CN105837827A - Epsilon-polylysine-polyethyleneimine-beta cyclodextrin polymer and preparation method and application thereof - Google Patents
Epsilon-polylysine-polyethyleneimine-beta cyclodextrin polymer and preparation method and application thereof Download PDFInfo
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- CN105837827A CN105837827A CN201610307704.2A CN201610307704A CN105837827A CN 105837827 A CN105837827 A CN 105837827A CN 201610307704 A CN201610307704 A CN 201610307704A CN 105837827 A CN105837827 A CN 105837827A
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- Prior art keywords
- polylysine
- epsilon
- ethylene imine
- beta cyclodextrin
- succinyl
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- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 62
- 239000001116 FEMA 4028 Substances 0.000 title claims abstract description 47
- 229960004853 betadex Drugs 0.000 title claims abstract description 47
- 229920000642 polymer Polymers 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 108010039918 Polylysine Proteins 0.000 claims abstract description 43
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 53
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 34
- 239000005977 Ethylene Substances 0.000 claims description 33
- 229920000656 polylysine Polymers 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 238000009833 condensation Methods 0.000 claims description 11
- 230000005494 condensation Effects 0.000 claims description 11
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 238000000502 dialysis Methods 0.000 claims description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 230000000240 adjuvant effect Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 claims description 3
- 150000001336 alkenes Chemical class 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- FNPXQPLDGZMBSL-UHFFFAOYSA-N n,n'-dicyclohexylethane-1,2-diimine Chemical compound C1CCCCC1N=CC=NC1CCCCC1 FNPXQPLDGZMBSL-UHFFFAOYSA-N 0.000 claims 1
- 150000003457 sulfones Chemical class 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 11
- 229920002873 Polyethylenimine Polymers 0.000 abstract description 9
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 235000011175 beta-cyclodextrine Nutrition 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003937 drug carrier Substances 0.000 abstract description 4
- 238000012637 gene transfection Methods 0.000 abstract description 4
- 108090000623 proteins and genes Proteins 0.000 abstract description 4
- 239000002105 nanoparticle Substances 0.000 abstract description 3
- 108091029865 Exogenous DNA Proteins 0.000 abstract 1
- 239000000969 carrier Substances 0.000 abstract 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 14
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 241000588724 Escherichia coli Species 0.000 description 7
- 230000009182 swimming Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 150000001412 amines Chemical group 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000000246 agarose gel electrophoresis Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229910000071 diazene Inorganic materials 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920001601 polyetherimide Polymers 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- 238000011938 amidation process Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229960002521 artenimol Drugs 0.000 description 1
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 description 1
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 description 1
- 229960004991 artesunate Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 229930016266 dihydroartemisinin Natural products 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 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 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000013598 vector Substances 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
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
-
- 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
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/48—Polymers modified by chemical after-treatment
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
- General Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Plant Pathology (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Materials Engineering (AREA)
- General Chemical & Material Sciences (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Medicinal Preparation (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
Abstract
The invention provides an epsilon-polylysine-polyethyleneimine-beta cyclodextrin polymer and a preparation method and application thereof. Epsilon-polylysine serves as a main chain, modified epsilon-polylysine and beta cyclodextrin grafted polyethyleneimine are coupled, and finally the epsilon-polylysine-polyethyleneimine-beta cyclodextrin polymer is obtained. According to the epsilon-polylysine-polyethyleneimine-beta cyclodextrin polymer, a cavity of beta cyclodextrin can include some drugs with poor water solubility to form an inclusion compound, and then the water solubility of the drugs is improved. In addition, polyethyleneimine in a carrier and exogenous DNA can agglomerate to form nano-particles for gene transfection, and the novel polymer has high application potential in the field of drug carriers and gene carriers.
Description
Technical field
The invention belongs to the preparation method field of medicinal supermolecule carrier, be specifically related to a kind of with the good poly-second of water solubility
Alkene imines beta cyclodextrin and N-succinyl polylysine are raw material, the novel ε constructing a kind of excellent aqueous solubility by amide condensed-
The method of polylysine-ethylene imine-beta cyclodextrin polymer.
Background technology
In the last few years, high molecular polymer such as particulate or nanoparticle, cause widely as a kind of new pharmaceutical carrier
Interest.By the hydrophobic grouping on copolymer or the interaction between hydrophilic radical or the intermolecular phase interaction of oppositely charged
With forming a kind of new miniature or nanometre glue self-assembly.These pharmaceutical carriers can have bioactive point with many
Son interacts, such as anti-tumor drug molecule, enzyme, protide etc..
Epsilon-polylysine is a kind of biosynthetic non-ribosomal lysine polymers, containing 25 ~ 35 lysine monomers,
And each lysine unit is attached by the peptide bond between epsilon-amino and carboxyl, molecular weight is about 3500 ~ 4500, has good
Good security, bacteriostasis property and heat endurance.Epsilon-polylysine rich in cation, has strong quiet with the material with anion
Electrical forces and biomembrane is had good penetration power.Based on above characteristic, epsilon-polylysine can be used for pharmaceutical carrier, at material
Material science and pharmaceutical sanitary field are used widely.
Ethylene imine (polyethylenimine, PEI), is a kind of polycationic material being in daily use.Polycation
Material, such as: ethylene imine (polyethylenimine, PEI), shitosan (chitosan), dendritic
(dendrimer) it is and other polycation derivative, the Non-viral gene vectors of a quasi-representative.And ethylene imine
Acting on especially prominent, it all shows the highest efficiency gene transfection in testing in vitro and in vivo.In polyethyleneimine amine structure
-NH2There is the strongest DNA combination, and after-NH-and=N-is protonated, there is the strongest cushioning effect, can protect
DNA not by nuclease degradation, promotes that DNA escapes from inclusion body in Cytolysosome.The gene transfection effect of ethylene imine
Rate has very close relationship with its molecular weight, surface charge and buffer capacity.The ethylene imine of HMW (is more than
25KDa) transfection efficiency is the highest, but toxicity is the biggest, it is impossible to be biodegradable and in vivo the holdup time longer；Low-molecular-weight
Ethylene imine toxicity is low, and efficiency gene transfection is the lowest simultaneously, therefore can not be separately as the carrier of genomic medicine.
Cyclodextrin (cyclodextrin) has another name called loop chain starch, is that 6 ~ 8 D-Glucose molecules are by α-Isosorbide-5-Nitrae-glycosidic bond
Connect, the cyclic compound of chair conformation each other.It is referred to as alpha-cyclodextrin, by seven molecule D-by six molecule D-Glucose institute makers-ups
Glucose institute makers-up is referred to as beta-schardinger dextrin, eight molecule D-Glucose institute makers-ups be referred to as gamma-cyclodextrin.Cyclodextrin molecular in
Circularly cylindrical, surface and hydrophilic outer and inner chamber is hydrophobic.The hydrophobic internal cavities of cyclodextrin can form bag with the molecule of some spatial match
Compound, thus be modified by the molecule of inclusion this, as improved stability and water solubility.This property due to cyclodextrin
Matter, it is more and more utilized at biomedicine field.
Supermolecule polymer carrier constructed jointly by epsilon-polylysine and cyclodextrin is a study hotspot now, the most
(1. Kang M H. Rapid Commun, 2002,23:179-182. 2. Hak S is reported through there being some documents to carry out
C. Macromolecules, 2003, 36: 5342-5347. ③ Wei H L. Macromolecules, 2005, 38:
8833-8899.). these reports are directly grafted with cyclodextrin and derivative thereof by epsilon-polylysine, but not over
The report of the polymer that butanedioic acid and ethylene imine are attached.
Summary of the invention
It is an object of the present invention to provide a kind of excellent aqueous solubility, stability is splendid, do not have the novel ε of toxic and side effect-poly-to rely ammonia
The preparation method of acid-ethylene imine-beta cyclodextrin polymer.This polymer is passed through self to dissociate by N-succinyl polylysine
Carboxyl, condensing agent and condensation adjuvant effect under, with beta cyclodextrin modify ethylene imine on any one primary amine groups send out
Give birth to amidation process and obtain.
Novel epsilon-polylysine-ethylene imine-beta cyclodextrin polymer that the present invention obtains is that a kind of water solubility is fabulous
Medicine/gene carrier, it utilizes cyclodextrin hydrophobicity inner chamber can form inclusion compound with the medicine of some spatial match, thus to this
Plant and be modified by the medicine of inclusion, improve stability and the water solubility of medicine.There are many reactive compounds on the market now
There is good curative effect, but owing to itself is water-soluble or stability is not good enough, be difficult to independent patent medicine, such as cancer therapy drug
Adriamycin, Artesunate, containing dihydroartemisinin, lamp-dish flower acetic and 5 FU 5 fluorouracil.Owing to being grafted polyethyleneimine on carrier
Amine, has the strongest cohesion to DNA, can form nanoparticle, therefore can also be as genophore.It is contemplated that obtain one
Kind of excellent aqueous solubility, stability is splendid, do not have the medicine/gene carrier of toxic and side effect.
The concrete preparation process of Inventive polymers is as follows:
(1) succinyl oxide and molecular weight are reacted 5 at the polylysine of 3500 ~ 4500 scopes in dimethyl sulfoxide (DMSO) at 50 DEG C
It obtains N-succinyl polylysine；(concrete grammar sees Yang Bo etc. the preparation method [P] of a kind of novel epsilon-polylysine.
China: CN 103483583 is A.2014-01-01)；
(2) by the ethylene imine of 6-tolysulfonyl-beta cyclodextrin and different molecular weight in dimethyl sulfoxide (DMSO) at 80 DEG C anti-
Answer 3 days the ethylene imine-beta cyclodextrin of different molecular weight (method sees Yuan P. Biomaterials 32 (2011)
8328-8341)；
(3) N-succinyl polylysine is added in intensive polar solvent, then under condensing agent and condensation adjuvant effect,
Reacting 15 ~ 120min under the conditions of-4 ~ 25 DEG C, wherein N-succinyl polylysine concentration in a solvent is 0.001 ~ 0.0025
Mol/L, condensing agent is 25 ~ 35 1 with the mol ratio of N-succinyl polylysine, condensation adjuvant and N-succinyl polylysine
Mol ratio be 8 ~ 35 1；In obtained mixed liquor, add ethylene imine-beta cyclodextrin at 25 ~ 60 DEG C, react 2 ~ 5d,
Wherein ethylene imine cyclodextrin is 20 ~ 35 1 with the mol ratio of N-succinyl polylysine；After completion of the reaction, steam after dialysis
Drying product.
Heretofore described intensive polar solvent is DMF, dimethyl sulfoxide (DMSO) or mixed solvent (N, N-
Dimethylformamide and dimethyl sulfoxide (DMSO) are by 1 10 ~ 15 volume ratio mixing).The preferred dimethyl sulfoxide (DMSO) of reaction dissolvent, by experiment
Screening, N-succinyl polylysine concentration in a solvent is 0.001 ~ 0.002 mol/L, can obtain satisfied percent grafting.
Condensing agent used in the present invention is EDC hydrochloride, two hexamethylenes
Base diimine, N, the one in N '-carbonyl dimidazoles, and condensing agent are 25 ~ 35 1 with the mol ratio of N-succinyl polylysine.
Because EDC hydrochloride require mild condition and condensation effect higher than remaining two
Kind, it is advantageous to it.By experiment screening, condensing agent is preferably 25 ~ 27 1 with the mol ratio of N-succinyl polylysine；Used
Condensation adjuvant be DMAP, N-hydroxy-succinamide or I-hydroxybenzotriazole, and condensation adjuvant with
The mol ratio of N-succinyl polylysine is 8 ~ 35 1, by experiment screening, condensation adjuvant and N-succinyl polylysine
Mol ratio is preferably 15 ~ 27 1.
It is anti-under the conditions of-4 ~ 25 DEG C that N-succinyl polylysine of the present invention and condensing agent and condensation adjuvant react
Answer 15 ~ 120min, under the conditions of preferably 0 ~ 5 DEG C, react 60 ~ 90min.
Ethylene imine molecular weight used in the present invention is 600 ~ 25000.
Ethylene imine cyclodextrin of the present invention and N-succinyl polylysine react 2 ~ 5d at 25 ~ 60 DEG C, excellent
It is selected at 25 ~ 35 DEG C reaction 3 ~ 4d.Wherein ethylene imine cyclodextrin is 20 ~ 35 with the mol ratio of N-succinyl polylysine:
1, preferably 25 ~ 30:1.
Reaction structure formula of the present invention is as follows:
Wherein n=ethylene imine molecular weight/600, x value is 6 ~ 14.
The present invention another object is that and applied by epsilon-polylysine-ethylene imine-beta cyclodextrin polymer in DNA condenses.
Advantages of the present invention and effect are as follows:
Novel epsilon-polylysine-ethylene imine-beta cyclodextrin polymer that the present invention provides is on N-succinyl polylysine
It is grafted multiple ethylene imine cyclodextrin, is expected to as a kind of excellent aqueous solubility, stability is splendid, do not have the medicine of toxic and side effect
Thing/genophore.On the other hand, the system of novel epsilon-polylysine-ethylene imine-beta cyclodextrin polymer of the present invention
Preparation Method, simple to operate, reaction condition is gentle, and products obtained therefrom yield is high, and percent grafting is high, and purity is high, can be used for industrialized production.
Accompanying drawing explanation
Fig. 1 be N-succinyl polylysine proton nmr spectra (1H NMR) figure；
Fig. 2 be ethylene imine (molecular weight 600) beta cyclodextrin proton nmr spectra (1H NMR) figure；
Fig. 3 is the hydrogen nuclear magnetic resonance of epsilon-polylysine-ethylene imine in the present invention (molecular weight 1800)-beta cyclodextrin polymer
Spectrum (1H NMR) figure；
Fig. 4 is that epsilon-polylysine-ethylene imine in the present invention (molecular weight 10000)-beta cyclodextrin polymer is under variable concentrations
With e. coli bl21 (DE3) DNA agarose gel electrophoresis figure；
Fig. 5 is epsilon-polylysine-ethylene imine in the present invention (molecular weight 1800)-beta cyclodextrin polymer and Escherichia coli
The AFM figure of BL21 (DE3) DNA；Wherein a figure is simple e. coli bl21 (DE3) DNA atom
Force microscope figure；B figure is this polymer and the AFM figure of e. coli bl21 (DE3) DNA effect.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in detail, but is not limited to embodiment disclosure.
The preparation of embodiment 1:N-succinyl polylysine
5g (1.25mmol) epsilon-polylysine is joined and 100mL dimethyl sulfoxide (DMSO) is stirred at room temperature uniformly, toward made
Obtaining addition 4.5g (45.0mmol) succinyl oxide in solution stir and be heated to 50 DEG C of reaction 5d, it is cold that reaction terminates standing
But after, being instilled by reactant liquor in 600mL acetone and stir, separating out suction filtration after precipitation, gained faint yellow solid is N-succinyl
Polylysine, yield is 84%, and percent grafting is 71.6%(Fig. 1).
Embodiment 2: the preparation of different molecular weight ethylene imine cyclodextrin
Take the ethylene imine of 0.75g (1.25mmol) molecular weight 600,2.25g(1.25mmol) polyethylene of molecular weight 1800
Imines, the ethylene imine of 12.50g (1.25mmol) molecular weight 10000,31.25g (1.25mmol) molecular weight 25000
Ethylene imine is separately added in 100mL dimethyl sulfoxide (DMSO) and stirs under room temperature, is separately added into 1.61g in obtained solution
(1.25mmol), 4.83g (3.75mmol), 26.73g (20.75mmol), 67.14g (52.13mmol) 6-is to toluene sulphur
Acyl-beta-schardinger dextrin, stirs and is heated to 80 DEG C of reaction 3d, after reaction terminates to stand cooling, reactant liquor dialysis is evaporated, gained
Yellow solid is ethylene imine-beta cyclodextrin, and yield is respectively 75%, 72%, 81%, 79%(Fig. 2).
Embodiment 3: epsilon-polylysine-ethylene imine-beta cyclodextrin polymer must prepare that (ethylene imine molecular weight is
600)
0.655g (0.1mmol) N-succinyl polylysine is added in 100mL dimethyl sulfoxide (DMSO), is subsequently adding 0.50g
(2.6mmol) EDC hydrochloride and 0.23g(2mmol) N-hydroxysuccinimidyl acyl Asia
Amine, activates 90min at 0 DEG C, adds 4.72g(2mmol in obtained mixed liquor) ethylene imine-beta cyclodextrin (poly-second
Alkene imines molecular weight is 600) at 30 DEG C, react 4d.After completion of the reaction, after dialysis, it is evaporated prepared product, yield 76.8%, connects
Branch rate 45.1%.
Embodiment 4: epsilon-polylysine-ethylene imine-beta cyclodextrin polymer must prepare that (ethylene imine molecular weight is
1800)
0.655g (0.1mmol) N-succinyl polylysine is added in 100mL dimethyl sulfoxide (DMSO), is subsequently adding 0.50g
(2.6mmol) EDC hydrochloride and 0.23g(2mmol) N-hydroxysuccinimidyl acyl Asia
Amine, activates 90min at 0 DEG C, adds 14.16g(2mmol in obtained mixed liquor) ethylene imine-beta cyclodextrin is (poly-
Aziridine molecular weight is 1800) at 30 DEG C, react 4d.After completion of the reaction, after dialysis, it is evaporated prepared product, yield
73.4%, percent grafting 34.5%(Fig. 3).
Fig. 5 is epsilon-polylysine-ethylene imine (molecular weight 1800)-beta cyclodextrin polymer and e. coli bl21
(DE3) the AFM figure of DNA, (a) is simple e. coli bl21 (DE3) DNA AFM
Figure；B () is this polymer and the AFM figure of e. coli bl21 (DE3) DNA effect, show in figure: this gathers
Compound can effectively by DNA from the loose netted aggregation being condensed into uniform particle diameter.
Embodiment 5: epsilon-polylysine-ethylene imine-beta cyclodextrin polymer must prepare that (ethylene imine molecular weight is
10000)
0.066g (0.01mmol) N-succinyl polylysine is added in 10mL dimethyl sulfoxide (DMSO), is subsequently adding 0.05g
(0.26mmol) EDC hydrochloride and 0.023g(0.2mmol) N-hydroxysuccinimidyl
Acid imide, activates 90min at 0 DEG C, adds 7.65g(0.2mmol in obtained mixed liquor) ethylene imine-β ring paste
Essence (ethylene imine molecular weight is 10000) reacts 4d at 30 DEG C.After completion of the reaction, after dialysis, it is evaporated prepared product, receives
Rate 69%, percent grafting 29.3%.
Epsilon-polylysine-ethylene imine (molecular weight 10000)-beta cyclodextrin polymer under variable concentrations with large intestine bar
Bacterium BL21 (DE3) DNA agarose gel electrophoresis is tested
As shown in Figure 4, wherein: swimming lane 1 is independent DNA (0.5 μ g/mL), swimming lane 2 be DNA (0.5 ng/ μ L)+
PEI(molecular weight 10000) (2.5 × 10-4Mol/L), swimming lane 3 is DNA (0.5 ng/ μ L)+polymer (0.5 × 10-5
Mol/L), swimming lane 4 is DNA (0.5 ng/ μ L)+polymer (1.0 × 10-4 Mol/L), swimming lane 5 is DNA (0.5
Ng/ μ L)+polymer (2.0 × 10-4Mol/L), swimming lane 6 is DNA (4.0 ng/ μ L)+polymer (0.5 × 10-4
Mol/L), swimming lane 7 is DNA (0.5 ng/ μ L)+polymer (8.0 × 10-4mol/L)；Show from figure, this polymer
Can effectively condense DNA at low concentrations.
Embodiment 6: epsilon-polylysine-ethylene imine-beta cyclodextrin polymer must prepare that (ethylene imine molecular weight is
25000)
0.066g (0.01mmol) N-succinyl polylysine is added in 10mL dimethyl sulfoxide (DMSO), is subsequently adding 0.05g
(0.26mmol) EDC hydrochloride and 0.023g(0.2mmol) N-hydroxysuccinimidyl
Acid imide, activates 90min at 0 DEG C, adds 19.68g(0.2mmol in obtained mixed liquor) ethylene imine cyclodextrin
(ethylene imine molecular weight is 25000) reacts 4d at 30 DEG C.After completion of the reaction, after dialysis, it is evaporated prepared product, yield
66.4%, percent grafting 18.9%.
Embodiment 7: epsilon-polylysine-ethylene imine-beta cyclodextrin polymer must prepare that (ethylene imine molecular weight is
10000)
0.01mmol N-succinyl polylysine is added in 5mL DMF, is subsequently adding 0.3mmol bis-
Cyclohexyl diimine and 0.1mmol DMAP, activate 30min at 20 DEG C, add in obtained mixed liquor
0.25mmol ethylene imine-beta cyclodextrin (ethylene imine molecular weight is 10000) reacts 3d at 40 DEG C.After completion of the reaction,
It is evaporated prepared product, yield 66%, percent grafting 25.8% after dialysis.
Embodiment 8: epsilon-polylysine-ethylene imine-beta cyclodextrin polymer must prepare that (ethylene imine molecular weight is
600)
Add 0.01mmol N-succinyl polylysine to 7mL highly polar aprotic solvent (DMF and two
Methyl sulfoxide 1 10 mixing by volume) in, it is subsequently adding 0.35mmol N, N '-carbonyl dimidazoles and 0.3mmol 1-hydroxyl
BTA, activates 60min at 15 DEG C, adds 0.32mmol ethylene imine-beta cyclodextrin in obtained mixed liquor
(ethylene imine molecular weight is 600) reacts 2d at 60 DEG C.After completion of the reaction, after dialysis, it is evaporated prepared product, yield
74.4%, percent grafting 43.2%.
Claims (9)
1. epsilon-polylysine-ethylene imine-beta cyclodextrin polymer, its structural formula is as follows:
Wherein n=ethylene imine molecular weight/600, x value is 6 ~ 14.
2. the preparation method of the epsilon-polylysine-ethylene imine-beta cyclodextrin polymer described in claim 1, it is characterised in that
Carry out as follows:
(1) N-succinyl polylysine is added in highly polar aprotic solvent, under condensing agent and condensation adjuvant effect,
Reacting 15 ~ 120min under the conditions of-4 ~ 25 DEG C, wherein N-succinyl polylysine concentration in a solvent is 0.001 ~ 0.0025
Mol/L, condensing agent is 25 ~ 35 1 with the mol ratio of N-succinyl polylysine, condensation adjuvant and N-succinyl polylysine
Mol ratio be 8 ~ 35 1；
(2) in the mixed liquor of step (1), add ethylene imine-beta cyclodextrin to react 2 ~ 5 days at 25 ~ 60 DEG C, the most poly-second
Alkene imines-beta cyclodextrin is 20 ~ 35 1 with the mol ratio of N-succinyl polylysine；
(3) after completion of the reaction, after dialysis, it is evaporated prepared epsilon-polylysine-ethylene imine-beta cyclodextrin polymer.
The preparation method of epsilon-polylysine-ethylene imine-beta cyclodextrin polymer the most according to claim 2, its feature
It is: N-succinyl polylysine is sub-at dimethyl by succinyl oxide and the epsilon-polylysine that molecular weight is 3500 ~ 4500
In sulfone, reaction prepares.
The preparation method of epsilon-polylysine-ethylene imine-beta cyclodextrin polymer the most according to claim 2, its feature
It is: highly polar aprotic solvent is DMF and/or dimethyl sulfoxide (DMSO).
The preparation method of epsilon-polylysine-ethylene imine-beta cyclodextrin polymer the most according to claim 4, its feature
It is: 1 10 ~ 15 mixing by volume of DMF and dimethyl sulfoxide (DMSO).
The preparation method of epsilon-polylysine-ethylene imine-beta cyclodextrin polymer the most according to claim 2, its feature
It is: condensing agent is EDC hydrochloride, dicyclohexyl diimine, N, N '-carbonyl
One in diimidazole.
The preparation method of epsilon-polylysine-ethylene imine-beta cyclodextrin polymer the most according to claim 2, its feature
It is: condensation adjuvant is DMAP, N-hydroxy-succinamide or I-hydroxybenzotriazole.
The preparation method of epsilon-polylysine-ethylene imine-beta cyclodextrin polymer the most according to claim 2, its feature
Be: the structural formula of ethylene imine-beta cyclodextrin shown in formula I:
,
Wherein n=ethylene imine molecular weight/600.
9. the application in DNA condenses of the epsilon-polylysine-ethylene imine-beta cyclodextrin polymer described in claim 1.
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