CN104592525B - Amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush and its preparation method and application - Google Patents
Amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush and its preparation method and application Download PDFInfo
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- CN104592525B CN104592525B CN201510026348.2A CN201510026348A CN104592525B CN 104592525 B CN104592525 B CN 104592525B CN 201510026348 A CN201510026348 A CN 201510026348A CN 104592525 B CN104592525 B CN 104592525B
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Abstract
The invention discloses a kind of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush, it is by the connected polymer brush of hydrophobic segment, hydrophilic segment.Wherein, the hydrophobic segment is poly- (L benzyl glutamates) block, and the hydrophilic segment is the poly- polypeptide block for being grafted alcoxyl ethers dendrimer.Shown in its structure such as formula (1).The invention also discloses the preparation method of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush; with glutamic acid, phenmethylol, gallicin, triethylene-glycol, triethylene glycol monomethyl ether and triethylene glycol monoethyl ether etc. for raw material; pass through esterification; oxinane is protected; the series reaction such as deprotection and alpha amino acid N carboxyl inner-acid anhydride ring-opening polymerisations, prepares amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush.The poly- polypeptide block copolymer molecule brush of the present invention has good biocompatibility, degradability and excellent Thermo-sensitive, is had broad application prospects in technical field of biological material.
Description
Technical field
The invention belongs to polyphosphazene polymer peptide symthesis technology field, especially amphipathic temperature sensitive type poly polypeptide block copolymer molecule
Brush and its preparation method and application.
Background technology
Amphipathic peptide (Amphiphilic Polypeptide) has the parents characteristic of similar natural phospholipid molecule, rich
Rich multilevel hierarchy, unique novel package assembly and special biodegradability and good biocompatibility, can be wide
It is general to be applied to pharmaceutical carrier, tissue engineering bracket, the biomedical aspect such as genophore.Amphipathic peptide has hydrophilic and hydrophobic poor
Different group, can be aligned in the two ends of main chain or be arranged in the both sides of main chain, or the mixing of hydrophilic and hydrophobic group
Arrangement.By design, the poly- peptide of synthesis different structure, its molecular structure is controlled, so that the purpose for changing its different performance is reached,
And then excavate its application more extensively and profoundly.For example：Drug loading and release are carried out using the assembly of amphiphilic poly- peptide, from
And solve at present due to difficult, the low problem of utilization rate being administered caused by the slightly solubility of hydrophobic drug；Utilize poly- peptide
To prepare poly- peptide hydrogel, by its abundant water-holding capacity, porous and be dissolved in open arms the medium characteristic of cellular matrix come
Construct soft tissue.
Polymer molecule brush refers to short chain linear polymer or dendrimer is highly dense by chemical bond as side base
It is grafted on main polymer chain, so as to form a kind of highdensity graft polymers degree.When its side chain density reaches certain journey
When spending, due to steric reasons so that side chain is vertical with main chain to be flexed outward, to avoid side chain overlapping, so that whole
The structure of the more regular similar and Brush Shapes of individual molecule formation structure.Due to its unique architectural characteristic and for structure
With the controllability of assembling morphology so that polymer molecule brush has in terms of drug delivery, catalysis and preparation nanometer linear material
Have wide practical use.
Alcoxyl ethers dendrimer be a class by structural motif of triethylene glycol monomethyl ether, gallic acid be branched list
An a series of generation and the branch chemoattractant molecule in two generations that member is constructed.Its unique structure imparts its unique performance, for example：Well
Dissolubility, such dendrimer shows good dissolubility in organic phase and aqueous phase；Excellent biocompatibility, body
Outer cytotoxicity test result shows that they do not show toxicity to cell；In addition, such dendrimer is due to its ether oxygen
Key causes it to show Thermo-sensitive.
Present invention firstly provides hydrophilic alcoxyl ethers dendrimer is incorporated on poly- peptide to prepare peptide molecule brush, with reference to
The advantage of the unique secondary structure of poly- peptide and molecular brush system prepares the embedding copolymer molecule brush of amphipathic temperature sensitive type poly peptide,
There is important researching value in fields such as the assembling of supermolecule, nano catalytic material and Biofunctional materials and it is good should
Use prospect.
The content of the invention
One of the object of the invention is a kind of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush of offer, and it is by hydrophobic
The connected polymer brush of segment, hydrophilic segment.Wherein, the hydrophobic segment is poly- (Pidolidone benzyl ester) block, described
Hydrophilic segment is the poly- polypeptide block for being grafted with alcoxyl ethers dendrimer.
The amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush of the present invention, its structure is such as with following formula (1) Suo Shi：
Wherein, m=50~300, n=50~300；
R structure is as follows：
Wherein, X is methyl (Me) or ethyl (Et).
In the present invention, the temperature sensitive temperature range of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush 35~40 DEG C it
Between.Preferably, its temperature sensitive temperature is close to normal body temperature.
The amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush of the present invention,
When R structure is following,
The temperature sensitive temperature range of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush is 35~37 DEG C；
When R structure is following,
The temperature sensitive temperature range of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush is 37~40 DEG C.
The two of the object of the invention are the preparation method for providing this kind of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush,
Present invention firstly provides this method using Pidolidone as raw material, combine a-amino acid-N- carboxyls inner-acid anhydride (NCA) ring-opening polymerisation
Synthesize a kind of poly- polypeptide block copolymer of AB types with click chemistry method (click chemistry) --- i.e., gathered by two kinds of differences
Polymer obtained from peptide segment links together, and using the poly- polypeptide block its as the main chain of molecular brush, selection is wherein one embedding
There is the large scale alcoxyl ethers dendrimer of hydrophilic interaction as side chain in section grafting, constitute poly- polypeptide block copolymerization of the invention
Thing molecular brush, and then impart the temperature sensitivity of poly- polypeptide block copolymer molecule brush.
To achieve the above objectives, present invention design synthesis thinking mainly includes at following 4 points：(1) chlorine atom is introduced into poly- peptide
Thus main chain is made L-glutamic acid-γ-chloroethene alcohol ester PCELG homopolymers as the avtive spot of grafting；(2) in order to increase
Chain rigidity and introduce phenyl ring, L-glutamic acid-γ-benzyl ester PBLG homopolymers are thus made；(3) by both of which polymers passing point
Hit chemistry and obtain poly- polypeptide block copolymer p BLG-b-PCELG, be used as molecular brush main chain；(4) alcoxyl in click chemistry, grafting is used
Ethers dendrimer generation G1 and two generation G2.The present invention with glutamic acid, phenmethylol, gallicin, triethylene-glycol,
Triethylene glycol monomethyl ether and triethylene glycol monoethyl ether etc. are raw material, and by esterification, oxinane (THP) protection takes off
The series reaction such as protection and NCA (a-amino acid-N- carboxyls inner-acid anhydride) ring-opening polymerisation, prepares amphipathic temperature sensitive type poly
Polypeptide block copolymer molecule brush.The preparation method of the present invention, its specific synthetic route is as follows：
In the preparation method of the amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush of the present invention, combine a-amino acid-N- carboxylics
The ring-opening polymerisation of base inner-acid anhydride and click chemistry (Click Chemistry), block is prepared by initiation material of Pidolidone
Copolymer, and further prepare poly- polypeptide block copolymer molecule brush.
In preparation method of the present invention, Pidolidone-γ-chloroethene alcohol ester is prepared using Pidolidone and chlorethanol as raw material, is passed through
A-amino acid-N- carboxyl inner-acid anhydride ring-opening polymerisations, synthesis L-glutamic acid-γ-chloroethene alcohol ester；Using Pidolidone and phenmethylol as
Raw material prepares Pidolidone-γ-benzyl ester, through a-amino acid-N- carboxyl inner-acid anhydride ring-opening polymerisations, synthesis L-glutamic acid-γ-benzyl
Ester.Pidolidone-the γ-chloroethene alcohol ester and L-glutamic acid-γ-benzyl ester are prepared into poly- polypeptide block by click chemistry reaction
Copolymer, poly- [Pidolidone-γ-benzyl ester-b-L- glutamic acid-γ-chloroethene alcohol ester]；, will be described through Azide and click-reaction
The poly- polypeptide block copolymer in dendrimer generation G1 or two generation G2 grafting, synthesizes the amphipathic temperature sensitive type poly polypeptide block
Copolymer molecule brush.
The preparation method of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush of the present invention, comprises the following steps：
The first step：Synthesized using Pidolidone and chlorethanol as initial feed and obtain Pidolidone-γ-chloroethene alcohol ester, with third
Ynamine is initiator, by NCA (a-amino acid-N- carboxyls inner-acid anhydride) ring-opening polymerisation, prepares the poly- L- as shown in formula (2)
Glutamic acid-γ-chloroethene alcohol ester (PCELG)；
Wherein, m=50~300.
Second step：Synthesized using Pidolidone and phenmethylol as initial feed and obtain Pidolidone-γ-benzyl ester (BLG), with 3-
Nitrine propylamine is initiator, by a-amino acid-N- carboxyl inner-acid anhydride ring-opening polymerisations, prepares the poly- L- as shown in formula (3)
Glutamic acid-γ-benzyl ester (PBLG)；
Wherein, n=50~300.
3rd step：With triethylene-glycol, gallicin, propine bromine, triethylene glycol monomethyl ether or two contractings three
Ethylene glycol monoethyl ether is raw material, by reactions such as protection, deprotections, prepares dendrimer generation G1 and two generation G2, it is changed
Learn shown in structure such as formula (4)；
Wherein, X is methyl or ethyl.
4th step：By L-glutamic acid-γ obtained above-chloroethene alcohol ester (PCELG) and L-glutamic acid-γ-benzyl ester
(PBLG) reacted by click chemistry, prepare shown in formula (5) it is poly- [Pidolidone-γ-benzyl ester-b-L- glutamic acid-γ-
Chloroethene alcohol ester] (PBLG-b-PCELG)；
Wherein, m=50~300, n=50~300；
Poly- polypeptide block copolymer p BLG-b-PCELG in the present invention, is formed by alkynyl-azido by click chemistry method
Five-membered ring is connected and formed.
5th step：By poly- [Pidolidone-γ-benzyl ester-b-L- glutamic acid-γ-chloroethene alcohol ester] (PBLG- obtained above
B-PCELG) by azido reaction, dendrimer G1 or G2 are grafted on block copolymer by joint click chemistry reaction,
Prepare the described embedding copolymer molecule brush of amphipathic temperature sensitive type poly peptide.In the step, an alcoxyl ethers dendrimer generation
G1 and two generation G2, upper poly- polypeptide block copolymer p BLG-b-PCELG main chain is grafted by click chemistry method.
In one embodiment, the preparation side of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush of the invention
Method, including concretely comprise the following steps：
(1) under protective atmosphere, by Pidolidone and chlorethanol using mol ratio as 1：1.0~2.5 feed intake, and are well mixed
Afterwards, add with 60% concentrated sulfuric acid of Pidolidone equimolar amounts as catalyst, reaction 2 days be stirred at room temperature, then with NaOH and
NaHCO3Regulation reaction solution pH is used in combination to neutrality, white crystal precipitation is obtained, and with 80 DEG C of water：Methanol volume ratio=1:
3~5 mixed liquor is recrystallized, suction filtration, and white needle-like crystals, i.e. Pidolidone-γ-chloroethene alcohol ester are obtained after drying
(CELG) monomer.Course of reaction is as follows：
(2) by CELG monomer dispersions in dry tetrahydrofuran (THF), boiling is heated under nitrogen protection, is added
The triphosgene of 1/3 mole of CELG monomers is reacted, and obtains water white transparency reaction solution, and rotary evaporation removes THF, and by oil
Shape liquid is transferred in dry ethyl acetate, by distilled water, dilute NaHCO3After solution and saturated common salt water washing, with nothing
Aqueous sodium persulfate is dried, and rotary evaporation falls ethyl acetate after filtering, with petroleum ether precipitation, and freezes 3min under liquid nitrogen, inclines
Supernatant is removed, Cl-L-Glu NCA are obtained.Intermediate Cl-L-Glu NCA are dissolved in dry DMF,
And trigger the ring-opening polymerisation of ring inner-acid anhydride with propine ammonia, reactive polymeric is stirred at room temperature two days, rotary evaporation removes N, N- dimethyl
Formamide, by ether deposition and purification, obtains the PCELG homopolymers that White Flocculus, i.e. end carry alkynyl after drying.Reaction
Process is as follows：
(3) by benzylalcohol and Pidolidone using mol ratio as 1:1.0-2.5 feeds intake, after being well mixed, and adds and Pidolidone
60% concentrated sulfuric acid of equimolar amounts reacts 2h, then with NaOH and NaHCO as catalyst3Regulation reaction solution pH is used in combination
To neutral, white crystal precipitation is obtained, and is recrystallized with hot water, suction filtration, white needle-like crystals, i.e. L- paddy are obtained after drying
Propylhomoserin-γ benzyl esters (BLG) monomer.Course of reaction is as follows：
(4) by BLG monomer dispersions in dry ethyl acetate, boiling is heated in a nitrogen atmosphere, adds BLG monomers
The triphosgene of 1/3 mole reacted, obtain faint yellow close to colourless reaction solution, by distilled water, dilute NaHCO3Solution
And after saturated common salt water washing, be dried with anhydrous sodium sulfate, revolving removes ethyl acetate after filtering, heavy with petroleum ether
Form sediment, separate out a large amount of white solids, rapid filtration under suction is dried in vacuo 2~3h, obtains White Flocculus i.e. Bz-L-Glu NCA.By in
Mesosome Bz-L-Glu NCA are dissolved in dry DMF, and trigger the open loop of ring inner-acid anhydride to gather with nitrine ammonia
Close, reactive polymeric is stirred at room temperature two days, revolving removes DMF, by ether deposition and purification, obtained after drying
White Flocculus, i.e. end carry the PBLG homopolymers of azido.Course of reaction is as follows：
(5) according to azido：Amount=1 of alkynyl material:1.05 weigh the PBLG homopolymers and end that end is azido
It is dissolved in for the PCELG homopolymers of alkynyl in DMF, and adds micro copper powder, is stirred under nitrogen protection
30min, the CuBr/ pentamethyldiethylenetriamines (PMDETA) added with alkynyl equimolar amounts carry out click chemistry reaction, lucifuge
Two days later, revolving removes solvent to stirring reaction, adds a small amount of dichloromethane dissolving, precipitation purification three times in ether, after drying
Obtain the partially flaxen floccule of white, i.e., poly- polypeptide block copolymer p BLG-b-PCELG.Course of reaction is as follows：
(6) poly- polypeptide block copolymer p BLG-b-PCELG is dissolved in DMF, treats that it is completely dissolved,
Weak yellow liquid is obtained, the sodium azide for weighing 2-10 times of chlorine atom mole adds reaction bulb, seals bottleneck, is kept for 45 DEG C and kept away
Light stirring reaction two days, revolving removes solvent, dissolved with dichloromethane, the deposition and purification in ether, and Azide is obtained after drying
Poly- polypeptide block copolymer.Course of reaction is as follows：
(7) triethylene glycol monomethyl ether is dissolved in THF, paratoluensulfonyl chloride (TsCl) is added under conditions of 0 DEG C, is stirred
Reaction 1 hour is mixed, by washing, saturated common salt washing, and after anhydrous sodium sulfate drying, colourless transparent liquid, i.e., one is obtained
Hold the triethylene glycol monomethyl ether of p-toluenesulfonyl activation.The triethylene glycol monomethyl ether that one end is activated is dissolved in N,
In dinethylformamide (DMF), gallicin is added, KI KI, potassium carbonate K is used2CO3As catalyst, end is obtained
Hold the methyl alkyloxy-ethers generation G1-COOMe for ester group.Use lithium aluminium hydride reduction H4AlLi reduces ester group, obtains the first that end is hydroxyl
Base alkyloxy-ethers generation G1-OH.Then substitution reaction is carried out with propine bromine, obtains the methyl alkyloxy-ethers generation G1 that end is alkynyl.
Its reaction equation and structural formula are as follows：
The methyl alkyloxy-ethers generation G1 that end is the ethyl alkyloxy-ethers generation G1 of alkynyl preparation method and end is alkynyl
It is similar.
(8) triethylene-glycol is subjected to one end proton activation under alkalescence and 0 DEG C of environment with paratoluensulfonyl chloride,
Through brine, after anhydrous sodium sulfate drying, the triethylene-glycol of colourless transparent oil liquid, i.e. one end activation is obtained；Will
The triethylene-glycol of one end activation is dissolved in DMF, is added gallicin, is used KI KI, carbonic acid
Potassium K2CO3As catalyst, 80 DEG C of reaction 24h, brine, drying, and chromatographic column purification excessively obtain pale yellow oily liquid
Body, i.e. end are the hydroxy alkoxy ethers generation HO-G1-COOMe of ester group；Again with hydroxyl of the paratoluensulfonyl chloride to end ester group
Alkyloxy-ethers generation progress tail end is hydroxy activated, obtains Ts-G1-COOH；Then the methyl alkyloxy-ethers generation with terminal hydroxyl is reacted
Obtain the generation of methyl alkyloxy-ethers two of terminal carboxyl group, i.e. Me-G2-COOH；In dry dichloromethane DCM, carried out with propilolic alcohol
Esterification obtains the methyl alkyloxy-ethers two generations molecule G2 of terminal acetylene, and its reaction equation and structural formula are as follows：
The methyl alkyloxy-ethers generation G2 that end is the ethyl alkyloxy-ethers generation G2 of alkynyl preparation method and end is alkynyl
It is similar.
(9) first (second) base for modifying the poly- polypeptide block copolymer p BLG-b-PCELG after Azide with terminal acetylene respectively
In alcoxyl ethers generation G1 or two generation G2 input DMFs, rate of charge is according to alkynyl：Azido=1.5:1,
Under nitrogen protection, the CuBr/PMDETA with azido equimolar amounts is added, then sealing reaction two days, revolving removes solvent, uses
Dichloromethane is dissolved, and grafting first (second) base alkyloxy-ethers generation G1 poly- polypeptide block copolymer point is respectively obtained after ether precipitation purification
The poly- polypeptide block copolymer molecule brush (yellow oily of son brush (faint yellow solid) or grafting first (second) base alkyloxy-ethers two generations Me-G2
Liquid), its structural formula is as follows：
The present invention using first synthesizing poly- polypeptide block copolymer, in conjunction with graft modification method poly- polypeptide block copolymer main chain
Upper grafting hydrophilic radical alcoxyl ethers dendrimer, poly- polypeptide block copolymer molecule brush is obtained so as to construct.Used is poly-
Polypeptide block copolymer can carry out the helical conformation of secondary structure, ensure the possibility that dendrimers are grafted in restricted clearance
Property.Using the of the invention molecular brush as template, containing inner chamber is brought using its grafting molecules, and molecular brush of the present invention is showed
Close to the Thermo-sensitive of normal body temperature, nanometer materials can be prepared, in medicine controlled releasing, catalytic carrier, information storage etc.
Aspect is respectively provided with the prospect of being widely applied.
The poly- polypeptide block copolymer molecule brush of the present invention has good biocompatibility, degradability and excellent temperature
Quick property, can be applied to the carrier of hydrophobic drug, temperature-sensitive switch etc., have in technical field of biological material before wide application
Scape.
Brief description of the drawings
Fig. 1 show grafting methyl alkyloxy-ethers generation dendroid small molecule G1 molecular brush PBLG-b-PCELG-g-G1's1H NMR scheme；
Fig. 2 show grafting methyl alkyloxy-ethers two generations dendroid small molecule G2 molecular brush PBLG-b-PCELG-g-G2's1H NMR scheme；
Fig. 3 show amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush PBLG-b-PCELG-g-G FT-IR spectrograms.
(in figure, a.PBLG58-N3b.PCELG60c.PBLG58-b-PCELG60d.PBLG58-b-PCELG60-N3e.PBLG58-b-
PCELG60-g-G1f.PBLG58-b-PCELG60-g-G2)；
Fig. 4 show amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush PBLG-b-PCELG-g-G GPC spectrograms.
(in figure, a.PBLG58-N3b.PCELG60c.PBLG58-b-PCELG60d.PBLG58-b-PCELG60-g-G1e.PBLG58-b-
PCELG60-g-G2)；
Fig. 5 show amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush PBLG-b-PCELG-g-G alternating temperature UV-Vis
Curve map.Wherein, Fig. 5 (a) shows that the temperature sensitive temperature range of molecular brush for being grafted G1 is 34~37 DEG C, and Fig. 5 (b) shows to be grafted G2's
The temperature sensitive temperature range of molecular brush is 36~39 DEG C.
Embodiment
With reference to specific examples below and accompanying drawing, the present invention is described in further detail.The process of the implementation present invention,
Condition, reagent, experimental method etc., are the universal knowledege and common knowledge of this area in addition to the following content specially referred to,
Content is not particularly limited in the present invention.
The preparation method of the amphipathic temperature sensitive type poly polypeptide block polymer molecule brush of the present invention, comprises the following steps：
1. the synthesis of monomer：
(a) under protective atmosphere, Pidolidone (10.0g 0.068mol) and chlorethanol (9.12mL 0.136mol) are mixed
Close uniform, obtain white paste material, under the conditions of ice-water bath, the concentrated sulfuric acid (3.60mL 0.066mol) is added dropwise into reaction bulb,
White paste dissolves gradually, and question response liquid becomes after clarification, removes ice-water bath, and reaction two days is stirred at room temperature.Configuration concentration
1mol·L-1NaOH and mass fraction be 5% NaHCO3Solution is some, and both are used in combination, and adjusts anti-under ice-water bath
The pH of liquid is answered to neutrality, until a large amount of White Flocculus are separated out, suction filtration goes out insoluble matter, with the water of heat：Methanol volume ratio=1:3 mix
Close solution to be recrystallized, go out precipitate after suction filtration after its cooling, vacuum drying obtains white needle-like crystals, i.e. L- paddy after 2 days
Propylhomoserin-γ-chloroethene alcohol ester (CELG).Yield is 60%.
(b) Pidolidone (10.00g 0.068mol) is well mixed with benzylalcohol (14.4mL 0.136mol), obtains white
Color pasty mass, under the conditions of ice-water bath, 60% concentrated sulfuric acid (3.60mL 0.066mol), white paste are added dropwise into reaction bulb
Thing is dissolved gradually, and reaction is transferred into back flow reaction 2h in 60 DEG C of oil bath pans, then transfers to and reaction is rotated in 60 DEG C of water-baths
1h, final reaction liquid is in colorless viscous shape liquid.Configuration concentration 1molL-1NaOH and mass fraction be 5% NaHCO3It is molten
Liquid is some, and both are used in combination, and the pH of reaction solution is adjusted under ice-water bath to neutrality, until a large amount of White Flocculus are separated out,
Suction filtration goes out insoluble matter, is recrystallized with hot water, and suction filtration goes out precipitate after cooling, and vacuum drying obtains white needles after 2 days
Crystal, i.e. Pidolidone-γ-benzyl ester (BLG), yield is 85%.
2. Macroscopic single crystal：
(a) it is dispersed in after monomer CELG (5.0g 0.024mol) grindings in dried THF, leads to nitrogen gas stirring 30min
Afterwards, back flow reaction in 50 DEG C of oil bath pans is transferred to, after after its stable micro-boiling, triphosgene (2.48g 0.0084mol), system is added
It is rapid to become clarification, continue the 2h that flows back, water white transparency slightly band yellow is presented in reaction solution, and revolving removes THF, adds dry acetic acid second
Ester, then uses distilled water, NaHCO at low ambient temperatures3Dried after buck and saturated common salt water washing, revolving removes most of
Solvent, petroleum ether precipitation, and be dried in vacuo, obtain Cl-L-Glu NCA.Under nitrogen protection with dry N, N- dimethyl methyls
Acid amides is solvent, using propine ammonia as initiator, after lucifuge reaction 48h, is precipitated in ether, suction filtration, white flock is obtained after drying
Polymer, i.e. end carry the PCELG of alkynyl60Homopolymer (60 be the degree of polymerization), yield is 93%.
(b) it is dispersed in after monomer BLG (5.0g 0.021mol) grindings in dried ethyl acetate, leads to nitrogen gas stirring
After 30min, back flow reaction in 80 DEG C of oil bath pans is transferred to, after after its stable micro-boiling, triphosgene (2.19g is added
0.0074mol), system becomes rapidly clarification, continues the 2h that flows back, and light yellow transparent is presented in reaction solution, then at low ambient temperatures
With distilled water, NaHCO3Dried after buck and saturated common salt water washing, rotate solvent, petroleum ether precipitation, vacuum drying is obtained
To Bz-L-GluNCA.Under nitrogen protection using dry DMF as solvent, using the ammonia of nitrine third as initiator,
After lucifuge reaction 48h, precipitated in ether, suction filtration, white flocculent polymer, i.e. end are obtained after drying and carries azido
PBLG58Homopolymer (58 be the degree of polymerization), yield is 95%.
(c) by the PBLG (1.29g 0.097mmol) of end azido and the PCELG (1.20g of terminal acetylene
In the DMF for 0.10mmol) being dissolved in 35mL dryings, weak yellow liquid is obtained, leads to nitrogen 20min, quick note
Enter CuBr (0.049g 0.34mmol)/PMDETA (0.072mL 0.34mmol) mixed liquor, then sealing progress click chemistry is anti-
Answer two days, revolving removes DMF solvent, is dissolved with dichloromethane, saturated common salt water washing, anhydrous sodium sulfate
Dry, precipitation purification in ether, white slightly band faint yellow solid, i.e., poly- polypeptide block copolymer p BLG are obtained after vacuum drying58-b-
PCELG60, yield 85%.
3. dendrimer is synthesized：
(a) dendrimer G1：Triethylene glycol monomethyl ether (45.0mL, 0.28mol) is dissolved in THF, in 0 DEG C of bar
Paratoluensulfonyl chloride (TsCl) (53.00g, 0.28mol), stirring reaction 1 hour, by washing, saturated aqueous common salt are added under part
Wash, and after anhydrous sodium sulfate drying, obtain the triethylene-glycol of colourless transparent liquid, the i.e. activation of one end p-toluenesulfonyl
Monomethyl ether (91.96g, 0.28mol).The triethylene glycol monomethyl ether (49.94g, 0.16mol) that one end is activated is dissolved in N,
In dinethylformamide (DMF), add gallicin (7.24g, 0.042mol), with KI KI (5.02,
0.031mol), potassium carbonate K2CO3(54.22g, 0.39mol) obtains the methyl alkyloxy-ethers generation that end is ester group as catalyst
G1-COOMe(22.00g,0.035mol).Use lithium aluminium hydride reduction H4AlLi (1.32g, 0.035mol) reduction end is the first of ester group
Base alkyloxy-ethers generation G1-COOMe (10.80g, 0.017mol), obtains the methyl alkyloxy-ethers generation G1-OH that end is hydroxyl
(9.30g,0.016).Then substitution reaction is carried out with propine bromine (1.83mL, 0.023mol), obtains the methyl that end is alkynyl
Alkyloxy-ethers generation G1 (8.89g, 0.014mol).
The methyl alkyloxy-ethers generation G1 that end is the ethyl alkyloxy-ethers generation G1 of alkynyl preparation method and end is alkynyl
It is essentially identical, wherein, triethylene glycol monomethyl ether is replaced with into triethylene glycol monoethyl ether.
(b) dendrimer G2：By triethylene-glycol (424.00mL, 2.53mol) under alkalescence and 0 DEG C of environment,
One end proton activation is carried out with paratoluensulfonyl chloride (60.01g, 0.32mol), through brine, after anhydrous sodium sulfate drying, is obtained
To the triethylene-glycol (90.35g.0.30mol) of colourless transparent oil liquid, i.e. one end activation；Two contractings that one end is activated
Triethylene glycol (65.00g, 0.21mol) is dissolved in DMF, addition gallicin (9.82g,
0.053mol), with KI KI (7.09g, 0.043mol), potassium carbonate K2CO3(73.65g, 0.53mol) is used as catalyst, 80
DEG C reaction 24h, brine, dry, and cross chromatographic column purification obtain the hydroxyl that pale yellow oily liquid, i.e. end are ester groups
Alcoxyl ethers generation HO-G1-COOMe (27.74g, 0.048mol)；Again with paratoluensulfonyl chloride (8.89g, 0.047mol) to end
Hold ester group a hydroxy alkoxy ether generation (4.50g, 0.0077mol) carry out tail end it is hydroxy activated, obtain Ts-G1-COOH (5.03g,
0.0048mol)；Then Ts-G1-COOH (3.53g, 0.0034mol) and terminal hydroxyl a methyl alkyloxy-ethers generation (6.59g,
0.0011mol) reaction obtains the generation of methyl alkyloxy-ethers two of terminal carboxyl group, i.e. Me-G2-COOH (2.01g, 0.87mmol)；Dry
In dry dichloromethane DCM, the methyl alkyloxy-ethers two generations molecule G2 that esterification obtains terminal acetylene is carried out with propilolic alcohol.
The methyl alkyloxy-ethers generation G2 that end is the ethyl alkyloxy-ethers generation G2 of alkynyl preparation method and end is alkynyl
It is essentially identical, wherein, a methyl alkyloxy-ethers generation for terminal hydroxyl is replaced with to an ethyl alkyloxy-ethers generation for terminal hydroxyl.
4. the synthesis of molecular brush：
(a) molecular brush of poly- polypeptide block copolymer grafted methyl alkyloxy-ethers generation G1 molecules：Poly- peptide after Azide is embedding
Section copolymer p BLG58-b-PCELG60(1.10g 0.044mmol) and terminal acetylene methyl alkyloxy-ethers generation G1 (0.59g
0.18mmol) it is dissolved in DMF, it is possible to additionally incorporate micro copper powder, leads to nitrogen 20min, and under nitrogen protection
CuBr (0.38g, 0.0026mol) and PMDETA (0.54nL, 0.0026mol) is added, bottleneck, 45 DEG C of oil bath reactions of lucifuge is sealed
Two days, saturated common salt water washing was precipitated in ether, and suction filtration, vacuum drying obtain faint yellow solid, i.e. target product grafting first
(second) base alkyloxy-ethers generation G1 poly- polypeptide block copolymer molecule brush, PBLG58-b-PCELG60- g-G1, yield 82%.
(b) molecular brush of poly- polypeptide block copolymer grafted methyl alkyloxy-ethers two generations G2 molecules：Poly- peptide after Azide is embedding
Section copolymer p BLG58-b-PCELG60(1.00g 0.040mmol) and terminal acetylene methyl alkyloxy-ethers generation G2 (8.24g,
0.0036mol) it is dissolved in DMF, it is possible to additionally incorporate micro copper powder, leads to nitrogen 20min, and in nitrogen protection
Lower addition CuBr (0.52,0.0036mol) and PMDETA (0.75mL, 0.0036mol), seal bottleneck, and 45 DEG C of oil baths of lucifuge are anti-
Answer two days, saturated common salt water washing, precipitated in ether, suction filtration, vacuum drying obtain yellow, viscous liquid, i.e. target product and connect
Branch first (second) base alkyloxy-ethers two generations Me-G2 poly- polypeptide block copolymer molecule brush, PBLG58-b-PCELG60- g-G2, yield
87%.
For the above-mentioned amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush prepared, its chemical constitution passes through core
Magnetic1The means such as H NMR, infrared FT-IR, GPC are characterized.Testing result is as shown in figures 1-4.Fig. 1：1H NMR(CDCl3, δ/ppm)：
δ=a (5.20, s, 2H, CH2)；B (3.30-3.50, s, 9H, CH3)；C (7.89, s, H, CH)；D (4.55, s, 2H, CH2).Figure
2：1H NMR(CDCl3, δ/ppm)：δ=a (3.30-3.50, s, 27H, CH3)；B (7.05-7.10, s, 2H, CH)；C (4.05, s,
2H, CH2)；D (7.55-7.65, s, H, CH)；E (4.31, s, 2H, CH2).Fig. 3：In FT-IR collection of illustrative plates, the absworption peak of azido exists
2100cm-1PBLG in place, a curves58Azido after end azido and d curve block copolymer Azides all it is obvious that
F curves 1134cm-1For the ether-oxygen bond absworption peak in dendroid small molecule.Fig. 4：Each curve GPC data of a-e：A, Mn=
21000, PDI=1.30；B, Mn=24500, PDI=1.35；C, Mn=35700, PDI=1.37；D, Mn=76800, PDI=
1.14；E, Mn=92300, PDI=1.11.
For the temperature sensitive performance of the above-mentioned amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush prepared, pass through alternating temperature
The means such as UV-Vis are characterized.Testing result is as shown in Figure 5.Wherein, Fig. 5 (a) shows to be grafted the G1 temperature sensitive temperature of molecular brush
Scope is 35~37 DEG C, and Fig. 5 (b) shows that the temperature sensitive temperature range of molecular brush for being grafted G2 is 37~40 DEG C.
The protection content of the present invention is not limited to above example.Under the spirit and scope without departing substantially from inventive concept, this
Art personnel it is conceivable that change and advantage be all included in the present invention, and using appended claims as protect
Protect scope.
Claims (8)
1. a kind of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush, it is characterised in that the amphipathic temperature sensitive type poly peptide is embedding
Section copolymer molecule brush is by the connected polymer brush of hydrophobic segment, hydrophilic segment；Wherein, the hydrophobic segment is poly-
(Pidolidone benzyl ester) block, the hydrophilic segment is the poly- polypeptide block for being grafted with alcoxyl ethers dendrimer.
2. amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush as claimed in claim 1, it is characterised in that its structure such as with
Shown in following formula (1)：
Wherein, m=50~300, n=50~300；
R structure is as follows：
Wherein, X is methyl or ethyl.
3. amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush as claimed in claim 1 or 2, it is characterised in that its is temperature sensitive
Temperature range is between 35~40 DEG C.
4. amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush as claimed in claim 2, it is characterised in that
When R structure is following,
The temperature sensitive temperature range of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush is 35~37 DEG C；
When R structure is following,
The temperature sensitive temperature range of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush is 37~40 DEG C.
5. the preparation method of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush as claimed in claim 1 or 2, its feature exists
In preparing Pidolidone-γ-chloroethene alcohol ester using Pidolidone and chlorethanol as raw material, opened through a-amino acid-N- carboxyl inner-acid anhydrides
Cyclopolymerization, synthesis L-glutamic acid-γ-chloroethene alcohol ester；Pidolidone-γ-benzyl is prepared using Pidolidone and phenmethylol as raw material
Ester, through a-amino acid-N- carboxyl inner-acid anhydride ring-opening polymerisations, synthesis L-glutamic acid-γ-benzyl ester；By the Pidolidone-γ-
Chloroethene alcohol ester and L-glutamic acid-γ-benzyl ester by click chemistry reaction prepare poly- polypeptide block copolymer it is poly- [Pidolidone-γ-
Benzyl ester-b-L- glutamic acid-γ-chloroethene alcohol ester]；Through Azide and click-reaction, by the dendrimer generation G1 or two generations
The poly- polypeptide block copolymer in G2 grafting, synthesizes the amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush.
6. the preparation method of amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush as claimed in claim 5, it is characterised in that bag
Include following steps：
The first step：Obtain Pidolidone-γ-chloroethene alcohol ester by Material synthesis of Pidolidone and chlorethanol, then using propargylamine as
Initiator, by a-amino acid-N- carboxyl inner-acid anhydride ring-opening polymerisations, prepare L-glutamic acid-γ as shown in formula (2)-
Chloroethene alcohol ester；
Wherein, m=50~300；
Second step：Obtain Pidolidone-γ-benzyl ester by Material synthesis of Pidolidone and phenmethylol, then using 3- nitrine propylamine as
Initiator, by a-amino acid-N- carboxyl inner-acid anhydride ring-opening polymerisations, prepare L-glutamic acid-γ as shown in formula (3)-
Benzyl ester；
Wherein, n=50~300；
3rd step：With triethylene-glycol, gallicin, propine bromine, triethylene glycol monomethyl ether or two three second two of contracting
Alcohol list ether is raw material, by protection, deprotection reaction, prepares dendrimer G1 and G2, its structure such as formula (4) institute
Show；
Wherein, X is methyl or ethyl；
4th step：L-glutamic acid-the γ-chloroethene alcohol ester and L-glutamic acid-γ-benzyl ester are reacted by click chemistry,
Prepare poly- [Pidolidone-γ-benzyl ester-b-L- glutamic acid-γ-chloroethene alcohol ester] shown in formula (5)；
Wherein, m=50~300, n=50~300；
5th step：Poly- [Pidolidone-γ-benzyl ester-b-L- glutamic acid-γ-chloroethene alcohol ester] is passed through into azido reaction, connection
Chalaza hits chemical reaction and the dendrimer G1 or G2 is grafted on block copolymer, prepares described amphipathic temperature sensitive
The poly- polypeptide block copolymer molecule brush of type.
7. amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush as claimed in claim 1 or 2 is preparing hydrophobic drug
Carrier in application.
8. amphipathic temperature sensitive type poly polypeptide block copolymer molecule brush as claimed in claim 1 or 2 answering in temperature-sensitive switch is prepared
With.
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| CN108440727B (en) * | 2018-04-11 | 2019-07-12 | 中国科学院化学研究所 | Geminized amphipathic polymer brush and the preparation method and application thereof |
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| CN110862490B (en) * | 2019-11-22 | 2020-10-27 | 西安交通大学 | Polymer molecular brush with hyperbranched side chain and preparation method thereof |
| CN113509550B (en) * | 2021-06-10 | 2023-04-14 | 广州市第一人民医院（广州消化疾病中心、广州医科大学附属市一人民医院、华南理工大学附属第二医院） | Molecular brush nano particle and preparation method and application thereof |
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