CN106727284A - A kind of magnetizing reduction enhanced medicaments insensitive release nanogel and its preparation and store method - Google Patents
A kind of magnetizing reduction enhanced medicaments insensitive release nanogel and its preparation and store method Download PDFInfo
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- CN106727284A CN106727284A CN201710012359.4A CN201710012359A CN106727284A CN 106727284 A CN106727284 A CN 106727284A CN 201710012359 A CN201710012359 A CN 201710012359A CN 106727284 A CN106727284 A CN 106727284A
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- 239000003814 drug Substances 0.000 title claims abstract description 45
- 230000009467 reduction Effects 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 229940079593 drug Drugs 0.000 claims abstract description 14
- VIDTVPHHDGRGAF-UHFFFAOYSA-N selenium sulfide Chemical compound [Se]=S VIDTVPHHDGRGAF-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000005576 amination reaction Methods 0.000 claims abstract description 12
- 229960005265 selenium sulfide Drugs 0.000 claims abstract description 11
- 241000399119 Spio Species 0.000 claims abstract description 6
- 238000011275 oncology therapy Methods 0.000 claims abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 claims abstract 2
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 14
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 14
- 239000012498 ultrapure water Substances 0.000 claims description 14
- 235000010413 sodium alginate Nutrition 0.000 claims description 13
- 229940005550 sodium alginate Drugs 0.000 claims description 13
- 239000000661 sodium alginate Substances 0.000 claims description 13
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 10
- 229920001503 Glucan Polymers 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 229910052711 selenium Inorganic materials 0.000 claims description 7
- 239000011669 selenium Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 229960001305 cysteine hydrochloride Drugs 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 229920002521 macromolecule Polymers 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229920002807 Thiomer Polymers 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000000502 dialysis Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229960000485 methotrexate Drugs 0.000 claims description 4
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000005190 thiohydroxy group Chemical group 0.000 claims description 4
- 239000003643 water by type Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 150000001718 carbodiimides Chemical class 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229920001661 Chitosan Polymers 0.000 claims description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 claims description 2
- 229930192392 Mitomycin Natural products 0.000 claims description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 229960001330 hydroxycarbamide Drugs 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 229960004857 mitomycin Drugs 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 239000012429 reaction media Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 108010006654 Bleomycin Proteins 0.000 claims 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims 1
- 230000001093 anti-cancer Effects 0.000 claims 1
- 229960001561 bleomycin Drugs 0.000 claims 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000008685 targeting Effects 0.000 abstract description 4
- 231100000614 poison Toxicity 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 230000007096 poisonous effect Effects 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract 1
- 238000001338 self-assembly Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 24
- 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 description 16
- 206010028980 Neoplasm Diseases 0.000 description 13
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 12
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 229940009456 adriamycin Drugs 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 6
- 229960003180 glutathione Drugs 0.000 description 6
- 230000037396 body weight Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 230000005408 paramagnetism Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- -1 1- Ethyl Chemical group 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 108700016226 indium-bleomycin Proteins 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
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- 239000002574 poison Substances 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
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- 230000004936 stimulating effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 238000000015 thermotherapy Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a kind of magnetizing reduction enhanced medicaments insensitive release nanogel and its preparation and store method.The enhanced medicaments insensitive release nanogel of the magnetizing reduction is contained the polymeric derivative and cancer therapy drug (1 2) in mass ratio of selenium sulfide linkage by the SPIO of surface amination, side chain：1：(0.2 0.5) it is obtained.Preparation method is specially：1) synthesis side chain contains the polymeric derivative of selenium sulfide linkage；2) by SPION NH2, cancer therapy drug and step 1) obtain the polymeric derivative self assembly that side chain contains selenium sulfide linkage and obtain final product.During the store method of gained nanogel of the invention is the environment being stored at 2~4 DEG C.Preparation condition of the present invention is gentle, do not introduce poisonous and harmful substance, process is simple is reproducible, the nanogel of preparation has strong reduction sensitivity release property, the violent release being prevented effectively from normal physiological context and medicine are revealed, and with active magnetic targeting, had broad application prospects in anti-tumor drugs targeting field.
Description
Technical field
The present invention relates to a kind of magnetizing reduction enhanced medicaments insensitive release nanogel and its preparation and store method, category
In field of nanometer material technology and drug controlled release technical field.
Background technology
Nanogel refer to size for nanoscale (10-1000nm), formed after chemically or physically by macromolecule
Tridimensional network.Nanogel is loaded medicine as pharmaceutical carrier in the way of adsorbing or embed, and is passed through
The otherness inside and outside combination or normal structure and cell and tumour between targeting ligand and acceptor, designs with actively or passively
The pharmaceutical carrier of Targeting Performance.With reference to the EPR effects of tumor locus, structure using its larger space between cells and loosely,
Promote passing through for nano carrier, so that it can preferably be enriched in lesions position, be remarkably improved the biological utilisation of medicine
Degree and medicine conveying in vivo and release performance, the system for be class safety, being worth with potential source biomolecule medical application.
Recently, the drug delivery system of multiple stimulation response obtains quick in the research of cancer diagnosis and treatment
Development.It is well known that the concentration of tumour cell external environment glutathione (GSH) is at 2~10 μM, and endosome and lysosome
GSH values are 2~10mM, and both differ hundreds of times.And GSH has reproducibility, therefore, design is containing double sulphur in nanogel structure
Key, double selenium keys etc. are reduced the chemical bond of fracture, are capable of achieving the reduction stimulating responsive of nanogel, effectively improve controlling for cancer
Therapeutic effect.
In external source magnetic field carrier can be effectively enriched with SPIO in target site, and
The performances such as its magnetic thermotherapy effect, magnetic resonance imaging, make it equally be widely used in pharmaceutical carrier.
Therefore, reproducible, the Nano medication load with the sensitive stimulation release of well reduction is prepared under mild conditions
Body, is one of urgent problem in current chemotherapeutics application.
The content of the invention
For above-mentioned problems of the prior art, mesh of the invention is to be to provide a kind of enhanced medicine of magnetizing reduction
Sensitivity release nanogel and its preparation and store method.The enhanced medicaments insensitive release nanogel of magnetizing reduction has
Reduction response susceptibility higher, it is possible to decrease carrier burst size in the normal tissue, so as to reduce toxic and side effect, raising is controlled
Curative effect rate, and preparation method of the present invention is gentle, does not introduce poisonous and harmful substance.
To achieve the above object, the technical solution adopted by the present invention is as follows：
A kind of enhanced medicaments insensitive release nanogel of magnetizing reduction, it is characterised in that by following raw materials in mass ratio
(1-2)：1：(0.2-0.5) is prepared：
The SPIO of surface amination, side chain contain selenium sulfide linkage polymeric derivative,
Cancer therapy drug.
By such scheme, it is preferable that the polymeric derivative that the side chain contains selenium sulfide linkage is prepared by following step：
Room temperature, nitrogen protection under, the PBS solution with concentration as 0.01mol/L as reaction medium, with mass ratio as 1-
1.5：The macromolecule of 1 side chain thiohydroxy-containing group and the compound containing double selenium keys are reaction raw materials, adjust reaction system
PH value be 6.5-7.4, at 37 DEG C, stirring reaction 5-8 hour, dialyse, obtain the polymeric derivative that side chain contains selenium sulfide linkage.
Preferably, the medium of the dialysis is ultra-pure water.
By such scheme, it is preferable that the macromolecule of the side chain thiohydroxy-containing group is sulfhydrylation sodium alginate, sulfhydrylation
One kind in glucan, Chitosan-Thiolated Polymers.
Above-mentioned sulfhydrylation sodium alginate, sulfhydrylation glucan, the preparation method of Chitosan-Thiolated Polymers are：
1) appropriate sodium alginate or amination glucan or shitosan are dissolved in a certain amount of ultra-pure water；2) by appropriate 1-
Ethyl -3- (3- dimethyl aminopropyls) carbodiimide (EDC) and N-hydroxy-succinamide (NHS) are dissolved into appropriate ultra-pure water
In；3) under nitrogen protective condition, by step 2) obtained in EDC/NHS solution be added drop-wise to step 1) obtained in sodium alginate or ammonia
In base glucan or chitosan solution, 30min is activated；4) appropriate cysteine hydrochloride is dissolved in appropriate ultra-pure water, and
It is 6-7 or so to adjust pH with the sodium hydroxide solution of 6mol/L, and step 3 is added drop-wise to afterwards) in the solution that obtains, continue to stir
12h, whole lucifuge treatment；After reaction terminates, reaction solution is fitted into bag filter and is dialysed 2 days, freezed, be dried to obtain solid powder
End.By such scheme, it is preferable that the carboxyl of the sodium alginate is 1 with the mol ratio of the amino of the cysteine hydrochloride：
(1~1.2).By such scheme, it is preferable that the amino of the amination glucan or shitosan and the carboxylic of cysteine hydrochloride
The mol ratio of base is 1：(1~1.2).
By such scheme, it is preferable that the compound containing double selenium keys is 3,3 '-two seleno dipropionic acids or 4,4 '-two
The butyric acid of seleno two.Wherein, 3,3 '-two seleno dipropionic acids can refer to document (Langmuir, 2006,22 (13):5552-5565)、
(Int J Nanomed,2012,7(17):3991-4006) it is obtained, described 4, the butyric acid of 4 '-two seleno two can be by the following method
It is obtained：
3.95g selenium powders and 2.00g NaOH are dissolved in 25mL frozen water respectively；Then by 0.25g sodium borohydrides and
0.20g NaOH is dissolved in 5mL frozen water, and is expelled in the above-mentioned solution containing selenium powder, anti-in 0 DEG C under whole nitrogen protection
Should be completely dissolved up to selenium powder, solution is presented colorless state.Then continue to react 30min after solution being warming up into 90 DEG C, until
Untill solution colour is changed into rufous.5.42g4- chloropropionic acids are dissolved in 20mL ultra-pure waters, and pH value is adjusted most with sodium carbonate
After 8.0, it is added in above-mentioned red tan solution, is stirred overnight under a nitrogen atmosphere.After reaction terminates, reaction solution is through filtering
To yellow solution, it is 3~4 to adjust its pH with the hydrochloric acid of 1.0mol/L afterwards, is extracted with ethyl acetate twice, then use anhydrous slufuric acid
Magnesium is dried, filtering, and revolving finally obtains yellow solid product with re-crystallizing in ethyl acetate.
By such scheme, it is preferable that the cancer therapy drug be ADMh, methotrexate (MTX), mitomycin, hydroxycarbamide,
One or more in bleomycin.
Present invention also offers the preparation method that the enhanced medicaments insensitive of above-mentioned magnetizing reduction discharges nanogel, its feature
It is to comprise the steps：
1) polymeric derivative that side chain contains selenium sulfide linkage is incorporated in ultra-pure water, the pH value for adjusting solution is 6-7.4；
2) SPIO and cancer therapy drug of surface amination are dissolved in hydrochloric acid, are controlled molten
The pH value of liquid is in 4.5-5.5；
3) under the conditions of lucifuge, by step 2) solution that obtains drops to step 1) in the solution that obtains, regulation solution
PH value is 7.2-7.4, stirs 5-7h, and dialysis obtains the enhanced medicaments insensitive release nanogel of magnetizing reduction.
By such scheme, it is preferable that step 3) described in dialyse medium be ultra-pure water, the bag filter molecular cut off
It is 10KDa.
Present invention also offers the store method that the enhanced medicaments insensitive of above-mentioned magnetizing reduction discharges nanogel, its feature
In being the environment being stored at 2~4 DEG C.
Compared to prior art, the beneficial effects of the present invention are：
Reaction condition of the present invention is gentle, and raw material toxic and side effect is low, is realized to medicine by way of electrostatic interaction
Contain, while the use of selenium sulfide linkage ensures that insoluble drug release has strong reduction-sensitive, be prevented effectively from normal physiological context
Violent release and the ill effect such as medicine leakage, and in reproducibility environment in cancer cell, realize a large amount of quick releases of medicine,
With low toxic and side effect and therapeutic effect high.
Brief description of the drawings
Fig. 1 is the saturating of the magnetizing reduction responsive nano pharmaceutical carrier based on sodium alginate prepared by the embodiment of the present invention 1
Penetrate electron microscope (a), grain size distribution (b), magnetic absorption figure (c) and hysteresis curve (d).
Fig. 2 is the magnetizing reduction responsive nano pharmaceutical carrier based on sodium alginate of the preparation of the embodiment of the present invention 1 not
With the drug release patterns figure under environment.
Fig. 3 is the magnetizing reduction responsive nano pharmaceutical carrier little Bai based on sodium alginate prepared by the embodiment of the present invention 1
Mouse biological assessment, tumour real scene shooting (a), tumor Volume Changes figure (b), tumor control rate (c) and mouse body weight variation diagram (d).
Specific embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.
Embodiment 1
1st, reference literature (Biomaterials, 2009,30:4716-4722) method synthesis is super with surface amination
Paramagnetism ferriferrous oxide nano-particle (SPION-NH2)。
2nd, sodium alginate polymeric derivative (SA-SSe-COOH) of the side chain containing selenium sulfide linkage is prepared, is comprised the following steps that：
1) reference literature (J controlled release, 2009,136:38-44)、(Materials Science
and Engineering C,2015,46:41-51) etc. method, sulfydryl is introduced by sodium alginate side chain, obtains sulfhydrylation marine alga
Sour sodium (SA-SH).
2) reference literature (Langmuir, 2006,22 (13):5552-5565)、(Int J Nanomed,2012,7(17):
The method synthesis seleno dipropionic acids (DSeDPA) of 3,3'- bis- such as 3991-4006).
3) under room temperature, nitrogen protection, 0.1g DSeDPA are claimed to be incorporated in PBS (0.01mol/L, pH equipped with 30mL
6.56) in there-necked flask, stirring dissolves it.0.125g SA-SH are claimed to be dissolved in PBS (the 0.01mol L-1, pH of 30mL
6.56) in, and it is expelled in above-mentioned DSeDPA solution, reaction condition is 37 DEG C, is stirred 7 hours.Reaction resulting solution is with ultrapure
Water is dialysed 3 days, obtains the SA-SSe-COOH of 1.81mg/mL.
3rd, the SA-SSe-COOH of 2.76mL 1.81mg/mL is transferred in the there-necked flask containing 2.24mL ultra-pure waters,
And it is 6.5 to adjust its pH value with HCl；Take the SPION-NH of 0.908mL 5.508mg/mL2With Ah mould of 0.625mL 4mg/mL
Element is dissolved in the hydrochloric acid of 3.07mL pH 5.0, and is added drop-wise in above-mentioned there-necked flask, is finally adjusted with the NaOH of 0.1mol/L
Section pH is 7.4, is stirred 5 hours at room temperature, and whole process takes lucifuge measure.Reaction solution is transferred in bag filter and is dialysed with ultra-pure water
After 2 days, the molecular cut off of bag filter used is 10KDa, and the aqueous solution for obtaining nanogel is preserved at 4 DEG C.Gained magnetic
The carrying drug ratio and envelop rate of nanogel are respectively 18.2% and 95.6%.
The performance measurement of the present embodiment gained Magnetic nanogels：
The particle diameter for using laser particle analyzer (DLS) to measure the nanogel prepared by the present embodiment is 110 ± 15nm, as a result
Such as Fig. 1-a.Measured particle size is consistent with transmission electron microscope results.Using transmission electron microscope (TEM) observation period pattern and size point
Cloth situation, as a result as shown in Fig. 1-b.The particle morphology of preparation is homogeneous and stable.
Prepared magnetic drug-carrying nanometer is analyzed using permanent magnet migration and electromagnet vibrating specimen magnetometer (VSM) respectively
Gel with the time swimming behavior, hysteresis curve and saturation magnetic intensity, as a result as shown in Fig. 1-c and 1-d.It can be seen that prepared magnetic
Property reduction enhancement type nanometer gel there is good magnetic, can quickly near magnet enrichment.The carrier has without obvious magnetic hysteresis
Superparamagnetism, and saturation magnetic intensity reaches 53.4emu/g Fe.
Medicament-carried nano gel prepared by the present embodiment has significant reduction response release characteristics, as shown in Figure 2.In pH
Burst size in the environment of=5.0PBS and 10mM GSH reaches 97.5%, and its cumulative release amount is highest under all environment.
And under conditions of pH=5.0PBS, cumulative release amount is 54.2%, prepared carrier is indicated quick with significantly reducing
Perception.Additionally, the carrier also shows obvious pH responses.Under pH and GSH double actions, magnetic drug-carrying nanogel
Burst size is significantly improved.
Nanogel prepared by the present embodiment carries out biological evaluation result by model of experiment mice, as shown in Figure 3.
Cancer cell is subcutaneously implanted in mouse first, treats that tumour grows to 100mm3During left and right, mouse is divided into blank control group (PBS control
Group), adriamycin control group and magnetic drug-carrying nanogel group.By tail vein injection, adriamycin control group group and magnetic drug-carrying
The injection volume of the adriamycin of nanogel group is 3.3mg/kg/week, at the same carried out with the PBS control group of not drug containing it is right
Than.By the observation of 21 days, there is no significant change by the body weight of magnetic drug-carrying nanogel and the treated mouse of PBS, and pass through
Cross adriamycin treatment mouse at second day body weight significantly reduce (Fig. 3-a).In follow-up observation, with PBS control group phase
Than, the body weight increase of the mouse of adriamycin group is more slow, and the Mouse Weight of magnetic drug-carrying nanogel group and PBS control group
Growth is more or less the same, and magnetic drug-carrying nanogel group toxic and side effect is small.The mouse of another aspect magnetic drug-carrying nanogel group is swollen
The gross tumor volume growth rate that knurl volume increases substantially than adriamycin group mouse is slow (Fig. 3-b), suppression of the adriamycin to tumour
Rate is 52.6%, and magnetic drug-carrying nanogel is 76.6% (Fig. 3-c and d) to the inhibiting rate of tumour.Result shows, prepared
Magnetic drug-carrying nanogel there is the adriamycin of specific ionization to have a more preferable tumor inhibition effect, and produce less poison secondary
Effect.
Embodiment 2
1st, reference literature (Biomaterials, 2009,30:4716-4722) method synthesis is super with surface amination
Paramagnetism ferriferrous oxide nano-particle (SPION-NH2)。
2nd, CS-SSe-COOH is prepared, is comprised the following steps that：
1) reference literature (J controlled release, 2009,136:38-44)、(Materials Science
and EngineeringC,2015,46:41-51) etc. method, sulfydryl is introduced by amination shitosan side chain, obtains sulfhydrylation shell
Glycan (CS-SH).
2) reference literature (Langmuir, 2006,22 (13):5552-5565)、(Int J Nanomed,2012,7(17):
The method synthesis seleno dipropionic acids (DSeDPA) of 3,3'- bis- such as 3991-4006).
3) room temperature, nitrogen protection under, claim 0.1g DSeDPA be incorporated in equipped with 30mL PBS (0.01mol/L,
PH6.56 in there-necked flask), stirring dissolves it.Claim 0.215g CS-SH be dissolved in 30mL PBS (0.01mol L-1,
PH6.56 in), and it is expelled in above-mentioned DSeDPA solution, reaction condition is 37 DEG C, is stirred 7 hours.Reaction resulting solution uses super
Pure water is dialysed 3 days, obtains the CS-SSe-COOH of 2.10mg/mL.
3rd, the CS-SSe-COOH of 2.50mL 2.10mg/mL is transferred in the there-necked flask containing 2.50mL ultra-pure waters,
And it is 5.0 to adjust its pH value with the hydrochloric acid of 1.0mol/L；Take the SPION-NH of 0.454mL 5.508mg/mL2With
The adriamycin of 0.625mL4mg/mL is dissolved in the hydrochloric acid of 3.524mL pH 5.0, and is added drop-wise in above-mentioned there-necked flask, is finally used
The NaOH regulation pH of 0.1mol/L is 7.4, is stirred 5 hours at room temperature, and whole process takes lucifuge measure.Reaction solution is transferred to
After being dialysed 2 days with ultra-pure water in bag filter, the molecular cut off of bag filter used is 10KDa, obtains the aqueous solution of nanogel
Preserved at 4 DEG C.The carrying drug ratio and envelop rate of gained Magnetic nanogels are respectively 10.8% and 86.2%.
Claims (12)
1. a kind of enhanced medicaments insensitive of magnetizing reduction discharges nanogel, it is characterised in that by following raw materials (1- in mass ratio
2)：1：(0.2-0.5) is prepared：
The SPIO of surface amination, side chain contain the polymeric derivative of selenium sulfide linkage, anticancer
Medicine.
2. the enhanced medicaments insensitive of magnetizing reduction according to claim 1 discharges nanogel, it is characterised in that the side
The polymeric derivative that chain contains selenium sulfide linkage is prepared by following step：
Room temperature, nitrogen protection under, the PBS solution with concentration as 0.01mol/L as reaction medium, with mass ratio as 1-1.5：1
Side chain thiohydroxy-containing group macromolecule and compound containing double selenium keys be reaction raw materials, the pH value for adjusting reaction system is
6.5-7.4, at 37 DEG C, stirring reaction 5-8 hours, dialysis obtained the polymeric derivative that side chain contains selenium sulfide linkage.
3. the enhanced medicaments insensitive of magnetizing reduction according to claim 2 discharges nanogel, it is characterised in that the side
The macromolecule of chain thiohydroxy-containing group is the one kind in sulfhydrylation sodium alginate, sulfhydrylation glucan, Chitosan-Thiolated Polymers.
4. the enhanced medicaments insensitive of magnetizing reduction according to claim 3 discharges nanogel, it is characterised in that the mercapto
Base sodium alginate, sulfhydrylation glucan, the preparation method of Chitosan-Thiolated Polymers are：
1) sodium alginate or amination glucan or shitosan are dissolved in ultra-pure water；
2) 1- ethyls -3- (3- dimethyl aminopropyls) carbodiimides and N-hydroxy-succinamide are dissolved in ultra-pure water, are obtained
EDC/NHS solution；
3) under nitrogen protective condition, by step 2) obtained in EDC/NHS solution be added drop-wise to step 1) obtained in sodium alginate or
In amination glucan or chitosan solution, 30min is activated；
4) cysteine hydrochloride is dissolved in ultra-pure water, and it is 6-7 or so to adjust pH with the sodium hydroxide solution of 6mol/L, it
Step 3 is added drop-wise to afterwards) in the solution that obtains, 12h is stirred, dialyse, freeze, be dried to obtain solid powder.
5. the enhanced medicaments insensitive of magnetizing reduction according to claim 4 discharges nanogel, it is characterised in that the sea
The carboxyl of mosanom is 1 with the mol ratio of the amino of the cysteine hydrochloride：(1~1.2).
6. the enhanced medicaments insensitive of magnetizing reduction according to claim 4 discharges nanogel, it is characterised in that the ammonia
The amino of base glucan or shitosan is 1 with the mol ratio of the carboxyl of cysteine hydrochloride：(1~1.2).
7. the enhanced medicaments insensitive of magnetizing reduction according to claim 2 discharges nanogel, it is characterised in that described to contain
The compound for having double selenium keys is 3,3 '-two seleno dipropionic acids or the butyric acid of 4,4 '-two seleno two.
8. the enhanced medicaments insensitive of magnetizing reduction according to claim 7 discharges nanogel, it is characterised in that described 4,
The butyric acid of 4 '-two seleno two can be obtained by the following method：
1) 3.95g selenium powders and 2.00g NaOH are dissolved in 25mL frozen water respectively first, then by 0.25g sodium borohydrides and
0.20g NaOH is dissolved in 5mL frozen water, and is expelled in the above-mentioned solution containing selenium powder, anti-in 0 DEG C under whole nitrogen protection
Should be completely dissolved up to selenium powder, continue to react 30min after then heating to 90 DEG C, untill solution colour is changed into rufous；
2) 5.42g4- chloropropionic acids are dissolved in 20mL ultra-pure waters, and with sodium carbonate adjust pH value most 8.0 after, be added to step
1) in red tan solution obtained in, it is stirred overnight under a nitrogen atmosphere, after reaction terminates, by reacting liquid filtering, uses 1.0mol/L
Hydrochloric acid adjust its pH for 3~4, be extracted with ethyl acetate twice, then dried with anhydrous magnesium sulfate, filtering, revolving finally uses second
Acetoacetic ester is recrystallized to give the butyric acid of 4,4 '-two seleno two.
9. the enhanced medicaments insensitive of magnetizing reduction according to claim 1 discharges nanogel, it is characterised in that described anti-
Cancer drug is one or more in ADMh, methotrexate (MTX), mitomycin, hydroxycarbamide, bleomycin.
10. the enhanced medicaments insensitive of magnetizing reduction described in any one of claim 1-9 discharges the preparation method of nanogel, and it is special
Levy and be, comprise the steps：
1) polymeric derivative that side chain contains selenium sulfide linkage is incorporated in ultra-pure water, the pH value for adjusting solution is 6-7.4；
2) SPIO and cancer therapy drug of surface amination are dissolved in hydrochloric acid, control solution
PH value is in 4.5-5.5；
3) under the conditions of lucifuge, by step 2) solution that obtains drops to step 1) in the solution that obtains, adjust the pH value of solution
It is 7.2-7.4, stirs 5-7h, dialysis obtains the enhanced medicaments insensitive release nanogel of magnetizing reduction.
11. according to claim 10 the enhanced medicaments insensitive of magnetizing reduction discharge the preparation method of nanogel, its feature
Be, step 3) described in the medium dialysed for ultra-pure water, the bag filter molecular cut off is 10KDa.
The enhanced medicaments insensitive of magnetizing reduction described in 12. claim any one of 1-9 discharges the store method of nanogel, and it is special
Levy and be, be stored in the environment at 2~4 DEG C.
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