CN105524271B - The synthesis and application of the polyamino acid block copolymer of cholic acid modification - Google Patents
The synthesis and application of the polyamino acid block copolymer of cholic acid modification Download PDFInfo
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- 239000004380 Cholic acid Substances 0.000 title claims abstract description 31
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 title claims abstract description 31
- 229960002471 cholic acid Drugs 0.000 title claims abstract description 31
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 235000019416 cholic acid Nutrition 0.000 title claims abstract description 30
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 239000002253 acid Substances 0.000 title claims abstract description 16
- 229920001400 block copolymer Polymers 0.000 title claims abstract description 16
- 230000004048 modification Effects 0.000 title claims abstract description 15
- 238000012986 modification Methods 0.000 title claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 title abstract description 5
- 239000000693 micelle Substances 0.000 claims abstract description 48
- 238000004132 cross linking Methods 0.000 claims abstract description 47
- 239000003814 drug Substances 0.000 claims abstract description 39
- 229920000642 polymer Polymers 0.000 claims abstract description 37
- 229940079593 drug Drugs 0.000 claims abstract description 28
- 229920001308 poly(aminoacid) Polymers 0.000 claims abstract description 28
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 24
- 239000005864 Sulphur Substances 0.000 claims abstract description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 12
- 238000001338 self-assembly Methods 0.000 claims abstract description 9
- 150000003384 small molecules Chemical class 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- -1 benzyl ester Chemical class 0.000 claims description 5
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 5
- 238000004806 packaging method and process Methods 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229960003067 cystine Drugs 0.000 claims description 2
- 108010064470 polyaspartate Proteins 0.000 claims description 2
- 230000034005 thiol-disulfide exchange Effects 0.000 claims description 2
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 claims 1
- 108010039918 Polylysine Proteins 0.000 claims 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 1
- 125000003716 cholic acid group Chemical group 0.000 claims 1
- DHQUQYYPAWHGAR-UHFFFAOYSA-N dibenzyl 2-aminopentanedioate Chemical compound C=1C=CC=CC=1COC(=O)C(N)CCC(=O)OCC1=CC=CC=C1 DHQUQYYPAWHGAR-UHFFFAOYSA-N 0.000 claims 1
- 229920000656 polylysine Polymers 0.000 claims 1
- 229960002663 thioctic acid Drugs 0.000 abstract description 9
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 abstract description 8
- 235000019136 lipoic acid Nutrition 0.000 abstract description 8
- 239000008280 blood Substances 0.000 abstract description 7
- 210000004369 blood Anatomy 0.000 abstract description 7
- 238000001727 in vivo Methods 0.000 abstract description 7
- 230000009467 reduction Effects 0.000 abstract description 3
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 2
- 230000007812 deficiency Effects 0.000 abstract description 2
- 229940088679 drug related substance Drugs 0.000 abstract description 2
- 230000003834 intracellular effect Effects 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 8
- 150000005846 sugar alcohols Polymers 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 235000013339 cereals Nutrition 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 229920000835 poly(gamma-benzyl-L-glutamate) polymer Polymers 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-threitol Chemical compound OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
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- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 229920000388 Polyphosphate Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000007098 aminolysis reaction Methods 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 229920006037 cross link polymer Polymers 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
- 230000002121 endocytic effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- 239000002539 nanocarrier Substances 0.000 description 2
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 2
- 239000001205 polyphosphate Substances 0.000 description 2
- 235000011176 polyphosphates Nutrition 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
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- 102000005962 receptors Human genes 0.000 description 2
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- 235000009566 rice Nutrition 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 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 1
- 108010024636 Glutathione Proteins 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000011938 amidation process Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019728 animal nutrition Nutrition 0.000 description 1
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- 229910052786 argon Inorganic materials 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
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- 229960000304 folic acid Drugs 0.000 description 1
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- 239000008103 glucose Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
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- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
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- 239000002574 poison Substances 0.000 description 1
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- 229920000768 polyamine Polymers 0.000 description 1
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- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses the synthesis and application of the polyamino acid block copolymer of cholic acid modification; the hydrophilic chain of the block copolymer is polyethylene glycol; hydrophobic chain is polyaminoacid; small molecule cholic acid modification polyaminoacid end; the side chain of polyaminoacid is sulphur caprylyl, and lipoic acid reacts to form amido bond with the amino in hydrophobic polyaminoacid；It can be crosslinked by the nano-micelle being self-assembly of to the polyamino acid block copolymer that cholic acid is modified, obtain the polymer nano micelle of stable crosslinked reduction sensitivity, so that nano-micelle is not easy to be destroyed in extracellular and blood, so as to ensure the drug substance stable of nano-micelle package；Once into tumour cell, nano-micelle then can quickly solve crosslinking and dissociate, and drug quick release comes out, and generates efficient therapeutic effect；Overcome the deficiencies of drug discharges in advance in vivo, delivery efficiency is low, intracellular release is slow.
Description
Technical field
The present invention relates to a kind of polyamino acid block copolymers of cholic acid modification, and in particular to a kind of polyaminoacid and poly-
Amino-terminal end modifies cholic acid, the Amphipathilic block polymer that side chain is modified with lipoic acid.
Background technology
Polymer micelle is to pass through intermolecular interaction (hydrogen bond, parent/hydrophobic effect and model moral by amphipathic nature polyalcohol
Magnificent power etc.) in aqueous solution self assembly obtain.It using hydrophobic grouping as kernel, hydrophilic radical is shell by being self-assembly of to be
Orderly molecular aggregates.Polymer micelle in addition to have the advantages that nano-medicament carrier some it is common other than, also with respect to it
(such as liposome and polymer nanoparticle) more superior physics and biochemical property for his nano-carrier：With apparent nucleocapsid
Structure, wherein hydrophobic core part can be used to wrap up dewatering medicament, and it is superior that hydrophilic shell can so that micella has in aqueous solution
Stability；The phagocytosis of human body reticuloendothelial system (RES) macrophage can be effectively reduced, space between cells can be passed through, can be passed through
The capillary and blood-brain barrier (BBB) of human body minimum are simultaneously absorbed by cell tissue；The water solubility and bioavilability of enhancing；
Extend the circulation time of drug, reduce side effect；Nano-micelle pharmaceutical carrier can achieve the purpose that targeting conveying can simultaneously control
Drug release is conducive to treatment of the drug to some privileged sites.The plurality of advantages of nano-micelle releases its control in drug
It puts with huge applications prospect.
It is to prepare two that the hydrophilic segment of end-functionalization is carried out ring-opening polymerization to monomer as macromole evocating agent
One of main method of close polymer.Common hydrophilic backbone includes polyethylene glycol (PEG) or polyphosphate (PEEP) etc..It is common
Biodegradable hydrophobic segment have polyaminoacid (such as poly- β-benzoyl-L-Aspartic acid, poly- γ-benzyl-Pidolidone and
Poly-aspartate etc.).As hydrophilic backbone, polyethylene glycol (PEG) is pH neutral, nontoxic, water-soluble, no antigen and immunogene
Property polymer,, can as the shell of micella with superior water-soluble and good biocompatibility and blood compatibility
To avoid identification of the drug-loading system in reticuloendothelial system and the absorption of protein, so as to extend drug-loading system in blood
Circulation time, improve the bioavilability of drug.As hydrophobic segment, natural and synthesis polyaminoacid has good
Biocompatibility, metabolite is harmless；For amino acid material, it is needed by human, can voluntarily degrades, generation
It thanks and is absorbed by organisms and drains, have the advantages that other materials are unsurpassable.Have polyaminoacid material and be used as suture
Material, artificial skin etc. have been widely used in fields such as drug degradation, antitumor drug controlled releases.
Cholic acid is main bile acid in human body, is present in human body, has been reported and shows that the modification of cholic acid can be bright
It is aobvious to increase the drugloading rate and envelop rate of polymer, and successfully apply to drug release.
However amphipathic polymer is often not sufficiently stable by the micella being self-assembly of, and is injected in vivo by blood Macrodilution
And dissociate or the cell with being present in blood and bio-molecular interaction cause drug to discharge too early, it is impossible to by medicine
Object is delivered to target site.Crosslinking can effectively improve micella stability.In recent years, there is environment (pH, temperature, redox
Environment etc.) response nano-carrier become research hotspot (Sang Cheon Lee, et al.Biomaterials 2012,
33：1489-1499；Chen et al, Journal of Controlled Release, 2013,69：171-179).Disulfide bond
Crosslinked micella has superior biocompatibility, inhibits drug release under physiological environment, highly stable in vivo long to follow
Ring into after cell, can have vivo environment response and release crosslinking, release medicine out, higher so as to produce
Antitumor activity.
Invention content
It is an object of the present invention to provide a kind of methods of preparation and the application of amphiphilic block polymer.
In order to achieve the above objectives, specific technical solution of the present invention is the synthesis of the polyamino acid block copolymer of cholic acid modification
And application, the main chain of the block copolymer are made of hydrophilic section and hydrophobic section, the end modified cholic acid small molecule of hydrophobic section is hydrophobic
Section side chain is sulphur caprylyl.
In above-mentioned technical proposal, raw material that the available raw material of hydrophilic polymer is known to the skilled person,
The hydrophilic polymer may be selected from but be not limited to：One kind in polyethylene glycol (PEG), polyphosphate；The amphipathic
The molecular weight for closing object is 5000~30000.
In above-mentioned technical proposal, the hydrophobic section side chain of the polyamino acid block copolymer of the cholic acid modification includes sulphur decoyl
Base.
The technology that the method for preparing above-mentioned amphipathic nature polyalcohol is known to the skilled person, with polyethylene glycol (ammonia
Base acid-lipoic acid)-cholic acid (PEG-pGlu (EDA-LA)-CA) preparation for come illustrate cholic acid modification amphipathic block gather
The preparation method of object is closed, polyethylene glycol amino acid is conveniently obtained by ring-opening polymerization：PEG-NH is used first2As big
Then initiator molecule, open loop BLG-NCA connect cholic acid in polyaminoacid end, then carry out aminolysis to polyamine portion, even
Upper lipoic acid, synthetic route are as shown in Figure 1.
In above-mentioned technical proposal, the number of sulphur caprylyl can pass through the poly- second of addition in the polyamino acid block copolymer
The ratio of glycol and BLG-NCA, reaction time, reaction temperature etc. are adjusted.
In above-mentioned technical proposal, sulphur caprylyl is introduced to the side chain of hydrophobic polymer polyaminoacid, obtained amphipathic
Object is closed, by being self-assembly of nano-micelle, then by reducing agent if 1.4- dithiothreitol dithios (DTT) are to sulphur caprylyl
Five-membered ring is crosslinked, and to increase the stability of nano-micelle, forms crosslinking nano micella, this crosslinking nano micella is to cell
Interior reducing environment has response, can release crosslinking.
In above-mentioned technical proposal, the end modified cholic acid of polyaminoacid can increase the hydrophobic area of micella core, so as to increase
Load dose.
Another object of the present invention is provides a kind of crosslinking nano micella.
In order to achieve the above objectives, specific technical solution of the present invention is a kind of crosslinking nano micella, the parent of the nano-micelle
Water layer is made of hydrophilic polymer, and hydrophobic layer is made of cholic acid and polyaminoacid, and the sulphur caprylyl of polyaminoacid side chain can be with
Crosslinking.
In above-mentioned technical proposal, the grain size of the crosslinking nano micella is 100~150 nanometers, and particle diameter distribution PDI is 0.10
~0.25.
The method for preparing above-mentioned crosslinking nano micella includes the following steps：
(1) by the Amphipathilic block polymer that above-mentioned cholic acid is modified by being self-assembly of nano-micelle, the nanometre glue
The hydrophilic outer layer of beam is made of polyethylene glycol, and hydrophobic layer is made of small molecule cholic acid and polyaminoacid and sulphur caprylyl；
(2) core of nano-micelle in step (1) is crosslinked, by stablizing nanometer to the pentacyclic crosslinking of sulphur caprylyl
Micellar structure obtains crosslinking nano micella.
In above-mentioned technical proposal, amphipathic polymer described in step (1) is self-assembly of in water to be modified with sulphur caprylyl
Polyaminoacid be hydrophobic part dimensionally stable, be distributed uniform nano-micelle, the grain size of the nano-micelle for 100~
150nm。
In above-mentioned technical proposal, the crosslinking described in step (2) can be used but be not limited to following method：
(thiol-disulfide exchange) is exchanged using thiol disulfide to react, and passes through the thio threose of Isosorbide-5-Nitrae-two
Alcohol (DTT) is chemically crosslinked the five-membered ring containing disulfide bond in nano-micelle obtained by step (1)；Wherein, Isosorbide-5-Nitrae-two is thio
The dosage of threitol (DTT) is the 10% of the molal quantity of the sulphur caprylyl in polymer, and nano-micelle can be successfully crosslinked.
The stability of crosslinking nano micella is greatly improved relative to no crosslinked nano-micelle obtained by above-mentioned technical proposal,
It is not dissociated 1000 times of dilution (simulation IV injections)；To the stabilized aqueous solution of the sodium chloride of 150mM and 2M, grain size and
Changes in distribution is little；Organic solvent such as dimethyl sulfoxide is stablized, grain size only slightly becomes larger in a certain range.
Solution crosslinking can occur in reducing environment for crosslinking nano micella obtained by above-mentioned technical proposal, for solving crosslinked go back
Former agent may be selected from but be not limited to：Molecule containing sulfydryl, such as Isosorbide-5-Nitrae-dithiothreitol dithio (DTT), glutathione (GSH) or containing trivalent
The compound of phosphorus, such as tributyl phosphate (Bu3P) three (2- chloroethyls) phosphates (tris (2-carboxyethyl)-
Phosphine, TCEP)；Such as when a concentration of 10mM of DTT, above-mentioned crosslinking nano micella can be crosslinked by solution, such as Fig. 2
It is shown.
Because above-mentioned crosslinking nano micella has reduction-sensitive, it is possible to which the application crosslinking nano micella is as medicine
Object carrier, the end modified cholic acid of Amphipathilic block polymer can improve contain efficiency of the crosslinking nano micella to drug, improve and hand over
The stability that connection nano-micelle is recycled in blood in vivo improves crosslinking nano micella by the efficiency of tumour cell endocytosis, so as to
The bioavilability of drug is improved, while crosslinking nano micella can facilitate exclusion external, as shown in Figure 2.
Another object of the present invention is to provide the application of above-mentioned crosslinking nano micella, and the crosslinking nano micella is as drug
The application of carrier.
In order to achieve the above objectives, the specific technical solution of the present invention is the amphipathic nature polyalcohol modified using above-mentioned cholic acid
As the method for pharmaceutical carrier, include the following steps：
(1) drug is first dissolved in organic solution, then is stirred together for the organic solution of the amphipathic polymer, is then dripped again
Add secondary water, dialyse 24 hours after obtained solution is stirred 0.5 hour, obtain the nano-micelle of packaging medicine；
(2) 10mol% is added in the nano-micelle of formation to carry out relative to Isosorbide-5-Nitrae-dithiothreitol dithio (DTT) of cystine linkage
Crosslinking obtains the crosslinking nano micella of packaging medicine.
In above-mentioned technical proposal, the drug may be selected from but be not limited to：One kind in hydrophobic drug.Art technology
Personnel can select the required drug molecule encapsulated as needed.
In further technical solution, in order to solve the problems, such as cell-penetrating/poor permeability of carrier in drug release, usually
Can cellular uptake be promoted by receptor-mediated cell endocytic (receptor mediated endocytosis).Receptor
The cell endocytic of mediation is generally realized thin by the biological targeting molecule such as active targeting of monoclonal antibody, polypeptide (such as RGD) and folic acid
Intracellular gulps down, so as to increase the bioavilability of drug.
By taking PEG-pGlu (EDA-LA)-CA as an example, pass through PEG-NH first2Ring-opening polymerisation BLG-NCA obtains amphipathic
Object is closed, polyaminoacid end carries out esterification and connects cholic acid, the benzyloxycarbonyl group part in polyaminoacid is carried out with ethylenediamine
Aminolysis connects lipoic acid using amidation process.
In preferred technical solution, PEG-pGlu (EDA-LA)-CA, wherein, PEG is dissolved in water and many solvents, and should
Polymer has excellent biocompatibility, can rapidly be excluded external and not produce any toxic side effects by body, also have and be easy to
The advantages of modified；Polyaminoacid is the basic composition unit of biological function macro-molecular protein, is to form egg needed for Animal nutrition
The base substance of white matter.Polyaminoacid can be degraded to amino acid, good biocompatibility, and safe nothing under the action of enzyme in vivo
Poison, the research of polyaminoacid are widely paid close attention to.Polyaminoacid is a kind of low toxicity, good biocompatibility, easily by body
Absorb, the Biodegradable high molecular of metabolism, polyaminoacid and drug by formation of chemical bond conjugate, in vivo acidic environment and
Chemical bond rupture discharges drug under the action of enzyme, has the function that sustained release, targeting, and can reduce the toxicity of drug.Sulphur is pungent
Acid is a kind of endogenic antioxidant of FDA approvals, can remove body free radical, reduces blood glucose.Therefore whole system tool
There is very excellent biocompatibility.
Since above-mentioned technical proposal is used, the present invention has following advantages compared with prior art：
(1) since the hydrophobic part of the amphipathic nature polyalcohol of the present invention is polyaminoacid and cholic acid, cholic acid can increase micella
Middle long term voyage always improves drugloading rate, and polyaminoacid side chain connects lipoic acid, can be by amphipathic polymer self assembly shape
Into nano-micelle carry out core crosslinking, obtain the polymer nano micelle of stable crosslinked reduction sensitivity, which exists
It is not easy to dissociate in extracellular and blood, so as to ensure the drug substance stable of nano-micelle package；Drug is overcome to release in advance in vivo
It puts, deliver the deficiencies such as efficiency is low.
(2) once into tumour cell, nano-micelle quickly solves crosslinking and dissociates, and drug quick release comes out, so as to produce
Raw efficient therapeutic effect.
Description of the drawings
Fig. 1 is the synthetic route chart of polyamino acid block copolymer PEG-pGlu (EDA-LA)-CA of cholic acid modification；
Fig. 2 is that PEG-pGlu (EDA-LA)-CA carries the preparation of medicine crosslinking micella and its restores response condition in the cell
Lower drug release process schematic；
Specific embodiment
The invention will be further described with reference to the accompanying drawings and embodiments：
Embodiment one, synthetic polymer PEG-pGlu (EDA-LA)15- CA under nitrogen protection, by CH3O-PEG-NH2
(1.00g, 0.20mmol) is dissolved in dry DMF (4mL), is added in the confined reaction bottle of 50mL, then add in thereto
Bottle is put into 40 DEG C of oil baths, is stirred to react 48h, is settled with anhydrous ether by BLG-NCA (1.05g, 4mmol), sand core funnel
It filters, is finally dried in vacuo for 24 hours, obtains white solid, i.e. PEG-b-PBLG amphipathic nature polyalcohols.Yield：85%.
Under nitrogen protection, CA (0.33g, 0.04mmol) is dissolved in dry THF (4mL) and 1mL anhydrous acetonitriles
In, then NHS (0.03g, 0.23mmol) and DCC (0.04g, 0.19mmol) be dissolved in anhydrous THF respectively add in it is above-mentioned molten
In liquid, it is stirred to react 18h at ambient temperature；With 0.45 μm of membrane filtration, by PEG-b-PBLG polymer (0.50g,
It 0.06mmol) is dissolved in anhydrous THF, adds in closed reactor, then the good solution of above-mentioned filter is added in, room temperature reaction for 24 hours, is used
Absolute ethyl alcohol sedimentation washes twice, and centrifuges, vacuum drying.Yield：69%.
Under nitrogen protection, PEG-b-PBLG-CA (0.33g, 0.55mmol) is dissolved in anhydrous DMF (5mL), added in
Into 100mL closed reactors, distilled ethylenediamine (1.84mL, 2.75mmol) is added in thereto, and bottle is placed in 40 DEG C
In oil bath, after being stirred to react 36h, 10% acetic acid solution (30mL) is added dropwise into system, with the HCl/water solution dialysis 3 of 0.01M
Secondary, distilled water is dialysed 3 times, and freeze-drying obtains PEG-pGlu (EDA)15- CA polymer.Yield：92%.
Under nitrogen protection, by previous step polymer P EG-pGlu (EDA)15- CA is dissolved in 11mL DCM/2mL DMF,
It is added in 100mL confined reaction bottles, adds lipoic acid (0.05g, 0.25mmol), DCC ((0.05g, 0.25mmol), NHS
Reaction 2 days is stirred at room temperature in (0.03g, 0.25mmol) and triethylamine (0.06g, 0.55mmol), at the end of reaction, filtering removal
The dicyclohexylurea (DCU) generated in reaction, then concentrated by rotary evaporation, anhydrous ether settle twice, and sand core funnel filters, vacuum drying
For 24 hours, yield：94%.
Embodiment two, synthetic polymer PEG-pGlu (EDA-LA)26-CA
Under nitrogen protection, by CH3O-PEG-NH2(0.50g, 0.10mmol) is dissolved in dry DMF (5mL), is added to
In the confined reaction bottle of 50mL, then BLG-NCA (0.71g, 2.70mmol) is added in thereto, bottle is put into 40 DEG C of oil baths,
48h is stirred to react, is settled with anhydrous ether, sand core funnel filters, and is finally dried in vacuo for 24 hours, obtains white solid, i.e. PEG-
PBLG amphipathic nature polyalcohols.Yield：84%.
Under nitrogen protection, CA (0.13g, 0.34mmol) is dissolved in dry THF (3mL) and 1mL anhydrous acetonitriles
In, it adds in closed reactor, then NHS (0.05g, 0.40mmol) and DCC (0.07g, 0.34mmol) are dissolved in nothing respectively
It is added in water THF in above-mentioned solution, is stirred to react 18h at ambient temperature；With 0.45 μm of membrane filtration, PEG-b-PBLG is gathered
It closes object (0.40g, 0.04mmol) to be dissolved in anhydrous THF, add in closed reactor, then the solution filtered above is added in it instead
It answers in device, room temperature reaction for 24 hours, is washed twice with absolute ethyl alcohol sedimentation, centrifuged, vacuum drying.Yield：75%.
Under nitrogen protection, by PEG-b-PBLG26- CA (0.3g, 0.03mmol) is dissolved in anhydrous DMF (5mL), is added in
Into 100mL closed reactors, distilled ethylenediamine (2.1g/2.34mL, 35.1mmol) is added in thereto, bottle is placed in
In 40 DEG C of oil baths, after being stirred to react 36h, 10% acetic acid solution (30mL) is added dropwise into system, with the HCl/water solution of 0.01M
Dialysis 3 times, distilled water are dialysed 3 times, and freeze-drying obtains PEG-pGlu (EDA)26- CA polymer.Yield：88%.
Under nitrogen protection, by polymer P EG-pGlu (EDA-LA)26- CA is dissolved in 6mL DCM, and it is close to be added to 50mL
It closes in reaction bulb, adds lipoic acid (0.03g, 0.15mmol), DCC (0.03g, 0.15mmol), NHS (0.02g,
0.15mmol) and reaction 2 days is stirred at room temperature in triethylamine (0.03g/45.26 μ L, 0.32mmol), at the end of reaction, filtering removal
The dicyclohexylurea (DCU) generated in reaction, then concentrated by rotary evaporation, anhydrous ether settle twice, and sand core funnel filters, vacuum drying
For 24 hours, yield：90%.
The polymer of different degree of substitution is prepared, and test resulting polymers shape in secondary water according to embodiment one and example two
Into nano-micelle size and distribution, the results are shown in Table 1：
The amphipathic nature polyalcohol nano-micelle of the cholic acid modification of 1 different molecular weight of table
Embodiment three, polymer P EG-pGlu (EDA-LA)15It is prepared by-CA nano-micelles
Polymer P EG-LA nano-micelles are prepared by dialysis process.Detailed process is：By 1mg polymer Ps EG-pGlu
(EDA-LA)15- CA is dissolved in 1mL dimethyl sulfoxides, and under 25 DEG C of stirring conditions, 3mL secondary waters are added dropwise thereto.Obtained solution
It after stirring 0.5h, is fitted into preprepared bag filter (MWCO 3500), deionized water dialysis obtains polymer nanocomposite for 24 hours
Micella.
Example IV, polymer P EG-pGlu (EDA-LA)15- CA nano-micelles are crosslinked
Crosslinked polymer nano micelle in order to obtain, by the polymer nano micelle formed in embodiment three (0.2 milli
Grams per milliliter) to adjust pH value with 0.7M borate buffer solutions be 8.5, lead to nitrogen 10 minutes, it is thio to add in 1mg/mL Isosorbide-5-Nitraes-two
13 μ L of threitol (DTT) solution, mixed liquor is stirred to react 22 hours under room temperature under nitrogen protective condition.What is obtained crosslinked receives
Rice glue beam is dialysed with deionized water, removes unreacted DTT.Crosslinked nano-micelle size is 109 nanometers, and particle diameter distribution is
0.15, there is significant stability to high dilution (simulation is injected intravenously) and physiological salt concentration (0.15M) and high salt concentration (2M).
Embodiment five, polymer P EG-pGlu (EDA-LA)26- CA nano-micelles are crosslinked
Crosslinked polymer nano micelle in order to obtain, by the polymer nano micelle formed in embodiment five (0.2 milli
Grams per milliliter) to adjust pH value with 0.7M borate buffer solutions be 8.5, and logical nitrogen 10 minutes, add in-two sulphur of 1mg/mL Isosorbide-5-Nitraes
For 19 μ L of threitol (DTT), mixed liquor is stirred to react 22 hours under room temperature argon gas protective condition.Obtained crosslinked nanometer
Micella is dialysed with deionized water, removes the DTT not reacted.Crosslinked nano-micelle size is 134 nanometers, and particle diameter distribution is
0.19, there is significant stability to high dilution (simulation is injected intravenously) and physiological salt concentration (0.15M).
The crosslinked nano-micelle of the polymer of different degree of substitution is prepared according to example IV, and the crosslinking for testing formation is received
The size of rice glue beam and distribution, the results are shown in Table 2：
The amphipathic nature block polymer nano-micelle of the lipoic acid modification of 2 different degree of substitution of table
Claims (5)
1. a kind of crosslinking nano micella, it is characterised in that：The polyaminoacid block that the crosslinking nano micella is modified by cholic acid is total to
Polymers is formed, and the polyamino acid block copolymer of cholic acid modification has amphipathic, and main chain contains hydrophilic segment and hydrophobic
Segment, and in the end modified small molecule cholic acid of hydrophobic section；The hydrophilic chain of the polyamino acid block copolymer of the cholic acid modification
For polyethylene glycol；The molecular weight of the polyamino acid block copolymer of the cholic acid modification is 5000~30000；The hydrophobic chain
The one kind of section in poly-aspartate benzyl ester, poly benzyl glutamate, polylysine benzyl ester；The molecular weight of the hydrophobic segment is
3000~25000Da；The external hydrophilic layer of the crosslinking nano micella is made of hydrophilic polymer, and inner hydrophobic layer is by cholic acid
And the five-membered ring crosslinking of polyaminoacid side chain sulphur caprylyl is formed.
2. crosslinking nano micella according to claim 1, it is characterised in that：The grain size of the crosslinking nano micella is 100
~150 nanometers, particle diameter distribution PDI is 0.10~0.25.
3. crosslinking nano micella according to claim 1, it is characterised in that：Prepare the method packet of above-mentioned crosslinking nano micella
Include following steps：
(1) by the polyamino acid block copolymer that cholic acid described in claim 1 is modified by being self-assembly of nano-micelle, institute
The hydrophilic outer layer for stating nano-micelle is made of hydrophilic polymer, inner hydrophobic layer by polyaminoacid side chain sulphur caprylyl and courage
Acid is formed；
(2) inner hydrophobic layer of nano-micelle in step (1) is crosslinked, passes through five yuan of the sulphur caprylyl to polyaminoacid side chain
The crosslinking of ring carrys out stable nanometer micelle structure, obtains crosslinking micella.
4. crosslinking nano micella according to claim 3, it is characterised in that：Cross-linking method described in step (2) is：
Using thiol disulfide exchange reaction, as Isosorbide-5-Nitrae-dithiothreitol dithio to containing two in nano-micelle obtained by step (1)
The five-membered ring of sulfide linkage is chemically crosslinked；Wherein, the dosage of Isosorbide-5-Nitrae-dithiothreitol dithio is disulfide bond mole in polymer micelle
Several 5~20%.
5. method of the crosslinking nano micella as pharmaceutical carrier described in application claim 1, includes the following steps：
(1) drug is first dissolved in organic solution, then the polyamino acid block copolymer modified with cholic acid described in claim 1
Organic solution is stirred together for, and secondary water is then slowly added dropwise again, is dialysed after obtained solution is stirred 30min, obtains package medicine
The nano-micelle of object；
(2) 5~20mol% is added in the nano-micelle of formation relative to Isosorbide-5-Nitrae-dithiothreitol dithio of cystine linkage be crosslinked
To the crosslinking nano micella of packaging medicine；
(3) for the crosslinking nano micella of the packaging medicine described in step (2) in reproducibility environment, DTT contents are more than or equal to 2mM
When, solution crosslinking can release drug.
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| CN106496571B (en) * | 2016-10-17 | 2019-10-11 | 江苏师范大学 | Restore responsiveness Amphipathilic block polymer and nano-micelle and application |
| CN106727307B (en) * | 2016-12-12 | 2019-07-02 | 江苏师范大学 | A kind of preparation and application restoring sensitive nano-micelle |
| CN107233581A (en) * | 2017-06-15 | 2017-10-10 | 中山大学 | One kind can carry out the imaging of MR fluorescent dual module states lymph, degradable small particle nano-micelle and its preparation method and application |
| CN110496231B (en) * | 2018-05-16 | 2020-09-18 | 浙江大学 | Amphiphilic polymer nano micelle containing polydopa amino acid chelated ferric ions and application |
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