CN102352042B - Biodegradable amphiphilic polyester with functionally modified side chains - Google Patents
Biodegradable amphiphilic polyester with functionally modified side chains Download PDFInfo
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Abstract
The invention discloses biodegradable amphiphilic polyester with functionally modified side chains. The biodegradable amphiphilic polyester comprises cyclic ester monomers and annular phosphate ester monomers which have biocompatibility and biodegradability. According to the invention, block or random polyester containing (methyl)acrylic acid ester groups is prepared by preparing the annular phosphate ester monomers and subjecting the annular phosphate ester monomers and other cyclic ester monomers to a ring-opening copolymerization reaction, free of the processes of protection and deprotection; because side chains of the block or random polyester containing (methyl)acrylic acid ester groups contain (methyl)acrylic acid ester groups, Michael addition reaction can be utilized for further functional modification so as to prepare the biodegradable amphiphilic polyester with functionally modified side chains finally.
Description
Technical field
The invention belongs to the biological medical polymer material scientific domain, be specifically related to the preparation method who contains poly phosphate amphipathic nature block polymer and random copolymers and the functional modification of one type of physiologically acceptable, biodegradability.
Background technology
Along with medical science and Materials science development, Biodegradable polymer material more and more receives people's attention.Study and use more Biodegradable polymer material at present and comprise synthesising biological degradable macromolecule [Prog. Polym. Sci. such as natural biological degradable materials such as collagen, gelatin, chitin, starch and poe, polycarbonate, poly phosphate, aliphatic polyester; 2007; 32,762-798.].Compare with the natural degradable material, Biodegradable polymer material have preparation flexibly, various, the degradation property of structure and mechanical property etc. all can comparatively make things convenient for controlled and especially receive publicity.Biodegradable polymer material is generally perhaps constituted by the structural unit of mikrobe and enzyme liberating by hydrolysis can take place, and its degraded product can be excreted along with organism metabolism.Therefore, they are widely used in fields such as medicine, genophore and organizational projects.Aliphatic polyester such as polycaprolactone (PCL), polylactide (PLA), rac-Lactide-glycolide copolymer (PLGA) and polycarbonate such as polytrimethylene cyclic carbonate ester (PTMC) etc. are the most frequently used synthesising biological degradable macromolecules.Yet traditional biodegradable polymer also has some self deficiency, and for example: strong excessively hydrophobicity, texture ratio be more single, lack modifiable functional group or reaction site etc.; On the other hand, the development need of biomedical technology is polyfunctional, the synthesising biological material of biologically active [Nat. Mater., 2009,8,457-470.].Therefore, to existing synthesising biological degradation material carry out modification, give its multiple functional be a very significant research.In recent years; The synthetic biodegradable polymer that contains acryloxy, allyl group or alkynyl/azido-functional group of more existing bibliographical informations; And can further carry out various modifications [Angew. Chem., Int. Ed., 2009 at an easy rate to these functional groups through the method for modifying after the polymerization; 48,48-58.].
Yet the researchs that many relevant biodegradable polymers are modified mainly concentrate on the hydrophobicity polyester, and like polycaprolactone, polycarbonate etc., and the research of modifying for biodegradable amphipathic polyester is less relatively.Amphipathic nature polyalcohol is meant and in same macromolecular chain, contains hydrophilic and the different segmental polymkeric substance of two kinds of chemical property of oleophylic simultaneously.Because have the segment of two kinds of chemical structures, its SOLUTION PROPERTIES often has the performance that is different from general multipolymer, amphipathic nature polyalcohol can be assembled into various forms in elective medium, like micella, vesica etc.Especially at biomedical sector, kernel is hydrophobic, the hydrophilic polymer/nanometer particle of shell because amphipathic multipolymer is assembled at aqueous phase, and the efficient drug delivery system of these nanoparticles causes scientific worker's extensive interest.Wherein, Introduce in the amphipathic nature polyalcohol structure Biodegradable high-molecular and the research that is used to make up drug delivery system has the potential using value; Because solid support material was organized accumulated at human organ after the use of Biodegradable material can be avoided drug release, produce toxic side effect.In addition, in the hydrophilic segment of these multipolymers, can introduce hydroxyl, carboxyl, amino groups, further with other organic compound reaction and give its new function.Yet although the normal at present hydrophilic segment of using all possesses excellent biological compatibility, like polyoxyethylene glycol (PEG), polymethyl acrylic acid hydroxypropyl acrylate (PHPMA) etc., their biodegradability is generally all poor; The method of the functional modification that can carry out them in addition, is also more single and step is comparatively loaded down with trivial details.Therefore, seek a kind ofly not only to have had both excellent biological compatibility and biodegradable performance, but also can solve the problems referred to above by the simple and easy to do macromolecular material that carries out functional modification, seem particularly important, and have important significance for theories and potential using value.
Poly phosphate (Polyphosphoester) is one type and connects the unitary Biodegradable polymer material of backbone structure by the phosphoric acid ester bond; Its similar is in natural phosphorous macromole; Penetrating ability with stronger biocompatibility, cellular affinity and cytolemma, [Macromol. Biosci., 2009 more and more receive publicity in biomedical sector; 9,1154-1164.].And owing to contain the phosphorus atom of pentavalent on the poly phosphate main chain, side chain can be modified various functional groups easily more easily by functionalization.Publication number is that the Chinese invention patent application of CN 101633730 discloses the preparation method of the triblock copolymer of a kind of poly phosphate and POLYACTIC ACID, and is made into nano particle and is used as pharmaceutical carrier.Publication number is the triblock copolymer that the Chinese invention patent application of CN 101205302 discloses a kind of poly phosphate and polycaprolactone, and the nano particle that is made by this segmented copolymer.Publication number is that the Chinese invention patent application of CN 101585919 discloses a kind of hyper branched polyphosphate ester with biocompatibility and preparation method thereof.
But these reports all are to prepare the polyphosphate ester copolymer that contains a certain particular functional group.As far as we know, also do not have so far this class of document or patent report can carry out easily functional group regulation and control, fully can biodegradable amphipathic multipolymer model.
Summary of the invention
Goal of the invention of the present invention provides a kind of compound method and method of wetting ability poly phosphate side group being carried out functional modification of amphipathic polyester of biodegradable.
For reaching the foregoing invention purpose; The technical scheme that the present invention adopts is: the amphipathic polyester of the biodegradable of functional side chain modification; Be made up of cyclic ester class monomer with biocompatibility and biodegradability and annular phosphate monomer, the structural formula of the amphipathic polyester of biodegradable of said functional side chain modification is selected from a kind of in following two kinds of structural formulas:
Segmented copolymer
Or random copolymers
;
In the formula, wherein, R
1Be selected from: a kind of in methyl or the Wasserstoffatoms; R
2Be selected from:
,
Or
In a kind of; R
3Be selected from:
,
,
,
Or
In a kind of; The number-average molecular weight of multipolymer is 8000～50000 g/mol, m=30～100, n=4～50, y/ (x+y)=10%～60%.
The preparation method of the amphipathic polyester of biodegradable of above-mentioned said functional side chain modification may further comprise the steps:
(1) preparation contains the annular phosphate monomer of (methyl) esters of acrylic acid functional group: with THF (THF) is that solvent, triethylamine (TEA) are acid binding agent; With a kind of and 2-chloro-2-oxo-1 in Hydroxyethyl acrylate (HEA) or the Rocryl 400 (HEMA); 3; 2-dioxaphospholane (COP)
is a reactant; Prepare the annular phosphate monomer 2-ethyl propenoate oxygen base-2-oxo-1 that contains (methyl) esters of acrylic acid functional group; 3,2-dioxaphospholane (OPEA) or ethyl 2-methacrylate oxygen base-2-oxo-1,3; 2-dioxaphospholane (OPEMA), its chemical structural formula is:
(2) the preparation side chain contains the amphipathic polyester of (methyl) esters of acrylic acid functional group: with benzylalcohol is that initiator, toluene are made solvent, stannous octoate is a catalyzer; The annular phosphate monomer of (methyl) esters of acrylic acid functional group that makes with step (1) and other cyclic ester monomer carry out block copolymerization reaction or random copolymerization reaction; Obtain the amphipathic polyester that side chain contains (methyl) esters of acrylic acid functional group, its chemical structural formula is:
Segmented copolymer
Or random copolymers
;
Said other cyclic ester monomer can be selected from but be not limited to: caprolactone (a kind of in ε-CL), rac-Lactide (LA) or the trimethylammonium cyclic carbonate ester (TMC).
In the technique scheme, the detailed process that the annular phosphate monomer of (methyl) esters of acrylic acid functional group that makes with step (1) and other cyclic ester monomer carry out the block copolymerization reaction is:
(a) in toluene solution, be catalyzer with the stannous octoate, under 90 ℃ of conditions, benzylalcohol causes the cyclic ester monomer ring-opening polymerization, reacts 24 hours, and product obtains terminal hydroxyl macromole evocating agent with icing ether sedimentation 2 times;
(b) macromole evocating agent that above-mentioned (a) is obtained further causes the cyclic polyester ring-opening polymerization of preparation in the step (1) in toluene solution, prepare the segmented copolymer that side chain contains (methyl) esters of acrylic acid functional group.
In the technique scheme; The detailed process that the annular phosphate monomer of (methyl) esters of acrylic acid functional group that makes with step (1) and other cyclic ester monomer carry out the random copolymerization reaction is: the method that adopts ring-opening polymerization; With the stannous octoate is catalyzer; Cyclic polyester, another kind of cyclic ester monomer and the stannous octoate of preparation in benzylalcohol, the step (1) are added toluene solution successively, under 90 ℃ of conditions, reacted 24 hours; Product precipitates 2 times with ice ether/methyl alcohol=10/1 (v/v) mixing solutions, obtains the random copolymers that side chain contains (methyl) esters of acrylic acid functional group.
Because above-mentioned side chain contains the amphipathic polyester of (methyl) esters of acrylic acid functional group and all contains (methyl) esters of acrylic acid functional groups, can utilize Michael reaction that polymkeric substance is carried out side chain and modify, selectivity keyed jointing-COOH ,-OH ,-NH
2,-groups such as RGD; In the optimized technical scheme; Further step (2) gained side chain is contained the functional side chain modification of the amphipathic polyester of (methyl) esters of acrylic acid functional group: utilize Michael reaction; (organic cpds SH) and above-mentioned side chain contain the pendant double bonds of the poly phosphate in the amphipathic polyester of (methyl) esters of acrylic acid functional group and react with containing sulfydryl; Amphipathic polyester is carried out functional modification, obtain the amphipathic polyester of biodegradable of functional side chain modification; Saidly contain sulfydryl (organic cpds SH) is selected from: a kind of in thiohydracrylic acid, 3-Mercapto-1, Mercaptamine or the cysteine hydrochloride;
The structural formula of the amphipathic polyester of biodegradable of said functional side chain modification is selected from a kind of in following two kinds of structural formulas:
Segmented copolymer
,
Or random copolymers
;
In the formula, wherein, R
1Be selected from: a kind of in methyl or the Wasserstoffatoms; R
2Be selected from:
,
Or
In a kind of; R
3Be selected from:
,
,
,
Or
In a kind of; The number-average molecular weight of multipolymer is 8000～50000 g/mol, m=30～100, n=4～50, y/ (x+y)=10%～60%.
In the technique scheme; The concrete grammar of functional side chain modification that step (2) gained side chain is contained the amphipathic polyester of (methyl) esters of acrylic acid functional group is: with DMF is solvent, is catalyzer with weak base, in molar ratio; [(methyl) propenoate]: [SH]=1: 1～20; [SH]: [weak base]=1: 1, under room temperature, stirred 72 hours, obtain the amphipathic polyester of biodegradable of functional side chain modification; Said weak base catalyst can be selected from but be not limited to: a kind of in pyridine, triethylamine or the tetrabutyl ammonium fluoride.
The present invention requires to protect the application of the amphipathic polyester of biodegradable in preparation bioengineered tissue support and drug delivery system of above-mentioned functional side chain modification simultaneously.
Main thought of the present invention is: the annular phosphate monomer that at first prepares (methyl) esters of acrylic acid functional group of a kind of containing; Block copolymerization or random copolymerization can take place in this type monomer and other cyclic ester monomer; Obtain segmented copolymer or random copolymers that side chain has (methyl) esters of acrylic acid functional group; At last through Michael reaction; With contain sulfydryl (pendant double bonds of poly phosphate is reacted in organic cpds SH) and the above-mentioned multipolymer, optionally on this biodegradable amphipathic ester molecule side group keyed jointing-COOH ,-OH ,-NH
2,-functional groups such as RGD.
Because the utilization of technique scheme, the present invention has following characteristics with respect to prior art:
1. the present invention carries out the ring opening copolymer reaction through a kind of annular phosphate monomer of preparation with other cyclic ester monomer, prepares the block or the random polyester that contain (methyl) esters of acrylic acid group, need not protection and deprotection process; And the block or the random polyester side chains of (methyl) esters of acrylic acid group contain (methyl) esters of acrylic acid group owing to said containing; Can further utilize Michael reaction that it is carried out functional modification, finally make the amphipathic polyester of biodegradable of functional side chain modification.
Description of drawings
Fig. 1 be among the embodiment one preparation phosphate ester monomer OPEA proton nmr spectra (
1H NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 2 be among the embodiment one preparation phosphate ester monomer OPEA carbon-13 nmr spectra (
13C NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 3 is the macromole evocating agent PCL of preparation among the embodiment two
40Proton nmr spectra (
1H NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Table 1 is molecular weight and the distribution thereof of the macromole evocating agent PCL of preparation among embodiment two, three and four;
Fig. 4 is the polycaprolactone of the different ratios of preparation among embodiment five, six and seven and the segmented copolymer PCL-of poly phosphate
bThe proton nmr spectra of-POPEA (
1H NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 5 is segmented copolymer PCL among the embodiment five
70-
b-POPEA
50Carbon-13 nmr spectra (
13C NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 6 is the caprolactone and the SULPHOSUCCINIC ACID ESTER random copolymers PCL-of preparation among the embodiment eight
CoThe proton nmr spectra of-OPEA (
1H NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 7 prepares poly phosphate based block copolymer PCL among phosphate ester monomer OPEA (Fig. 7 (A)) and the embodiment five of preparation among the embodiment one
70-
b-POPEA
50The nucleus magnetic resonance phosphorus spectrum of (Fig. 7 (B)) (
31P NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 8 is segmented copolymer PCL among the embodiment nine, ten, 11 and 12
70-
b-POPEA
50Through Michael reaction, the proton nmr spectra of modified outcome (
1H NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 9 is segmented copolymer PCL among the embodiment 13
70-
b-POPEA
50Fluorometric investigation figure;
Figure 10 is segmented copolymer PCL among the embodiment 13
70-
b-POPEA
50ESEM (TEM) photo;
Table 2 is micelle-forming concentration (CMC), size and the distribution thereof of segmented copolymer among embodiment five, six and seven;
Figure 11 is segmented copolymer PCL among the embodiment five, nine, ten, 11 and 12
70-
b-POPEA
50And the cytotoxicity test pattern of Michael addition adducts;
Figure 12 is embodiment 15 block polymer PCL
70-
b-POPEA
50Bag carries the drug release curve of Zorubicin;
Figure 13 is embodiment 16 block polymer PCL
70-
b-POPEA
50The fluorescence of the endocytosis in the A549 tumour cell is followed the tracks of photo.
Embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is further described:
Embodiment one describes phosphate ester monomer 2-ethyl propenoate oxygen base-2-oxo-1,3, the preparation method of 2-dioxaphospholane (OPEA).
Embodiment one: the compound method of OPEA (HEA:TEA:COP=1:1:1)
In advance reaction unit and syringe are placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, be placed on and be cooled to room temperature in the exsiccator.
In having 250 mL three-necked flasks of constant pressure funnel; In argon gas atmosphere, add 10.2915 g Hydroxyethyl Acrylate (HEA, 0.0886 mol) earlier; After injecting 100 mL dry THF and fully dissolve with syringe; The 8.7910 g acid binding agent triethylamines (TEA, 0.0886 mol) that reinject stir.In constant pressure funnel, inject 11.4861 g 2-chloro-2-oxos-1,3 with syringe, 2-dioxaphospholane (COP, 0.0886 mol) adds the dissolving of 25 mL dry THF again.Fed argon gas about 5 minutes, and reaction unit was moved to during-20 ℃ of low-temp reactions bathe, open and stir, after cooling half a hour, begin slowly to drip COP and the mixture of THF in the constant pressure funnel while stirring, drip off half a hour approximately, continue to react 12 hours.The a large amount of white precipitates that produce in the reaction process are triethylamine hydrochloride.
After reaction finishes, reaction unit is shifted out low-temp reaction bathe, leave standstill to reaching room temperature, remove by filter triethylamine hydrochloride, filtrating is removed THF through revolving to steam, and obtains crude product.Crude product joined in the 50 mL exsiccant anhydrous diethyl ethers precipitate, remove by filter a small amount of triethylamine hydrochloride, collect filtrating, revolve to steam and remove ether, the glutinous shape liquid of the water white transparency that obtains is product OPEA, and productive rate is about 67%.Product through proton nmr spectra (
1H NMR), carbon-13 nmr spectra (
13C NMR) and nucleus magnetic resonance phosphorus spectrum (
31P NMR) verify its structure, the proton nmr spectra spectrogram of phosphate ester monomer OPEA (
1H NMR) see shown in Figure 1, the carbon-13 nmr spectra spectrogram (
13C NMR) see shown in Figure 2, nucleus magnetic resonance phosphorus spectrum spectrogram (
31P NMR) sees shown in Fig. 7 (A).
Embodiment two～four describes the preparation method of macromole evocating agent PCL-OH.
Embodiment two: PCL
40-OH (BzOH: ε-CL:Sn (Oct)
2=2:80:1) preparation method
Reaction flask and the syringe that stirrer will be housed in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of 50 mL side tube flasks of argon gas, add 4.9038 g caprolactone (ε-CL; 0.043 mol), syringe injects the toluene stirring and dissolving of 10 mL, injects 0.1161 g benzylalcohol (BzOH with microsyringe; 1.075 mmol); Charge and discharge gas drive and remove side tube flask air and oxygen, reaction flask is moved to 90 ℃ of oil baths, stirring reaction adds 0.1740 g stannous octoate (Sn (Oct) rapidly after 30 minutes
2, 5.375 mmol), reacted 24 hours down at 90 ℃.Add two acetic acid termination reactions, revolve to steam and remove partial solvent, crude product is dissolved in the chloroform, ice ether sedimentation 2 times with 80 ml, filtering products obtained therefrom is the white powder thing, places vacuum drying oven to be dried to constant weight.Weigh, calculate productive rate and be about 73.3 %.The employing proton nmr spectra (
1H NMR) checking polycaprolactone (PCL) structure, (see figure 3), gel permeation chromatography (GPC) verify its number-average molecular weight (
) and MWD (
/
).Table 1 is seen in molecular weight and distribution thereof.
The molecular weight and the distribution thereof of table 1 PCL macromole evocating agent
a By
1H NMR decision.
b Determine by GPC.
Polycaprolactone (the PCL that obtains
n-OH), molecule chain end contains hydroxyl, and (OH), can be used as the initiator of next step phosphate ester monomer ring-opening polymerization, its subscript n is represented the polymerization degree of polycaprolactone.
Embodiment three: PCL
70-OH (BzOH: ε-CL:Sn (Oct)
2=2:140:1) preparation method
Reaction flask and the syringe that stirrer will be housed in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of 50 mL side tube flasks of argon gas, add 5.80 g caprolactone (ε-CL; 0.0509 mol), syringe injects the toluene stirring and dissolving of 10 mL, injects 0.0785 g benzylalcohol (BzOH with microsyringe; 7.268 mmol); Charge and discharge gas drive and remove side tube flask air and oxygen, reaction flask is moved to 90 ℃ of oil baths, stirring reaction adds 0.13 g stannous octoate (Sn (Oct) rapidly after 30 minutes
2, 3.643 mmol), reacted 24 hours down at 90 ℃.Reaction is stopped by two acetic acid, revolves to steam to remove partial solvent, and crude product is dissolved in the chloroform, ices ether sedimentation 2 times with 80 mL, and filtering products obtained therefrom is the white powder thing, places vacuum drying oven to be dried to constant weight.Weigh, calculate productive rate and be about 85.6 %.The employing proton nmr spectra (
1H NMR) structure of checking polycaprolactone, the chemical shift peak of the nucleus magnetic hydrogen spectrum spectrogram of polymkeric substance and Fig. 3 of embodiment 2 are similar; Gel permeation chromatography (GPC) verify its number-average molecular weight (
) and MWD (
/
).Table 1 is seen in molecular weight and distribution thereof.
Embodiment four: PCL
96-OH (BzOH: ε-CL:Sn (Oct)
2=2:200:1) preparation method
Reaction flask and the syringe that stirrer will be housed in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of 50 mL side tube flasks of argon gas, add 4.159 g caprolactone (ε-CL; 0.03648 mol), syringe injects the toluene stirring and dissolving of 10 mL, injects 0.0394 g benzylalcohol (BzOH with microsyringe; 3.648 mmol); Charge and discharge gas drive and remove side tube flask air and oxygen, reaction flask is moved to 90 ℃ of oil baths, stirring reaction adds 0.07 g stannous octoate (Sn (Oct) rapidly after 30 minutes
2, 1.824 mmol), reacted 24 hours down at 90 ℃.Add 2 acetic acid termination reactions, revolve to steam and remove partial solvent, crude product is dissolved in the chloroform, ice ether sedimentation 2 times with 80 mL, filtering products obtained therefrom is the white powder thing, places vacuum drying oven to be dried to constant weight.Weigh, calculate productive rate and be about 70%.The employing proton nmr spectra (
1H NMR) checking polycaprolactone structure, each displacement peak of the nucleus magnetic hydrogen spectrum spectrogram of polymkeric substance and Fig. 3 of embodiment 2 are similar, gel permeation chromatography (GPC) verify its number-average molecular weight (
) and MWD (
/
).Table 1 is seen in molecular weight and distribution thereof.
Embodiment five～seven describes poly phosphate segmented copolymer PCL-
bThe preparation method of-POPEA.
Embodiment five: PCL
40-
b-POPEA
23(PCL
40: OPEA:Sn (Oct)
2=2:80:1) preparation
Reaction flask and the syringe that stirrer will be housed in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of 50 mL side tube flasks of argon gas, add 1.0438 g macromole evocating agent PCL40 (0.226 mmol); After charging and discharging gas 3 times, inject 1.97 g OPEA (9.06 mmol), the toluene of 10 mL that reinject with syringe; Stirring and dissolving; Charge and discharge gas drive and remove side tube flask air and oxygen, reaction flask is moved to 80 ℃ of oil baths, stirring reaction adds 0.04g Sn (Oct) rapidly after 30 minutes
2(0.113mmol), reacted 24 hours down at 80 ℃.Add 2 acetic acid termination reactions, revolve to steam and remove partial solvent, crude product is dissolved in the chloroform; Ice ether/methyl alcohol=10/1 (v/v) mixing solutions deposition 2 times with 100mL; Filter, products obtained therefrom is the glutinous sprills shape thing of white, places vacuum drying oven to be dried to constant weight.Weigh, calculate productive rate and be about 41%.The proton nmr spectra of segmented copolymer (
1H NMR) spectrogram is seen Fig. 4 (A), carbon-13 nmr spectra (
13CNMR) see Fig. 5, the nucleus magnetic resonance phosphorus spectrum of segmented copolymer (
31PNMR) spectrogram is seen Fig. 7 (B).
Embodiment six: PCL
70-b-POPEA
50(PCL
70: OPEA: Sn (Oct)
2=2: 140: 1) reaction flask and the syringe that preparation will be equipped with stirrer in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of the 50mL side tube flask of argon gas, add 12192g macromole evocating agent PCL70 (0.153mmol); After charging and discharging gas 3 times; Inject 2.38g OPEA (10.71mmol) with syringe, inject the toluene stirring and dissolving of 10mL again with syringe, charge and discharge gas drive and remove side tube flask air and oxygen; Reaction flask is moved to 80 ℃ of oil baths, and stirring reaction adds 0.03g Sn (Oct) rapidly after 30 minutes
2(0.076mmol), reacted 24 hours down at 80 ℃.Add 2 acetic acid termination reactions; Revolve to steam and remove partial solvent, crude product is dissolved in the chloroform, the mixing solutions of icing ether/methyl alcohol=10/1 (v/v) with 100mL precipitates 2 times; Filtering products obtained therefrom is the glutinous sprills shape thing of white, places vacuum drying oven to be dried to constant weight.Weigh, calculate productive rate and be about 36%.The proton nmr spectra spectrogram of segmented copolymer is seen Fig. 4 (B), and the spectrogram among the carbon-13 nmr spectra of segmented copolymer and phosphorus spectrum spectrogram and the embodiment 5 is similar.
Embodiment seven: PCL
96-b-POPEA
4(PCL
96: OPEA: Sn (Oct)
2=2: 80: 1) reaction flask and the syringe that preparation will be equipped with stirrer in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of the 50mL side tube flask of argon gas, add 1.0538g macromole evocating agent PCL96 (0.096mmol); After charging and discharging gas 3 times; Inject 0.85g OPEA (3.83mmol) with syringe, inject the toluene stirring and dissolving of 10ml again with syringe, charge and discharge gas drive and remove side tube flask air and oxygen; Reaction flask is moved to 80 ℃ of oil baths, add 0.02g Sn (Oct) behind the stirring reaction 30min rapidly
2(0.048mmol), reacted 24 hours down at 80 ℃.Reaction is stopped by two acetic acid; Revolve to steam and remove partial solvent, crude product is dissolved in the chloroform, the mixing solutions of icing ether/methyl alcohol=10/1 (v/v) with 100mL precipitates 2 times; Filtering products obtained therefrom is the glutinous sprills shape thing of white, places vacuum drying oven to be dried to constant weight.Weigh, calculate productive rate and be about 16%.The proton nmr spectra spectrogram of segmented copolymer is seen Fig. 4 (C), similar among the carbon-13 nmr spectra of segmented copolymer and phosphorus spectrum spectrogram and the embodiment 5.
Embodiment eight describes poly phosphate random copolymers PCL-
CoThe preparation method of-OPEA
Embodiment eight: P (CL-
Co-OPEA) 10% (BzOH: ε-CL:OPEA:Sn (Oct)
2=1:7:0.7:0.5) preparation
Reaction flask and the syringe that stirrer will be housed in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of 50 mL side tube flasks of argon gas, inject 0.1052 g initiator B zOH (0.01 mol) successively with syringe; 8.007 g ε-CL (0.07 mol) and 1.56 g OPEA (0.007 mol); Inject the toluene stirring and dissolving of 10 mL again with syringe; Charge and discharge gas drive and remove side tube flask air and oxygen, reaction flask is moved to 80 ℃ of oil baths, add 0.19 g Sn (Oct) behind stirring reaction 30 min rapidly
2(0.005 mol) reacted 24 hours down at 80 ℃.Reaction is stopped by two acetic acid; Revolve to steam and remove partial solvent, crude product is dissolved in the chloroform, the mixing solutions of icing ether/methyl alcohol=10/1 (v/v) with 100 mL precipitates 2 times; Filtering products obtained therefrom is the glutinous sprills shape thing of white, places vacuum drying oven to be dried to constant weight.Weigh, calculate productive rate and be about 60%.The proton nmr spectra spectrogram of random copolymers is seen Fig. 6.
Four, embodiment nine～12 describes and contains sulfydryl (organic cpds SH) carries out Michael reaction to the poly phosphate segmented copolymer and modifies.
With PCL
70-b-POPEA
50Be example, carry out Michael reaction with thiohydracrylic acid, 3-Mercapto-1, Mercaptamine and cysteine hydrochloride respectively, the Michael of all the other segmented copolymers and random copolymers modifies similarly.
Embodiment nine: the preparation ([propenoate]: [SH]: [pyridine]=1:10:10) of the segmented copolymer
that the poly phosphate side group is modified
Reaction flask and the syringe that stirrer will be housed in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of 50 mL side tube flasks of argon gas, add charge and discharge gas 3 times after, add segmented copolymer 50 mg PCL successively
70-
b-POPEA
50(0.004 mmol), 0.09 g thiohydracrylic acid (0.88 mmol) and 0.07 g catalyzer pyridine (0.88 mmol); Inject the DMF stirring and dissolving of 3 mL again with syringe; Charge and discharge gas and drive side tube flask air and oxygen away, at room temperature stirring reaction is 72 hours.Reaction product is iced ether sedimentation 2 times with 50 mL; The collecting precipitation thing, with transferring in the dialysis tubing after the DMF dissolving, not reacted sulfydryl small molecules and DMF are removed in dialysis; Dialysed 3 days; Changed a deionized water in per 12 hours, last lyophilize obtains the product of white powder; Be the segmented copolymer
of carboxyl modified poly phosphate side group, productive rate is about: 30%.Product through nucleus magnetic resonance (
1H NMR) checking, the nucleus magnetic hydrogen spectrum spectrogram of polymkeric substance is seen Fig. 8 (B).
Embodiment ten: the preparation ([propenoate]: [SH]: [pyridine]=1:10:10) of the segmented copolymer
that the poly phosphate side group is modified
Reaction flask and the syringe that stirrer will be housed in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of 50 mL side tube flasks of argon gas, add charge and discharge gas 3 times after, add segmented copolymer 50 mg PCL70-successively
b-POPEA50 (0.004 mmol), 0.096 g 3-sulfydryl-1; 2-Ucar 35 (0.89 mmol); And 0.07 g catalyzer pyridine (0.88 mmol); Inject the DMF stirring and dissolving of 3 mL again with syringe, charge and discharge gas and drive side tube flask air and oxygen away, at room temperature stirring reaction is 72 hours.Reaction product is iced ether sedimentation 2 times with 50 mL; The collecting precipitation thing, with transferring in the dialysis tubing after the DMF dissolving, not reacted sulfydryl small molecules and DMF are removed in dialysis; Dialysed 3 days; Changed a deionized water in per 12 hours, last lyophilize obtains the product of white powder; Be the segmented copolymer
that dihydroxyl is modified the poly phosphate side group, productive rate is about: 27%.Product through proton nmr spectra (
1H NMR) checking proves to obtain title product.The nuclear magnetic spectrogram of polymkeric substance is seen Fig. 8 (C).
Embodiment 11: the preparation ([propenoate]: [SH]: [pyridine]=1:10:10) of the segmented copolymer
that the poly phosphate side group is modified
Reaction flask and the syringe that stirrer will be housed in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of 50 mL side tube flasks of argon gas, add charge and discharge gas 3 times after, add segmented copolymer 50 mg PCL successively
70-
b-POPEA
50(0.004 mmol), 0.1 g Mercaptamine (0.88 mmol) and 0.07 g catalyzer pyridine (0.88 mmol); Inject the DMF stirring and dissolving of 3 mL again with syringe; Charge and discharge gas drive and remove side tube flask air and oxygen, at room temperature stirring reaction is 72 hours.Reaction product removes by filter pyridine hydrochloride earlier, ices ether sedimentation 2 times with 50 mL again, the collecting precipitation thing; With transferring in the dialysis tubing after the DMF dissolving; Not reacted sulfydryl small molecules and DMF are removed in dialysis, dialyse deionized water of replacing in per 12 hours 3 days; Last lyophilize; Obtain the product of white powder, the segmented copolymer of promptly amido modified poly phosphate side group
, productive rate is about: 41%.Product through proton nmr spectra (
1H NMR) checking, the nmr spectrum of polymkeric substance is seen Fig. 8 (D).
Embodiment 12: the preparation ([propenoate]: [SH]: [pyridine]=1:10:10) of the segmented copolymer
that the poly phosphate side group is modified
Reaction flask and the syringe that stirrer will be housed in advance is placed in 120 ℃ of baking ovens dry 6 hours at least.After the taking-up, use the bungee tighten behind the stopper, fill high-purity argon gas while vacuumizing with the vacuum oil pump again, repeatedly three times after reaction flask cooling, it is for use to be full of high-purity argon gas in the bottle.
In being full of 50 mL side tube flasks of argon gas, add charge and discharge gas 3 times after, add segmented copolymer 50 mg PCL successively
70-
b-POPEA
50(0.004 mmol), 0.16 g L-cysteine hydrochloride (0.88 mmol) and 0.14 g catalyzer pyridine (0.88 mmol); Inject the DMF stirring and dissolving of 3 mL again with syringe; Charge and discharge gas drive and remove side tube flask air and oxygen, at room temperature stirring reaction is 72 hours.Reaction product removes by filter pyridine hydrochloride earlier, ices ether sedimentation 2 times with 50 mL again, the collecting precipitation thing; With transferring in the dialysis tubing after the DMF dissolving; Not reacted sulfydryl small molecules and DMF are removed in dialysis, dialyse deionized water of replacing in per 12 hours 3 days; Last lyophilize; Obtain the product of white powder, the segmented copolymer of promptly amino acid modified poly phosphate side group
, productive rate is about: 32%.Product through proton nmr spectra (
1H NMR) checking, the nmr spectrum of polymkeric substance is seen Fig. 8 (E).
Embodiment 13 describes the preparation of poly phosphate block copolymer micelle and the test of micella performance.
Embodiment 13: the test of the preparation of poly phosphate block copolymer micelle and micella performance
With segmented copolymer PCL
70-
b-POPEA
50Be example, the preparation of all the other block copolymer micelles and performance study method thereof are similarly.
(1) preparation of Amphipathilic block polymer micelle
Prepare the micella of amphipathic nature block polymer through dialysis method, concrete preparation method is following:
In the round-bottomed flask of 50 mL, get 25 mg segmented copolymer PCL
70-
b-POPEA
50Be dissolved among the DMF of 5 mL, be made into the solution of 5 mg/mL, under intense stirring condition, dropwise add people's deionized water, slightly become muddy and blue opalescence occurs, obtain stable micellar solution until solution.It is transferred in the dialysis tubing, places deionized water to dialyse, deionized water of replacing in per 12 hours in the dialysis procedure.After 3 days, be made into the aqueous solution of 1.0 mg/mL.
(2) test of the micelle-forming concentration of Amphipathilic block polymer (CMC)
With the micelle-forming concentration of fluorescent probe method mensuration Amphipathilic block polymer micelle, be the fluorescent probe agent with the pyrene.With the block copolymer micelle aqueous solution of 1.0 mg/mL respectively compound concentration be 1.0 * 10
-5The solution of-1.0 * 10 mg/mL pipettes 5 mL respectively again in volumetric flask, injects 5 respectively again
μL concentration is 6 * 10
-4The acetone soln of mol/L pyrene extracts acetone with water pump, and obtaining pyrene concentration is 6 * 10
-7The polymers soln of mol/L.Then above-mentioned solution lucifuge was stirred 24 hours, test with spectrophotofluorometer.
Under 25 ℃, with solution
I 373With
I 383Strength ratio is mapped to polymer concentration, and the intersection point of the sea line of curve and oblique line tangent line is segmented copolymer PCL
70-
b-POPEA
50Micelle-forming concentration (CMC).Fig. 9 is segmented copolymer PCL
70-
b-POPEA
50Fluorescence curve figure, micelle-forming concentration that can this segmented copolymer from figure is 1.5 * 10
-2Mg/mL.
(3) ESEM of Amphipathilic block polymer micelle (TEM) and particle diameter (DLS) test
Amphipathic nature block polymer PCL
70-
b-POPEA
50Micellar ESEM (TEM) and particle diameter and distribution thereof are to test in the aqueous solution under its 1 mg/mL concentration.Concrete outcome is seen Figure 10 and table 2.
The micelle-forming concentration of each block polymer of table 2. (CMC), size and distribution thereof
| CAC (g/L) |  | Size PDI | |
| PCL 40- b-POPEA 20 | 3.0 * 10 -3 | 173 | 0.442 |
| PCL 70- b-POPEA 50 | 1.5 * 10 -2 | 114 | 0.173 |
| PCL 96- b-POPEA 4 | 3.0 * 10 -4 | 186 | 0.392 |
From chart, can find out the formation of Amphipathilic block polymer micelle and in water, have good dispersiveness.
What embodiment 14 described is the cytotoxicity test of poly phosphate segmented copolymer and Michael addition modified outcome thereof.
Embodiment 14: with segmented copolymer PCL
70-
b-POPEA
50And the Michael addition modified outcome is example, and the toxotest of all the other multipolymers similarly.
Through 3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt (MTT method) is measured PCL under the different concns
70-
b-POPEA
50It steps the cytotoxicity test of gram addition modified outcome.Be aqueous solutions of polymers and the MCF-7 cell co-cultivation of 0.4,0.2,0.1,0.05,0.025,0.0125 mg/mL after 24 hours with concentration respectively, survey cell survival rate.Figure 11 is the toxotest result of this base polymer and Michael addition modified outcome thereof, and the result shows this base polymer and step gram addition modified outcome and be low toxicity therefore have excellent biological compatibility; The structural formula of said gram addition modified outcome advanced in years is:
Amphipathic SULPHOSUCCINIC ACID ESTER segmented copolymer is described as pharmaceutical carrier in embodiment 15 ~ 16.
With segmented copolymer PCL
70-
b-POPEA
50Be example, bag carrying anti-tumor medicine Zorubicin (DOX), the medicine carrying of all the other multipolymers is used similarly.
Embodiment 15: segmented copolymer PCL
70-
b-POPEA
50Bag carries DOX and drug release thereof
(1) block polymer PCL
70-
b-POPEA
50Bag carries the micellar preparation of DOX
Prepare segmented copolymer PCL through dialysis method
70-
b-POPEA
50Carrier micelle, concrete preparation method is following:
In the round-bottomed flask of 50 mL, get 25 mg segmented copolymer PCL
70-
b-POPEA
50, 5mg Zorubicin (DOX) is dissolved among the DMF of 5 mL; Be made into the solution of 5 mg/mL, under the lucifuge condition, vigorous stirring limit, limit dropwise adds people's deionized water; After obtaining stablizing polypeptide drug-loaded micelle solution; It is transferred in the dialysis tubing, places deionized water to dialyse, deionized water of replacing in per 12 hours in the dialysis procedure.After 3 days, be made into the medicine carrying solution of 1.0 mg/mL, keep in Dark Place.
(2) block polymer PCL
70-
b-POPEA
50The drug release of carrier micelle
Get 5mL block polymer PCL
70-
b-POPEA
50It is 14000 dialysis tubing that polypeptide drug-loaded micelle solution places molecular weight cut-off; Dialysis tubing is transferred in the centrifuge tube that fills 20mL PBS buffered soln (pH=7.4); Put into 37 ℃ water bath chader then; At the time sampling of setting, take out the PBS solution (DOX that contains release) of 5mL, the PBS buffered soln that restock 5 mL are fresh at every turn.Solution to taking out is tested with spectrophotofluorometer, and the specific fluorescent absorption value that converts and excite at 480 nm places obtains the cumulative release amount of Zorubicin, and the time is mapped, draw the drug release curve.Figure 12 is block polymer PCL
70-
b-POPEA
50Bag carries the drug release curve of Zorubicin, and as can be seen from the figure the amphipathic phosphate ester polymer of the present invention's preparation has slow release action to the Zorubicin that bag carries.
Embodiment 16: segmented copolymer PCL
70-
b-POPEA
50The endocytosis of carrier micelle.
Get 0.5 mL block polymer PCL
70-
b-POPEA
50Polypeptide drug-loaded micelle solution is added in the A549 tumor cell culture liquid, and this nutrient solution is transferred to viable cell workstation (Living Cell Imaging System), measures the phenomenon that carrier micelle gets into the A549 tumour cell through fluorescent microscope.Figure 13 (a) is the fluorescence photo of tumour cell A549, and Figure 13 (b) just is added to the photo in the A549 tumor cell culture liquid for carrier micelle, and photo shows does not have fluorescent substance; When incubation time is increased to 20 minutes; Have obvious red fluorescence to occur, showing has Zorubicin (DOX) begins to get into cell, and along with the time increases; Fluorescence intensity strengthens, and segmented copolymer PCL is described
70-
b-POPEA
50Carrier micelle can successfully get into tumour cell, and interact with cell.
Claims (3)
1. the amphipathic polyester of the biodegradable of functional side chain modification; It is characterized in that: the amphipathic polyester of the biodegradable of said functional side chain modification is made up of cyclic ester class monomer with biocompatibility and biodegradability and annular phosphate monomer, and the structural formula of the amphipathic polyester of biodegradable of said functional side chain modification is selected from a kind of in following two kinds of structural formulas:
Segmented copolymer
Or random copolymers
;
In the formula, wherein, R
1Be selected from: a kind of in methyl or the Wasserstoffatoms; R
2Be selected from:
,
Or
In a kind of; R
3Be selected from:
,
,
,
Or
In a kind of; The number-average molecular weight of multipolymer is 8000～50000 g/mol, m=30～100, n=4～50, y/ (x+y)=10%～60%.
2. the preparation method of the amphipathic polyester of biodegradable of the said functional side chain modification of claim 1 is characterized in that, may further comprise the steps:
(1) preparation contains the annular phosphate monomer of (methyl) esters of acrylic acid functional group: with the THF is that solvent, triethylamine are acid binding agent; With a kind of and 2-chloro-2-oxo-1 in Hydroxyethyl acrylate or the Rocryl 400; 3; 2-dioxaphospholane
is a reactant; Prepare the annular phosphate monomer 2-ethyl propenoate oxygen base-2-oxo-1 that contains (methyl) esters of acrylic acid functional group; 3,2-dioxaphospholane or ethyl 2-methacrylate oxygen base-2-oxo-1,3; The 2-dioxaphospholane, its chemical structural formula is:
(2) the preparation side chain contains the amphipathic polyester of (methyl) esters of acrylic acid functional group: with benzylalcohol is that initiator, toluene are made solvent, stannous octoate is a catalyzer; The annular phosphate monomer of (methyl) esters of acrylic acid functional group that makes with step (1) and other cyclic ester monomer carry out block copolymerization reaction or random copolymerization reaction; Obtain the amphipathic polyester that side chain contains (methyl) esters of acrylic acid functional group, its chemical structural formula is:
Segmented copolymer
Or random copolymers
;
Said other cyclic ester monomer is selected from: a kind of in caprolactone, rac-Lactide or the trimethylammonium cyclic carbonate ester;
(3) step (2) gained side chain is contained the functional side chain modification of the amphipathic polyester of (methyl) esters of acrylic acid functional group: utilize Michael reaction; Pendant double bonds with containing the poly phosphate in the organic cpds of sulfydryl and the amphipathic polyester that above-mentioned side chain contains (methyl) esters of acrylic acid functional group is reacted; Amphipathic polyester is carried out functional modification, obtain the amphipathic polyester of biodegradable of functional side chain modification;
The structural formula of the amphipathic polyester of biodegradable of said functional side chain modification is selected from a kind of in following two kinds of structural formulas:
Segmented copolymer
Or random copolymers
;
In the formula, wherein, R
1Be selected from: a kind of in methyl or the Wasserstoffatoms; R
2Be selected from:
,
Or
In a kind of; R
3Be selected from:
,
,
,
Or
In a kind of; The number-average molecular weight of multipolymer is 8000～50000 g/mol, m=30～100, n=4～50, y/ (x+y)=10%～60%; Wherein, the organic cpds that contains sulfydryl is selected from: a kind of in thiohydracrylic acid, 3-Mercapto-1, Mercaptamine or the cysteine hydrochloride.
3. side chain contains the amphipathic polyester of (methyl) esters of acrylic acid functional group, it is characterized in that, the chemical structural formula that said side chain contains the amphipathic polyester of (methyl) esters of acrylic acid functional group is selected from:
Segmented copolymer
Or random copolymers
;
Wherein, R
1Be selected from: a kind of in methyl or the Wasserstoffatoms; R
2Be selected from:
,
Or
In a kind of; The number-average molecular weight of multipolymer is 8000～50000 g/mol, m=30～100, n=4～50, y/ (x+y)=10%～60%.
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| CN105968169A (en) * | 2016-03-25 | 2016-09-28 | 安徽红太阳新材料有限公司 | Quantum dot-polypeptide compound with linear polycaprolactone joint arm |
| CN106496531A (en) * | 2016-10-26 | 2017-03-15 | 安徽红太阳新材料有限公司 | A kind of preparation method of polycaprolactone block polylactide co polymer |
| CN110591066B (en) * | 2019-10-12 | 2021-08-17 | 黄山市向荣新材料有限公司 | Polyester resin for high-leveling self-curing powder coating and preparation method of two-kettle combined polyester resin |
| CN110564123B (en) * | 2019-10-29 | 2021-07-20 | 吉林大学 | Polylactic acid/bioglass composite material and preparation method thereof |
| CN112759720B (en) * | 2021-01-11 | 2023-01-31 | 广东锐涂精细化工有限公司 | Boiling-resistant phosphorus-containing waterborne acrylic modified polyester dispersion resin and preparation method and application thereof |
| CN113527648A (en) * | 2021-08-13 | 2021-10-22 | 温州医科大学 | Polyester with functional group at long chain end and preparation method thereof |
| CN115806673A (en) * | 2022-12-29 | 2023-03-17 | 华南理工大学 | Hyperbranched polyphosphate ester material containing thioether bonds as well as preparation method and application thereof |
| CN116695272A (en) * | 2023-08-08 | 2023-09-05 | 江苏恒科新材料有限公司 | Breathable cationic dyeable polyester fiber and preparation method thereof |
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