CN117603382A - polyfructose-BPA boron medicine, preparation method and application thereof - Google Patents
polyfructose-BPA boron medicine, preparation method and application thereof Download PDFInfo
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- CN117603382A CN117603382A CN202311573566.9A CN202311573566A CN117603382A CN 117603382 A CN117603382 A CN 117603382A CN 202311573566 A CN202311573566 A CN 202311573566A CN 117603382 A CN117603382 A CN 117603382A
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- polyfructose
- bpa
- boron
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- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 229910052796 boron Inorganic materials 0.000 title claims abstract description 55
- 239000003814 drug Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 47
- 229920000157 polyfructose Polymers 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 27
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 21
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Chemical compound CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 229930091371 Fructose Natural products 0.000 claims description 14
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 14
- 239000005715 Fructose Substances 0.000 claims description 14
- 229910052786 argon Inorganic materials 0.000 claims description 14
- 239000000178 monomer Substances 0.000 claims description 13
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 239000011261 inert gas Substances 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- 238000000502 dialysis Methods 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 8
- -1 azo compound Chemical class 0.000 claims description 7
- 239000012986 chain transfer agent Substances 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 239000012528 membrane Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000037361 pathway Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 238000006116 polymerization reaction Methods 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 238000007710 freezing Methods 0.000 claims description 3
- 230000008014 freezing Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 150000003462 sulfoxides Chemical class 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000004064 recycling Methods 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 10
- 230000002194 synthesizing effect Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002609 medium Substances 0.000 description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000003760 magnetic stirring Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- AUBOIAPNLUHLAF-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,4-nonafluorobutylphosphonic acid Chemical compound OP(O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F AUBOIAPNLUHLAF-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- JGHKDVSIFPFNIJ-UHFFFAOYSA-N dodecylsulfanylmethanedithioic acid Chemical group CCCCCCCCCCCCSC(S)=S JGHKDVSIFPFNIJ-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000004700 cellular uptake Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
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- 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
- C08F120/00—Homopolymers 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
- C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F120/10—Esters
- C08F120/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F120/28—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
- A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- C08F8/00—Chemical modification by after-treatment
- C08F8/42—Introducing metal atoms or metal-containing groups
-
- 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
- C08F2438/00—Living radical polymerisation
- C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Polymers & Plastics (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to a polyfructose-BPA boron drug, a preparation method and application thereof. A polyfructose-BPA boron drug having the structural formula:r represents a C1-C12 alkane chain, and n is any integer between 30 and 300. The preparation method not only can improve the uptake capacity of the boron drug, but also can improve the detention capacity of the boron drug and prolong the detention time of the boron drug in tumor cells, thereby effectively improving the treatment effect of BNCT treatment.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a polyfructose-BPA boron drug, a preparation method and application thereof.
Background
BNCT (boron neutron capture therapy) is a novel radiotherapy technology, BNCT delivers a 10B medicament with tumor targeting capability to tumor cells for thermal neutron irradiation, 4He2+ (alpha particles) and 7Li3+ particles generated through nuclear reaction have very high radiation energy and very short radiation range (9 mu m and 5 mu m respectively), and the killing effect is limited to the cells which ingest 10B, so that target cells can be selectively killed, and normal tissues which do not ingest 10B are minimally damaged.
The key to the success of BNCT is the highly selective delivery of sufficient boron drug into tumor cells, and at present, the complex of (L) -4-dihydroxyborophenylalanine (BPA) and fructose, fructose-BPA, is clinically used as a therapeutic drug for BNCT. However, the retention time of the small molecular boron drug in tumor tissues is very short, so that intravenous injection mode is needed to be adopted for administration in clinical application, and the accumulated T/N ratio of the boron drug in the tissues is difficult to break through the range of 3:1-4:1, so that the effect of BNCT is severely limited. Therefore, the development of small molecular boron drugs with better retention capacity and tumor enrichment capacity is important for improving the clinical tumor BNCT curative effect.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a polyfructose-BPA boron drug, a preparation method and application thereof. The polyfructose-BPA boron drug provided by the embodiment of the invention not only can improve the intake capacity of the boron drug, but also can improve the detention capacity of the boron drug and prolong the detention time of the boron drug in tumor cells, thereby effectively improving the therapeutic effect of BNCT treatment.
The invention is realized in the following way:
in a first aspect, the present invention provides a polyfructose-BPA boron drug having the structural formula:
r represents a C1-C12 alkane chain, and n is any integer between 30 and 300.
In an alternative embodiment, R represents a C1-C10 alkane chain, preferably a C1-C10 linear alkane chain.
In a second aspect, the present invention provides a method for preparing a polyfructose-BPA boron drug according to the previous embodiment, comprising: the polyfructose and BPA are mixed for reaction.
In an alternative embodiment, the method comprises: mixing the polyfructose, the BPA and water, then adjusting the pH to 10-12, stirring for 1-24 hours at 20-30 ℃, and then performing post-treatment;
preferably, the pH of the reaction system is adjusted to 7-7.5 after the stirring reaction is finished, and then filtration and freeze-drying are carried out.
In an alternative embodiment, the polyfructose is synthesized using a PAFT polymerization process;
preferably, the polyfructose is synthesized with reference to the following synthetic pathway:
in an alternative embodiment, the method comprises: (1) Mixing 98.55-985.5mg of fructose diacetone methacrylate monomer, 2.1-3.65mg of chain transfer agent, 3.3mg of azo compound and 0.788-7.88mL of solvent, stirring under inert gas atmosphere, and recycling freezing, vacuumizing and filling inert gas; stirring at 60-70deg.C for 6-12 hr, cooling, and circularly dissolving and precipitating to obtain polyfructose diacetone;
(2) Mixing 60-200mg of fructo-diacetone with 1.50mL of trifluoroacetic acid aqueous solution for reaction, and dialyzing after the reaction is finished;
preferably, the volume ratio of trifluoroacetic acid to water in the aqueous solution of trifluoroacetic acid is 7-9:1.
In an alternative embodiment, the azo compound in step (1) comprises azobisisobutyronitrile, the solvent comprises one of a carbon-oxygen heterocyclic solvent, an amide solvent, a sulfoxide solvent, and an alcohol solvent, and is an anhydrous reagent; the inert gas comprises one of nitrogen or argon, preferably argon;
preferably, the solvent comprises one of anhydrous 1, 4-dioxane, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and methanol, and is an anhydrous reagent, preferably anhydrous 1, 4-dioxane;
the reaction time in the step (2) is 20-60min, preferably 40min, and the molecular weight cut-off of a dialysis membrane used for dialysis is 1000-14000Da.
In an alternative embodiment, the fructose diacetone methacrylate monomer is synthesized with reference to the following synthetic pathway:
in an alternative embodiment, the BPA is 10 And a compound with B abundance higher than 95%.
In a third aspect, the invention provides an application of the polyfructose-BPA boron drug in preparing a drug for boron neutron capture treatment.
The invention has the following beneficial effects: the boron drug provided by the embodiment of the invention can not only have good water solubility, but also improve the detention capability of the boron drug by bonding the polyfructose and the BPA through covalent bonds, so that the detention time and enrichment amount of the boron drug in tumor cells are improved, and the boron drug has application potential in BNCT clinical treatment. The preparation method provided by the embodiment of the invention is simple in process and easy to operate.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a nuclear magnetic resonance spectrum of fructose diacetone methacrylate monomer provided in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance spectrum of the fructodiacetone provided in example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance spectrum of the polyfructose provided in example 1 of the present invention;
FIG. 4 is a nuclear magnetic resonance spectrum of a polyfructose-BPA boron drug provided in example 2 of the present invention;
FIG. 5 is a graph showing the detection results provided in Experimental example 1 of the present invention;
FIG. 6 is a graph showing the detection results provided in Experimental example 2 of the present invention;
FIG. 7 is a graph showing the results of the test provided in Experimental example 3 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The embodiment of the invention provides a polyfructose-BPA boron drug, which has the following structural formula:
the number of repeating units of the monomer, i.e., the degree of polymerization, n is any integer between 30 and 300. For example, R represents a C1-C10 alkane chain, preferably a C1-C10 straight alkane chain.
In a second aspect, an embodiment of the present invention provides a method for preparing the above-described polyfructose-BPA boron drug, comprising:
(1) Synthesis of fructose-diacetone methacrylate monomer:
the synthesis was performed with reference to the following synthesis route:
specifically: fructose diacetone and amine (e.g. triethylamine) are added to a three necked round bottom flask with a magnetic stir bar. Halogen substituted alkane solvents (e.g., anhydrous methylene chloride) are added to dissolve the compound under an inert gas atmosphere (e.g., nitrogen) and the solution is cooled in an ice water bath. Methacryloyl chloride is dissolved in a dry halogen substituted alkane solvent (e.g., methylene chloride) and added dropwise through a dropping funnel while stirring under a stream of inert gas. The solution was stirred further overnight. Subsequently, the reaction mixture was poured into ice-cold water, extracted three times with a halogen-substituted alkane solvent, and then dried. The solvent was removed under reduced pressure to give a crude product of high viscosity orange liquid. The crude product was further purified by column chromatography on silica gel using a mixture of ethyl acetate: petroleum ether=1:3 volume ratio as eluent.
S2, synthesizing polyfructose;
synthesizing the polyfructose by using a PAFT polymerization method; specifically, the polyfructose is synthesized with reference to the following synthesis pathway:
the specific process is as follows:
(1) Mixing 98.55-985.5mg of fructose diacetone methacrylate monomer, 2.1-3.65mg of chain transfer agent, 3.3mg of azo compound and 0.788-7.88mL of solvent, stirring for 10-30min (preferably 30 min) under the atmosphere of inert gas (nitrogen or argon, preferably argon), and then freezing, vacuumizing and filling the inert gas; stirring at 60-70deg.C for 6-12 hr (for reaction at 70deg.C in oil bath), cooling, and circularly dissolving and precipitating to obtain polyfructose diacetone.
The amount of the fructose diacetone methacrylate monomer is selected according to the requirement of n, for example, when n=30, the mass is selected to be 98.55mg; when n=70, the mass is selected to be 230mg; when n=300, the mass was chosen to be 985.5mg.
The chain transfer agent has a mass of 2.1-3.65mg, and the amount is selected according to the requirement of R, for example, when R is a methyl group of C, the mass is selected to be 2.1mg; when R is 12C methyl groups, the mass is 3.65mg.
The volume of the solvent is 0.788-7.88mL, and is specifically selected according to the requirement of n. For example, when n=30, the selected volume is 0.788mL; when n=70, the mass is selected to be 1.84mL; at n=300, the selected volume was 7.88mL.
The azo compound comprises azodiisobutyronitrile, and the solvent comprises one of a carbon oxygen heterocyclic solvent, an amide solvent, a sulfoxide solvent and an alcohol solvent and is an anhydrous reagent; the inert gas comprises one of nitrogen or argon, preferably argon;
preferably, the solvent comprises one of anhydrous 1, 4-dioxane, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and methanol, and is an anhydrous reagent, preferably anhydrous 1, 4-dioxane.
(2) 60-200mg of fructo-diacetone is mixed with 1.50mL of trifluoroacetic acid aqueous solution for reaction, and dialysis is carried out after the reaction is finished.
Specifically, 60-200mg (preferably 80 mg) of fructo-diacetone and 1.50mL of trifluoroacetic acid (TFA): H are taken 2 The O solution (7-9:1 v/v) was mixed in a bottle equipped with a magnetic stirring bar. The mixture is stirred at room temperature for 20-60min (preferably 40 min) and then quenched with excess methanol. Then, the solution is subjected to dialysis treatment for three days by passing through a cellulose membrane having a molecular weight cut-off of 1000-10000 Da. And then freeze-drying to obtain white solid, namely the artificial polyfructose.
The molecular weight cut-off of the dialysis membrane is 1000-14000Da, preferably 1000 (n=30-40), 6000 (n=41-100) and 14000 (n=101-300).
S3, synthesizing a polyfructose-BPA boron drug;
polyfructose-BPA boron drug was synthesized with reference to the following synthetic pathway:
specifically, the polyfructose, the BPA and water are mixed and then the pH is adjusted to 10-12 (preferably 10.5 And then stirring at 20-30deg.C (e.g. 25deg.C) for 1-24 hr (preferably 12 hr), then adjusting pH of the reaction system to 7-7.5 after stirring, filtering and lyophilizing.
Wherein BPA is 10 And a compound with B abundance higher than 95%.
In a third aspect, the invention provides an application of the polyfructose-BPA boron drug in preparing a drug for boron neutron capture treatment. Wherein the medicine also comprises pharmaceutically acceptable auxiliary materials.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment of the invention provides a preparation method of polyfructose, which comprises the following steps:
s1, synthesizing a fructose diacetone methacrylate monomer;
3.0g of fructose diacetone and 2.33g of triethylamine are introduced into a three-necked round bottom flask with a magnetic stirrer bar. Anhydrous dichloromethane (140 mL) was added to dissolve the compound under nitrogen and the solution was cooled in an ice-water bath. 1.85g of methacryloyl chloride was dissolved in 50mL of dried dichloromethane and added dropwise via a dropping funnel while stirring under a nitrogen stream. The solution was stirred further overnight. Subsequently, the reaction mixture was poured into ice-cold water, and extracted three times with methylene chloride, followed by drying over sodium persulfate. The solvent was removed under reduced pressure to give a crude product of high viscosity orange liquid. The crude product was further purified by column chromatography on silica gel using a mixture of ethyl acetate: petroleum ether=1:3 volume ratio as eluent.
S2, synthesizing fructo-diacetone;
230mg of fructodiacetone methacrylate monomer (n=70), 3.65mg of chain transfer agent (R=C) 12 2- (dodecyl trithiocarbonate group) -2-methylpropanoic acid), 3.3mg of Azobisisobutyronitrile (AIBN) was added to the reaction flask, 1.84mL of anhydrous 1, 4-dioxane was added, dissolved, stirred for 30min by introducing argon gas, and then the cycle of freezing-vacuum-argon charging was performed three times, and stirred for 6h at 70℃in an oil bath. Cooling with ice water, introducing into atmosphere to terminate reaction, dissolving with small amount of tetrahydrofuran, and precipitatingFiltering in cold diethyl ether to obtain the product, and performing redissolution-precipitation circulation for at least three times to obtain white solid, namely the fructo-diacetone.
S3, synthesizing polyfructose (n=70);
80mg of the fructodiacetone synthesized in S2 was taken and mixed with 1.50mL of TFA 2 The O solution (9:1 v/v) was mixed in a bottle equipped with a magnetic stirring bar. The mixture was stirred at room temperature for 30min, and then quenched with excess methanol. Then, the solution was subjected to dialysis treatment for three days through a cellulose membrane having a molecular weight cut-off of 6000 Da. The white solid was then prepared by lyophilization as an artificial polyfructose (n=70).
Characterization of
The product synthesized in example 1, S1, was dissolved in deuterated chloroform; s2, dissolving a product obtained by synthesis in deuterated chloroform, and dissolving a product obtained by synthesis of S3 in heavy water; the nuclear magnetic hydrogen spectra were then separately tested and the results are shown in figures 1-3.
As can be seen from FIG. 2, delta shows characteristic peaks of isopropylmethylene protected fructose between 3.5 and 4.8, demonstrating successful synthesis of polyfructodiacetone. As a result, as shown in FIG. 3, delta shows characteristic peaks between 3.5 and 4.5 for fructose deprotected by isopropylidene, demonstrating successful synthesis of polyfructose.
Example 2
The embodiment of the invention provides a preparation method of a polyfructose-BPA boron drug (namely PFBPA70, n=70), which comprises the following steps:
34mg of the polyfructose obtained in the synthesis of example 1 and 60mg of BPA are taken and added into 10mL of deionized water, the pH is adjusted to 10.5, then the mixture is stirred for 12 hours at 25 ℃, the pH is adjusted to 7.4 again, and then the mixture is filtered and freeze-dried to obtain white solid, namely the poly (fructose-BPA) (PFBPA 70, n=70) macromolecular boron drug.
The resulting product was dissolved in heavy water and tested for nuclear magnetic hydrogen spectra, see figure 4. As can be seen from FIG. 4, the characteristic peaks of shifted BPA appear between 7.0 and 8.0 in delta, demonstrating successful synthesis of polyfructose-BPA boron drug.
Example 3
The embodiment of the invention provides a preparation method of a polyfructose-BPA boron drug (namely PFBPA40, n=40), which comprises the following steps:
s1, synthesizing polyfructose;
131.4mg of fructose diacetone methacrylate monomer (n=40), 3.65mg of chain transfer agent (r=c) 12 2- (dodecyl trithiocarbonate group) -2-methylpropanoic acid), 3.3mg of Azobisisobutyronitrile (AIBN) was added to the reaction flask, 1.05mL of anhydrous 1, 4-dioxane was added, dissolved, stirred for 30min by introducing argon gas, and then the cycle of freezing-vacuum-argon charging was performed three times, and stirred for 6h at 70℃in an oil bath. Cooling with ice water, introducing into atmosphere to terminate reaction, dissolving with a small amount of tetrahydrofuran, precipitating in cold diethyl ether, filtering to obtain product, and performing redissolution-precipitation cycle at least three times to obtain white solid namely polyfructose diacetone.
The synthesized fructodiacetone was then combined with 1.50mL TFA: H at 80mg 2 The O solution (9:1 v/v) was mixed in a bottle equipped with a magnetic stirring bar. The mixture was stirred at room temperature for 30min, and then quenched with excess methanol. The solution was then subjected to dialysis against a cellulose membrane of 1000Da molecular weight cut-off for three days. The white solid was then prepared by lyophilization as an artificial polyfructose (n=40).
S2, synthesizing a polyfructose-BPA boron drug;
adding 34mg of synthesized artificial polyfructose and 60mg of BPA into 10mL of deionized water, regulating the pH to 10.5, stirring for 12 hours at 25 ℃, regulating the pH to 7.5 again, filtering, and freeze-drying to obtain white solid, namely the poly (fructose-BPA) (PFBPA 40, n=40) macromolecular boron drug.
Example 4
The embodiment of the invention provides a preparation method of a polyfructose-BPA boron drug (namely PFBPA250, n=250), which comprises the following steps:
s1, synthesizing polyfructose;
821.4mg of fructodiacetone methacrylate monomer (n=250), 3.65mg of chain transfer agent (r=c) 12 2- (dodecyl trithiocarbonate group) -2-methylpropanoic acid), 3.3mg of Azobisisobutyronitrile (AIBN) was added to the reaction flask, 6.57mL of anhydrous 1, 4-dioxane was added, dissolved, stirred for 30min by introducing argon gas, and then the cycle of freezing-vacuum-argon charging was performed three times, and stirred for 6h at 70℃in an oil bath. Then cooled by ice waterAnd introducing the air to terminate the reaction, dissolving the mixture with a small amount of tetrahydrofuran, precipitating the mixture in cold diethyl ether, filtering the mixture to obtain a product, and carrying out re-dissolution-precipitation circulation at least three times to obtain white solid namely the polyfructose diacetone.
The synthesized fructodiacetone was then combined with 1.50mL TFA: H at 80mg 2 The O solution (9:1 v/v) was mixed in a bottle equipped with a magnetic stirring bar. The mixture was stirred at room temperature for 30min, and then quenched with excess methanol. Then, the solution was subjected to dialysis treatment for three days through a cellulose membrane having a molecular weight cut-off of 14000Da. The white solid was then prepared by lyophilization as an artificial polyfructose (n=250).
S2, synthesizing a polyfructose-BPA boron drug;
adding 34mg of synthesized artificial polyfructose and 60mg of BPA into 10mL of deionized water, regulating the pH to 10.5, stirring for 12 hours at 25 ℃, regulating the pH to 7.2 again, filtering, and freeze-drying to obtain white solid, namely the poly (fructose-BPA) (PFBPA 250, n=250) macromolecular boron drug.
Experimental example 1
fructose-BPA, PFBPA40, PFBPA70 and PFBPA250 solutions of the same boron content were prepared separately. Mouse breast cancer cells (4T 1) (cell density 1x 10) 6 ) Spreading in six-hole plate for culturing for 24h, changing fresh culture medium, adding fructose-BPA, PFBPA40, PFBPA70 and PFBPA250 solution, and incubating for 3h. After the incubation, the well plate solutions were blotted off and washed 3 times with PBS. After TE digestion, the cells were removed by aspiration, stopped by adding medium, and the cells were collected in 1.5mL EP tubes, centrifuged at 1000rpm for 3min, medium was discarded, and 600. Mu.L of HNO was added to each 3 The mixture was digested with heat for 12 hours to obtain a film, and the boron concentration was measured by ICP-MS.
The cell uptake of each sample was compared and the test results are shown in figure 5. The results show that poly (fructose-BPA) PFBPA40, PFBPA70 and PFBPA250 all showed greater cellular uptake capacity than fructose-BPA, with PFBPA70 having the strongest cellular uptake capacity.
Experimental example 2
fructose-BPA, PFBPA40, PFBPA70 and PFBPA250 solutions of the same boron content were prepared separately. Mouse breast cancer cells (4T 1) (cell density 1x 10) 6 ) Spread on six hole platesAfter 24h of medium culture and fresh medium exchange, fructose-BPA, PFBPA40, PFBPA70 and PFBPA250 solution are respectively added for 3h of incubation. After the liquid is changed, fresh culture medium without BPA is added for additional culture for 1h and 2h respectively. After the incubation, the well plate solutions were blotted off and washed 3 times with PBS. After TE digestion, the cells were removed by aspiration, stopped by adding medium, and the cells were collected in 1.5mL EP tubes, centrifuged at 1000rpm for 3min, medium was discarded, and 600. Mu.L of HNO was added to each 3 The mixture was digested with heat for 12 hours to obtain a film, and the boron concentration was measured by ICP-MS.
The cell uptake of each sample was compared and the test results are shown in figure 6. The results show that poly (fructose-BPA) PFBPA40, PFBPA70 and PFBPA250 all showed stronger tumor cell retention than fructose-BPA, especially the difference in retention was greatest 2h after liquid exchange.
Experimental example 3
The PFBPA70 prepared in example 2 was tested for its effect on BNCT treatment at the cellular level with fructose-BPA using mouse breast cancer cells (4T 1) as a subject. The method specifically comprises the following steps:
(1) Will be 5x10 4 4T1 cells with good cell state are placed in a centrifuge tube with 0.6mL, fructose-BPA and PFBPA70 (with the same boron content: 13.725 mug/mL and 2.745 mug/mL) with the same boron content are added into 400uL cell culture medium respectively, incubated for 3 hours, and irradiated for 1 hour under neutron source equipment.
(2) After the irradiation, the cells were digested with 0.25% pancreatin, centrifuged and resuspended in single-cell suspension. A 6-well plate was selected as the cloning plate, and 1000 cells were added to each well.
(3) Culturing for about 5 days (when macroscopic cell colonies appear), stopping culturing, removing supernatant, and washing with PBS three times. Fixation with 4% paraformaldehyde followed by addition of crystal violet dye, incubation for 10 min followed by slow washing with PBS followed by air drying.
(4) Under the same conditions, a control group was set, the boron drug was replaced with PBS, and the neutron irradiation was not performed.
Six well plates of the stained cell clones were photographed as shown in fig. 7. It can be seen that the experimental group to which the boron drug was added and neutron irradiation was performed showed a very high killing effect on 4T1 cells, and that poly (fructose-BPA) PFBPA70 was better than fructose-BPA.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A polyfructose-BPA boron drug characterized by the structural formula:
r represents a C1-C12 alkane chain, and n is any integer between 30 and 300.
2. The polyfructose-BPA boron drug according to claim 1, characterized in that R represents a C1-C10 alkane chain, preferably a C1-C10 straight alkane chain.
3. A method of preparing the polyfructose-BPA boron drug of claim 1, comprising: the polyfructose and BPA are mixed for reaction.
4. A method of preparing as claimed in claim 3, comprising: mixing the polyfructose, the BPA and water, then adjusting the pH to 10-12, stirring for 1-24 hours at 20-30 ℃, and then performing post-treatment;
preferably, the pH of the reaction system is adjusted to 7-7.5 after the stirring reaction is finished, and then filtration and freeze-drying are carried out.
5. A method of preparation according to claim 3, wherein the polyfructose is synthesized by PAFT polymerization;
preferably, the polyfructose is synthesized with reference to the following synthetic pathway:
6. the method according to claim 5, comprising: (1) Mixing 98.55-985.5mg of fructose diacetone methacrylate monomer, 2.1-3.65mg of chain transfer agent, 3.3mg of azo compound and 0.788-7.88mL of solvent, stirring under inert gas atmosphere, and recycling freezing, vacuumizing and filling inert gas; stirring at 60-70deg.C for 6-12 hr, cooling, and circularly dissolving and precipitating to obtain polyfructose diacetone;
(2) Mixing 60-200mg of fructo-diacetone with 1.50mL of trifluoroacetic acid aqueous solution for reaction, and dialyzing after the reaction is finished;
preferably, the volume ratio of trifluoroacetic acid to water in the aqueous solution of trifluoroacetic acid is 7-9:1.
7. The method according to claim 6, wherein the azo compound in the step (1) comprises azobisisobutyronitrile, and the solvent comprises one of a carbon-oxygen heterocyclic solvent, an amide solvent, a sulfoxide solvent and an alcohol solvent, and is an anhydrous reagent; the inert gas comprises one of nitrogen or argon, preferably argon;
preferably, the solvent comprises one of anhydrous 1, 4-dioxane, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and methanol, and is an anhydrous reagent, preferably anhydrous 1, 4-dioxane;
the reaction time in the step (2) is 20-60min, preferably 40min, and the molecular weight cut-off of a dialysis membrane used for dialysis is 1000-14000Da.
8. The method according to claim 6, wherein the fructose diacetone methacrylate monomer is synthesized with reference to the following synthesis pathway:
9. the process of claim 3, wherein the BPA is 10 And a compound with B abundance higher than 95%.
10. Use of the polyfructose-BPA boron drug of claim 1 in the manufacture of a medicament for boron neutron capture therapy.
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