CN105968367B - A kind of amphipathic Polypeptide copolymer, self-assembly and preparation method and application - Google Patents
A kind of amphipathic Polypeptide copolymer, self-assembly and preparation method and application Download PDFInfo
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- CN105968367B CN105968367B CN201610303977.XA CN201610303977A CN105968367B CN 105968367 B CN105968367 B CN 105968367B CN 201610303977 A CN201610303977 A CN 201610303977A CN 105968367 B CN105968367 B CN 105968367B
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
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- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
Abstract
The invention discloses a kind of novel amphiphilic Polypeptide copolymer, the amphipathic Polypeptide copolymer is made of the poly- peptide of oil-soluble and water-soluble poly peptide, is a kind of amphiphilic species of good biocompatibility.The invention also discloses the preparation methods of the amphipathic Polypeptide copolymer, using two derived from amino acid objects after chemical modification as monomer, obtain the poly- peptide of the different both of which of dissolubility by N- carboxyl-α amino acid anhydrides ring-opening polymerisation method (NCA-ROP);It connects the poly- peptide of both of which to form the amphipathic Polypeptide copolymer by click chemistry process again.The invention also discloses the self-assemblies being prepared by the amphipathic Polypeptide copolymer.Preparation method of the invention is easy to operate, easy;The block copolymer of preparation has huge application prospect in fields such as drug release, function of organization's materials.
Description
Technical field
The invention belongs to biomaterial, self-assembled material technical field, be related to a kind of novel amphiphilic Polypeptide copolymer and
Preparation method and application.
Background technique
Copolymer (copolymer) refers to the macromolecule polyalcohol being made of two or more polymer unit, again
Referred to as copolymer.For di-block copolymer, solvability has a bigger difference in a solvent for two blocks, and referred to as two
Parent's property block copolymer or amphiphilic diblock copolymer.Wherein with hydrophilic segment (Hydrophilic Chain) and hydrophobic segment
" Hydrophile-Lipophile " type di-block copolymer of (Hydrophobic Chain) composition is most commonly seen, the polymerization with this structure
Object in aqueous solution, often will form using oleophylic segment as core, and using hydrophilic segment as the ordered structure of shell, this is a kind of good
Self-assembled material, the conveying and release of drug, diagnostic image, in terms of have a wide range of applications.
Poly- peptide is a kind of high molecular polymer for being obtained by carboxyl and amino dehydrating condensation by amino acid monomer.According to
Poly- peptide can be divided into poly- peptide homopolymer and poly- polypeptide block copolymer by the difference of constituent.The poly- peptide of homopolymer is by widely
Research and report, but the synthesis of the poly- peptide of block is just gradually reported until recent decades, it may be possible to and polymerization is limited to multiple
The building of the miscellaneous poly- peptide of structure.The poly- peptide of block is segmented into again: 1. blocks are the poly- peptide (block of block of poly- peptide structure
copolypepdite);2. containing the poly- polypeptide block polymer of hydridization (polypeptide hybrid) of poly- peptide segment in block.
From the structure of poly- peptide, since there is strong hydrogen bond actions on peptide chain, poly- peptide chain is enabled to form unique second level
Structure (alpha-helix or beta sheet) imparts many excellent performances of poly- peptide, in biomaterial, self-assembled material, tissue function
There is huge application prospect in the fields such as energy material.
However, limited by polymerization, polymer architecture etc., it is often embedding with hydridization in the synthesis of Polypeptide copolymer
The poly- peptide of section is in the majority, and the report of the poly- peptide of block is actually rare, and obtained product profile exponent is wide, and molecular weight is smaller, this limit
The development of the poly- peptide of block is made.
Summary of the invention
For the drawbacks described above for overcoming the prior art, the invention proposes a kind of amphipathic poly- peptide of block and preparation method thereof,
The advantages of of the invention method is simple, makes full use of click chemistry, the profile exponent of the obtained poly- peptide of amphipathic block compared with
It is narrow.The invention also provides the self-assembled material by the amphipathic Polypeptide copolymer preparation, the self-assembled material has
Sequence structure.
Present invention aims at: 1. provide a kind of new preparation method, are synthesized with it a kind of new structural amphipathic
Polypeptide copolymer, application of the quasi polymer in fields such as biomaterial, self-assembled material, function of organization's materials provide new one
Class amphipathic peptide copolymer material.2. using obtained amphipathic Polypeptide copolymer be prepared for having the poly- peptide of ordered structure from
Assembled material, application of such material in fields such as the conveyings and release of drug provide new a kind of self-assembled material.
Amphipathic Polypeptide copolymer proposed by the present invention, by the poly- polypeptide block of oil-soluble (end have alkynyl homopolymerization peptide:
PBLG) with water-soluble poly polypeptide block (end have azido homopolymerization peptide: PCysPEGMA) composition, that is, by a block be oil
The poly- peptide of dissolubility, another block is water-soluble poly- peptide composition, shown in chemical structure such as formula (I):
In formula (I), the degree of polymerization x of polyethylene glycol is 3-5;N=20-80;M=10-30.
Preferably, the degree of polymerization x of polyethylene glycol is 4;N=30;M=15
The poly- peptide of oil-soluble is poly- (Pidolidone benzyl ester), shown in structure such as formula (a),
Wherein, n=20-80, it is preferable that n=30.
The water-soluble poly polypeptide block is poly- cysteine methoxypolyethylene glycol methacrylate, structure such as formula (b) institute
Show,
Wherein, the degree of polymerization x of polyethylene glycol is 3-5;M=10-30;
Preferably, the degree of polymerization x of polyethylene glycol is 4;M=15.
Amphipathic Polypeptide copolymer of the invention passes through N- carboxylic using two derived from amino acid objects after chemical modification as monomer
Base-alpha-amido acid anhydrides ring-opening polymerisation method (NCA-ROP) has obtained the poly- peptide of the different both of which of dissolubility (homopolymer), i.e. formula (a)
Shown in water-soluble poly peptide shown in the poly- peptide of oil-soluble and formula (b);Passing through click chemistry process (click chemistry) again will
Two kinds of poly- peptides connect and form the poly- fret peptide of amphipathic block.The existing technology for preparing amino acid polypeptide mainly passes through substep
The method for adding monomer gradually ring-opening polymerisation.The prior art is compared, substantive distinguishing features of the invention and advantage are: 1. selectivity
Height has the amphipathic amino acid polypeptide application value with higher of specific aggregation degree for designing.In the synthesis of poly- peptide
In, the control of the product degree of polymerization is often more difficult.For homopolymer, usually controlled using the molar ratio of NCA monomer and initiator.
But for more block polyaminoacid polypeptides, the prior art needs first to synthesize the homopolymerization peptide that end has amino, then with this
As macromole evocating agent, cause another amino acid N CA monomer polymerization.In this process, poly- peptide macromole evocating agent
Amount is difficult to control, and therefore, it is difficult to control the degree of polymerization of another poly- peptide unit.Method provided by the invention can pass through control respectively
The molar ratio of small molecule initiator and NCA monomer, design obtain having the poly- peptide of the both of which of specific aggregation degree, then pass through clickization
The two is combined, to obtain the block polyaminoacid polypeptide of specific aggregation degree.2. the polydispersity index (PDI) of product is narrow.Phase
The block polypeptide PDI distribution of ring-opening polymerisation method gradually than substep addition monomer, the preparation of click chemistry method is narrower.Fig. 2 is to utilize this
The data of amphipathic block peptide-based gel permeation chromatography (GPC) test of inventive method preparation, PDI=1.30;Fig. 3 is to utilize to divide
Step addition monomer gradually ring-opening polymerisation method preparation amphipathic amino acid polypeptide GPC test data, PDI=1.65.
Both comparisons are it is found that the product prepared using this law, dispersion index are obviously narrowed.3. applicability is wide.By change propargylamine with
The ratio of BLG-NCA monomer, the ratio of 1- nitrine -3- aminopropane and CysPEGMA-NCA monomer can be prepared different poly-
Right homopolymerization peptide PBLG/PCysPEGMA, then reacted by click chemistry, obtain the amphipathic peptide of different polymerization degree composition
Copolymer.4. easy to operate.In the synthesis process of poly- peptide, NCA monomer is easily hydrolyzed, therefore the requirement to operation is special
Height, especially during substep adds monomer.The method of the present invention for synthesizing amphipathic Polypeptide copolymer provide it is a kind of it is easy,
Effective method.The profile exponent of the poly- peptide of amphipathic block is relatively narrow, good biocompatibility.Amphipathic peptide copolymerization of the present invention
Object self-assembled material, function of organization's material, in terms of there is broad application prospects.
The preparation method of amphipathic Polypeptide copolymer proposed by the present invention, including homopolymerization and modified two of click chemistry are instead
It answers:
(1) homopolymerization is reacted
I) the poly- peptide preparation process of the oil-soluble are as follows:
Wherein, n=20-80;Preferably, n=30.
Using Pidolidone benzyl ester-N carboxyl-α amino acid anhydrides as raw material, in organic solvent, using propargylamine as initiator, instead
Answer temperature control at 60~80 DEG C, the reaction time is 72-96 hours, obtains the poly- peptide of oil-soluble shown in formula (a).Preferably, institute
Stating reaction temperature is 75 DEG C;The reaction time is 72 hours.
Wherein, the raw material Pidolidone benzyl ester-N carboxyl-α amino acid anhydrides, propargylamine molar ratio be 20-80:1;It is excellent
Selection of land is 30:1.
The organic solvent is selected from tetrahydrofuran, dioxane, N,N-dimethylformamide or dimethylsulfoxide solvent;It is preferred that
Ground is n,N-Dimethylformamide.
Ii) the water-soluble poly peptide preparation process are as follows:
Wherein, the degree of polymerization x of polyethylene glycol is 3-5;M=10-30.
Preferably, the degree of polymerization x of polyethylene glycol is 4;M=15.
Using L-cysteine (methoxypolyethylene glycol methacrylate)-N carboxyl-α amino acid anhydrides as raw material, organic molten
In agent, using 1- nitrine -3- aminopropane as initiator, at 45~75 DEG C, the reaction time is 72-84 hours for reaction temperature control,
Obtain water-soluble poly peptide shown in formula (b).Preferably, the reaction temperature is 65 DEG C;The reaction time is 72 hours.
Wherein, raw material L-cysteine (methoxypolyethylene glycol the methacrylate)-N carboxyl-α amino acid anhydrides, 1-
The molar ratio of nitrine -3- aminopropane is 10-30:1;It preferably, is 15:1.
Wherein, the organic solvent is selected from tetrahydrofuran, dioxane, n,N-Dimethylformamide or dimethyl sulfoxide;It is excellent
Selection of land is tetrahydrofuran.
(2) click chemistry reacts
Wherein, the degree of polymerization x of polyethylene glycol is 3-5;M=10-30;N=20-80.
Preferably, the degree of polymerization x of polyethylene glycol is 4;N=30;M=15.
It is added the poly- peptide of oil-soluble and water-soluble poly peptide of step (1) preparation into organic solvent, the oxygen in removing system, then
Be added by the catalyst system of cuprous bromide, N, N, N ', N ', N "-pentamethyldiethylenetriamine composition, reaction temperature control 40~
110 DEG C, the reaction time is 20-70 hours, obtains the amphipathic Polypeptide copolymer.
Wherein, the group of the catalyst system becomes cuprous bromide: N, N, N ', N ', N "-pentamethyldiethylenetriamine mole
Than for 1:1~1.5;Preferably, the molar ratio of the two is 1:1.2.
Wherein, the poly- peptide of oil-soluble and water-soluble poly peptide of step (1) preparation, the molar ratio of catalyst system are 1:1~1.5:1
~1.5;It preferably, is 1:1.2:1.2.
Wherein, the organic solvent is selected from tetrahydrofuran, dioxane or n,N-Dimethylformamide;It preferably, is N, N
Dimethylformamide.
Reaction mechanism of the present invention: the present invention is specific with two kinds respectively using two different amino acid derivativges as raw material
Primary amine is initiator, is prepared for the homopolymerization peptide that end has alkynyl using N- carboxyl-α amino acid anhydrides ring-opening polymerisation method (NCA method)
PBLG and end have the homopolymerization peptide PCysPEGMA of azido.Secondly, " alkynyl-azido " click chemistry is utilized to react, selection
Property use cuprous bromide, N, N, N ', N ', N "-pentamethyldiethylenetriamine be catalyst system, prepare amphipathic Polypeptide copolymer
PBLG-b-PCysPEGMA。
The existing technology for preparing amino acid polypeptide, the main method that monomer gradually ring-opening polymerisation is added by substep.It is right
Than the prior art, substantive distinguishing features of the invention and advantage are: 1. selectivity are high, have the two of specific aggregation degree for designing
Parent's property polyaminoacid polypeptide application value with higher.In the synthesis of poly- peptide, the control of the product degree of polymerization is often more difficult.It is right
In homopolymer, usually controlled using the molar ratio of NCA monomer and initiator.But for more block polyaminoacid polypeptides and
Speech, the prior art needs first to synthesize the homopolymerization peptide that end has amino, then in this, as macromole evocating agent, causes another ammonia
Base acid NCA monomer polymerization.In this process, the amount of poly- peptide macromole evocating agent is difficult to control, and therefore, it is difficult to control another
The degree of polymerization of poly- peptide unit.Method provided by the invention can pass through mole of control small molecule initiator and NCA monomer respectively
Than design obtains having the poly- peptide of the both of which of specific aggregation degree, then is combined the two by click chemistry, to obtain specific aggregation
The block polyaminoacid polypeptide of degree.2. the polydispersity index (PDI) of product is narrow.Monomer gradually ring-opening polymerisation is added compared to distribution
The block polypeptide PDI distribution of method, the preparation of click chemistry method is narrower.Monomer gradually ring-opening polymerisation method, clickization are added compared to distribution
The block polypeptide PDI distribution of method preparation is narrower.As shown below: Fig. 2 is the amphipathic block using the method for the present invention preparation
The data of peptide-based gel permeation chromatography (GPC) test, PDI=1.30;Fig. 3 adds monomer gradually ring-opening polymerisation using substep
The GPC test data of the amphipathic amino acid polypeptide of method preparation, PDI=1.65.Both comparisons using this law it is found that prepared
Product, dispersion index obviously narrows.3. applicability is wide.By changing the ratio of propargylamine and BLG-NCA monomer, 1- nitrine-
The homopolymerization peptide PBLG/ of different polymerization degree can be prepared in the ratio of 3- aminopropane and CysPEGMA-NCA monomer
PCysPEGMA, then reacted by click chemistry, obtain the amphipathic peptide of different polymerization degree composition.4. easy to operate.In poly- peptide
Synthesis process in, NCA monomer easily hydrolyzes, thus to operation require it is especially high, especially substep add monomer mistake
Cheng Zhong.The method of the present invention provides a kind of easy, effective method for synthesizing amphipathic polyaminoacid polypeptide.
In a specific embodiment, the amphipathic block Polypeptide copolymer the preparation method comprises the following steps: with chemical modification
Two derived from amino acid objects afterwards are monomer, are dissolved by N- carboxyl-α amino acid anhydrides ring-opening polymerisation method (NCA-ROP)
The different poly- peptide of both of which of property;Two kinds of poly- peptide connections are formed two by click chemistry process (click chemistry) again
The poly- fret peptide of parent's property block.
Under nitrogen protection, by Pidolidone benzyl ester 3.01g, (12.6mmol), triphosgene 1.32g, (4.2mmol) and acetic acid
Ethyl ester 90ml is added to equipped in the dry 250ml there-necked flask of condensing reflux pipe, in 85 DEG C of oil bath return stirring react to
System clear, the reaction time about 5 hours or so.Stop after reacting and being cooled to room temperature, with ice water and ice sodium bicarbonate
Solution is washed till neutrality and is dried with anhydrous sodium sulfate.It is recrystallized with petroleum ether, is dried in vacuo, obtains white solid Pidolidone benzyl
Ester-N- carboxyl inner-acid anhydride (BLG-NCA) yield 48%.
The DMF that 1.60g (6.1mmol) BLG-NCA monomer and 16ml drying are added in dry 50ml bottle with two necks is molten
Agent, letting nitrogen in and deoxidizing 60mins.The propargylamine of 5 μ l is added, causes polymerization.It is protected from light 72hours.After reaction, methanol is heavy
It forms sediment, repetitive operation 3 times, it is poly- (Pidolidone benzyl ester) to obtain white solid, yield 80%.
6.0g (50mmol) L-cysteine is added in single port bottle of the 100ml with magneton and is dissolved in 60ml deionization
Water adjusts pH value of solution to 6~9 with the sodium hydroxide solution of 1mol/L.Methoxypolyethylene glycol methacrylic acid is added into system
Ester (Mn=300) 16.12g (53mmol), is stirred overnight at room temperature.After reaction, ethyl acetate extracts and retains water layer product.
Freeze-drying, obtains white cream solid L-cysteine methoxypolyethylene glycol methacrylate (CysPEGMA), yield
90%.
Under nitrogen protection, by CysPEGMA 7.41g (18.6mmol), triphosgene 1.81g, (6.2mmol) and 150ml are dry
Dry THF is added to equipped in the dry 250ml there-necked flask of condensing reflux pipe, and return stirring is reacted to body in 60 DEG C of oil bath
It is clear, the reaction time about 8 hours or so.Stop after reacting and being cooled to room temperature, with n-hexane precipitating and vacuum is done
It is dry, obtain yellowish-brown cream solid Pidolidone benzyl ester-N- carboxyl inner-acid anhydride (PCysPEGMA-NCA) 5.62g, yield 71%.
In twoport flask of the 100ml with magneton, 5.04g (11.9mmol) CysPEGMA-NCA is added and is dissolved in 50ml
Dry THF solvent, letting nitrogen in and deoxidizing 60mins.- 3 aminopropane of 1- nitrine of 22 μ l is added into system using microsyringe
Cause polymerization.It is protected from light logical nitrogen reaction 72hours.After reaction, concentrate is precipitated with n-hexane, obtains yellowish crude product.Vacuum
Crude product is dissolved in water after drying, is dialysed 3 days.Finally, " freeze-drying " is used to obtain yellow solid, poly- (L-cysteine is poly-
Ethylene glycol monomethyl ether methacrylate), yield 82%.
In 20ml dry test tube, the PBLG 0.20g (1equiv) prepared, PCysPEGMA are sequentially added
0.25g (1.4equiv), purified cuprous bromide 44mg (1equiv), and be dissolved in the dry DMF of 5ml.Letting nitrogen in and deoxidizing
Ligand N, N, N ' are added after 30mins, 6.4 μ l of N ', N "-pentamethyldiethylenetriamine (PMDETA) simultaneously seals test tube, is transferred to 50 DEG C
Oil bath pan, be protected from light 70hours.After reaction, quenching.Product methanol extraction simultaneously filters.After repetitive operation 3 times
It is dried in vacuo 100hours, obtains faint yellow solid particle, yield 70%.
The advantages of preparation method of the invention is simple and easy to do, makes full use of click chemistry;It is existing to prepare amino acid polypeptide
Technology, the main method that monomer gradually ring-opening polymerisation is added by substep.Compare the prior art, substantive distinguishing features of the invention
Be with advantage: 1. selectivity are high, have the amphipathic amino acid polypeptide of specific aggregation degree is with higher to answer for designing
With value.In the synthesis of poly- peptide, the control of the product degree of polymerization is often more difficult.For homopolymer, usually utilizes NCA monomer and draw
The molar ratio of agent is sent out to control.But for more block polyaminoacid polypeptides, the prior art, which needs first to synthesize end, to be had
The homopolymerization peptide of amino, then in this, as macromole evocating agent, cause another amino acid N CA monomer polymerization.In this process,
The amount of poly- peptide macromole evocating agent is difficult to control, and therefore, it is difficult to control the degree of polymerization of another poly- peptide unit.It is provided by the invention
Method, can be respectively by the molar ratio of control small molecule initiator and NCA monomer, and design obtains two kinds with specific aggregation degree
Homopolymerization peptide, then combined the two by click chemistry, to obtain the block polyaminoacid polypeptide of specific aggregation degree.2. product is more
Dispersion index (PDI) is narrow.Compared to distribution addition monomer, gradually ring-opening polymerisation method, the block polypeptide PDI of click chemistry method preparation divide
Cloth is narrower.Compared to distribution addition monomer, gradually ring-opening polymerisation method, the block polypeptide PDI distribution of click chemistry method preparation are narrower.Such as
Shown in the following figure: Fig. 2 is the data tested using the amphipathic block peptide-based gel permeation chromatography (GPC) of the method for the present invention preparation,
PDI=1.30;Fig. 3 be using substep addition monomer gradually ring-opening polymerisation method preparation amphipathic amino acid polypeptide
GPC test data, PDI=1.65.Both comparisons are it is found that the product prepared using this law, dispersion index are obviously narrowed.3. being applicable in
Property is wide.By changing the ratio of propargylamine and BLG-NCA monomer, 1- nitrine -3- aminopropane and CysPEGMA-NCA monomer
Ratio can be prepared the homopolymerization peptide PBLG/PCysPEGMA of different polymerization degree, then be reacted by click chemistry, obtain different poly-
The amphipathic peptide of right composition.4. easy to operate.In the synthesis process of poly- peptide, NCA monomer is easily hydrolyzed, therefore right
Operation requirement is especially high, especially during substep adds monomer.The method of the present invention is synthesizing amphipathic polyaminoacid polypeptide
Provide a kind of easy, effective method.
The invention also provides a kind of self-assembly, the self-assembly is the self-assembled material with ordered structure, by
Above-mentioned amphipathic Polypeptide copolymer is self-assembly of, and has Hydrophile-Lipophile structure;For bowl-shape micella, cylindrical micellar, shuttle-type piece
Layer micella.Compared with prior art, it is characterized in that: 1. self-assembled materials are usually by amphipathic small molecules (such as dodecyl
Sodium sulphate etc.) or amphiphilic block copolymer (such as PEO-b-PS) composition.Using amphipathic amino acid polypeptide as self assembly
It is actually rare to be capable of forming orderly self-assembled material for precursor.2. for self-assembly, especially micella has special parent
Water-oleophylic structure is a kind of good potential drug carrier material.However, non-poly- peptides self-assembled precursor material common at present
Material is there is poor biocompatibility, the disadvantages of toxicity is big, limits the development of this material.Poly- peptide, as composition living matter
The important component of protein, with excellent biocompatibility not available for other materials, using it as self assembly before
Body material is expected to solve the problems, such as it in application fields such as pharmaceutical carriers.
The invention also provides the preparation method for the self-assembly being prepared by the amphipathic block Polypeptide copolymer,
Include: to dissolve the amphipathic block Polypeptide copolymer in organic solvent, forms the weak solution of copolymer, instill thereto
The water of 1~2 times of volume of the weak solution of copolymer, drop rate are 1~5ml/min;Excessive ultrapure water is added to be quenched;By saturating
Analysis removes excessive organic solvent, obtains the self-assembly.The self-assembly is the self-assembled material with ordered structure:
When organic solvent is tetrahydrofuran, the self-assembly is bowl-shape micella, and certain of spherical micella collapses on one side and forms bowl
The micellar structure of type, by measurement, the average grain diameter of self-assembly is 55nm, bowl-type micella to collapse direction different;It is organic molten
When agent is n,N-Dimethylformamide, the self-assembly is cylindrical micellar, is connected with each other between tubulose micella, overlapping, and contain
There is hollow-out part, forms similar to space net structure;When organic solvent is Isosorbide-5-Nitrae-dioxane, the self-assembly is shuttle
Matrix layer micella, structure centre is wide, and both ends are narrow, and have burr shape more outstanding, through measuring, the average length of micella at both ends
Degree is 600nm, width average out to 200nm.Wherein, after described " excess " refers to that dilute polymer adds water self assembly, solution body
Long-pending 5~10 times.
Wherein, the condition of described " dialysis " is to select the molecular cut off of bag filter for 3500Da, and material is regenerated fiber
Plain ester.
Wherein, the mass ratio of the amphipathic block Polypeptide copolymer, organic solvent: 1000-3000:1;Preferably, it is
2000:1。
Wherein, the organic solvent is selected from tetrahydrofuran, n,N-Dimethylformamide or Isosorbide-5-Nitrae-dioxane solvent.
The drop rate of 1~5ml/min is very important technological means, if rate exceeds this range, it is difficult to obtain
Orderly self-assembled structures.As shown in fig. 6, the block polypeptide being dissolved in THF, is added dropwise ultrapure water with the rate of 8ml/min
The TEM of acquired self-assembly schemes, and structure is simultaneously irregular.Fig. 8 is dissolved in the block polypeptide in Dioxane, with 10ml/
The TEM figure of self-assembly obtained by ultrapure water is added dropwise in the rate of min, and structure is simultaneously irregular.
The invention also provides amphipathic Polypeptide copolymers shown in formula (I) to prepare self-assembled material, function of organization's material
Application in material, biomaterial.Wherein, the self-assembled material, function of organization's material, biomaterial for drug conveying and
Release.
The invention also provides amphipathic Polypeptide copolymer shown in formula (I) or the self-assemblies in the conveying of drug
With the application in release.
The invention also provides the self-assembly of preparation the conveying of drug and in terms of there is be widely applied
Prospect.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance figure of novel amphiphilic Polypeptide copolymer (PBLG-b-PCysPEGMA).
Fig. 2 is the gpc chromatogram of novel amphiphilic Polypeptide copolymer (PBLG-b-PCysPEGMA)
Fig. 3 be using substep addition monomer gradually ring-opening polymerisation method preparation amphipathic amino acid polypeptide GPC
Test data, PDI=1.65.
Fig. 4 is the saturating of the self-assembly that the novel amphiphilic Polypeptide copolymer being dissolved in N,N-dimethylformamide is formed
Penetrate electron microscope.
Fig. 5 is the transmission electron microscope for the self-assembly that the novel amphiphilic Polypeptide copolymer being dissolved in tetrahydrofuran is formed
Figure.
Fig. 6 is the transmission electron microscope for the self-assembly that the novel amphiphilic Polypeptide copolymer being dissolved in tetrahydrofuran is formed
Figure;The rate that ultrapure water is added dropwise is 8ml/min, is irregular structure.
Fig. 7 is the transmission electricity for the self-assembly that the novel amphiphilic Polypeptide copolymer being dissolved in 1,4- dioxane is formed
Mirror figure.
Fig. 8 is the transmission electricity for the self-assembly that the novel amphiphilic Polypeptide copolymer being dissolved in 1,4- dioxane is formed
Mirror figure.
The rate that ultrapure water is added dropwise is 10ml/min, is irregular structure.
Specific embodiment
In conjunction with following specific embodiments and attached drawing, the present invention is described in further detail.Implement process of the invention,
Condition, experimental method etc. are among the general principles and common general knowledge in the art, this hair in addition to what is specifically mentioned below
It is bright that there are no special restrictions to content.
The preparation of the amphipathic Polypeptide copolymer of embodiment 1
Pidolidone benzyl ester is transformed into monomer Pidolidone benzyl ester-N- carboxyl inner-acid anhydride by triphosgene, with alkynes third
Amine is initiator, n,N-Dimethylformamide (DMF) is solvent, by solution ring-opening polymerisation method, prepares poly- (Pidolidone benzyl
Ester), i.e. PBLG.It is reacted by " sulfydryl-ethylene " click chemistry by L-cysteine and methoxypolyethylene glycol methacrylate
Reaction obtains L-cysteine methoxypolyethylene glycol methacrylate (CysPEGMA), then is changed by triphosgene
It is to draw with 1- nitrine -3- aminopropane for monomer L-cysteine methoxypolyethylene glycol methacrylate-N- carboxyl inner-acid anhydride
Agent is sent out, tetrahydrofuran is solvent, by ring-opening polymerisation method, prepares poly- (L-cysteine methoxypolyethylene glycol methacrylic acid
Ester), i.e. PCysPEGMA.Homopolymer PBLG and PCysPEGMA are dissolved in DMF again, the oxygen in removing system, are added by bromination
After the catalyst system of cuprous, N, N, N ', N ', N "-pentamethyldiethylenetriamine (PMDETA) composition, reacted by " click chemistry "
Obtain novel amphiphilic Polypeptide copolymer.
Under nitrogen protection, by Pidolidone benzyl ester 3.01g, (12.6mmol), triphosgene 1.32g, (4.2mmol) and acetic acid
Ethyl ester 90ml is added to equipped in the dry 250ml there-necked flask of condensing reflux pipe, in 85 DEG C of oil bath return stirring react to
System clear, the reaction time about 5 hours or so.Stop after reacting and being cooled to room temperature, with ice water and ice sodium bicarbonate
Solution is washed till neutrality and is dried with anhydrous sodium sulfate.It is recrystallized with petroleum ether, is dried in vacuo, obtains white solid Pidolidone benzyl
Ester-N- carboxyl inner-acid anhydride (BLG-NCA) yield 48%.
The DMF that 1.60g (6.1mmol) BLG-NCA monomer and 16ml drying are added in dry 50ml bottle with two necks is molten
Agent, letting nitrogen in and deoxidizing 60mins.The propargylamine of 5 μ l is added, causes polymerization.It is protected from light 72hours.After reaction, methanol is heavy
It forms sediment, repetitive operation 3 times, it is poly- (Pidolidone benzyl ester) to obtain white solid, yield 80%.
6.0g (50mmol) L-cysteine is added in single port bottle of the 100ml with magneton and is dissolved in 60ml deionization
Water adjusts pH value of solution to 6~9 with the sodium hydroxide solution of 1mol/L.Methoxypolyethylene glycol methacrylic acid is added into system
Ester (Mn=300) 16.12g (53mmol), is stirred overnight at room temperature.After reaction, ethyl acetate extracts and retains water layer product.
Freeze-drying, obtains white cream solid L-cysteine methoxypolyethylene glycol methacrylate (CysPEGMA), yield
90%.
Under nitrogen protection, by CysPEGMA 7.41g (18.6mmol), triphosgene 1.81g, (6.2mmol) and 150ml are dry
Dry THF is added to equipped in the dry 250ml there-necked flask of condensing reflux pipe, and return stirring is reacted to body in 60 DEG C of oil bath
It is clear, the reaction time about 8 hours or so.Stop after reacting and being cooled to room temperature, with n-hexane precipitating and vacuum is done
It is dry, obtain yellowish-brown cream solid Pidolidone benzyl ester-N- carboxyl inner-acid anhydride (PCysPEGMA-NCA) 5.62g, yield 71%.
In twoport flask of the 100ml with magneton, 5.04g (11.9mmol) CysPEGMA-NCA is added and is dissolved in 50ml
Dry THF solvent, letting nitrogen in and deoxidizing 60mins.- 3 aminopropane of 1- nitrine of 22 μ l is added into system using microsyringe
Cause polymerization.It is protected from light logical nitrogen reaction 72hours.After reaction, concentrate is precipitated with n-hexane, obtains yellowish crude product.Vacuum
Crude product is dissolved in water after drying, is dialysed 3 days.Finally, " freeze-drying " is used to obtain yellow solid, poly- (L-cysteine is poly-
Ethylene glycol monomethyl ether methacrylate), yield 82%.
In 20ml dry test tube, the PBLG 0.20g (1equiv) prepared, PCysPEGMA are sequentially added
0.25g (1.4equiv), purified cuprous bromide 44mg (1equiv), and be dissolved in the dry DMF of 5ml.Letting nitrogen in and deoxidizing
Ligand N, N, N ' are added after 30mins, 6.4 μ l of N ', N "-pentamethyldiethylenetriamine (PMDETA) simultaneously seals test tube, is transferred to 50 DEG C
Oil bath pan, be protected from light 70hours.After reaction, quenching.Product methanol extraction simultaneously filters.After repetitive operation 3 times
It is dried in vacuo 100hours, obtains faint yellow solid particle, yield 70%.
As shown in Figure 1, Fig. 1 is poly- (the L-cysteine polyethylene glycol of amphipathic Polypeptide copolymer-poly-L-glutamic acid acid benzyl ester-
Methyl ether methacrylate), i.e. the nuclear magnetic resonance spectroscopy of PBLG-b-PCysPEGMA, characteristic peak (7.25,5.06,3.75,
3.50,1.25,0.15ppm) and its corresponding integral area ratio demonstrates the successful synthesis of PBLG-b-PCysPEGMA copolymer.
As shown in Fig. 2, Fig. 2 is poly- (the L-cysteine polyethylene glycol of amphipathic Polypeptide copolymer-poly-L-glutamic acid acid benzyl ester-
Methyl ether methacrylate), i.e. the gpc chromatogram of PBLG-b-PCysPEGMA, by map it can be seen that polymer have it is relatively narrow
Profile exponent (PDI=1.30).
Fig. 3 be using substep addition monomer gradually ring-opening polymerisation method preparation amphipathic amino acid polypeptide GPC
Test data, PDI=1.65.Both comparisons are it is found that the product prepared using the method for the present invention, dispersion index are obviously narrowed.Institute
It states " method of distribution addition monomer gradually ring-opening polymerisation " to refer to: with L-cysteine (methoxypolyethylene glycol methacrylic acid
Ester)-N carboxyl-α amino acid anhydrides (i.e. CysPEGMA-NCA) is that monomer using n-butylamine as initiator passes through NCA ring-opening polymerisation method
Contain the homopolymerization peptide PCysPEGMA-NH of amino in obtained end2.Then, in this, as macromole evocating agent, cause Pidolidone
Benzyl ester-N- carboxyl inner-acid anhydride (i.e. BLG-NCA) monomer polymerization, obtains the poly- peptide PBLG-b-PCysPEGMA of two blocks.It is as follows:
Specific step is as follows:
It uses n-butylamine as small molecule initiator first, causes CysPEGMA-NCA ring-opening polymerisation and obtain homopolymer
PCysPEGMA.1.31g (3.09mmol) CysPEGMA-NCA is dissolved in the dry THF solvent of 13ml, letting nitrogen in and deoxidizing
30mins.Using microsyringe, the n-butylamine that 6 μ l (0.0618mmol) are added into system causes polymerization.Logical nitrogen is protected from light item
12hours is reacted under part.Secondly, using PCysPEGMA-NH2As macromole evocating agent, cause polymerization BLG-NCA monomer.?
When CysPEGMA-NCA ring-opening polymerization is to 12hours, weighs BLG-NCA monomer 1.22g (4.6mmol), be dissolved in 12ml
In dry THF, after letting nitrogen in and deoxidizing, take 3ml liquid that this is added from the reaction system of CysPEGMA-NCA ring-opening polymerisation rapidly
System causes BLG-NCA polymerization.Room temperature is protected from light 72hours.After reaction, methanol extraction, it is light yellow cotton-shaped heavy to obtain
It forms sediment, suction filtration obtains crude product.After crude product is dissolved with THF, methanol extraction.Repetitive operation twice, further purified product.Very
Sky is dry, obtains yellow solid particle, yield 56%.
The preparation of the amphipathic Polypeptide copolymer self-assembled material of embodiment 2
Amphipathic peptide copolymer p BLG-b-PCysPEGMA prepared by embodiment 1 is molten with the concentration difference of 0.5mg/ml
Solution is in DMF, THF, 1,4-Dioxane.A certain amount of water is added drop-wise to the dilute of configured polymer with the rate of 1ml/min
In solution.After being added dropwise to complete, a large amount of ultrapure water of fast drop is quenched.Dialysis collected product after 3 days.
Fig. 4 is by the self-assembled material for the polymer preparation being dissolved in DMF, and structure is the tubulose micella of rule, pipe
It is connected with each other, is overlapped between shape micella, and there are hollow-out parts to separate elder generation, form similar to space net structure.Fig. 5 is dissolved in
The self-assembled material of polymer preparation in tetrahydrofuran (THF), structure are the bowl-shape micellas of rule, for spherical micella
Certain collapses on one side and forms the micellar structure of bowl-type, and by measurement, the average grain diameter of self-assembly is 55nm, bowl-type micella
It is different to collapse direction.
Other conditions are identical, and amphipathic peptide copolymer p BLG-b-PCysPEGMA is dissolved in tetrahydrofuran, work as dropwise addition
When the rate of ultrapure water is 8ml/min, Fig. 6 is the transmission electron microscope picture for the self-assembly that amphipathic Polypeptide copolymer is formed, by scheming
It is found that it is irregular structure comprising the self assembly for not yet forming ordered arrangement of part bowl structure and obscure portions
Body.
Fig. 7 is dissolved in the self-assembled material of the preparation of the polymer in Isosorbide-5-Nitrae-Dioxane, and structure is the shuttle-type piece of rule
Shape micella, structure centre is wide, and both ends are narrow, and have burr shape more outstanding at both ends;Through measuring, the average length of micella is
600nm, width average out to 200nm.
Other conditions are identical, and amphipathic peptide copolymer p BLG-b-PCysPEGMA is dissolved in Isosorbide-5-Nitrae-dioxane, when
When the rate that ultrapure water is added dropwise is 10ml/min, Fig. 8 is the transmission electron microscope picture for the self-assembly that amphipathic Polypeptide copolymer is formed,
As seen from the figure, be irregular structure, including 4 it is interconnected, contrast is higher, similar to spherical structure, but due to
Its structural fuzzy can not yet form complete micella;Meanwhile having lamellar structure similar to aciculiform around it, but it is simultaneously
Imperfect, independent, distribution is also inhomogenous, also fails to form orderly self-assembly.
Protection content of the invention is not limited to above embodiments.Without departing from the spirit and scope of the invention, originally
Field technical staff it is conceivable that variation and advantage be all included in the present invention, and with appended claims be protect
Protect range.
Claims (11)
1. a kind of amphipathic Polypeptide copolymer, which is characterized in that the amphipathic Polypeptide copolymer includes the poly- polypeptide block of oil-soluble
With water-soluble poly polypeptide block, shown in structure such as formula (I):
In formula (I), the degree of polymerization x of polyethylene glycol is 3-5;M=10-30;N=20-80.
2. amphipathic Polypeptide copolymer according to claim 1, which is characterized in that the amphipathic Polypeptide copolymer is to change
Learning modified two derived from amino acid object is monomer, obtains dissolubility not by N carboxy α amino acid anhydride ring-opening polymerisation method
The same poly- peptide of both of which;It connects the poly- peptide of both of which to form the amphipathic Polypeptide copolymer by click chemistry process again.
3. a kind of preparation method of amphipathic Polypeptide copolymer, which is characterized in that modified anti-comprising homopolymerization reaction, click chemistry
It answers:
(1) homopolymerization is reacted:
I) preparation of the poly- peptide of oil-soluble:
Using Pidolidone benzyl ester-N carboxyl-α amino acid anhydrides as raw material, in organic solvent, using propargylamine as initiator, reaction temperature
At 60~80 DEG C, the reaction time is 72-96 hours for degree control, the poly- peptide of oil-soluble shown in formula (a) is obtained, such as reaction equation (1) institute
Show;
Reaction equation (1)
Wherein, n=20-80;
Ii) the preparation of water-soluble poly peptide:
Using L-cysteine (methoxypolyethylene glycol methacrylate)-N carboxyl-α amino acid anhydrides as raw material, in organic solvent
In, using 1- nitrine -3- aminopropane as initiator, at 45~75 DEG C, the reaction time is 72-84 hours for reaction temperature control, is obtained
To water-soluble poly peptide shown in formula (b), as shown in reaction equation (2);
Reaction equation (2)
Wherein, the degree of polymerization x of polyethylene glycol is 3-5;M=10-30;
(2) click chemistry modified-reaction:
The poly- peptide of oil-soluble and water-soluble poly peptide of step (1) preparation are added into organic solvent, the oxygen in removing system adds
By cuprous bromide, N, N, N ', N ', N "-pentamethyldiethylenetriamine composition catalyst system, reaction temperature is controlled 40~110
DEG C, the reaction time is 20-70 hours, the amphipathic Polypeptide copolymer is obtained, as shown in reaction equation (3);
Reaction equation (3)
Wherein, the degree of polymerization x of polyethylene glycol is 3-5;M=10-30;N=20-80.
4. preparation method according to claim 3, which is characterized in that in the preparation of the poly- peptide of step (1) oil-soluble, institute
State raw material Pidolidone benzyl ester-N carboxyl-α amino acid anhydrides, the molar ratio of propargylamine is 20~80:1.
5. preparation method according to claim 3, which is characterized in that in the preparation of step (1) the water-soluble poly peptide, institute
State raw material L-cysteine (methoxypolyethylene glycol methacrylate)-N carboxyl-α amino acid anhydrides, 1- nitrine -3- aminopropane
Molar ratio be 10-30:1.
6. preparation method according to claim 3, which is characterized in that in the step (2), the poly- peptide of the oil-soluble and water
The poly- peptide of dissolubility, catalyst system molar ratio be 1:1~1.5:1~1.5.
7. a kind of self-assembly, which is characterized in that the self-assembly is by amphipathic Polypeptide copolymer as described in claim 1
It is self-assembly of, there is Hydrophile-Lipophile structure;For bowl-shape micella, cylindrical micellar, shuttle-type lamella micellar structure.
8. a kind of preparation method of self-assembly, which is characterized in that amphipathic Polypeptide copolymer as described in claim 1 is molten
Solution in organic solvent, forms the weak solution of copolymer, instills the water of 1~2 times of volume of the weak solution of copolymer, drop thereto
Rate of acceleration is 1~5ml/min;Excessive ultrapure water is added to be quenched;Excessive organic solvent is removed by dialysing, right such as is obtained and wants
Self-assembly described in asking 7.
9. preparation method according to claim 8, which is characterized in that the self-assembly, with ordered structure from group
Package material, when organic solvent is n,N-Dimethylformamide, obtained self-assembly is cylindrical micellar;When organic solvent is four
When hydrogen furans, obtained self-assembly is bowl-shape micella;When organic solvent is Isosorbide-5-Nitrae-dioxane, obtained self-assembly is
Shuttle-type lamella micella.
10. amphipathic Polypeptide copolymer shown in formula (I) according to claim 1 or claim 2 is preparing self-assembled material, tissue function
Application in energy material, biomaterial.
11. amphipathic Polypeptide copolymer shown in formula (I) according to claim 1 or claim 2 or it is according to claim 7 from
Application of the assembly in the conveying and release of drug.
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