CN116172992A - Water-phase dispersed transition metal ion/shikonin composite nano particle and two-phase preparation method thereof - Google Patents
Water-phase dispersed transition metal ion/shikonin composite nano particle and two-phase preparation method thereof Download PDFInfo
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- CN116172992A CN116172992A CN202211600600.2A CN202211600600A CN116172992A CN 116172992 A CN116172992 A CN 116172992A CN 202211600600 A CN202211600600 A CN 202211600600A CN 116172992 A CN116172992 A CN 116172992A
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- shikonin
- transition metal
- metal ion
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- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 title claims abstract description 178
- 241001071917 Lithospermum Species 0.000 title claims abstract description 178
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 title claims abstract description 178
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 119
- 239000002131 composite material Substances 0.000 title claims abstract description 117
- 229910001428 transition metal ion Inorganic materials 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 63
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 238000000746 purification Methods 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 150
- 239000000243 solution Substances 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 239000012071 phase Substances 0.000 claims description 39
- 238000002156 mixing Methods 0.000 claims description 26
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 15
- 239000008367 deionised water Substances 0.000 claims description 15
- 229910021641 deionized water Inorganic materials 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- 239000006228 supernatant Substances 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 11
- 239000008346 aqueous phase Substances 0.000 claims description 9
- OSCVBYCJUSOYPN-UHFFFAOYSA-K ytterbium(3+);triacetate Chemical compound [Yb+3].CC([O-])=O.CC([O-])=O.CC([O-])=O OSCVBYCJUSOYPN-UHFFFAOYSA-K 0.000 claims description 8
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 7
- LNYNHRRKSYMFHF-UHFFFAOYSA-K europium(3+);triacetate Chemical compound [Eu+3].CC([O-])=O.CC([O-])=O.CC([O-])=O LNYNHRRKSYMFHF-UHFFFAOYSA-K 0.000 claims description 7
- DVMZCYSFPFUKKE-UHFFFAOYSA-K scandium chloride Chemical compound Cl[Sc](Cl)Cl DVMZCYSFPFUKKE-UHFFFAOYSA-K 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 6
- VGBWDOLBWVJTRZ-UHFFFAOYSA-K cerium(3+);triacetate Chemical compound [Ce+3].CC([O-])=O.CC([O-])=O.CC([O-])=O VGBWDOLBWVJTRZ-UHFFFAOYSA-K 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 claims description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 4
- GAGGCOKRLXYWIV-UHFFFAOYSA-N europium(3+);trinitrate Chemical compound [Eu+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O GAGGCOKRLXYWIV-UHFFFAOYSA-N 0.000 claims description 4
- MIVBAHRSNUNMPP-UHFFFAOYSA-N manganese(2+);dinitrate Chemical compound [Mn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MIVBAHRSNUNMPP-UHFFFAOYSA-N 0.000 claims description 4
- DFCYEXJMCFQPPA-UHFFFAOYSA-N scandium(3+);trinitrate Chemical compound [Sc+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O DFCYEXJMCFQPPA-UHFFFAOYSA-N 0.000 claims description 4
- CKLHRQNQYIJFFX-UHFFFAOYSA-K ytterbium(III) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Yb+3] CKLHRQNQYIJFFX-UHFFFAOYSA-K 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007983 Tris buffer Substances 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims description 2
- KHSBAWXKALEJFR-UHFFFAOYSA-H cerium(3+);tricarbonate;hydrate Chemical compound O.[Ce+3].[Ce+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O KHSBAWXKALEJFR-UHFFFAOYSA-H 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 2
- FBUHTUYBHREGEH-UHFFFAOYSA-H europium(3+);trisulfate Chemical compound [Eu+3].[Eu+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O FBUHTUYBHREGEH-UHFFFAOYSA-H 0.000 claims description 2
- NNMXSTWQJRPBJZ-UHFFFAOYSA-K europium(iii) chloride Chemical compound Cl[Eu](Cl)Cl NNMXSTWQJRPBJZ-UHFFFAOYSA-K 0.000 claims description 2
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical compound [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 claims description 2
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000357 manganese(II) sulfate Inorganic materials 0.000 claims description 2
- 229910000346 scandium sulfate Inorganic materials 0.000 claims description 2
- DBTMQFKUVICLQN-UHFFFAOYSA-K scandium(3+);triacetate Chemical compound [Sc+3].CC([O-])=O.CC([O-])=O.CC([O-])=O DBTMQFKUVICLQN-UHFFFAOYSA-K 0.000 claims description 2
- QHYMYKHVGWATOS-UHFFFAOYSA-H scandium(3+);trisulfate Chemical compound [Sc+3].[Sc+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O QHYMYKHVGWATOS-UHFFFAOYSA-H 0.000 claims description 2
- XLSAVKCEHVNUQT-UHFFFAOYSA-N sulfuric acid ytterbium Chemical compound [Yb].[Yb].OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O XLSAVKCEHVNUQT-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- KUBYTSCYMRPPAG-UHFFFAOYSA-N ytterbium(3+);trinitrate Chemical compound [Yb+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O KUBYTSCYMRPPAG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000381 ytterbium(III) sulfate Inorganic materials 0.000 claims description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 abstract description 17
- 108010024636 Glutathione Proteins 0.000 abstract description 7
- 229960003180 glutathione Drugs 0.000 abstract description 7
- 229910021645 metal ion Inorganic materials 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 230000000975 bioactive effect Effects 0.000 abstract description 2
- 230000002028 premature Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000006185 dispersion Substances 0.000 abstract 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 21
- 229910052802 copper Inorganic materials 0.000 description 21
- 239000010949 copper Substances 0.000 description 21
- 238000000862 absorption spectrum Methods 0.000 description 19
- 239000007864 aqueous solution Substances 0.000 description 17
- 238000010521 absorption reaction Methods 0.000 description 16
- 239000000178 monomer Substances 0.000 description 14
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 13
- 230000005540 biological transmission Effects 0.000 description 13
- 229910052748 manganese Inorganic materials 0.000 description 13
- 239000011572 manganese Substances 0.000 description 13
- -1 ferric iron ions Chemical class 0.000 description 12
- 229910052769 Ytterbium Inorganic materials 0.000 description 11
- 238000005119 centrifugation Methods 0.000 description 11
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical class [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 9
- 239000012062 aqueous buffer Substances 0.000 description 9
- 229910052706 scandium Inorganic materials 0.000 description 9
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 8
- 229910052693 Europium Inorganic materials 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229960003280 cupric chloride Drugs 0.000 description 7
- MSQSMJBRWZRGQA-UHFFFAOYSA-L [Cu](Cl)Cl.C(C)#N Chemical compound [Cu](Cl)Cl.C(C)#N MSQSMJBRWZRGQA-UHFFFAOYSA-L 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 description 6
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 6
- 229910052684 Cerium Inorganic materials 0.000 description 5
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 5
- 235000002867 manganese chloride Nutrition 0.000 description 5
- 239000011565 manganese chloride Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical class [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 description 4
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 229910001431 copper ion Inorganic materials 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- ALJCLXGXZFZGEM-UHFFFAOYSA-K ytterbium(3+);triacetate;tetrahydrate Chemical compound O.O.O.O.[Yb+3].CC([O-])=O.CC([O-])=O.CC([O-])=O ALJCLXGXZFZGEM-UHFFFAOYSA-K 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- JGJIXMFWDPQYRL-UHFFFAOYSA-K europium(3+);triacetate;hydrate Chemical compound O.[Eu+3].CC([O-])=O.CC([O-])=O.CC([O-])=O JGJIXMFWDPQYRL-UHFFFAOYSA-K 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000002539 nanocarrier Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- FKZFOHABAHJDIK-UHFFFAOYSA-K trichloroscandium;hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Sc+3] FKZFOHABAHJDIK-UHFFFAOYSA-K 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- AERUOEZHIAYQQL-UHFFFAOYSA-K cerium(3+);triacetate;hydrate Chemical compound O.[Ce+3].CC([O-])=O.CC([O-])=O.CC([O-])=O AERUOEZHIAYQQL-UHFFFAOYSA-K 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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Abstract
A transition metal ion/shikonin composite nanoparticle with water phase dispersion and a two-phase preparation method thereof belong to the technical field of biomedical materials. According to the invention, transition metal ion salt and shikonin are used as raw materials, shikonin is dissolved in an organic solvent phase which is mutually soluble with water in advance, transition metal ion is dissolved in a water phase or an organic solvent phase which is mutually soluble with water, two phases are mixed in a vortex manner at room temperature, and centrifugal purification is carried out to obtain the transition metal ion/shikonin composite nano particles with the size range of 30-200 nm. The composite nano particles prepared by the invention have good water phase dispersibility and can be uniformly dispersed in water to form transparent solution. The composite nano particles have pH and redox disassembly characteristics, are beneficial to playing a role in the tumor microenvironment with weak acidity and high glutathione concentration, avoid the premature leakage of metal ions in normal tissues, and can be used as a carrier to load small molecular drugs or bioactive substances, thereby expanding the deep application in the biomedical field.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a transition metal ion/shikonin composite nanoparticle dispersed in a water phase and a two-phase preparation method thereof.
Background
Transition metal ions play an important role in the life system, are important components of biological macromolecules, participate in signal transmission and catalysis biochemical reaction in-vivo physiological activities, and are closely related to the occurrence, development and treatment of a plurality of serious diseases. In recent years, transition metal ions have great potential in the biomedical fields of antibiosis, anti-inflammation, anti-tumor and the like, and have particularly outstanding imaging and treatment functions in the aspect of cancer diagnosis and treatment. The transition metal ion has imaging functions such as nuclear magnetic resonance imaging, photoacoustic imaging, fluorescence imaging, X-ray tomography imaging and the like, and can also cause cancer cell death by inducing DNA damage, catalyzing Fenton reaction to generate high-toxicity hydroxyl free radicals, activating cGAS-STING immune channel and other mechanisms. However, free transition metal ions lack targeting, have great toxic and side effects on normal tissues, and must be subjected to complexation treatment in practical use.
Shikonin is a main active substance extracted from radix Arnebiae, and has anti-inflammatory, anti-tumor, antioxidant, and immunity regulating effects. From the aspect of an anti-tumor action mechanism, shikonin has the effects of inhibiting cell proliferation, inducing cell cycle arrest, promoting apoptosis and necrosis, inducing mitochondrial dysfunction and the like. The main problems of limiting shikonin application at present include poor water solubility, low bioavailability, short half-life and the like.
If the combination of transition metal ions and shikonin can be realized by means of nanotechnology, especially the functions of the transition metal ions and the shikonin are integrated and optimized, a new material is provided for the biomedical field. However, due to the strong hydrophobicity of shikonin, its metal complex rapidly precipitates in aqueous solutions, and it is difficult to obtain nano-scale particles suitable for biomedical applications. At present, only ferric iron ions with strong coordination can form composite nano particles with shikonin, and other transition metal ions/shikonin composite nano particles have not been developed successfully. This is because the coordination abilities of different transition metal ions vary greatly, and it is difficult to establish a general method for preparing composite nanoparticles. Therefore, the development of the preparation method of the water-phase dispersed transition metal ion/shikonin composite nano particles has important practical value.
Disclosure of Invention
The invention aims to provide a transition metal ion/shikonin composite nanoparticle dispersed in a water phase and a two-phase preparation method thereof.
According to the preparation method, transition metal ion salt and shikonin are used as raw materials, shikonin is dissolved in an organic solvent phase which is mutually soluble with water in advance, transition metal ion is dissolved in a water phase or an organic solvent phase which is mutually soluble with water, and two phases are mixed for a plurality of seconds in a vortex mode at room temperature to complete preparation of the transition metal ion/shikonin composite nano particles, and the two phases of solvents play a role in promoting the formation of the composite nano particles of metal ions and shikonin. The composition and the size of the composite nano particles can be regulated and controlled by controlling the types and the amounts of the transition metal ion salt and the reaction solvent, the composite nano particles have good water phase dispersibility, and the composite nano particles can be uniformly dispersed in water to form transparent solution. The preparation method has the advantages of short time consumption, good repeatability, mild condition and simple purification, and is suitable for mass production. More importantly, the composite nanoparticle has pH and redox disassembly characteristics, which are beneficial to function in the tumor microenvironment with weak acidity and high glutathione concentration, and meanwhile, premature leakage of metal ions in normal tissues is avoided (as in example 14 and example 15). In addition, the composite nano particles can also be used as carriers for loading small molecular drugs or bioactive substances, so that the deep application in the biomedical field is expanded.
The invention relates to a two-phase preparation method of aqueous phase dispersed transition metal ion/shikonin composite nano particles, which comprises the following steps:
dissolving shikonin in an organic solvent phase which is mutually soluble with water in advance, dissolving transition metal ions in a water phase or an organic solvent phase which is mutually soluble with water, directly mixing the two solutions or adding the water phase solvent after mixing, mixing uniformly by vortex, and obtaining the water phase dispersed transition metal ion/shikonin composite nano particles after centrifugal purification.
Wherein the transition metal ion salt is copper (II) acetate, copper (II) dichloride, copper (II) sulfate, copper (II) nitrate, manganese (II) acetate, manganese (II) dichloride, manganese (II) sulfate, manganese (II) nitrate, scandium (III) acetate, scandium (III) trichloride, scandium (III) sulfate, scandium (III) nitrate, cerium (III) acetate, cerium (III) chloride, cerium (III) carbonate, ytterbium (III) acetate, ytterbium (III) chloride, ytterbium (III) sulfate, ytterbium (III) nitrate, europium (III) acetate, europium (III) chloride, europium (III) sulfate, europium (III) nitrate and the like; the transition metal ion salt may be used either alone or in combination of two or more of the above; the water-miscible organic solvent is acetonitrile, methanol, ethanol, isopropanol, tertiary butanol, acetone, dimethyl sulfoxide, N-dimethylformamide or tetrahydrofuran; the water phase is pure water or a tris water phase buffer; the final concentration of the metal ion salt in the mixed reaction system is 0.005-0.6 mg/mL, the final concentration of shikonin in the mixed reaction system is 0.04-0.1 mg/mL (further, the final concentration of the transition metal ion salt in the mixed reaction system is 0.008-0.58 mg/mL, and the final concentration of shikonin in the mixed reaction system is 0.041-0.082 mg/mL); vortex mixing time is 5-10 seconds; the water-phase-dispersed transition metal ion/shikonin composite nano particles with the size range of 30-200 nm are obtained by adjusting the dosage of shikonin, the type and the dosage of metal ion salt and the type and the volume of organic solvent and water phase; the centrifugal purification is to centrifuge for 5 to 10 minutes at the rotation speed of 6000 to 10000 revolutions per minute, discard the supernatant and wash the centrifugal product with deionized water for 2 to 4 times.
Compared with the prior art, the invention has the following beneficial technical effects:
(1) The transition metal ion/shikonin composite nano particles prepared by the invention exist in water and aqueous phase solution in nano size, and have good dispersibility and good biological stability.
(2) The transition metal ion in the transition metal ion/shikonin composite nano particles prepared by the invention can be one or more, and the content of the transition metal ion/shikonin composite nano particles can be regulated and controlled by the use level of metal ion salts, has the functions of various transition metal ions, and is better used in the field of nano medicine.
(3) The transition metal ion/shikonin composite nano particles prepared by the invention can be used as nano carriers for loading small molecular medicines and the like, and can also be used for modifying targeting molecules on the surfaces of the nano carriers, so that the functionality is increased, the targeting property is improved, and the nano particles have larger application potential in the field of biomedicine.
(4) The preparation method has mild and simple reaction conditions, fast process, complete reaction within a few seconds and low time cost; the composition and the size of the transition metal ion/shikonin composite nano particles can be regulated and controlled by regulating the dosage of shikonin, the type and the dosage of transition metal ion salt, and the type and the volume of an organic solvent and a water phase; the method is simple, has good repeatability and is suitable for batch production.
Drawings
Fig. 1: the transmission electron microscope photograph of the copper/shikonin composite nano particle prepared in the corresponding example 1 shows that the water consumption is 4mL, and the diameter of the composite nano particle is 80nm.
Fig. 2: the transmission electron microscope photograph of the copper/shikonin composite nano particle prepared in the corresponding example 2 shows that the water consumption is 5mL, and the diameter of the composite nano particle is 70nm.
Fig. 3: the transmission electron microscope photograph of the copper/shikonin composite nano particle prepared in the corresponding example 3 shows that the water consumption is 6mL, and the diameter of the composite nano particle is 90nm.
Fig. 4: the ultraviolet-visible absorption spectrum of copper/shikonin composite nano particles and shikonin monomers prepared in example 2 and copper dichloride. From the ultraviolet-visible absorption spectrum, the composite nanoparticle shows a characteristic coordination absorption peak of metal and shikonin at 330nm, and after the composite nanoparticle is formed, the absorption peak at 516nm of shikonin monomer is red shifted to 520nm, which is due to the reduction of energy caused by the accumulation of shikonin in the composite nanoparticle, thus proving the formation of copper/shikonin composite nanoparticle.
Fig. 5: the organic solvent used in the transmission electron microscope photograph of the manganese/shikonin composite nano particles prepared in the corresponding example 4 is acetone, and the diameter of the composite nano particles is 60nm.
Fig. 6: the organic solvent used in the transmission electron microscope photograph of the manganese/shikonin composite nano-particles prepared in the corresponding example 5 is acetonitrile, and the diameter of the composite nano-particles is 55nm.
Fig. 7: the manganese/shikonin composite nanoparticle prepared in example 4 and an ultraviolet-visible absorption spectrum of shikonin monomer and manganese dichloride. From the ultraviolet-visible absorption spectrum, the composite nanoparticle shows a characteristic coordination absorption peak of metal and shikonin at 330nm, and after the composite nanoparticle is formed, the absorption peak at 516nm of shikonin monomer is red shifted to 560nm, which is due to the reduction of energy caused by the accumulation of shikonin in the composite nanoparticle, thus proving the formation of manganese/shikonin composite nanoparticle.
Fig. 8: the diameter of the scandium/shikonin composite nano particles prepared in the corresponding example 6 is 80nm in a transmission electron microscope photograph.
Fig. 9: scandium/shikonin composite nano particles prepared in example 6 and ultraviolet-visible absorption spectrum diagram of shikonin monomer and scandium trichloride. From the ultraviolet-visible absorption spectrum, the composite nanoparticle shows a characteristic coordination absorption peak of metal and shikonin at 330nm, and after the composite nanoparticle is formed, the absorption peak at 516nm of shikonin monomer is red shifted to 560nm, which is due to the reduction of energy caused by the accumulation of shikonin in the composite nanoparticle, thus proving the formation of scandium/shikonin composite nanoparticle.
Fig. 10: transmission electron microscope pictures of cerium/shikonin composite nano particles prepared in corresponding example 7, wherein the diameter of the composite nano particles is 75nm.
Fig. 11: the cerium/shikonin composite nanoparticle prepared in example 7 has an ultraviolet-visible absorption spectrum of shikonin monomer and cerium acetate. From the ultraviolet-visible absorption spectrum, the composite nanoparticle shows a characteristic coordination absorption peak of metal and shikonin at 330nm, and after the composite nanoparticle is formed, the absorption peak at 516nm of shikonin monomer is red shifted to 560nm, which is due to the reduction of energy caused by the accumulation of shikonin in the composite nanoparticle, thus proving the formation of cerium/shikonin composite nanoparticle.
Fig. 12: transmission electron microscope pictures of ytterbium/shikonin composite nano particles prepared in corresponding example 8, wherein the diameter of the composite nano particles is 65nm.
Fig. 13: ytterbium/shikonin composite nano particles prepared in example 8 and ultraviolet-visible absorption spectrum diagram of shikonin monomer and ytterbium acetate. From the ultraviolet-visible absorption spectrum, the composite nanoparticle shows a characteristic coordination absorption peak of metal and shikonin at 330nm, and after the composite nanoparticle is formed, the absorption peak at 516nm of shikonin monomer is red shifted to 560nm, which is due to the energy reduction caused by shikonin accumulation in the composite nanoparticle, thus proving the formation of ytterbium/shikonin composite nanoparticle.
Fig. 14: transmission electron microscope pictures of europium/shikonin composite nano particles prepared in corresponding example 9, wherein the diameter of the composite nano particles is 85nm.
Fig. 15: europium/shikonin composite nano particles prepared in example 9 and ultraviolet-visible absorption spectrum diagram of shikonin monomer and europium acetate. As can be seen from the ultraviolet-visible absorption spectrum, the composite nanoparticle shows a characteristic coordination absorption peak of metal and shikonin at 330nm, and after the composite nanoparticle is formed, the absorption peak at 516nm of shikonin monomer is red shifted to 560nm, which is due to the reduction of energy caused by the accumulation of shikonin in the composite nanoparticle, thus proving the formation of europium/shikonin composite nanoparticle.
Fig. 16: transmission electron microscope pictures of copper/scandium/shikonin composite nano particles prepared in the corresponding example 10, wherein the diameter of the composite nano particles is 50nm.
Fig. 17: transmission electron microscope pictures of copper/ytterbium/shikonin composite nano particles prepared in corresponding example 11, wherein the diameter of the composite nano particles is 150nm.
Fig. 18: transmission electron microscope pictures of copper/europium/shikonin composite nano particles prepared in corresponding example 12, wherein the diameter of the composite nano particles is 200nm.
Fig. 19: transmission electron microscope pictures of manganese/ytterbium/shikonin composite nano particles prepared in corresponding example 13, wherein the diameter of the composite nano particles is 90nm.
Fig. 20: the ultraviolet-visible absorption spectrum of the copper/shikonin composite nanoparticle of example 14 corresponds to that of the disassembly experimental curve.
Fig. 21: the ultraviolet-visible absorption spectrum of the manganese/shikonin composite nanoparticle in the condition of pH 6.5 corresponds to that of the manganese/shikonin composite nanoparticle in the example 15, namely a disassembly experimental curve.
Detailed Description
The invention is further illustrated below in conjunction with examples, which are not intended to limit the invention thereto.
Example 1
Dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; copper dichloride dihydrate is dissolved in acetonitrile to prepare copper dichloride acetonitrile solution with the concentration of 5 mg/mL; mixing 50 mu L of shikonin acetonitrile solution with 10 mu L of cupric chloride acetonitrile solution to prepare a mixed solution; the mixed solution is added into 4mL of pure water at room temperature (the final concentration of copper ion salt in the mixed reaction system is 0.012mg/mL, the final concentration of shikonin in the mixed reaction system is 0.062 mg/mL), vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at a rotating speed of 6000 rpm, the supernatant is discarded, and the centrifugal product is washed for 2 times by using the deionized water, so that the copper/shikonin composite nano particle with the average diameter of 80nm is obtained.
Example 2
Dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; copper dichloride dihydrate is dissolved in acetonitrile to prepare copper dichloride acetonitrile solution with the concentration of 5 mg/mL; mixing 50 mu L of shikonin acetonitrile solution with 10 mu L of cupric chloride acetonitrile solution to prepare a mixed solution; the mixed solution is added into 5mL of pure water at room temperature (the final concentration of copper ion salt in the mixed reaction system is 0.010mg/mL, the final concentration of shikonin in the mixed reaction system is 0.049 mg/mL), vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at the rotation speed of 6000 rpm, the supernatant is discarded, and the centrifugal product is washed for 2 times by the deionized water, so that the copper/shikonin composite nano particle with the average diameter of 70nm is obtained.
Example 3
Dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; copper dichloride dihydrate is dissolved in acetonitrile to prepare copper dichloride acetonitrile solution with the concentration of 5 mg/mL; mixing 50 mu L of shikonin acetonitrile solution with 10 mu L of cupric chloride acetonitrile solution to prepare a mixed solution; the mixed solution is added into 6mL of pure water at room temperature (the final concentration of copper ion salt in the mixed reaction system is 0.008mg/mL, the final concentration of shikonin in the mixed reaction system is 0.041 mg/mL), vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at 6000 rpm, the supernatant is discarded, and the centrifugal product is washed for 2 times by using the deionized water, so that the copper/shikonin composite nano particle with the average diameter of 90nm is obtained.
Example 4
Dissolving shikonin in acetone to prepare shikonin acetone solution with the concentration of 5 mg/mL; dissolving anhydrous manganese dichloride in a tris (hydroxymethyl) aminomethane aqueous buffer (ph=8.5) to prepare a tris (hydroxymethyl) aminomethane aqueous buffer with a concentration of 0.08 mg/mL; 50 mu L of shikonin acetone solution is added into 3mL of manganese dichloride tris (hydroxymethyl) aminomethane aqueous buffer solution (the final concentration of manganese ion salt in a mixed reaction system is 0.079mg/mL, the final concentration of shikonin in the mixed reaction system is 0.082 mg/mL) at room temperature, vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at 10000 revolutions per minute, the supernatant is discarded, and the centrifugal product is washed for 2 times by deionized water, so that manganese/shikonin composite nano particles with the average diameter of 60nm are obtained.
Example 5
Dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; dissolving anhydrous manganese dichloride in a tris (hydroxymethyl) aminomethane aqueous buffer (ph=8.5) to prepare a manganese dichloride tris (hydroxymethyl) aminomethane aqueous buffer with a concentration of 0.08 mg/mL; 50 mu L of shikonin acetonitrile solution is added into 3mL of manganese dichloride tris (hydroxymethyl) aminomethane aqueous buffer solution (the final concentration of manganese ion salt in a mixed reaction system is 0.079mg/mL, the final concentration of shikonin in the mixed reaction system is 0.082 mg/mL) at room temperature, vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at 10000 revolutions per minute, the supernatant is discarded, and the centrifugal product is washed for 2 times by deionized water, so that manganese/shikonin composite nano particles with the average diameter of 55nm are obtained.
Example 6
Dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; scandium trichloride hexahydrate is dissolved in water to prepare scandium trichloride aqueous solution with the concentration of 0.033 mg/mL; 50 mu L of shikonin acetonitrile solution is added into 3mL of scandium trichloride aqueous solution at room temperature (the final concentration of scandium ion salt in a mixed reaction system is 0.032mg/mL, the final concentration of shikonin in the mixed reaction system is 0.082 mg/mL), vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at a rotating speed of 8000 revolutions per minute, the supernatant is discarded, and the centrifugal product is washed for 2 times by deionized water, so that scandium/shikonin composite nano particles with an average diameter of 80nm are obtained.
Example 7
Dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; dissolving cerium acetate hydrate in water to prepare cerium acetate aqueous solution with the concentration of 0.59 mg/mL; 50 mu L of shikonin acetonitrile solution is added into 3mL of cerium acetate aqueous solution (the final concentration of cerium ion salt in a mixed reaction system is 0.58mg/mL, the final concentration of shikonin in the mixed reaction system is 0.082 mg/mL) at room temperature, vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at a rotating speed of 8000 revolutions per minute, the supernatant is discarded, and the centrifugal product is washed for 2 times by deionized water, so that cerium/shikonin composite nano particles with an average diameter of 75nm are obtained.
Example 8
Dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; ytterbium acetate tetrahydrate is dissolved in water to prepare ytterbium acetate aqueous solution with the concentration of 0.16 mg/mL; 50 mu L of shikonin acetonitrile solution is added into 3mL of ytterbium acetate water solution (the final concentration of ytterbium ion salt in a mixed reaction system is 0.157mg/mL, the final concentration of shikonin in the mixed reaction system is 0.082 mg/mL) at room temperature, vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at a rotating speed of 8000 revolutions per minute, the supernatant is discarded, and the centrifugal product is washed for 2 times by deionized water, so that 65nm ytterbium/shikonin composite nano particles with average diameter are obtained.
Example 9
Dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; dissolving europium acetate hydrate in water to prepare a europium acetate aqueous solution with the concentration of 0.16 mg/mL; 50 mu L of shikonin acetonitrile solution is added into 3mL of europium acetate aqueous solution (the final concentration of manganese ion salt in a mixed reaction system is 0.157mg/mL, the final concentration of shikonin in the mixed reaction system is 0.082 mg/mL) at room temperature, vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at a rotating speed of 8000 revolutions per minute, the supernatant is discarded, and the centrifugal product is washed for 2 times by deionized water, so as to obtain europium/shikonin composite nano particles with an average diameter of 85nm.
Example 10
Scandium trichloride hexahydrate is dissolved in water to prepare scandium trichloride aqueous solution with the concentration of 0.033 mg/mL; dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; copper dichloride dihydrate is dissolved in acetonitrile to prepare copper dichloride acetonitrile solution with the concentration of 5 mg/mL; mixing 50 mu L of shikonin acetonitrile solution with 10 mu L of cupric chloride acetonitrile solution to prepare a mixed solution; 3mL of scandium trichloride aqueous solution (scandium ion salt, copper ion salt and shikonin are added into the mixed solution at room temperature, wherein the final concentration of scandium ion salt in the mixed reaction system is 0.032mg/mL, the final concentration of shikonin the mixed reaction system is 0.016mg/mL, the final concentration of shikonin in the mixed reaction system is 0.082 mg/mL), vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at 8000 revolutions per minute, the supernatant is discarded, and the centrifugal product is washed for 2 times by deionized water, so that copper/scandium/shikonin composite nano particles with the average diameter of 50nm are obtained.
Example 11
Ytterbium acetate tetrahydrate is dissolved in water to prepare ytterbium acetate aqueous solution with the concentration of 0.16 mg/mL; dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; copper dichloride dihydrate is dissolved in acetonitrile to prepare copper dichloride acetonitrile solution with the concentration of 5 mg/mL; mixing 50 mu L of shikonin acetonitrile solution with 10 mu L of cupric chloride acetonitrile solution to prepare a mixed solution; adding 3mL of ytterbium acetate aqueous solution (final concentration of ytterbium ion salt in a mixed reaction system is 0.157mg/mL, final concentration of copper ion salt in the mixed reaction system is 0.016 mg/mL), vortex mixing for 10 seconds, centrifuging for 5 minutes at 8000 revolutions per minute, discarding the supernatant and washing the centrifuged product with deionized water for 2 times, thereby obtaining copper/ytterbium/shikonin composite nano particles with average diameter of 150nm.
Example 12
Dissolving europium acetate hydrate in water to prepare a europium acetate aqueous solution with the concentration of 0.16 mg/mL; dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; copper dichloride dihydrate is dissolved in acetonitrile to prepare copper dichloride acetonitrile solution with the concentration of 5 mg/mL; mixing 50 mu L of shikonin acetonitrile solution with 10 mu L of cupric chloride acetonitrile solution to prepare a mixed solution; adding 3mL of europium acetate aqueous solution (the final concentration of europium ion salt in the mixed reaction system is 0.157mg/mL, the final concentration of copper ion salt in the mixed reaction system is 0.016 mg/mL), vortex mixing for 10 seconds, centrifuging for 5 minutes at 8000 rpm, discarding the supernatant and washing the centrifuged product with deionized water for 2 times, thereby obtaining the copper/europium/shikonin composite nanoparticle with the average diameter of 200nm.
Example 13
Ytterbium acetate tetrahydrate and anhydrous manganese dichloride are simultaneously dissolved in a tris (hydroxymethyl) aminomethane aqueous buffer (pH=8.5) to prepare tris (hydroxymethyl) aminomethane aqueous buffer with the ytterbium acetate and manganese dichloride concentrations of 0.16 and 0.08mg/mL respectively; dissolving shikonin in acetonitrile to prepare shikonin acetonitrile solution with the concentration of 5 mg/mL; 50 mu L of shikonin acetonitrile solution is added into 3mL of the tris (hydroxymethyl) aminomethane aqueous buffer solution (the final concentration of ytterbium ion salt in a mixed reaction system is 0.157mg/mL, the final concentration of manganese ion salt in the mixed reaction system is 0.079mg/mL, the final concentration of shikonin in the mixed reaction system is 0.082 mg/mL), vortex mixing is carried out for 10 seconds, centrifugation is carried out for 5 minutes at 8000 revolutions per minute, the supernatant is discarded, and the centrifugal product is washed for 2 times by deionized water, so that manganese/ytterbium/shikonin composite nano particles with the average diameter of 90nm are obtained.
Example 14
Glutathione+neocuprous group: 200. Mu.L of 10mM glutathione aqueous solution is mixed with 800. Mu.L of 10mM of neocuprous reagent ethanol solution, and the mixture is reacted at room temperature for 20min, and the ultraviolet visible absorption spectrum is measured.
Copper/shikonin composite nanoparticle+glutathione group: 200. Mu.L of 10mM glutathione aqueous solution and 800. Mu.L of 50. Mu.g/mL copper/shikonin composite nanoparticle (prepared in example 2) ethanol solution were mixed and reacted at room temperature for 20min, and the ultraviolet-visible absorption spectrum was measured.
Copper/shikonin composite nanoparticle+glutathione+neocuprous group: 200. Mu.L of a 10mM glutathione aqueous solution was mixed with 800. Mu.L of an ethanol solution containing 50. Mu.g/mL copper/shikonin composite nanoparticles (prepared in example 2) and 10mM of a neocuprous reagent, reacted at room temperature for 20 minutes, and the ultraviolet-visible absorption spectrum was measured, as shown in FIG. 20.
Compared with other groups, the copper/shikonin composite nano particle, glutathione and neocuprous group has a characteristic absorption peak at 460nm in an ultraviolet-visible absorption spectrum, and the glutathione is proved to reduce bivalent copper ions in the copper/shikonin composite nano particle into monovalent copper ions, and the monovalent copper ions and the neocuprous agent specifically react to generate a yellow complex with the absorption peak at 460 nm.
Example 15
Dispersing manganese/shikonin composite nano particles (prepared in example 4) in water, phosphate Buffer Saline (PBS) with pH of 7.4 and PBS with pH of 6.5 (the final concentration of the manganese/shikonin composite nano particles in each solution is 50 mug/mL); shikonin was dissolved in acetonitrile (final shikonin concentration of 0.1 mg/mL), and the ultraviolet-visible absorption spectrum of each solution was measured on a shaker for 1 hour, as shown in fig. 21. Under the condition of pH 6.5, the absorption peak at 330nm disappears, the peak at 560nm is blue-shifted to 516nm, the whole absorption peak is basically consistent with the shikonin monomer, and the manganese/shikonin composite nano particles are disassembled under the acidic condition to release the shikonin monomer.
Claims (7)
1. A two-phase preparation method of aqueous phase dispersed transition metal ion/shikonin composite nano particles is characterized by comprising the following steps of: dissolving shikonin in an organic solvent phase which is mutually soluble with water in advance, dissolving transition metal ions in a water phase or an organic solvent phase which is mutually soluble with water, directly mixing the two solutions or adding the mixed solutions into the water phase solvent to obtain a mixed reaction system, carrying out vortex mixing uniformly, and carrying out centrifugal purification to obtain water-phase-dispersed transition metal ion/shikonin composite nano particles; the organic solvent is acetonitrile, methanol, ethanol, isopropanol, tertiary butanol, acetone, dimethyl sulfoxide, N-dimethylformamide or tetrahydrofuran; the water phase is pure water or a tris water phase buffer; the transition metal ion salt is one or more of copper (II) acetate, copper (II) dichloride, copper (II) sulfate, copper (II) nitrate, manganese (II) acetate, manganese (II) dichloride, manganese (II) sulfate, manganese (II) nitrate, scandium (III) acetate, scandium (III) trichloride, scandium (III) sulfate, scandium (III) nitrate, cerium (III) acetate, cerium (III) chloride, cerium (III) carbonate, ytterbium (III) acetate, ytterbium (III) chloride, ytterbium (III) sulfate, ytterbium (III) nitrate, europium (III) acetate, europium (III) chloride, europium (III) sulfate or europium (III) nitrate.
2. The two-phase preparation method of the aqueous phase dispersed transition metal ion/shikonin composite nano particles as claimed in claim 1, which is characterized in that: the final concentration of the transition metal ion salt in the mixed reaction system is 0.005-0.6 mg/mL, and the final concentration of shikonin in the mixed reaction system is 0.04-0.1 mg/mL; vortex mixing time is 5-10 seconds.
3. The two-phase preparation method of the aqueous phase dispersed transition metal ion/shikonin composite nano particles as claimed in claim 1, which is characterized in that: the centrifugal purification is to centrifuge for 5 to 10 minutes at the rotation speed of 6000 to 10000 revolutions per minute, discard the supernatant and wash the centrifugal product with deionized water for 2 to 4 times.
4. The two-phase preparation method of the aqueous phase dispersed transition metal ion/shikonin composite nano particles as claimed in claim 1, which is characterized in that: the final concentration of the transition metal ion salt in the mixed reaction system is 0.008-0.58 mg/mL, and the final concentration of shikonin in the mixed reaction system is 0.041-0.082 mg/mL.
5. The two-phase preparation method of the aqueous phase dispersed transition metal ion/shikonin composite nano particles as claimed in claim 1, which is characterized in that: the water-phase dispersed transition metal ion/shikonin composite nano particles with the size ranging from 30nm to 200nm are obtained by adjusting the dosage of shikonin, the type and the dosage of transition metal ion salt and the type and the volume of organic solvent phase and water phase.
6. The two-phase preparation method of the aqueous phase dispersed transition metal ion/shikonin composite nano particles as set forth in claim 5, which is characterized in that: obtaining the aqueous phase dispersed transition metal ion/shikonin composite nano particles with the size range of 50-200 nm.
7. A water-phase dispersed transition metal ion/shikonin composite nano particle is characterized in that: is prepared by the method of any one of claims 1 to 6.
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