CN107596383B - The preparation method of the amphipathic rodlike adriamycin polymeric prodrugs of a kind of pH response - Google Patents
The preparation method of the amphipathic rodlike adriamycin polymeric prodrugs of a kind of pH response Download PDFInfo
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- CN107596383B CN107596383B CN201710837083.3A CN201710837083A CN107596383B CN 107596383 B CN107596383 B CN 107596383B CN 201710837083 A CN201710837083 A CN 201710837083A CN 107596383 B CN107596383 B CN 107596383B
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- oegma
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 title claims abstract description 71
- 229940002612 prodrug Drugs 0.000 title claims abstract description 42
- 239000000651 prodrug Substances 0.000 title claims abstract description 42
- 229940009456 adriamycin Drugs 0.000 title claims abstract description 31
- 230000004044 response Effects 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 229920001503 Glucan Polymers 0.000 claims abstract description 10
- 239000000463 material Substances 0.000 claims abstract description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003999 initiator Substances 0.000 claims abstract description 3
- 101710141544 Allatotropin-related peptide Proteins 0.000 claims abstract 4
- 238000010560 atom transfer radical polymerization reaction Methods 0.000 claims abstract 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 35
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
- 229910052786 argon Inorganic materials 0.000 claims description 17
- 239000003446 ligand Substances 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- 239000000693 micelle Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
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- 239000011259 mixed solution Substances 0.000 claims description 7
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- 239000012046 mixed solvent Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000008367 deionised water Substances 0.000 claims description 5
- 229910021641 deionized water Inorganic materials 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 5
- 239000013067 intermediate product Substances 0.000 claims description 5
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000000502 dialysis Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000001226 reprecipitation Methods 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- VMGSQCIDWAUGLQ-UHFFFAOYSA-N n',n'-bis[2-(dimethylamino)ethyl]-n,n-dimethylethane-1,2-diamine Chemical compound CN(C)CCN(CCN(C)C)CCN(C)C VMGSQCIDWAUGLQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 claims description 2
- QVRCRKLLQYOIKY-UHFFFAOYSA-M 1-methyl-3-prop-2-enylimidazol-1-ium;chloride Chemical compound [Cl-].C[N+]=1C=CN(CC=C)C=1 QVRCRKLLQYOIKY-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 229910052593 corundum Inorganic materials 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 239000002105 nanoparticle Substances 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 claims description 2
- 229910001845 yogo sapphire Inorganic materials 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 7
- YOCIJWAHRAJQFT-UHFFFAOYSA-N 2-bromo-2-methylpropanoyl bromide Chemical compound CC(C)(Br)C(Br)=O YOCIJWAHRAJQFT-UHFFFAOYSA-N 0.000 claims 2
- STCBHSHARMAIOM-UHFFFAOYSA-N 1-methyl-1h-imidazol-1-ium;chloride Chemical compound Cl.CN1C=CN=C1 STCBHSHARMAIOM-UHFFFAOYSA-N 0.000 claims 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 1
- 240000007594 Oryza sativa Species 0.000 claims 1
- 235000007164 Oryza sativa Nutrition 0.000 claims 1
- 150000001262 acyl bromides Chemical class 0.000 claims 1
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 239000002244 precipitate Substances 0.000 claims 1
- 235000009566 rice Nutrition 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical compound NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 21
- 229940079593 drug Drugs 0.000 abstract description 19
- 206010028980 Neoplasm Diseases 0.000 abstract description 8
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- 238000003786 synthesis reaction Methods 0.000 abstract description 7
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- 230000002209 hydrophobic effect Effects 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 125000004185 ester group Chemical group 0.000 abstract 1
- 239000002243 precursor Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 239000007789 gas Substances 0.000 description 11
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 229940041181 antineoplastic drug Drugs 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- UKODFQOELJFMII-UHFFFAOYSA-N pentamethyldiethylenetriamine Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 description 4
- 230000005311 nuclear magnetism Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- -1 Methylaminoethyl Chemical group 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
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- 231100000135 cytotoxicity Toxicity 0.000 description 2
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- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
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- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the synthesis field of chemistry and the representational fields of biology, are more specifically designed into the preparation method and purposes of the amphipathic rodlike polymerization prodrug of the pH response of Figure of abstract.The preparation method of amphipathic rodlike polymeric material synthesizes rodlike ATRP initiator the following steps are included: (1) is based on glucan；(2) hydrophobic block for introducing pH response is reacted based on ATRP；(3) hydrophilic block is introduced based on ATRP reaction and amphipathic condensation material is obtained with this；(4) replace the ester group of the end MGMA using hydrazine hydrate and obtain pH response precursor；(5) the polymerization prodrug of pH response is obtained using the amino formation hydrazone bond of the carbonyl and polymeric material on adriamycin.The amphipathic rodlike polymerization prodrug of gained selectively releases drug by pH stimuli responsive using faintly acid in cancer cell.This polymerization prodrug has many advantages, such as the drug release that higher micella stability, high drug load, stimuli responsive control.
Description
Technical field
The present invention relates to chemicals and biologic applications fields, and in particular to a kind of pH stimuli responsive it is amphipathic rodlike poly-
Close prodrug and its preparation and application thereof.
Background technique
Adriamycin (Doxorubicin, DOX) is common one of anticancer drug, No. CAS: 23214-92-8, chemistry
Structural formula: C27H29NO11, relative molecular weight: 543.52, it can inhibit the synthesis of RNA and DNA, most to the inhibiting effect of RNA
By force, adriamycin category cell cycle nonspecific agent (CCNSA) has effect to kinds of tumors, therefore, to the tumour cell of various growth cycles
There is killing effect.Adriamycin is primarily adapted for use in acute leukemia, equal to acute lymphoblastic leukemia and granulocytic leukemia
There is certain therapeutic effect, generally as Second line Drug, i.e., is contemplated that in choice drug drug resistance using this medicine.It acts on machine
Manage the synthesis for being mainly the drug intercalation of DNA and inhibiting nucleic acid.
Anti-tumor drug molecule includes that the most common problem of adriamycin is that water solubility is poor, molecular dimension is smaller and non-selection
Property, in delivery process, that there are blood circulation stability is poor, drug bioavailability is low, toxic side effect is relatively strong and doctor
The problems such as curative effect rate is low.In order to realize the application of clinical treatment early, researcher be concentrated mainly at present by nanotechnology with
The delivery system that anticancer drug combines protects its bio-pharmaceutical active, and increase drug and upload to enhance its water solubility
Amount, this has important scientific meaning to the development for pushing treatment of cancer.
In the delivery system for transmitting drug combined using nanotechnology with drug, before the amphipathic polymerization of stimuli responsive
Medicine delivery system possesses the advantages such as programmable structure and function, drug bioavailability height, can effectively reduce cancer chemotherapy and controls
Poisonous side effect of medicine and the disadvantages such as therapeutic efficiency is low, always were the hot spot studied both at home and abroad in recent years during treatment.
For example, CN105943496A discloses a kind of pH response poly- second two of galactose chitosan-with neighboring group effect
The adriamycin bonded prodrug of alkoxide polymer, it is passed through on chemical combination key by the chitosan-polyethylene glycol grafting responded with pH
Adriamycin in modification and the polymerization prodrug obtained, obtained micella have good pH responsiveness and hepatic targeting, can be into one
Step is developed as the novel targeted preparation for the treatment of liver cancer.In addition, CN105251013A discloses one kind there is redox to ring
The degradable water-soluble antitumor polymeric prodrugs of answering property, the polymerization prodrug have using polylactide as main chain, bonded big on side chain
Measure the special comb-type structure of oligomeric polyethylene glycol branch and anti-tumor drug molecule.This water-soluble antitumor polymeric prodrugs carries
Dose is moderate and controllable, degradable, and has redox responsiveness.
Therefore, it designs, construct the polymerization prodrug delivery system that collection has the functions such as carrying capacity and high micella stability on high drug
System has very strong necessity.
Summary of the invention
For the unstability of the micella of current medical delivery system, carrying capacity on lower drug, it is also difficult to guarantee drug
Selective controlled release the defects of, the present invention is intended to provide the superelevation drugloading rate of one kind pH stimuli responsive is amphipathic rodlike poly-
The preparation method of prodrug is closed, the amphipathic rodlike polymerization prodrug of the method synthesis has higher drug burst size and cytotoxicity,
To realize the effective delivering and efficiently release of drug.
Technical solution of the present invention is specific as follows:
The amphipathic rodlike adriamycin polymeric prodrugs of a kind of pH response, preparation method the following steps are included:
(1) rodlike atomic radicals polymerization reaction (ATRP) the initiator glucan bromine (Dex- based on glucan is prepared
Br), reaction equation is as follows, comprising the following steps: a) under argon gas (Ar, 1-12Pa) ambient conditions, will be dissolved in ionic liquid
The glucan (Dex) of body (1- allyl -3- methylimidazolium chloride) is cooled to 0 DEG C, add N-Methyl pyrrolidone (NMP) with
The mixed solution of n,N-Dimethylformamide (DMF) is then slowly added to 2- bromine isobutyl acylbromide (BIBB), ice bath 0.5-2h, so
After be warmed to room temperature (25 DEG C) and be protected from light 12-72h, resulting mixed solution is added dropwise in deionized water and is precipitated, is used
Precipitating obtained by acetone solution repeats purification and obtains faint yellow intermediate product three times, dries vacuum oven (25-30 DEG C) is inner
It is dry, b) then the faint yellow intermediate product of gained is dissolved in NMP again, it is cooled to 0 DEG C, is then slowly added to BIBB, ice bath 0.5-
Then 2h is warmed to room temperature (25 DEG C) and is protected from light 12-72h, is then deposited in deionized water, heavy obtained by acetone solution
It forms sediment, repeats purification and obtain pale yellow powder three times, 25-30 DEG C of drying under vacuum condition obtains product Dex-Br；
(2) the monomer 2- methoxyl group -2- oxygen ethyl-methyl acrylate (MGMA) of pH response, the following institute of reaction equation are prepared
Show, comprising the following steps: under temperature≤0 DEG C and argon gas (Ar, 1-12Pa) ambient conditions, be dissolved in anhydrous methylene chloride
(DCM) solution of a certain amount of methacrylic chloride is slowly dropped to the methyl glycollate being dispersed in anhydrous DCM and three second
It in amine (TEA) mixed solution, is stirred overnight, washing purifying, silica gel column chromatography obtains pure product MGMA；
(3) the rodlike polymerization prodrug (Dex-P (MGMA)) prepared, reaction equation is as follows, comprising the following steps: in room
Under warm (25 DEG C) and argon gas (Ar, 1-12Pa) ambient conditions, the Dex-Br that step (1) is obtained, the MGMA that step (2) obtains
It is dissolved in dimethyl sulfoxide (DMSO) (or methanol) solvent with CuBr, freeze-thaw recycles three times, and (the 2- bis- of ligand three is added
Methylaminoethyl) amine (Me6TREN) (or ligand N, N, N ', N ' ', N- pentamethyl-diethylenetriamine (PMEDTA)), then freeze-solve
Freeze circulation twice, reaction 8-24h is stirred at room temperature, obtained mixture diluted Al with tetrahydrofuran (THF)2O3Pillar is dense
Contracting, reprecipitation are dissolved with THF and are deposited in ether again in ether, dried, obtain Dex- (PMGMA)；Wherein DEX-P
(MGMA) m value range is 20-100 in, and degree of polymerization x value range is 1~100, its molecular weight ranges of obtained polymer are
15900~114900 gmol-1；
(4) amphipathic rodlike polymerization prodrug (Dex-P (MGMA)-b-P (OEGMA), (DMO)) is prepared, reaction equation is as follows
It is shown, comprising the following steps: under room temperature (25 DEG C) and argon gas (Ar, 1-12Pa) ambient conditions, Dex- that step (3) is obtained
P (MGMA), glycolmethacrylate (OEGMA) and CuBr are dissolved in the in the mixed solvent of DMF and DMSO, freeze-thaw
Three times, ligand Me is added in circulation6TREN(or ligand PMEDTA), then freeze-thaw circulation is twice, reacts 12- at 25 DEG C
48h, obtained mixture cross Al after being diluted with THF2O3Pillar, concentration, then dissolved with THF and be deposited in ether again, it dries
It is dry, obtain Dex-P (MGMA)-b-P (OEGMA)；Wherein m value range is 20-100, x value in Dex-P (MGMA)-b-P (OEGMA)
Range be 1~100, n value can be 2~9, the range of degree of polymerization y value is 1~50, its molecular weight ranges of obtained polymer are
18600~249900gmol-1；
(5) the amphipathic rodlike polymerization prodrug (Dex-P (MGMA-NH of pH response is prepared2)-b-P(OEGMA), DMO-
Hydrazide), reaction equation is as follows, comprising the following steps: in room temperature (25 DEG C) and argon gas (Ar, 1-12Pa) atmosphere item
Under part, Dex-P (MGMA)-P (OEGMA) is dissolved in a certain proportion of anhydrous methanol and the in the mixed solvent of DMF, is then added
A certain amount of hydrazine hydrate reacts 6-36h at 25 DEG C, and obtained mixture is dialysed two days with water, and freeze-drying obtains Dex-P
(MGMA-NH2)-b-P(OEGMA)；Wherein Dex-P (MGMA-NH2) m value range is 20-100, the model of x value in-b-P (OEGMA)
Enclosing for 1~100, n value can be 2~9, and the range of degree of polymerization y value is 1~50；
(6) prepare pH response amphipathic rodlike adriamycin polymerization prodrug (Dex-P (MGMA-DOX)-b-P (OEGMA),
DMO@DOX), reaction equation is as follows, comprising the following steps: in room temperature (25 DEG C) and argon gas (Ar, 1-12Pa) ambient conditions
Under, by Dex-P (MGMA-NH2)-b-P (OEGMA) and adriamycin (DOX) be dissolved in a certain amount of anhydrous methanol and DMF, drip
The trifluoroacetic acid (TFA) for entering 2-3 drop, is protected from light 12-72h at 25 DEG C, and obtained mixture is dialysed with methanol, and freezing is dry
It is dry, obtain product Dex-P (MGMA-DOX)-b-P (OEGMA)；Wherein m value range in Dex-P (MGMA-DOX)-b-P (OEGMA)
For 20-100, the range of x value is that 1~100, n value can be 2~9, and the range of degree of polymerization y value is 1~50；
(7) the amphipathic spherical nano-micelle of pH response is prepared, comprising the following steps: at room temperature (25 DEG C), take a certain amount of
Dex-P (MGMA-DOX)-b-P (OEGMA) material that step (6) obtains is dissolved in suitable DMF or DMSO, be protected from light stirring 5~
120min is slowly dropped under stiring in a certain amount of water, stirs 5~60min, is removed organic solvent with water dialysis and is just obtained
Spherical nano-micelle aqueous solution.
Further, step (1) a) in glucan (Dex) and ionic liquid (1- allyl -3- methyl chloride miaow
Azoles) molar ratio be 1:(10~1000), the volume ratio of anhydrous NMP and DMF solution is 1:(0.1~10), NMP and DMF's is mixed
The total volume for closing solution is 2 times of ionic liquid volume, step (1) b) in be dissolved in faint yellow centre in anhydrous NMP
0.015~0.03 molL of molar concentration range of product-1。
Further, the molar concentration range point of the methyl glycollate and TEA in anhydrous DCM is dissolved in the step (2)
It Wei not 0.2~10 molL-1With 0.3~20 molL-1；It is dissolved in the molar concentration model of the methacrylic chloride in anhydrous DCM
It encloses for 0.5~18 molL-1。
Further, Dex-Br, MGMA, CuBr and ligand Me in the step (3)6TREN(or ligand PMEDTA) rub
You are 1:(6~3000 than range): (2~100): (4~400)；Wherein the molar concentration of Dex-Br is 0.2~20 mmol
L-1。
Further, Dex-P (MGMA), OEGMA, CuBr and ligand Me in the step (4)6TREN(or ligand
PMEDTA molar ratio range) is 1:(6~2000): (3~100): (3~100)；In the in the mixed solvent of DMF and DMSO
The volume ratio of DMF:DMSO is 1:(0.1~5).
Further, it is dissolved in Dex-P (the MGMA)-b-P's (OEGMA) in anhydrous methanol and DMF in the step (5)
Molar concentration range is 0.001~1mmolL-1；The volume ratio range of hydrazine hydrate, methanol and DMF is 1:(5~30): (1~
15)。
Further, Dex-P (MGMA-NH in the step (6)2)-b-P (OEGMA) and DOX molar concentration range point
It Wei not 0.001~0.5 molL-1With 0.001~1 molL-1, the volume ratio of anhydrous methanol and DMF are 1:(0.1~10).
Further, the concentration range of adriamycin obtained in the step (7) polymerization prodrug amphipathic molecule is
0.01mg·L-1~1000 mgL-1;The proportional region of organic solvent and water is 1:(3~1000);It is resulting after being dialysed with water
Its diameter range of spherical nanoparticle is 5~1000nm.
Major advantage:
1. this project is creative for the problems such as micella existing for current drug delivery system is unstable and low drugloading rate
Ground proposes the delivery system of the amphipathic rodlike adriamycin polymerization prodrug of one kind pH response, this polymeric material can be by adjusting parent
Hydrophobic ratio can effectively improve carrying capacity and micella stability on drug, and the size of regulation nano-micelle, solve current
Some shortcomings existing for drug delivery system make it possible that the Precise Diagnosis of tumour is treated early.
2. the amphipathic rodlike adriamycin in the present invention polymerize prodrug, there is pH stimulating responsive, according to phase in cancer cell
To lower pH value, the hydrazone bond in material can be promoted to be broken and effectively therefore quick release anticancer drug is realized to cancer
Effective treatment.
Detailed description of the invention
In order to keep the purpose of the present invention, technical scheme and beneficial effects clearer, the present invention provides following attached drawing:
Fig. 1 is that amphipathic pH responds rodlike adriamycin polymerization prodrug (Dex-P (MGMA-DOX)-b-P in embodiment 1
(OEGMA), DMO@DOX) synthetic line schematic diagram.
Fig. 2 is that amphipathic pH responds rodlike adriamycin polymer (Dex-P (MGMA-DOX)-b-P in embodiment 1
(OEGMA), DMO@DOX) nuclear-magnetism schematic diagram.
Fig. 3 is TEM the and DLS schematic diagram of amphipathic rodlike polymer/nanometer micella in embodiment 1.
Fig. 4 is that the sensitive rodlike polymerization prodrug of amphipathic pH discharges schematic diagram in embodiment 1.
Fig. 5 is that amphipathic pH responds rodlike adriamycin polymerization prodrug (Dex-P (MGMA-DOX)-b-P in embodiment 1
(OEGMA), DMO@DOX) toxicity schematic diagram.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..
Embodiment 1 prepares the amphipathic rodlike polymerization prodrug of Dex-P (MGMA)-b-P (OEGMA) of pH response
(1) it prepares Dex-Br: under the conditions of argon atmosphere, ionic liquid (1- allyl -3- methyl chloride miaow will be dissolved in
Azoles) glucan (Dex) be cooled to 0 DEG C, add N-Methyl pyrrolidone (NMP) and n,N-Dimethylformamide (DMF)
Mixed solution is then slowly added to 2- bromine isobutyl acylbromide (BIBB), ice bath 0.5-2h, is then warmed to room temperature (25 DEG C) and is protected from light anti-
12-72h is answered, is then deposited in deionized water, is precipitated obtained by acetone solution, purification is repeated and obtains faint yellow centre three times
Product dries vacuum oven (25-30 DEG C) is inner, then the yellowish intermediate product of gained is dissolved in NMP, is cooled to 0 DEG C, with
After be slowly added to BIBB, ice bath 0.5-2h, be then warmed to room temperature (25 DEG C) and be protected from light 12-72h, be then deposited in deionization
It in water, is precipitated obtained by acetone solution, repeats purification and obtain pale yellow powder three times, 25-30 DEG C of drying under vacuum condition obtains
Product Dex-Br；
(2) MGMA is prepared: a certain amount of to be dissolved in anhydrous DCM(60 under temperature≤0 DEG C and argon gas (Ar) ambient conditions
ML methacrylic chloride (0.144 mol)) is added dropwise to methyl glycollate (0.144 mol), TEA(0.288mol), nothing
Water DCM(100 mL) in solution, it is stirred overnight, washing purifying, column chromatographs to obtain pure product.
(3) Dex-P (MGMA) is prepared: under room temperature and argon gas (Ar) ambient conditions, by Dex-Br(0.01 mmol),
MGMA(8.4 mmol), CuBr(0.21mmol) it is dissolved in DMSO(5 mL) and in solvent, freeze-thaw recycles three times, and addition is matched
Body Me6TREN(0.42 mmol), then freeze-thaw circulation is twice, reacts 8-24h at 25 DEG C.Obtained mixture THF
Diluted Al2O3Pillar, concentration, reprecipitation is in ether, drying.
(4) Dex-P (MGMA)-b-P (OEGMA) (DMO) is prepared: under room temperature and argon gas (Ar) ambient conditions, by Dex-P
(MGMA) (0.01 mmol), OEGMA(5.25 mmol), CuBr(0.21 mmol) it is dissolved in DMF(3.0 mL) and DMSO(3.0
ML) in solvent, freeze-thaw is recycled three times, and ligand Me is added6TREN(0.21 mmol), then freeze-thaw circulation is twice,
12-48h is reacted at 25 DEG C.Obtained mixture diluted Al with THF2O3Pillar, concentration, reprecipitation is in ether, drying.Such as
The nuclear-magnetism figure of DMO in Fig. 2, the peak that 3.38 ppm and 3.65 ppm occur in figure can be seen that Dex-P (MGMA)-b-P
(OEGMA) successful synthesis.
(5) Dex-P (MGMA-NH of pH response is prepared2)-b-P (OEGMA) (DMO-hydrazide): in room temperature and argon
Under gas (Ar) ambient conditions, by Dex-P (MGMA)-b-P (OEGMA) (0.005 mmol) be dissolved in anhydrous methanol (10 mL) and
DMF(3.75 mL) in, a certain amount of hydrazine hydrate (1.5 mL) is added, reacts 6-36h at 25 DEG C.Obtained mixture water
Dialysis, freeze-drying.The nuclear-magnetism figure of DMO-hydrazide in 2 in such as figure, characteristic peak of the MGMA at 3.76 ppm in figure
Disappearance it can be seen that diazanyl success instead of MGMA methoxyl group, be Dex-P (MGMA-NH2)-b-P (OEGMA) success
Synthesis.
(6) amphipathic adriamycin polymerization prodrug Dex-P (MGMA-DOX)-b-P (OEGMA) (DMO@DOX) is prepared: in room temperature
Under argon gas (Ar) ambient conditions, by Dex-P (MGMA-NH2)-b-P (OEGMA) (0.128mmol) and DOX(0.32mmol) molten
Solution instills the TFA of 2-3 drop, is protected from light 12-72h at 25 DEG C in anhydrous methanol (8 mL) and DMF (8 mL).It obtains
Mixture is dialysed with methanol, freeze-drying.As the peak in Fig. 2 in DMO@DOX near 8 ppm between 4-6 ppm shows Dex-
The successful synthesis of P (MGMA-DOX)-b-P (OEGMA).
(7) it prepares adriamycin polymerization prodrug nano-micelle: 5 mg Dex-P (MGMA-DOX)-b-P (OEGMA) being taken to be dissolved in
It in the DMF or DMSO of 1 mL, is distributed in the water of 6 mL, micella is made with water dialysis 48h.In the size such as Fig. 3 of micella
TEM and water phase and DMF phase DLS figure, it can be seen that the size of micella is thirties nanometers and of uniform size, is shown
This micella can rapidly enter cell.The drug release profiles of Fig. 4 can be seen that burst size is up to 91% to this micella after 72 hours,
The cytotoxicity figure of Fig. 5 can be seen that drug effect cervical cancer cell (HeLa) and human breast cancer cell (MCF- after 72 hours
7) survival rate illustrates that this pharmaceutical carrier is more toxic cancer cell down to 20% and 15%.
Finally, it is stated that preferred embodiment above is only used to illustrate the technical scheme of the present invention and not to limit it, although logical
It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (8)
1. a kind of preparation method of the amphipathic rodlike adriamycin polymeric prodrugs nano-micelle of pH response, it is characterised in that: packet
Include following steps:
(1) the rodlike atomic radicals polymerization reaction ATRP initiator glucan bromine Dex-Br based on glucan, reaction are prepared
Formula is as follows, comprising the following steps: a) under the argon Ar ambient conditions of 1-12Pa, will be dissolved in ionic liquid 1- allyl-
The glucan Dex of 3- methylimidazolium chloride is cooled to 0 DEG C, adds N-Methyl pyrrolidone NMP and n,N-Dimethylformamide
The mixed solution of DMF is then slowly added to 2- bromine isobutyl acylbromide BIBB, ice bath 0.5-2h, is then warmed to room temperature 25 DEG C and is protected from light
12-72h is reacted, resulting mixed solution is added dropwise in deionized water and is precipitated, precipitates, repeats obtained by acetone solution
Purification obtains faint yellow intermediate product three times, dries in 25-30 DEG C of vacuum oven, b) then again by the faint yellow centre of gained
Product is dissolved in NMP, is cooled to 0 DEG C, is then slowly added to BIBB, ice bath 0.5-2h, is then warmed to room temperature 25 DEG C and is protected from light anti-
12-72h is answered, is then deposited in deionized water, is precipitated obtained by acetone solution, purification is repeated and obtains pale yellow powder three times,
25-30 DEG C of drying, obtains product Dex-Br under vacuum condition；
(2) the monomer 2- methoxyl group -2- oxygen ethyl-methyl acrylate MGMA of pH response is prepared, reaction equation is as follows, including
Following steps: under the argon Ar ambient conditions of temperature≤0 DEG C and 1-12Pa, it is dissolved in the certain of anhydrous methylene chloride DCM
The solution of the methacrylic chloride of amount is slowly dropped to the methyl glycollate being dispersed in anhydrous DCM and triethylamine TEA mixing is molten
It in liquid, is stirred overnight, washing purifying, silica gel column chromatography obtains pure product MGMA；
(3) the rodlike polymerization prodrug Dex-P (MGMA) prepared, reaction equation is as follows, comprising the following steps: at 25 DEG C of room temperature
Under the argon Ar ambient conditions of 1-12Pa, the Dex-Br that step (1) is obtained, the MGMA and CuBr that step (2) obtains dissolves
In dimethyl sulfoxide DMSO or methanol solvate, freeze-thaw is recycled three times, and ligand three (2- dimethylaminoethyl) amine is added
Me6TREN or ligand N, N, N ', N ' ', N- pentamethyl-diethylenetriamine PMEDTA, then freeze-thaw circulation is twice, at room temperature
It is stirred to react 8-24h, obtained mixture diluted Al with tetrahydrofuran THF2O3Pillar, concentration, reprecipitation are used in ether
THF is dissolved and is deposited in ether again, is dried, is obtained Dex- (PMGMA)；Wherein m value range is 20- in DEX-P (MGMA)
100, degree of polymerization x value range is 1~100, its molecular weight ranges of obtained polymer are 15900~114900 gmol-1；
(4) amphipathic rodlike polymerization prodrug Dex-P (MGMA)-b-P (OEGMA) is prepared, DMO, the following institute of reaction equation are abbreviated as
Show, comprising the following steps: under the argon Ar ambient conditions of 25 DEG C of room temperature and 1-12Pa, Dex-P that step (3) is obtained
(MGMA), glycolmethacrylate OEGMA and CuBr is dissolved in the in the mixed solvent of DMF and DMSO, freeze-thaw circulation
Three times, ligand Me is added6TREN or ligand PMEDTA, then freeze-thaw circulation is twice, reacts 12-48h at 25 DEG C, obtains
Mixture diluted with THF after cross Al2O3Pillar, concentration, then dissolved with THF and be deposited in ether again, it dries, obtains
Dex-P(MGMA)-b-P(OEGMA)；Wherein m value range is 20-100, the range of x value in Dex-P (MGMA)-b-P (OEGMA)
It is 2~9 for 1~100, n value, the range of degree of polymerization y value is 1~50, its molecular weight ranges of obtained polymer are 18600~
249900g·mol-1；
(5) the amphipathic rodlike polymerization prodrug Dex-P (MGMA-NH of pH response is prepared2)-b-P (OEGMA), it is abbreviated as DMO-
Hydrazide, reaction equation are as follows, comprising the following steps: under the argon Ar ambient conditions of 25 DEG C of room temperature and 1-12Pa,
Dex-P (MGMA)-P (OEGMA) is dissolved in a certain proportion of anhydrous methanol and the in the mixed solvent of DMF, is then added certain
The hydrazine hydrate of amount reacts 6-36h at 25 DEG C, and obtained mixture is dialysed two days with water, and freeze-drying obtains Dex-P
(MGMA-NH2)-b-P(OEGMA)；Wherein Dex-P (MGMA-NH2) m value range is 20-100, the model of x value in-b-P (OEGMA)
Enclosing for 1~100, n value is 2~9, and the range of degree of polymerization y value is 1~50；
(6) amphipathic rodlike adriamycin polymerization prodrug Dex-P (the MGMA-DOX)-b-P (OEGMA) for preparing pH response, is abbreviated as
DMO@DOX, reaction equation are as follows, comprising the following steps:, will under the argon Ar ambient conditions of 25 DEG C of room temperature and 1-12Pa
Dex-P(MGMA-NH2)-b-P (OEGMA) and adriamycin DOX be dissolved in a certain amount of anhydrous methanol and DMF, instill 2-3 drop
Trifluoroacetic acid TFA, be protected from light 12-72h at 25 DEG C, obtained mixture is dialysed with methanol, freeze-drying, obtain product
Dex-P(MGMA-DOX)-b-P(OEGMA)；Wherein m value range is 20-100, x in Dex-P (MGMA-DOX)-b-P (OEGMA)
The range of value is that 1~100, n value is 2~9, and the range of degree of polymerization y value is 1~50；
(7) the amphipathic spherical nano-micelle of pH response is prepared, comprising the following steps: at 25 DEG C of room temperature, take a certain amount of step (6)
Obtained Dex-P (MGMA-DOX)-b-P (OEGMA) material is dissolved in suitable DMF or DMSO, is protected from light 5~120min of stirring and is existed
It is slowly dropped under stirring in a certain amount of water, stirs 5~60min, removed organic solvent with water dialysis and just obtain spherical receive
Rice micellar aqueous solution.
2. a kind of preparation of the amphipathic rodlike adriamycin polymeric prodrugs nano-micelle of pH response according to claim 1
Method, it is characterised in that: step (1) a) in glucan Dex and ionic liquid 1- allyl -3- methylimidazolium chloride rub
You are than being 1:(10~1000), the volume ratio of anhydrous NMP and DMF solution is 1:(0.1~10), the mixed solution of NMP and DMF
Total volume is 2 times of ionic liquid volume, step (1) b) in the faint yellow intermediate product that is dissolved in anhydrous NMP rub
You are 0.015~0.03 molL of concentration range-1。
3. a kind of preparation of the amphipathic rodlike adriamycin polymeric prodrugs nano-micelle of pH response according to claim 1
Method, it is characterised in that: the molar concentration range point of the methyl glycollate and TEA in anhydrous DCM is dissolved in the step (2)
It Wei not 0.2~10 molL-1With 0.3~20 molL-1；It is dissolved in the molar concentration model of the methacrylic chloride in anhydrous DCM
It encloses for 0.5~18 molL-1。
4. a kind of preparation of the amphipathic rodlike adriamycin polymeric prodrugs nano-micelle of pH response according to claim 1
Method, it is characterised in that: Dex-Br, MGMA, CuBr, ligand Me in the step (3)6The molar ratio of TREN or ligand PMEDTA
Range is 1:(6~3000): (2~100): (4~400)；Wherein the molar concentration of Dex-Br is 0.2~20 mmolL-1。
5. a kind of preparation of the amphipathic rodlike adriamycin polymeric prodrugs nano-micelle of pH response according to claim 1
Method, it is characterised in that: Dex-P (MGMA), OEGMA, CuBr, ligand Me in the step (4)6TREN's or ligand PMEDTA
Molar ratio range is 1:(6~2000): (3~100): (3~100)；In the body of the in the mixed solvent DMF:DMSO of DMF and DMSO
Product is than being 1:(0.1~5).
6. a kind of preparation of the amphipathic rodlike adriamycin polymeric prodrugs nano-micelle of pH response according to claim 1
Method, it is characterised in that: be dissolved in Dex-P (the MGMA)-b-P's (OEGMA) in anhydrous methanol and DMF in the step (5)
Molar concentration range is 0.001~1mmolL-1；The volume ratio range of hydrazine hydrate, methanol and DMF is 1:(5~30): (1~
15)。
7. a kind of preparation of the amphipathic rodlike adriamycin polymeric prodrugs nano-micelle of pH response according to claim 1
Method, it is characterised in that: Dex-P (MGMA-NH in the step (6)2)-b-P (OEGMA) and DOX molar concentration range point
It Wei not 0.001~0.5 molL-1With 0.001~1 molL-1, the volume ratio of anhydrous methanol and DMF are 1:(0.1~10).
8. a kind of preparation of the amphipathic rodlike adriamycin polymeric prodrugs nano-micelle of pH response according to claim 1
Method, it is characterised in that: the concentration range of obtained adriamycin polymerization prodrug amphipathic molecule is in the step (7)
0.01mg·L-1~1000 mgL-1;The proportional region of organic solvent and water is 1:(3~1000);It is resulting after being dialysed with water
Its diameter range of spherical nanoparticle is 5~1000nm.
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