CN105056243B - A kind of pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow and preparation method and application - Google Patents
A kind of pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow and preparation method and application Download PDFInfo
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- OMZSGWSJDCOLKM-UHFFFAOYSA-N copper(II) sulfide Chemical compound [S-2].[Cu+2] OMZSGWSJDCOLKM-UHFFFAOYSA-N 0.000 title claims abstract description 86
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 33
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 33
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 36
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 35
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims abstract description 32
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000002105 nanoparticle Substances 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 229940056319 ferrosoferric oxide Drugs 0.000 claims abstract description 13
- 239000002245 particle Substances 0.000 claims abstract description 7
- 230000004048 modification Effects 0.000 claims abstract description 6
- 238000012986 modification Methods 0.000 claims abstract description 6
- BWFPGXWASODCHM-UHFFFAOYSA-N copper monosulfide Chemical compound [Cu]=S BWFPGXWASODCHM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000010521 absorption reaction Methods 0.000 claims abstract description 4
- 125000003368 amide group Chemical group 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 31
- 238000005119 centrifugation Methods 0.000 claims description 25
- 238000005576 amination reaction Methods 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 20
- 235000013339 cereals Nutrition 0.000 claims description 18
- 239000008363 phosphate buffer Substances 0.000 claims description 16
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 16
- 239000012498 ultrapure water Substances 0.000 claims description 16
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 15
- 229910052802 copper Inorganic materials 0.000 claims description 15
- 239000010949 copper Substances 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 14
- 238000004073 vulcanization Methods 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 11
- 239000000523 sample Substances 0.000 claims description 11
- 238000002604 ultrasonography Methods 0.000 claims description 11
- 238000002512 chemotherapy Methods 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 241000209094 Oryza Species 0.000 claims description 8
- 235000007164 Oryza sativa Nutrition 0.000 claims description 8
- 229940009456 adriamycin Drugs 0.000 claims description 8
- 235000009566 rice Nutrition 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 7
- 238000002595 magnetic resonance imaging Methods 0.000 claims description 7
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 7
- 229910021577 Iron(II) chloride Inorganic materials 0.000 claims description 6
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 229910052927 chalcanthite Inorganic materials 0.000 claims description 6
- 238000000502 dialysis Methods 0.000 claims description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical class O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- 239000003643 water by type Substances 0.000 claims description 6
- 229940034982 antineoplastic agent Drugs 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 238000011068 loading method Methods 0.000 claims description 5
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 4
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 4
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000012377 drug delivery Methods 0.000 claims description 3
- PAEZRCINULFAGO-OAQYLSRUSA-N (R)-homocamptothecin Chemical compound CC[C@@]1(O)CC(=O)OCC(C2=O)=C1C=C1N2CC2=CC3=CC=CC=C3N=C21 PAEZRCINULFAGO-OAQYLSRUSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims description 2
- 229960003668 docetaxel Drugs 0.000 claims description 2
- 239000007943 implant Substances 0.000 claims description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 2
- 229960001156 mitoxantrone Drugs 0.000 claims description 2
- 239000013049 sediment Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 244000050510 Cunninghamia lanceolata Species 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 230000001276 controlling effect Effects 0.000 claims 1
- 238000011010 flushing procedure Methods 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 22
- 230000010415 tropism Effects 0.000 abstract description 8
- 238000000015 thermotherapy Methods 0.000 abstract description 7
- 231100000331 toxic Toxicity 0.000 abstract description 6
- 230000002588 toxic effect Effects 0.000 abstract description 6
- 238000013270 controlled release Methods 0.000 abstract description 5
- 230000003111 delayed effect Effects 0.000 abstract 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 10
- 238000007626 photothermal therapy Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 230000037396 body weight Effects 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
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- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 210000001364 upper extremity Anatomy 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 244000162450 Taxus cuspidata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
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- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000000006 cell growth inhibition assay Methods 0.000 description 1
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
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- 235000021590 normal diet Nutrition 0.000 description 1
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- -1 oxygen Ion Chemical class 0.000 description 1
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- 239000012071 phase Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- 150000003233 pyrroles Chemical class 0.000 description 1
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Abstract
The present invention relates to pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow and preparation method and application, can effectively solve good biocompatibility, magnetic target tropism is strong, toxic side effect is small, the problem of to improve oncotherapy effect, method is, antineoplastic is loaded on the amidized copper sulfide that hollow mesoporous copper sulphide nano particles and mercaptoethylmaine react to obtain, the upper ferriferrous oxide nano grain of copper sulfide surface electrostatic absorption, through amido link reaction hyaluronic acid in surface modification, into the pharmaceutical composition of the hyaluronic acid decorated mesoporous copper sulfide of magnetic hollow；Described ferroso-ferric oxide and the mass content ratio of copper sulfide are 1 ~ 8 ︰ 1, the particle diameter of the mesoporous copper sulfide of magnetic hollow is 50 ~ 300nm, the present invention is easy to operate, method is reliable and stable, there is good biocompatibility, magnetic target tropism is strong, toxic side effect is small, thermotherapy can be played in terms of oncotherapy, the effect such as controlled release medicine is delayed in diagnosing tumor, magnetic field.
Description
Technical field
The present invention relates to medicine, particularly a kind of pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow
And preparation method and application.
Background technology
Operation and the three big conventional means that radiotherapy, chemotherapy are oncotherapies.However, operation is only capable of cutting off
Macroscopic knurl body, sightless subclinical focus is but difficult to clean off；Targeting difference and dosage often be present in classic chemotherapy
The problem of limiting toxicity；Photo-thermal therapy is a kind of novel method for the treatment of occurred after operation, chemicotherapy.Photo-thermal therapy technology
It is a kind of minimal invasive techniques for the energy of near infrared light being converted into using optical-thermal conversion material heat energy, photo-thermal therapy is to cancer
Local heating can be realized in treatment and then kills cancer cell, and normal cell is not damaged, is a kind of safer, high
The oncotherapy means of effect.
As a kind of semiconductor crystalline material, copper sulphide nano particles have very strong near infrared absorption and higher photo-thermal
Conversion efficiency.Compared with other noble metal nanometer materials, its region of ultra-red absorbing wavelength by environment and size influenceed compared with
It is small.Other latest report finds that the copper sulfide nano grain of rice can produce active oxygen under near infrared light（Born including singlet oxygen, super oxygen
Ion etc.）.These active oxygens are highly reactive, can show obvious cytotoxicity.Poison of the copper sulfide to organism
Property is smaller, can be degraded by organism, be a kind of safe material of comparison, thus its in terms of the photo-thermal therapy of tumour by
Extensive concern.
Pore space structure inside the mesoporous copper sulfide of magnetic hollow of functionalization makes it possess the drug load amount of superelevation.Its grain
Footpath is small, and physicochemical properties are stable, have excellent magnetic target tropism, pass through the water soluble group such as hyalomitome in its surface modification
Acid, the mesoporous copper sulfide of magnetic hollow biocompatibility in vivo and mobility can be significantly improved, is advantageous in externally-applied magnetic field
Under conditions of by medicine cross-docking to focus.Because ferroso-ferric oxide also has the effect of plug-hole concurrently in the carrier, therefore
Rotated under action of alternating magnetic field and vibrating and then deforming opens hole, so as to which regulation and control are issued to medicine controlled releasing in magnetic field
Effect.
Chemotherapeutics is loaded in the nano-carrier with photo-thermal effect, passes through EPR effects targeting delivery to tumour portion
Position, so as to further improve therapeutic effect, reduce the toxic side effect of normal tissue and cell.The carrier and its pharmaceutical composition
Synthetic method it is simple, and by the significant photo-thermal effect of copper sulfide, the magnetic target tropism of ferroso-ferric oxide and its under magnetic fields
Good biocompatibility of controlled release, hyaluronic acid to medicine etc. is organically integrated in one, can have in addition with physical load
The chemotherapeutics of antitumor activity, there is efficient, controllable advantage, and its photo-thermal therapy and chemotherapy skill compared with traditional method
The combination of art more embodies the theory of cancer complex treatment.Therefore, study a kind of targeting merging photo-thermal therapy and chemotherapy in same
The treatment preparation of nano platform has great importance and is worth.
The content of the invention
For the above situation, to overcome the defect of prior art, the purpose of the present invention is just to provide a kind of hyaluronic acid and repaiied
Pharmaceutical composition of the mesoporous copper sulfide of magnetic hollow of decorations and preparation method and application, can effectively solve good biocompatibility,
Magnetic target tropism is strong, toxic side effect is small, the problem of to improve oncotherapy effect.
The technical scheme that the present invention solves is, in the ammonia that hollow mesoporous copper sulphide nano particles and mercaptoethylmaine react to obtain
Antineoplastic is loaded on the copper sulfide of base, the upper ferriferrous oxide nano grain of copper sulfide surface electrostatic absorption is anti-through amido link
Should in surface modification hyaluronic acid, into the pharmaceutical composition of the hyaluronic acid decorated mesoporous copper sulfide of magnetic hollow；Described
The mass content of ferroso-ferric oxide and copper sulfide ratio is 1 ~ 8 ︰ 1, and the particle diameter of the mesoporous copper sulfide of magnetic hollow is 50 ~ 300nm, by with
Lower step is realized：
（1）, by 0.7-0.8g CuSO4·5H2O is dissolved in 180-220ml water, stirring, adds 5-7g polyvinyl pyrroles
Alkanone, 10 ~ 20min is reacted, add 1.1-1.3g sodium hydroxides, stir, then 11-13ml hydrazine hydrates are added dropwise, stirring 5 ~
10min, 1.2-1.4ml ammonium sulfate is added, 1h is stirred, with ultra-pure water 12000-15000rpm（That is 12000-15000r/min）From
Heart 5-10min is washed to neutrality, is freeze-dried 48h, obtains hollow mesoporous nano copper sulfate particle；
（2）, by hollow mesoporous copper sulfide nano grain of rice 90-110mg ultrasonic disperses in 90-110ml ultra-pure waters, ultrasound 10 ~
30min, lower addition 180-220mg mercaptoethylmaines are stirred, stir 24h, 12000-15000rpm centrifugations 5-10min must be precipitated, sunk
Forming sediment plus ultra-pure water redissolves, then must be precipitated in 12000-15000rpm centrifugations 5-10min, precipitation plus ultra-pure water redissolve, and so repeatedly 2
~ 3 times, until being neutrality, freeze-drying, obtain the hollow mesoporous vulcanization copper composition (CuS-NH of amination2)；
（3）, synthesis ferriferrous oxide nano grain：Take 0.8-0.9 g FeCl2With 2.3-2.4 g FeCl3Stirring is lower to dissolve
In 35-45ml water, 80 DEG C are heated under nitrogen protection, 4-6ml ammoniacal liquor is slowly added dropwise, oil bath stirring 30min, it is dense to add quality
Spend 0.5gml-1Citric acid 1.8-2.2ml, be warming up to 95 DEG C, react 90min, room temperature is cooled under stirring, dialysis removes not
Reactive material, freeze-drying, produces water-soluble ferroferric oxide nanoparticle；
（4）, take step（2）The obtained hollow mesoporous vulcanization copper composition (CuS-NH of amination2) 4.5-5.5mg, point
Dissipate in pH7-9 phosphate buffer 4.5-5.5ml, 10 ~ 30 min of ultrasound under ice bath, with the phosphoric acid containing antineoplastic
Salt buffer mixes, and contains 9g antineoplastics in every 3ml phosphate buffers, and 24h is stirred at room temperature, and centrifugation is washed with water 3 times,
Probe Ultrasonic Searching is dispersed in water, and is freeze-dried the amination copper sulfide for producing load antineoplastic；
（5）, the amination copper sulfide for loading antineoplastic is scattered in 18-22ml water, stir and lower add four oxidations
Three-iron nanoparticle, is stirred at room temperature 6-48h, and 12000-15000rpm centrifugations 5-10min must be precipitated, is freeze-dried, it is anti-produce load
The mesoporous copper sulfide of magnetic hollow of tumour medicine；
（6）, by the mesoporous copper sulfide ultrasonic disperse of the magnetic hollow of above-mentioned carrying medicament in 18-22ml water, addition water
The hyaluronic acid 180-220mg of solution, stirring reaction 6-48h, the hyaluronic acid decorated mesoporous copper sulfide of magnetic hollow
Pharmaceutical composition.
The present invention is easy to operate, and method is reliable and stable, and obtained copper sulfide and its pharmaceutical composition have bio-compatible
Property it is good, magnetic target tropism is strong, toxic side effect is small the advantages that, can be played in terms of oncotherapy thermotherapy, diagnosing tumor, magnetic field delay controlled release
Medicine etc. acts on, and is the innovation on anti-tumor medicine, economic and social benefit is huge.
Embodiment
The embodiment of the present invention is elaborated below in conjunction with concrete condition and embodiment.
Embodiment 1
The present invention is in specific implementation, the system of the pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow
Preparation Method is realized by following methods：
（1）, by 0.75g CuSO4·5H2O is dissolved in 200ml water, stirring, adds 6.0g polyvinylpyrrolidones, instead
10 ~ 20min is answered, adds 1.2g sodium hydroxides, after stirring, 12ml hydrazine hydrates is added dropwise with syringe, stir 5 ~ 10min, most
1.29ml ammonium sulfate is added afterwards, stirs 1h, is washed to neutrality with ultra-pure water 15000rpm centrifugations 5-10min, is freeze-dried 48h,
Obtain hollow mesoporous nano copper sulfate particle；
（2）, hollow mesoporous copper sulfide nano grain of rice 100mg Probe Ultrasonic Searchings are scattered in 100ml ultra-pure waters, ultrasound 10 ~
30min, 200mg mercaptoethylmaines are added under stirring condition, stir 24h, 15000rpm centrifugations 5-10min must be precipitated, and add ultra-pure water
Redissolve, then centrifuge, so repeatedly 2 ~ 3 times, until being neutrality, freeze-drying, obtain the hollow mesoporous vulcanization copper composition of amination
(CuS-NH2)；
（3）, synthesis ferriferrous oxide nano grain：Take 0.86 g FeCl2With 2.35 g FeCl340ml is dissolved under stirring
In water, 80 DEG C are heated under nitrogen protection, 5ml ammoniacal liquor is slowly added dropwise with syringe, oil bath stirring 30min, adds quality afterwards
Concentration 0.5gml-1Citric acid 2ml, be warming up to 95 DEG C, react 90min, room temperature is cooled under stirring, dialysis removes unreacted
Material, freeze-drying, produces water-soluble ferroferric oxide nanoparticle；
（4）, take the hollow mesoporous vulcanization copper composition 5mg of amination, be scattered in 5ml phosphate buffers, ice bath test
Head 10 ~ 30 min of ultrasound, are mixed with the phosphate buffer containing antineoplastic, contain 9g in every 3ml phosphate buffers
Antineoplastic, 24h is stirred at room temperature, 15000rpm centrifugations 5-10min is washed with water 3 times, and Probe Ultrasonic Searching is dispersed in water, freezing
It is drying to obtain the amination copper sulfide of load antineoplastic；
（5）, by load antineoplastic amination copper sulfide be scattered in 20ml water, under stirring condition add be scattered in
Ferroso-ferric oxide in water, is stirred at room temperature 24h, and centrifuging to precipitate, freeze-drying, produces the magnetic hollow of load antineoplastic
Mesoporous copper sulfide；
（6）, the mesoporous copper sulfide Probe Ultrasonic Searching of the magnetic hollow of carrying medicament is scattered in 20ml water, it is saturating to add 200mg
Bright matter aqueous acid, stirring reaction 24h, produce the pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow.
Embodiment 2
The present invention is in specific implementation, the system of the pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow
Preparation Method is realized by following methods：
（1）, by 0.7g CuSO4·5H2O is dissolved in 180ml water, stirring, adds 5g polyvinylpyrrolidones, reaction
10 ~ 20min, 1.1g sodium hydroxides are added, are stirred, then 11ml hydrazine hydrates are added dropwise, stir 5 ~ 10min, add 1.2ml sulfuric acid
Ammonium, 1h is stirred, be washed to neutrality with ultra-pure water 12000rpm centrifugations 10min, be freeze-dried 48h, obtain hollow mesoporous copper sulfide nano
Rice grain；
（2）, by hollow mesoporous copper sulfide nano grain of rice 90mg ultrasonic disperses in 90ml ultra-pure waters, 10 ~ 30min of ultrasound, stir
Lower addition 180mg mercaptoethylmaines are mixed, stir 24h, 12000rpm centrifugations 10min must be precipitated, and precipitation plus ultra-pure water redissolve, then
12000rpm centrifugations 10min must be precipitated, and precipitation plus ultra-pure water redissolve, so repeatedly 2 ~ 3 times, until being neutrality, freeze-drying, be obtained
The hollow mesoporous vulcanization copper composition (CuS-NH of amination2)；
（3）, synthesis ferriferrous oxide nano grain：Take 0.8 g FeCl2With 2.3 g FeCl335ml water is dissolved under stirring
In, 80 DEG C are heated under nitrogen protection, 4-6ml ammoniacal liquor is slowly added dropwise, oil bath stirring 30min, adds mass concentration 0.5gml-1
Citric acid 1.8ml, be warming up to 95 DEG C, react 90min, room temperature is cooled under stirring, dialysis removes unreacting substance, and freezing is dry
It is dry, produce water-soluble ferroferric oxide nanoparticle；
（4）, take step（2）The obtained hollow mesoporous vulcanization copper composition (CuS-NH of amination2) 4.5mg, it is scattered in
In pH7-9 phosphate buffer 4.5ml, 10 ~ 30 min of ultrasound under ice bath, with the phosphate buffer containing antineoplastic
Mix, contain 9g antineoplastics in every 3ml phosphate buffers, 24h is stirred at room temperature, centrifugation is washed with water 3 times, Probe Ultrasonic Searching
It is dispersed in water, is freeze-dried the amination copper sulfide for producing load antineoplastic；
（5）, the amination copper sulfide for loading antineoplastic is scattered in 18ml water, stir and lower add ferroso-ferric oxide
Nanoparticle, is stirred at room temperature 6-48h, and 12000rpm centrifugations 10min must be precipitated, is freeze-dried, produce the magnetic of load antineoplastic
The hollow mesoporous copper sulfide of property；
（6）, by the mesoporous copper sulfide ultrasonic disperse of the magnetic hollow of above-mentioned carrying medicament in 18ml water, the addition aqueous solution
Hyaluronic acid 180mg, stirring reaction 6-48h, the hyaluronic acid decorated mesoporous copper sulfide of magnetic hollow drug regimen
Thing.
Embodiment 3
The present invention is in specific implementation, the system of the pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow
Preparation Method is realized by following methods：
（1）, by 0.8g CuSO4·5H2O is dissolved in 220ml water, stirring, adds 7g polyvinylpyrrolidones, reaction
10 ~ 20min, 1.3g sodium hydroxides are added, are stirred, then 13ml hydrazine hydrates are added dropwise, stir 5 ~ 10min, add 1.4ml sulfuric acid
Ammonium, 1h is stirred, be washed to neutrality with ultra-pure water 13000rpm centrifugations 8min, be freeze-dried 48h, obtain hollow mesoporous copper sulphide nano
Particle；
（2）, by hollow mesoporous copper sulfide nano grain of rice 110mg ultrasonic disperses in 110ml ultra-pure waters, 10 ~ 30min of ultrasound,
Stirring is lower to add 220mg mercaptoethylmaines, stirs 24h, and 13000rpm centrifugations 8min must be precipitated, and precipitation plus ultra-pure water redissolve, then
13000rpm centrifugations 8min must be precipitated, and precipitation plus ultra-pure water redissolve, so repeatedly 2 ~ 3 times, until being neutrality, freeze-drying, be obtained
The hollow mesoporous vulcanization copper composition (CuS-NH of amination2)；
（3）, synthesis ferriferrous oxide nano grain：Take 0.9 g FeCl2With 2.4 g FeCl345ml water is dissolved under stirring
In, 80 DEG C are heated under nitrogen protection, 6ml ammoniacal liquor is slowly added dropwise, oil bath stirring 30min, adds mass concentration 0.5gml-1's
Citric acid 2.2ml, 95 DEG C are warming up to, react 90min, room temperature is cooled under stirring, dialysis removes unreacting substance, and freezing is dry
It is dry, produce water-soluble ferroferric oxide nanoparticle；
（4）, take step（2）The obtained hollow mesoporous vulcanization copper composition 5.5mg of amination, it is scattered in pH7-9 phosphorus
In phthalate buffer 5.5ml, 10 ~ 30 min of ultrasound, are mixed, often with the phosphate buffer containing antineoplastic under ice bath
Contain 9g antineoplastics in 3ml phosphate buffers, 24h is stirred at room temperature, centrifugation is washed with water 3 times, and Probe Ultrasonic Searching is scattered in
In water, the amination copper sulfide for producing load antineoplastic is freeze-dried；
（5）, the amination copper sulfide for loading antineoplastic is scattered in 22ml water, stir and lower add ferroso-ferric oxide
Nanoparticle, is stirred at room temperature 6-48h, and 13000rpm centrifugations 8min must be precipitated, is freeze-dried, produce the magnetic of load antineoplastic
Hollow mesoporous copper sulfide；
（6）, by the mesoporous copper sulfide ultrasonic disperse of the magnetic hollow of above-mentioned carrying medicament in 22ml water, the addition aqueous solution
Hyaluronic acid 220mg, stirring reaction 6-48h, the hyaluronic acid decorated mesoporous copper sulfide of magnetic hollow drug regimen
Thing.
The pharmaceutical composition of the described mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow is preparing tumor
Application in injection, oral agents or drug delivery implant agent.
The pharmaceutical composition of the described mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow is in antineoplastic is prepared
Application, by the pharmaceutical composition and pharmaceutical active or pharmacological activity molecule of the hyaluronic acid decorated mesoporous copper sulfide of magnetic hollow
It is combined and nano medicament carrying system is made, described pharmaceutical active or adriamycin, Japanese yew that pharmacological activity molecule is antineoplastic
Alcohol, Docetaxel, HCPT, mitoxantrone.
The pharmaceutical composition of the described mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow is preparing tumor thermal therapy
Combined chemotherapy, magnetic field regulate and control the application in drug release, magnetic resonance imaging medicine at a distance.
The pharmaceutical composition of the hyaluronic acid decorated mesoporous copper sulfide of magnetic hollow of the present invention has good bio-compatible
Property and relatively low toxicity, tumor locus can be transported to by what medicine oriented by the magnetic target tropism of ferroso-ferric oxide, and should
Drug-loading system can regulate and control in the presence of externally-applied magnetic field to the release of medicine, laser irradiation under can realize thermotherapy and
The synergy of chemotherapy, effectively kills cancer cell.Obtained compound is provided simultaneously with photo-thermal therapy, drug therapy, magnetic targeted
Property, the multi-efficiency such as magnetic resonance imaging is easy to operate, and method is reliable and stable, obtained copper sulfide and its pharmaceutical composition tool
Have the advantages that good biocompatibility, magnetic target tropism is strong, toxic side effect is small, can be played in terms of oncotherapy thermotherapy, diagnosing tumor,
Delay the effect such as controlled release medicine in magnetic field.Relevant information is as follows：
First, the extrinsic heat therapy experiment of the mesoporous copper sulfide compositions of magnetic hollow of adriamycin is loaded
A series of mesoporous vulcanization copper solution of magnetic hollow of the load adriamycin of concentration is prepared, vulcanization copper concentration is respectively：
200ug/ml、100ug/ml、50ug/ml、25ug/ml、12.5ug/ml、0ug/ml.808 nm near-infrared lasers are used with 2
W/cm2Energy density be irradiated, and measure solution respectively in 0,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5 min
Temperature, record result show, formulation concentrations 200ug/ml, 100ug/ml, 50ug/ml, 25ug/ml, 12.5ug/ml,
During 0ug/ml, temperature increases 54 DEG C, 38.9 DEG C, 28.5 DEG C, 19.4 DEG C, 11.2 DEG C, 2.5 DEG C respectively in 5min.As a result show,
The mesoporous copper sulfide of magnetic hollow has excellent photothermal conversion effect, and concentration dependent is presented in its photothermal deformation effect.
2nd, the drug release experiment of the mesoporous copper sulfide compositions of magnetic hollow of adriamycin is loaded
2 parts of CuS-IONP-HA/DOX nano-complexes, respectively alternating magnetic field group and non-alternating magnetic field group are taken respectively, point
Dissipate in 50ml pH7.4 phosphate buffer salts, be positioned over shaking table（37 DEG C, 100rpm）, respectively at 1h, 3h, 6h, 8h, 12h,
14h is sampled, and each sampling amount is 0.5ml, adds 0.5ml dissolution medium afterwards, magnetic field group each time point is in alternation magnetic
30min is placed off field, and alternating magnetic field parameter is：Frequency 50kHz, magnetic field intensity 2.5kA/m.Sample is detected with efficient liquid phase, is released
After medicine 14h, the drug release amount of CuS-IONP-HA/DOX nano-complex alternating magnetic field groups is higher by 41% than non-alternating magnetic field group.As a result
Show, under the conditions of having existing for alternating magnetic field, the ferroso-ferric oxide in CuS-IONP-HA/DOX compounds can revolve
Turn and vibrate and then deform, open the hole of hollow mesoporous copper sulfide, and then promote the release of medicine.
3rd, the cell growth inhibition assay of the mesoporous copper sulfide compositions of magnetic hollow of adriamycin is loaded
Using srb assay, the MCF-7 human breast cancer cells of exponential phase are selected, adjustment cell number is 5 × 104/ ml is inoculated with
In 96 well culture plates, per the μ 1 of hole 100（Edge hole is filled with sterile PBS）, cell attachment growth 24h after dosing, be followed successively by blank
Group, CuS-IONP-HA groups, DOX groups, CuS-IONP-HA/DOX groups, medicine final concentration is set to 4 μ g/ml, and sets up laser group separately
（2W/cm2, laser is shone after 3min, dosing 4h）With non-laser group, every group sets 6 multiple holes.After 24 h, 4 DEG C of 50 μ l are added per hole
50% trichloroacetic acid of precooling（TCA）Fixed cell, 4 DEG C of refrigerators fixation 1h are moved into after fixing 10min, taking-up discards fixer, used
Deionization is washed 5 times, is dried, natural drying at room temperature.After room temperature is dried, the μ 1 of SRB dye liquors 50, room temperature avoid light place 15 are added per hole
~ 30min is dyed, and is abandoned dye liquor, is washed 5 times with 1% glacial acetic acid, drying at room temperature.Afterwards, with the non-buffered Tris alkali lye of 150 μ l（10mM,
pH=10.5）Dissolve the dyestuff combined with cell protein, shaking table micro oscillation（37 DEG C, 100rpm, 10min）Afterwards, in ELIASA 515
The OD values of each aperture are surveyed at nm wavelength, calculate growth of tumour cell inhibiting rate (%)=(1- experimental groups OD values/control group OD
Value) × 100%, CuS-IONP-HA groups, CuS-IONP-HA-laser groups, DOX groups, DOX-laser groups, CuS- is calculated
IONP-HA/DOX groups, the inhibitory rate of cell growth of CuS-IONP-HA/DOX-laser group each groups are respectively：4.9%,
25.8%, 49.7%, 53.3%, 51.2%, 77.4%.As a result show, support C uS-IONP is under test dose to cell without obvious
Toxicity, but near infrared light（808nm）There is obvious photo-thermal effect under irradiation；Preparation group and raw material when without near infrared light
The cytotoxicity difference of medicine group is little, and inhibitory action of the CuS-IONP-HA/DOX to tumour cell near infrared light
It is most strong, then it is the result of chemotherapy and thermotherapy synergistic treatment.
4th, the pharmacodynamic study of the mesoporous copper sulfide compositions of magnetic hollow of adriamycin is loaded
Buy kunming mice（Female, 3 ~ 4 week old）, S-180 Ascitic Tumor Cells are inoculated with the right upper extremity dorsal sc of mouse,
Gross tumor volume is measured after 7 days, takes the mm of gross tumor volume >=1003And the mouse that gross tumor volume is similar with body weight, it is randomly divided into
10 groups, every group 6.Specifically it is grouped as follows：Physiological saline group, physiological saline-laser groups, CuS-IONP-HA groups, CuS-IONP-
HA-laser groups, CuS-IONP-HA-laser/magnet groups, DOX groups, DOX-laser groups, CuS-IONP-HA/DOX groups,
CuS-IONP-HA/DOX-laser groups, CuS-IONP-HA/DOX-laser/magnet groups, the light source that laser group uses are
808nm near-infrared lasers, power 2W/cm2, laser irradiation tumor locus after 3h is administered, each irradiation time is 1min.Each group
The administering mode of mouse uses tail vein injection, per once two days, is administered 7 times altogether.Ensure that mouse is every in whole experiment process
Day normal diet, the every two days body weight for weighing every mouse, and use the major diameter of electronic digital indicator measurement tumor-bearing mice sarcoma
(A) with minor axis (B), by formula gross tumor volume V=A × B2/ 2 calculate gross tumor volume.The data of record show, CuS-IONP-HA
Group, CuS-IONP-HA-laser groups, CuS-IONP-HA-laser/magnet groups, DOX groups, DOX-laser groups, CuS-
IONP-HA/DOX groups, CuS-IONP-HA/DOX-laser groups, the tumour inhibiting rate of CuS-IONP-HA/DOX-laser/magnet groups
Respectively 4.49%, 26.82%, 41.56%, 43.85%, 46.03%, 68.75%, 81.43%, 87.68%.As a result show, CuS-
The drug effect of IONP-HA/DOX-laser/magnet groups is notable, when the mesoporous copper sulfide of administration magnetic hollow and its pharmaceutical composition exist
When laser is irradiated with externally-applied magnetic field collective effect, the knurl volume of mouse has obtained obvious suppression, illustrates CuS-IONP-HA/
Chemotherapy, 808nm laserthermias, the magnetic targeted joint of DOX-laser/magnet Tumor Targeting Drug Delivery Systems can significantly increase swollen
The therapeutic effect of knurl.
5th, the magnetic resonance imaging experiment of the mesoporous copper sulfide compositions of magnetic hollow of adriamycin is loaded
S-180 Ascitic Tumor Cells are inoculated with the right upper extremity dorsal sc of mouse, gross tumor volume is measured after 7 days, take 12 to swell
The mm of knurl volume >=1003And the mouse that gross tumor volume is similar with body weight, 2 groups are randomly divided into, every group 6, specific packet is such as
Under：Physiological saline group, CuS-IONP-HA/DOX groups.Fiber crops are carried out to two groups of yellow Jackets of mouse peritoneal injection 0.04ml 3%
It is liquor-saturated, after fixing to two groups of mouse by the way of intravenously administrable, wherein physiological saline 200 μ 1,2mg/ml CuS-IONP-
The μ 1 of HA/DOX normal saline solutions 200.24h carries out T2WI magnetic resonance imagings to mouse after injection.Wherein sweep parameter is：It is cross-section
Position SE-T2WI, TR4240ms, TE1108.47ms, FOV8cm, thickness（Cross-section position 2mm, Coronal 3mm）, interlamellar spacing 1mm, square
Battle array 256*256.It is real that region of interest ROI measurements tumour of the same size is drawn on the T2WI images of the tumor region of two groups of mouse
Body portion signal intensity（SIT）, average, measurement area is not less than 6mm2.As a result CuS-IONP-HA/DOX group tumours are shown
Compared with the signal of control group mice respective regions, signal substantially lowers the T2WI signals in region, MRI positive effect enhancing.
Experiment shows that the present invention compared with prior art, has advantageous effects following prominent：
（1）The mesoporous copper sulfide of magnetic hollow provided by the invention and its pharmaceutical composition, have excellent biocompatibility,
Water dispersible and stability, and the efficient photo-thermal therapy activity of copper sulfide is remained, integrate thermotherapy and chemotherapy；
（2）Present invention selection ferroso-ferric oxide modification copper sulfide, can both provide magnetic targeted work in drug transport processes
With can be used as block agent again, prevent the leakage of medicine, and in the presence of externally-applied magnetic field, release that can be to medicine rises
To the effect of controlled release, while ferroso-ferric oxide can carry out magnetic resonance imaging, can in real time be monitored over the course for the treatment of, be
The diagnosis and treatment of tumour provide new direction.
Claims (4)
- A kind of 1. preparation method of the pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow, it is characterised in that Antineoplastic, sulphur are loaded on the amidized copper sulfide that hollow mesoporous copper sulphide nano particles and mercaptoethylmaine react to obtain Change the upper ferriferrous oxide nano grain of copper surface electrostatic absorption, through amido link reaction hyaluronic acid in surface modification, into hyalomitome The pharmaceutical composition of the mesoporous copper sulfide of magnetic hollow of acid modification；Described ferroso-ferric oxide and the mass content ratio of copper sulfide are 1 ~ 8 ︰ 1, the particle diameter of the mesoporous copper sulfide of magnetic hollow is 50 ~ 300nm, and preparation method comprises the following steps：（1）, by 0.7-0.8g CuSO4·5H2O is dissolved in 180-220ml water, stirring, adds 5-7g polyvinylpyrrolidines Ketone, 10 ~ 20min is reacted, add 1.1-1.3g sodium hydroxides, stir, then 11-13ml hydrazine hydrates are added dropwise, stirring 5 ~ 10min, 1.2-1.4ml ammonium sulfate is added, 1h is stirred, with ultra-pure water 12000-15000rpm（That is 12000-15000r/min）From Heart 5-10min is washed to neutrality, is freeze-dried 48h, obtains hollow mesoporous nano copper sulfate particle；（2）, by hollow mesoporous copper sulfide nano grain of rice 90-110mg ultrasonic disperses in 90-110ml ultra-pure waters, ultrasound 10 ~ 30min, lower addition 180-220mg mercaptoethylmaines are stirred, stir 24h, 12000-15000rpm centrifugations 5-10min must be precipitated, sunk Forming sediment plus ultra-pure water redissolves, then must be precipitated in 12000-15000rpm centrifugations 5-10min, precipitation plus ultra-pure water redissolve, and so repeatedly 2 ~ 3 times, until being neutrality, freeze-drying, obtain the hollow mesoporous vulcanization copper composition (CuS-NH of amination2)；（3）, synthesis ferriferrous oxide nano grain：Take 0.8-0.9 g FeCl2With 2.3-2.4 g FeCl335- is dissolved under stirring In 45ml water, 80 DEG C are heated under nitrogen protection, 4-6ml ammoniacal liquor is slowly added dropwise, oil bath stirring 30min, adds mass concentration 0.5g·ml-1Citric acid 1.8-2.2ml, be warming up to 95 DEG C, react 90min, room temperature is cooled under stirring, dialysis removes not anti- Material is answered, is freeze-dried, produces water-soluble ferroferric oxide nanoparticle；（4）, take step（2）The obtained hollow mesoporous vulcanization copper composition (CuS-NH of amination2) 4.5-5.5mg, it is scattered in In pH7-9 phosphate buffer 4.5-5.5ml, 10 ~ 30 min of ultrasound, delay with the phosphate containing antineoplastic under ice bath Fliud flushing mixes, and contains 9g antineoplastics in every 3ml phosphate buffers, and 24h is stirred at room temperature, and centrifugation is washed with water 3 times, pops one's head in Ultrasonic disperse is freeze-dried the amination copper sulfide for producing load antineoplastic in water；（5）, the amination copper sulfide for loading antineoplastic is scattered in 18-22ml water, stir and lower add ferroso-ferric oxide Nanoparticle, is stirred at room temperature 6-48h, and 12000-15000rpm centrifugations 5-10min must be precipitated, is freeze-dried, it is antitumor produce load The mesoporous copper sulfide of magnetic hollow of medicine；（6）, by the mesoporous copper sulfide ultrasonic disperse of the magnetic hollow of above-mentioned carrying medicament in 18-22ml water, add 180-220mg Hyaluronic acid aqueous solution, stirring reaction 6-48h, the hyaluronic acid decorated mesoporous copper sulfide of magnetic hollow drug regimen Thing.
- 2. the preparation side of the pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow according to claim 1 Method, it is characterised in that comprise the following steps：（1）, by 0.75g CuSO4·5H2O is dissolved in 200ml water, stirring, adds 6.0g polyvinylpyrrolidones, reaction 10 ~ 20min, 1.2g sodium hydroxides are added, after stirring, 12ml hydrazine hydrates are added dropwise with syringe, stir 5 ~ 10min, finally add Enter 1.29ml ammonium sulfate, stir 1h, be washed to neutrality with ultra-pure water 15000rpm centrifugations 5-10min, be freeze-dried 48h, obtain Hollow mesoporous nano copper sulfate particle；（2）, hollow mesoporous copper sulfide nano grain of rice 100mg Probe Ultrasonic Searchings are scattered in 100ml ultra-pure waters, 10 ~ 30min of ultrasound, 200mg mercaptoethylmaines are added under stirring condition, stir 24h, 15000rpm centrifugations 5-10min must be precipitated, and add ultra-pure water to redissolve, then Centrifugation, so repeatedly 2 ~ 3 times, until being neutrality, freeze-drying, obtain the hollow mesoporous vulcanization copper composition (CuS- of amination NH2)；（3）, synthesis ferriferrous oxide nano grain：Take 0.86 g FeCl2With 2.35 g FeCl3It is dissolved under stirring in 40ml water, 80 DEG C are heated under nitrogen protection, 5ml ammoniacal liquor is slowly added dropwise with syringe, oil bath stirring 30min, adds mass concentration afterwards 0.5g·ml-1Citric acid 2ml, be warming up to 95 DEG C, react 90min, room temperature is cooled under stirring, dialysis removes unreacted reactant Matter, freeze-drying, produces water-soluble ferroferric oxide nanoparticle；（4）, take the hollow mesoporous vulcanization copper composition 5mg of amination, be scattered in pH7-9 5ml phosphate buffers, under ice bath The min of Probe Ultrasonic Searching 10 ~ 30, is mixed with the phosphate buffer containing antineoplastic, is contained in every 3ml phosphate buffers 9g antineoplastics, 24h is stirred at room temperature, 15000rpm centrifugations 5-10min is washed with water 3 times, and Probe Ultrasonic Searching is dispersed in water, cold Freeze the amination copper sulfide for being drying to obtain load antineoplastic；（5）, by load antineoplastic amination copper sulfide be scattered in 20ml water, under stirring condition add be dispersed in water Ferriferrous oxide nano grain, 24h is stirred at room temperature, centrifuging to precipitate, freeze-drying, produce load antineoplastic magnetic in Empty mesoporous copper sulfide；（6）, the mesoporous copper sulfide Probe Ultrasonic Searching of the magnetic hollow of carrying medicament is scattered in 20ml water, add 200mg hyalomitomes Aqueous acid, stirring reaction 24h, produce the pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow.
- 3. the pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow prepared by the methods described of claim 1 or 2 Application in antineoplastic composition injection, oral agents or drug delivery implant agent is prepared, adriamycin, the purple of described antineoplastic China fir alcohol, Docetaxel, HCPT, mitoxantrone.
- 4. the pharmaceutical composition of the mesoporous copper sulfide of hyaluronic acid decorated magnetic hollow prepared by the methods described of claim 1 or 2 Application in preparing tumor thermal therapy combined chemotherapy, magnetic field and regulating and controlling drug release, magnetic resonance imaging medicine at a distance.
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| Activatable Hyaluronic Acid Nanoparticle as a Theranostic Agent for Optical/Photoacoustic Image-Guided Photothermal Therapy;Liwen Zhang et al.;《ACS NANO》;20141130;第8卷(第12期);摘要和第12256页右栏倒数第2段；第12257页左栏第7段和右栏第2段 * |
| Hollow Copper Sulfide Nanoparticle-Mediated Transdermal Drug Delivery;Samy Ramadan et al.;《Small》;20120731;第8卷(第20期);摘要；第3144页左栏倒数第2段；第3149页左栏第1段 * |
| Sub-10 nm Fe3O4@Cu2−xS Core−Shell Nanoparticles for Dual-Modal Imaging and Photothermal Therapy;Qiwei Tian et al.;《Journal of the American Chemical Society》;20130520;摘要 * |
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