CN108484848A - A kind of polymer nano micelle of Anaerobic response and preparation method thereof - Google Patents
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Abstract
The present invention relates to a kind of synthetic methods of Anaerobic response copolymer nano micella.Poly glycol monomethyl ether and toluene azeotropic water removing, obtain anhydrous poly glycol monomethyl ether, then carry out that brominated poly glycol monomethyl ether is obtained by the reaction with 2 bromine isobutyl acylbromides.ATRP initiators, mPEG Br cause Tert-butyl Methacrylate polymerization and generate diblock copolymer mPEGb‑PtBMA.By mPEGbPtBMA is hydrolyzed obtain mPEG in acid conditionbPMAA, and then connect with hypoxia sensitivity group-nitroaromatic derivative, Anaerobic response polymer is obtained, self assembly obtains corresponding nano-micelle.Polymer nano micelle prepared by the present invention has Anaerobic response, and the controlled release of drug can be completed in vitro by changing oxygen content, can also be directed to the targeted drug release that tumor tissues carry out Anaerobic response in vivo.Therefore in biosensor, medical diagnosis on disease, biological reducing prodrug design, the fields such as targeting cancer therapy have a wide range of applications.
Description
Technical field
The invention belongs to intellectual material, high molecular material and biomedical engineering field, and in particular to a kind of Anaerobic response
Polymer nano micelle and preparation method thereof.
Background technology
Poly glycol monomethyl ether(mPEG-OH)With excellent biological degradability, biocompatibility and drug permeability,
And the certification of FDA has been obtained, it is therefore widely used in the hydrophilic segment of polymer, is allowed to be copolymerized with other polymers and make
Standby amphipathic nature block polymer is self-assembly of micellar nanoparticles in turn, is used for medicament slow release.
Intelligent macromolecule material obtains extensive concern in recent years, these materials can to environmental stimuli, as temperature, pH value, light,
Salt, sugar etc. respond, and are all widely used in nanosecond science and technology, biomedical sector.And Anaerobic response is to send out in recent years
A kind of new response that exhibition is got up, anoxia phenomenon is mainly related to disease, including cancer, Myocardial damage, anaemia, rheumatoid
Arthritis and vascular diseases etc., these diseases all will be along with the generations of anoxia phenomenon.In the present invention, we are used
Nitroaromatic derivative, it can be changed into hydrophilic knot with relatively high sensitivity by hydrophobic structure under anoxic conditions
Structure, to make the polymer nano micelle where it rupture, internal drug achievees the effect that targeting NO release.
Invention content
The purpose of the present invention is to provide a kind of preparation methods of the polymer nano micelle of Anaerobic response.
The purpose of the present invention is by poly glycol monomethyl ether and toluene azeotropic water removing, obtain anhydrous polyethyleneglycol first
Ether then carries out that brominated poly glycol monomethyl ether is obtained by the reaction with 2- bromine isobutyl acylbromides(mPEG-Br).ATRP initiators,
MPEG-Br causes Tert-butyl Methacrylate polymerization and generates diblock copolymer mPEG-b-PtBMA.By mPEG-b-PtBMA exists
Hydrolyzed under acidic conditions obtains mPEG-b- PMAA, so with hypoxia sensitivity group --- nitroaromatic derivative is connect, and is obtained
Anaerobic response polymer, self assembly obtain corresponding nano-micelle.The nano-micelle can be completed under anoxic conditions after carrying medicine
Targeted drug discharges, as shown in the figure.
The preparation method of the polymer nano micelle of Anaerobic response proposed by the present invention, is as follows:
(1)Poly glycol monomethyl ether is dissolved in solvent A, is azeotroped off at 120 ~ 160 DEG C in poly glycol monomethyl ether permanent
The moisture of amount, is cooled to room temperature later.
(2)Under nitrogen protection, will(1)Middle products therefrom, triethylamine and 2- bromine isobutyl acylbromides are with molar ratio for 1:3~5:3
~ 5 are dissolved in solvent B, react under ice-water bath 1 ~ 2 hour, react 24 ~ 48 hours at room temperature;It filters, is saturated after being diluted with solvent C
Sodium bicarbonate solution is washed, deionization washing, and magnesium sulfate drying precipitates in solvent D, is purified after filtering, is dry.
(3)It will(2)Middle products therefrom, catalyst E, tBMA monomer be dissolved in solvent F, and wherein initiator and monomer feeds intake
Than according to required molecular weight and degree of polymerization design.System is reacted under argon gas or nitrogen protection, and reaction temperature is 50~120 DEG C,
Reaction time is 1~48 hour, after removing catalyst, through solvent G precipitation, is dried in vacuo to get to mPEG-b-PtBMA。
(4)It will(3)Middle products therefrom hydrolyzes in sour H and obtains mPEG-b-PMAA。
(5)It will(4)Middle products therefrom is obtained by the reaction required with nitroaromatic derivative in EDC, NHS under acting on
Anaerobic response polymer.
(6)It will(5)Middle products therefrom, occurs self assembly, and packaging medicine in deionized water at room temperature, and synthesis anoxic is rung
Answering property polymer nano micelle.
In the present invention, solvent A is one or both of toluene, acetone.
In the present invention, solvent B is one or more of chloroform, dichloromethane or tetrahydrofuran.
In the present invention, solvent C is one or both of dichloromethane or anhydrous ether.
In the present invention, solvent D is one or more of methanol, n-hexane or anhydrous ether.
In the present invention, catalyst E is stannous chloride/bipyridyl, cuprous bromide/bipyridyl, stannous chloride/pentamethyl diethyl
Alkene triamine, cuprous bromide/pentamethyl-diethylenetriamine, stannous chloride/hexamethyl trien or cuprous bromide/hexamethyl
One or more of trien.
In the present invention, solvent F is toluene, butanone, tetrahydrofuran, isopropyl acetone, methyl phenyl ethers anisole, n,N-Dimethylformamide, N,
The one or more of N- diethylformamides or DMAC N,N' dimethyl acetamide.
In the present invention, solvent G is one or more of methanol, n-hexane or anhydrous ether.
In the present invention, sour H is one or more of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid.
The advantage of the invention is that:Raw material sources are extensive, poly glycol monomethyl ether used, Tert-butyl Methacrylate,
Solvent, precipitating reagent etc. can industrialized production, synthetic method is simple and practicable.The mPEG-b-PMAA- of preparation(NH2-NI)With scarce
Oxygen response, and it is degradable, Drug controlled release can be targeted.The intellectual material can realize that structure turns when oxygen concentration is low
Change, provides a kind of thinking for the treatment of the diseases such as cancer, and have in the design aspect of disease treatment, biological reducing prodrug
It is widely applied.
Description of the drawings
Fig. 1 is a kind of structural schematic diagram of the polymer of the Anaerobic response prepared.
Specific implementation mode
The following examples are further illustrations of the invention, it rather than limits the scope of the invention.
Embodiment 1
By poly glycol monomethyl ether 10g(M=2000g/mol, 0.005mol)Dry round-bottomed flask is added with 60ml toluene solutions
In, the air-distillation at 140 DEG C, azeotropic removes the moisture of trace in poly glycol monomethyl ether, is then cooled to room temperature;To flask
The middle dichloromethane that 15ml dryings are added makes system dissolve, and adds dry triethylamine 2.28ml(0.02mol), 2- bromos are different
Butyryl bromide 5.747g(0.025mol)It is dissolved in 15ml dichloromethane, reaction 1h is slowly added dropwise under ice bath, reacts at room temperature
24h;It is filtered under diminished pressure after adding 30ml chloroforms to dilute, saturated sodium bicarbonate solution is washed, deionization washing, magnesium carbonate drying, Zhi Hou
It is precipitated in 200ml ice ether, is purified after filtering, is dry, obtaining mPEG-Br;By the mPEG-Br of 10g(0.0045mol),
PMDETA 0.78g(0.0045mol), tBMA monomers 12.79g(0.09mol)It is added in dry round-bottomed flask, adds 20ml first
Benzene dissolves, and vacuumizes under protection of argon gas three times, is eventually adding CuBr 0.65g(0.0045mol), reacted at 60 DEG C later
6h, after reaction plus 60ml tetrahydrofurans dilute, and neutral alumina column and concentrated by rotary evaporation are crossed, with 100ml n-hexanes/anhydrous second
Ether precipitates three times, and decompression filters, vacuum drying obtains mPEG-b-PtBMA diblock copolymers;The mPEG-b-PtBMA that will be obtained
In excessive trifluoroacetic acid(30ml)The lower progress acidic hydrolysis of effect obtains mPEG-b-PMAA diblock copolymers;By what is obtained
MPEG-b-PMAA is in EDC(0.6g, 3.6mmol)、NHS(0.41g, 3.6mmol)Act on lower and nitroaromatic derivative
(0.15g, 3mmol)It dissolves together in aqueous solution, is stirred to react 6h, filtration drying purification at room temperature;The polymer that will be obtained
Self assembly obtains corresponding polymer nano micelle in deionized water, further can packaging medicine.
Embodiment 2
By poly glycol monomethyl ether 10g(M=2000g/mol, 0.005mol)Dry round-bottomed flask is added with 60ml toluene solutions
In, the air-distillation at 140 DEG C, azeotropic removes the moisture of trace in poly glycol monomethyl ether, is then cooled to room temperature;To flask
The middle dichloromethane that 20ml dryings are added makes system dissolve, and adds dry triethylamine 4.56ml(0.04mol), 2- bromos are different
Butyryl bromide 11.5g(0.05mol)It is dissolved in 30ml dichloromethane, reaction 1h is slowly added dropwise under ice bath, reacts at room temperature for 24 hours;
It is filtered under diminished pressure after adding 60ml chloroforms to dilute, saturated sodium bicarbonate solution is washed, deionization washing, magnesium carbonate drying, later in 500ml
It is precipitated in ice ether, is purified after filtering, is dry, obtaining mPEG-Br;By the mPEG-Br of 10g(0.0045mol), PMDETA
0.78g(0.0045mol), tBMA monomers 12.79g(0.09mol)It is added in dry round-bottomed flask, 30ml toluene is added to dissolve,
It vacuumizes under protection of argon gas three times, is eventually adding CuBr 0.65g(0.0045mol), 6h is reacted at 80 DEG C later, is reacted
After plus the dilution of 60ml tetrahydrofurans, cross neutral alumina column and concentrated by rotary evaporation, precipitated with 100ml n-hexanes/anhydrous ether
Three times, decompression filters, vacuum drying obtains mPEG-b-PtBMA diblock copolymers;By obtained mPEG-b-PtBMA in excess
Trifluoroacetic acid(50ml)The lower progress acidic hydrolysis of effect obtains mPEG-b-PMAA diblock copolymers;The mPEG-b- that will be obtained
PMAA is in EDC(0.6g, 3.6mmol)、NHS(0.41g, 3.6mmol)Act on lower and nitroaromatic derivative(0.15g, 3mmol)
It dissolves together in aqueous solution, is stirred to react 8h, filtration drying purification at room temperature;In deionized water certainly by obtained polymer
Assembling obtains corresponding polymer nano micelle, further can packaging medicine.
Embodiment 3
By poly glycol monomethyl ether 10g(M=2000g/mol, 0.005mol)Dry round-bottomed flask is added with 60ml toluene solutions
In, the air-distillation at 140 DEG C, azeotropic removes the moisture of trace in poly glycol monomethyl ether, is then cooled to room temperature;To flask
The middle dichloromethane that 20ml dryings are added makes system dissolve, and adds dry triethylamine 2.28ml(0.02mol), 2- bromos are different
Butyryl bromide 5.747g(0.025mol)It is dissolved in 15ml dichloromethane, reaction 1h is slowly added dropwise under ice bath, reacts at room temperature
48h;It is filtered under diminished pressure after adding 60ml chloroforms to dilute, saturated sodium bicarbonate solution is washed, deionization washing, magnesium carbonate drying, Zhi Hou
It is precipitated in 200ml ice ether, is purified after filtering, is dry, obtaining mPEG-Br;By the mPEG-Br of 10g(0.0045mol),
PMDETA 0.78g(0.0045mol), tBMA monomers 12.79g(0.09mol)It is added in dry round-bottomed flask, adds 30ml first
Benzene dissolves, and vacuumizes under protection of argon gas three times, is eventually adding CuBr 0.65g(0.0045mol), reacted at 100 DEG C later
6h, after reaction plus 60ml tetrahydrofurans dilute, and neutral alumina column and concentrated by rotary evaporation are crossed, with 200ml n-hexanes/anhydrous second
Ether precipitates three times, and decompression filters, vacuum drying obtains mPEG-b-PtBMA diblock copolymers;The mPEG-b-PtBMA that will be obtained
In excessive trifluoroacetic acid(60ml)The lower progress acidic hydrolysis of effect obtains mPEG-b-PMAA diblock copolymers;By what is obtained
MPEG-b-PMAA is in EDC(0.6g, 3.6mmol)、NHS(0.41g, 3.6mmol)Act on lower and nitroaromatic derivative
(0.15g, 3mmol)It dissolves together in aqueous solution, is stirred to react 12h, filtration drying purification at room temperature;The polymer that will be obtained
Self assembly obtains corresponding polymer nano micelle in deionized water, further can packaging medicine.
Embodiment 4
By poly glycol monomethyl ether 20g(M=2000g/mol, 0.01mol)Dry round-bottomed flask is added with 120ml toluene solutions
In, the air-distillation at 140 DEG C, azeotropic removes the moisture of trace in poly glycol monomethyl ether, is then cooled to room temperature;To flask
The middle dichloromethane that 30ml dryings are added makes system dissolve, and adds dry triethylamine 4.56ml(0.04mol), 2- bromos are different
Butyryl bromide 11.5g(0.05mol)It is dissolved in 30ml dichloromethane, reaction 1h is slowly added dropwise under ice bath, reacts 30h at room temperature;
It is filtered under diminished pressure after adding 50ml chloroforms to dilute, saturated sodium bicarbonate solution is washed, deionization washing, magnesium carbonate drying, later in 500ml
It is precipitated in ice ether, is purified after filtering, is dry, obtaining mPEG-Br;By the mPEG-Br of 20g(0.009mol), PMDETA
1.56g(0.009mol), tBMA monomers 25.58g(0.18mol)It is added in dry round-bottomed flask, 40ml toluene is added to dissolve,
It is vacuumized three times under argon gas protection, is eventually adding CuBr 1.3g(0.009mol), 10h, reaction knot are reacted at 100 DEG C later
Shu Houjia 100ml tetrahydrofurans dilute, and cross neutral alumina column and concentrated by rotary evaporation, with 500ml n-hexanes/anhydrous ether precipitation three
Secondary, decompression filters, vacuum drying obtains mPEG-b-PtBMA diblock copolymers;By obtained mPEG-b-PtBMA excessive three
Fluoroacetic acid(100ml)The lower progress acidic hydrolysis of effect obtains mPEG-b-PMAA diblock copolymers;The mPEG-b- that will be obtained
PMAA is in EDC(1.2g, 7.2mmol)、NHS(0.82g, 7.2mmol)Act on lower and nitroaromatic derivative(0.3g, 6mmol)
It dissolves together in aqueous solution, is stirred to react 12h, filtration drying purification at room temperature;In deionized water by obtained polymer
Self assembly obtains corresponding polymer nano micelle, further can packaging medicine.
Embodiment 5
By poly glycol monomethyl ether 20g(M=2000g/mol, 0.01mol)Dry round-bottomed flask is added with 120ml toluene solutions
In, the air-distillation at 140 DEG C, azeotropic removes the moisture of trace in poly glycol monomethyl ether, is then cooled to room temperature;To flask
The middle dichloromethane that 30ml dryings are added makes system dissolve, and adds dry triethylamine 4.56ml(0.04mol), 2- bromos are different
Butyryl bromide 11.5g(0.05mol)It is dissolved in 30ml dichloromethane, reaction 1h is slowly added dropwise under ice bath, reacts 48h at room temperature;
It is filtered under diminished pressure after adding 60ml chloroforms to dilute, saturated sodium bicarbonate solution is washed, deionization washing, magnesium carbonate drying, later in 500ml
It is precipitated in ice ether, is purified after filtering, is dry, obtaining mPEG-Br;By the mPEG-Br of 20g(0.009mol), PMDETA
1.56g(0.009mol), tBMA monomers 25.58g(0.18mol)It is added in dry round-bottomed flask, 60ml toluene is added to dissolve,
It is vacuumized three times under argon gas protection, is eventually adding CuBr 1.3g(0.009mol), 12h, reaction knot are reacted at 120 DEG C later
Shu Houjia 100ml tetrahydrofurans dilute, and cross neutral alumina column and concentrated by rotary evaporation, with 500ml n-hexanes/anhydrous ether precipitation three
Secondary, decompression filters, vacuum drying obtains mPEG-b-PtBMA diblock copolymers;By obtained mPEG-b-PtBMA excessive three
Fluoroacetic acid(100ml)The lower progress acidic hydrolysis of effect obtains mPEG-b-PMAA diblock copolymers;The mPEG-b- that will be obtained
PMAA is in EDC(1.2g, 7.2mmol)、NHS(0.82g, 7.2mmol)Act on lower and nitroaromatic derivative(0.3g, 6mmol)
It dissolves in aqueous solution, is stirred to react at room temperature for 24 hours together, filtration drying purification;In deionized water by obtained polymer
Self assembly obtains corresponding polymer nano micelle, further can packaging medicine.
Claims (11)
1. the diblock polymer needed for a kind of polymer nano micelle of Anaerobic response, it is characterised in that the following institute of structural formula
Show:
Wherein m is 6 ~ 20;N is 20 ~ 50.
2. a kind of preparation side of the diblock polymer needed for polymer nano micelle of Anaerobic response as described in claim 1
Method, it is characterised in that be as follows:
(1)Poly glycol monomethyl ether is dissolved in solvent A, is azeotroped off at 120 ~ 160 DEG C in poly glycol monomethyl ether permanent
The moisture of amount, is cooled to room temperature later;
(2)Under nitrogen protection, will(1)Middle products therefrom, triethylamine and 2- bromine isobutyl acylbromides are with molar ratio for 1:3~5:3 ~ 5 is molten
In solvent B, reacts under ice-water bath 1 ~ 2 hour, react 24 ~ 48 hours at room temperature;It is filtered after being diluted with solvent C, unsaturated carbonate
Hydrogen sodium solution is washed, deionization washing, and magnesium sulfate drying precipitates in solvent D, is purified after filtering, is dry;
(3)It will(2)Middle products therefrom, catalyst E, tBMA monomer are dissolved in solvent F, and the rate of charge of wherein initiator and monomer is pressed
It is designed according to required molecular weight and the degree of polymerization;System is reacted under argon gas or nitrogen protection, and reaction temperature is 50~120 DEG C, reaction
Time is 1~48 hour, after removing catalyst, through solvent G precipitation, is dried in vacuo to get to mPEG-b-PtBMA;
(4)It will(3)Middle products therefrom hydrolyzes in sour H and obtains mPEG-b-PMAA;
(5)It will(4)Middle products therefrom, with nitroaromatic derivative in EDC, NHS effects are lower to be obtained by the reaction required anoxic
Responsive polymer.
3. a kind of preparation method of the polymer nano micelle of Anaerobic response according to claim 2, it is characterised in that tool
Steps are as follows for body:
By finally obtained product, self assembly, and packaging medicine occurs in deionized water at room temperature, synthesis Anaerobic response is poly-
Close object nano-micelle.
4. the preparation of the diblock polymer needed for a kind of polymer nano micelle of Anaerobic response according to claim 2
Method, it is characterized in that solvent A is one or both of toluene or acetone.
5. the preparation of the diblock polymer needed for a kind of polymer nano micelle of Anaerobic response according to claim 2
Method, it is characterized in that solvent B is one or more of chloroform, dichloromethane or tetrahydrofuran.
6. the preparation of the diblock polymer needed for a kind of polymer nano micelle of Anaerobic response according to claim 2
Method, it is characterized in that solvent C is one or both of dichloromethane or anhydrous ether.
7. the preparation of the diblock polymer needed for a kind of polymer nano micelle of Anaerobic response according to claim 2
Method, it is characterized in that solvent D is one or more of methanol, n-hexane or anhydrous ether.
8. the preparation of the diblock polymer needed for a kind of polymer nano micelle of Anaerobic response according to claim 2
Method, it is characterized in that catalyst E is stannous chloride/bipyridyl, cuprous bromide/bipyridyl, stannous chloride/pentamethyl divinyl three
Amine, cuprous bromide/pentamethyl-diethylenetriamine, stannous chloride/hexamethyl trien or cuprous bromide/hexamethyl Sanya
One or more of tetramine.
9. the preparation of the diblock polymer needed for a kind of polymer nano micelle of Anaerobic response according to claim 2
Method, it is characterized in that solvent F is toluene, butanone, tetrahydrofuran, isopropyl acetone, methyl phenyl ethers anisole, n,N-Dimethylformamide, N, N-
The one or more of diethylformamide or DMAC N,N' dimethyl acetamide.
10. the system of the diblock polymer needed for a kind of polymer nano micelle of Anaerobic response according to claim 2
Preparation Method, it is characterized in that solvent G is one or more of methanol, n-hexane or anhydrous ether.
11. the system of the diblock polymer needed for a kind of polymer nano micelle of Anaerobic response according to claim 2
Preparation Method, it is characterized in that acid H is one or more of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid.
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CN110396161A (en) * | 2019-07-03 | 2019-11-01 | 同济大学 | Weary oxygen responsiveness micella with fluorescent characteristic and preparation method thereof |
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