CN105396149A - Nanometer alloy anti-cancer drug with functions of independent targeting and imaging, and preparation method thereof - Google Patents

Abstract

The invention relates to a nanometer alloy anti-cancer drug with functions of independent targeting and imaging, and a preparation method thereof, and belongs to the technical field of anti-cancer drugs. The nanometer alloy anti-cancer drug mainly comprises a metal, a metal compound and a nonmetal, wherein the metal comprises at least one selected from precious metal components such as Au, Ag, Pt, Cu, Ru, Pd, Rh, Re, Os and Ir and is named a first component, the nonmetal is at least one selected from nonmetal element components such as B, C, Si, O, S and Se and is named a second component, O exists in the form of the metal oxide or the hydroxyl OH or carboxyl COOH on the particle surface, S and Se exist mainly in the form of the sulfide or selenide formed from S or Se and the metal, B and Si are doped in the metal to form the alloy, and C exists in the form of the carbon allotrope, or the surface-coated organic carbon, or the metal carbide formed from C and the metal.

Description

A kind of Nanoalloy cancer therapy drug with autonomous targeting and imaging function and preparation method thereof

Technical field

The invention belongs to Nano medication preparation and the application in biomedical engineering thereof, be specifically related to prepare and there is amorphous state to a kind of method of the metal alloy-metallic compound hetero nano structure particle of crystalline phases structure and these particles to the treatment of mid and late liver cancer, pulmonary carcinoma, lymphatic cancer, breast carcinoma, blood class cancer, belong to cancer therapy drug technical field.

Background technology

Due to the aggravation of environmental pollution and the change of dietary structure, in the past few decades, the mankind to suffer from the probability of various cancer more and more high.Such as due to the pollution of air, nearly 5 years China with the haze that Beijing-tianjin-hebei Region, Yangtze River Delta Area are representative make the prevalence of the pulmonary carcinoma in these areas with more than 10% annual rate of growth raise; And in water body due to the pollution to local water body of heavy metal or carcinogenic compound etc. in the sewage of regional industry discharge in cause a lot of cancer village altogether, it is former that the pollution occurring in the cadmium metal that exceeds standard in the cereal crops such as rice is that human liver cancer, osteocarcinoma, lymphatic cancer and blood class cancer potential causes a disease.To the treatment being in middle early-stage cancer, intervene while can using operation and Drug therapy at present, some cancer can be treated, but once transfer, just be very difficult to cure, to the cancer being in late period, even if operation and anti-cancer herb medicine, also be very difficult to cure, often in half a year or several years, patient will be dead.Therefore, except strengthening environment protection, Devoting Major Efforts To Developing cancer therapy drug is also necessary.Since being found along platinum-containing anticancer drug, people have dropped into a large amount of manpower in the exploitation of cancer therapy drug, material resources and financial resources, have developed a lot of cancer therapy drug, as to the medicable Pexa-Vec of hepatocarcinoma, to the medicable S-1/ cisplatin of pulmonary carcinoma and docetaxel/cisplatin medicine, to the medicable Trastuzumab of breast carcinoma (HER-2), to the medicable CIK biological immune treatment of lymphoma, medicine is used in conjunction to cervical cancer and the medicable Trastuzumab/carboplatin of scale cancer, to metastatic colorectal carcinoma treatment and colon cancer auxiliary treatment medicine oxaliplatin and successfully breast carcinoma is developed to the medical expert of united states army forces, colon cancer, carcinoma of prostate, " E-75 " super anticarcinogen of the equal tool inhibition such as pulmonary carcinoma.But, these medicines are very expensive, often need long-term taking, once stop using, cancerous cell again can amount reproduction and diffusion, and in using, cancerous cell is except spreading simultaneously, also can make a variation, often start effective medicine, just there is no too large effect after using one section, namely often cause cancer to occur drug resistance problems; Even if the super anticarcinogen of these cancer therapy drugs " E-75 " all can not treat cancers all at present simultaneously.Therefore, exploitation have permanently effective, do not cause cancerous cell to make a variation or the medicine directly eradicated is the targets of the mankind to treatment of cancer.

More medicable anticancer in order to develop, the metabolism mechanism of scientist to Normocellular Carcinogenesis Mechanism and cancerous cell has carried out large quantity research with relevant gene therapy.Research worker is known, cancerous cell needs to consume a large amount of glucose, as the energy supporting improper quick growth and division, does not but know how cancerous cell obtains institute's energy requirement.Further research display, cancerous cell obtains energy to accelerate cell autophagy mode.Cell autophagy is a kind of important defence of body and protection mechanism, is the protein of impaired, degeneration or aging and organelle are transported to lysosome, then digests the process of degraded.Shiva university Einstein medical college developer molecule is taught Anna Ku Aiwo and think biology: " lysosome is not only refuse bin, more as small-sized recycle bin.There, cell debris is transformed into energy.Cancerous cell seems to know how to optimize this process, the energy requirement to obtain ".Scientists also finds in more than 40 kinds of human lungs, mammary gland and liver tumor cells, the autophagy level that molecular chaperones guides higher than normal condition, and this type autophagy of tumor surrounding normal tissue to be in level normal.Therefore change gene, block this recycling process, cancerous cell stops division dead immediately.Scientist also this approach application in mice, the remarkable atrophy of tumor of result mice, almost stop completely transfer.Research worker is thought, the autophagy blocking the mediation of cancerous cell molecular chaperones selectively may become " available strategy " that reduce tumor, stop cancer cell metastasis.From now in research, we will wish developing drugs, to realize the effect that operator is reached; Continuation is explored how to treat dissimilar pulmonary carcinoma by genetically manipulated means by us simultaneously.For developing more effective cancer therapy drug, people also study from the immunologic function aspect of organism (as normal cell or cancerous cell).Such as " working method " research of cancer therapy drug " E-75 " is shown, " E-75 " successfully can set up a distinctive immune system in people's body, the protein being presented on polytype cancer cell surfaces can be searched, distinguishes and be confirmed to this system, thus correspondence carry out immunity.But also not all tumor is all made up of the cell of this protein molecule of secretion, and this is also the main cause why cancer therapy drug " E-75 " can not treat current all cancer types.In addition, some cancerous cell has " deception " immune function, so that when immune system is distinguished, and these cancerous cell can be thought by mistake be the part of human body.Therefore, immune system must be enable " to expose " " the camouflage mask " of these cancerous cell.But, how to help Normocellular immune system " to expose " " the camouflage mask " of these cancerous cell very difficult, also can only study from gene therapy aspect at present.Be not difficult to find out, the path that these scientists further investigate rear proposition developing drugs has finally all turned to gene therapy.But gene therapy itself varies with each individual, need to carry out a large amount of basic research separately to patient, just the gene can developed for this patient is intervened, expensive, the lead time is very long, the patient being in middle and advanced stage wait often less than.In fact, research shows that cancerous cell and the most obvious Normocellular difference are exactly that cancerous cell ceaselessly carries out constantly dividing the cell of growing up, and Normocellular division is controlled already, and being can need automatically to stop according to organism.Therefore, the growth certainty of cancerous cell and normal cell are competed on energy and nutrition (particularly protein and sugar class etc.), and cancerous cell is due to the activity of self, must than normal cell to competitive on energy and nutrition, cancerous cell can not exercise Normocellular physiological function simultaneously, when large energy and nutrition are consumed by cancerous cell and oneself grows up, Normocellular activity space, nutrition and energy all can not catch up with body or tissue carry out the needing of normal physiological activity time, normal body or tissue will atrophy so that dead, finally cause the end of life.We can find these analysis of research achievements, and they have said the simplest and the most direct path of Effect of Anti cancer drug already, are exactly to block the chance that cancerous cell obtains the protein of energy or needs.Recently, American Studies personnel also find, growth of cancer cells energy source recycles the process of protein from body.Mouse experiment shows, and block this process, tumor starts atrophy, and cancerous cell almost no longer shifts.Therefore: how selectively exploitation cancer curing medicine key is this medicine anticancer recycling protein.

Biochemical ultimate principle tells us, the source of energy mainly by carbohydrate synthesis the adenosine class (as ATP) that can store or directly carried the oxygen of coming by activated red blood cells by carbohydrate oxidase, by glycoxidative acquisition, the main feature of saccharide is polyhydroxy hydrocarbon (if glucose is by the six carbon hydrocarbon having a hydroxyl to form on carbon).Vital signs is primarily of its protein expression, and the synthesis of cell to the synthesis of adenosine class, the oxidation of saccharide and protein all needs synthesis or oxidasic participation, and cancerous cell is no exception, and a lot of enzymes self in life entity are made up of protein exactly.We know, protein, by Amino acid profile, contains the methionine (Met) of the unsaturated element sulphur of valence link and the selenium amino acid containing the unsaturated selenium element of valence link in the essential amino acid of synthesis human protein.We also know, the synthesis of protein is controlled by DNA or RNA, and containing phosphate radical in the skeleton of DNA or RNA.Therefore, we can develop simultaneously can and sulfur, the medicine of selenium or phosphate radical coordination, be sent in the organism environment of canceration, because the seize dynamics of cancerous cell to energy and nutrition is more much larger than normal cell, by the control of dosage, in the incipient stage, these nutrition are absorbed by cancerous cell substantially, when its schizogamy, due to the degeneration (as amino acid whose sulfur or the ligancy change of selenium and the change of phosphate radical valence state) of aminoacid and phosphate radical, it can not normally synthesize various DNA, RNA, the normal protein matter of cancerous cell self needs can not be synthesized, its function just can not normal expression, the energy that its breeding needs simultaneously also cannot normally obtain, so just directly can cut off large energy and the nutrition of cancerous cell needs, finally cause the death of cancerous cell, because these medicines are by the biomolecule coordination saturation of a large amount of cancerous cell, just can not be utilized by normal cell, also effective murder by poisoning would not be caused to normal cell, after metabolism, excreted by Excretory system.If now coordinate a kind of differentiation-inducing agents again, a large amount of Carcinoma cell differentiation just can be made to become normal cell, control development and the diffusion of cancer.

In addition, in order to improve the curative effect of medicine, people are developing all kinds of targeted anticancer medicine.The at present exploitation of such targeted drug substantially based on the antibody-antigene of biomolecular science to the principle recognized each other, as passed through the research cancerous cell antigen different with Normocellular surface of cell membrane or antibody, synthesis has antibody or the antigen of recognition function to the antigen of cancer cell surfaces or antibody, then by the load simultaneously of itself and medicine on carrier, this medicine just can be automatically found cancerous cell by body fluid circulatory like this, medicine is supplied cancerous cell, and killed, such as Mylotarg, be first and ratified the drug-antibody conjugate for oncotherapy by FDA, it is the conjugate of antitumor antibiotics Calicheamicin and anti-CD 33 monoclonal antibody, can be used for the acute myeloid leukaemia for the treatment of recurrence, as " bullet " medicine, Calicheamicin has strong lethal effect to tumor cell.But this is found and is different from the right research of Normocellular distinct antibodies-antigen very time-consuming and cost gold, simultaneously some cancerous cell and the right difference of Normocellular antibody-antigene are very small, be difficult to distinguish, therefore, be easy to a large amount of normal cell to kill, toxic and side effects is very large.Therefore, by there is autonomous target function (as introduction by magnetic field, guiding) to the research of normal cell and cancerous cell metabolic physiological activity feature itself development and can be extremely important by the medicine of common medical procedure (as NMR (Nuclear Magnetic Resonance)-imaging or infrared imaging) spike.

In addition, in order to reduce the cost of medicine, generally oblige patient all over the world, developing low-cost large-scale preparation method is also a very important content of the present invention.

Summary of the invention

At above Research Thinking with under instructing the requirement of cancer therapy drug; started from 2003; inventor through more than ten years research and constantly bring forth new ideas, develop the Nanoalloy cancer therapy drug with following composition and structure, and the scale technology of preparing of having invented program microfluid produces such medicine.This patent is patent of invention " a kind of extra small Core-shell Structure Nanoparticles and preparation method thereof, application number: 201310446082.8 at us; The applying date: on JIUYUE 26th, 2013 " on further innovation and expansion.

The feature of such multicomponent heterogeneous structural nano alloy particle is: multicomponent heterogeneous structural nano alloy compound particle is primarily of metal and nonmetal composition, wherein (1) metal must at least containing, for example one or more in lower noble metal component: Au, Ag, Pt, Cu, Ru, Pd, Rh, Re, Os, Ir, Eu, be called first kind composition; (2) nonmetal one or more elements that must be at least in following nonmetalloid B, C, Si, O, S, Se, are called Equations of The Second Kind composition.

If only containing above-mentioned two constituents, then multicomponent nanocomposite alloy compound particle is preferably nucleocapsid structure, and first kind composition noble metal belongs to stratum nucleare, Equations of The Second Kind becomes to belong to shell, O is to be formed metal-oxide with described metal or to be present in the form of the hydroxyl OH of particle surface existence or carboxy CO OH, the form forming metal (M) and oxygen covalent bond (M-O) by O and metal at the preferred hydroxyl OH or carboxy CO OH of particle surface exists, and S and Se mainly with metal formed sulfide or selenides form exist, B and Si forms alloy in a metal for adulterating, C is with the allotrope of carbon (Graphene (Gp), CNT (CNT) or vitreous carbon (GC)) or with the organic carbon of surface-coated (as polyvinylpyrrolidone, ginsenoside, vitamin C, maleic anhydride etc.) form existence, or exist with the form that described metal forms metal carbides.

Preferred: the metal described in multicomponent nanocomposite alloy compound particle also comprises one or more in following magnetic components: Fe, Co, Ni, Gd, Sm, Eu, Nd, Tb, be called the 3rd constituents;

Also comprise one or more the composition in following element in metal preferably described further, Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La, Na, Mg, Li, K, Ca, be called the 4th constituents.Element self in 4th constituents forms alloy, or forms alloy or metallic compound, as FeZn, MnBSn, FeBZn, CoAl with one or more in the element of the 3rd constituents, Equations of The Second Kind composition, first kind composition; MnO, SnO ₂, TiO ₂, SnSe, MnS, ZnS, ZnSe, FeS, CoSe, ZrSe ₂, CeO ₂; Fe _(1-x)zn _xo, Co _(1-x)al _xo, FeAl ₂o ₄, Fe _(1-x)zn _xs, Fe _(1-x)zn _xse, Fe _(1-x)sn _xse etc.

Comprise first kind composition, Equations of The Second Kind composition, the 3rd constituents multicomponent nanocomposite alloy compound particle and comprise first kind composition, Equations of The Second Kind composition, the 3rd constituents, the 4th constituents multicomponent nanocomposite alloy compound particle be the form of alloy structure or heterojunction structure.The form of heterojunction structure is the nucleocapsid structure that part applies or applies completely.If the form of hetero-junctions then preferably first and the 3rd or/and four-component form alloy or the heterogeneous inside stratum nucleare (as FePtAuZn or AuZnFePt) becoming many components Nanoalloy compound particle, Equations of The Second Kind composition and the 3rd class are or/and the 4th constituents compound is shell, its shell be monolayer or multilamellar, (as Fe _(1-x)zn _xse), the representative configurations of constituent particle is FePtAuZnFe _(1-x)zn _xse or AuZnFePtFe _(1-x)zn _xse etc.

B and Si in Equations of The Second Kind composition is wherein entrained in the first kind or/and in the alloy that forms of the 3rd constituents, and C is with the allotrope of carbon (Graphene (Gp), CNT (CNT) or vitreous carbon (GC)) or exists with the organic carbon of surface-coated (as polyvinylpyrrolidone, ginsenoside, vitamin C, maleic anhydride etc.) form or exist with the form being formed metal carbides with above-mentioned magnetic components or noble metal component; O exists with the form of the metal-oxide formed with metal in the first kind, the 3rd class or the 4th constituents or the hydroxyl OH existed with particle surface or carboxy CO OH, the form forming metal (M) and oxygen covalent bond (M-O) by O and metal at the preferred hydroxyl OH or carboxy CO OH of particle surface exists, and S and Se mainly with the first kind, the 3rd class or the 4th metalloid formed sulfide or selenides form exist.

The crystal structure of the alloy that above-mentioned each component element is formed or compound can be amorphous or amorphous state mixes with partiallycrystalline states or complete crystalline state.

Multicomponent nanocomposite alloy compound particle, size in 0.2-80 nanometer, comparitive study good in 0.5-50 nanometer, better in 0.5-20 nanometer, best in 1-10 nanometer.Such as size is at CoBPt, FeBPtC, FeSnPtB, AuCoFeB, AuCoFeBCoFeOOH, AgCoFeB, FePtFeOx, AuAgFeZn, FeCoAlAgGp, CoSmPt-CNT, FePtAgAu-Gp, FePtBFe of 2-6 nanometer ₃o ₄, AgPtCoFeB-Gp, AuPtCoFeB-Gp.

Preparation method of the present invention, is characterized in that, adopt Y shape microfluid preparation facilities to be prepared, this device comprises two syringe pumps arranged side by side, a Y shape threeway blender reactor, three coil pipe preheaters, three temperature chambers, product receiving systems; Two syringe pumps arranged side by side are connected with the Liang Ge branch of the second coil pipe preheater (4) with Y shape threeway blender reactor respectively by the first coil pipe preheater (3), first coil pipe preheater and the second coil pipe preheater are arranged in temperature chamber a, 3rd branch of Y shape threeway blender reactor is connected with product receiving system by the 3rd coil pipe preheater (6), 3rd coil pipe preheater is arranged in temperature chamber b, product receiving system is arranged in temperature chamber c, and product receiving system is also provided with inert gas import and inert gas outlet;

Metallic element in first kind composition is that the form of the presoma being adds in reactant liquor with slaine, generates simple substance atom, and form nanoparticle through nucleation and growth by reduction reaction; B in Equations of The Second Kind composition is added as reducing agent using the form of metallic boron hydrides, if there is Na, Mg, Li, K, Ca in the 4th constituents, then forms metallic boron hydrides with Na, Mg, Li, K, Ca in the 4th constituents; C adds with the form of the organic material (as polyvinylpyrrolidone, ginsenoside, vitamin C, maleic anhydride etc.) of the allotrope of carbon (Graphene (Gp), CNT (CNT) or vitreous carbon (GC)) or carbon, after wherein the allotrope (Graphene (Gp), CNT (CNT) or vitreous carbon (GC)) of carbon adds or form the allotrope of carbon, the organic material of carbon forms the organic material on top layer or forms alloy due to high-temperature heating and metal;

S and Se has two kinds of modes to introduce, one is in reduction reaction, the part water mercaptan introduced or selenol are replaced, play the effect same with-OH in water, metal sulfide or selenides is formed in dry run, be by anion exchange reaction in addition, after reaction defines metal-oxide, then add sulphite or selenite and reducing agent reaction forms S ^2-or Se ^2-the sulfide that can be formed with metal ion due to these aniones and selenides is more stable, more indissoluble (less solubility product constant), therefore can with oxygen anion generation displacement reaction, form the more difficult stable and metal sulfide that is more easily distributed in water or selenides.

Metallic element in 3rd constituents adds in reactant liquor with the form of the presoma of slaine, by reduction reaction generate simple substance atom or having water and carry out under the condition of solvent autolysis aerobic precipitation formed metal-oxide, and through nucleation and growth form metal nanometer cluster form or be outer field many components nanoparticle with metal-oxide.Under metallic element in 3rd constituents has the slaine of the first composition to exist in reactant liquor, metal alloy nanoparticles can be formed with the metallic atom of the first component being reduced out, when reacting under the condition having water and solvent autolysis aerobic, because the 3rd component slaine can precipitate generation hydroxide, this metal alloy nanoparticles surface can by the hydroxide of the 3rd class component generation or oxide be coated or part is overmolding to nucleocapsid structure;

Na, Mg, Li, K, Ca in 4th constituents add using metallic boron hydrides as the form of reducing agent, by selecting the content of wash conditions (as solvent and washing times etc.) control Na, Mg, Li, K, Ca of product; Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La element in 4th class component adds with the form of soluble metallic salt;

The slaine of first kind component is when being reduced, add the metal nanometer cluster (being usually less than 5 nanometers) be made up of the 3rd constituents, the initial nanoparticle (being usually less than 5nm) that the metal nanometer cluster that 3rd constituents is formed can grow up in the metallic atom nucleation by first kind component carries out outer nanoparticle and merges epitaxial growth, form with first kind multicomponent metallic nanoparticle for stratum nucleare, the 3rd constituents metal is the core-shell nano of shell; If now have water in reaction solution and oxygen containing autolysis in system exists, it has the metal hydroxides be made up of the 3rd multicomponent metallic outside shell, the metal hydroxides that 3rd multicomponent metallic is formed by dehydration in further dry run, can form the outer metal-oxide be made up of the metal of the 3rd constituents.

The element of the 4th constituents adds in two ways, to Na, Mg, Li, K, Ca etc. can with the form of metallic boron hydrides, as reduction first, the reducing agent of the 3rd constituents slaine adds, first, three metalloid salt are reduced into atomic building alloy or compound and Na in nucleation, Mg, Li, K, Ca becomes wrappage and enters into wherein, wash according to follow-up requirement, as such Na of needs, Mg, Li, K, Ca tenor is high, use such Na, Mg, Li, K, the washing liquid (as alcohols) that Ca metal ion dissolubility is low or washing times reduce (as on common 3 times, carry out 1-2 washing), regulate wash conditions, part is made to continue to remain in the nanoparticle of formation, as needs are removed clean, as long as use is repeatedly washed the solvent (as water) that this Na, Mg, Li, K, Ca metalloid ion has highly dissoluble, the nanoparticle with this constituents of low content just can be obtained.To have redox potential lower than Na, Mg, Li, K, Ca metalloid ion as Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La metalloid, can directly its soluble metallic salt be joined in the first kind and/or the 3rd metalloid saline solution, in nanoparticle forming process, form alloy with major metal or form compound with nonmetal oxygen group elements;

In Equations of The Second Kind composition, element B is mainly from reducing agent metallic boron hydrides, and while reducing agent decomposition is played reducing metal ions effect, have pure boron or boron oxide generation, pure boron can add in the metal alloy of formation with the form of alloying element; S and Se has two kinds of modes to introduce, one is in reduction reaction, the part water mercaptan introduced or selenol are replaced, play the effect same with-OH in water, metal sulfide or selenides is formed in dry run, be by anion exchange reaction in addition, after reaction defines metal-oxide, then add sulphite or selenite and reducing agent reaction forms S ^2-or Se ^2-the sulfide that can be formed with metal ion due to these aniones and selenides is more stable, more indissoluble (less solubility product constant), therefore can with oxygen anion generation displacement reaction, form more stable, indissoluble but the metal sulfide be more easily distributed in water or selenides.

In the present invention in alloy particle when not needing containing B, then what reducing agent adopted other can not containing the reducing agent of B, as hydrazine hydrate etc.

If such nanoparticle surface contains polyhydroxy or other specific functional groups (organic material that the form of C exists) as glycine, alanine, cysteine, the aminoacid such as phenylalanine, Fructus Vitis viniferae sodium carbonate, sodium citrate, sulfydryl dodecylic acid, lauric acid etc.) the compound compatible with organism (as ginsenoside, anthocyanidin, Radix Betae soda acid, vitamin C, vitamin B12 etc.), namely its biocompatibility and body fluid stability can be improved, protective effect is had again to normal cell, and have stealth to cancerous cell, cancerous cell inside can be entered into, destroy its nucleus and make its apoptosis, or to guide in it hereditary material (as DNA, RNA) revert to and Normocellular production function is copied to biomolecule such as protein.

With the other medicines ratio of exploitation at present, such multicomponent nanocomposite complex cancer therapy drug of invention has the following advantages: in (1) such medicine, ferromagnetism composition can use the magnetic resonance imaging method employing of medical science to pharmaceutical indications, such medicine has autonomous target function to liver, spleen, lung, bone marrow etc. simultaneously, also can carry out targeted therapy to the cancerous cell of other position of health (as mammary gland, rectum) under induced by magnetic field, (2) noble metal component (as Au, Ag, Pt, Cu, Ru, Pd, Rh, Re, Os, Ir) in medicine has optical effect, can by visible light wave range laser to the means (PET-CT) etc. of the method for infrared light spike and X-ray tomoscan to pharmaceutical indications, (3) the 3rd constituents contained can as the carrier of the first and second constituents (as Graphene and CNT), or with magnetic or/and noble metal component forms compound (as ferrum and oxygen form ferrum oxide at nano grain surface, manganese and oxygen form manganese oxide at nano grain surface) or alloy (as boron and ferrum form ferrum boron non-crystaline amorphous metal, silicon and gold form gold silicon non-crystaline amorphous metal), or self form oxide (as titanium and oxygen form titanium oxide, aluminum and oxygen form aluminium oxide, zinc and formation zinc oxide, zinc and selenium form zinc selenide) construct Nanoalloy or complex, play stabilized magnetic and noble metal component and improve its biocompatibility, the oxide particularly formed can form top layer polyhydroxy layer, it is made to have stealthy effect to organic foreign substance removing function, reduce organism to its rejection, improve the persistency of its curative effect and drug effect, (4) because transport of substances channel size (as aquaporin, ion channel, protein channel) normal on cell membrane is basic below 80 nanometers, much below 50 nanometers.Therefore, the aerodynamic particle size of the Nano medication of preparation must below 80 nanometers, reasonable is below 50 nanometers, more excellent particle diameter is below 20 nanometers, in order to not block cellular water passage, improve the degree of freedom of its turnover cell, according to Hydrodynamics Theory, its aerodynamic size should be less than 1/3rd of channel internal diameter, and its aerodynamic size is preferably below 10 nanometers like this, (6) in order to improve its Stealth and curative effect, such particle often coated one deck and the good macromolecule of the organism compatibility or Organic substance (as polyvinylpyrrolidone, Polyethylene Glycol, polyvinyl alcohol, citric acid, maleic anhydride, vitamin C, vitamin B12, each seed amino acid, Fructus Vitis viniferae sodium carbonate, sodium citrate, sulfydryl dodecylic acid, lauric acid, ginsenoside, ginkgoic acid, ginkgetin, ginkgol, tea polyphenols, anthocyanidin oligomer (ProanthoCyanidins), Radix Betae soda acid (SB12), or directly because the oxidation effect of surface-element forms polyhydroxy decorative layer (Fe-O (OH) _x, Au-O (OH) _x), general 0.2 ~ 3 nanometer of this layer, although this layer improves its aerodynamic size, but the biocompatibility of medicine entirety and the dispersibility in body fluid can be improved, but preferably still make the overall dimensions of multicomponent nanocomposite complex particles remain on below 10 nanometers, optimum below 5 nanometers, curative effect is best.

In order to above multicomponent nanocomposite alloy complex is prepared in scale; prepare on the basis of ultra micro hybrid particle technique at microfluid, the present invention will have emulative reduction reaction nucleation and the precipitation method be coupling in multi-step sequence microfluid prepares above multicomponent heterogeneous structural nano complex.All chemical drugss are all purity or the market purchase directly use of more than chemical pure.Whole reaction is carried out under the protection of nitrogen, carbon dioxide or argon gas atmosphere.

Fig. 1 is a program microfluid primitive operation composition sketch of this multi-step sequence microfluidic methods.

Main processes comprises and uses syringe pump (1) and (2), transports all kinds of reactant liquors (as reducing agent/stabiliser solution and metal salt solution) that prepare and passes through to be heated in preheating fluid channel (3) that temperature chamber a (8) heats and (4) temperature before the hybrid reaction of setting to respective; Then reaction in Y type mixing reactor (5) is entered into; Afterwards, enter in the fluid channel (6) by temperature chamber b (9) control temperature and carry out moment nucleation and controllable growth special time; Finally enter in the product-collecting device by temperature chamber c temperature control and inert gas shielding and stop growing up of granule, and collect product.The temperature of temperature chamber a and b can control at 25 DEG C to 200 DEG C; The temperature of temperature chamber c (10) can be controlled at-40 DEG C to 15 DEG C by refrigeration machine or dry ice.

This program microfluid primitive operation comprises following step.

Step one: by first kind component and the 3rd class component or/and the precursor that the 4th class component removes Na, Mg, Li, K, Ca is dissolved in solvent (organic solvent or ultra-pure water) mixing salt solution obtaining macromolecule dispersing agent dispersion, if containing C, then also add allotrope or the Organic substance material of carbon; Wherein solvent is N-Methyl pyrrolidone, dimethyl formamide, dimethyl sulfoxide, oxolane, dimethyl acetylamide or water; Organic substance material is the macromolecule organic or the biochemical reagents that are dissolved in above solvent, as polyvinylpyrrolidone, Polyethylene Glycol, polyvinyl alcohol, citric acid, maleic anhydride, vitamin C, vitamin B12, aminoacid, Fructus Vitis viniferae sodium carbonate, sodium citrate, sulfydryl dodecylic acid, lauric acid, ginsenoside, ginkgoic acid, ginkgetin, ginkgol, tea polyphenols, 6-sulfydryl 1-ethanol, anthocyanidin oligomer (ProanthoCyanidins), Radix Betae soda acid etc.The ratio of Organic substance material and slaine and solvent is: the mole/solvent volume of Organic substance quality of materials/slaine or its compound is (0.05 ~ 4.0g)/0.5 ~ 15mmol)/50ml.

Step 2: reducing agent is dissolved in N-Methyl pyrrolidone, dimethyl sulfoxide, dimethyl formamide, oxolane or dimethyl acetylamide, obtains reductant solution; The wherein corresponding 50ml solvent of every 0.03g-3g reducing agent; The consumption of general reducing agent is 1.5-2 times of slaine equivalent, if reducing agent is containing B, be the reducing agent containing B, reducing agent can be solid-state NaBH ₄, KBH ₄, LiBH ₄, Ca (BH ₄) ₂, Zn (BH ₄) ₂or Al (BH ₄) ₃, also can be Li [B (C ₂h ₅) ₃h] tetrahydrofuran solution; If not containing B in product, adopt the reducing agents such as hydrazine hydrate.

Step 3: extract with syringe the reactant liquor that configured by step one and step 2 respectively and be placed in two syringe pumps (1) arranged side by side and (2) respectively, by the flow rate regulation of syringe pump be: 0.01ml/min ~ 20ml/min, flow through after the coil pipe preheater (3) that is immersed in temperature chamber a (8) and (4) are preheating to uniform temperature (40-200 DEG C) separately, enter the threeway blender hybrid concurrency raw reaction nucleation in Fig. 1, then nucleation and growth process a period of time in the 3rd coil pipe preheater is entered, final reaction product enters into the product receiving system (by temperature chamber c (10) control temperature) of the lower temperature of inertia protection, product is frozen in specific growth stage, obtain the solution of homodisperse extra small nano-particle, noble gas can be nitrogen, argon and carbon dioxide.

In preparation method step of the present invention, the core-shell nano that following methods also can be adopted directly to prepare with metal alloy core and metallic compound is shell.By controlling the kind of two or more slaine (as the slaine of two kinds of metals that electrochemical potential differs greatly, as FeCl ₂and H ₂ptCl ₆) and concentration difference and reducing agent consumption, obtain nucleocapsid (as FeCl ₂amount much larger than H ₂ptCl ₆amount, FeCl ₂/ H ₂ptCl ₆or part nucleocapsid structure (FeCl >4) ₂/ H ₂ptCl ₆<4) nanoparticle; Wherein the metallic element such as Na, K, Ca, Li adds in step 2, has little time to be diffused in solution, and be introduced directly in nanoparticle with alloy in step 3 in nanoparticle fast nucleation growth process;

Extra small nano-particle is utilized jointly to build the multicomponent nanocomposite particle with heterojunction structure for seed and composition other material diverse, use such nanoparticle as seed, and the reduction dose construction adding needs in its solution form the nanoparticle seed-reducing agent of heterojunction structure needs; Build the solution of the raw material of the other component that heterojunction structure needs again as another kind of feed liquid; Use above-mentioned same reaction unit, repeat step 3, regulate reaction process parameter, obtain the multicomponent nanocomposite particle with heterojunction structure, the solution centrifugal of the nano-particle product obtained is separated, makes it settle down from mother solution, outwell supernatant, obtain precipitum, the cleaning mixture of volume same with supernatant (is joined in precipitum, sonic oscillation, centrifugal sedimentation; Repeatedly after 2-3 time, obtain the multicomponent nanocomposite particle slurry class precipitate of heterojunction structure, now the inner 3rd constituents metal of shell exists with the form of MOx, and top layer the 3rd constituents metal and oxygen are with M-O (OH) _xform exists.If dry for standby in the vacuum drying oven of 40-100 DEG C, now nanoparticle surface M-O (OH) _xa large amount of dehydration can be transformed into MO _xcomposition.

The slaine of first kind component is when being reduced, add the metal nanometer cluster be made up of the 3rd constituents, the initial nanoparticle that the metal nanometer cluster that 3rd constituents is formed can grow up in the metallic atom nucleation by first kind component carries out outer nanoparticle and merges epitaxial growth, form with first kind multicomponent metallic nanoparticle for stratum nucleare, the 3rd constituents metal is the core-shell nano of shell; If now have water in reaction solution and oxygen containing autolysis in system exists, it has the metal hydroxides be made up of the 3rd multicomponent metallic outside shell, the metal hydroxides that 3rd multicomponent metallic is formed further by dehydration in the process of drying, can form the outer metal-oxide be made up of the metal of the 3rd constituents;

And have two kinds of forms to enter nanoparticle during nonmetal carbon employing organic material, one is when reaction temperature very high (being generally greater than 120 DEG C), realize by regulating temperature, partial organic substances is decomposed and has produced simple substance carbon or carbon radicals, this carbon very vivaciously can form metal-carbon alloy (as Fe with metal ₃thus enter into metal alloy in alloying element mode C); Major part still exists in organic skeleton carbochain in addition, is coated on outside particle with the form of surface stabilizer.When reaction temperature is low, when Organic substance can not decompose, then to be coated on particle skin.

The multicomponent nanocomposite particle slurry of the clean undried heterojunction structure obtained is dissolved in the normal saline nutritional solution prepared again, after ultraviolet disinfection, just can surveys it to the toxicity of each quasi-cancer cell by vitro cytotoxicity test; And then to be entered by intravenous injection kind be implanted with all kinds of cancerous cell laboratory mice or white rabbit body in, survey its therapeutic effect to each quasi-cancer cell.

Sub-diamidogen (EDC) coupled reaction of the carbon that nanoparticle of the present invention can continue to use in use authority patent (ZL200910085973.9), to its finishing and functionalization, first uses Organic substance material with carboxyl functional group composition (as sulfydryl dodecylic acid: 12-MUA in above-mentioned nanoparticle preparation; Gluconic acid, citric acid, maleic acid glycosides etc.), finishing there is the surface organic matter material activation with carboxyl functional group, after such nanoparticle activates, the special medicaments needed in its surperficial coupling by the reaction (2) in patent ZL200910085973.9 and (3) or have the organic of recognition function or biomolecule to certain disease.Specifically, first EDC and carboxyl reaction form a urea ester reactive intermediate (reaction 1, is shown in accompanying drawing 15); A primary amine group reaction in the biomolecule that this reactive intermediate is very fast and added forms amido link by this biomolecule and nano-particle coupling (reaction 2, is shown in accompanying drawing 15).So just prepare a class Nano medication of finishing and functionalization.

Finishing is had to the nanoparticle of amido, by the similar reaction (4) in patent ZL200910085973.9, the special medicaments using disuccinimidyl suberate coupled reaction (reaction 3, is shown in accompanying drawing 15) to need in its surperficial coupling or have the organic of recognition function or biomolecule to certain disease.

The invention has the advantages that:

1, the advantage of composition, hierarchical structure, size, physical and chemical performance, biocompatibility, drug effect etc. of the cancer therapy drug of preparation is shown in and discusses above: the advantage of such multicomponent nanocomposite complex cancer therapy drug.

2, the multi-step sequence microfluid preparation method started can to the growth course of nanoparticle along microchannel linear expansion, realize time-space resolution and control particle formation, having can medicinal property as required, Nano medication can be controlled to need the stage in growth course, meticulous composition (the metal of online such medicine of flexible, metallic compound, nonmetallic compound, high polymer, biomolecule), hierarchical structure (multi-layer core-shell structure), micro structure (adjustable to polycrystalline again from amorphous phase to monocrystalline), finishing, autonomous targeting and particular target tropism, biocompatibility etc.

3, the multilayered shell Rotating fields built both there is the biocompatibility (as avoid all kinds of immune body or macrophage in body find it and destroy and have from stealthy function) that improves itself and cancerous cell and the ability in cancerous cell of entering into (as surface has the ferrum that a large amount of cancerous cell likes, cobalt, nickel, potassium, zinc, calcium, sulfur, the elements such as selenium), its shell composition (as metal-oxide and polyhydroxy surface) and crystal structure can be regulated (as built amorphous state simultaneously, or crystalline state and amorphous mixed state) there is after entering cancerous cell stripping stratum nucleare functional element (as Pt, Au, and the DNA of cancerous cell Ag), S in RNA or functional protein, Se, the ability that the elements such as P combine, and then change its DNA, the function of RNA or functional protein or make its degeneration.

The molecule of the outmost organic coating layer of the multilamellar shell 4, built is except can coupling have except the biomolecule of recognition function or treatment function to cancerous cell, also can Chinese medicine class organic molecule (as ginsenoside) in coupling, have and improve Normocellular activity, certain effect is had to the immunity improving body, contrary to the killing effect of organism normal cell with common chemotherapeutics, greatly improve the health level of patient.

Accompanying drawing explanation

Program microfluid primitive operation in Fig. 1 multi-step sequence microfluid preparation method forms sketch.

(1) and (2) syringe, (3) first coil pipe preheaters, (4) second coil pipe preheaters, (5) Y shape threeway mixing reactor, (6) the 3rd coil pipe preheaters, (7) product receiving system, (8) temperature chamber a, (9) temperature chamber b, (10) temperature chamber c.

Fig. 2 forms transmission electron microscope photo (a) of the CoFeB ultra micro nano-particle of shell, high resolution transmission electron microscopy photo (in a upper right illustration) and (b) particle size distribution statistics block diagram.

Fig. 3 forms the x-ray diffraction pattern of the CoFeB ultra micro nano-particle seed of shell.

AuCoFeB (CoFe)-O (OH) prepared by Fig. 4 _xtransmission electron microscope photo (a), high resolution transmission electron microscopy photo (in a upper right illustration) and (b) particle size distribution statistics block diagram

The single AuCoFeB of Fig. 5 (CoFe)-O (OH) _xnanoparticle core core place (a) and shell layer surface place (b) EDX spectrogram.

AuCoFeB (CoFe)-O (OH) prepared by Fig. 6 _x(HECATE) (a) and AuCoFeB (CoFe)-O (OH) _x(LHRH-HECATE) (b) nano anti-cancer medicines structure schematic diagram.

The agents on normal cells (TM4) of all kinds of Nano medication prepared by Fig. 7 and non-coupled nanosecond particle and the growth inhibitory effect of breast cancer cell line (MDA-MB-435S) cell.

Fig. 8 Fe/Pt salt mole dosage is than the FePtBFe for preparing during 11:1 ₃o ₄wide field's transmission electron microscope photo (a) of alloy nano particle and high-resolution-ration transmission electric-lens photo (b)

Wide field's transmission electron microscope photo (a) of the FePtB alloy nano particle prepared when Fig. 9 Fe/Pt salt amount ratio is 3:1 and high-resolution-ration transmission electric-lens photo (b).

Figure 10 intravenous injection FePtBFe-O (OH) _x(PVP-GS) the T2WI image of (a) (b) liver tissues of rats afterwards before medicine.

NiPtBNi-O (OH) prepared by Figure 11 _xthe transmission electron microscope photo of class nanoparticle medicine.

The transmission electron microscope photo of the Ag nanoparticle as shell seed particles prepared by Figure 12.

The Gp-AlPtMg that Graphene prepared by Figure 13 is stable _xal _ysi _zthe transmission electron microscope photo (a) of OPVP (2x+3y+4z=2) nanoparticle and element power dissipation wave spectrum (b) that its composition is done.

Figure 14 AgAlPtMg _xal _ysi _zca _jthe element power dissipation wave spectrum of the multi-layer core-shell structure nanoparticle of OPVP (2x+3y+4z+2j=2).

Reaction structure schematic diagram in Figure 15 embodiment 1.

Detailed description of the invention

below in conjunction with embodiment, the present invention will be further described, but the present invention is not limited to following examples.

Embodiment 1

Below with AuCoFeB (CoFe)-O (OH) _x(LHRH-HECATE) (LHRH: short sex hormones secretion hormone; HECATE: cell membrane lysin peptide) for example illustrate its preparation process and cancerous cell treatment on effect.

(1) in there-necked flask by a certain amount of slaine FeCl ₂4H ₂o (0.07g (0.35mmol), CoCl ₂6H ₂o (0.0833g, 0.35mmol) and a certain amount of stabilizing agent PVP (0.42g, Mw=10000) are dissolved in N-Methyl pyrrolidone (50mL, NMP), and keeping has nitrogen protection in bottle.(2) by a certain amount of reducing agent NaBH ₄(0.4g, 10.25mmol) is dissolved in the NMP of 50mL in the there-necked flask of nitrogen protection.(3) react in tubular type micro-fluid reactor, setting response speed is 3.0ml/min, reaction temperature (the temperature chamber a and b) that is 100 DEG C, collect product (temperature chamber c) for 4 DEG C, prepare the single dispersing CoFeB nano-particle of Stability Analysis of Structures and excellent performance, reaction equation is such as formula shown in (4):

CoCl ₂+FeCl ₂+NaBH ₄+H ₂O→CoFeB+NaCl+NaBO ₂+H ₂(4)

(4) AuCoFeB (CoFe)-O (OH) _xthe preparation of Core-shell Structure Nanoparticles.Treat that above-mentioned reaction terminates, extract 50mLCoFeB nano-particle solution immediately, and by 0.2g (5.13mmol) NaBH ₄be dissolved in the reaction mixture of this CoFeB nanoparticle, then by appropriate HAuCl ₄4H ₂o (2.5ml, gold content is 0.36mmol) is dissolved in other 50mLNMP, extracts this 50mLHAuCl with syringe ₄two pipe solution are placed in tubular type micro fluid reaction system, react immediately, and then use NaBH by solution ₄reduction HAuCl ₄4H ₂o, setting response speed is 3.0ml/min, and reaction temperature is 80 DEG C, collects product under room temperature.Because golden salt is easy to be reduced into gold atom fast, and gold atom is by being easy to generate ultra micro golden nanometer particle, therefore the CoFeB generated in advance can be that core also merges and extension generation AuCoFeB nanoparticle at its surface aggregation with gold particle, the hydrone that simultaneously some Co and Fe atoms on surface can be introduced into be oxidized to metal-oxide and and the oxide surface layer of the saturated Surface Fe of the hydroxyl formation polyhydroxy of solution and cobalt, obtain hierarchical structure as AuCoFeB (CoFe)-O (OH) _xmulti-layer core-shell structure type nano-particle, its outermost layer is still coated stable by surfactant PVP certainly.

The concrete reaction mechanism of nano-particle is as shown in chemical equation (5), and nucleocapsid formation basic theory is if reaction schematic diagram is as shown in (15):

HAuCl ₄+NaBH ₄+CoFeB+H ₂O→AuCoFeB(CoFe)-O(OH) _x+NaCl+BO ₂+H ₂(5)

(5) according to reaction equation (1) and (2), the s-NHS (N-hydroxy thiosuccinimide) of EDC and 0.36mmol of 0.27 μm of ol is joined in the aqueous solution of the core-shell magnetic nano-particle after 30mL surface modification (80nM), form the magnetic nanoparticle of s-NHS coupling, after stirred at ambient temperature half an hour, excessive EDC and s-NHS is removed with magnetic method desalination, then nano-particle is dissolved in (pH=7.4) in PBS buffer, the polyvinyl alcohol (PVA) or the Polyethylene Glycol (PEG) that add 0.05%w/v block possible non-specific bonding.Then by part to join in the solution of magnetic nanoparticles being dissolved in PBS buffer with nano-particle than the ratio being 0.97, by this mixed liquor at 4 DEG C, mix 12 hours with rotary shaker.Then the magnetic nanoparticle that magnetic method separation functionization is good is used, and with PBS buffer solution 2 to 3 times.The magnetic nanoparticle of the nucleocapsid structure that the functionalization of gained is good is dissolved in the PBS buffer containing 0.05%w/vPEG (Polyethylene Glycol) again, stores for future use at 4 DEG C.

(6) then luteinizing hormone-releasing hormone (LHRH) receptor, cell membrane lysin peptide (HECATE) and nanoparticle mass are joined in the nanoparticles solution being dissolved in PBS buffer than the ratio being 2/10/1 to 5/50/1, by this mixed liquor at 4 DEG C, mix 12 hours with rotary shaker.Then the magnetic nanoparticle that magnetic method separation functionization is good is used, and with PBS buffer solution 2 to 3 times.What obtain functionally has the LHRH of specific recognition to breast cancer cell and kills the multi-layer core-shell structure type nanoparticulate drug of effect.This nano biological molecular medicine is put into the PBS buffer containing 0.05%w/vPEG, stores for future use at 4 DEG C.

Accompanying drawing 2a is the transmission electron microscope image of the CoFe nanoparticle for building shell of preparation.Its distribution of sizes is shown in Fig. 2 b, is 2.4 ± 0.3nm according to the particle diameter of its granule of statistical result.High-resolution-ration transmission electric-lens characterizes the crystal structure (Fig. 2 a upper right illustration) of its single particle and shows x-ray diffraction (accompanying drawing 3) result of integral particles: it is body-centered cubic (bcc) crystal structure that degree of crystallinity is very high.

Accompanying drawing 4a is AuCoFeB (the CoFe)-O (OH) of preparation _xtransmission electron microscope photo, its distribution of sizes is shown in Fig. 4 b, is 5.6 ± 0.4nm according to the particle diameter of its granule of statistical result.High-resolution-ration transmission electric-lens characterizes the crystal structure (Fig. 2 a upper right illustration) of its single particle, in conjunction with face-centered cubic (fcc) gold and the lattice paprmeter analysis of body-centered cubic crystal structure, and core correspond to (200) crystal face of fcc-Au (JCPDS:04-0784); Housing parts, (100) crystal face of what lattice paprmeter was corresponding is bcc-CoFe (JCPDS:44-1433), tentatively judges that the structure obtained is AuCoFe.

For determining that the CoFe layer of its nucleocapsid structure and surface portion oxidation can form (CoFe)-O (OH) further _xoutermost layer forms, and use element power dissipation wave spectrum (EDX) to characterize the core of multiple single nanoparticle and skin, one of them EDX characterization result as shown in Figure 5.Result shows that the content of the Au at its kernel place is obviously higher than particle shell surface layer Au content a lot, and the content of particle shell surface layer Co, Fe and oxygen is more a lot of than the height at core place.In addition, because in the raw material in reaction, itself contains water, add the water etc. in washing process, as NiFePt class core-shell nano, shell outer surface part CoFe can be oxidized and form the chemical combination state of Fe-OOH and Co-OOH, thus form AuCoFeB (the CoFe)-O (OH) with hydrophilic outer layer _xthree-decker, has good biocompatibility and further coupling is biological or the ability of drug molecule.

Fig. 6 is AuCoFeB (the CoFe)-O (OH) prepared _xand AuCoFeB (CoFe)-O (OH) (HECATE) _x(LHRH-HECATE) nano anti-cancer medicines structure schematic diagram.

By preparation various kinds of drug and the action effect (as Fig. 7) of nanoparticle to normal nucleus cancerous cell visible, TM4 cell line (non-cancerous) only produces reaction to Hecate, the functionally nanoparticle probe biomolecule of recognition group and Lysin peptide and medicine (LHRH+Hecate+ nanoparticle: molecular structure mimics figure is shown in Fig. 6 b), the efficiency that its efficiency ratio killing breast cancer cell (MDA-MB-435S) kills normal cell (TM4) is high 85 times; And nanoparticle self also has very high kill ratio (65%) to this quasi-cancer cell, slightly lower than HECATE (25%), and the two more effectively can kill cancerous cell (85%) after coordinating; No matter nanoparticle or HECATE, by with LHRH coupling, the kill ratio of cancerous cell is significantly improved again (about 5%).

Embodiment 2

This example is illustrated and is adopted a program microfluid primitive operation in multi-step sequence microfluid preparation method to regulate preparation to have the FePtBFe of different-shape (nucleocapsid or crystal structure of alloy) by reactant ratio by mixed salt method ₃o ₄nanoparticle, and and only compare containing the ferrum of single component or the anticancer effect of Pt particle.

Single program microfluid primitive operation prepares FePtBFe ₃o ₄the case method of nanoparticle is as follows.

(1) by the FeCl of 0.07g (0.35mmol) ₂4H ₂the PVP (Mw=10000) of O, 0.3g and the H of 0.017g (0.032mmol) ₂ptCl ₆6H ₂o is dissolved in the nmp solvent of 50mL and forms mixed salt solution, and being preheating to 120 DEG C in pumping into this mixed salt solution by temperature chamber a temperature control micro-preheating channel (3) by pump (1), preheating channel internal diameter is 127 μm, long 15cm;

(2) 0.3g (7.9mmol) NaBH4 is dissolved in the nmp solvent of 50mL forms reducing solution system, and being preheating to 120 DEG C of suctions in pumping into this reductant solution by temperature chamber a temperature control micro-preheating channel (4) by pump (2), preheating channel internal diameter is 127 μm, long 15cm;

(3) two kinds of solution are 250 μm at internal diameter, grow mixing in the Y type blender (5) of 4 ~ 10 ㎜, what coupling occurred has emulative mixed metal salt reduction nucleation becomes shell reaction with molysite deposition, and formation reduction reaction formation alloy core core and precipitation form the process of shell presoma;

(4) the initial particle formed is in one section of microchannel (internal diameter=250 μm being placed in temperature chamber b (temperature: 30 DEG C), long=30 ㎝) enter after interior growth a period of time and collect by the catcher (7) of temperature chamber c control temperature (2 DEG C), and stop growing by low temperature.

By centrifugal for this product, precipitation and after washing 4 times with pure water, vacuum drying at 60 DEG C of temperature, obtain FePtBFe ₃o ₄nanoparticle powder body.Accompanying drawing 8a be preparation with FePtB alloy be sandwich layer, with Fe ₃o ₄for the nanoparticle of shell, as can be seen from its high-resolution-ration transmission electric-lens photo Fig. 8 a, its stratum nucleare and shell are amorphous state.Its stratum nucleare size is about 1.3 ± 0.2nm, shell thickness about 2.1 ± 0.4 nanometer.Such nanoparticle is re-dispersed in the aqueous solution detected for cytotoxicity, carry out 3 anticancer contrast experiments's (normal cell and hepatoma carcinoma cell) to such nanoparticle to show: such particle on average can reach 70% (Percent mortality) to the kill ratio of hepatoma carcinoma cell under same condition of culture, and does not originally have kill ratio (being less than 3%) to normal cell based.

Embodiment 3

By the H in embodiment 2 ₂ptCl ₆6H ₂o consumption rises to 0.061g (0.117mmol); And the temperature chamber b temperature of growth stage is brought up to 85 DEG C, remaining reaction condition is constant.The transmission electron microscope photo of the nanoparticle of preparation is as Fig. 9 a, and statistical result shows that its particle diameter is 2.1 ± 0.4nm.Although shell has segregation phenomena when being formed, can its nucleocapsid pattern as apparent from the contrast on the high-resolution-ration transmission electric-lens photo internal layer of its single particle and top layer, the darker core of its color is FePtB alloy sandwich layer (middle dotted line is enclosed), lattice paprmeter be 0.211nm be face-centered cubic FePtB (111) face, the shell (ring part that two broken circles enclose) that the oxide that the more shallow part of color is Fe and Fe is formed.Also can find out, the crystalline state mass ratio of core layer is better simultaneously, and the blending constituent that shell is formed due to two kinds of compositions, be amorphous state substantially.Carry out 3 anticancer contrast experiments's (normal cell and hepatoma carcinoma cell) with such nanoparticle to show: such particle on average can reach 77% (high by 7% than Fe/Pt=11/1 in example 2) to the kill ratio of hepatoma carcinoma cell under same condition of culture, and does not originally have kill ratio (being less than 5%) to normal cell based.

Embodiment 4

Change the gold chloride in embodiment 1 into H ₂ptCl ₆6H ₂o, all the other composition and preparation technology constant, PtCoFeB (the CoFe)-O (OH) that similar particle diameter is 5.2 ± 0.4nm can be prepared _xbe 6.0 ± 0.5nmPtCoFeB (CoFe)-O (OH) with particle diameter _x(LHRH-HECATE) Nano medication such as.This type nano granular can in normal saline stable existence more than 2 years, occur without obvious sedimentation.PtCoFeB (CoFe)-O (OH) _x(LHRH-HECATE) more than 90% can be reached to the kill rate of breast cancer cell line (MDA-MB-435S), simultaneously by there being the mouse mainline effect highly significant of such tumor to termination, after 3 times (every other day once) treatment, observed through 1 week, this breast cancer cell heading line off, through 6 months trace detection, without the phenomenon again recurred.Also find in addition, PtCoFeB (CoFe)-O (OH) _xnanoparticle self also has kill rate to breast cancer cell line (MDA-MB-435S) can reach more than 75%.

We also studied PtCoFeB (CoFe)-O (OH) _xto the curative effect of hepatoma carcinoma cell, by intravenous injection in Mice Body, magnetic resonance imaging shows that such particle has obvious concentration effect in mouse liver, a shot, 3 is simultaneously filled out observation and is found, more than 75% is reached to the kill ratio of all kinds of hepatoma carcinoma cell, through the treatment of a week of 3 magnetic, the mortality rate of hepatoma carcinoma cell reaches more than 99%, within one month, review result shows, can't detect all kinds of hepatoma carcinoma cell of planting on mice, the reinspection of 6 months does not find that there is the rebound phenomenon of such hepatoma carcinoma cell of plantation yet.We also so that in various-advanced liver cancer patient uses, at present through the clinical research (patient is voluntary user) of 30 multiple-cases, (intravenous injection in day 10mL was containing such nanoparticle through 3-4 month to find all kinds of patient, effective dose is 20 micrograms) the course for the treatment of after, hepatoma carcinoma cell drops to normal level, repetition measurement after half a year, for finding that there is the recurrent cases of such hepatoma carcinoma cell.

Embodiment 5

Iron salt in embodiment 2 is changed into the CoCl of 0.0833g (0.35mmol) ₂6H ₂o; And the temperature chamber b temperature of growth stage is brought up to 150 DEG C, remaining reaction condition is constant.Because now reaction temperature is very high, part PVP can decompose under the Co simple substance catalysis generated, produce the C atom that some are free, this atom can form CoPtC alloy with Pt together with Co, prepares CoPtCBCo-Co to the slurry product obtained in 120 DEG C of vacuum drying ovens after drying ₃o ₄class nanoparticle, particle diameter is 3.5 ± 0.4nm.The crystal mass of its stratum nucleare and shell is all relatively good at this point in the reaction.Carry out 3 anticancer contrast experiments's (normal cell and hepatoma carcinoma cell) with such nanoparticle to show: such particle on average can reach 80% (high by 10% than Fe/Pt=11/1 in example 2) to the kill ratio of hepatoma carcinoma cell under same condition of culture, and does not originally have kill ratio (being less than 5%) to normal cell based.

Embodiment 6

Ginsenoside (the GS of 0.2g will be added in the metal salt solution of step (1) in embodiment 3, in GS, Rg3 and Rh2 mass percentage content is not less than 10%), reaction temperature is adjusted to 50 DEG C, prepares the FePtBFe-O (OH) that ginsenoside modifies _x(PVP-GS).Such Nano medication is used for the treatment of breast carcinoma, find, to the growth of breast cancer cell line (MDA-MB-435S) cell, there is high inhibition effect, its cell mortality reaches more than 80%, and to normal cell growth not only unrestraint effect, also have value-added effect, under similarity condition, its cell quantity can improve more than 7%.The research structure such Nano medication being killed to hepatoma carcinoma cell shows, with be used alone ginsenoside and compare, the kill ratio of its hepatoma carcinoma cell is enhanced about more than once, ginsenoside is 30-40% to the kill ratio of hepatoma carcinoma cell, and such medicine is 80-85%, find that have value-added effect on the contrary, under similarity condition, its cell quantity can improve more than 5% to normal cell not only without killing effect too.Such medicine can use nmr molecular image method to carry out real-time monitored to the target hepatic tissue that medicine after vein or stomach perfusion arrives simultaneously.Figure 10 is the T2WI shade change contrast figure by murine liver tissue before and after intravenous injection (medicine 5mg metal/kg mice), can observe after injection after 3-5 minute, the image contrast of murine liver tissue is obviously than more clear before not having injectable drug.

Embodiment 7

Iron salt in embodiment 2 is changed into the nickel acetate (Ni (CH of 0.0566g ₃cOO) ₂4H ₂oMw=176.78; 0.32mmol); And the temperature chamber b temperature of growth stage is brought up to 200 DEG C, remaining reaction condition is constant.Because now reaction temperature is very high, part PVP can decompose under the Ni simple substance catalysis generated, produce the C atom that some are free, this atom can form NiPtBC alloy together with the B in Ni with Pt restored and reducing agent, NiPtBCNiO class nanoparticle is prepared after drying in 100 DEG C of vacuum drying ovens to the slurry product obtained and (in embodiment 2, has B, but do not embody B in this embodiment product) nano particle diameter is 26.0± 9.0nm, its representational transmission electron microscope, by appended Figure 11 a, has obvious nucleocapsid structure; Show the high-resolution-ration transmission electric-lens photo (Figure 11 b) of its single particle, the crystal mass of its stratum nucleare and shell is all relatively good at this point in the reaction.Carry out 5 anticancer contrast experiments's (normal cell and hepatoma carcinoma cell) with such nanoparticle to show: such particle on average also can reach 80% (high by 10% than Fe/Pt=11/1 in example 2) to the kill ratio of hepatoma carcinoma cell under same condition of culture, and to Normocellular kill ratio very little (about 6%).

Embodiment 8

Ferrous salt in embodiment 3 is changed into gadolinium salt (GdCl ₃), in mixing salt solution, add 0.3g pentose (Pts, pentose), remaining reaction condition is constant simultaneously, prepares GdPtBGd to the slurry product obtained in 40 DEG C of vacuum drying ovens after drying ₂o ₃(PVP-PTs) Nano medication, particle diameter is at 3.8 ± 0.4nm.Although this type nano granular magnetic is very strong, but still has very excellent water solublity, but in aqueous phase stable existence more than 1.5 years, occur without obvious sedimentation, reason is that the pentose of finishing has very high water solublity.Carry out 3 anticancer contrast experiments's (normal cell and hepatoma carcinoma cell) with such nanoparticle to show: such particle on average also can reach 85% to the kill ratio of hepatoma carcinoma cell under same condition of culture, and to Normocellular kill ratio very little (about 3%).

Embodiment 9

By the gadolinium salt (GdCl in embodiment 8 ₃) change europium salt (EuCl into ₃), particle diameter can be prepared at 2.6 ± 0.3nmEuPtBEu ₂o ₃(PVP-PTs) Nano medication, has the anticancer effect same with example 8.

Embodiment 10

By the gadolinium salt (GdCl in embodiment 8 ₃) change neodymium salt (NdCl into ₃), particle diameter can be prepared at 1.5 ± 0.2nmNdPtBNd ₂o ₃(PVP-PTs) Nano medication, has the anticancer effect same with example 8.

Embodiment 11

By the gadolinium salt (GdCl in embodiment 8 ₃) change samarium salt (SmCl into ₃), particle diameter can be prepared at 1.0 ± 0.2nmSmPtBSm ₂o ₃(PVP-PTs) Nano medication, has the anticancer effect same with example 8.

Embodiment 12

By the gadolinium salt (GdCl in embodiment 8 ₃) change acetic acid terbium (Tb (CH3COO) into ₃), particle diameter can be prepared at 2.5 ± 0.3nmTbPtBTb ₂o ₃(PVP-PTs) Nano medication, has the anticancer effect same with example 8.

Embodiment 13

In the step (1) of the multi-step sequence microfluid preparation method of embodiment 1, the scheme of preparation CoFeB seed grain prepares the method for Ag seed grain below changing into.By 0.25gAgNO ₃, 0.75g sodium citrate (STC) 1.0mL concentration be 30% hydrogenperoxide steam generator, 0.35gPVP be dissolved in 50mL water, as metal salt solution; Be the hydrazine hydrate (N of 85% by 0.046mL concentration ₂h ₄h ₂o) be dissolved in 50mL water, as reductant solution.By in the two program micro fluid reaction unit in FIG, be 1.0mL at each syringe pump flow velocity, carry out at each elementary reaction temperature is 25 DEG C, prepare the Ag nano-particle of the seed particles as shell, its transmission electron microscope photo as shown in figure 12.Show that its particle diameter is 2.5 ± 0.3nm to the statistics of grain diameter, characterize the high resolution electron microscopy (in Figure 12 illustration) of single particle and illustrate, it has good degree of crystallinity.

Then proceed all the other steps in embodiment 1, prepare the AuAgAg that particle diameter is 6.2 ± 0.5nm ₂o nanoparticle.Carry out 3 anticancer contrast experiments's (normal cell and hepatoma carcinoma cell) with such nanoparticle to show: such particle on average also can reach 70% to the kill ratio of hepatoma carcinoma cell under same condition of culture, and does not have kill ratio to normal cell.

Embodiment 14

(1) prepare Ag nanoparticle by embodiment 13, and by after centrifugal sedimentation, by bottom slurry, be again dissolved in the nmp solvent of 50mL.

(2) then by the FeCl of 0.07g (0.35mmol) ₂4H ₂the PEG (Mw=2000) of O, 0.3g and the H of 0.017g (0.032mmol) ₂ptCl ₆6H ₂o is dissolved in the nmp solution of the Ag nanoparticle of this 50mL the metal salt solution forming nanoparticle mixing, and being preheating to 120 DEG C in pumping into this mixed salt solution by temperature chamber a temperature control micro-preheating channel (3) by pump (1), preheating channel internal diameter is 127 μm, long 15cm;

(3) by 0.3g (7.9mmol) NaBH ₄be dissolved in the nmp solvent of 50mL and form reducing solution system, and being preheating to 120 DEG C of suctions in pumping into this reductant solution by temperature chamber a temperature control micro-preheating channel (4) by pump (2), preheating channel internal diameter is 127 μm, long 15cm;

(4) two kinds of solution are 250 μm at internal diameter, grow mixing in the Y type blender (5) of 4 ~ 10 ㎜, what coupling occurred has emulative mixed metal salt reduction nucleation becomes shell reaction with molysite deposition, and formation reduction reaction formation alloy core core (FePtB alloy) and precipitation form the process of shell presoma (ferrum and hydrated ferric oxide. mixture);

(5) the initial particle formed is in one section of microchannel (internal diameter=250 μm being placed in temperature chamber b (temperature: 30 DEG C), long=30 ㎝) enter after interior growth a period of time and collect by the catcher (7) of temperature chamber c control temperature (2 DEG C), and stop growing by low temperature.

By centrifugal sedimentation, obtain bottom slurry, and then be distributed to 20mL pure water; Centrifugal sedimentation is re-dispersed into secondary in pure water again, obtains AgFePtBFe ₃o ₄(PEG-STC) nanoparticle.Cross the method and can prepare AgFePtBFe ₃o ₄nanoparticle.This type nano granular can in aqueous phase stable existence more than 1 year, occur without obvious sedimentation.

The contrast experiment's (normal cell and hepatoma carcinoma cell) carrying out 5 anti-hepatoma carcinoma cell with such nanoparticle shows: such particle on average also can reach 85% to the kill ratio of hepatoma carcinoma cell under same condition of culture, and does not have kill ratio to normal cell.

Also with such medicine, inhibiting tumor cell performance test is carried out to small cell lung cancer NCIH446 cell strain, height transfer maxicell lung cancer cell line L9981 and NL9980, maxicell lung cancer cell line WCQH-9801, people's squamous lung carcinoma cell SK-MES-1, human A549 cell lines and lymphatic metastasis type lung carcinoma cell NCI-H292, find that it all has the kill ratio of more than 75% to such lung carcinoma cell.By suffering from the result of use of the middle and advanced stage patient of small cell lung cancer NCIH446 to 10 examples, show through the 250mL glucose injection containing 10mL/ agent (effective content 20 μ g) of Neulized inhalation twice daily, 1-2 month is a course for the treatment of, after 2-3 the course for the treatment of, 9 routine patient symptoms disappear substantially, 1 example patients symptomatic in mid-term is suppressed firmly, no longer worsens.To suffering from, height shifts maxicell lung cancer cell line L9981 and NL9980 and people's squamous lung carcinoma cell SK-MES-1, the patient of human A549 cell lines does same experiment, show that treated effect also reaches more than 80%, and be 70% to patient's effective percentage of lymphatic metastasis type pulmonary carcinoma NCI-H292.

Embodiment 15

By the FeCl of the 0.07g (0.35mmol) of (2) in embodiment 14 step ₂4H ₂the Radix Betae soda acid (SB12) that O changes 0.025g copper sulphate pentahydrate into, the PEG (Mw=2000) of 0.3g changes 0.3g into and 0.2gPVP, can prepare AgCuPtBCu ₂o (STC-PVP-SB12) nanoparticle, this particle also can in aqueous phase stable existence more than 1 year, occur without obvious sedimentation.Show with Contrast on effect experiment (normal cell and hepatoma carcinoma cell) that kills of such medicine to hepatoma carcinoma cell: such particle on average also can reach 85% to the kill ratio of hepatoma carcinoma cell under same condition of culture, and does not originally have kill ratio (being less than 5%) to normal cell based.Such medicine carries out inhibiting tumor cell performance test to human lung carcinoma cell H125 and 95D, human lung adenocarcinoma cell SPC-A-1, the classical small cell lung cancer cell H1688 of people, height transfer maxicell lung cancer cell line L9981 and NL9980, Non-small cell lung carcinoma cell H1299, maxicell lung cancer cell line WCQH-9801, people's squamous lung carcinoma cell SK-MES-1, human lung adenocarcinoma cell H1975 and lymphatic metastasis type lung carcinoma cell NCI-H292, find that it all has the kill ratio of more than 80% to such lung carcinoma cell, but also have normal cell and necessarily kill effect (about 6%).By suffering from the result of use of the middle and advanced stage patient of above cell type strain pulmonary carcinoma to 10 examples, show through Neulized inhalation twice daily containing the 250mL glucose injection of 10mL/ agent (effective content 20 μ g) or normal saline solution, 1-2 month is a course for the treatment of, after 2-3 the course for the treatment of, 9 routine patient symptoms disappear substantially, 1 example patients symptomatic in mid-term is suppressed firmly, no longer worsens.To suffering from, height shifts maxicell lung cancer cell line L9981 and NL9980 and people's squamous lung carcinoma cell SK-MES-1, the patient of human A549 cell lines does same experiment, show that treated effect also reaches more than 85%, and be 80% to patient's effective percentage of lymphatic metastasis type pulmonary carcinoma NCI-H292.

Embodiment 16

By the FeCl of the 0.07g (0.35mmol) of (2) in embodiment 14 step ₂4H ₂o changes the Zr (NO of 0.040g into ₃) ₄5H ₂the PEG (Mw=2000) of O, 0.3g changes the ginkgoic acid (GA) of 0.3g into, by 0.3g (7.9mmol) NaBH ₄change the Ca (BH of 0.44g into ₄) ₄, can AgZrPtBZr be prepared _1-xca _xo (GA-STC-PVP) nanoparticle, this particle also can in aqueous phase stable existence more than 1 year, occur without obvious sedimentation.Experiment shows, such nanoparticle medicine and AgCuPtBCu ₂o (STC-PVP-SB12) nanoparticle has same anticancer effect, but it is less than 4% to Normocellular kill ratio.

Embodiment 17

By the FeCl of the 0.07g (0.35mmol) of (2) in embodiment 14 step ₂4H ₂o changes the Ru (NO of 0.03g into ₃) ₃, 0.3g PEG (Mw=2000) change the ginkgetin (Gbb) of 0.3g into, by 0.3g (7.9mmol) NaBH ₄change the LiBH of 0.44g into ₄, can AgRuPtBRu be prepared _1-xli _xo (Gbb-STC-PVP).Such medicine and AgZrPtBZr _1-xca _xo (GA-STC-PVP) nanoparticle equally has same curative effect to hepatocarcinoma and pulmonary carcinoma.

Embodiment 18

By the H in embodiment 14 ₂ptCl ₆6H ₂o replaces with the H of 0.054g ₂irCl ₆3H ₂the FeCl of O, 0.07g (0.35mmol) ₂4H ₂o changes the prochloraz-manganese chloride complex ([C of 0.57g into ₁₅h ₁₆cl ₃n ₃o ₂] ₄mnCl ₂); In step (2) PVP change the bilobalide (Ggl) of 0.3g into, by 0.3g (7.9mmol) NaBH ₄change the Al (BH of 0.44g into ₄) ₃, AgAlMn (IrBMn can be prepared _1-xal _xo (Ggl-STC-PVP).Such medicine and AgZrPtBZr _1-xca _xo (GA-STC-PVP) nanoparticle equally has same curative effect to hepatocarcinoma and pulmonary carcinoma.

Embodiment 19

By the FeCl in embodiment 2 ₂change 0.05g copper sulphate pentahydrate and 0.02gAl (NO into ₃); PVP changes the bilobalide (Ggl) of 0.3g into; By 0.3g (7.9mmol) NaBH ₄change the Mg (BH of 0.44g into ₄) ₃, and add in the nmp solution of 0.1g organo-silicon compound (as silane etc.), can Gp-AlPtCuBMg be prepared _xysi _zoGgl (2x+3y+4z=2).Such nanoparticle can in aqueous phase stable existence more than 1 year, occur without obvious sedimentation.Figure 13 a is the transmission electron microscope photo of such nanoparticle medicine, the nanoparticle can finding out into granule disperses very even on Graphene, its element energy level dispersion wave spectrum (Figure 13 b) also shows that it contains Mg, Al, Si, Cu and Pt element, and mass percent is respectively 25/1.6/9.5/7.8/6.9.

Such medicine and AgZrPtBZr _1-xca _xo (GA-STC-PVP) nanoparticle equally has same curative effect to hepatocarcinoma and pulmonary carcinoma.

Embodiment 20

With a small amount of Ag nanoparticle (about 10mg solid powder) of preparation in embodiment 13 for seed, and the Al (NO of the 0.04g copper sulphate pentahydrate be distributed in embodiment 19 and 0.02g ₃) nmp solution in; At the Mg (BH containing 0.6g ₄) ₂reducing agent in add a small amount of (~ 0.05g) Ca (BH ₄) ₂, all the other conditions are identical with embodiment 19, can prepare AgAlPtCuBMg _xal _ysi _zca _jthe multi-layer core-shell structure nanoparticle of OPVP (2x+3y+4z+2j=2), appended Figure 14 is element energy level dispersion wave spectrum (note: gold element is think to add) done such nanoparticle, show that it contains Mg, Al, Si, Cu, Ag and Pt element, mass percent is respectively 35/1.4/5.9/0.5/3.9/0.35/1.6.Such medicine and AgZrPtBZr _1-xca _xo (GA-STC-PVP) nanoparticle equally has same curative effect to hepatocarcinoma and pulmonary carcinoma.

Embodiment 21

With the FePtBFe of preparation in embodiment 2 ₃o ₄for seed particles, proceed reaction below.(1) by this nanoparticle dissolution in the aqueous solution containing 0.165g zinc gluconate, 0.162g zincium selenious acid, 0.3g anthocyanidin oligomer and 0.15g maleic anhydride, form the mixed solution of nanoparticle and slaine; (2) will containing 0.24 gram of Li [B (C ₂h ₅) ₃h] tetrahydrofuran solution be dissolved in nmp solution, formed reductant solution; Through being preheating to, (3) two kinds of solution to enter after 100 DEG C that internal diameter is 250 μm in Fig. 1 shown device, mix in the Y type blender of long 4 ~ 10 ㎜, and Zn salt and part Fe occur ₃o ₄reduction reaction, at FePtBFe ₃o ₄outer formation Zn _(1-x)fe _xthe second layer shell of Se; (4) the initial multi-layer core-shell structure nanoparticle that formed is in one section of microchannel (internal diameter=250 μm being placed in temperature chamber b (temperature: 30 DEG C), long=30 ㎝) enter after interior growth a period of time and collect by the catcher of temperature chamber c control temperature (2 DEG C), and stop growing by low temperature.

After centrifugal sedimentation, milli-Q water 2-3 time, obtain anthocyanidin oligomer and the stable FePtBFe of maleic anhydride ₃o ₄zn _(1-x)fe _xse slurry, is then dissolved in the aqueous solution containing 0.1g ginsenoside, 4 DEG C of preservations.

Show the therapeutic effect of this nanoparticle to the hepatocarcinoma in embodiment 14 and 15 and pulmonary carcinoma, such nanoparticle has the function in hepatocarcinoma and the automatic enrichment of pulmonary carcinoma affected area, reaches more than 90% to the kill ratio of hepatoma carcinoma cell and all kinds of lung carcinoma cell.Shown by the result of use of the middle and advanced stage patient 20 examples being suffered to above type pulmonary carcinoma or hepatocarcinoma: through Neulized inhalation twice daily containing the 250mL glucose injection of 10mL/ agent (effective content 20 μ g) or normal saline solution, 1-2 month is a course for the treatment of, after 2-3 the course for the treatment of, 19 routine patient symptoms disappear substantially, 1 example patients with lung cancer symptom in mid-term is suppressed firmly, no longer worsens.

Embodiment 22

Proceeded by the nanoparticle that embodiment 21 obtains as the 5th step of example 1 and the reaction of the 6th step, what can obtain LHRH and Hecate biomolecule in coupling has to breast cancer cell the targeted nano-particle medicine FePtBFe identifying and kill function ₃o ₄zn _(1-x)fe _xse (LHRH+HECATE).The kill ratio of this medicine to breast cancer cell line (MDA-MB-435S) can reach more than 96%, and to normal cell TM4 without obviously killing effect (<3%).

Embodiment 23

0.162g zincium selenious acid in embodiment 21 is changed into the zinc sulfite of 0.129g, can FePtBFe be prepared ₃o ₄zn _(1-x)fe _xs nanoparticle, and FePtBFe ₃o ₄zn _(1-x)fe _xse particle has same anticancer effect.

Embodiment 24

Substantially with in embodiment 19, CNT-AlPtBMg can be prepared _xal _ysi _zoPVP (2x+3y+4z=2), and Gp-AlPtBMg _xal _ysi _zoPVP particle, has same anticancer effect.

Embodiment 25

Preheat temperature in step 1 in embodiment 2 and 2 is brought up to 180 DEG C, because now reaction temperature is very high, part PVP can decompose under the Fe simple substance catalysis generated, and produces the C atom that some are free, this atom can form FePtCB alloy with Pt together with Fe, prepares FePtCBFe ₃o ₄nanoparticle.Because reaction temperature improves, its shell crystal structure improves, and the carbon of stratum nucleare exists, and makes Pt easier to be free out from stratum nucleare, and FePtBFe prepared by embodiment 2 ₃o ₄particle is compared, and drug effect can be improved significantly, and such particle on average can reach 80% (Percent mortality) to the kill ratio of hepatoma carcinoma cell under same condition of culture, and does not originally have kill ratio to normal cell based.

Embodiment 26

Change the ginsenoside of the 0.2g added in the metal salt solution of step (1) in embodiment 6 into each seed amino acid (amac) (as glycine, alanine, cysteine, phenylalanine etc.), other condition is constant, prepares the FePtBFe-O (OH) that amino acid surface is modified _x(PVP-amac), there is the curative effect same with product in example 6.

Embodiment 27

The ginsenoside of the 0.2g added in the metal salt solution of step (1) in embodiment 6 is changed into various carboxylic multifunctional Organic substance (MFG) (as Fructus Vitis viniferae sodium carbonate, sodium citrate, sulfydryl dodecylic acid, lauric acid, maleic acid glycosides, Fructus Vitis viniferae carbonic acid, citric acid etc.), other condition is constant, prepares the FePtBFe-O (OH) of polyfunctional group finishing _x(PVP-MFG), there is the curative effect same with product in example 6.

Embodiment 28

Iron salt in embodiment 2 is changed into the nickel acetate (Ni (CH of 0.0283g ₃cOO) ₂4H ₂oMw=176.78; 0.16mmol), the Zr (NO of 0.034g ₃) ₄5H ₂o (Mw=429.39; 0.08mmol), the dibutyitin maleate (Mw=346.99 of 0.014g; 0.04mmol); Use KBH ₄replace NaBH ₄make reducing agent, and the temperature chamber b temperature of growth stage is brought up to 180 DEG C, remaining reaction condition is constant.Because now reaction temperature is very high, part PVP can decompose under the simple substance catalysis such as Ni, Sn of generating, produce the C atom that some are free, this atom can form NiPtC alloy with Pt together with Ni, Sn, Zr, prepares PtNiSnZrBC (Ni to the slurry product obtained in 120 DEG C of vacuum drying ovens after drying _1-x-ysn _xzr _y) O-K ₂o class nanoparticle.Carry out 3 anticancer contrast experiments's (normal cell and hepatoma carcinoma cell) with such nanoparticle to show: such particle on average also can reach 80% (high by 10% than Fe/Pt=11/1 in example 2) to the kill ratio of hepatoma carcinoma cell under same condition of culture, and to Normocellular kill ratio very little (about 3%).

Embodiment 29

Sm, Nd, Tb, be called first kind composition; (2) must containing, for example one or more in lower noble metal component: Au, Ag, Pt, Cu, Ru, Pd, Rh, Re, Os, Ir; Be called that Equations of The Second Kind composition (3) must containing, for example the composition of the three kinds or more in lower element in above-mentioned magnetic components or noble metal component, Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La, Na, Mg, Li, K, Ca.

Iron salt part in embodiment 2 is changed into the Lithium metaniobate (Mw=147.85 of 0.006g; 0.04mmol), the acetic acid terbium hydrate (Mw=354.07 of 0.014g; 0.04mmol), the ruthenium acetate (Mw=278.20 of 0.011g; 0.04mmol); 0.0056 hexachloro iridium acid sodium hexahydrate (Mw=559.01,0.01mmol) and 0.0028 ruthenium acetate (Mw=278.20,0.01mmol) replace part chloroplatinic acid; Use LiBH ₄replace the NaBH of same amount ₄make reducing agent, and the temperature chamber b temperature of growth stage is brought up to 150 DEG C, remaining reaction condition is constant.Because now reaction temperature is very high, part PVP can decompose under the simple substance catalysis such as Nb, Fe, Pt, Ir of generating, produce the C atom that some are free, this atom can form with Nb, Fe, Pt, Ir etc. the FePtBC alloy containing Nb, Ir, Ru, Tb, prepares (NbIrRuTb) FePtBC (NbIrRuTbFe) O to the slurry product obtained in 120 DEG C of vacuum drying ovens after drying _x-Li ₂o class nanoparticle.Carry out 5 anticancer contrast experiments's (normal cell and hepatoma carcinoma cell) with such nanoparticle to show: such particle on average also can reach 85% (high by 15% than Fe/Pt=11/1 in example 2) to the kill ratio of hepatoma carcinoma cell under same condition of culture, and to Normocellular kill ratio very little (about 7%).

Claims (10)

1. a multicomponent nanocomposite alloy compound particle cancer therapy drug, it is characterized in that, multicomponent nanocomposite alloy compound particle is primarily of metal and nonmetal composition, wherein (1) metal must at least containing, for example one or more in lower noble metal component: Au, Ag, Pt, Cu, Ru, Pd, Rh, Re, Os, Ir, be called first kind composition; (2) nonmetal one or more elements that must be at least in following nonmetalloid B, C, Si, O, S, Se, are called Equations of The Second Kind composition;

Or described metal also comprises one or more in following magnetic components: Fe, Co, Ni, Gd, Sm, Eu, Nd, Tb, be called the 3rd constituents;

Or one or more the composition also comprised in described metal in following element, Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La, Na, Mg, Li, K, Ca, be called the 4th constituents;

If multicomponent nanocomposite alloy compound particle cancer therapy drug only contains above-mentioned first kind composition and is called Equations of The Second Kind composition two constituents, then multicomponent nanocomposite alloy compound particle is nucleocapsid structure, and first kind composition noble metal belongs to stratum nucleare, and Equations of The Second Kind becomes to belong to shell; O is to be formed metal-oxide with described metal or to exist with the form of the hydroxyl OH of particle surface existence or carboxy CO OH, and S and Se mainly with metal formed sulfide or selenides form exist, B and Si forms alloy in a metal for doping, and C is with the allotrope of carbon or exists with the organic carbon form of surface-coated or the form that formed metal carbides with described metal exists.

If multicomponent nanocomposite alloy compound particle cancer therapy drug comprises first kind composition, Equations of The Second Kind composition, the 3rd constituents or comprises first kind composition, Equations of The Second Kind composition, the 3rd constituents, the 4th constituents, then multicomponent nanocomposite alloy compound particle is the form of alloy structure or hetero-junctions; The form of hetero-junctions is the nucleocapsid structure that part applies or applies completely; If the form of hetero-junctions, then first and the 3rd or/and four-component forms alloy or the heterogeneous inside stratum nucleare becoming the hetero-junctions of many components Nanoalloy compound particle; Equations of The Second Kind composition and the 3rd class or/and the 4th constituents compound is shell, its shell be monolayer or multilamellar; B and Si in Equations of The Second Kind composition is entrained in the first kind or/and in the alloy that forms of the 3rd constituents, and C is with the allotrope of carbon or exists with the organic carbon form of surface-coated or exist with the form being formed metal carbides with above-mentioned magnetic components or noble metal component; O exists with the form of the metal-oxide formed with metal in the first kind, the 3rd class or the 4th constituents or the hydroxyl OH existed with particle surface or carboxy CO OH, the form forming metal (M) and oxygen covalent bond (M-O) by O and metal at the preferred hydroxyl OH or carboxy CO OH of particle surface exists, and S and Se mainly with the first kind, the 3rd class or the 4th metalloid formed sulfide or selenides form exist.

2., according to the multicomponent nanocomposite alloy compound particle cancer therapy drug of claim 1, it is characterized in that, multicomponent nanocomposite alloy compound particle, is of a size of 0.2-80 nanometer.

3., according to the multicomponent nanocomposite alloy compound particle cancer therapy drug of claim 1, it is characterized in that, multicomponent nanocomposite alloy compound particle, is of a size of 0.5-20 nanometer.

4., according to the multicomponent nanocomposite alloy compound particle cancer therapy drug of claim 1, it is characterized in that, multicomponent nanocomposite alloy compound particle, is of a size of 1-6 nanometer.

5. the method for multicomponent nanocomposite alloy compound particle cancer therapy drug described in any one preparing claim 1, it is characterized in that, Y shape microfluid preparation facilities is adopted to be prepared, this device comprises two syringe pumps arranged side by side, a Y shape threeway blender reactor, three coil pipe preheaters, three temperature chambers, product receiving systems; Two syringe pumps arranged side by side are connected with the Liang Ge branch of the second coil pipe preheater (4) with Y shape threeway blender reactor respectively by the first coil pipe preheater (3), first coil pipe preheater and the second coil pipe preheater are arranged in temperature chamber a, 3rd branch of Y shape threeway blender reactor is connected with product receiving system by the 3rd coil pipe preheater (6), 3rd coil pipe preheater is arranged in temperature chamber b, product receiving system is arranged in temperature chamber c, and product receiving system is also provided with inert gas import and inert gas outlet;

Step one: by first kind component or first kind component and the 3rd class component or/and the 4th class component is dissolved in solvent the mixing salt solution obtaining macromolecule dispersing agent dispersion except the precursor of Na, Mg, Li, K, Ca, if containing C, then also add allotrope or the Organic substance material of carbon; Wherein solvent is N-Methyl pyrrolidone, dimethyl formamide, dimethyl sulfoxide, oxolane, dimethyl acetylamide or water; Organic substance material is the macromolecule organic or the biochemical reagents that are dissolved in above solvent;

Step 2: reducing agent is dissolved in N-Methyl pyrrolidone, dimethyl sulfoxide, dimethyl formamide, oxolane or dimethyl acetylamide, obtains reductant solution; The wherein corresponding 50ml solvent of every 0.03g-3g reducing agent; The consumption of general reducing agent is 1.5-2 times of slaine equivalent, if reducing agent is containing B, is the reducing agent containing B; If not containing B in product, adopt hydrazine hydrate;

Step 3: extract with syringe the reactant liquor that configured by step one and step 2 respectively and be placed in two syringe pumps (1) arranged side by side and (2) respectively, by the flow rate regulation of syringe pump be: 0.01ml/min ~ 20ml/min, flow through separately be immersed in temperature chamber a (8) coil pipe preheater preheats after uniform temperature, enter threeway blender hybrid concurrency raw reaction nucleation, then nucleation and growth process a period of time in the 3rd coil pipe preheater is entered, final reaction product enters into the product receiving system of the lower temperature of inertia protection, product is frozen in specific growth stage, obtain the solution of homodisperse extra small nano-particle, noble gas can be nitrogen, argon and carbon dioxide.

6. according to the method for claim 5, it is characterized in that, the metallic element in first kind composition is that the form of the presoma being adds in reactant liquor with slaine, generates simple substance atom, and form nanoparticle through nucleation and growth by reduction reaction; B in Equations of The Second Kind composition is added as reducing agent using the form of metallic boron hydrides, if there is Na, Mg, Li, K, Ca in the 4th constituents, then forms metallic boron hydrides with Na, Mg, Li, K, Ca in the 4th constituents; C adds with the form of the organic material of the allotrope of carbon or carbon, and after wherein the allotrope of carbon adds or form the allotrope of carbon, the organic material of carbon forms the organic material on top layer or forms alloy due to high-temperature heating and metal; S and Se has two kinds of modes to introduce, one is in reduction reaction, the part water mercaptan introduced or selenol are replaced, play the effect same with-OH in water, metal sulfide or selenides is formed in dry run, be by anion exchange reaction in addition, after reaction defines metal-oxide, then add sulphite or selenite and reducing agent reaction forms S ^2-or Se ^2-, the sulfide that can be formed with metal ion due to these aniones and selenides is more stable, more indissoluble, therefore can with oxygen anion generation displacement reaction, forms the more difficult stable and metal sulfide that is more easily distributed in water or selenides.

Metallic element in 3rd constituents adds in reactant liquor with the form of the presoma of slaine, by reduction reaction generate simple substance atom or having water and carry out under the condition of solvent autolysis aerobic precipitation formed metal-oxide, and through nucleation and growth form metal nanometer cluster form or be outer field many components nanoparticle with metal-oxide;

Under metallic element in 3rd constituents has the slaine of the first composition to exist in reactant liquor, and the metallic atom of the first component being reduced out forms metal alloy nanoparticles; When reacting under the condition having water and solvent autolysis aerobic, because the 3rd component slaine can precipitate generation hydroxide, this metal alloy nanoparticles surface can by the hydroxide of the 3rd class component generation or oxide be coated or part is overmolding to nucleocapsid structure;

Na, Mg, Li, K, Ca in 4th constituents add using metallic boron hydrides as the form of reducing agent, by selecting the content of wash conditions control Na, Mg, Li, K, Ca of product; Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La element in 4th class component adds with the form of soluble metallic salt.

7. according to the method for claim 5, it is characterized in that, extra small nano-particle is utilized jointly to build the multicomponent nanocomposite particle with heterojunction structure for seed and composition other material diverse, use such nanoparticle as seed, and the reduction dose construction adding needs in its solution form the nanoparticle seed-reducing agent of heterojunction structure needs; Build the solution of the raw material of the other component that heterojunction structure needs again as another kind of feed liquid; Use above-mentioned same reaction unit, repeat step 3, regulate reaction process parameter, obtain the multicomponent nanocomposite particle with heterojunction structure, the solution centrifugal of the nano-particle product obtained is separated, makes it settle down from mother solution, outwell supernatant, obtain precipitum, the cleaning mixture of volume same with supernatant (is joined in precipitum, sonic oscillation, centrifugal sedimentation; Repeatedly after 2-3 time, obtain the multicomponent nanocomposite particle slurry class precipitate of heterojunction structure, now the inner 3rd constituents metal of shell exists with the form of MOx, and top layer the 3rd constituents metal and oxygen are with M-O (OH) _xform exists; If dry for standby in the vacuum drying oven of 40-100 DEG C, now nanoparticle surface M-O (OH) _xa large amount of dehydration can be transformed into MO _xcomposition;

Or the slaine of first kind component is when being reduced, add the metal nanometer cluster be made up of the 3rd constituents, the initial nanoparticle that the metal nanometer cluster that 3rd constituents is formed can grow up in the metallic atom nucleation by first kind component carries out outer nanoparticle and merges epitaxial growth, form with first kind multicomponent metallic nanoparticle for stratum nucleare, the 3rd constituents metal is the core-shell nano of shell; If now have water in reaction solution and oxygen containing autolysis in system exists, it has the metal hydroxides be made up of the 3rd multicomponent metallic outside shell, the metal hydroxides that 3rd multicomponent metallic is formed further by dehydration in the process of drying, can form the outer metal-oxide be made up of the metal of the 3rd constituents.

8. according to the either method of claim 5-7, it is characterized in that, the element of the 4th constituents adds in two ways, to Na, Mg, Li, K, Ca with the form of metallic boron hydrides, reducing agent as reduction first, the 3rd constituents slaine adds, be reduced into atomic building alloy or compound and in nucleation, Na, Mg, Li, K, Ca become wrappage and enter into wherein at first and third metalloid salt, wash according to follow-up requirement; To having redox potential Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La metalloid lower than Na, Mg, Li, K, Ca metalloid ion, directly it is joined in the first kind and/or the 3rd metalloid saline solution with the form of soluble metallic salt.

9. according to the method for claim 5, it is characterized in that, not containing B in alloy particle, then reducing agent adopts other the reducing agent that can not contain B.

10. according to the method for claim 5, it is characterized in that, non-metal carbon element adopts during organic material has two kinds of forms to enter nanoparticle, one is when reaction temperature is very high, realize by regulating temperature, partial organic substances is decomposed and has produced simple substance carbon or carbon radicals, such active carbon can form metal-carbon alloy with metal, thus enters into metal alloy in alloying element mode; Major part is still present in organic skeleton carbochain in addition, is coated on outside particle with the form of surface stabilizer; When reaction temperature is low, when Organic substance can not decompose, then to be coated on particle skin.