CN110734460B - Preparation and application of sulfonic acid-phosphonic acid ligand - Google Patents
Preparation and application of sulfonic acid-phosphonic acid ligand Download PDFInfo
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- CN110734460B CN110734460B CN201911004660.6A CN201911004660A CN110734460B CN 110734460 B CN110734460 B CN 110734460B CN 201911004660 A CN201911004660 A CN 201911004660A CN 110734460 B CN110734460 B CN 110734460B
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- acid
- solution
- sulfonic
- ligand
- sulfonic acid
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- 239000003446 ligand Substances 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 229960000759 risedronic acid Drugs 0.000 claims abstract description 21
- 229960004276 zoledronic acid Drugs 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 19
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 14
- 239000008346 aqueous phase Substances 0.000 claims abstract description 9
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims abstract description 8
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001453 quaternary ammonium group Chemical group 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 98
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 56
- 230000004048 modification Effects 0.000 claims description 40
- 238000012986 modification Methods 0.000 claims description 40
- 239000002105 nanoparticle Substances 0.000 claims description 36
- 239000012071 phase Substances 0.000 claims description 35
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 34
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 24
- 238000002347 injection Methods 0.000 claims description 22
- 239000007924 injection Substances 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 16
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- FSSPGSAQUIYDCN-UHFFFAOYSA-N 1,3-Propane sultone Chemical compound O=S1(=O)CCCO1 FSSPGSAQUIYDCN-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000003444 phase transfer catalyst Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- QCYOIFVBYZNUNW-UHFFFAOYSA-N 2-(dimethylazaniumyl)propanoate Chemical compound CN(C)C(C)C(O)=O QCYOIFVBYZNUNW-UHFFFAOYSA-N 0.000 claims description 8
- 238000002390 rotary evaporation Methods 0.000 claims description 8
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 5
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 claims description 5
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 claims description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
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- 238000000502 dialysis Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- LPSKDVINWQNWFE-UHFFFAOYSA-M tetrapropylazanium;hydroxide Chemical compound [OH-].CCC[N+](CCC)(CCC)CCC LPSKDVINWQNWFE-UHFFFAOYSA-M 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
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- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Chemical class 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 229910052788 barium Inorganic materials 0.000 claims description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052793 cadmium Inorganic materials 0.000 claims description 2
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052804 chromium Inorganic materials 0.000 claims description 2
- 239000011651 chromium Substances 0.000 claims description 2
- 229910017052 cobalt Inorganic materials 0.000 claims description 2
- 239000010941 cobalt Substances 0.000 claims description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 2
- HDFXRQJQZBPDLF-UHFFFAOYSA-L disodium hydrogen carbonate Chemical compound [Na+].[Na+].OC([O-])=O.OC([O-])=O HDFXRQJQZBPDLF-UHFFFAOYSA-L 0.000 claims description 2
- DBLXOVFQHHSKRC-UHFFFAOYSA-N ethanesulfonic acid;2-piperazin-1-ylethanol Chemical compound CCS(O)(=O)=O.OCCN1CCNCC1 DBLXOVFQHHSKRC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 2
- 150000002602 lanthanoids Chemical class 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 2
- 229910052750 molybdenum Inorganic materials 0.000 claims description 2
- 239000011733 molybdenum Substances 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052758 niobium Inorganic materials 0.000 claims description 2
- 239000010955 niobium Substances 0.000 claims description 2
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical compound [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 229910052706 scandium Inorganic materials 0.000 claims description 2
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052719 titanium Inorganic materials 0.000 claims description 2
- 239000010936 titanium Substances 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
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- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000002994 raw material Substances 0.000 claims 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical class [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical class [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 claims 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 claims 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 claims 1
- 239000002086 nanomaterial Substances 0.000 abstract description 16
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- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 8
- AMWRITDGCCNYAT-UHFFFAOYSA-L manganese oxide Inorganic materials [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 8
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- 239000013049 sediment Substances 0.000 description 8
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 7
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- UGEPSJNLORCRBO-UHFFFAOYSA-N [3-(dimethylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid Chemical compound CN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O UGEPSJNLORCRBO-UHFFFAOYSA-N 0.000 description 5
- -1 and therefore Substances 0.000 description 5
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- GEYXPJBPASPPLI-UHFFFAOYSA-N manganese(III) oxide Inorganic materials O=[Mn]O[Mn]=O GEYXPJBPASPPLI-UHFFFAOYSA-N 0.000 description 3
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- 230000001376 precipitating effect Effects 0.000 description 3
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- 125000000542 sulfonic acid group Chemical group 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
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- 239000000047 product Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
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- DTLOPXMGVOMEBH-UHFFFAOYSA-I barium(2+);gadolinium(3+);pentafluoride Chemical compound [F-].[F-].[F-].[F-].[F-].[Ba+2].[Gd+3] DTLOPXMGVOMEBH-UHFFFAOYSA-I 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- OWFHVHWXOGAVRB-UHFFFAOYSA-J sodium;gadolinium(3+);tetrafluoride Chemical compound [F-].[F-].[F-].[F-].[Na+].[Gd+3] OWFHVHWXOGAVRB-UHFFFAOYSA-J 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
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Abstract
The invention relates to preparation and application of a sulfonic acid-phosphonic acid ligand. The sulfonic acid-phosphonic acid ligand structure comprises sulfonic acid, quaternary ammonium and phosphonic acid groups, and specifically comprises a sulfonic acid betaine-phosphonic acid ligand, a sulfonic acid-zoledronic acid ligand and a sulfonic acid-risedronic acid ligand; the formula of the sulfobetaine-phosphonic acid ligand is as follows: c8H21NO10P2S, molecular weight 384.2; the sulfonic acid-zoledronic acid ligand has the molecular formula: c8H16O10N2P2S, molecular weight 394.23; the sulfonic acid-risedronic acid ligand has the molecular formula: c10H17O10NP2S, molecular weight 405.25. The sulfonic acid-phosphonic acid ligand has excellent hydrophilicity and can coordinate with various metal elements. Such molecules have important applications in two areas: firstly, the method is used for modifying hydrophobic nano materials, thereby obviously improving the hydrophilicity of the materialsSo that it can be dispersed in the aqueous phase; secondly, the traditional Chinese medicine composition has certain inhibition effect on tumors.
Description
Technical Field
The invention belongs to the technical field of biological materials, and particularly relates to preparation and application of a sulfonic acid-phosphonic acid ligand.
Background
Inorganic nanomaterials have received much attention in the biomedical field due to their unique physical and chemical properties. For example: the materials such as magnetic iron oxide particles, semiconductor quantum dots, up-conversion luminescent nanoparticles and the like have prominent expression in the application research of analysis sensing, biological labeling, imaging, disease treatment and other aspects. However, these materials are limited in clinical transformation, especially in application to human body, and there are few inorganic nanomaterials approved clinically for application to human body at present, mainly because inorganic nanomaterials are easily captured by immune system after entering into body, and easily dissolved to release toxic metal ions during long-term retention in body, which causes safety concerns. Therefore, the surface modification is carried out on the inorganic nano material through proper ligand molecules so as to improve the biocompatibility of the inorganic nano material and improve the metabolic efficiency of the inorganic nano material, and the method has important significance for improving the clinical application potential of the inorganic nano material.
In order to prepare inorganic nano-materials with high purity, excellent performance, good crystallinity and uniform particle size, researchers often adopt a synthesis method of high-temperature thermal decomposition. The synthesis is usually carried out in a hydrophobic high-boiling-point solvent, hydrophobic molecules such as oleic acid and oleylamine are used as surfactants, and the obtained nanoparticles are wrapped by the molecules such as oleic acid and oleylamine, so that the nanoparticles show obvious hydrophobicity. In order to improve the biocompatibility of the nanoparticles, it is necessary to perform a phase inversion process, i.e., to change the surface property of the nanoparticles from hydrophobic to hydrophilic by encapsulation or competitive adsorption. The most common phase inversion methods at present are coating of nanoparticles with amphiphilic polymers or competing for hydrophobic molecules with polymers bearing carboxyl, phosphate, etc. groups that can be covalently attached to the nanoparticle surface. Although the polymer-based phase inversion method can prepare inorganic nanoparticles with good hydrophilicity, the method has two problems: (1) the preparation process of the amphiphilic polymer and the end group modified polymer is complex, high chemical synthesis skill is required, and the synthesis cost is high. (2) The molecular weight of the polymer is often very large, the whole particle size (hydrated particle size) of the polymer is inevitably increased when the polymer is modified on the surface of the nano-particles, and even if the particle size of the inner core of the nano-particles is extremely small, the polymer cannot be metabolized out of a body through glomerular filtration after the polymer is modified.
The modification of inorganic nanomaterials by zwitterions is a phase inversion method with remarkable advantages which has been proposed in recent years. The zwitterion contains cationic and anionic groups, has strong hydration capability, can form a compact hydration layer, and therefore has great attention in the aspects of material surface modification and anti-fouling. In recent years, it has been proposed to phase-convert Fe by sulfonic acid dopamine Zwitterion (ZDS)3O4Nanoparticles, particles obtained by preparation (ZDS-Fe)3O4) Has excellent hydrophilicity, and the modification of ZDS does not substantially increase the hydrated particle size of the particles, which is beneficial to the rapid metabolism of the particles. However, ZDS is easily oxidized and has a limited force with inorganic nanoparticles other than iron oxide, and thus has a limited range of application as a phase-inversion ligand.
From the background, the currently reported phase inversion schemes have respective defects, and a new ligand with high efficiency and adaptability is still required to be developed for phase inversion of inorganic nanoparticles.
Disclosure of Invention
In order to overcome the defects and shortcomings of the prior art, the invention mainly aims to provide a ligand molecule represented by a sulfonic acid-phosphonic acid ligand, which comprises a sulfonic acid betaine-phosphonic acid ligand (ZPO for short), a sulfonic acid-zoledronic acid ligand (ZOL for short) and a sulfonic acid-risedronic acid ligand (LSL for short).
Another object of the present invention is to provide a process for the preparation of the above three sulfonic acid-phosphonic acid ligands.
It is a further object of the present invention to provide the use of the three sulfonic-phosphonic acid ligands described above.
The purpose of the invention is realized by the following technical scheme:
a sulfobetaine-phosphonic acid ligand having the formula: c8H21NO10P2S, molecular weight is 384.2, and the chemical structural formula is as follows:
a sulfonic acid-zoledronic acid ligand with the molecular formula of C8H16O10N2P2S, molecular weight is 394.23, and the chemical structural formula is as follows:
a sulfonic acid-risedronic acid ligand of the formula C10H17O10NP2S, molecular weight is 405.25, and the chemical structural formula is as follows:
the sulfonic acid-phosphonic acid ligand structure: the phosphonic acid group has strong binding effect on the surfaces of various nano particles; the sulfonic acid group can provide extremely high hydrophilicity, so that various nano materials can be subjected to surface modification, and the hydrophilicity of the nano materials is improved. In addition, ZPO, ZOL and LSL can be efficiently bonded on the surface of bone, thereby being used as an osteoclast activity inhibitor and playing roles in relieving bone pain, resisting tumors, inhibiting tumor bone metastasis and the like.
The preparation method of the sulfobetaine-phosphonic acid ligand comprises the following steps:
(1) slowly dropwise adding concentrated hydrochloric acid into N, N-dimethyl propionitrile, cooling the solution to room temperature, concentrating the filtrate under reduced pressure, filtering to collect solid, washing and drying to obtain N, N-dimethyl amino propionic acid;
(2) mixing N, N-dimethyl amino propionic acid and phosphorous acid, heating to 70-80 ℃ to form an oily solution, slowly dropwise adding phosphorus oxychloride, finishing dropping within 1-2 h, maintaining the solution at 75-85 ℃, and refluxing for 5-8 h; after the solution is cooled to room temperature, slowly adding water to carry out quenching reaction, stirring at room temperature for 3-6 h, concentrating the solution to colorless oily liquid, adding water with the same volume as the solution, stirring and refluxing for 1-3 h, then carrying out spin-drying, and repeating the steps of adding water, refluxing and spin-drying for a plurality of times to obtain an oily solution; washing and drying to obtain 3-dimethylamino-1-hydroxy-1, 1-propane diphosphonic acid;
(3) adding 3-dimethylamino-1-hydroxy-1, 1-propane diphosphonic acid into solvent (such as methanol, etc.), adding appropriate amount of phase transfer catalyst, and completely dissolving 3-dimethylamino-1-hydroxy-1, 1-propane diphosphonic acid; and (2) dropwise adding 1, 3-propane sultone dissolved in a solvent (such as ethanol and the like) into a 3-dimethylamino-1-hydroxy-1, 1-propane diphosphonic acid solution, reacting at room temperature for 18-72 hours, then, performing rotary evaporation to remove most of the solvent, separating out a solid, washing and precipitating for several times, and drying to obtain the ZPO ligand.
Preferably, the molar ratio of the concentrated hydrochloric acid to the N, N-dimethylpropionitrile in step (1) is 6: 1.
Preferably, the concentration of concentrated hydrochloric acid is 12mol/L, the concentrated hydrochloric acid is dripped into N, N-dimethyl propionitrile at the speed of 5-10 mL/min, and then the mixture is stirred for 3 hours at room temperature; the washing in the steps (1), (2) and (3) refers to washing with isopropanol or/and ethanol.
Preferably, the molar ratio of the N, N-dimethyl amino propionic acid to the phosphorous acid to the phosphorus oxychloride in the step (2) is controlled to be 1: 1-1.5: 2-3.
Preferably, the molar ratio of the 3-dimethylamino-1-hydroxy-1, 1-propane diphosphonic acid to the 1, 3-propane sultone in the step (3) is controlled to be 1: 1-1.2.
Preferably, the phase transfer catalyst in step (3) is one of tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide or a mixture thereof.
More preferably, the phase transfer catalyst is added in an amount such that the 3-dimethylamino-1-hydroxy-1, 1-propanediphosphonic acid is completely dissolved.
Preferably, the reaction time in the step (3) is 36-72 hours.
Preferably, step (3) further comprises the following purification steps: and dissolving the obtained ZPO crude product in a small amount of deionized water, adding a DMF/ethanol mixed solution, heating and refluxing for 3-8 hours at 55-80 ℃, cooling to room temperature, adding sufficient ethanol or isopropanol to precipitate again, and drying to obtain the high-purity ZPO.
More preferably, the volume ratio of DMF to ethanol is 1: 10.
The preparation method of the sulfonic acid-zoledronic acid ligand comprises the following steps:
adding zoledronic acid into solvent (such as ethanol, etc.), and adding appropriate amount of phase transfer catalyst to completely dissolve zoledronic acid; dropwise adding 1, 3-propane sultone dissolved in a solvent (such as ethanol and the like) into a zoledronic acid solution, reacting at room temperature for 18-72 hours, then, performing rotary evaporation to remove the solvent, adding concentrated hydrochloric acid and ethanol, separating out a precipitate, washing the precipitate for several times by using ethanol, and drying to obtain the sulfonic acid-zoledronic acid ligand.
Preferably, the phase transfer catalyst is one of tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide or a mixture thereof.
Preferably, the molar ratio of the zoledronic acid to the 1, 3-propane sultone is controlled to be 1: 1-1.5.
Preferably, the addition amount of the concentrated hydrochloric acid is 2 to 10 times (molar ratio) of the phase transfer catalyst.
The preparation method of the sulfonic acid-risedronic acid comprises the following steps:
adding risedronic acid into a solvent (such as ethanol and the like), and adding a proper amount of phase transfer catalyst to completely dissolve risedronic acid; dropwise adding 1, 3-propane sultone dissolved in a solvent (such as ethanol and the like) into a risedronic acid solution, reacting at room temperature for 18-72 hours, then, removing the solvent by rotary evaporation, adding concentrated hydrochloric acid and ethanol, separating out a solid, washing and precipitating for several times by using ethanol, and drying to obtain the sulfonic acid-risedronic acid.
Preferably, the phase transfer catalyst is one of tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide or a mixture thereof.
More preferably, the phase transfer catalyst is added in an amount such that risedronic acid is completely dissolved.
Preferably, the molar ratio of risedronic acid to 1, 3-propane sultone is controlled to be 1: 1-1.5.
Preferably, the addition amount of the concentrated hydrochloric acid is 2 to 10 times (molar ratio) of the phase transfer catalyst.
The above provides only one synthesis route and step for synthesizing ZPO, ZOL and LSL, respectively, and ZPO, ZOL and LSL prepared by other routes and steps should also be covered by the scope of the present invention. In addition, ZPO, ZOL, and LSL are highly ionized in neutral and alkaline solutions, and therefore, water soluble salts of ZPO, ZOL, and LSL are also intended to be encompassed within the scope of the present invention.
The three sulfonic acid-phosphonic acid ligands can be used for surface modification of hydrophobic inorganic nanoparticles to prepare hydrophilic nanoparticles or prepare tumor inhibitors.
Hydrophilic nanoparticles prepared by the steps of: dispersing hydrophobic inorganic nano particles in an organic solvent to form an oil phase solution; dissolving a sulfonic acid-phosphonic acid ligand (any one of ZPO, ZOL and LSL) in water, and adding a small amount of alkali solution or alkaline buffer solution to make the solution alkaline to obtain an aqueous phase solution; mixing the oil phase solution and the water phase solution according to a certain proportion, fully stirring, and then washing, dialyzing and drying to realize the hydrophilic modification of the nano particles.
The inorganic nanoparticles comprise oxides, fluorides, sulfides or acid salts containing one or more of magnesium, calcium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, zinc, yttrium, zirconium, niobium, molybdenum, ruthenium, cadmium, barium and lanthanide;
the organic solvent comprises at least one of organic solvents such as tetrahydrofuran, dichloromethane, ethyl acetate, cyclohexane, toluene and the like;
the concentration of the oil phase solution is controlled to be 10 mg/L-2 g/L; the concentration of the sulfonic acid-phosphonic acid ligand aqueous solution (aqueous phase solution) is 10 g/L; the volume ratio of the oil phase solution to the water phase solution is controlled to be 1-10: 1. the specific use ratio and concentration are determined according to the type of the converted nanoparticles and the pH value of the solution.
The alkali solution is one or a mixture of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and ammonia water; the buffer solution is one or a mixture of sodium carbonate-sodium bicarbonate, tris (hydroxymethyl) aminomethane-hydrochloric acid, 4-hydroxyethyl piperazine ethanesulfonic acid and other buffer solutions.
The solvent used for washing is one or a mixture of ethanol, tetrahydrofuran, isopropanol and ethyl acetate; the interception molecular weight of the dialysis bag used for dialysis purification is 1000-100000 Da.
The components of the injection of three sulfonic acid-phosphonic acid ligand tumor suppressors are shown in the following table 1-3, and the preparation method comprises the following steps: (a) dissolution of sulfonic acid-phosphonic acid ligand: dissolving sodium citrate in water for injection, adding a prescribed amount of sulfonic acid-phosphonic acid ligand, and stirring to dissolve the sulfonic acid-phosphonic acid ligand to obtain a sulfonic acid-phosphonic acid ligand dissolving solution; (b) dissolution of osmotic pressure regulator: dissolving the osmotic pressure regulator in the prescription amount in water for injection, adding 0.2% of activated carbon of the total mass of the injection, and filtering to remove carbon to obtain an osmotic pressure regulator solution; (c) preparation of injection: uniformly mixing a sulfonic acid-phosphonic acid ligand solution and an osmotic pressure regulator solution, and fixing the volume to a theoretical amount to obtain an injection; (d) filling and sterilizing: filling after the product is qualified, and sterilizing at 121 ℃; cooling to room temperature, and refrigerating in refrigerator.
Preferably, the pH value of the three sulfonic acid-phosphonic acid ligand injection solutions is 6.5-7.4.
The dosage of the three components of the sulfonic acid-phosphonic acid ligand injection is also covered in the protection scope of the invention.
Table 1 composition of ZPO injection.
Table 2 composition of ZOL injection.
Table 3 ingredients of LSL injection.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the sulfonic acid-phosphonic acid ligand mainly comprises hydrophilic sulfonic acid groups and phosphonic acid groups, the sulfonic acid groups have excellent hydrophilicity, and the phosphonic acid groups can coordinate with various metal elements. The small molecules have important applications in two aspects: firstly, the modified hydrophobic nano material is used for modifying the hydrophobic nano material, so that the hydrophilicity of the material is obviously improved, and the material can be dispersed in a water phase; secondly, the composition has certain inhibition effect on tumors.
Drawings
FIG. 1 is a flow chart for the synthesis of ZPO of the present invention.
FIG. 2 is a diagram of ZPO synthesized by the present invention1H NMR chart (400MHz, D)2O is a solvent).
FIG. 3 is a chart of the infrared absorption spectrum of ZPO synthesized by the present invention.
FIG. 4 is a flow chart of the synthesis of a ZOL of the present invention.
FIG. 5 is a chart of ZOL synthesized in accordance with the present invention1H NMR chart (400MHz, D)2O is a solvent).
FIG. 6 is a flow diagram of the synthesis of LSL of the present invention.
FIG. 7 is a schematic representation of LSL synthesized according to the present invention1H NMR chart (400MHz, D)2O is a solvent).
FIG. 8 is Fe3O4Photographs before (left) and after (right) modification. Left (before modification): the upper brownish red layer is formed by dissolving ferroferric oxide in cyclohexane in an oil phase, and the lower colorless layer is formed by deionized water; right (after modification): the upper colorless layer is cyclohexane, and the lower brownish red layer is ZPO modified ferroferric oxide dissolved in deionized water.
FIG. 9 shows Mn3O4Photographs before (left) and after (right) modification. Left (before modification): the upper black brown layer is formed by dissolving the oil-phase manganous-manganic oxide in cyclohexane, and the lower colorless layer is formed by deionized water. Right (after modification): the upper colorless layer is cyclohexane, and the lower black brown layer is ZPO modified manganous-manganic oxide dissolved in deionized water.
FIG. 10 shows NaGdF4Photographs before (left) and after (right) modification. Left (modification)Before): the upper colorless layer is formed by dissolving oil-phase sodium gadolinium tetrafluoride in cyclohexane, and the lower colorless layer is formed by deionized water. Right (after modification): the upper colorless layer is cyclohexane, and the lower colorless layer is ZPO modified sodium tetrafluoro gadolinium oxide dissolved in deionized water.
FIG. 11 shows BaGdF5Photographs before (left) and after (right) modification. Left (before modification): the upper colorless layer is formed by dissolving oil-phase barium gadolinium pentafluoride in cyclohexane, and the lower colorless layer is formed by deionized water. Right (after modification): the upper colorless layer is cyclohexane, and the lower colorless layer is ZPO modified barium gadolinium pentafluoride dissolved in deionized water.
FIG. 12 is a photograph of upconversion luminescent nanoparticles before (two left panels) and after (two right panels) modification. Left two panels (before modification): the upper colorless layer is oil phase UCNP dissolved in cyclohexane (a); the color of the film is green after being excited by 980nm laser, and the lower colorless layer is deionized water (b). Two panels on the right (after modification): the upper colorless layer is cyclohexane, and the lower colorless layer is UCNP modified by ZPO and dissolved in deionized water (c); and the color of the green (d) is shown after being excited by 980nm laser.
FIG. 13 is a photograph of CdSe @ ZnS quantum dots before (two left) and after (two right) modification. Left two panels (before modification): the upper layer of the reddish layer is formed by dissolving oil phase CdSe @ ZnS in cyclohexane (a); after being excited by ultraviolet light, the fluorescent material emits red fluorescence, and the lower layer is colorless deionized water (b). Two panels on the right (after modification): the upper colorless layer is cyclohexane, and the lower reddish layer is CdSe @ ZnS modified by ZPO and dissolved in deionized water (c); after excitation with uv light, red fluorescence (d) is emitted.
FIG. 14 is Fe3O4Before (left) and after (right) ZOL modification. Left (before modification): the upper brownish red layer is formed by dissolving ferroferric oxide in cyclohexane in an oil phase, and the lower colorless layer is formed by deionized water; right (after modification): the upper colorless layer is cyclohexane, and the lower brownish red layer is ZOL modified ferroferric oxide dissolved in deionized water.
FIG. 15 shows Mn3O4Photographs of LSL before (left) and after (right) modification. Left (before modification): the upper black brown layer is formed by dissolving the oil-phase manganous-manganic oxide in cyclohexane, and the lower colorless layer is formed by deionized water. Right (after modification): the upper colorless layer is a ringHexane, the lower black brown layer is LSL modified mangano-manganic oxide dissolved in deionized water.
FIG. 16 is a graph showing the change in tumor volume in mice.
FIG. 17 is a graph showing the change in the number of mice surviving.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto.
Example 1: preparation of ZPO
(1) Preparation of N, N-dimethylaminopropionic acid
20.2g N, N-Dimethylpropanenitrile was added to a 250mL round bottom flask, 100mL concentrated HCl was added dropwise, then stirred at room temperature for 3h, the solution was cooled to room temperature, the solution was filtered, the filtrate was concentrated under reduced pressure, and 40mL isopropanol was added and washed twice to obtain a white precipitate, N-dimethylaminopropionic acid.
(2) Preparation of 3-dimethylamino-1-hydroxy-1, 1-propanediphosphonic acid
7.6g N, N-dimethylaminopropionic acid, 15.7g phosphorous acid were mixed and charged into a 100mL round-bottomed flask, and the temperature was maintained at 75 ℃ and heated with stirring for 30 min. Then 18.4g of phosphorus oxychloride is slowly dripped in 1 hour, the mixture is heated to 80 ℃ and refluxed for 5 hours. After the solution is cooled to room temperature, water is slowly added to quench the reaction, then the solution is stirred for 3 hours at room temperature, the solution is concentrated to colorless oil, water is added to stir and rotary evaporation is carried out, and the steps are repeated twice. The final oily solution is washed twice with isopropanol and anhydrous ethanol to obtain white precipitate, i.e. 3-dimethylamino-1-hydroxy-1, 1-propanediphosphonic acid.
(3) Preparation of sulfobetaine-phosphonic acid ligands (ZPO)
2.5mmol of 3-dimethylamino-1-hydroxy-1, 1-propanediphosphonic acid are added to 50mL of methanol. 2.0mL of a methanol solution of tetraethylammonium hydroxide (25% by mass) was added dropwise with stirring to completely dissolve 3-dimethylamino-1-hydroxy-1, 1-propanediphosphonic acid in methanol. Adding 1, 3-propane sultone solution (3.0mmol1, 3-propane sultone dissolved in 5mL ethanol) into the reaction solution drop by drop, reacting at room temperature for 24h, removing the solvent by rotary evaporation, and finally using isopropanol and absolute ethanolWashing twice respectively to obtain the final product ZPO. Of ZPO1The H NMR chart and the infrared absorption spectrum are shown in FIG. 2 and FIG. 3, respectively.
Example 2: preparation of ZOL
0.5g of zoledronic acid was added to 50mL of ethanol, and 1.2mL of a methanol solution containing 25% tetramethylammonium hydroxide was added to completely dissolve zoledronic acid. Adding 1, 3-propane sultone (0.269g) dissolved in 5mL of ethanol into zoledronic acid solution dropwise, reacting at room temperature for 24 hours, then performing rotary evaporation to remove the solvent, adding 1.2mL of concentrated hydrochloric acid and 50mL of ethanol, separating out a precipitate, washing the precipitate with ethanol for several times, and drying to obtain the sulfonic acid-zoledronic acid. Of ZOL1The H NMR chart is shown in FIG. 5.
Example 3: preparation of LSL
0.52g risedronic acid was added to 50mL ethanol, and 1.2mL methanol solution containing 25% tetramethylammonium hydroxide was added to dissolve risedronic acid completely. Adding 1, 3-propane sultone (0.269g) dissolved in 5mL of ethanol into risedronic acid solution dropwise, reacting at room temperature for 24 hours, removing the solvent by rotary evaporation, adding 1.2mL of concentrated hydrochloric acid and 50mL of ethanol, precipitating, washing the precipitate with ethanol for several times, and drying to obtain the sulfonic acid-risedronic acid. Of LSL1The H NMR chart is shown in FIG. 7.
Example 4: ZPO to Fe3O4Surface modification of nanoparticles
Mixing 3mg of Fe3O4Dispersing in 5mL tetrahydrofuran, mixing with 1mL and 10mg/mL ZPO aqueous solution, adding into a 20mL glass bottle, stirring at room temperature, and completing the reaction when a large amount of colored precipitate adheres to the wall. The glass vial supernatant was removed and 0.5mL of deionized water was added to dissolve the bottom sediment. The solution was taken out into a 1.5mL EP tube, washed twice with cyclohexane and ethanol, respectively, and finally dispersed in water for stand-by or vacuum-dried storage. Fe of oil phase3O4Was successfully transferred to the aqueous phase, the effect is as shown in FIG. 8 (left: upper Fe)3O4Cyclohexane solution, lower aqueous layer solution; and (3) right: cyclohexane solution in the upper layer and Fe in the lower layer3O4An aqueous solution).
Example 5: by ZPO pairsMn3O4Surface modification of nanoparticles
Adding 3mg of Mn3O4Dispersing in 5mL tetrahydrofuran, mixing with 1mL and 10mg/mL ZPO aqueous solution, adding into a 20mL glass bottle, stirring at room temperature, and completing the reaction when a large amount of colored precipitate adheres to the wall. The glass vial supernatant was removed and 0.5mL of deionized water was added to dissolve the bottom sediment. The solution was taken out into a 1.5mL EP tube, washed twice with cyclohexane and ethanol, respectively, and finally dispersed in deionized water for stand-by or vacuum-dried storage. Mn of oil phase3O4Was successfully transferred to the aqueous phase, the effect is shown in FIG. 9 (left: upper Mn)3O4Cyclohexane solution, lower aqueous layer solution; and (3) right: upper cyclohexane solution, lower Mn3O4An aqueous solution).
Example 6: ZPO on NaGdF4Surface modification of nanoparticles
3mg of NaGdF4Dispersing in 5mL tetrahydrofuran, mixing with 1mL and 10mg/mL ZPO aqueous solution, adding into a 20mL glass bottle, stirring at room temperature, and completing the reaction when a large amount of colored precipitate adheres to the wall. The glass vial supernatant was removed and 0.5mL of deionized water was added to dissolve the bottom sediment. The solution was taken out into a 1.5mL EP tube, washed twice with cyclohexane and ethanol, respectively, and finally dispersed in water for stand-by or vacuum-dried storage. NaGdF of oil phase4Was successfully converted to the aqueous phase with the effect as shown in figure 10 (left: upper NaGdF)4Cyclohexane solution, lower aqueous layer solution; and (3) right: cyclohexane solution at the upper layer and NaGdF at the lower layer4An aqueous solution).
Example 7: ZPO on BaGdF5Surface modification of nanoparticles
4mg of BaGdF5Dispersing in 5mL tetrahydrofuran, mixing with 1mL and 10mg/mL ZPO aqueous solution, adding into a 20mL glass bottle, stirring at room temperature, and completing the reaction when a large amount of colored precipitate adheres to the wall. The glass vial supernatant was removed and 0.5mL of deionized water was added to dissolve the bottom sediment. The solution was taken out into a 1.5mL EP tube, washed twice with cyclohexane and ethanol, respectively, and finally dispersed in water for stand-by or vacuum-dried storage. BaGdF of oil phase5Is successfully converted intoThe water phase has the effect shown in figure 11 (left: upper BaGdF)5Cyclohexane solution, lower aqueous layer solution; and (3) right: cyclohexane solution in the upper layer and BaGdF in the lower layer5An aqueous solution).
Example 8: surface modification of upconversion luminescent nanoparticles (UCNPs) with ZPO
Dispersing 6mg UCNP in 5mL tetrahydrofuran, mixing with 1mL and 10mg/mL ZPO aqueous solution, adding into a 20mL glass bottle, stirring at room temperature, and completing the reaction when a large amount of colored precipitates adhere to the wall. The glass vial supernatant was removed and 0.5mL of deionized water was added to dissolve the bottom sediment. The solution was taken out into a 1.5mL EP tube, washed twice with cyclohexane and ethanol, respectively, and finally dispersed in water for stand-by or vacuum-dried storage. The UCNP in the oil phase was successfully converted into the water phase, and the solution containing UCNP emitted green light after excitation with 980nm laser, as shown in fig. 12 (left: upper UCNP cyclohexane solution, lower aqueous solution; right: upper cyclohexane solution, lower UCNP aqueous solution).
Example 9: surface modification of CdSe @ ZnS nanoparticles by ZPO
Dispersing 5mg CdSe @ ZnS in 5mL tetrahydrofuran, mixing with 1mL and 10mg/mL ZPO aqueous solution, adding into a 20mL glass bottle, stirring at room temperature, and reacting when a large amount of colored precipitates adhere to the wall. The glass vial supernatant was removed and 0.5mL of deionized water was added to dissolve the bottom sediment. The solution was taken out into a 1.5mL EP tube, washed twice with cyclohexane and ethanol, respectively, and finally dispersed in water for stand-by or vacuum-dried storage. The CdSe @ ZnS in the oil phase is successfully converted into the water phase, and the solution containing CdSe @ ZnS quantum dots can emit red light under the excitation of 365nm ultraviolet light, and the effect is shown in figure 13 (left: upper CdSe @ ZnS cyclohexane solution, lower aqueous solution; right: upper cyclohexane solution, lower CdSe @ ZnS aqueous solution).
Example 10: ZOL-modified hydrophobic Fe3O4Nano material
Mixing 5mg of Fe3O4Dispersing in 5mL tetrahydrofuran, mixing with 1mL and 10mg/mL ZOL aqueous solution, adding into a 20mL glass bottle, stirring at room temperature, and completing the reaction when a large amount of colored precipitate adheres to the wall. Removing the supernatant from the vial, adding0.5mL of deionized water was added to dissolve the bottom sediment. The solution was taken out into a 1.5mL EP tube, washed twice with cyclohexane and ethanol, respectively, and finally dispersed in water for stand-by or vacuum-dried storage. Fe of oil phase3O4Was successfully transferred to the aqueous phase, the effect was as shown in FIG. 14 (left: upper Fe)3O4Cyclohexane solution, lower aqueous layer solution; and (3) right: cyclohexane solution in the upper layer and Fe in the lower layer3O4An aqueous solution).
Example 11: LSL modified hydrophobic Mn3O4Nano material
Adding 6mg of Mn3O4Dispersing in 5mL tetrahydrofuran, mixing with 1mL and 10mg/mL LSL aqueous solution, adding into a 20mL glass bottle, stirring at room temperature, and completing the reaction when a large amount of colored precipitate adheres to the wall. The glass vial supernatant was removed and 0.5mL of deionized water was added to dissolve the bottom sediment. The solution was taken out into a 1.5mL EP tube, washed twice with cyclohexane and ethanol, respectively, and finally dispersed in deionized water for stand-by or vacuum-dried storage. Mn of oil phase3O4Was successfully transferred to the aqueous phase, the effect is as shown in FIG. 15 (left: upper Mn)3O4Cyclohexane solution, lower aqueous layer solution; and (3) right: upper cyclohexane solution, lower Mn3O4An aqueous solution).
Example 12: preparation and application of three sulfonic acid-phosphonic acid injection solutions
(1) Preparation of three sulfonic acid-phosphonic acid injection
TABLE 4 ZPO injecta formulations
TABLE 5 ZOL injection formulations
TABLE 6 LSL injection formulations
(a) Dissolution of sulfonic acid-phosphonic acid: dissolving sodium citrate in water for injection, adding sulfonic acid-phosphonic acid molecules in a prescribed amount, and stirring to dissolve the sulfonic acid-phosphonic acid molecules to obtain a sulfonic acid-phosphonic acid dissolved solution;
(b) dissolution of osmotic pressure regulator: dissolving the osmotic pressure regulator in the prescription amount in water for injection, adding 0.2% of activated carbon, and filtering to remove the carbon to obtain an osmotic pressure regulator solution;
(c) preparation of injection: and uniformly mixing the sulfonic acid-phosphonic acid solution and the osmotic pressure regulator solution, and fixing the volume to a theoretical amount to obtain the sulfonic acid-phosphonic acid injection, wherein the pH value of the sulfonic acid-phosphonic acid injection is 6.5-7.4.
(d) Filling and sterilizing: filling after the product is qualified, and sterilizing at 121 ℃. Cooling to room temperature, and refrigerating in refrigerator.
(2) Animal experiments
Experimental materials: BALB/C mice (inbred, female, 5-6 week old size, 25, purchased from southern medical university animal center), sulfonic acid-phosphonic acid injection, EMT6 cells (purchased from Guangzhou Securio Biotechnology Co., Ltd.), PBS (0.1 mmol/L).
Ethical statement: all experimental procedures of the study strictly comply with the Chinese welfare act on laboratory animals and are approved by the ethical committee for the use of laboratory animals of the university of south China.
Establishing an animal model: the tumor cells were inoculated as EMT6 cells, and the 5 th day after cell inoculation was set as 0 day, and 150 μ L of injection solution was quantitatively injected daily.
Experimental implementation and results: BALB/C mice were divided into 5 groups of 5 mice each, numbered A-PBS, B-None, C-ZPO, D-ZOL, E-LSL, and the injection dosage was as follows.
TABLE 7 treatment regimen for each group of mice
Tumor volumes were measured continuously and mouse survival recorded over one month. It can be seen that ZPO injection has certain inhibition effect on tumor growth (figure 11), and the survival conditions of mice in each group are also obviously different (figure 12).
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A sulfonic acid-phosphonic acid ligand is characterized in that the structure of the sulfonic acid-phosphonic acid ligand comprises sulfonic acid, quaternary ammonium and phosphonic acid groups, and specifically comprises three molecules which are respectively:
(1) a sulfobetaine-phosphonic acid ligand having the formula: c8H21NO10P2S, the chemical structural formula is as follows:
(2) a sulfonic acid-zoledronic acid ligand with the molecular formula of C8H16O10N2P2S, the chemical structural formula is as follows:
(3) a sulfonic acid-risedronic acid ligand of the formula C10H17O10NP2S, the chemical structural formula is as follows:
2. a process for the preparation of a sulfonic-phosphonic acid ligand according to claim 1, characterized by the steps of:
adding 3-dimethylamino-1-hydroxy-1, 1-propane diphosphonic acid, zoledronic acid or risedronic acid into a solvent for dissolving, and then adding a phase transfer catalyst to obtain a solution 1; dissolving 1, 3-propane sultone in a solvent to obtain a solution 2; adding the solution 2 into the solution 1, reacting at room temperature for 18-72 hours, then performing rotary evaporation to remove most of the solvent, separating out a solid, taking the solid, washing and drying to obtain the sulfonic acid-phosphonic acid ligand;
wherein when the raw material is 3-dimethylamino-1-hydroxy-1, 1-propane diphosphonic acid, a sulfobetaine-phosphonic acid ligand is obtained; when the raw material is zoledronic acid, a sulfonic acid-zoledronic acid ligand is obtained; when the raw material is risedronic acid, a sulfonic acid-risedronic acid ligand is obtained;
wherein the 3-dimethylamino-1-hydroxy-1, 1-propane diphosphonic acid is prepared by the steps of:
(1) adding concentrated hydrochloric acid into N, N-dimethyl propionitrile, cooling the solution to room temperature, concentrating the filtrate under reduced pressure, filtering to collect solid, washing and drying to obtain N, N-dimethyl amino propionic acid;
(2) mixing and heating N, N-dimethyl amino propionic acid and phosphorous acid at 70-80 ℃ to form an oily solution, dropwise adding phosphorus oxychloride, finishing the dropwise adding within 1-2 h, maintaining the temperature of the solution at 75-85 ℃, and refluxing for 5-8 h; cooling the solution to room temperature, adding water to carry out quenching reaction, stirring at room temperature for 3-6 h, concentrating the solution to colorless oily liquid, adding water, continuously refluxing for 1-3 h, then carrying out spin-drying, and repeating the steps of adding water, refluxing and spin-drying for a plurality of times; washing and drying the obtained oily solution to obtain the 3-dimethylamino-1-hydroxy-1, 1-propane diphosphonic acid.
3. The process for preparing a sulfonic-phosphonic acid ligand of claim 2,
the molar ratio of the concentrated hydrochloric acid to the N, N-dimethyl propionitrile in the step (1) is 6: 1;
in the step (2), the molar ratio of the N, N-dimethyl amino propionic acid to the phosphorous acid to the phosphorus oxychloride is controlled to be 1: 1-1.5: 2-3.
4. The process for preparing a sulfonic-phosphonic acid ligand of claim 2,
the molar ratio of the 3-dimethylamino-1-hydroxy-1, 1-propane diphosphonic acid to the 1, 3-propane sultone is controlled to be 1: 1-1.2;
the molar ratio of the zoledronic acid to the 1, 3-propane sultone is controlled to be 1: 1-1.5;
the molar ratio of risedronic acid to 1, 3-propane sultone is controlled to be 1: 1-1.5.
5. The process for preparing a sulfonic-phosphonic acid ligand of claim 2,
the reaction time is 36-72 hours;
the phase transfer catalyst is one or a mixture of more than two of tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide, tetrapropyl ammonium hydroxide and tetrabutyl ammonium hydroxide.
6. Use of the sulfonic-phosphonic acid ligand of claim 1 for the preparation of hydrophilic nanoparticles, tumor suppressors and water-soluble salts of ZPO.
7. A hydrophilic nanoparticle obtained by surface-modifying a hydrophobic inorganic nanoparticle with the sulfonic-phosphonic acid ligand of claim 1, wherein the hydrophobic inorganic nanoparticle comprises an oxide, fluoride, sulfide, or acid salt of one or more of magnesium, calcium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, zinc, yttrium, zirconium, niobium, molybdenum, ruthenium, cadmium, barium, and lanthanoids.
8. The hydrophilic nanoparticle as claimed in claim 7, wherein the hydrophilic nanoparticle is prepared by the steps of: dispersing hydrophobic inorganic nano particles in an organic solvent to form an oil phase solution; dissolving the sulfonic acid-phosphonic acid ligand of claim 1 in water, adding a small amount of alkali solution or alkaline buffer solution to make the solution alkaline to obtain an aqueous solution; mixing the oil phase solution and the water phase solution according to a certain proportion, fully stirring, and then washing, dialyzing and drying to realize the hydrophilic modification of the nano particles;
the concentration of the oil phase solution is controlled to be 10 mg/L-2 g/L; the concentration of the aqueous phase solution is 10 mg/mL; the volume ratio of the oil phase solution to the water phase solution is controlled to be 1-10: 1;
the organic solvent comprises at least one of tetrahydrofuran, dichloromethane, ethyl acetate, cyclohexane and toluene;
the alkali solution is one or a mixture of more than two of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and ammonia water; the buffer solution is one or a mixture of more than two of sodium carbonate-sodium bicarbonate, tris (hydroxymethyl) aminomethane-hydrochloric acid and 4-hydroxyethyl piperazine ethanesulfonic acid;
the solvent used for washing is one or a mixture of ethanol, tetrahydrofuran, isopropanol and ethyl acetate; the interception molecular weight of the dialysis bag used for dialysis purification is 1000-100000 Da.
9. An injection of sulfonic acid-phosphonic acid tumor suppressor, characterized in that the injection contains a prescribed amount of any one of the sulfonic acid betaine-phosphonic acid ligand, sulfonic acid zoledronic acid ligand and sulfonic acid risedronic acid ligand of claim 1.
10. A water-soluble sulfonic-phosphonic acid salt obtained by dissolving the sulfonic-phosphonic acid of claim 1 in a neutral or alkaline solution.
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