CN105968367A - Amphiphilic polypeptide copolymer and self-assembled body as well as preparation method and application thereof - Google Patents
Amphiphilic polypeptide copolymer and self-assembled body as well as preparation method and application thereof Download PDFInfo
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- CN105968367A CN105968367A CN201610303977.XA CN201610303977A CN105968367A CN 105968367 A CN105968367 A CN 105968367A CN 201610303977 A CN201610303977 A CN 201610303977A CN 105968367 A CN105968367 A CN 105968367A
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- DZRBPTUSRRPYIT-FLNCGGNMSA-N CCC(C)C/C(/C)=N/C(C(CSCC(C)C=[U])C(C)C)=O Chemical compound CCC(C)C/C(/C)=N/C(C(CSCC(C)C=[U])C(C)C)=O DZRBPTUSRRPYIT-FLNCGGNMSA-N 0.000 description 1
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Abstract
The invention discloses a novel amphiphilic polypeptide copolymer. The amphiphilic polypeptide copolymer comprises an oil-soluble polypeptide and a water-soluble polypeptide, and is an amphiphilic substance with good biocompatibility. The invention also discloses a preparation method of the amphiphilic polypeptide copolymer, two kinds of amino acid derivatives after chemical modification are used as monomers, an N-carboxyl-alpha-amino acid anhydride ring-opening polymerization method (NCA-ROP) is used in order to obtain two kinds of homopolypeptides with different dissolvabilities; and the amphiphilic polypeptide copolymer is formed by connecting the two kinds of homopolypeptides by means of a click chemistry process. The invention also discloses a self-assembled body which is prepared by the amphiphilic polypeptide copolymer. The preparation method is simple and easy to operate; the segmented copolymer has enormous application prospects in the fields of drug release, tissue functional materials, and the like.
Description
Technical field
The invention belongs to biomaterial, self-assembled material technical field, relate to a kind of novel amphiphilic Polypeptide copolymer and
Its preparation method and application.
Background technology
Copolymer (copolymer) refers to the macromolecule polyalcohol being made up of two or more polymer unit, again
It is referred to as copolymer.For di-block copolymer, two block solvabilities in a solvent have bigger difference, 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 that (Hydrophobic Chain) forms is most commonly seen, has the polymerization of this structure
Thing in aqueous, is often formed with oleophylic segment as core, the ordered structure with hydrophilic segment as shell, and this is a kind of good
Self-assembled material, conveying and the aspect such as release, diagnostic image, nano-reactor at medicine have a wide range of applications.
Poly-peptide is by amino acid monomer, the family macromolecule polymer obtained by carboxyl and amino dehydrating condensation.According to
The difference of constituent, can be divided into poly-peptide homopolymer and poly-polypeptide block copolymer by poly-peptide.The poly-peptide of homopolymer is by widely
Research and report, but the synthesis of the poly-peptide of block is until recent decades is the most gradually in the news, it may be possible to and polymerization limits multiple
The structure of the poly-peptide of miscellaneous structure.The poly-peptide of block is segmented into again: 1. block is the block poly-peptide (block of poly-peptide structure
copolypepdite)；2. block contains the hydridization poly-polypeptide block polymer (polypeptide hybrid) of poly-peptide segment.
From the structure of poly-peptide, owing to there is strong hydrogen bond action on peptide chain so that poly-peptide chain can form two grades of uniqueness
Structure (alpha-helix or beta sheet), imparts the performance that poly-peptide many is excellent, in biomaterial, self-assembled material, tissue merit
There is huge application prospect in the fields such as energy material.
But, limited by polymerization, polymer architecture etc., in the synthesis of Polypeptide copolymer, often embedding with hydridization
The poly-peptide of section is in the majority, and the report of the poly-peptide of block is actually rare, and the products distribution index width obtained, molecular weight, this limit
Make the development of the poly-peptide of block.
Summary of the invention
For overcoming the drawbacks described above of prior art, the present invention proposes a kind of poly-peptide of amphipathic block and preparation method thereof,
Method is simple for the present invention, the advantage making full use of click chemistry, and the profile exponent of the poly-peptide of amphipathic block obtained is relatively
Narrow.The invention allows for the self-assembled material prepared by described amphipathic Polypeptide copolymer, described self-assembled material has and has
Sequence structure.
Present invention aim at: 1. a kind of new preparation method is provided, synthesizes the amphipathic of a class new structure with it
Polypeptide copolymer, the application in fields such as biomaterial, self-assembled material, function of organization's materials of this base polymer provides new one
Class amphipathic peptide copolymer material.2. utilize the amphipathic Polypeptide copolymer obtained to be prepared for having the poly-peptide of ordered structure certainly
Assembled material, the application in fields such as the conveying of medicine and releases of such material provides a new class self-assembled material.
The present invention propose amphipathic Polypeptide copolymer, by the poly-polypeptide block of oil-soluble (end is with the homopolymerization peptide of alkynyl:
PBLG) form with water-soluble poly polypeptide block (end is with the homopolymerization peptide of azido: PCysPEGMA), i.e. be oil by block
The poly-peptide of dissolubility, another block is water miscible poly-peptide composition, shown in its chemical constitution such as formula (I):
In formula (I), degree of polymerization x of Polyethylene Glycol is 3-5；N=20-80；M=10-30.
Preferably, degree of polymerization x of Polyethylene Glycol is 4；N=30；M=15
The poly-peptide of described oil-soluble is poly-(Pidolidone benzyl ester), shown in structure such as formula (a),
Wherein, n=20-80, it is preferable that n=30.
Described water-soluble poly polypeptide block is poly-cysteine methoxypolyethylene glycol methacrylate, structure such as formula (b) institute
Show,
Wherein, degree of polymerization x of Polyethylene Glycol is 3-5；M=10-30；
Preferably, degree of polymerization x of Polyethylene Glycol is 4；M=15.
The amphipathic Polypeptide copolymer of the present invention is with two derived from amino acid things after chemical modification as monomer, by N-carboxylic
Base-alpha-amido anhydride ring-opening polymerisation method (NCA-ROP) has obtained the poly-peptide of the different both of which of dissolubility (homopolymer), i.e. formula (a)
Water-soluble poly peptide shown in the poly-peptide of shown 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 preparing amino acid polypeptide, main by substep
The method adding monomer progressively ring-opening polymerisation.Contrasting prior art, substantive distinguishing features and the advantage of the present invention are: 1. selectivity
Height, amphipathic amino acid polypeptide design to specific aggregation degree has higher using value.Synthesis at poly-peptide
In, the control of the product degree of polymerization is the most difficult.For homopolymer, the mol ratio of NCA monomer and initiator is generally utilized to control.
But, for many blocks polyamino acid polypeptide, prior art needs the homopolymerization peptide first synthesizing end with amino, then with this
As macromole evocating agent, another amino acid N CA monomer is caused to be polymerized.In this process, poly-peptide macromole evocating agent
Amount is difficult to control to, therefore, it is difficult to control the degree of polymerization of another poly-peptide unit.The method that the present invention provides, can be respectively by controlling
Little initiator molecule and the mol ratio of NCA monomer, design the poly-peptide of both of which obtaining having specific aggregation degree, then by click
Learn and both are combined, to obtain the block polyamino acid polypeptide of specific aggregation degree.2. the polydispersity index (PDI) of product is narrow.Phase
Adding monomer progressively ring-opening polymerisation method than substep, block polypeptide PDI distribution prepared by click chemistry method is narrower.Fig. 2 is to utilize this
The data that amphipathic block peptide-based gel permeation chromatography (GPC) prepared by inventive method is tested, PDI=1.30；Fig. 3 is to utilize to divide
The GPC of amphipathic amino acid polypeptide prepared by the method for step interpolation monomer progressively ring-opening polymerisation tests data, PDI=1.65.
Both contrasts understand, and utilize product prepared by this law, and dispersion index substantially narrows.3. the suitability is wide.By change propargylamine with
The ratio of BLG-NCA monomer, 1-nitrine-3-aminopropane and the ratio of CysPEGMA-NCA monomer, can prepare different poly-
Right homopolymerization peptide PBLG/PCysPEGMA, then reacted by click chemistry, obtain the amphipathic peptide of different polymerization degree composition
Copolymer.The most simple to operate.In the building-up process of poly-peptide, NCA monomer easily hydrolyzes, and therefore the requirement to operation is special
Height, especially during substep adds monomer.The inventive method be synthesizing amphipathic Polypeptide copolymer provide a kind of easy,
Effective method.The profile exponent of the described poly-peptide of amphipathic block is narrower, good biocompatibility.Amphipathic peptide copolymerization of the present invention
Thing also exists, at aspects such as self-assembled material, function of organization's material, biomaterials, the prospect of being widely applied.
The preparation method of the amphipathic Polypeptide copolymer that the present invention proposes, anti-with click chemistry modification two including being all polymerized
Should:
(1) equal polyreaction
I) described oil-soluble poly-peptide preparation process is:
Wherein, n=20-80；Preferably, n=30.
With Pidolidone benzyl ester-N carboxyl-alpha amino acid acid anhydride as raw material, in organic solvent, with propargylamine as initiator, instead
Answering temperature to control at 60～80 DEG C, the response time is 72-96 hour, obtains the poly-peptide of the oil-soluble shown in formula (a).Preferably, institute
Stating reaction temperature is 75 DEG C；The described response time is 72 hours.
Wherein, described raw material Pidolidone benzyl ester-N carboxyl-alpha amino acid acid anhydride, the mol ratio of propargylamine are 20-80:1；Excellent
Selection of land, for 30:1.
Described organic solvent is selected from oxolane, dioxane, N,N-dimethylformamide or dimethylsulfoxide solvent；Preferably
Ground, for DMF.
Ii) described water-soluble poly peptide preparation process is:
Wherein, degree of polymerization x of Polyethylene Glycol is 3-5；M=10-30.
Preferably, degree of polymerization x of Polyethylene Glycol is 4；M=15.
With Cys (methoxypolyethylene glycol methacrylate)-N carboxyl-alpha amino acid acid anhydride as raw material, organic molten
In agent, with 1-nitrine-3-aminopropane as initiator, reaction temperature controls at 45～75 DEG C, and the response time is 72-84 hour,
Obtain the water-soluble poly peptide shown in formula (b).Preferably, described reaction temperature is 65 DEG C；The described response time is 72 hours.
Wherein, described raw material Cys (methoxypolyethylene glycol methacrylate)-N carboxyl-alpha amino acid acid anhydride, 1-
The mol ratio of nitrine-3-aminopropane is 10-30:1；Preferably, for 15:1.
Wherein, described organic solvent is selected from oxolane, dioxane, DMF or dimethyl sulfoxide；Excellent
Selection of land, for oxolane.
(2) click chemistry reaction
Wherein, degree of polymerization x of Polyethylene Glycol is 3-5；M=10-30；N=20-80.
Preferably, degree of polymerization x of Polyethylene Glycol is 4；N=30；M=15.
Step (1) the poly-peptide of oil-soluble prepared and water-soluble poly peptide is added in organic solvent, the oxygen in removing system, then
Add by cuprous bromide, N, N, N ', N ', N " catalyst system and catalyzing of-pentamethyldiethylenetriamine composition, reaction temperature control 40～
110 DEG C, the response time is 20-70 hour, obtains described amphipathic Polypeptide copolymer.
Wherein, described catalyst system and catalyzing consist of cuprous bromide: N, N, N ', N ', N "-pentamethyldiethylenetriamine mole
Ratio is 1:1～1.5；Preferably, both mol ratios are 1:1.2.
Wherein, the poly-peptide of oil-soluble and the mol ratio of water-soluble poly peptide, catalyst system and catalyzing that prepared by step (1) are 1:1～1.5:1
～1.5；Preferably, for 1:1.2:1.2.
Wherein, described organic solvent is selected from oxolane, dioxane or DMF；Preferably, for N, N
Dimethylformamide.
Reaction mechanism of the present invention: the present invention is respectively with two kinds of different amino acid derivativges as raw material, specific with two kinds
Primary amine is initiator, utilizes N-carboxyl-alpha amino acid acid anhydride ring-opening polymerisation method (NCA method) to be prepared for the end homopolymerization peptide with alkynyl
PBLG and end are with the homopolymerization peptide PCysPEGMA of azido.Secondly, utilize the reaction of " alkynyl-azido " click chemistry, select
The use cuprous bromide of property, N, "-pentamethyldiethylenetriamine is catalyst system and catalyzing, prepares amphipathic Polypeptide copolymer for N, N ', N ', N
PBLG-b-PCysPEGMA。
The existing technology preparing amino acid polypeptide, the main method adding monomer progressively ring-opening polymerisation by substep.Right
Ratio prior art, substantive distinguishing features and the advantage of the present invention be: 1. selectivity is high, has the two of specific aggregation degree for design
Parent's property polyamino acid polypeptide has higher using value.In the synthesis of poly-peptide, the control of the product degree of polymerization is the most difficult.Right
In homopolymer, the mol ratio of NCA monomer and initiator is generally utilized to control.But, for many blocks polyamino acid polypeptide
Speech, prior art needs the homopolymerization peptide first synthesizing end with amino, then in this, as macromole evocating agent, causes another ammonia
Base acid NCA monomer is polymerized.In this process, the amount of poly-peptide macromole evocating agent is difficult to control to, therefore, it is difficult to control another
The degree of polymerization of poly-peptide unit.The method that the present invention provides, can respectively by control little initiator molecule and NCA monomer mole
Ratio, design is obtained the poly-peptide of both of which with specific aggregation degree, then both is combined by click chemistry, to obtain specific aggregation
The block polyamino acid polypeptide of degree.2. the polydispersity index (PDI) of product is narrow.Compare distribution and add monomer progressively ring-opening polymerisation
Method, block polypeptide PDI distribution prepared by click chemistry method is narrower.Compare distribution and add monomer progressively ring-opening polymerisation method, clickization
Block polypeptide PDI distribution prepared by method is narrower.As shown below: Fig. 2 is the amphipathic block utilizing the inventive method to prepare
The data that peptide-based gel permeation chromatography (GPC) is tested, PDI=1.30；Fig. 3 is to utilize substep to add monomer progressively ring-opening polymerisation
The GPC of amphipathic amino acid polypeptide prepared by method tests data, PDI=1.65.Both contrasts understand, and utilize this law to prepare
Product, dispersion index substantially narrows.3. the suitability is wide.By changing the ratio of propargylamine and BLG-NCA monomer, 1-nitrine-
3-aminopropane and the ratio of CysPEGMA-NCA monomer, can prepare the homopolymerization peptide PBLG/ of different polymerization degree
PCysPEGMA, then reacted by click chemistry, obtain the amphipathic peptide of different polymerization degree composition.The most simple to operate.At poly-peptide
Building-up process in, NCA monomer easily hydrolyzes, therefore to operation require the highest, especially substep add monomer mistake
Cheng Zhong.The inventive method is that synthesizing amphipathic polyamino acid polypeptide provides a kind of method easy, effective.
In a specific embodiment, the preparation method of described amphipathic block Polypeptide copolymer is: with chemical modification
After two derived from amino acid things be monomer, dissolved by N-carboxyl-alpha amino acid acid anhydride ring-opening polymerisation method (NCA-ROP)
The poly-peptide of both of which that property is different；By click chemistry process (click chemistry), two kinds of poly-peptides are connected again and form two
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 joins in the 250ml there-necked flask being dried equipped with condensing reflux pipe, and in the oil bath of 85 DEG C, return stirring reacts extremely
System clear, about about 5 hours response time.Stopped reaction after being cooled to room temperature, with frozen water and ice sodium bicarbonate
Solution is washed till neutrality and is dried with anhydrous sodium sulfate.Use petroleum ether recrystallization, vacuum drying, obtain white solid Pidolidone benzyl
Ester-N-carboxyl inner-acid anhydride (BLG-NCA) productivity 48%.
The DMF that addition 1.60g (6.1mmol) BLG-NCA monomer and 16ml are dried in dry 50ml bottle with two necks is molten
Agent, letting nitrogen in and deoxidizing 60mins.Add the propargylamine of 5 μ l, cause polymerization.Lucifuge reaction 72hours.After reaction terminates, methanol sinks
Form sediment, repetitive operation 3 times, obtain white solid poly-(Pidolidone benzyl ester), productivity 80%.
In the 100ml single port bottle with magneton, add 6.0g (50mmol) Cys and be dissolved in 60ml deionization
Water, regulates pH value of solution to 6～9 with the sodium hydroxide solution of 1mol/L.Methoxypolyethylene glycol methacrylic acid is added in system
Ester (Mn=300) 16.12g (53mmol), stirred overnight at room temperature.After reaction terminates, ethyl acetate extracts and retains water layer product.
Lyophilization, obtains white cream solid Cys methoxypolyethylene glycol methacrylate (CysPEGMA), productivity
90%.
Under nitrogen protection, CysPEGMA 7.41g (18.6mmol), triphosgene 1.81g, (6.2mmol) and 150ml is dry
Dry THF joins in the 250ml there-necked flask being dried equipped with condensing reflux pipe, and in the oil bath of 60 DEG C, return stirring reacts to body
It is clear, about about 8 hours response time.Stopped reaction after being cooled to room temperature, does by normal hexane precipitation vacuum
Dry, obtain yellowish-brown cream solid Pidolidone benzyl ester-N-carboxyl inner-acid anhydride (PCysPEGMA-NCA) 5.62g, productivity 71%.
In the 100ml twoport flask with magneton, add 5.04g (11.9mmol) CysPEGMA-NCA and be dissolved in 50ml
The THF solvent being dried, letting nitrogen in and deoxidizing 60mins.Use 1-nitrine-3 aminopropane that microsyringe adds 22 μ l in system
Cause polymerization.Lucifuge leads to nitrogen reaction 72hours.After reaction terminates, concentration, precipitates with normal hexane, obtains yellowish crude product.Vacuum
After drying thick product is dissolved in water, dialyses 3 days.Finally, use " freeze-drying " obtain yellow solid poly-(Cys gather
Ethylene glycol monomethyl ether methacrylate), productivity 82%.
In the test tube that 20ml is dried, it is sequentially added into the PBLG 0.20g (1equiv) prepared, PCysPEGMA
0.25g (1.4equiv), purified cuprous bromide 44mg (1equiv), and be dissolved in the DMF that 5ml is dried.Letting nitrogen in and deoxidizing
Adding part N after 30mins, "-pentamethyldiethylenetriamine (PMDETA) 6.4 μ l also seals test tube, proceeds to 50 DEG C for N, N ', N ', N
Oil bath pan, lucifuge reaction 70hours.After reaction terminates, quenching.Product with methylalcohol precipitation sucking filtration.After repetitive operation 3 times
Vacuum drying 100hours, obtains faint yellow solid granule, productivity 70%.
The preparation method of the present invention is simple and easy to do, the advantage making full use of click chemistry；Existing prepare amino acid polypeptide
Technology, the main method adding monomer progressively ring-opening polymerisation by substep.Contrast prior art, the substantive distinguishing features of the present invention
Being with advantage: 1. selectivity is high, amphipathic amino acid polypeptide design to specific aggregation degree has higher answering
By value.In the synthesis of poly-peptide, the control of the product degree of polymerization is the most difficult.For homopolymer, generally utilize NCA monomer and draw
The mol ratio sending out agent controls.But, for many blocks polyamino acid polypeptide, prior art need first to synthesize end with
The homopolymerization peptide of amino, then in this, as macromole evocating agent, cause another amino acid N CA monomer to be polymerized.In this process,
The amount of poly-peptide macromole evocating agent is difficult to control to, therefore, it is difficult to control the degree of polymerization of another poly-peptide unit.The present invention provides
Method, can be respectively by controlling the mol ratio of little initiator molecule and NCA monomer, and design obtains two kinds with specific aggregation degree
Homopolymerization peptide, then by click chemistry, both are combined, to obtain the block polyamino acid polypeptide of specific aggregation degree.2. product is many
Dispersion index (PDI) is narrow.Comparing distribution and add monomer progressively ring-opening polymerisation method, block polypeptide PDI prepared by click chemistry method divides
Cloth is narrower.Comparing distribution and add monomer progressively ring-opening polymerisation method, block polypeptide PDI distribution prepared by click chemistry method is narrower.As
Shown in figure below: Fig. 2 is the data that amphipathic block peptide-based gel permeation chromatography (GPC) utilizing the inventive method to prepare is tested,
PDI=1.30；Fig. 3 is to utilize substep to add amphipathic amino acid polypeptide prepared by the method for monomer progressively ring-opening polymerisation
GPC tests data, PDI=1.65.Both contrasts understand, and utilize product prepared by this law, and dispersion index substantially narrows.3. it is suitable for
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, obtains different poly-
The amphipathic peptide of right composition.The most simple to operate.In the building-up process of poly-peptide, NCA monomer easily hydrolyzes, the most right
Operation requires the highest, especially during substep adds monomer.The inventive method is synthesizing amphipathic polyamino acid polypeptide
Provide a kind of method easy, effective.
The invention allows for a kind of self-assembly, described 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 micelle, cylindrical micellar, shuttle-type sheet
Layer micelle.Compared with prior art, its feature is: 1. self-assembled material generally by amphipathic small molecules (such as dodecyl
Sodium sulfate etc.) or amphipathic block copolymer (such as PEO-b-PS etc.) constitute.With amphipathic amino acid polypeptide as self assembly
Precursor, it is possible to form orderly self-assembled material the most actually rare.2. for self-assembly, especially micelle, there is special parent
Water-oleophylic structure, is a kind of good potential drug carrier material.But, the most common non-poly-peptides self-assembled precursor material
Material also exists poor biocompatibility, and the shortcomings such as toxicity is big limit the development of this material.Poly-peptide, as constituting living matter
The important component part of protein, has the excellent biocompatibility not available for other material, using it as self assembly before
Body material, is expected to solve its difficult problem in applications such as pharmaceutical carriers.
The invention allows for the preparation method of the self-assembly prepared by described amphipathic block Polypeptide copolymer,
Including: described amphipathic block Polypeptide copolymer is dissolved in organic solvent, forms the weak solution of copolymer, instill wherein
The water of 1～2 times of volume of the weak solution of copolymer, drop rate is 1～5ml/min；Add the ultra-pure water cancellation of excess；By thoroughly
Analyse and excessive organic solvent is removed, obtain described self-assembly.Described self-assembly is the self-assembled material with ordered structure:
When organic solvent is oxolane, described self-assembly is bowl-shape micelle, and certain one side of spherical micelle is subsided and defined bowl
The micellar structure of type, measured, the mean diameter of self-assembly is 55nm, differs in the direction that subsides of bowl-type micelle；Organic molten
When agent is DMF, described self-assembly is cylindrical micellar, is connected with each other, overlapping between tubulose micelle, and contains
There is openwork part, define and be similar to space net structure；When organic solvent is Isosorbide-5-Nitrae-dioxane, described self-assembly is shuttle
Matrix layer micelle, its structure is middle wide, and two is narrow, and has more prominent burr shape at two ends, through measuring, the average length of micelle
Degree is 600nm, width average out to 200nm.Wherein, described " excessive " refers to that dilute polymer adds water after self assembly, solution body
Long-pending 5～10 times.
Wherein, the condition of described " dialysis " be select bag filter molecular cut off be 3500Da, material is regenerated fiber
Element ester.
Wherein, described amphipathic block Polypeptide copolymer, the mass ratio of organic solvent: 1000-3000:1；Preferably, for
2000:1。
Wherein, described organic solvent is selected from oxolane, DMF or Isosorbide-5-Nitrae-dioxane solvent.
The drop rate of 1～5ml/min is very important technological means, if speed is beyond this scope, it is difficult to obtain
Orderly self-assembled structures.As shown in Figure 6, the block polypeptide being dissolved in THF, drip ultra-pure water with the speed of 8ml/min
The TEM figure of obtained self-assembly, its structure is the most irregular.The block polypeptide that Fig. 8 is dissolved in Dioxane, with 10ml/
The TEM figure of self-assembly obtained by the speed dropping ultra-pure water of min, its structure is the most irregular.
The invention allows for the amphipathic Polypeptide copolymer shown in formula (I) and prepare self-assembled material, function of organization's material
Application in material, biomaterial.Wherein, described self-assembled material, function of organization's material, biomaterial for medicine conveying and
Release.
The invention allows for the conveying at medicine of the amphipathic Polypeptide copolymer shown in formula (I) or described self-assembly
With the application in release.
The invention allows for the self-assembly of preparation to also exist at aspects such as the conveying of medicine and releases and be widely applied
Prospect.
Accompanying drawing explanation
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 is the GPC of amphipathic amino acid polypeptide prepared by the method utilizing substep to add monomer progressively ring-opening polymerisation
Test data, PDI=1.65.
Fig. 4 is the saturating of the self-assembly of the novel amphiphilic Polypeptide copolymer formation being dissolved in N,N-dimethylformamide
Radio mirror figure.
Fig. 5 is the transmission electron microscope of the self-assembly that the novel amphiphilic Polypeptide copolymer being dissolved in oxolane is formed
Figure.
Fig. 6 is the transmission electron microscope of the self-assembly that the novel amphiphilic Polypeptide copolymer being dissolved in oxolane is formed
Figure；The speed of dropping ultra-pure water is 8ml/min, and it is irregular structure.
Fig. 7 is the transmission electricity of 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 of the self-assembly that the novel amphiphilic Polypeptide copolymer being dissolved in 1,4-dioxane is formed
Mirror figure.
The speed of dropping ultra-pure water is 10ml/min, and it is irregular structure.
Detailed description of the invention
In conjunction with specific examples below and accompanying drawing, the present invention is described in further detail.Implement the present invention process,
Condition, experimental technique etc., outside the lower content mentioned specially, be universal knowledege and the common knowledge of this area, this
Bright content is not particularly limited.
The preparation of the amphipathic Polypeptide copolymer of embodiment 1
By triphosgene, Pidolidone benzyl ester is transformed into monomer Pidolidone benzyl ester-N-carboxyl inner-acid anhydride, with propargyl
Amine be initiator, DMF (DMF) be solvent, by solution ring-opening polymerisation method, prepare poly-(Pidolidone benzyl
Ester), i.e. PBLG.By the reaction of " sulfydryl-ethylene " click chemistry by Cys and methoxypolyethylene glycol methacrylate
Reaction, is obtained Cys methoxypolyethylene glycol methacrylate (CysPEGMA), then is changed by triphosgene
For monomer Cys methoxypolyethylene glycol methacrylate-N-carboxyl inner-acid anhydride, with 1-nitrine-3-aminopropane for drawing
Sending out agent, oxolane is solvent, by ring-opening polymerisation method, prepares poly-(Cys methoxypolyethylene glycol methacrylic acid
Ester), i.e. PCysPEGMA.Again homopolymer PBLG and PCysPEGMA is dissolved in DMF, the oxygen in removing system, adds by bromination
Cuprous, N, N, N ', N ', N " after the catalyst system and catalyzing that-pentamethyldiethylenetriamine (PMDETA) forms, are 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 joins in the 250ml there-necked flask being dried equipped with condensing reflux pipe, and in the oil bath of 85 DEG C, return stirring reacts extremely
System clear, about about 5 hours response time.Stopped reaction after being cooled to room temperature, with frozen water and ice sodium bicarbonate
Solution is washed till neutrality and is dried with anhydrous sodium sulfate.Use petroleum ether recrystallization, vacuum drying, obtain white solid Pidolidone benzyl
Ester-N-carboxyl inner-acid anhydride (BLG-NCA) productivity 48%.
The DMF that addition 1.60g (6.1mmol) BLG-NCA monomer and 16ml are dried in dry 50ml bottle with two necks is molten
Agent, letting nitrogen in and deoxidizing 60mins.Add the propargylamine of 5 μ l, cause polymerization.Lucifuge reaction 72hours.After reaction terminates, methanol sinks
Form sediment, repetitive operation 3 times, obtain white solid poly-(Pidolidone benzyl ester), productivity 80%.
In the 100ml single port bottle with magneton, add 6.0g (50mmol) Cys and be dissolved in 60ml deionization
Water, regulates pH value of solution to 6～9 with the sodium hydroxide solution of 1mol/L.Methoxypolyethylene glycol methacrylic acid is added in system
Ester (Mn=300) 16.12g (53mmol), stirred overnight at room temperature.After reaction terminates, ethyl acetate extracts and retains water layer product.
Lyophilization, obtains white cream solid Cys methoxypolyethylene glycol methacrylate (CysPEGMA), productivity
90%.
Under nitrogen protection, CysPEGMA 7.41g (18.6mmol), triphosgene 1.81g, (6.2mmol) and 150ml is dry
Dry THF joins in the 250ml there-necked flask being dried equipped with condensing reflux pipe, and in the oil bath of 60 DEG C, return stirring reacts to body
It is clear, about about 8 hours response time.Stopped reaction after being cooled to room temperature, does by normal hexane precipitation vacuum
Dry, obtain yellowish-brown cream solid Pidolidone benzyl ester-N-carboxyl inner-acid anhydride (PCysPEGMA-NCA) 5.62g, productivity 71%.
In the 100ml twoport flask with magneton, add 5.04g (11.9mmol) CysPEGMA-NCA and be dissolved in 50ml
The THF solvent being dried, letting nitrogen in and deoxidizing 60mins.Use 1-nitrine-3 aminopropane that microsyringe adds 22 μ l in system
Cause polymerization.Lucifuge leads to nitrogen reaction 72hours.After reaction terminates, concentration, precipitates with normal hexane, obtains yellowish crude product.Vacuum
After drying thick product is dissolved in water, dialyses 3 days.Finally, use " freeze-drying " obtain yellow solid poly-(Cys gather
Ethylene glycol monomethyl ether methacrylate), productivity 82%.
In the test tube that 20ml is dried, it is sequentially added into the PBLG 0.20g (1equiv) prepared, PCysPEGMA
0.25g (1.4equiv), purified cuprous bromide 44mg (1equiv), and be dissolved in the DMF that 5ml is dried.Letting nitrogen in and deoxidizing
Adding part N after 30mins, "-pentamethyldiethylenetriamine (PMDETA) 6.4 μ l also seals test tube, proceeds to 50 DEG C for N, N ', N ', N
Oil bath pan, lucifuge reaction 70hours.After reaction terminates, quenching.Product with methylalcohol precipitation sucking filtration.After repetitive operation 3 times
Vacuum drying 100hours, obtains faint yellow solid granule, productivity 70%.
As it is shown in figure 1, Fig. 1 is amphipathic Polypeptide copolymer poly-L-glutamic acid acid benzyl ester-poly-(Cys Polyethylene Glycol
Methyl ether methacrylate), i.e. the proton nmr spectra of PBLG-b-PCysPEGMA, its characteristic peak (7.25,5.06,3.75,
3.50,1.25,0.15ppm) and the integral area ratio of correspondence demonstrates the successful synthesis of PBLG-b-PCysPEGMA copolymer.
As in figure 2 it is shown, Fig. 2 is amphipathic Polypeptide copolymer poly-L-glutamic acid acid benzyl ester-poly-(Cys Polyethylene Glycol
Methyl ether methacrylate), i.e. the gpc chromatogram of PBLG-b-PCysPEGMA, can be seen that polymer has by collection of illustrative plates narrower
Profile exponent (PDI=1.30).
Fig. 3 is the GPC of amphipathic amino acid polypeptide prepared by the method utilizing substep to add monomer progressively ring-opening polymerisation
Test data, PDI=1.65.Both contrasts understand, and utilize product prepared by the inventive method, and dispersion index substantially narrows.Institute
State " method of monomer progressively ring-opening polymerisation is added in distribution " to refer to: with Cys (methoxypolyethylene glycol methacrylic acid
Ester)-N carboxyl-alpha amino acid acid anhydride (i.e. CysPEGMA-NCA) is monomer, with n-butylamine as initiator, by NCA ring-opening polymerisation method
Prepared end contains the homopolymerization peptide PCysPEGMA-NH of amino2.Then, in this, as macromole evocating agent, cause Pidolidone
Benzyl ester-N-carboxyl inner-acid anhydride (i.e. BLG-NCA) monomer is polymerized, and obtains two blocks poly-peptide PBLG-b-PCysPEGMA.As follows:
Specifically comprise the following steps that
First by n-butylamine as little initiator molecule, CysPEGMA-NCA ring-opening polymerisation is caused to obtain homopolymer
PCysPEGMA.1.31g (3.09mmol) CysPEGMA-NCA is dissolved in the THF solvent that 13ml is dried, letting nitrogen in and deoxidizing
30mins.Using microsyringe, the n-butylamine adding 6 μ l (0.0618mmol) in system causes polymerization.Logical nitrogen lucifuge bar
12hours is reacted under part.Secondly, PCysPEGMA-NH is used2As 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 the THF being dried, after letting nitrogen in and deoxidizing, from the reaction system of CysPEGMA-NCA ring-opening polymerisation, take rapidly 3ml liquid add this
System, inducing B LG-NCA is polymerized.Room temperature lucifuge reaction 72hours.After reaction terminates, methanol extraction, it is light yellow cotton-shaped heavy to obtain
Forming sediment, sucking filtration obtains thick product.After thick product THF is dissolved, methanol extraction.Repetitive operation twice, further purified product.Very
Empty dry, obtain yellow solid granule, productivity 56%.
The preparation of embodiment 2 amphipathic Polypeptide copolymer self-assembled material
Amphipathic peptide copolymer p BLG-b-PCysPEGMA embodiment 1 prepared is the most molten with the concentration of 0.5mg/ml
Solution is in DMF, THF, 1,4-Dioxane.The polymer being added drop-wise to a certain amount of water with the speed of 1ml/min to have configured dilute
In solution.After being added dropwise to complete, fast drop substantial amounts of ultra-pure water cancellation.Product is collected after dialysing 3 days.
Fig. 4 is the self-assembled material prepared by the polymer being dissolved in DMF, and its structure is the tubulose micelle of rule, pipe
Be connected with each other between shape micelle, overlapping, and have hollow-out parts to separate elder generation, define and be similar to space net structure.Fig. 5 is dissolved in
Self-assembled material prepared by the polymer in oxolane (THF), its structure is the bowl-shape micelle of rule, for spherical micelle
Certain one side is subsided and is defined the micellar structure of bowl-type, and measured, the mean diameter of self-assembly is 55nm, bowl-type micelle
Differ in the direction that subsides.
Other conditions are identical, and amphipathic peptide copolymer p BLG-b-PCysPEGMA is dissolved in oxolane, works as dropping
When the speed of ultra-pure water is 8ml/min, Fig. 6 is the transmission electron microscope picture of the self-assembly that amphipathic Polypeptide copolymer is formed, by scheming
Understanding, it is irregular structure, and it includes the self assembly not yet forming ordered arrangement of part bowl assembling structure and obscure portions
Body.
Self-assembled material prepared by the polymer that Fig. 7 is dissolved in Isosorbide-5-Nitrae-Dioxane, its structure is the shuttle-type sheet of rule
Shape micelle, wide in the middle of its structure, two is narrow, and has more prominent burr shape at two ends；Through measuring, the average length of micelle 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 speed of dropping ultra-pure water is 10ml/min, Fig. 8 is the transmission electron microscope picture of the self-assembly that amphipathic Polypeptide copolymer is formed,
As seen from the figure, it is irregular structure, including 4 interconnective, contrast is higher, be similar to spherical structure, but due to
Its structural fuzzy, not yet can form complete micelle；Meanwhile, there iing the lamellar structure being similar to aciculiform about, but it is also
Imperfect, independent, it is distributed also heterogeneity, also fails to form orderly self-assembly.
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
Skilled person it is conceivable that change and advantage be all included in the present invention, and with appending claims for protect
Protect scope.
Claims (11)
1. an amphipathic Polypeptide copolymer, it is characterised in that described amphipathic Polypeptide copolymer includes the poly-polypeptide block of oil-soluble
With water-soluble poly polypeptide block, its structure such as formula (I) is shown:
In formula (I), degree of polymerization x of Polyethylene Glycol is 3-5；M=10-30；N=20-80.
Amphipathic Polypeptide copolymer the most according to claim 1, it is characterised in that described amphipathic Polypeptide copolymer is to change
Learning two modified derived from amino acid things is monomer, obtains dissolubility not by N carboxy α amino acid anhydride ring-opening polymerisation method
The same poly-peptide of both of which；By click chemistry process, the connection of poly-for both of which peptide is formed described amphipathic Polypeptide copolymer again.
3. the preparation method of an amphipathic Polypeptide copolymer, it is characterised in that comprise equal polyreaction, click chemistry modification instead
Should:
(1) equal polyreaction:
I) preparation of the poly-peptide of oil-soluble:
With Pidolidone benzyl ester-N carboxyl-alpha amino acid acid anhydride as raw material, in organic solvent, with propargylamine as initiator, reaction temperature
Degree controls at 60～80 DEG C, and the response time is 72-96 hour, obtains the poly-peptide of the oil-soluble shown in formula (a), such as reaction equation (1) institute
Show；
Wherein, n=20-80；
Ii) preparation of water-soluble poly peptide:
With Cys (methoxypolyethylene glycol methacrylate)-N carboxyl-alpha amino acid acid anhydride as raw material, at organic solvent
In, with 1-nitrine-3-aminopropane as initiator, reaction temperature controls at 45～75 DEG C, and the response time is 72-84 hour,
To the water-soluble poly peptide shown in formula (b), as shown in reaction equation (2)；
Wherein, degree of polymerization x of Polyethylene Glycol is 3-5；M=10-30；
(2) click chemistry modified-reaction:
In organic solvent, add the poly-peptide of oil-soluble and water-soluble poly peptide, the oxygen in removing system prepared by step (1), add
By cuprous bromide, N, N, N ', N ', N, " catalyst system and catalyzing of-pentamethyldiethylenetriamine composition, reaction temperature controls 40～110
DEG C, the response time is 20-70 hour, obtains described amphipathic Polypeptide copolymer, as shown in reaction equation (3)；
Wherein, degree of polymerization x of Polyethylene Glycol is 3-5；M=10-30；N=20-80.
Preparation method the most according to claim 3, it is characterised in that in the preparation of the poly-peptide of described step (1) oil-soluble, institute
State raw material Pidolidone benzyl ester-N carboxyl-alpha amino acid acid anhydride, the mol ratio of propargylamine is 20～80:1.
Preparation method the most according to claim 3, it is characterised in that in the preparation of described step (1) water-soluble poly peptide, institute
State raw material Cys (methoxypolyethylene glycol methacrylate)-N carboxyl-alpha amino acid acid anhydride, 1-nitrine-3-aminopropane
Mol ratio be 10-30:1.
Preparation method the most according to claim 3, it is characterised in that in described step (2), the poly-peptide of described oil-soluble and water
The poly-peptide of dissolubility, the mol ratio of catalyst system and catalyzing are 1:1～1.5:1～1.5.
7. a self-assembly, it is characterised in that described self-assembly is by amphipathic Polypeptide copolymer as claimed in claim 1
It is self-assembly of, there is Hydrophile-Lipophile structure；For bowl-shape micelle, cylindrical micellar, shuttle-type lamella micellar structure.
8. the preparation method of a self-assembly, it is characterised in that by molten for amphipathic Polypeptide copolymer as claimed in claim 1
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 wherein, drips
Rate of acceleration is 1～5ml/min；Add the ultra-pure water cancellation of excess；By dialysis, excessive organic solvent is removed, obtain right such as and want
Seek the self-assembly described in 7.
Preparation method the most according to claim 8, it is characterised in that described self-assembly, have ordered structure from group
Package material, when organic solvent is DMF, the self-assembly obtained is cylindrical micellar；When organic solvent is four
During hydrogen furan, the self-assembly obtained is bowl-shape micelle；When organic solvent is Isosorbide-5-Nitrae-dioxane, the self-assembly obtained is
Shuttle-type lamella micelle.
Amphipathic Polypeptide copolymer shown in formula the most according to claim 1 or claim 2 (I) is preparing self-assembled material, tissue merit
Application in energy material, biomaterial.
Amphipathic Polypeptide copolymer shown in 11. formulas according to claim 1 or claim 2 (I) or according to claim 7 from
Assembly application in the conveying and release of medicine.
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| CN112442179B (en) * | 2019-09-04 | 2021-07-23 | 深圳市第二人民医院 | Amphiphilic polymer for surface biological functionalization and preparation method and application thereof |
| CN112442181B (en) * | 2019-09-04 | 2021-07-23 | 深圳市第二人民医院 | Amphiphilic polymer with surface biological functionalization performed in modular mode |
| CN112442181A (en) * | 2019-09-04 | 2021-03-05 | 深圳市第二人民医院 | Amphiphilic polymer with surface biological functionalization performed in modular mode |
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