better thermodynamic stability is shown, but still there are some uncontrollable factors to may result in block copolymer group
Destruction and dissociation, such as temperature, concentration and solvent condition of dress body etc. (Elsabahy M, Heo G S, LimSM,
Chemical revlews, 2015,115 (19): 10967-11011).For using block copolymer assembly as the drug of carrier
Delivery system, the stability of assembly is in release in advance, extension blood circulation time and the increase curative effect of medication for avoiding drug
Etc. particularly important (Talelli M, Barz M, Rijcken C JF, Nano today, 2015,10 (1): 93-117).Together
When be directed to increase drug delivery accuracy and improve drug bioactivity be also the emphasis studied always in recent years.For
The responsive polymer of physiology coherent signal is also always a big research hotspot.Compared to normal tissue cell, human tumor portion
The low ph conditions that position is showed are an important reference points.Research for the polymeric system of pH sensitivity is also that layer goes out not
Thoroughly.
How pH and illumination stimuli-responsive polymeric system are utilized, designs the nanometre glue of shell crosslinking
Beam, to effectively improve the stability of Nanoscale assemblies, the release simultaneously for drug can also achieve the purpose that controllable, this is always
It is scientific worker in the research topic explored diligently.
Summary of the invention
The purpose of the invention is to construct a kind of can be stabilized under the conditions of the pH of normal physiological context in weak
The polymer nano micelle of stimuli responsive under acid environment and red light irradiation provides a kind of the amphipathic embedding of stimulating responsive thus
Section copolymer, the polymer nanocomposite shell crosslinking micella being made of the amphipathic nature block polymer and its preparation method and application.
For this purpose, the present invention provides the invention of following various aspects:
<1>a kind of amphipathic nature block polymer of, the amphipathic nature block polymer include hydrophilic segment and hydrophobic segment,
The hydrophobic segment is following hydrophobic segment shown in formula A.
Formula A:
Wherein m=0.95~0.99, n=0.05~0.01, a=52~58.
Wherein the hydrophilic segment is by oligomeric ethylene glycol methacrylate and with the aldehyde radical function for shell crosslinking
The methyl acrylic ester compound of group is copolymerized to obtain, and the hydrophilic segment molecular weight is 5000~10000Da.
<2>is according to<1>amphipathic nature block polymer, wherein the hydrophobic segment be the formula A hydrophobic segment with
Hydrophobic segment obtained from photosensitizer Covalent bonding together with red emission.
<3>is according to<2>amphipathic nature block polymer, wherein the photosensitizer with red emission is under
The photosensitizer PpIX of formula structure, and hydrophobic segment shown in obtained following formula B,
PpIX:
Formula B:
<4>amphipathic nature block polymer according to any one of<1>-<3>, wherein the amphiphilic block
Object has following formula I structure
Formulas I:
Wherein m=0.95~0.99, n=0.05~0.01, x=0.6~0.8, y=0.4~0.2, a=52~58, b=
15~20.
<5>a kind of method for preparing amphipathic nature block polymer described in any one of<1>-<4>of, the method includes
Following steps:
A) polymerization ofathe reactants shown in micromolecule chain transfer agent and Formula II and formula III and obtain large hydrophilic molecular chain and turn
Move agent；
B) be further continued for reactant reaction shown in formula IV and Formula V as large hydrophilic molecular chain-transferring agent obtained above and
Obtain amphipathic nature block polymer；
C) optionally, b) amphipathic nature block polymer obtained is reacted with the photosensitizer with red emission, is obtained
The amphipathic nature block polymer, wherein the photosensitizer with red emission is preferably photosensitizer shown in following formula C
PpIX,
Formula II:
Formula III:
Formula IV:
Formula V:
Formula C:
<6>a kind of polymer nanocomposite shell of is crosslinked micella, wherein by<1>-<4>in the aqueous systems of pH=7.3-7.4
After described in any item amphipathic nature block polymers are assembled into micella, the micella is subjected to shell friendship using the shell crosslinking agent of formula D
Joining and obtains, the size of the polymer nanocomposite shell crosslinking micella is 50~80nm, and has pH and feux rouges optical Response,
Formula D:
<7>amphipathic nature block polymer nanoshell according to<6>is crosslinked micella, wherein the polymer nanocomposite shell
Being crosslinked micella also includes drug to be released.
<8>amphipathic nature block polymer nanoshell crosslinking micella dissociation described in a kind of any one of control<6>-<7>of
Method the described method comprises the following steps:
A) amphipathic nature block polymer nanoshell crosslinking micella is prepared into aqueous dispersions；
B) pH value of gained aqueous dispersions is slowly acidified to 5.0-5.5 by the range of 7.3-7.4, so that the amphiphilic
Hydrophobic segment in property block copolymer is changed into hydrophily；
C) feux rouges illumination is used, by the interconnecting piece of the formula D in the amphipathic nature block polymer nanoshell crosslinking micella
It decomposes from finally disintegrating nano-micelle assembly.
<9>amphipathic nature block polymer nanoshell according to any one of<6>-<7>crosslinking micella is carried as drug
The application of body.
<10>amphipathic nature block polymer nanoshell according to any one of<6>-<7>crosslinking micella is used for weak
The purposes of the controlled release of dewatering medicament is realized under the microenvironment of acid and the excitation of red light irradiation.
Detailed description of the invention
Fig. 1 shows large hydrophilic molecular chain-transferring agent according to one embodiment of the present invention and amphipathic block is total
The nuclear magnetic resonance spectroscopy spectrogram of polymers, for the chemical structure and chain structure characterization to the block copolymer.Wherein shown in a curve
For the nuclear magnetic resonance spectroscopy of large hydrophilic molecular chain-transferring agent, b curve show the hydrogen nuclear magnetic resonance of amphipathic nature block polymer
Spectrum.
Fig. 2 shows according to one embodiment of the present invention large hydrophilic molecular chain-transferring agent and amphipathic block it is total
The gel permeation chromatography spectrogram of polymers, the characterization for molecular weight and polydispersity coefficient to the block copolymer.Wherein a is bent
Line show the gel permeation chromatography of large hydrophilic molecular chain-transferring agent, and b curve is the gel infiltration of amphipathic nature block polymer
Chromatography.
Fig. 3 shows amphipathic nature block polymer nano-micelle according to one embodiment of the present invention in different pH environment
Dynamic light scattering and electromicroscopic photograph in the case where the crosslinking of lower and shell, wherein figure a show amphipathic nature block polymer nanometer
The particle size results of dynamic light scattering test of the micella under different pH environment and under shell cross-linked state, figure b show amphipathic embedding
Electromicroscopic photograph of the section copolymer nano micella in pH=7.3~7.4 and under shell cross-linked state, figure c show amphipathic embedding
Electromicroscopic photograph of the section copolymer nano micella in pH=5.0~5.5 and under shell cross-linked state.
Fig. 4 shows the crosslinking micella of amphipathic nature block polymer nanoshell according to one embodiment of the present invention in difference
The variation of photosensitizer fluorescence intensity and corresponding fluorescence intensity normalized curve in pH environment, wherein figure a show shell friendship
Join micella with the reduction of locating aqueous systems pH value, photosensitizer PpIX fluorescent emission (625nm) intensity increases, shows photosensitive
The recovery of the photodynamics ability of agent；Figure b show the shell crosslinking micella in photosensitizer fluorescence transmitting (625nm) intensity with
The variation of aqueous systems pH value and the trend for showing corresponding change.
Fig. 5 shows the crosslinking micella of amphipathic nature block polymer nanoshell according to one embodiment of the present invention in pH=
In 5 environment, the variation of micella particle (also referred to as micella) shell crosslinking agent fluorescence intensity, wherein figure a show the shell cross-linked rubber
Beam persistently uses under feux rouges (wave-length coverage is 570nm~590nm) light stimulation, shell in the environment of pH=5.0~5.5
Crosslinking agent 9,10- ammonia ethyoxyl anthracene (An-2NH2) fluorescent emission (430nm) intensity persistently reduce therewith, show shell crosslinking agent
From micella particle shell interrupt cracking from；Figure b show the fluorescence of shell crosslinking micella its shell crosslinking agent under different pH environment
Emit (430nm) intensity with the variation of light application time, also indicates that out that shell crosslinking micella in pH=5.0~5.5 environment, continues
Light stimulation can make its shell crosslinking agent obtain more efficiently fracture dissociation.
Fig. 6 shows the crosslinking micella of amphipathic nature block polymer nanoshell according to one embodiment of the present invention in pH=
In the varying environment of 5.0~5.5 and pH=7.3~7.4, the variation and micella particle of micella particle shell crosslinking agent fluorescence intensity
The control of diameter variation, when showing pH=5.0~5.5 in figure, shell crosslinking agent 9,10- ammonia ethyoxyl anthracene (An-2NH2) fluorescence
Transmitting (430nm) intensity is persistently reduced as light application time increases, and partial size has slightly due to incipient swelling action
The process that becomes larger, later with the fracture of shell crosslinking agent connection structure, assembly is dissociated, and last partial size becomes smaller until intimate
The single-stranded partial size state of polymer；However in pH=7.3~7.4, shell crosslinking agent fluorescence intensity and assembly partial size do not have
Apparent variation occurs, indicates good stability.
Fig. 7 shows dredging in the crosslinking micella of amphipathic nature block polymer nanoshell according to one embodiment of the present invention
Water camptothecin drug (CPT) cumulative release curve at any time has illumination and no light item when being shown in pH=7.3~7.4 in figure
Drug cumulative release amount is to start to tend to be balanced after 17h under part, and the cumulative release amount of CPT is 30% under illumination condition,
There was only 25% raw medicine release when no light.And in the environment of pH=5.0~5.5, after red light irradiation 40h, CPT raw medicine
Cumulative release amount can reach 80%.It should be the result shows that the shell be crosslinked micella in weakly acidic condition and feux rouges (wave-length coverage 570nm
~590nm) loaded hydrophobic drug can be effectively discharged under light stimulation.
Specific embodiment
Technical solution of the present invention is elaborated further below.It should be pointed out that each embodiment of the invention can
To combine in any way as needed.
Polymer nano micelle is usually to be obtained by amphipathic nature block polymer self assembly, contains an oleophylic (also referred to as
Make hydrophobic) kernel and hydrophilic shell.Therefore, hydrophobic substance, if dewatering medicament can be loaded in nano-micelle kernel,
Then the controlled release of dewatering medicament can be realized by designing responsive polymer nanoparticle.However, most of blocks
There are stability problems for copolymer nano assembly, may dissociate during blood circulation, lead to shifting to an earlier date for drug
The circulation time of assembly and drug in vivo is shortened in release.It not only affects in this way to normal cell, while right
Ideal effect is also unable to reach in the release of lesions position in drug.
In the present invention, the stability problem of polymer nanocomposite assembly is solved we have proposed a kind of completely new strategy.
Specifically, we devise a kind of block copolymer, which contains the hydrophobic segment of pH sensitivity.The segment is in
Hydrophobic property is showed in property and alkaline environment (pH > 7), and under faintly acid (pH=5~6) environment, then by hydrophobic property
It is changed into water-wet behavior.By photosensitizer of the Covalent bonding together on hydrophobic segment such as protoporphyrin IX (PpIX) photosensitizer due to
The assembling of polymer nano micelle and flock together, at this point, the fluorescent emission of PpIX and photodynamics ability pass through micella core
Layer amino photo induced electron transfer effect (PET) and self-quenching effect and weaken.When the hydrophobic chain of polymer nanocomposite assembly
Section is changed into hydrophilic segment after being swollen, and restores the fluorescent emission of PpIX and photodynamics ability, then by extraneous
Singlet oxygen is generated after feux rouges light stimulation, so that assembling body shell crosslinking agent connection structure is broken, finally along with micella
The dissociation of particle releases the dewatering medicament of assembly internal load.
In the present invention, being suitble to the photosensitizer used is the photosensitizer with red emission.The photosensitizer preferably selects
From protoporphyrin IX (PpIX) photosensitizer, eosin Y photosensitizer, Porphyrin-Based Sensitizer, Nile blue photosensitizer and phthalein blueness photosensitizer etc.
At least one of, and most preferably protoporphyrin IX (PpIX) photosensitizer.
In general, on the one hand, the present invention provides a kind of amphipathic nature block polymer, by hydrophilic segment and hydrophobic chain
Section by polymerization reaction, such as reversible addion-fragmentation chain transfer (RAFT) polymerization reaction and obtain.Amphipathic nature block polymer
Hydrophilic segment is oligomeric ethylene glycol methacrylate and the methyl acrylic ester with the aldehyde radical functional group for shell crosslinking
(such as 4- formylphenyl oxygen ethylmethyl acrylate) copolymerization obtains, and hydrophilic segment molecular weight is 5000~10000
Er Dun (Da), preferably 6000~9000Da, more preferably 6000~8000Da, most preferably 7000~8000Da.It is described to dredge
Water segment has the chemical structure as shown in following formula A or formula B.
Formula A:
Formula B:
Wherein m=0.95~0.99, preferably 0.96~0.98, more preferable 0.97~0.98, n=0.05~0.01, preferably
0.04~0.02, more preferable 0.03~0.02, a=52~58, preferably 53~57, more preferable 54~56.
Refer in ester group side group in term as used herein " oligomeric ethylene glycol methacrylate " and exists containing the degree of polymerization
The methyl acrylic ester compound of oligomeric ethylene glycol structure within the scope of 8-9.
Refer to and taken in term as used herein " methacrylate with the aldehyde radical functional group being crosslinked for shell "
The aldehyde radical functional group of band can carry out the methyl acrylic ester compound of cross-linking reaction, one with the shell crosslinking agent in the present invention
A specific example is 4- formylphenyl oxygen ethylmethyl acrylate etc..
In a preferred embodiment, the amphipathic nature block polymer has the chemical structure of following formula I, and by formula
The progress of 4- formylphenyl oxygen ethylmethyl acrylate shown in oligomeric ethylene glycol methacrylate and formula III shown in II can
Inverse addition-fracture chain tra nsfer (RAFT) polymerize obtained hydrophilic segment, and the N as shown in formula IV, N '-diisopropyl aminoethyl
Hydroxyethyl methacrylate shown in methacrylate and Formula V carries out reversible addion-fragmentation chain transfer (RAFT) polymerization and obtains
Hydrophobic segment.Finally by rear modification and formula C occur esterification obtain to the end with red emission photosensitizer (PpIX)
Amphipathic nature block polymer.
Formulas I:
Formula II:
Formula III:
Formula IV:
Formula V:
Formula C:
Wherein m=0.95~0.99, preferably 0.96~0.98, more preferable 0.97~0.98；N=0.05~0.01, preferably
0.04~0.02, more preferable 0.03~0.02；X=0.6~0.8, preferably 0.65~0.8, more preferable 0.7~0.8；Y=0.4~
0.2, preferably 0.35~0.2, more preferable 0.3~0.2；A=52~58, preferably 53~57, more preferable 54~56；B=15~20,
It is preferred that 16~19, more preferable 17~19.
In the present invention, term " reversible addion-fragmentation chain transfer (RAFT) " has general in Polymer Synthesizing field
Meaning, specifically refer to using a kind of double thioesters or three thioes derivatives as chain transfer agents, in the course of the polymerization process with freedom
Base forms the intermediate of suspend mode, limits the irreversible biradical termination side reaction between growing chain free radical, obtains polymerization reaction
Effectively to control.The intermediate of this suspend mode simultaneously can self-cleavage, released again from corresponding sulphur atom new activity from
By base, growing chain is formed in conjunction with monomer.Since the rate of addition or fracture is more faster than the rate of chain growth, double thioesters and three
Thioes derivatives shift rapidly between living radical and suspend mode free radical, make molecular weight distribution sharp, to make condensate
Now controllable/" activity " feature.This is a kind of controllable extremely efficient method of the activity for realizing free radical polymerization, is proposed from 1998
It uses till today always afterwards.
On the other hand, the present invention provides a kind of polymer nano being made of amphipathic nature block polymer of the present invention
Rice shell is crosslinked micella, and the polymer nano micelle is uniformly dispersed, having a size of 50~80nm.In a preferred embodiment,
The nano-micelle size is about 50nm or so.In a further preferred embodiment, the nano-micelle have pH and
Feux rouges optical Response.
In another aspect of the invention, a kind of method of control polymer nanocomposite shell crosslinking micella dissociation is provided, it is special
Sign is, the described method comprises the following steps: by the amphipathic nature block polymer in the environment of pH=7.3~7.4 group
Dress up the aqueous dispersions of polymer nanocomposite shell crosslinking micella；It is then that the pH value of the assembly aqueous systems is slowly sour by 7.3~7.4
Change to 5.0~5.5, after stirring a period of time, carries out feux rouges (wave-length coverage is 570nm~590nm) light stimulation from the external world, into
And the coupling part for being crosslinked nano-micelle shell is dissociated, and nano-micelle assembly is finally disintegrated.
In a preferred embodiment, the polymer nano micelle aqueous dispersions are formed as follows: will be described amphipathic
Block copolymer takes 5mg to be dissolved in the organic solvent as cosolvent, is added dropwise thereto under certain temperature and stirring condition
The deionized water for entering pH=10~10.1 of 9mL continues stirring volatilization after deionized water drips and finishes and removes organic solvent simultaneously
It is diluted with phosphate buffer solution (pH=7.3~7.4).Then shell crosslinking agent and cyano boron are added into the dispersion liquid of micella
Sodium hydride removes unreacted impurity by dialysing in pure water after reaction overnight.Phosphate buffer solution (pH is finally used again
=7.3~7.4) being diluted to total volume is 10mL to obtain the polymer nano-particle aqueous dispersions of the 0.5mg/mL.
In a preferred embodiment, the reaction is following occurs: by the amphipathic nature block polymer in pH=
It assembles, be crosslinked in the environment of 7.3~7.4, dispersion obtains the aqueous dispersions of polymer nanocomposite shell crosslinking micella；Then by the assembling
The pH value of body aqueous systems is slowly acidified to 5.0~5.5 by 7.3~7.4 range, original in assembly after stirring a period of time
Hydrophobic segment be transformed into hydrophilic segment in acid condition, nano-micelle is swollen, then by covalent bonding hydrophobic
The photodynamics ability of the red emission photosensitizer (PpIX) of segment is restored, extraneous feux rouges (wave-length coverage be 570nm~
Singlet oxygen 590nm) is generated under light stimulation, and then the coupling part that nano-micelle shell is crosslinked is dissociated, and nanometer is finally disintegrated
Micella assembly.
On the other hand, the present invention provides above-mentioned amphipathic nature block polymer nanoshell crosslinking micellas as pharmaceutical carrier
Application, be used for example as the carrier of hydrophobic anticancer drug camptothecine (CPT) etc..
On the other hand, the present invention provides above-mentioned amphipathic nature block polymer nanoshells to be crosslinked micella in the micro-loop of weak acid
The controlled release of dewatering medicament can be achieved under border.
On the other hand, the present invention provides above-mentioned amphipathic nature block polymer nanoshell crosslinking micellas to be used in weak acid
The purposes of microenvironment and the lower controlled release for realizing dewatering medicament of red light irradiation excitation.
The purpose of the present invention can be achieved through the following technical solutions:
Be first in conjunction in organic chemistry chemical reaction come prepare have for shell be crosslinked aldehyde radical functional group monomer, and
And it is named as ABEMA, with shell crosslinking agent such as 9,10- ammonia ethyoxyl anthracene dihydrochloride (An-2NH2) combination reaction occurs, make
The crosslinking of polymer micelle particle shell.The monomer ABEMA and shell crosslinking agent 9,10- ammonia ethyoxyl anthracene (An-2NH2) have with
Flowering structure:
Then, using micromolecule chain transfer agent such as CEP (2- cyano -2- propyl propyl trisulfide is for carbonic ester) first to oligomerization
Glycolmethacrylate (for example, molecular weight is 475Da) and ABEMA carry out polymerization reaction, and it is disconnected preferably to carry out reversible addition-
Chain tra nsfer (RAFT) polymerization reaction is split, later again and N, N '-diisopropyl aminoethyl methacrylate and hydroxyethyl methacrylate
Ethyl ester carries out polymerization reaction, preferably progress reversible addion-fragmentation chain transfer (RAFT) polymerization reaction.Amphipathic block is obtained with this
Copolymer, finally by it is rear modification with photosensitizer (such as PpIX) occur esterification obtain to the end with red emission it is photosensitive
The amphipathic nature block polymer of agent (for example, PpIX).The micromolecule chain transfer agent CEP has a structure that with photosensitizer
CEP:
PIX:
Eosin Y:
Porphyrin:
Nile blue:
Phthalein is green:
Preferably, obtained suitable hydrophilic and the amphipathic nature block polymer of hydrophobic segment length are added using cosolvent-
The method of water carries out self assembly.Detailed process are as follows: polymer is substantially dissolved in tetrahydrofuran, is made in certain temperature and stirring
With the lower deionized water for being slowly added to pH=10~10.1 to it, continues stirring volatilization removing organic solvent after assembling and be used in combination
Phosphate buffer solution (pH=7.3~7.4) dilution.Then shell crosslinking agent such as 9,10- ammonia is added into the dispersion liquid of micella
Ethyoxyl anthracene dihydrochloride (An-2NH2) and sodium cyanoborohydride, it is after reaction overnight, not anti-by removing of dialysing in pure water
Answer impurity.It is finally diluted to obtain more than 50 to eight ten nano-scales with phosphate buffer solution (pH=7.3~7.4) again
Nanoparticle aqueous dispersions.
It is crosslinked micella using above-mentioned obtained nanoshell, the pH value by changing external water system can change micella
The hydrophilic property of kernel, nano-micelle is swollen after hydrophobic segment is transformed into hydrophilic segment, is then existed by covalent bonding
The photodynamics ability of the red emission photosensitizer (for example, PpIX) of hydrophobic segment is restored, and produces under extraneous feux rouges light stimulation
Raw singlet oxygen, and then the connection structure that nano-micelle shell is crosslinked dissociates, and finally disintegrates nano-micelle assembly, to realize
Dissociation release dewatering medicament.
The invention will be further described for following embodiment, and purpose, which is only that, more fully understands the purpose of the present invention,
Rather than it limits the scope of the invention.
Embodiment
Preparation example 1
The first step prepares the ABEMA of the functional group containing aldehyde radical:
It is characterized in that: the monomer can be copolymerized well with hydrophilic monomer oligomeric ethylene glycol methacrylate and obtain parent
Water segment, while containing aldehyde radical functional group in the side group of the monomer, it can be handed over shell crosslinking agent 9,10- ammonia ethyoxyl anthracene
Connection reaction, finally obtains the nano-micelle assembly of shell crosslinking.
Preparation method:
2.44g4- hydroxy benzaldehyde (traditional Chinese medicines) is dissolved in 50mL acetone, potassium carbonate is then added into system
(4.146g, 30mmol, traditional Chinese medicines) and bromoethanol (3.75g, 30mmol, traditional Chinese medicines), is refluxed overnight.It is filtered to remove inorganic salts later again
Revolving removes acetone, extracts after then being dissolved with methylene chloride, retains organic phase, and revolving removes methylene chloride, finally uses silica gel
The method of column chromatography purifies to obtain intermediate 1 (1.89g, 57%).Its structural formula is as follows:
1.66g intermediate 1 is dissolved in 40mL anhydrous methylene chloride later, triethylamine (TEA, the state of 2mL is added in ice bath
Medicine), it then keeps that the anhydrous methylene chloride dissolved with methacrylic chloride (1.568g, 15mmol, traditional Chinese medicines) is added dropwise under condition of ice bath
5mL.After dripping, 1h is stirred under the conditions of 0 DEG C, stirs 4h under room temperature later.Then with the sodium bicarbonate salt of saturation
Washing, extraction retain organic phase three times, are dried overnight with anhydrous sodium sulfate.Finally use the method separating-purifying list of silica gel column chromatography
Body obtains ABEMA (1.05g, 45%).
Second step further prepares amphipathic nature block polymer with RAFT polymerization, and reaction formula is as follows:
It is characterized in that: oligomeric ethylene glycol methacrylate and ABEMA cosegment are as hydrophilic segment, segment polymerization
Degree is 15~20 degree of polymerization, wherein x=0.6~0.8, y=0.4~0.2.N, N '-diisopropyl aminoethyl methacrylic acid
Ester and hydroxyethyl methacrylate cosegment are hydrophobic segment, and the segment degree of polymerization is 52~58, wherein m=0.95~
0.99, n=0.05~0.01.
Preparation method: being added three monothioester CEP (0.32g, 1.52mmol) of chain-transferring agent in the glass tube sealing of 50mL, few
Polyethylene glycol methacrylate-styrene polymer OEGMA (21.66g, 45.6mmol, aldrich reagent), monomer ABEMA (3.56g,
15.2mmol), azodiisobutyronitrile AIBN (1.28g, 7.6mmol, traditional Chinese medicines) and 25mL dioxane and stirring magneton.Entirely
After system passes through freezing-degassing-thaw cycles degassing process three times in tube sealing, tube sealing under conditions of vacuum and freezing, in
Polymerization reaction 8h is carried out under 70 DEG C of stirring conditions.Stop polymerization reaction with liquid nitrogen after reaction, opening tube sealing keeps system sudden and violent
In airbreak gas, restore to room temperature to be added dropwise in excessive ice ether after diluting reaction mixture, collects sediment on a small quantity
It is precipitated in excessive ice ether again after methylene chloride dissolution；Dissolution-the precipitation process in triplicate after, by what is finally obtained
Precipitated product is put to be dried overnight in a vacuum drying oven, obtains large hydrophilic molecular chain-transferring agent (17.21g, 67%).
Large hydrophilic molecular chain-transferring agent (2.28g, 0.3mmol) is added in the glass tube sealing of 50mL later, N, N '-two
Isopropyl aminoethyl methacrylate (3.42g, 30mmol, aldrich reagent), hydroxyethyl methacrylate (1.95g,
15mmol, Shanghai element your biotechnology), it azodiisobutyronitrile (1.28g, 7.6mmol, traditional Chinese medicines) and 25mL dioxane and stirs
Mix magneton.After whole system passes through freezing-degassing-thaw cycles degassing process three times in tube sealing, in the item of vacuum and freezing
Tube sealing under part carries out polymerization reaction 8h under 70 DEG C of stirring conditions.Stop polymerization reaction with liquid nitrogen later, opening tube sealing makes body
It is that reaction mixture is added dropwise in excessive petroleum ether after restoring to room temperature in exposure air, collects sediment with a small amount of two
It is precipitated in excessive oil ether again after chloromethanes dissolution；Dissolution-the precipitation process in triplicate after, it is heavy by what is finally obtained
Shallow lake product is put to be dried overnight in a vacuum drying oven, obtains yellow solid.Next, by above-mentioned yellow solid and excessive idol
Nitrogen bis-isobutyronitrile and DMSO solvent are transferred into glass tube sealing and stirring magneton are added.Whole system is in tube sealing by three times
After freezing-degassing-thaw cycles degassing process, tube sealing under conditions of vacuum and freezing is gathered under 70 DEG C of stirring conditions
Close reaction 2h.Stop polymerization reaction with liquid nitrogen after reaction, opening tube sealing makes in system exposure air, restores to room temperature
It is added dropwise in excessive petroleum ether, is collected after sediment is dissolved with a small amount of methylene chloride again in excess after reaction mixture is diluted
It is precipitated in petroleum ether；Dissolution-the precipitation process in triplicate after, the precipitated product finally obtained is put in vacuum oven
In be dried overnight, finally obtain solid white polymer 4.32g (56%).
The chemical structure and chain structure and its molecular weight of large hydrophilic molecular chain-transferring agent and amphipathic nature block polymer with
Molecular weight distribution passes through nuclear magnetic resonance spectroscopy respectively and gel permeation chromatography is tested to obtain, and is as a result shown in Fig. 1 and Fig. 2.
Third step, modification occurs to be esterified anti-with the photosensitizer with carboxylic acid group after last amphipathic nature block polymer passes through
The deserved amphipathic nature block polymer with red emission photosensitizer (PpIX) to the end, esterification and photosensitizer structure
Formula is as follows:
Preparation method: the polymer 4.3g for taking second step to obtain, 4-dimethylaminopyridine (DMAP, 0.03g, traditional Chinese medicines), two
Carbodicyclo hexylimide (DCC, 0.1g, traditional Chinese medicines), photosensitizer protoporphyrin IX (PpIX, 0.15g, aldrich reagent) are dissolved in nothing
In water methylene chloride.And it is stirred at room temperature overnight.Later by alkali alumina column chromatography remove it is unmodified up it is photosensitive
Agent protoporphyrin IX.Finally product is spin-dried for, obtains dark red solid powder polymer 3.92g (88%).
Step 4: the self assembly preparation nanoshell crosslinking of amphipathic nature block polymer load dewatering medicament camptothecine (CPT)
Micella particle.It is specific as follows:
5mg polymer is weighed first and 1mg camptothecine is dissolved in THF (1mL).Then the adding with 9mL/h under room temperature environment
The deionized water (pH=10~10.1) of water speed addition 9mL.Volatilization removes organic solvent under stiring later, undissolved to dredge
Aqueous anticancer drug is removed by water membrane filtration.It will finally be assembled after liquid solution is diluted to 9mL with deionized water and use phosphoric acid again
It is 10mL that salt buffer solution (PBS, 0.2mol/L, pH=7.3~7.4, traditional Chinese medicines), which is diluted to total volume,.Then take above-mentioned 2mL glue
Simultaneously crosslinking agent 9 is added in beam dispersion liquid (0.5g/L, PBS, 0.02mol/L, pH=7.3~7.4), two hydrochloric acid of 10- ammonia ethyoxyl anthracene
Salt (An-2NH2), and 4h is stirred at room temperature.Then NaBH is added3CN (0.1mg, traditional Chinese medicines) is obtained most for restoring imine linkage
Whole shell crosslinking nano micella particle.After reaction overnight, unreacted impurity is removed by dialysing in pure water.Finally use phosphate
It is 2mL that buffer solution (PBS, 0.2mol/L, pH=7.3~7.4, traditional Chinese medicines), which is diluted to total volume, and obtaining load has dewatering medicament
The polymer nanocomposite shell cross-linked rubber bundle of particle of camptothecine.
The feature of nanoparticle obtained by method as above is as follows:
1) nano-micelle particle constitutes hydrophilic shell by the cosegment of oligomeric ethylene glycol methacrylate and ABEMA,
With N, the cosegment structure of N '-diisopropyl aminoethyl methacrylate and the methacrylate-based monomer for being connected to photosensitizer
At hydrophobic inner core.Its partial size is 50nm or so, and size distribution is more uniform.Fig. 3 shows dynamic light scattering data and TEM shines
Piece.
2) polymer nanocomposite shell cross-linked rubber bundle of particle can be stabilized under neutral and alkaline environment, in weak acid environment
And the dewatering medicament of internal cladding can be effectively dissociated and discharged under feux rouges illumination.Fig. 4 shows the shell cross-linked rubber bundle of particle to weak
Acid environment can effectively make relevant response.Fig. 5, which is shown, is crosslinked micella by feux rouges illumination rear shell only in weakly acidic condition
Particle assembly body could dissociate, and discharge dewatering medicament.
Step 5: a kind of method of control amphipathic nature block polymer nanoshell cross-linked rubber bundle of particle dissociation.It is specific as follows:
It in pH=7.3~7.4 and temperature is 37 DEG C by the aqueous dispersions of the polymer nanocomposite shell cross-linked rubber bundle of particle
Under the conditions of, the pH value of resulting polymers nanoshell cross-linked rubber bundle of particle aqueous dispersions is slowly adjusted to pH=by 7.3~7.4
5.0~5.5.Former hydrophobic segment is set to be changed into hydrophily, the swelling of shell cross-linked rubber bundle of particle assembly.Then use red-light source pair
System carries out illumination.At this point, the photosensitizer in micella stratum nucleare restores photodynamics ability due to the swelling of assembly,
Under the illumination of red light wavelength, singlet oxygen can be effectively generated.Shell-crosslinked structure is sent out under the action of singlet oxygen later
Raw fracture.Last assembly dissociation, discharges dewatering medicament.Assembly is comparatively under the conditions of Fig. 6 is shown in pH=7.3~7.4
Stablize, and when pH=5.0~5.5, assembly can effectively dissociate under feux rouges (580nm) illumination.
Application examples 1: load and controlled release of the amphipathic nature block polymer nanoshell cross-linked rubber bundle of particle to dewatering medicament
In the polymer nanocomposite shell cross-linked rubber bundle of particle of the load dewatering medicament camptothecine of above-mentioned preparation, fluorescence light is utilized
Spectrum tracking under faintly acid pH value condition and under conditions of feux rouges irradiation camptothecine (CPT) raw medicine from micellar nanoparticles
The process released in hydrophobic region.Add respectively firstly, the load medicine shell that 0.3mL mass concentration is 0.5mg/mL is crosslinked micella
Enter into four dialysis vessels.PH=5.0~5.5 in two groups of systems, in addition two groups of system pH=7.3~7.4..In room temperature condition
Under, one group will be respectively taken in the system of different pH value with feux rouges (580nm) illumination, two groups in addition are placed in darkroom.Every one section
Time measures the UV absorption at 228nm of the camptothecine in dialyzate, and timing updates dialyzate, with corresponding volume, pH value
Phosphate buffer solution replace dialyzate.According to standard ultraviolet absorption curve of the CPT surveyed in advance at 228nm, calculate
The cumulative release amount of CPT.The result shows that in the environment of pH=7.3~7.4 in contrast hydrophobic drug can be stabilized
Inside assembly.And in pH=5.0~5.5, hydrophobic drug can be released effectively, and feux rouges is especially combined
Under (580nm) illumination condition, cumulative release amount is up to as many as 80%.Fig. 7 show in different pH environment and whether there is or not
Under illumination condition, the camptothecine cumulative release curve that is coated in hydrophobic core.
Industrial applicability
The present invention realizes the controlled release of the carrier loaded dewatering medicament of polymer nanocomposite shell crosslinking micella, while amphiphilic
Property block copolymer in Covalent bonding together photosensitizer with red emission and the aldehyde radical functional group cooperation for shell crosslinking
It is presented the hydrophobic segment of hydrophobic property in neutral and alkaline environment, it can be in the microenvironment of weak acid and red light irradiation
The controlled release of drug is accurately realized under excitation, thus it is huge by having in terms of as the controlled release of pharmaceutical carrier or drug
Big potential industrial use.
Claims (10)
1. a kind of amphipathic nature block polymer, the amphipathic nature block polymer includes hydrophilic segment and hydrophobic segment, described to dredge
Water segment is following hydrophobic segment shown in formula A,
Formula A:
Wherein m=0.95~0.99, n=0.05~0.01, a=52~58, wherein the hydrophilic segment is by oligomeric ethylene glycol
Methacrylate is copolymerized to obtain with the methyl acrylic ester compound with the aldehyde radical functional group for shell crosslinking, and institute
Stating hydrophilic segment molecular weight is 5000~10000 dalton (Da).
2. amphipathic nature block polymer according to claim 1, wherein the hydrophobic segment be the formula A hydrophobic segment with
Hydrophobic segment obtained from photosensitizer Covalent bonding together with red emission.
3. amphipathic nature block polymer according to claim 2, wherein the photosensitizer with red emission is under
The photosensitizer PpIX of formula structure, and hydrophobic segment shown in following formula B is obtained,
PpIX:
Formula B:
4. amphipathic nature block polymer according to any one of claim 1-3, wherein the amphipathic nature block polymer
With following formula I structure,
Formulas I:
Wherein m=0.95~0.99, n=0.05~0.01, x=0.6~0.8, y=0.4~0.2, a=52~58, b=15~
20。
5. a kind of method for preparing amphipathic nature block polymer of any of claims 1-4, the method includes with
Lower step:
A) polymerization ofathe reactants shown in micromolecule chain transfer agent and Formula II and formula III and obtain large hydrophilic molecular chain tra nsfer
Agent；
B) it is further continued for obtaining with reactant reaction shown in formula IV and Formula V as large hydrophilic molecular chain-transferring agent obtained above
Amphipathic nature block polymer；
C) optionally, b) amphipathic nature block polymer obtained is reacted with the photosensitizer with red emission, is obtained described
Amphipathic nature block polymer, wherein the photosensitizer with red emission is preferably photosensitizer PpIX shown in following formula C,
Formula II:
Formula III:
Formula IV:
Formula V:
Formula C:
6. a kind of polymer nanocomposite shell is crosslinked micella, wherein any by claim 1-4 in the aqueous systems of pH=7.3-7.4
After amphipathic nature block polymer described in is assembled into micella, the micella shell is crosslinked using the shell crosslinking agent of formula D and is obtained,
The size of the polymer nanocomposite shell crosslinking micella is 50~80nm, and has pH and feux rouges optical Response,
Formula D:
7. amphipathic nature block polymer nanoshell according to claim 6 is crosslinked micella, wherein the polymer nanocomposite shell
Being crosslinked micella also includes drug to be released.
8. the side of amphipathic nature block polymer nanoshell crosslinking micella dissociation described in a kind of any one of control claim 6-7
Method the described method comprises the following steps:
A) amphipathic nature block polymer nanoshell crosslinking micella is prepared into aqueous dispersions；
B) pH value of gained aqueous dispersions is slowly acidified to 5.0-5.5 by the range of 7.3-7.4, so that described amphipathic embedding
Hydrophobic segment in section copolymer is transformed into hydrophily；
C) feux rouges illumination is used, the interconnecting piece of the formula D in the amphipathic nature block polymer nanoshell crosslinking micella is decomposed
From finally disintegrating nano-micelle assembly.
9. the amphipathic nature block polymer nanoshell according to any one of claim 6-7 is crosslinked micella as pharmaceutical carrier
Application.
10. the amphipathic nature block polymer nanoshell according to any one of claim 6-7 is crosslinked micella and is used in weak acid
Microenvironment and red light irradiation excitation under realize dewatering medicament controlled release purposes.
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| CN114158551B (en) * | 2021-11-22 | 2022-09-30 | 定远众邦生物工程有限公司 | Nano pesticide preparation capable of rapidly responding to weak alkaline environment, preparation method and application thereof |
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