CN105254899B - Segmented copolymer and its micella based on molecular glue - Google Patents
Segmented copolymer and its micella based on molecular glue Download PDFInfo
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Abstract
The invention provides a kind of PLA PEG amphipathic multi-block copolymers based on molecular glue, its structure is shown in formula I：Wherein, n is the arbitrary integer between 2~200, and m is the arbitrary integer between 2~150, and t is 1 or 2.The preparation method of the described PLA PEG amphipathic multi-block copolymers based on molecular glue comprises the following steps：Hydrophilic segment compound S3 PEG S3 are prepared respectivelyWith hydrophobic patch compound Z1 PLA Z1The hydrophilic segment compound S3 PEG S3 and hydrophobic patch compound Z1 PLA Z1 are subjected to oxidation reaction, obtain the PLA PEG amphipathic multi-block copolymersThe present invention has following beneficial effect：Analysis and characterization is carried out to the segmented copolymer using gel chromatography technology, the control group copolymer of the sign by synthesizing the amphipathic multi-block copolymer based on molecular glue, effectively and accurately calculates percentage composition of each block in the copolymer.
Description
Technical field
The present invention relates to a kind of PLA-PEG amphipathic multi-blocks copolymer and its control group polymer based on molecular glue,
Especially a kind of PLA-PEG amphipathic multi-blocks copolymer and its control group polymer based on molecular glue.
Background technology
Block copolymer is the spy formed by two or more property difference polymer unit by chemical bond linkage
Different polymer, it can combine the advantageous property of different polymer, obtain the more superior functional polymer of performance
Material.It is different according to the quantity of the link unit of composition block copolymer, it can be divided into di-block copolymer, triblock copolymer,
Segmented copolymer etc..
Amphipathic nature block polymer is combined by hydrophobic patches and hydrophilic fractions, generally with polyethylene glycol (PEG)
Deng being hydrophobic section for hydrophilic section, PLA (PLA) etc..With lipophilicity and hydrophilic block copolymer in the solvent of selectivity
The micella of nanoscale can be self-assembly of, its particle diameter is typically distributed across in the range of 10-1000nm, can be answered as pharmaceutical carrier
Research (Advanced drug delivery devices via self- in terms of for drug delivery and drug controlled release
assembly of amphiphilic block copolymers.Adv.Drug Del.Rev.2012,64,270-279)。
There is PLA (PLA) good biocompatibility, nontoxic, catabolite can be excreted by metabolism,
With thermoplasticity, easy processing, therefore it is widely used as biomaterial.Polyethylene glycol (PEG) is nontoxic, has good bio-compatible
Property, have hydrophily, can be excreted by kidney, also be widely used as biomaterial (Polymeric biomaterials
for tissue and organ regeneration[J].Materials Science and Engineering,2001,
R34:147-230).The block copolymer that PLA is formed with polyethylene glycol, while there is PLA and PEG advantages, while assign again
The new performance of material, is widely used in controlled drug delivery system.
The present inventor introduces the molecule with the effect of hydrogen bond sequence selectivity respectively in polymer P LA and PEG
Glue is single-stranded, is allowed to that molecular glue can be effectively formed under given conditions, so as to optionally imitate a series of differences of synthesis
The amphipathic multi-block copolymer of molecular weight, inventor has synthesized molecular glue and a series of two block copolymerizations in previous work
(number of patent application is respectively 201110023046.1 to thing；201110418589.3；201210442360.8)；In the present invention,
Inventor has synthesized a series of amphipathic multi-block copolymers by molecular glue group, and can be using self assembly as micella.
The content of the invention
For in the prior art the defects of, it is an object of the invention to provide a kind of PLA-PEG based on molecular glue is amphipathic
Segmented copolymer and its control group polymer, the present invention use the molecular glue with hydrogen bond matching effect of organic synthesis first
It is single-stranded, multiple hydrophobic patch compound Z1-PLA-Z1 and hydrophilic segment compound S3-PEG-S3 are connected, form amphiphilic
Property segmented copolymer.
The present invention is achieved by the following technical solutions：
In a first aspect, the invention provides a kind of PLA-PEG amphipathic multi-block copolymers based on molecular glue, its structure
Shown in formula such as formula (I)：
Wherein, n is the arbitrary integer between 2~200, and m is the arbitrary integer between 2~150, and t is 1 or 2.
Preferably, the n is the arbitrary integer between 40~100, and m is the arbitrary integer between 30~80.
Second aspect, the invention provides a kind of PLA-PEG amphipathic multi-blocks copolymerization based on molecular glue as the aforementioned
The preparation method of thing, it comprises the following steps：
Hydrophilic segment compound S3-PEG-S3 is prepared respectively
With hydrophobic patch compound Z1-PLA-Z1
The hydrophilic segment compound S3-PEG-S3 and hydrophobic patch compound Z1-PLA-Z1 is subjected to oxidation reaction, obtained
To the PLA-PEG amphipathic multi-blocks copolymer
Preferably, the hydrophilic segment compound S3-PEG-S3, hydrophobic patch compound Z1-PLA-Z1 occur
The catalyst of oxidation reaction is elemental iodine, and the S3-PEG-S3, hydrophobic patch compound Z1-PLA-Z1 and elemental iodine rub
You are than being 1:1:12.
Preferably, the preparation method of the S3-PEG-S3 comprises the following steps：
By polyethylene glycol and 3,5- dinitros acyl chlorides carries out substitution reaction, obtains compound S1-PEG-S1
The compound S1-PEG-S1 is subjected to hydrogenation reduction, obtains compound S2-PEG-S2
By the compound S2-PEG-S2 and compound S3Reacted, obtain the hydrophilic sheet
Section compound S3-PEG-S3.
Preferably, in the substitution reaction that polyethylene glycol and 3,5- the dinitro acyl chlorides is carried out, solvent is dichloro
Methane, catalyst is triethylamine, and the mol ratio of polyethylene glycol, 3,5- dinitros acyl chlorides, triethylamine is 1：2：4；
In the hydrogenation reduction that the compound S1-PEG-S1 is carried out, solvent is methanol, and catalyst is 10% palladium
Carbon, and the mol ratio of compound S1-PEG-S1 and palladium carbon is 1：5；
The compound S1-PEG-S1 withIn the reaction of progress, solvent is dry N,
Dinethylformamide, catalyst are 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester and N-
Methyl morpholine, and the S2-PEG-S2, S3, N-methylmorpholine, 2- (7- azos BTA)-N, N, N ', N '-tetramethyl
The mol ratio of urea hexafluorophosphoric acid ester is 1.0：4.0：(4.0~4.5)：(6.0~8.0).
Preferably, the hydrophobic patch compound Z1-PLA-Z1
Preparation comprise the following steps：
By compound PLAEsterification is carried out with succinic anhydride, obtains the modification PLA with end carboxyl
Compound
By the modified PLA compoundsWith compound Z1
Generation amidation process, obtain the hydrophobic patch compound Z1-PLA-Z1.
Preferably, the compound PLAIn the esterification carried out with succinic anhydride,
Solvent is dichloromethane, and catalyst is DMAP, and the compound PLA, DMAP, succinic anhydride
Mol ratio be 1：2：3；
In the amidation process that the modified PLA compounds and compound Z1 are carried out, solvent is dry N, N- dimethyl
Formamide, catalyst are 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester and N-methylmorpholine,
And the modified PLA, Z1, N-methylmorpholine, 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester
Mol ratio be 1.0：2.0：(2.0~3.0)：(4.0~6.0).
The third aspect, present invention also offers one group of pair for being used to characterize foregoing PLA-PEG amphipathic multi-blocks copolymer
According to copolymer, including copolymer p EG-PEG and copolymer
With copolymer p LA-PLA
Preferably, the preparation method of the copolymer p EG-PEG comprises the following steps：
By poly glycol monomethyl ether and 3,5- dinitros acyl chlorides carries out substitution reaction, obtains compound S1-PEG-CH3
The compound S1-PEG-CH3 is subjected to reduction reaction in hydrogen, obtains compound S2-PEG-CH3
By the compound S2-PEG-CH3With compound S3Amidation process is carried out, obtains parent
Water fragment compound S3-PEG-CH3
By the hydrophilic segment compound S3-PEG-CH3Aoxidized, obtain PEG-PEG
The copolymer p LA-PLAPreparation method
Comprise the following steps：
By compound PLAWith compound Z1Occur
Amidation process, obtain hydrophobic patch compound PLA-Z1
The hydrophobic patch compound PLA-Z1 is subjected to oxidation reaction, obtains di-block copolymer PLA-PLA
In the substitution reaction that poly glycol monomethyl ether and 3,5- the dinitro acyl chlorides is carried out, solvent is dichloromethane, is urged
Agent is triethylamine, and the mol ratio of the poly glycol monomethyl ether, 3,5- dinitros acyl chlorides, triethylamine is 1：1：4；
The compound S1-PEG-CH3In the reduction reaction carried out in hydrogen, solvent is methanol, catalyst 10%
Palladium carbon, and the mol ratio of the compound S1-PEG-CH3 and palladium carbon be 1:5；
The S2-PEG-CH3In the amidation process carried out with compound S3, solvent is DMF, is urged
Agent is 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester and N-methylmorpholine, and the S2-
PEG-CH3, S3, N-methylmorpholine, 2- (7- azos BTA)-N, N, N ', mole of N '-tetramethylurea hexafluorophosphoric acid ester
Than for 1.0：2.0：(2.0~2.5)：(3.0~4.0)；
The S3-PEG-CH3The oxidant for carrying out oxidation reaction is iodine, and the S3-PEG-CH3With iodine
Mol ratio is 1:6.
In the amidation process that the compound PLA and compound Z1 occurs, solvent is DMF, catalysis
Agent is 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester and N-methylmorpholine, and the chemical combination
Thing PLA, Z1, N-methylmorpholine, 2- (7- azos BTA)-N, N, N ', the mol ratio of N '-tetramethylurea hexafluorophosphoric acid ester
For 1.0：(1.0~1.5)：(1.0~1.5)：(2.0~3.0)；
In the oxidation reaction that the compound PLA-Z1 is carried out, oxidant is elemental iodine, and PLA-Z1 and elemental iodine rub
You are than being 1:6.
Fourth aspect, it is described the present invention relates to a kind of PLA-PEG amphipathic multi-block copolymer micelles based on molecular glue
The preparation method of micella is as follows：
The foregoing PLA-PEG amphipathic multi-block copolymers based on molecular glue are dissolved in polar solvent and form solution A；
The solution A is slowly added dropwise in the aqueous phase of stirring and forms it into micro emulsion ball, the aqueous phase solution of the formation micro emulsion ball is filled
Enter bag filter and appear polar solvent, produce.Make in amphipathic nature block polymer prepared by the present invention containing double disulfide bond and hydrogen bond
Molecular glue, therefore, its micella prepared have reducing agent sensitiveness.
Preferably, the polar solvent is DMSO (dimethyl sulfoxide (DMSO)), DMF (DMF) or THF (tetrahydrochysenes
Furans).
Preferably, the aqueous phase is pure water, PBS or physiological saline.
Preferably, the bag filter molecular weight is 0.2KD.
Compared with prior art, the present invention has following beneficial effect：
1. using the method for organic synthesis first, terminal groups modification is carried out to PEG and PLA, introducing has hydrogen bond matching effect
Molecular glue it is single-stranded, be allowed to form molecular glue under given conditions, by multiple hydrophobic patch compound Z1-PLA-Z1 and hydrophilic sheet
Section compound S3-PEG-S3 is connected, and formation has amphipathic segmented copolymer, and the synthetic method step is less, former
Expect simple and easy to get, reaction condition is gentle, and building-up process is popular response, is adapted to fairly large production；
2. carrying out analysis and characterization to the segmented copolymer using gel chromatography technology (GPC), molecule is based on by synthesis
The control group copolymer of the sign of the PLA-PEG amphipathic multi-block copolymers of glue, effectively and accurately calculates each block at this
Percentage composition in copolymer；
3. the micella particle diameter of the PLA-PEG amphipathic multi-block copolymer self assemblies based on molecular glue prepared by the present invention is big
It is small suitable, narrow distribution, have good stability.
Brief description of the drawings
The detailed description made by reading with reference to the following drawings to non-limiting example, further feature of the invention,
Objects and advantages will become more apparent upon：
Fig. 1 is hydrophilic segment compound S3-PEG-S3 synthesis path figure；
Fig. 2 is hydrophobic patch compound Z1-PEG-Z1 synthesis path figure；
Fig. 3 is segmented copolymer [PLA-PEG] t synthesis path figure；
Fig. 4 is control group copolymer p EG-PEG synthesis path figure；
Fig. 5 is control group copolymer p LA-PLA synthesis path figure；
Fig. 6 is segmented copolymer [PEG4000-PLA5000]tNmr spectrum；
Fig. 7 is segmented copolymer [PEG4000-PLA3000]tNmr spectrum；
Fig. 8 is segmented copolymer [PEG2000-PLA3000]tNmr spectrum；
Fig. 9 is segmented copolymer [PEG4000-PLA5000]tGel chromatography figure (GPC spectrograms)；
Figure 10 is segmented copolymer [PEG4000-PLA3000]tGel chromatography figure (GPC spectrograms)；
Figure 11 is segmented copolymer [PEG2000-PLA3000]tGel chromatography figure (GPC spectrograms)；
Figure 12 is control group copolymer p EG-PEG gel chromatography figure (GPC spectrograms)；
Figure 13 is control group copolymer p LA-PLA gel chromatography figure (GPC spectrograms)；
Figure 14 is segmented copolymer [PEG4000-PLA3000]tGraph of a relation of the micellar concentration to absorbance A；
Figure 15 is segmented copolymer [PEG4000-PLA3000]tThe grain size distribution of micella；
Figure 16 is segmented copolymer [PEG4000-PLA3000]tThe stability test result of micella.
Embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention
Protection domain.
Raw material, reagent used in the present invention are commercially available AR, CP level.
Gained intermediate product and final product of the invention use1H-NMR, IR, GPC etc. are characterized.
Embodiment 1, amphipathic multi-block copolymer [PLA-PEG]tSynthesis
Hydrophilic segment S3-PEG-S3 synthesis
(1) as PEG n=44, Mn=2000；
As PEG n=44, Mn=2000, its synthetic route is as shown in Figure 1：Compound 3,5- dinitros acyl chlorides and PEG
After substitution reaction occurs, hydrogenated under hydrogen environment, the modified PE G2000 obtained after the reaction and compound S3 carries out acid amides
Change reaction, obtain compound S3-PEG2000-S3；
The step is specially：Compound 3, after with PEG2000 substitution reaction occurs for 5- dinitros acyl chlorides, in hydrogen environment
Lower hydrogenation, the modified PE G2000 obtained after the reaction and compound S3 carry out amidation process, obtain compound S3-PEG2000-
S3；
The step is specially：PEG-2000 (8g, 4.0mmol) is added in 150mL round-bottomed flasks, it is molten with 50mL DCM
Solve, after stirring and dissolving, add triethylamine (2.23mL, 16mmol), 3,5- dinitro acyl chlorides (1.84g, 8.0mmol)；Stirred at 0 DEG C
15min is mixed, reacts 6h under room temperature (25 DEG C).After stopping reaction, with saturation Na2CO3Solution washs, then is washed with saturation NaCl solution
Wash, organic phase is evaporated under reduced pressure, and obtains compound S1-PEG2000-S1.
Above compound S1-PEG2000-S1 (1.52g, 0.62mmol) is weighed in 100mL single-necked flasks, adds 30mL
Methanol makes its dissolving, adds 10% palladium carbon (0.33g, 3.1mmol), is passed through hydrogen, reacts 12h under room temperature (25 DEG C).Stop
After reaction, filtered with diatomite, remove palladium carbon, organic phase is evaporated under reduced pressure, and obtains compound S2-PEG2000-S2.
S3 (0.64g, 1.76mmol) is weighed, NMM (224 μ L, 2.0mmol), HATU (1.35g, 3.52mmol) is in 50mL
In single-necked flask, it is dissolved in 15mL and dries DMF, stir-activating 30min under ice bath, add above compound S2-PEG2000-S2
(1.00g, 0.44mmol), nitrogen environment are protected, and are warming up to after ice bath stirring 1h under room temperature (25 DEG C) and are reacted 24h.Reaction terminates
Afterwards, 30mL DCM extractions are added, washing three times, then with saturation NaCl solution is washed twice, and organic phase is evaporated under reduced pressure, and is obtained brown and is consolidated
Body 1.43g, column chromatography obtain product 1.19g, yield 74%.1H-NMR(600MHz,CDCl3) δ=8.11 (s, 2H, ArH), 7.88-
7.90(m,4H,ArH),7.52-7.39(m,24H,ArH),7.32-7.26(m,24H,ArH),7.24-7.19(m,12H,
ArH),3.80-3.59(m,168H,-OCH2CH2O-),2.31-2.25(m,16H,-COCH2-,-SCH2-),1.82-1.69(m,
8H,-CH2CH2CH2-).GPC：Mn=3712, Mw=3982, D=1.073.IR (KBr) 2916,1755,1650,1602,
1544,1451,1352,1252,1249,1192,1099,951,845,668,557.
(2) as PEG n=88, Mn=4000；
As PEG n=88, Mn=4000, its synthetic route is as shown in Figure 1：Compound 3,5- dinitros acyl chlorides with
After substitution reaction occurs for PEG4000, hydrogenated under hydrogen environment, the modified PE G4000 obtained after the reaction and compound S3 enters
Row amidation process, obtain compound S3-PEG4000-S3；
The step is specially：PEG-4000 (12g, 3.0mmol) is added in 150mL round-bottomed flasks, with 50mL DCM
Dissolve, after stirring and dissolving, add triethylamine (1.67mL, 12.0mmol), 3,5- dinitro acyl chlorides (1.38g, 6.0mmol)；0℃
Lower stirring 15min, 6h is reacted under room temperature (25 DEG C).After stopping reaction, with saturation Na2CO3Solution washs, then molten with saturation NaCl
Liquid is washed, and organic phase is evaporated under reduced pressure, and obtains compound S1-PEG4000-S1.
Above compound S1-PEG4000-S1 (2.76g, 0.62mmol) is weighed in 100mL single-necked flasks, adds 30mL
Methanol makes its dissolving, adds 10% palladium carbon (0.33g, 3.1mmol), is passed through hydrogen, reacts 12h under room temperature (25 DEG C).Stop
After reaction, filtered with diatomite, remove palladium carbon, organic phase is evaporated under reduced pressure, and obtains compound S2-PEG4000-S2.
S3 (0.64g, 1.76mmol) is weighed, NMM (224 μ L, 2.0mmol), HATU (1.35g, 3.52mmol) is in 50mL
In single-necked flask, it is dissolved in 15mL and dries DMF, stir-activating 30min under ice bath, add above compound S2-PEG4000-S2
(1.89g, 0.44mmol), nitrogen environment are protected, and are warming up to after ice bath stirring 1h under room temperature (25 DEG C) and are reacted 24h.Reaction terminates
Afterwards, 30mL DCM extractions are added, washing three times, then with saturation NaCl solution is washed twice, and organic phase is evaporated under reduced pressure, and is obtained brown and is consolidated
Body 2.14g, column chromatography obtain product 1.87g, yield 75%.1HNMR (400MHz, MeOD) δ=7.97-7.91 (m, 4H, ArH),
7.71(s,2H,ArH),7.41-7.39(m,24H,ArH),7.29-7.26(m,24H,ArH),7.22-7.20(m,12H,
ArH),3.70-3.54(m,389H,-OCH2CH2), O- 2.38 (t, J=7.2Hz, 8H ,-COCH2-), 2.25 (d, J=7.2Hz,
8H,-SCH2-),1.78-1.75(m,8H,-CH2CH2CH2-).GPC：Mn=5633, Mw=5832, D=1.035.IR(KBr)
2915,1756,1650,1602,1544,1451,1351,1192,1252,1185,1108,951,845,702,621,556.
Hydrophobic patch Z1-PEG-Z1 synthesis
(1) as PLA m=38, Mn=3000；
As PLA m=38, Mn=3000, its synthetic route is as shown in Figure 2：PLA3000 after terminal groups modification is held
Carboxyl PLA3000, under amidation reaction condition, compound Z1 is taken to carry out amidation process with modified end carboxyl PLA3000,
Obtain compound Z1-PLA3000-Z1；
The step is specially：PLA3000 (6.0g, 2mmol) is added in 100mL single-necked flasks, adds 25mL DCM
Make its dissolving, add DMAP (0.488g, 4mmol), succinic anhydride (0.6g, 6mmol), react 1h under ice-water bath, then room
Reaction stirring 12h under warm (25 DEG C).After stopping reaction, suitable quantity of water is added, is extracted with DCM, organic phase uses saturation NaHCO respectively3
The aqueous solution, saturated common salt washing, anhydrous sodium sulfate drying, organic phase are evaporated under reduced pressure, and obtain modified end carboxyl PLA3000.
Weigh the above modified end carboxyl PLA3000 (0.62g, 0.2mmol), the HATU (2- (nitrogen of 7- azos benzo three
Azoles)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester) (0.304g, 0.8mmol), Z1 (0.313g, 0.4mmol) is mono- in 100mL
In mouth flask, ice-water bath, nitrogen protection is lower to add dry DMF 20mL, NMM (N-methylmorpholine) (44.8 μ L, 0.4mmol),
25 DEG C of reaction 24h are warming up to after stirring 30min, stop reaction, appropriate DCM extractions is added, washes three times, then it is molten with saturation NaCl
Liquid is washed twice, and organic phase is evaporated under reduced pressure, and obtains faint yellow solid 0.86g, column chromatography obtains product 0.73g, yield 79%.1H
NMR (600MHz, CDCl3) δ=8.17-8.12 (m, 2H, ArH), 8.07-8.02 (m, 2H, ArH), 7.81-7.79 (m, 2H,
ArH),7.42-7.37(m,24H,ArH),7.28-7.21(m,24H,ArH),7.20-7.16(m,12H,ArH),6.44(brs,
4H,-NH-),5.29-5.01(m,24H,PLA-CH-),3.26(s,8H,-NCH2-),2.78-2.61(m,4H,-CH2-CH2-),
2.51 (t, J=3.4Hz, 8H ,-SCH2-),1.63-1.36(m,73H,PLA-CH3-).GPC：Mn=3156, Mw=3736, D=
1.184.IR (KBr) 3303,3058,2992,2927,1755,1657,1596,1557,1538,1489,1445,1379,
1362,1268,1187,1131,1092,1046,892,742,701,621,505.
(2) as PLA m=66, Mn=5000；
As PLA m=66, Mn=5000, its synthetic route is as shown in Figure 2：PLA5000 after terminal groups modification is held
Carboxyl PLA5000, under amidation reaction condition, compound Z1 is taken to carry out amidation process with modified end carboxyl PLA5000,
Obtain compound Z1-PLA5000-Z1；
The step is specially：The step is specially：In 100mL single-necked flasks add PLA5000 (10.0g,
2mmol), adding 25mL DCM makes its dissolving, adds succinic anhydride (0.6g, 6mmol), DMAP (0.488g, 4mmol), ice
1h is reacted under water-bath, then reaction stirring 12h under room temperature (25 DEG C).After stopping reaction, suitable quantity of water is added, is extracted with DCM, it is organic
Mutually saturation NaHCO is used respectively3The aqueous solution, saturated common salt washing, anhydrous sodium sulfate drying, organic phase are evaporated under reduced pressure, obtained modified
End carboxyl PLA5000.
Weigh the above modified end carboxyl PLA5000 (1.02g, 0.2mmol), the HATU (2- (nitrogen of 7- azos benzo three
Azoles)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester) (0.38g, 1.0mmol), Z1 (0.313g, 0.4mmol) is mono- in 100mL
In mouth flask, ice-water bath, nitrogen protection is lower to add dry DMF 25mL, NMM (N-methylmorpholine) (44.8 μ L, 0.4mmol),
25 DEG C of reaction 24h are warming up to after stirring 30min, stop reaction, appropriate DCM extractions is added, washes three times, then it is molten with saturation NaCl
Liquid is washed twice, and organic phase is evaporated under reduced pressure, and obtains faint yellow solid 1.33g, column chromatography obtains product 1.08g, yield 81%.1H
NMR (600MHz, CDCl3) δ=8.18-8.12 (m, 4H, ArH), 7.77-7.80 (m, 2H, ArH), 7.42-7.35 (m, 25H,
ArH),7.31-7.25(m,30H,ArH),7.23-7.18(m,10H,ArH),6.37(brs,4H,-NH-),5.27-5.04(m,
55H,PLA-CH-),3.25-3.37(m,8H,-NCH2-),2.50-2.54(m,8H,-SCH2-),1.68-1.31(m,166H,
PLA-CH3-).GPC：Mn=5669, Mw=6605, D=1.165.IR (KBr) 3417,2993,2943,1755,1650,
1597,1533,1449,1381,1268,1187,1131,1090,865,739,702,639,506.
Segmented copolymer [PLA-PEG]tSynthesis
(1)[PEG4000-PLA5000]tSynthesis；
As PEG n=88, Mn=4000；As PLA m=66, Mn=5000, its synthetic route is as shown in Figure 3：
Under oxidation reaction condition, take compound S3-PEG4000-S3 and Z1-PLA5000-Z1 to carry out oxidation reaction, obtain more blocks
Copolymer [PEG4000-PLA5000]t, its nuclear magnetic spectrogram is as shown in Figure 6.
The step is specially：In 250mL single-necked flasks, be separately added into Z1-PLA5000-Z1 (132.6mg,
0.02mmol) it is well mixed with S3-PEG4000-S3 (112.88mg, 0.02mmol), addition 20mL DCM dissolvings, stirring and dissolving
Dry, residue addition 80mL dichloromethane I is evaporated under reduced pressure afterwards2Solution (wherein I2For 6.0mM) dissolve, will be anti-after stirring at normal temperature 1h
Answer liquid to be cooled to 0 DEG C, add Na2S2O3The aqueous solution (3.0mM) is until I2Color disappear.Organic layer is washed with saturation NaCl solution
Wash, anhydrous Na2SO4Dry, be evaporated under reduced pressure to faint yellow solid 223mg, lamellae chromatography obtains product 161mg, separates yield
68%.1H NMR(400MHz,CDCl3) δ=8.21-7.34 (m, ArH), 5.29-5.18 (m, PLA-CH-), 3.90-3.42
(m,-OCH2CH2O-), 3.04-2.70 (m ,-NCH2-,-SCH2-), 2.54-2.03 (m ,-(C=O) CH2-,-SCH2- ,-
CH2-), 1.71-1.48 (m, PLA-CH3-).GPC：Mn=18295, Mw=22205, D=1.214.
(2)[PEG4000-PLA3000]tSynthesis；
As PEG n=88, Mn=4000；As PLA m=38, Mn=3000, its synthetic route is as shown in Figure 3：
Under oxidation reaction condition, take compound S3-PEG4000-S3 and Z1-PLA3000-Z1 to carry out oxidation reaction, obtain more blocks
Copolymer [PEG4000-PLA3000]t, its nuclear magnetic spectrogram is as shown in Figure 7.
The step is specially：In 250mL single-necked flasks, be separately added into Z1-PLA3000-Z1 (92.6mg,
0.02mmol) it is well mixed with S3-PEG4000-S3 (112.88mg, 0.02mmol), addition 20mL DCM dissolvings, stirring and dissolving
Dry, residue addition 80mL dichloromethane I is evaporated under reduced pressure afterwards2Solution (wherein I2For 6.0mM) dissolve, will be anti-after stirring at normal temperature 1h
Answer liquid to be cooled to 0 DEG C, add Na2S2O3The aqueous solution (3.0mM) is until I2 color disappears.Organic layer is washed with saturation NaCl solution
Wash, anhydrous Na2SO4Dry, be evaporated under reduced pressure to faint yellow solid 196mg, lamellae chromatography obtains product 114mg, separates yield
75%.1H NMR(400MHz,CDCl3) δ=8.17-7.08 (m, ArH), 5.31-5.01 (m, PLA-CH-), 3.87-3.46
(m,-OCH2CH2O-), 2.95-2.69 (m ,-NCH2-,-SCH2-), 2.62-1.81 (m ,-(C=O) CH2-,-SCH2-,-
CH2-), 1.75-1.45 (m, PLA-CH3-).GPC：Mn=15579, Mw=18632, D=1.196.
(3)[PEG2000-PLA3000]tSynthesis；
As PEG n=44, Mn=2000；As PLA m=38, Mn=3000, its synthetic route is as shown in Figure 3：
Under oxidation reaction condition, take compound S3-PEG2000-S3 and Z1-PLA3000-Z1 to carry out oxidation reaction, obtain more blocks
Copolymer [PEG2000-PLA3000]t。
The step is specially：In 250mL single-necked flasks, be separately added into Z1-PLA3000-Z1 (92.6mg,
0.02mmol) it is well mixed with S3-PEG2000-S3 (72.88mg, 0.02mmol), addition 20mL DCM dissolvings, stirring and dissolving
Dry, residue addition 80mL dichloromethane I is evaporated under reduced pressure afterwards2Solution (wherein I2For 6.0mM) dissolve, will be anti-after stirring at normal temperature 1h
Answer liquid to be cooled to 0 DEG C, add Na2S2O3The aqueous solution (3.0mM) is until I2 color disappears.Organic layer is washed with saturation NaCl solution
Wash, anhydrous Na2SO4Dry, be evaporated under reduced pressure to faint yellow solid 143mg, lamellae chromatography obtains product 72mg, produced after separation
Rate 76%.Nuclear magnetic spectrogram as shown in figure 8,1HNMR(400MHz,CDCl3) δ=8.20-7.30 (m, ArH), 5.30-5.07 (m,
PLA-CH-), 3.90-3.58 (m ,-OCH2CH2O-), 3.02-2.71 (m ,-NCH2-,-SCH2-), 2.64-1.94 (m ,-(C=
O)CH2-,-SCH2- ,-CH2-), 1.69-1.46 (m, PLA-CH3-).GPC：Mn=8726, Mw=10706, D=1.227.
Embodiment 2,The synthesis of the control group copolymer of the sign of segmented copolymer
Control group copolymer p EG-PEG
As PEG n=88, Mn=4000, its synthetic route is as shown in Figure 4：Compound 3,5- dinitros acyl chlorides is with gathering
After substitution reaction occurs for glycol monoethyl ether 4000, hydrogenated under hydrogen environment, the modified poly (ethylene glycol) list obtained after the reaction
Methyl ether 4000 and compound S3 carries out amidation process, obtains compound S3-PEG4000-CH3, in I2Under effect, S3-PEG4000-
CH3Oxidation reaction occurs in itself, generates di-block copolymer PEG-PEG, and its gel chromatography figure is as shown in figure 12.
The step is specially：Poly glycol monomethyl ether 4000 (12g, 3.0mmol) is added in 150mL round-bottomed flasks,
Dissolved with 50mL DCM, after stirring and dissolving, addition triethylamine (1.67mL, 12.0mmol), 3,5- dinitro acyl chlorides (1.38g,
6.0mmol)；15min is stirred at 0 DEG C, reacts 6h under room temperature (25 DEG C).After stopping reaction, with saturation Na2CO3Solution washs, then
Washed with saturation NaCl solution, organic phase is evaporated under reduced pressure, and obtains compound S1-PEG4000-CH3。
Weigh above compound S1-PEG4000-CH3(2.62g, 0.62mmol) is added in 100mL single-necked flasks
30mL methanol makes its dissolving, adds 10% palladium carbon (0.33g, 3.1mmol), is passed through hydrogen, reacts 12h under room temperature (25 DEG C).
After stopping reaction, filtered with diatomite, remove palladium carbon, organic phase is evaporated under reduced pressure, and obtains compound S2-PEG4000-CH3。
S3 (0.64g, 1.76mmol) is weighed, NMM (224 μ L, 2.0mmol), HATU (1.35g, 3.52mmol) is in 50mL
In single-necked flask, it is dissolved in 15mL and dries DMF, stir-activating 30min under ice bath, add above compound S2-PEG4000-CH3
(1.83g, 0.44mmol), nitrogen environment are protected, and are warming up to after ice bath stirring 1h under room temperature (25 DEG C) and are reacted 24h.Reaction terminates
Afterwards, 30mL DCM extractions are added, washing three times, then with saturation NaCl solution is washed twice, and organic phase is evaporated under reduced pressure, and is obtained brown and is consolidated
Body 1.97g, column chromatography obtain compound S3-PEG4000-CH3For 1.66g, yield 74%.
In 100mL single-necked flasks, above-claimed cpd S3-PEG4000-CH is added3(96.5mg, 0.02mmol), add
20mL dichloromethane I2Solution (wherein I2For 6.0mM) dissolve, reaction solution is cooled to 0 DEG C after stirring at normal temperature 1h, adds Na2S2O3
The aqueous solution (3.0mM) is until I2Color disappear.Organic layer is washed with saturation NaCl solution, anhydrous Na2SO4Dry, be evaporated under reduced pressure
Faint yellow solid 74mg is obtained, lamellae chromatography obtains product 56mg, yield 57% after separation.1H-NMR(400MHz,CDCl3)
δ=8.11 (s, 2H, ArH), 7.88 (s, 4H, ArH), 3.78-3.54 (m, 661H, PEG ,-OCH2CH2O-),3.48(s,6H,
PEG,CH3), O- 2.35-2.27 (m, 16H ,-(C=O) CH2-,-SCH2-),1.77-1.81(m,8H,-CH2CH2CH2-)；IR
(KBr) 3435,2882,1685,1601,1552,1552,1466,1359,1343,1279,1242,1146,1111,1060,
946,841,746,702,622.
Control group copolymer p LA-PLA
As PLA m=66, Mn=5000, its synthetic route is as shown in Figure 5：Under amidation reaction condition, chemical combination is taken
Thing Z1 and PLA5000 carries out amidation process, compound PLA5000-Z1 is obtained, in I2Under effect, PLA5000-Z1 itself occurs
Oxidation reaction, generates di-block copolymer PLA-PLA, and its gel chromatography figure is as shown in figure 13.
The step is specially：PLA5000 (5.0g, 1mmol), HATU are added in the single-necked flask of 25mL drying
(2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester) (0.76g, 2.0mmol), Z1 (1.174,
1.5mmol), under ice-water bath, nitrogen protection, NMM (N-methylmorpholine) (167 μ L, 1.5mmol), dry DMF 15mL are added,
(25 DEG C) reaction 12h of room temperature are warming up to after stirring 45min, stops reaction, adds appropriate DCM extractions, wash three times, saturation NaCl
Solution washes twice, and organic phase is evaporated under reduced pressure to faint yellow solid 5.8g, and it is 4.0g that column chromatography, which obtains compound PLA5000-Z1, production
Rate 71%.
In 100mL single-necked flasks, above-claimed cpd PLA5000-Z1 (115.32mg, 0.02mmol) is added, is added
20mL dichloromethane I2Solution (wherein I2For 6.0mM) dissolve, reaction solution is cooled to 0 DEG C after stirring at normal temperature 1h, adds Na2S2O3
The aqueous solution (3.0mM) is until I2Color disappear.Organic layer is washed with saturation NaCl solution, anhydrous Na2SO4Dry, be evaporated under reduced pressure
Faint yellow solid 81mg is obtained, lamellae chromatography obtains product 55mg, yield 54% after separation.1H-NMR(CDCl3, 400MHz) and δ
=8.18 (s, 4H, ArH), 7.83 (s, 2H, ArH), 6.37 (brs, 2H ,-NH-), 5.24-5.17 (m, 144H, PLA-CH-),
4.36(m,PLA-CH-),3.32-3.27(m,8H,-NCH2-),2.55-2.52(m,8H,-SCH2-),1.63-1.49(m,
441H,PLA-CH3-)；IR (KBr) 2993,2943,1755,1682,1532,1492,1451,1381,1301,1269,1188,
1130,1091,1050,955,894,865,638.
Embodiment 3,PLA-PEG amphipathic multi-block copolymers are characterized using gel chromatography technology (GPC)
Using the molecular weight of the block copolymer of gel chromatography (GPC) measure Examples 1 and 2 synthesis, and combine with reference to text
Offer Chunyan Liu, Shanshan Lin, Chixing Zhou, Wei Yu, Influence of catalyst on
transesterification between poly(lactic acid)and polycarbonate under flow
Method in field, Polymer 54 (2013) 310-319, calculate each block in the segmented copolymer synthesized in embodiment 1
Percentage composition；Instrument：Agilent1260 type gel permeation chromatographs, Malvern270 Dual Detector type static lights dissipate
Penetrate detector, gel chromatographic columnses：7.5*300mm, 10um chromatographic column, solvent are tetrahydrofuran, flow velocity 1.0mL/min, post
Temperature is 35 DEG C, sample size 20uL.In embodiment 1 the GPC graph of molecular weight distribution of each polymer as shown in figs. 9-11, each polymer
Test data as shown in Table 1 and Table 2：
Table 1：The molecular weight of each polymer, molecular weight distribution：
Table 2：The refractive index increment of segmented copolymer：
With reference to Chunyan Liu, Shanshan Lin, Chixing Zhou, Wei Yu, Influence of
catalyst on transesterification between poly(lactic acid)and polycarbonate
Method in (2013) 310-319 of under flow field, Polymer 54：
Wherein, RI (Refractive Index)：Show difference；LS(Light Scattering)：Light scattering；Kx：Represent inspection
The instrumental constant of device is surveyed, as KLS represents the instrumental constant of light scattering；dn/dc：Refractive index increment.(dn/dc values and macromolecule
Monomer is related to the property of solvent, and molecular weight, branched, structure is unrelated.) therefore, PLA block and the PEG for measuring modified are embedding
The dn/dc values of section, by parsing quadratic equation with one unknown group, you can obtain the content of each component in the copolymer.
C% (PLA)+C% (PEG)=1
Solution, PLA and PEG percentage composition are each about 50%, so as to the segmented copolymer [PEG- that must be synthesized
PLA]tMiddle t is 2, and the segmented copolymer is four blocks.
Embodiment 4The preparation of PLA-PEG amphipathic multi-block copolymer micelles and sign
With [PEG4000-PLA3000]tFor embodiment：
First, the preparation of blank micella
The accurate block copolymer weighed synthesized by 10m g, is dissolved in 2mL DMF (or DMSO or THF), block is total to
Polymers DMF solution is slowly dropped into the PBS cushioning liquid (or pure water or physiological saline) of 10mL stirrings (10min/mL),
It is transferred in bag filter, is dialysed 48 hours with PBS, 4h changes water once, gives DMF, produces self assembly after stirring 30min
Micella.
2nd, minimum aggregate concentration CMC measure
Determined with 1,6- diphenyl -1,3,5- hexatrienes (DPH) for ultraviolet molecular probe (a length of 313nm of maximum absorption wave)
CMC value, 10 10mL EP pipes are taken, 20 μ L 1mM DPH acetone solns, after acetone volatilization is dry, every are added in each tube
Various concentrations (concentration range is separately added into pipe：0.5mg/mL, 0.25mg/mL, 0.1mg/mL, 0.05mg/mL, 0.025mg/
ML, 5 × 10-3Mg/mL, 1 × 10-3Mg/mL, 0.25 × 10-3Mg/mL, 0.05 × 10-3Mg/mL, 0 × 10-3Mg/mL micella)
Solution 4mL, 4h is stirred at room temperature and determines absorbance respectively, using micellar concentration as abscissa, absorbance is that ordinate does curve map,
Minimum aggregate concentration CMC is determined by the incremental hop point of absorbance.Graph of a relation such as Figure 14 institute of the micellar concentration to absorbance A
Show, micella [PEG4000-PLA3000]tCMC value be 0.072mg/mL.
3rd, the measure of micella particle diameter distribution
1mL micellas are taken, insert laser particle analyzer measurement particle diameter, measurement temperature：25 DEG C of equilibration time 3min, LASER Light Source：
He-Ne laser, wavelength 633nm.The grain size distribution of blank micella is as shown in figure 15, micella [PEG4000-PLA3000]t's
Particle size determination value is 132nm, PDI 0.23.
4th, the stability test of micella
The blank micella that 2mL is prepared is taken in 5mL centrifuge tube, the change of compartment timing micella particle diameter, until
Significant change occurs for particle diameter, illustrates that micella changes.Micella [PEG4000-PLA3000]tChange of size in a week
Test result is as shown in figure 16, it can be seen that this micella can exist with long-time stable from figure.
The specific embodiment of the present invention is described above.It is to be appreciated that the invention is not limited in above-mentioned
Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow
Ring the substantive content of the present invention.
Claims (10)
1. a kind of PLA-PEG amphipathic multi-block copolymers based on molecular glue, it is characterised in that shown in structural formula such as formula (I)：
Wherein, n is the arbitrary integer between 2~200, and m is the arbitrary integer between 2~150, and t is 1 or 2.
2. the PLA-PEG amphipathic multi-block copolymers based on molecular glue as claimed in claim 1, it is characterised in that the n
For the arbitrary integer between 40~100, m is the arbitrary integer between 30~80.
A kind of 3. preparation side of the PLA-PEG amphipathic multi-block copolymers based on molecular glue as claimed in claim 1 or 2
Method, it is characterised in that comprise the following steps：
Hydrophilic polymer S3-PEG-S3 is prepared respectivelyGather with hydrophobic
Compound Z1-PLA-Z1
The hydrophilic polymer S3-PEG-S3 and hydrophobic polymer Z1-PLA-Z1 is subjected to oxidation reaction, obtains the PLA-
PEG amphipathic multi-block copolymers
The preparation method of the S3-PEG-S3 comprises the following steps：
By polyethylene glycol and 3,5- dinitrobenzoyl chlorides carry out substitution reaction, obtain polymer S1-PEG-S1
The polymer S1-PEG-S1 is subjected to hydrogenation reduction, obtains polymer S2-PEG-S2
By the polymer S2-PEG-S2 and compound S3Reacted, obtain the hydrophilic polymer
S3-PEG-S3；
The hydrophobic polymer Z1-PLA-Z1Preparation include
Following steps：
By polymer P LAEsterification is carried out with succinic anhydride, the modification PLA with end carboxyl is obtained and polymerize
Thing
By the modified PLA polymerWith compound
Z1Generation amidation process, obtain the hydrophobic polymer Z1-PLA-
Z1。
4. the preparation method of the PLA-PEG amphipathic multi-block copolymers based on molecular glue as claimed in claim 3, its feature
It is, the oxidant that oxidation reaction occurs for the hydrophilic polymer S3-PEG-S3, hydrophobic polymer Z1-PLA-Z1 is elemental iodine,
And the mol ratio of the hydrophilic polymer S3-PEG-S3, hydrophobic polymer Z1-PLA-Z1 and elemental iodine is 1:1:12.
5. the preparation method of the PLA-PEG amphipathic multi-block copolymers based on molecular glue as claimed in claim 3, its feature
It is,
In the substitution reaction that polyethylene glycol and 3, the 5- dinitrobenzoyl chloride is carried out, solvent is dichloromethane, and catalyst is
Triethylamine, and the mol ratio of polyethylene glycol, 3,5- dinitrobenzoyl chlorides, triethylamine is 1：2：4；
In the hydrogenation reduction that the polymer S1-PEG-S1 is carried out, solvent is methanol, and catalyst is 10% palladium carbon, and
The mol ratio of polymer S1-PEG-S1 and palladium carbon is 1：5；
The polymer S1-PEG-S1 withIn the reaction of progress, solvent is dry N, N- bis-
NMF, catalyst are 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester and N- methyl
Morpholine, and the S2-PEG-S2, S3, N-methylmorpholine, 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea six
The mol ratio of fluorophosphoric acid ester is 1.0：4.0：(4.0~4.5)：(6.0~8.0).
6. the preparation method of the PLA-PEG amphipathic multi-block copolymers based on molecular glue as claimed in claim 3, its feature
It is：
The polymer P LAIn the esterification carried out with succinic anhydride, solvent is dichloromethane, catalysis
Agent is DMAP, and the mol ratio of the polymer P LA, DMAP, succinic anhydride is 1：2：3；
In the amidation process that the modified PLA polymer and compound Z1 are carried out, solvent is dry N, N- dimethyl formyls
Amine, catalyst are 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester and N-methylmorpholine, and institute
Modified PLA, Z1, N-methylmorpholine, 2- (7- azos BTA)-N, N, N ' are stated, N '-tetramethylurea hexafluorophosphoric acid ester rubs
You are than being 1.0：2.0：(2.0~3.0)：(4.0~6.0).
7. one group of control copolymer for being used to characterize PLA-PEG amphipathic multi-blocks copolymer described in claim 1, its feature exist
In, including copolymer p EG-PEGWith copolymer p LA-
PLA
8. one group as claimed in claim 7 pair for being used to characterize PLA-PEG amphipathic multi-blocks copolymer described in claim 1
According to copolymer, it is characterised in that the preparation method of the copolymer p EG-PEG comprises the following steps：
By poly glycol monomethyl ether and 3,5- dinitrobenzoyl chlorides carry out substitution reaction, obtain polymer S1-PEG-CH3
By the polymer S1-PEG-CH3Reduction reaction is carried out in hydrogen, obtains polymer S2-PEG-CH3
By the polymer S2-PEG-CH3 and compound S3Amidation process is carried out, obtains hydrophilic polymeric
Thing S3-PEG-CH3
By the hydrophilic polymer S3-PEG-CH3Aoxidized, obtain PEG-PEG
The copolymer p LA-PLAPreparation method include
Following steps：
By polymer P LAWith compound Z1Generation acid amides
Change reaction, obtain hydrophobic polymer PLA-Z1
The hydrophobic polymer PLA-Z1 is subjected to oxidation reaction, obtains di-block copolymer PLA-PLA
9. a kind of amphipathic multi-block copolymer micelle, it is characterised in that the micella is the method by comprising the following steps
It is prepared：
Amphipathic multi-block copolymer as claimed in claim 1 is dissolved in polar solvent and forms solution A；
The solution A is slowly added dropwise in the aqueous phase of stirring and forms it into micro emulsion ball, the aqueous phase of the formation micro emulsion ball is molten
Liquid loads bag filter and appears polar solvent, produces the amphipathic multi-block copolymer micelle.
10. amphipathic multi-block copolymer micelle as claimed in claim 9, it is characterised in that the polar solvent be DMSO,
DMF or THF；The aqueous phase is pure water, PBS or physiological saline.
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