CN107033305B - A kind of preparation method of the amphipathic vermiform unimolecule prodrug of reproducibility response - Google Patents
A kind of preparation method of the amphipathic vermiform unimolecule prodrug of reproducibility response Download PDFInfo
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- 229940002612 prodrug Drugs 0.000 title claims abstract description 42
- 239000000651 prodrug Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 23
- 229940079593 drug Drugs 0.000 claims abstract description 21
- 239000013067 intermediate product Substances 0.000 claims abstract description 9
- 229920001503 Glucan Polymers 0.000 claims abstract description 8
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims abstract description 8
- 239000003999 initiator Substances 0.000 claims abstract description 6
- 239000000178 monomer Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 55
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 31
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 17
- 238000000746 purification Methods 0.000 claims description 14
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052786 argon Inorganic materials 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 9
- 239000002244 precipitate Substances 0.000 claims description 9
- 230000001376 precipitating effect Effects 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- 238000010257 thawing Methods 0.000 claims description 8
- 239000008367 deionised water Substances 0.000 claims description 7
- 229910021641 deionized water Inorganic materials 0.000 claims description 7
- 239000002608 ionic liquid Substances 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
- VMGSQCIDWAUGLQ-UHFFFAOYSA-N n',n'-bis[2-(dimethylamino)ethyl]-n,n-dimethylethane-1,2-diamine Chemical group CN(C)CCN(CCN(C)C)CCN(C)C VMGSQCIDWAUGLQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 4
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical compound NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- KYNFOMQIXZUKRK-UHFFFAOYSA-N 2,2'-dithiodiethanol Chemical compound OCCSSCCO KYNFOMQIXZUKRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- YOCIJWAHRAJQFT-UHFFFAOYSA-N 2-bromo-2-methylpropanoyl bromide Chemical compound CC(C)(Br)C(Br)=O YOCIJWAHRAJQFT-UHFFFAOYSA-N 0.000 claims 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 3
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 claims 1
- PBIDWHVVZCGMAR-UHFFFAOYSA-N 1-methyl-3-prop-2-enyl-2h-imidazole Chemical compound CN1CN(CC=C)C=C1 PBIDWHVVZCGMAR-UHFFFAOYSA-N 0.000 claims 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 claims 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 claims 1
- 239000000693 micelle Substances 0.000 abstract description 6
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 abstract description 3
- 238000013270 controlled release Methods 0.000 abstract description 3
- 229960003067 cystine Drugs 0.000 abstract description 3
- 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 abstract 2
- 108010024636 Glutathione Proteins 0.000 abstract 1
- 229960003180 glutathione Drugs 0.000 abstract 1
- 230000002209 hydrophobic effect Effects 0.000 abstract 1
- 238000002844 melting Methods 0.000 abstract 1
- 230000008018 melting Effects 0.000 abstract 1
- 229920000642 polymer Polymers 0.000 abstract 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 229940127093 camptothecin Drugs 0.000 description 11
- 239000007789 gas Substances 0.000 description 8
- 238000010586 diagram Methods 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 229920002307 Dextran Polymers 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- QVRCRKLLQYOIKY-UHFFFAOYSA-M 1-methyl-3-prop-2-enylimidazol-1-ium;chloride Chemical compound [Cl-].C[N+]=1C=CN(CC=C)C=1 QVRCRKLLQYOIKY-UHFFFAOYSA-M 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- WVUYNWCKWXAGLA-UHFFFAOYSA-N (ethoxydisulfanyl)oxyethane Chemical compound CCOSSOCC WVUYNWCKWXAGLA-UHFFFAOYSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- RQQDJYROSYLPPK-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 Chemical class N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 RQQDJYROSYLPPK-UHFFFAOYSA-N 0.000 description 1
- FPXWISWMBLVKOD-UHFFFAOYSA-N [4-(4-aminobenzoyl)oxyphenyl] 4-aminobenzoate Chemical compound C1=CC(N)=CC=C1C(=O)OC(C=C1)=CC=C1OC(=O)C1=CC=C(N)C=C1 FPXWISWMBLVKOD-UHFFFAOYSA-N 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- ORXJMBXYSGGCHG-UHFFFAOYSA-N dimethyl 2-methoxypropanedioate Chemical compound COC(=O)C(OC)C(=O)OC ORXJMBXYSGGCHG-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 201000003911 head and neck carcinoma Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F220/28—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/38—Esters containing sulfur
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F220/28—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety
- C08F220/285—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety and containing a polyether chain in the alcohol moiety
- C08F220/286—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety and containing a polyether chain in the alcohol moiety and containing polyethylene oxide in the alcohol moiety, e.g. methoxy polyethylene glycol (meth)acrylate
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/38—Esters containing sulfur
- C08F220/387—Esters containing sulfur and containing nitrogen and oxygen
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Abstract
The invention discloses a kind of preparation methods of the amphipathic vermiform unimolecule prodrug of reproducibility response, it is using glucan as carrier, using the cystine linkage in the glutathione stimuli responsive drug molecule of tumor microenvironment middle and high concentration, to realize the controlled release of drug.Preparation method includes the following steps: (1) preparation of the camptothecine monomer CPT-SS containing cystine linkage.(2) preparation of initiator DEX-Br.(3) preparation of the hydrophobic intermediate product of DEX-CPT-SS.(4) preparation of amphiphilic polymer DEX-CPT-OEGMA-SS, is named as DCO-SS.Gained prodrug can form water-soluble unimolecular micelle, have high drug load (> 23 wt%), high micella stability, sensitive stimuli responsive drug release, the advantages such as good biocompatibility.It efficiently solves the problems, such as that dewatering medicament molecular melting degree is low, provides a kind of efficient drug conveying carrier.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of amphipathic vermiform unimolecule prodrug of reproducibility response
Preparation method and its application in drug therapy cancer field.
Background technique
Glucan (Dextran, also known as dextran, a kind of polysaccharide, molecular formula (C6H10O5) n, No. CAS: 9004-54-
0), glucan can replace a part of whole blood, the expansion agent (referred to as dextran) as Plasma volumes in transfusion procedure.Commodity blood
Slurry substitute is that the glucan after partial hydrolysis is dissolved in physiological saline, thus glucan has good biocompatibility, to people
Body is harmless, biodegradable, is the good carrier material of anticancer drug.Camptothecine (Camptothecin, CPT, chemical structure
Formula: C20H16N2O4, No. CAS: 7689-03-4, relative molecular weight: 348.43) being a kind of camplotheca acuminata from Central-South, the southwestern distribution of China
It is middle to extract obtained phytogenic anticarcinogen.Intestines and stomach and head-neck carcinoma etc. are had a better effect.Camptothecine belongs to cytotoxicity quinoline
Quinoline Alkaloid can inhibit DNA topoisomerase (TOPO I).
Due to camptothecin drug molecular dimension is smaller and water in solubility it is extremely low, faced in delivery process non-
The problems such as specific selectivity, utilization ratio of drug are lower, renal clearance is higher and toxic side effect is stronger is urgently to be resolved, therefore improves
It is water-soluble and its bioactivity is protected to have important scientific meaning.Unimolecule prodrug delivery system can effectively combine unimolecule
The technological merit of drug and nanosystems optionally delivers the medicament to tumor locus, is reducing by introducing cystine linkage
Drug effect is played while toxic side effect.Compared to traditional unimolecule prodrug, based on vermiform pro-drug synthesized by glucan,
Drug uploads rate higher (being higher than 23 wt%) and vermicular texture facilitates drug particle and smoothly rapidly enters cell, and enhancing is thin
Intracellularization.
Summary of the invention
In view of this, an object of the present invention is to be directed to existing unimolecule anti-tumor drug poor selectivity, it can not controlled release
Put, drug uploads the low defect of rate, provide a kind of amphipathic vermiform unimolecule prodrug of reproducibility response preparation method and
Its application in drug therapy cancer field.
Specific technical solution of the present invention is as follows
A kind of preparation method of the amphipathic vermiform unimolecule prodrug of reproducibility response the following steps are included:
(1) the CPT presoma CPT-SS of preparation reproducibility response, comprising the following steps: in argon gas (Ar, 2-10Pa) atmosphere
It is 1. that 2- hydroxyethyl disulfide (BHD), methacrylic chloride, tetrahydrofuran (THF) and triethylamine (TEA) is mixed under the conditions of enclosing
Conjunction is stirred to react 24-72h, and column purifies to obtain MABHD；2. by CPT, triphosgene (BTC) and 4-dimethylaminopyridine (DMAP)
Mixture is distributed in methylene chloride (DCM), reacts 0.5-1h, then is added dropwise to MABHD and is stirred to react 24-72h, before purification obtains
Drive body CPT-SS；
(2) drug initiator DEX-Br is prepared, comprising the following steps: under argon gas (Ar, 2-10Pa) ambient conditions, by Portugal
Glycan (DEX) is dissolved in ionic liquid (1-Allyl-3-methylimidazolium chloride), cold after solid is completely dissolved
But to 0 DEG C, N-Methyl pyrrolidone (NMP) and n,N-Dimethylformamide (DMF) mixed solution is added to system, then to anti-
It answers system that 2- bromine isobutyl acylbromide (BIBB) is added, keeps ice bath 0.5-1h, be then warmed to room temperature and be protected from light 24-72h, then
It precipitates in deionized water, takes to be deposited in acetone and dissolve, repeat purification and obtain faint yellow intermediate product three times, in vacuum
The yellowish intermediate product of gained, is then dissolved in NMP, is cooled to 0 DEG C by 25-30 DEG C of drying, and BIBB is added then to reaction system,
Keep ice bath 0.5-1h, be then warmed to room temperature and be protected from light 24-72h, precipitate in deionized water, take be deposited in it is molten in acetone
Solution repeats purification and obtains pale yellow powder three times, dries at 25-30 DEG C of vacuum, obtain product DEX-Br；
(3) preparation of prodrug intermediate DEX-CPT-SS, comprising the following steps: in argon gas (Ar, 2-10Pa) ambient conditions
Under, the DEX-Br that step (2) obtains and the CPT-SS that step (1) obtains are dissolved in the mixing of DMF Yu dimethyl sulfoxide (DMSO)
Solution is added cuprous bromide (CuBr) then to system, freeze-pumping-and thaw 3 times, ligand three-(2- methylamino is added
Ethyl) amine (Me6TREN), freezing-pumping-defrosting 1 time is repeated later, 24-72h is protected from light at 25 DEG C, then in ether
Middle precipitating takes precipitating to be dissolved in methylene chloride (DCM), repeats purification and obtains pale yellow powder three times, dries at 25-30 DEG C of vacuum
It is dry, obtain prodrug intermediate DEX-CPT-SS；
(4) preparation of amphipathic prodrug DCO-SS, comprising the following steps:, will under argon gas (Ar, 2-10Pa) ambient conditions
OEGMA, DEX-CPT-SS are dissolved in the mixed solution of DMF and DMSO, and CuBr is added then to system, freeze-pumping-and thaws
3 times, ligand Me is added6Freezing-pumping-defrosting 1 time is repeated after TREN, 24-72h is protected from light at 25 DEG C, then in ether
Middle precipitating, takes precipitating to be dissolved in DCM, repeats purification and obtains pale yellow powder three times, dries at 25-30 DEG C of vacuum, obtain amphiphilic
Property prodrug DCO-SS.
Further, 1. middle BHD, methacrylic chloride and TEA three's the mass ratio of the material are 2:1:1 to step (1);Wherein
Methacrylic chloride need to first be scattered in anhydrous THF (mass concentration range is 216-108mg/mL) and is slowly added dropwise again to system
In；It is 15:1-20:1 that volume ratio, which is added, in solvent THF and TEA；Order of addition of ingredients is followed successively by BHD, THF, TEA and methacrylic chloride
THF solution.
Further, step (1) 2. in CPT is dispersed in DCM so that the mass concentration of the DCM solution of CPT is in 20-
25 mg/mL；CPT, DMAP, BTC and MABHD the mass ratio of the material are 2.4:6.7:1:1.4, and wherein BTC need to be first dissolved in anhydrous
In DCM (mass concentration range is 40-50mg/mL)；MABHD also needs to be first dissolved in anhydrous THF that (mass concentration range is 80-
120 mg/mL), then be slowly added dropwise into system；Order of addition of ingredients is followed successively by the DCM solution and MABHD of CPT, DMAP, DCM, BTC
THF solution.
Further, the mass ratio of DEX and ionic liquid is 1:5-1:10 in step (2), and when dissolution needs heat temperature raising
To 80 DEG C, the mixed liquor volume of NMP and DMF than for 1:1(total volume is ionic liquid 2 times)；Intermediate product and anhydrous NMP
Addition magnitude relation be 60-80mg/mL, BIBB need to be slowly added dropwise.
Further, in step (3), drug monomer CPT-SS, initiator DEX-Br, catalyst CuBr and ligand
Me6The mass ratio of the material of TREN is that the two volume ratio is 1:1 in the mixed solution of 30:1:30:30, DMSO and DMF, is added
Volume is subject to solid and is completely dissolved.
Further, the mass ratio of the material of DEX-CPT-SS, OEGMA, CuBr and Me6TREN are about in step (4)
Volume ratio both in 1:220:7.3:14.6, DMSO and DMF mixed solution is 1:1, be added volume with solid be completely dissolved for
It is quasi-.
Main advantages of the present invention are:
1. current unimolecule prodrug delivery system there are aiming at the problem that, this project creatively proposes a kind of based on also
Originality responds the delivery system of amphipathic vermiform unimolecule prodrug, can effectively improve the upper carrying capacity and selectivity release of drug,
It solves the problems, such as current unimolecule prodrug delivery system micella stability and drug selectivity controlled release, pushes the essence of tumour
Make a definite diagnosis disconnected and efficiently treatment.
2. in this project, vermicular texture facilitates drug particle and smoothly rapidly enters cell, enhance drug in cell
One of internalization and the greatest feature of this project.
Detailed description of the invention
In order to keep the purpose of the present invention, technical scheme and beneficial effects clearer, the present invention provides following attached drawing:
Fig. 1 is the synthesis schematic diagram of the amphipathic vermiform unimolecule prodrug DCO-SS of reproducibility response in embodiment 1.
Fig. 2 is the nuclear-magnetism schematic diagram of the amphipathic vermiform unimolecule prodrug DCO-SS of reproducibility response in embodiment 1.
Fig. 3 is the infrared schematic diagram of the amphipathic vermiform unimolecule prodrug DCO-SS of reproducibility response in embodiment 1.
Fig. 4 is DLS and the TEM figure of the amphipathic vermiform unimolecule prodrug nano-micelle of reproducibility response in embodiment 1.
The tablets in vitro signal that Fig. 5 is the amphipathic vermiform unimolecule prodrug DCO-SS of reproducibility response in embodiment 1
Figure.
Fig. 6 is the amphipathic vermiform unimolecule prodrug nano-micelle of reproducibility response in embodiment 1 to HeLa and MCF-
The toxicity comparison diagram of 7 cells.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..
Embodiment 1 prepares the amphipathic vermiform unimolecule prodrug DCO-SS of reproducibility response
(1) the CPT presoma CPT-SS of preparation reproducibility response: under argon gas (Ar) ambient conditions, 1. by 2- ethoxy
Disulphide (BHD, 6.25g, 40.5mmol), (2.2mL, 22.73mmoL are dissolved in the anhydrous THF of 15 mL to methacrylic chloride
In, it is slowly added dropwise into system), tetrahydrofuran (THF, 50mL) and triethylamine (TEA, 3.3mL, 24mmoL) are mixed
Overnight, column purifies to obtain MABHD；2. by CPT(1.39g, 4mmoL), (BTC, 500mg, 1.685mmoL are dissolved in 10 to triphosgene
In the anhydrous DCM of mL, it is slowly added dropwise into system), the mixture point of 4-dimethylaminopyridine (DMAP, 1.56g, 11.3mmoL)
It is scattered in the anhydrous DCM of 60mL, reacts 30min, then be added dropwise to MABHD(976mg, 2.375mmoL, be dissolved in the anhydrous THF of 10 mL
In, it is slowly added dropwise into system), it is stirred overnight, purifies to obtain presoma CPT-SS；
(2) prepare drug initiator DEX-Br: under argon gas (Ar) ambient conditions, 1. by glucan (DEX, 1 g, Mn=
3500) being dissolved in ionic liquid, (1-Allyl-3-methylimidazolium chloride, 5 g), 80 DEG C is warming up to, to solid
After being completely dissolved, N-Methyl pyrrolidone (NMP) and n,N-Dimethylformamide (DMF) mixed solution is added to system in ice bath
(volume ratio 1:1,10 mL of total volume), then to reaction system be added 2- bromine isobutyl acylbromide (BIBB, 15.2mL,
123mmoL), it is kept for ice bath one hour, is warmed to room temperature, is protected from light for 24 hours, precipitates in deionized water, take and be deposited in acetone
Dissolution repeats purification and obtains faint yellow intermediate product, 25 DEG C of vacuum drying three times.Gained intermediate product (1.5 g) is dissolved in nothing
Water NMP(20 mL) in, BIBB(10mL, 80.9mmoL is added then to reaction system in ice bath), ice bath 1h is kept, room is risen to
Temperature is protected from light for 24 hours, precipitates in deionized water, takes to be deposited in acetone and dissolve, and repeats purification and obtains yellowish toner three times
End, 25 DEG C of vacuum drying, obtains product DEX-Br(900 mg).
(3) preparation of prodrug intermediate DEX-CPT-SS: under argon gas (Ar) ambient conditions, by DEX-Br (12.12mg,
0.02mmoL) and CPT-SS(357.8mg, 0.6mmoL) be dissolved in the mixed solution (volume ratio of DMF Yu dimethyl sulfoxide (DMSO)
For 1:1,6 mL of total volume), cuprous bromide (CuBr, 8.607mg, 0.06mmoL) is added then to system, freeze-take out
Gas-defrosting 3 times, ligand three-(2- methylaminoethyl) amine (Me is added6TREN, 16.5 μ L, 0.06mmoL) repeated freezing-pumping
Gas-defrosting 1 time, 25 DEG C are protected from light for 24 hours, precipitate in 20 times of volume ether, precipitating is taken to be dissolved in methylene chloride (DCM, 6mL)
In, it repeats purification and obtains pale yellow powder three times, 25 DEG C of vacuum drying obtain prodrug intermediate DEX-CPT-SS.
(4) preparation of amphipathic prodrug DCO-SS: under argon gas (Ar) ambient conditions, by OEGMA (450mg,
0.9mmoL), DEX-CPT-SS (60mg, 0.0041mmoL) is dissolved in mixed solution (volume ratio 1:1, the totality of DMF and DMSO
6 mL of product), CuBr (4.3mg, 0.03mmoL) is added then to system, freeze-pumping-and thaws 3 times, ligand is added
Me6TREN (16 μ L, 0.06mmoL), repeated freezing-pumping-defrosting 1 time, 25 DEG C are protected from light for 24 hours, precipitate in ether,
It takes precipitating to be dissolved in DCM, repeats purification and obtain pale yellow powder three times, 25 DEG C of vacuum drying obtain amphipathic prodrug DCO-SS.Its
Synthesis process is shown in Fig. 1.Fig. 2 respectively shows the nuclear-magnetism schematic diagram of DEX-CPT-SS and DCO-SS.IR Characterization is shown in Fig. 3.
(5) it prepares unimolecule prodrug nano-micelle: under room ambient conditions, being equipped with the dimethyl sulfoxide of the DCO-SS of 5 mg/mL
(DMSO) solution is slowly dropped in deionized water, and after a certain period of time, dialysis obtains lurid unimolecule in secondary water for stirring
Prodrug nano-micelle (Fig. 4).Its DLS result (Fig. 4 A) shows that prodrug nano-micelle is 125.2 nm, and particle diameter distribution coefficient is
0.16, Fig. 4 B is the TEM shape appearance figure of gained nanoparticle.Fig. 5 is nano-prodrug DCO-SS release in vitro comparison diagram.Fig. 6 is glue
Beam and free drug act on HeLa and MCF-7 tumour cell the in vitro toxicity contrast schematic diagram of 72h.
Finally, it is stated that preferred embodiment above is only used to illustrate the technical scheme of the present invention and not to limit it, although logical
It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (6)
1. a kind of preparation method of the amphipathic vermiform unimolecule prodrug of reproducibility response, it is characterised in that: including following step
It is rapid:
(1) the camptothecine CPT presoma CPT-SS of preparation reproducibility response, the following steps are included: in the argon Ar atmosphere of 2-10Pa
Under the conditions of enclosing, 1. 2- hydroxyethyl disulfide BHD, methacrylic chloride, tetrahydrofuran THF and triethylamine TEA are mixed
24-72h is reacted, column purifies to obtain MABHD；2. by the mixing of camptothecine CPT, triphosgene BTC and 4-dimethylaminopyridine DMAP
Object is distributed in methylene chloride DCM, reacts 0.5-1h, then is added dropwise to MABHD and is stirred to react 24-72h, and purification obtains presoma
CPT-SS；
(2) drug initiator DEX-Br is prepared, comprising the following steps: under the argon Ar ambient conditions of 2-10Pa, by glucan
DEX is dissolved in ionic liquid chlorination 1- allyl -3- methylimidazole, after solid is completely dissolved, is cooled to 0 DEG C, and N- is added to system
2- bromine isobutyl acylbromide is added then to reaction system in methyl pyrrolidone NMP and n,N-Dimethylformamide DMF mixed solution
BIBB keeps ice bath 0.5-1h, is then warmed to room temperature and is protected from light 24-72h, then precipitate in deionized water, take precipitating
It is dissolved in acetone, repeats purification and obtain faint yellow intermediate product three times, dried at 25-30 DEG C of vacuum, it is then that gained is light
Yellow intermediate product is dissolved in NMP, is cooled to 0 DEG C, and BIBB is added then to reaction system, keeps ice bath 0.5-1h, then rises to
Room temperature is simultaneously protected from light 24-72h, precipitates in deionized water, takes to be deposited in acetone and dissolve, and repetition purification obtains yellowish three times
Color powder, 25-30 DEG C of drying, obtains product DEX-Br under vacuum condition；
(3) preparation of prodrug intermediate DEX-CPT-SS, comprising the following steps:, will under the argon Ar ambient conditions of 2-10Pa
The CPT-SS that the DEX-Br and step (1) that step (2) obtains are obtained is dissolved in the mixed solution of DMF Yu dimethyl sulfoxide DMSO, with
Cuprous bromide CuBr is added in backward system, freeze-pumping-and thaws 3 times, and ligand three-(2- methylaminoethyl) amine is added
Me6TREN repeats freezing-pumping-defrosting 1 time later, is protected from light 24-72h at 25 DEG C, then precipitates, take in ether
Precipitating is dissolved in methylene chloride DCM, is repeated purification and is obtained pale yellow powder three times, dries, obtained among prodrug at 25-30 DEG C of vacuum
Body DEX-CPT-SS；
(4) preparation of amphipathic prodrug DCO-SS, comprising the following steps: under the argon Ar ambient conditions of 2-10Pa, by poly- second
Glycol methacrylate OEGMA, DEX-CPT-SS are dissolved in the mixed solution of DMF and DMSO, and CuBr is added then to system, into
Ligand Me is added in row freezing-pumping-defrosting 3 times6Freezing-pumping-defrosting 1 time is repeated after TREN, is protected from light at 25 DEG C
Then 24-72h is precipitated in ether, precipitating is taken to be dissolved in DCM, is repeated purification and is obtained pale yellow powder three times, in vacuum 25-
30 DEG C of drying, obtain amphipathic prodrug DCO-SS.
2. a kind of preparation method of the amphipathic unimolecule vermiform prodrug of reproducibility response according to claim 1,
Be characterized in that: 1. middle BHD, methacrylic chloride and TEA three's the mass ratio of the material are 2:1:1 to the step (1);Wherein first
Base acryloyl chloride need to be first scattered in anhydrous THF, and mass concentration range is 216-108mg/mL, then is slowly added dropwise to system
In；It is 15:1-20:1 that volume ratio, which is added, in solvent THF and TEA；Order of addition of ingredients is followed successively by BHD, THF, TEA and methacrylic chloride
THF solution.
3. a kind of preparation method of the amphipathic unimolecule vermiform prodrug of reproducibility response according to claim 1,
Be characterized in that: the step (1) 2. in CPT is dispersed in DCM so that the mass concentration of the DCM solution of CPT is in 20-25
mg/mL；CPT, DMAP, BTC and MABHD the mass ratio of the material are 2.4:6.7:1:1.4；Wherein BTC need to be first dissolved in anhydrous DCM
In, mass concentration range is 40-50mg/mL；MABHD also needs to be first dissolved in anhydrous THF, and mass concentration range is 80-120
Mg/mL, then be slowly added dropwise into system；Order of addition of ingredients is followed successively by the DCM solution of CPT, DMAP, DCM, BTC and the THF of MABHD
Solution.
4. a kind of preparation method of the amphipathic unimolecule vermiform prodrug of reproducibility response according to claim 1,
Be characterized in that: the mass ratio of DEX and ionic liquid is 1:5-1:10 in the step (2), needs when dissolution to be heated to
80 DEG C, the mixed liquor volume ratio of NMP and DMF are 1:1, and mixed liquor total volume is 2 times of ionic liquid；Intermediate product with it is anhydrous
The addition magnitude relation of NMP is 60-80mg/mL, and BIBB need to be slowly added dropwise.
5. a kind of preparation method of the amphipathic unimolecule vermiform prodrug of reproducibility response according to claim 1,
It is characterized in that: in the step (3), drug monomer CPT-SS, initiator DEX-Br, catalyst CuBr and ligand Me6TREN
Four the mass ratio of the material is that the two volume ratio is 1:1 in the mixed solution of 30:1:30:30, DMSO and DMF.
6. a kind of preparation method of the amphipathic unimolecule vermiform prodrug of reproducibility response according to claim 1,
It is characterized in that: DEX-CPT-SS, OEGMA, CuBr and Me in the step (4)6The mass ratio of the material of TREN is 1:
Volume ratio both in 220:7.3:14.6, DMSO and DMF mixed solution is 1:1.
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