CN107312142A - A kind of amphipathic class ε polylysines alternate copolymer and its synthesis, the assembly of the copolymer and its preparation method and application - Google Patents
A kind of amphipathic class ε polylysines alternate copolymer and its synthesis, the assembly of the copolymer and its preparation method and application Download PDFInfo
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- CN107312142A CN107312142A CN201710508689.2A CN201710508689A CN107312142A CN 107312142 A CN107312142 A CN 107312142A CN 201710508689 A CN201710508689 A CN 201710508689A CN 107312142 A CN107312142 A CN 107312142A
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- diisocyanate
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- epsilon
- polylysine
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- 229920001577 copolymer Polymers 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229920000656 polylysine Polymers 0.000 title claims abstract 5
- 230000015572 biosynthetic process Effects 0.000 title abstract description 8
- 238000003786 synthesis reaction Methods 0.000 title abstract description 8
- 125000005442 diisocyanate group Chemical group 0.000 claims abstract description 20
- 238000001338 self-assembly Methods 0.000 claims abstract description 10
- 235000018977 lysine Nutrition 0.000 claims abstract description 9
- 108010039918 Polylysine Proteins 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 20
- 230000035484 reaction time Effects 0.000 claims description 20
- 239000000178 monomer Substances 0.000 claims description 18
- 239000003643 water by type Substances 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 238000006116 polymerization reaction Methods 0.000 claims description 11
- 239000005057 Hexamethylene diisocyanate Substances 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 229960000583 acetic acid Drugs 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 claims description 10
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 230000001376 precipitating effect Effects 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000006227 byproduct Substances 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- DFPJRUKWEPYFJT-UHFFFAOYSA-N 1,5-diisocyanatopentane Chemical compound O=C=NCCCCCN=C=O DFPJRUKWEPYFJT-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000002105 nanoparticle Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000012648 alternating copolymerization Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 238000005538 encapsulation Methods 0.000 claims description 3
- 239000012948 isocyanate Substances 0.000 claims description 3
- 150000002527 isonitriles Chemical class 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 230000008685 targeting Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 238000000859 sublimation Methods 0.000 claims description 2
- 230000008022 sublimation Effects 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 6
- ZXHZWRZAWJVPIC-UHFFFAOYSA-N 1,2-diisocyanatonaphthalene Chemical compound C1=CC=CC2=C(N=C=O)C(N=C=O)=CC=C21 ZXHZWRZAWJVPIC-UHFFFAOYSA-N 0.000 claims 2
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims 2
- 239000008367 deionised water Substances 0.000 claims 2
- 229910021641 deionized water Inorganic materials 0.000 claims 2
- -1 isocyanic acids Ester Chemical class 0.000 claims 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims 1
- 239000002244 precipitate Substances 0.000 claims 1
- 241000894006 Bacteria Species 0.000 abstract description 10
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 4
- 239000012620 biological material Substances 0.000 abstract description 3
- 239000007864 aqueous solution Substances 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 150000002669 lysines Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 10
- 241000191967 Staphylococcus aureus Species 0.000 description 7
- 241000588724 Escherichia coli Species 0.000 description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 6
- 0 C=[N+](C(C(CCCCN)*C(OCc1ccccc1)=O)=O)[O-] Chemical compound C=[N+](C(C(CCCCN)*C(OCc1ccccc1)=O)=O)[O-] 0.000 description 5
- DVKJHBMWWAPEIU-UHFFFAOYSA-N toluene 2,4-diisocyanate Chemical compound CC1=CC=C(N=C=O)C=C1N=C=O DVKJHBMWWAPEIU-UHFFFAOYSA-N 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 241000192125 Firmicutes Species 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 235000010633 broth Nutrition 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000006193 liquid solution Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- MTZUIIAIAKMWLI-UHFFFAOYSA-N 1,2-diisocyanatobenzene Chemical compound O=C=NC1=CC=CC=C1N=C=O MTZUIIAIAKMWLI-UHFFFAOYSA-N 0.000 description 1
- CWYZDPHNAGSFQB-UHFFFAOYSA-N CCCCNCCC Chemical compound CCCCNCCC CWYZDPHNAGSFQB-UHFFFAOYSA-N 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 235000013960 Lactobacillus bulgaricus Nutrition 0.000 description 1
- 241000186672 Lactobacillus delbrueckii subsp. bulgaricus Species 0.000 description 1
- 241000191938 Micrococcus luteus Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000187759 Streptomyces albus Species 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002882 anti-plaque Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003519 biomedical and dental material Substances 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229920000891 common polymer Polymers 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000005452 food preservative Substances 0.000 description 1
- 235000019249 food preservative Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229940004208 lactobacillus bulgaricus Drugs 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000010129 solution processing Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/30—Low-molecular-weight compounds
- C08G18/38—Low-molecular-weight compounds having heteroatoms other than oxygen
- C08G18/3819—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen
- C08G18/3823—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen containing -N-C=O groups
- C08G18/3831—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen containing -N-C=O groups containing urethane groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dispersion Chemistry (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polyurethanes Or Polyureas (AREA)
Abstract
The invention provides a kind of amphipathic class ε polylysines alternate copolymer and its synthesis, the assembly of the copolymer and its preparation method and application, the amphipathic class ε polylysines alternate copolymer is prepared from by α Z L lysines, diisocyanate, amphipathic class ε polylysines alternate copolymer prepared by the present invention is respectively provided with good antibacterial effect to Gram-positive and negative bacterium, biocompatibility is excellent, and assembly is easily self-assembly of under the aqueous solution.It is a kind of low toxicity, biomaterial stably, economic, is with a wide range of applications and is worth.
Description
Technical field
The invention belongs to antibacterial biological material field, and in particular to a kind of amphipathic class epsilon-polylysine alternate copolymer and
Its synthesis, assembly of the copolymer and its preparation method and application
Background technology
Epsilon-polylysine (EPL) is to form ε-amido link by the epsilon-amino of 1B and α-carboxyl of another 1B
It is polymerized, is fermented and produced by streptomyces albus.It can be decomposed into lysine in human body, and lysine exactly human body is tieed up
One of eight big amino acid necessary to holding normal physiological function.Therefore, early in the early 1980s, epsilon-polylysine (EPL)
Just it can be added into as a kind of natural preservative in food, this preservative has no toxic side effect to human body, than other chemical classes
Preservative has higher security.Epsilon-polylysine (EPL) can be as the main cause of food preservative its have efficiently,
The epsilon-polylysine (EPL) of the antibacterial activity of wide spectrum, especially 1B residue more than ten.It is to gram-positive bacteria
Such as staphylococcus aureus, lactobacillus bulgaricus, hot streptococcus, the bacterium such as micrococcus luteus, and Gram-negative bacteria such as sramana
Salmonella, Escherichia coli, the growth and breeding of aerogenesis arthrobacterium is all with very strong suppression and killing action.In addition, it is to fungi
It is inhibited.
Epsilon-polylysine (EPL) is as a kind of excellent hydrophilic macromolecule of biocompatibility, due to can not be in the solution
Nano-particle is self-assembly of, so as to inhibit its effect in terms of bio-medical material.
The content of the invention
In view of the shortcomings of the prior art, primary and foremost purpose is to provide a kind of amphipathic class epsilon-polylysine alternating copolymerization to the present invention
Thing.
Second object of the present invention is to provide a kind of synthesis of amphipathic class epsilon-polylysine alternate copolymer.
Third object of the present invention is to provide a kind of preparation method and application of assembly.
To reach above-mentioned purpose, solution of the invention is：
A kind of amphipathic class epsilon-polylysine alternate copolymer, its structural formula is as follows：
Wherein, n span is integer in 0~100 and is even number, and n represents the degree of polymerization of block, and R represents that two is different
Cyanate；
When n value is 0, structural formula is as follows：
The diisocyanate is hexamethylene diisocyanate (HDI), pentamethylene diisocyanate (PDI), toluene
Diisocyanate (TDI), methyl diphenylene diisocyanate (MDI), XDI (XDI), the isocyanide of naphthalene two
One kind in acid esters (NDI).
A kind of preparation method of above-mentioned amphipathic class EPL alternate copolymers, it comprises the following steps：
(1) 0.01~0.20mol monomers α-Z-L- lysines and 0.01~0.20mol sodium hydroxides, are added 20~
In 800ml deionized waters, reacted under normal temperature and pressure, the reaction time is 1~5h, freezed at a temperature of -50 DEG C~-20 DEG C it is dry
Dry 12~24h, obtains α-Z-L- Sodium lysinate monomers：
(2), by the α-Z-L- Sodium lysinates monomers and 0.005~0.10mol bis- obtained by 0.01~0.20mol steps (1)
Isocyanates reacts 12~48h in 20~500ml organic solvents under normal temperature and pressure, and is precipitated under precipitating reagent effect, obtains
Arrive：
Wherein, R represents diisocyanate.
(3), by products therefrom in 0.01~0.20mol steps (2), with 0~1.00mol diisocyanate in 50~
1~5h is reacted in 200ml organic solvents under normal temperature and pressure, after reaction terminates, 50~70 DEG C is continuously heating to, makes whole reactant
System 2~8h of heating, occurs CO of the back flow reaction to be produced during release reaction2, reaction is completed into products therefrom washing, is evaporated
Obtain：
Wherein, n span is integer in 0~100 and is even number, and n represents the degree of polymerization of block, and R represents that two is different
Cyanate；
When diisocyanate is 0mol, n value is 0, represents step (2) products therefrom without the anti-of step (3)
Answer and be directly entered step (4-2).
(4-1), by products therefrom and 10~50ml deprotection agents in 0.01~0.20mol steps (3) at normal temperatures and pressures
React 2~6h.Wash, dialyse after the completion of reaction, being evaporated and obtain：
Wherein, n span is integer in 0~100 and is even number, and n represents the degree of polymerization of block, and R is two isocyanides
Acid esters；
(4-2), when n values are 0, by products therefrom and 10~50ml deprotection agents in 0.01~0.20mol steps (2)
Reaction, the reaction time is possible in 2~6h, and reaction temperature is possible at 20~40 DEG C.Wash, dialyse after the completion of reaction,
It is evaporated and obtains：
Preferably, the synthesis of product comprises the following steps in step (2)：
(a), that the α-Z-L- Sodium lysinate monomers obtained by 0.01~0.20mol steps (1) are dissolved in into 20~500ml is organic molten
In agent, 0.005~0.10mol diisocyanate fully is added after dissolving, at normal temperatures and pressures, 12~48h of stirring reaction, reaction
After the completion of, organic solvent is removed under vacuum conditions.
(b), step (a) products therefrom is dissolved in 10ml~500ml deionized waters to obtaining light yellow settled solution,
Precipitating reagent is added dropwise dropwise and adjusts pH value to 3.5, white solid is constantly separated out in acidization.
(c), white solid obtained by step (b) is washed, dries, obtains product in the step (2).
Preferably, diisocyanate is hexamethylene diisocyanate (HDI), pentamethylene diisocyanate (PDI), first
Phenylene diisocyanate (TDI), methyl diphenylene diisocyanate (MDI), XDI (XDI), naphthalene two are different
Cyanate (NDI) is a kind of.
Preferably, organic solvent be in anhydrous DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO) it is a kind of with
On；
Preferably, precipitating reagent is one or more of watery hydrochloric acid, dilute sulfuric acid, acetic acid, trifluoroacetic acid；
It is preferred that, deprotection agent is one kind in the glacial acetic acid solution containing hydrogen bromide, trifluoroacetic acid；It is described containing hydrogen bromide
Mass fraction shared by hydrogen bromide is 33%-35% in glacial acetic acid solution；
Preferably, in step (1), under the reaction time is 2h, reaction temperature normal temperature, generally between 20~40 DEG C
Can；
Preferably, in step (2), under the reaction time is 12h, reaction temperature normal temperature, generally between 20~40 DEG C
；
Preferably, in step (3), under the reaction time is 2h, reaction temperature normal temperature, generally between 20~40 DEG C
Can；60 DEG C are continuously heating to, the whole reaction system time heats 3h, whole reaction system is occurred back flow reaction；
Preferably, in step (4), the reaction time is 4h, and reaction temperature normal temperature is equal generally between 20~40 DEG C
Can.
A kind of assembly, it is self-assembly of by amphipathic class epsilon-polylysine alternate copolymer described above.
A kind of preparation method of above-mentioned assembly, it comprises the following steps：
By the amphipathic class epsilon-polylysine alternate copolymers of 0.2mg-10mg：
It is dissolved in 2.0~5.0ml deionized waters, quickly
Stirring, that is, obtain assembly.
Wherein, mixing speed is 500~1500r/min, preferably 1000r/min；Mixing time is 12~24h, preferably
For 12h.
A kind of above-mentioned assembly is in the encapsulation of medicine, transport, Targeting delivery, synthesizing nano-particle and chemical microreactor
In terms of application.
Due to using such scheme, the beneficial effects of the invention are as follows：
Firstth, the amphipathic class epsilon-polylysine alternate copolymer for preparing of the present invention has good antibiotic property and excellent
Biocompatibility, and be easily self-assembly of assembly, form nano vesicle, before having very big application in terms of the bio-medical
Scape.
Secondth, raw material of the invention is cheap and easily-available, with low cost；The synthetic route of the present invention is simple, and condition is controllable.
3rd, amphipathic class epsilon-polylysine alternate copolymer prepared by the present invention is a kind of economy, low toxicity and stabilization
Biomaterial, is with a wide range of applications and is worth.
Brief description of the drawings
Figure 1A is TEM figure of the gained copolymer assembly of the embodiment of the present invention 1 when resolution ratio is 1.
Figure 1B is TEM figure of the gained copolymer assembly of the embodiment of the present invention 1 when resolution ratio is 0.5.
Fig. 2A is antibiotic property of the gained copolymer of embodiment 1 in Escherichia coli in the present invention, and abscissa is the time
(Time) the OD values (OD at 600nm) when, ordinate is 600nm.
Fig. 2 B are antibiotic property of the gained copolymer of embodiment 1 in staphylococcus aureus in the present invention, when abscissa is
Between (Time), ordinate be 600nm when OD values (OD at 600nm).
Fig. 3 is the cytotoxicity figure of the amphipathic class epsilon-polylysine alternate copolymer assembly of embodiment 1 of the present invention.
Embodiment
The invention provides a kind of amphipathic class epsilon-polylysine alternate copolymer and its synthesis, the assembly of the copolymer
And its preparation method and application.
<Amphipathic class epsilon-polylysine alternate copolymer>
A kind of amphipathic class epsilon-polylysine alternate copolymer, its structural formula is as follows：
Wherein, n span is integer in 0~100 and is even number, and n represents the degree of polymerization of block, and R represents that two is different
Cyanate；
When n value is 0, structural formula is as follows：
<The preparation method of amphipathic class epsilon-polylysine alternate copolymer>
A kind of preparation method of above-mentioned amphipathic class epsilon-polylysine alternate copolymer, it comprises the following steps：
(1) 0.01~0.20mol monomers α-Z-L- lysines and 0.01~0.20mol sodium hydroxides, are added 20~
In 800ml deionized waters, the reaction time be 1~5h be possible, reaction temperature is possible at 20~40 DEG C, after -50
DEG C~-20 DEG C at a temperature of be freeze-dried, sublimation drying be 12~24h be possible, obtain α-Z-L- Sodium lysinate monomers：
(2) it is the α-Z-L- Sodium lysinates monomers and 0.005~0.10mol bis- obtained by 0.01~0.20mol steps (1) is different
Cyanate reacts in 20~500ml organic solvents, and the reaction time is that 12~48h is possible, and acts in precipitating reagent
Form sediment, obtain：
Wherein, R represents diisocyanate.
(3), by products therefrom in 0.01~0.20mol steps (2), with 0~1.00mol diisocyanate in 50~
Reacted in 200ml organic solvents, the reaction time is possible in 1~5h, and reaction temperature is possible at 20~40 DEG C, reaction knot
Shu Hou, is continuously heating to 50~70 DEG C, whole reaction system is heated 2~8h, during occurring back flow reaction with release reaction
The CO of generation2, reaction is completed products therefrom washing, is evaporated and obtains：
Wherein, n span is integer in 0~100 and is even number, and n represents the degree of polymerization of block, and R represents that two is different
Cyanate；
In this step when diisocyanate is 0mol, n value is 0, represents step (2) products therefrom without step
(3) reaction and be directly entered step (4-2).
(4-1), products therefrom in 0.01~0.20mol steps (3) and 10~50ml deprotection agents reacted, the reaction time
It is possible in 2~6h, reaction temperature is possible at 20~40 DEG C.Wash, dialyse after the completion of reaction, being evaporated and obtain：
Wherein, n span is integer in 0~100 and is even number, and n represents the degree of polymerization of block, and R is two isocyanides
Acid esters；The step of when n value is 0, sees (4-2)；
(4-2), when n values are 0, by products therefrom and 10~50ml deprotection agents in 0.01~0.20mol steps (2)
Reaction, the reaction time is possible in 2~6h, and reaction temperature is possible at 20~40 DEG C.Wash, dialyse after the completion of reaction,
It is evaporated and obtains：
Preferably, the synthesis of product comprises the following steps in the step (2)：
(a), that the α-Z-L- Sodium lysinate monomers obtained by 0.01~0.20mol steps (1) are dissolved in into 20~500mL is organic molten
In agent, fully 0.005~0.10mol diisocyanate, at 20~40 DEG C, 12~48h of stirring reaction are added after dissolving.Reaction
After the completion of, organic solvent is removed under vacuum conditions.
(b), (a) products therefrom is dissolved in 10mL~500mL deionized waters, yellow clear solution is obtained, drips dropwise
Plus acidic precipitating reagent adjusts pH value to 3.5, and white solid is constantly separated out in acidization.
(c), the white solid is washed, dried, product in (2) is obtained.
Wherein, diisocyanate is hexamethylene diisocyanate (HDI), pentamethylene diisocyanate (PDI), toluene
Diisocyanate (TDI), methyl diphenylene diisocyanate (MDI), XDI (XDI), the isocyanide of naphthalene two
Acid esters (NDI) is a kind of.
Organic solvent is one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO)；
Precipitating reagent is one or more of watery hydrochloric acid, dilute sulfuric acid, acetic acid, trifluoroacetic acid；
Deprotection agent is the glacial acetic acid solution (hydrogen bromide mass fraction is 33%~35%) containing hydrogen bromide, in trifluoroacetic acid
One kind；
In step (1), it can be 1~5h, preferably 2h that the reaction time, which is, and reaction temperature reaction temperature normal temperature leads to
Often between 20~40 DEG C；
In step (2), it can be 12~48h, preferably 12h that the reaction time, which is, reaction temperature reaction temperature normal temperature,
Generally between 20~40 DEG C；
In step (3), the reaction time is can be with 1~5h, preferably 2h, reaction temperature normal temperature, generally 20~40
Between DEG C；Continue to be heated to 60~70 DEG C, the continuation heating response system time is 2~8h, makes system occur back flow reaction
With the CO produced during release reaction2；
In step (4), the reaction time can be 2~6h, preferably 4h, reaction temperature normal temperature, generally 20~40
Between DEG C.
<Assembly>
A kind of assembly, it is self-assembly of by above-mentioned amphipathic class epsilon-polylysine alternate copolymer.
Self assembly refer to basic structural unit be based on non-covalent interaction, such as hydrogen bond, hydrophobic effect, Van der Waals force and
Pi-pi bond accumulation etc., the stabilization or the meta-stable that spontaneously form and the process with certain regular geometric structure.
By hydrophilic α-Z-L- lysines and hydrophobic diisocyanate alternating copolymerization in the present invention, obtained amphiphilic
Property class epsilon-polylysine alternate copolymer, with good antibiotic property and excellent biocompatibility, and in aqueous environment
Under can be self-assembly of nano vesicle well.
<The preparation method of assembly>
A kind of preparation method of above-mentioned assembly, it comprises the following steps：
By the amphipathic class epsilon-polylysine copolymers of 0.2mg~10mg：
It is dissolved in 2.0-5.0ml deionized waters, soon
Speed stirring a few hours, obtain assembly..
Wherein, mixing speed is 500-1500r/min, preferably 1000r/min, and mixing time is 12-24h, is preferably
12h。
<The application of assembly>
A kind of above-mentioned assembly can apply the encapsulation in medicine, transport, Targeting delivery, synthesizing nano-particle and chemistry
In terms of microreactor.
The present invention will be further described with reference to the accompanying drawings.
Embodiment 1：The first step：The preparation method of amphipathic class epsilon-polylysine alternate copolymer
The preparation method of the amphipathic class epsilon-polylysine alternate copolymer of the present embodiment, it comprises the following steps：
(1), 20.000g (71.429mmol) α-Z-L- lysine monomers are dissolved in 500ml deionized waters, added
2.857g (71.425mmol) sodium hydroxide carries out dissolving neutralization, after reacting 2 hours at room temperature, is freezed at a temperature of -30 DEG C
12h is dried, α-Z-L- Sodium lysinate monomers are obtained；
(2), that the α-Z-L- Sodium lysinate monomers obtained by 15.000g (49.669mmol) step (1) are dissolved in into 150ml is anhydrous
DMF, adds 4.177g (24.835mmol) HDI (hexamethylene diisocyanate), stirs anti-at room temperature
Answer 12h.Reaction completes, after removing solvent under vacuum environment, to add 300ml deionized waters and dissolved, obtain clarification light yellow
Solution, is slowly added dropwise watery hydrochloric acid and adjusts pH value to 3.5, gradually there is white solid precipitation during dropwise addition dropwise.Then by white
Solid is washed three times with a large amount of deionized waters, is evaporated and is obtained：
(3) products therefrom in 10.000g (14.451mmol) step (2), is dissolved in the anhydrous N of 100mL, N- dimethyl formyls
In amine, disposably it is rapidly added 2.124g (13.735mmol) HDI and is well mixed, at room temperature stirring reaction 2h, after completion of the reaction
Continue to heat up, the back flow reaction 4h at 60 DEG C, the CO for producing course of reaction2Guarantee is released to polymerize successfully.Polymerization is completed
Afterwards, solvent is evaporated, repeatedly washed with a large amount of deionized waters, obtained after being evaporated：
(4) glacial acetic acid solution (brominations of the 25ml containing hydrogen bromide, is added into 5g (0.367mmol) step (3) products therefrom
Hydrogen content is 33%) to be deprotected, about 4 hours reaction time.Then acetone cyclic washing is used 5 times, being put into molecular weight is
3500 bag filter is dialysed, and is obtained after being evaporated：
Second step：It is self-assembly of amphipathic class epsilon-polylysine alternate copolymer vesica assembly
The preparation method of the copolymer vesica assembly of the present embodiment, it comprises the following steps：
Amphipathic class epsilon-polylysine alternate copolymer obtained by 4.0mg (0.608mmol) above-mentioned steps is dissolved in
In 2.000ml deionized waters, 12h is stirred under 1000r/min rotating speeds, you can obtain the amphipathic class EPL of the present embodiment alternately altogether
Polymers vesica assembly.
Embodiment 2：
The first step：The preparation method of amphipathic class epsilon-polylysine alternate copolymer
The preparation method of the amphipathic class epsilon-polylysine alternate copolymer of the present embodiment, it comprises the following steps：
(1), 20.000g (71.429mmol) α-Z-L- lysine monomers are dissolved in 500ml deionized waters, added
2.857g (71.425mmol) sodium hydroxide carries out dissolving neutralization, after reacting 2 hours at room temperature, is freezed at a temperature of -30 DEG C
12h is dried, α-Z-L- Sodium lysinate monomers are obtained；
(2), that the α-Z-L- Sodium lysinate monomers obtained by 15.000g (49.669mmol) step (1) are dissolved in into 150ml is anhydrous
DMF, adds 6.209g (24.835mmol) MDI ('-diphenylmethane diisocyanate), stirs anti-at room temperature
Answer 12h.Reaction completes, after removing solvent under vacuum environment, to add 300ml deionized waters and dissolved, and obtains clarifying glassy yellow
Solution, is slowly added dropwise watery hydrochloric acid and adjusts pH value to 3.5, gradually there is white solid precipitation during dropwise addition dropwise.Then by white
Solid is washed three times with a large amount of deionized waters, is evaporated and is obtained：
(3) products therefrom in 11.185g (14.451mmol) step (2), is dissolved in the anhydrous N of 100ml, N- dimethyl formyls
In amine, disposably it is rapidly added 3.161g (12.644mmol) MDI and is well mixed, at room temperature stirring reaction 2h.After completion of the reaction
Continue to heat up, the back flow reaction 4h at 60 DEG C, the CO for producing course of reaction2Guarantee is released to polymerize successfully.Polymerization is completed
Afterwards, solvent is evaporated, repeatedly washed with a large amount of deionized waters, obtained after being evaporated：
(4) acetic acid solution (the hydrogen bromide mass fraction of 25ml hydrogen bromides, is added to 5g (0.337mmol) step (3) product
33%) to be deprotected, about 4 hours reaction time.Then with acetone cyclic washing 5 times, be put into molecular weight for 3500 it is saturating
Analysis bag is dialysed, and is obtained after being evaporated：
Second step：It is self-assembly of amphipathic class epsilon-polylysine alternate copolymer vesica assembly
The preparation method of the copolymer vesica assembly of the present embodiment, it comprises the following steps：
Amphipathic class epsilon-polylysine alternate copolymer obtained by 4.0mg (0.512mmol) above-mentioned steps is dissolved in
In 2.000ml deionized waters, 12h is stirred under 1000r/min rotating speeds, you can obtain the amphipathic class epsilon-polylysine of the present embodiment
Alternate copolymer vesica assembly.
<Experiment>
Tested as follows as product using the amphipathic class epsilon-polylysine alternate copolymer and assembly of above-described embodiment.
<Experiment 1>
Figure 1A and Figure 1B are respectively that the amphipathic class epsilon-polylysine alternate copolymer assembly of the gained of embodiment 1 is dividing respectively
TEM figures when resolution is 1 μm and when resolution ratio is 0.5, are schemed from Figure 1A TEM, and the amphipathic class EPL of the gained of embodiment 1 is handed over
Nano vesicle can be assembled into water for copolymer；After multiplication factor, as shown in Figure 2 A, the shape of this vesica can be more clearly seen
Looks.
<Experiment 2>
This experiment is to verify the amphipathic class epsilon-polylysine alternate copolymer of the gained of embodiment 1 in gram-positive bacteria
Anti-microbial property in (staphylococcus aureus) and Gram-negative bacteria (Escherichia coli).
Minimal inhibitory concentration (MIC) is to assess the important parameter of antibacterial antiplaque agent performance.This experiment uses gram respectively
Negative bacterium (Escherichia coli) and gram-positive bacteria (staphylococcus aureus) are alternately common to determine amphipathic class epsilon-polylysine
The anti-microbial property of polymers.Experimental procedure is as follows：
(1) 10ml LB bone broths are added in culture dish；
(2) 100 μ L LB bone broths are added in every lattice of 96 orifice plate the first rows.Then 100 μ L are added in the first lattice
Concentration is the amphipathic class EPL alternate copolymer aqueous solution of the 5mg/ml gained of embodiment 1, is sufficiently mixed, and takes the 100 μ L mixing
Liquid is added in 96 the second lattice of orifice plate the first row, is well mixed, 100 μ L mixed liquors is then taken again to the lattice of row the 3rd, with this
Analogize；
(3) in the LB bone broths for the 10ml that the 10 μ L bacteriums activated are added in step (1), then therefrom respectively take
100 μ L are added in the grid of each mixed liquor in step (2).
Add after 100 μ L bacterium liquid (staphylococcus aureus or Escherichia coli), the institute of embodiment 1 in the mixed liquor of 96 orifice plates
Amphipathic class EPL alternate copolymer concentration is respectively 250 μ g/ml, 125 μ g/ml, 62.5 μ g/ml, 31 μ g/ml, 16 μ g/ml,
The optical density incubated in 37 DEG C of insulating boxs, it was determined with ultraviolet specrophotometer at 600nm every 2 hours is put into, is schemed
The OD values of ordinate refer to optical density (optical density) in 2A and Fig. 2 B, represent that the light that detected material is sponged is close
Degree, i.e. absorbance.OD values are bigger, and contained substance content is higher in liquid, and different material has its specific light absorption wavelength, and it is surveyed
As shown in Figure 2 A and 2 B, Fig. 2A and Fig. 2 B represent amphipathic class EPL alternate copolymers and are respectively acting on greatly test result respectively
Result after enterobacteria and staphylococcus aureus, i.e. antibiotic property, reflect the growth rate of bacterium under different situations, and OD values are got over
Greatly, illustrate that the growth rate of bacterium is bigger, schemed from Fig. 2A and Fig. 2 B, amphipathic class EPL alternate copolymers vesica has good
Antibiotic property, and at the 12nd hour, when amphipathic class EPL alternate copolymers concentration is 120 μ g/ml, the growth of two kinds of bacteriums
Gradually tend towards stability, the antiseptic is 120 μ g/ to the minimum inhibitory concentration MIC value of staphylococcus aureus and Escherichia coli
ml。
<Experiment 3>
The purpose of this experiment is to study poison of the amphipathic class epsilon-polylysine alternate copolymer assembly to L02 cells
Property.
This experiment determines amphipathic class epsilon-polylysine alternate copolymer group obtained by embodiment 1 as CCK-8 kits
Fill toxicity of the body for L02 (normal human liver cell).Researcher uses 96 hole bed boards, and 100 μ L cell suspensions are added per hole
(4000) and culture medium are cultivated together in 37 DEG C, the incubator of 5% relative humidity is full of CO in 24h, incubator2；So
50 μ g/ml, 100 μ g/ml, 200 μ g/ml, 400 μ g/ml, 600 μ g/ml, 800 are separately added into the cell suspension in each hole afterwards
μ g/ml and 1000 μ g/ml amphipathic class EPL alternate copolymers assembling liquid solution is cultivated for 24h, 48h and 72h.Use
The cell for not assembling liquid solution processing with amphipathic class epsilon-polylysine alternate copolymer is used as blank control group.Experimental group and right
Supported according to tissue culture after completing, CCK-8 coloring agents are added in each aperture, 1h is cultivated at 37 DEG C.Researcher passes through
ELIASA, uses absorbance of the sample of double-wavelength method measurement experiment group and control group at 450nm and 630nm.Experimental group and
Each sample duplicate measurements of control group four times, according to normal liver cell survival volume and the ratio calculation of control group liver cell total amount
Cell survival rate, test result are obtained as shown in figure 3, wherein, abscissa represents vesica concentration (Vesicle
Concentration), ordinate represents cell survival rate (relative cell viability).
Learnt from Fig. 3, the concentration with amphipathic class EPL alternate copolymer assemblies gradually increases, from 50 μ g/ml increases
To 1000 μ g/ml, cell survival rate is more than 100%, therefore be may determine that, the amphipathic class EPL in the present invention is alternately common
Polymers to cell be substantially have no toxic side effect i.e.：The polymer has excellent biocompatibility.
The above-mentioned description to embodiment is that this hair is understood that and used for the ease of those skilled in the art
It is bright.Those skilled in the art obviously can readily make various modifications to these embodiments, and described herein one
As principle be applied in other embodiment, without passing through performing creative labour.Therefore, the invention is not restricted to above-described embodiment.
Those skilled in the art do not depart from improvement that scope of the invention made and change all should be at these according to the principle of the present invention
Within the protection domain of invention.
Claims (10)
1. a kind of amphipathic class epsilon-polylysine alternate copolymer, it is characterised in that：Its structural formula is as follows：
Wherein, n spans are integer in 0~100 and are even number, and n represents the degree of polymerization of block, and R represents diisocyanate.
2. amphipathic class epsilon-polylysine alternate copolymer as claimed in claim 1, it is characterised in that：The diisocyanate
For hexamethylene diisocyanate, pentamethylene diisocyanate, toluene di-isocyanate(TDI), methyl diphenylene diisocyanate,
One kind in XDI, naphthalene diisocyanate.
3. a kind of preparation method of amphipathic class epsilon-polylysine alternate copolymer as claimed in claim 1 or 2, its feature exists
In：Comprise the following steps：
(1) 0.01~0.20mol α-Z-L- lysines monomers and 0.01~0.20mol sodium hydroxides, are added into 20~800ml to go
In ionized water, reacted under normal temperature and pressure, be freeze-dried afterwards, obtain α-Z-L- Sodium lysinate monomers：
(2), by the α-Z-L- Sodium lysinates monomers and the isocyanides of 0.005~0.10mol bis- obtained by 0.01~0.20mol steps (1)
Acid esters in 20~500ml organic solvents, under normal temperature and pressure react, after precipitating reagent effect under precipitate, obtain：
Wherein, R represents diisocyanate；
(3), by products therefrom in 0.01~0.20mol steps (2), have with 0~1.00mol diisocyanate in 50~200ml
Reacted at normal temperatures and pressures in machine solvent, after reaction terminates, being continuously heating to 50~70 DEG C heats whole reaction system, to release
Put back the CO produced during answering2, reaction is completed products therefrom washing, is evaporated and obtains：
Wherein, n span is integer in 0~100 and is even number, and n represents the degree of polymerization of block, and R represents two isocyanic acids
Ester；
(4), by under products therefrom and 10~50ml deprotection agent normal temperature and pressures in 0.01~0.20mol steps (3) or step (2)
Reaction, washs after the completion of reaction, dialyses, being evaporated and obtain：
Wherein, n span is integer in 0~100 and is even number, and n represents the degree of polymerization of block, and R is diisocyanate.
4. preparation method as claimed in claim 3, it is characterised in that：The step (2) includes：
(a) α-Z-L- Sodium lysinate monomers obtained by 0.01~0.20mol steps (1), are dissolved in 20~500ml organic solvents
In, fully added after dissolving under 0.005~0.10mol diisocyanate, normal temperature and pressure, 12~48h of stirring reaction, reaction is completed
Afterwards, organic solvent is removed；
(b) after, step (a) products therefrom is dissolved in 10mL~500mL deionized waters, add precipitating reagent adjust pH value to
3.5, to precipitation white solid；
(c), white solid obtained by step (b) is washed, dries, obtains product in the step (2).
5. preparation method as claimed in claim 3, it is characterised in that：In step (1), the reaction time is 1~5h；It is described
It is -50 DEG C~-20 DEG C to be freeze-dried temperature, and sublimation drying is 12~24h；
Preferably, in step (2), the reaction time in organic solvent is 12~48h；
Preferably, in step (3), the reaction time in organic solvent is 1~5h；
Preferably, in step (3), 60 DEG C are continuously heating to；Whole reaction system is set to heat 2~8h；
Preferably, it is 2~6h with the time that deprotection agent reacts in step (4)；It is highly preferred that with deprotection agent react when
Between be 4h.
6. preparation method as claimed in claim 3, it is characterised in that：The diisocyanate is the isocyanic acid of hexa-methylene two
Ester, pentamethylene diisocyanate, toluene di-isocyanate(TDI), methyl diphenylene diisocyanate, the isocyanic acid of phenylenedimethylidyne two
One kind in ester, naphthalene diisocyanate；
Preferably, the organic solvent is one or more of anhydrous DMF, dimethyl sulfoxide (DMSO)；
Preferably, the precipitating reagent is one or more of watery hydrochloric acid, dilute sulfuric acid, acetic acid, trifluoroacetic acid；
Preferably, the deprotection agent is the glacial acetic acid solution containing hydrogen bromide, one kind in trifluoroacetic acid；
It is highly preferred that the mass fraction of contained hydrogen bromide is 33%~35% in the glacial acetic acid solution containing hydrogen bromide.
7. a kind of assembly, it is characterised in that：By amphipathic class epsilon-polylysine alternating copolymerization as claimed in claim 1 or 2
Thing is self-assembly of.
8. a kind of preparation method of assembly as claimed in claim 7, it is characterised in that：Comprise the following steps：
By amphipathic class epsilon-polylysine alternate copolymer：
Stirring obtains assembly in deionized water.
9. the preparation method of assembly as claimed in claim 8, it is characterised in that：By amphipathic class ε of 0.2mg~10mg-poly-
Lysine alternate copolymer, which is dissolved in 2.0~5.0ml deionized water, to be stirred, and mixing time is 12~24h, and mixing speed is
500~1500r/min；
Preferably, the mixing time is 12h, and mixing speed is 1000r/min.
10. a kind of assembly as claimed in claim 7 the encapsulation and transport of medicine, Targeting delivery, synthesizing nano-particle and
Application in chemical microreactor.
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