CN105396149B - A kind of Nanoalloy anticancer drug and preparation method thereof with autonomous targeting and imaging function - Google Patents

Abstract

A kind of Nanoalloy anticancer drug and preparation method thereof with autonomous targeting and imaging function, belongs to anticancer drug technical field.Mainly by metal, metallic compound and it is nonmetallic form, wherein metal at least contain following noble metal component in one kind：Au, Ag, Pt, Cu, Ru, Pd, Rh, Re, Os, Ir, referred to as the first constituents；Nonmetallic one kind being at least in following nonmetalloid B, C, Si, O, S, Se, referred to as the second constituents；O is deposited by metal oxide or in the form of the hydroxyl OH of particle surface or carboxy CO OH, and S and Se mainly exist in the form of being constituted sulfide or selenides with metal, B and Si is that doping constitutes alloy in a metal, and C is to exist by the allotrope of carbon or in the form of the organic carbon that surface coats or exist in the form of being constituted metal carbides with the metal.

Description

A kind of Nanoalloy anticancer drug and its preparation with autonomous targeting and imaging function Method

Technical field

The invention belongs to Nano medication preparation and its application fields in biomedical engineering, and in particular to preparation has A kind of method and these particles pair of the amorphous state to metal alloy-metallic compound hetero nano structure particle of crystalline state phase structure The treatment of mid and late liver cancer, lung cancer, lymph cancer, breast cancer, blood class cancer, belongs to anticancer drug technical field.

Background technology

Due to the aggravation of environmental pollution and the variation of dietary structure, in the past few decades, the mankind suffer from the several of various cancers Rate is more and more high.Such as the pollution due to air, nearly 5 years in China using Beijing-tianjin-hebei Region, Yangtze River Delta Area as the haze of representative So that the illness rate of the lung cancer in these areas is increased with 10% or more annual growth；And due to regional industry discharge in water body The pollution to local water body of heavy metal or carcinogenic compound etc. causes many cancer villages altogether in sewage, is happened at rice The pollution of exceeded cadmium metal in the cereal crops such as rice is that the potential of human liver cancer, osteocarcinoma, lymph cancer and blood class cancer causes a disease It is former.To the treatment in middle early-stage cancer, it can use intervene while operation and drug therapy at present, certain cancers can be treated Disease, but once shift, it is just very difficult to cure, to the cancer in late period, even if very difficult if operation and anti-cancer herb medicine To cure, often patient will be dead in half a year or several years.Therefore, other than increasing environment protection, Devoting Major Efforts To Developing anticancer Drug is also necessary.Since being found along platinum-containing anticancer drug, people have put into largely in the exploitation of anticancer drug Human and material resources and financial resources have developed many anticancer drugs, Pexa-Vec such as medicable to liver cancer, medicable to lung cancer S-1/ cis-platinums and docetaxel/cisplatin medicine, to the medicable Trastuzumab of breast cancer (HER-2), CIK medicable to lymthoma Biological immune treatment, Trastuzumab/carboplatin medicable to cervical carcinoma and squamous carcinoma be used in conjunction drug, to metastatic colorectal carcinoma treatment and The drug oxaliplatin of colon cancer auxiliary treatment and breast cancer, colon are successfully developed to the medical expert of United States army forces Cancer, prostate cancer, lung cancer etc. have " E-75 " super anticarcinogen of inhibition.However, these drugs are very expensive, often need It takes for a long time, once it deactivates, cancer cell meeting mass propagation and diffusion again, while cancer cell can also other than diffusion in use Variation, often starts effective drug, is asked using just without too big effect, that is, often resulting in cancer after one section and drug resistance occur Topic；Even if the super anticarcinogen of these anticancer drugs " E-75 " cannot all treat cancers all at present simultaneously.Therefore, exploitation has Drug that is permanently effective, not causing cancer cell change exclusive or directly to be eradicated is target of the mankind to treatment of cancer.

In order to develop more medicable anticancer, metabolism of the scientist to the Carcinogenesis Mechanism and cancer cell of normal cell Mechanism and relevant gene therapy have carried out numerous studies.Researcher it is known that cancer cell needs to consume a large amount of glucose, As the energy for supporting improper fast-growth and division, do not know how cancer cell obtains required energy but.Further grind Study carefully display, cancer cell obtains energy in a manner of cell autophagy to accelerate.Cell autophagy is a kind of important defence of body and protection mechanism, It is that the protein and organelle of impaired, denaturation or aging are transported to lysosome, then digests the process of degradation.Shiva is big Einstein medical college developer molecule biology professor Anna Ku Aiwo is learned to think：" lysosome is not only dustbin, more like small Type recycle bin.There, cell debris is transformed into energy.Cancer cell seems to know how to optimize this process, needed for acquisition Energy ".Scientists also find in more than 40 kinds of human lungs, mammary gland and liver tumor cells, the autophagy of molecular chaperones guiding Level is higher than normal condition, and this type autophagy of tumour surrounding normal tissue is in horizontal normal.Therefore change gene, resistance This disconnected recycling process, it is dead that cancer cell stops division immediately.Scientist is as a result small also this approach application in mouse The notable atrophy of tumour of mouse almost stops transfer.Researcher thinks, selectively cancer cell molecular chaperones is blocked to mediate Autophagy be likely to become reduce tumour, prevent cancer metastasis " available strategy ".In studying from now on, it is intended that exploitation medicine Object, to realize effect that operator is reached；How we uses genetically manipulated means to treat different type if continuing to explore simultaneously Lung cancer.To develop more effective anticancer drug, people are also from the immune function side of organism (such as normal cell or cancer cell) It is studied in face.Such as to " working method " of anticancer drug " E-75 " studies have shown that " E-75 " can be successfully in people's body A distinctive immune system is inside established, this system, which can search, distinguishes and confirm, is presented on multiple types cancer cell table The protein in face is immunized to corresponding.But and not all tumour is all the cell by secreting this protein molecule Composition, this be also why the main cause that anticancer drug " E-75 " cannot treat current all cancer types.In addition, some cancers are thin Born of the same parents have the function of " cheating " immune system, so that when immune system distinguishes, can these cancer cells be mistakenly considered people A part for body.Therefore, it is necessary to which immune system is enable " to expose " " camouflage mask " of these cancer cells.However, how to help " the camouflage mask " that the immune system of normal cell " exposes " these cancer cells is extremely difficult, at present also can only be from gene therapy side It is studied in face.It is not difficult to find out, proposes that the path of exploitation drug has finally all turned to gene treatment after these scientists further investigation Method.But gene therapy itself varies with each individual, and needs individually to carry out a large amount of basic research to patient, can just develop to be directed to and be somebody's turn to do The gene of patient is intervened, expensive, the lead time is very long, the patient in middle and advanced stage be often it is equal less than.It is practical On, research is early to have shown that a most apparent difference for cancer cell and normal cell is exactly, and cancer cell is ceaselessly to carry out constantly The cell grown up is divided, and the division of normal cell is controllable, can need to terminate automatically according to organism.Therefore, cancer The growth of cell is inevitable and normal cell is competed on energy and nutrition (especially protein and carbohydrate etc.), and cancer cell Due to the activity of itself, necessarily than normal cell to competitive on energy and nutrition, while cancer cell cannot exercise normally carefully The physiological function of born of the same parents, when big energy and nutrition are consumed and self is grown up by cancer cell, the activity space of normal cell, nutrition and Energy cannot with when the needing of carry out normal physiological activity of upper machine body or tissue, normal body or tissue will atrophy with To death, the end of life is finally resulted in.We to these analysis of research achievements it can be found that they to have said research already anti- The most simple and direct path of cancer drug exactly blocks cancer cell to obtain the chance of the protein of energy or needs.Recently, American Studies people Member is, it was also found that growth of cancer cells energy is originated from the process that body recycles protein.Mouse experiment is shown, blocks this mistake Journey, tumour start atrophy, and cancer cell almost no longer shifts.Therefore：Exploitation cancer curing medicine key is how the medicine selectively presses down Cancer cell processed recycles protein.

Biochemical basic principle teaches that the source of energy is mainly the adenosine that can be stored by carbohydrate synthesis Class (such as ATP) directly conveys the oxygen that comes by carbohydrate oxidase by activated red blood cells, by glycoxidative acquisition, carbohydrate it is main Feature is polyhydroxy hydrocarbon (such as glucose is by every there are one the six carbon hydrocarbon that hydroxyl is constituted on carbon).Vital signs is mainly by its egg White matter expression, and cell is required to synthesis or oxidizing ferment to the synthesis of adenosine class, the oxidation of carbohydrate and the synthesis of protein Participation, cancer cell is no exception, and many enzymes itself in life entity be exactly be made of protein.It is known that protein It is the first sulphur ammonia containing valence link unsaturation element sulphur in the essential amino acid of synthesis human protein by Amino acid profile Sour (Met) and the selenium amino acid containing valence link unsaturation selenium element.We are also, it is understood that the synthesis of protein is controlled by DNA or RNA System, and contain phosphate radical in the skeleton of DNA or RNA.Therefore, we can develop while can be with sulphur, selenium or phosphate radical The drug of coordination is sent in the organism environment of canceration, due to cancer cell to energy and nutrition to seize dynamics ratio normally thin Born of the same parents are much larger, and by the control of dosage, in the incipient stage, these nutrition are absorbed by cancer cell substantially, when its schizogamy When, due to the denaturation (variation of the ligancy of the sulphur of such as amino acid or selenium variation and phosphate radical valence state) of amino acid and phosphate radical, It cannot normally synthesize various DNA, RNA, can not synthesize the normal protein of cancer cell itself needs, function cannot be just Often expression, while the energy that its breeding needs also can not be obtained normally, thus can directly cut off a large amount of of cancer cell needs Energy and nutrition eventually lead to the death of cancer cell, are saturated since these drugs are coordinated by the biomolecule of a large amount of cancer cells, It cannot be utilized by normal cell, also normal cell would not be caused effectively to poison, after metabolism, be drained System excretes.If coordinating a kind of differentiation-inducing agents again at this time, it will be able to make a large amount of Carcinoma cell differentiations at normal cell, control The development and diffusion of cancer processed.

In addition, the effect of in order to improve drug, people are developing all kinds of targeted anticancer medicines.Such targeted drug at present Exploitation be based substantially on the antibody-antigene of biomolecular science to the principle recognized each other, as by studying cancer cell and normal cell Cell membrane surface different antigen or antibody, synthesis have the antibody of identification function to the antigen or antibody of cancer cell surfaces or resist Then itself and drug are supported on carrier by original simultaneously, the drug can be automatically found cancer cell by body fluid circulatory in this way, Drug is supplied into cancer cell, and is killed, such as Mylotarg, is first drug-by FDA approvals for oncotherapy Antibody coupling matter, it is the conjugate of antitumor antibiotics Calicheamicin and anti-CD 33 monoclonal antibody, can be used for treating recurrence Acute myeloid leukaemia, as " bullet " drug, Calicheamicin has tumour cell strong lethal effect.However, this A research very time-consuming and cost gold found different from distinct antibodies-antigen pair of normal cell, while some cancer cells Difference with the antibody-antigene pair of normal cell is very small, it is difficult to distinguish, therefore, it is very easy to by a large amount of normal cells It kills, toxic side effect is very big.Therefore, pass through the research of the physiological activity feature to normal cell and cancer cell metabolism itself Development has autonomous target function (such as introduction by magnetic field guides) and can be by common medical procedure (such as Magnetic resonance imaging Or infrared imaging) tracer drug it is extremely important.

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

Invention content

Above Research Thinking and to anticancer drug requirement guidance under, since 2003, inventor pass through more than ten Year research and constantly bring forth new ideas, develop the Nanoalloy anticancer drug with following ingredient and structure, and it is micro- to have invented program The prepare with scale technology of fluid produces such drug.The patent is that " a kind of extra small nucleocapsid is received in our patent of invention Rice grain and preparation method thereof, application number：201310446082.8；The applying date：Further innovation on September 26th, 2013 " And expansion.

Such multicomponent heterogeneous structural nano alloy particle is characterized in that：The compound grain of multicomponent heterogeneous structural nano alloy Son mainly by metal and it is nonmetallic form, wherein (1) metal must at least contain following noble metal component in one kind or one kind More than：Au, Ag, Pt, Cu, Ru, Pd, Rh, Re, Os, Ir, Eu, referred to as the first constituents；(2) nonmetallic to be at least below One or more kinds of elements in nonmetalloid B, C, Si, O, S, Se, referred to as the second constituents.

If containing only above-mentioned two constituents, multicomponent nanocomposite alloy compound particle is preferably nucleocapsid, the first kind at Noble metal is divided to belong to stratum nucleare, the second constituents belong to shell；O is to be constituted metal oxide with the metal or with particle table The form of hydroxyl OH or carboxy CO OH existing for face are present in, and pass through O and gold in particle surface preferred hydroxyl OH or carboxy CO OH Belong to the form for constituting metal (M) and oxygen covalent bond (M-O) to exist, and S and Se with metal mainly to be constituted sulfide or selenides Form exist, B and Si are that doping constitutes alloy in a metal, and C is with the allotrope of carbon (graphene (Gp), carbon nanometer Manage (CNT) or vitreous carbon (GC)) or with organic carbon (such as polyvinylpyrrolidone, ginsenoside, vitamin C, the horse of surface coating Carry out acid anhydrides etc.) form exists or the form presence with metal composition metal carbides.

It is preferred that：Metal described in multicomponent nanocomposite alloy compound particle further includes one kind or several in following magnetic components Kind：Fe, Co, Ni, Gd, Sm, Eu, Nd, Tb, referred to as third constituents；

Further include one or more kinds of ingredients in following element in the further preferably described metal, Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La, Na, Mg, Li, K, Ca, referred to as the 4th constituents.Element in 4th constituents is from figure Alloy or metal are formed at alloy, or with one or more of the element of third constituents, the second constituents, the first constituents Compound, such as FeZn, MnBSn, FeBZn, CoAl；MnO、SnO₂、TiO₂、SnSe、MnS、ZnS、ZnSe、FeS、CoSe、ZrSe₂、 CeO₂；Fe_(1-x)Zn_xO、Co_(1-x)Al_xO、FeAl₂O₄、Fe_(1-x)Zn_xS、Fe_(1-x)Zn_xSe、Fe_(1-x)Sn_xSe etc..

Including the first constituents, the second constituents, the multicomponent nanocomposite alloy compound particle of third constituents and including The element of the first species, the second constituents, third constituents, the 4th constituents multicomponent nanocomposite alloy compound particle be alloy structure or The form of heterojunction structure.The form of heterojunction structure is the nucleocapsid that part coats or coats completely.If the form of hetero-junctions Then preferably first and the alloy that constitutes of third or/and the 4th ingredient or the heterogeneous inside for becoming multigroup part of Nanoalloy compound particle Stratum nucleare (such as FePt@AuZn or AuZn@FePt), the second constituents and third class or/and the 4th constituents compound are shell, shell To be single layer or multilayer, (such as Fe_(1-x)Zn_xSe), the representative configurations of constituent particle are FePt@AuZn@Fe_(1-x)Zn_xSe or AuZn@FePt@Fe_(1-x)Zn_xSe etc..

B and Si in second constituents therein are to be entrained in the alloy of the first kind or/and third constituents composition, C It is the organic carbon the allotrope of carbon (graphene (Gp), carbon nanotube (CNT) or vitreous carbon (GC)) or be coated with surface (such as polyvinylpyrrolidone, ginsenoside, vitamin C, maleic anhydride) form exist or with above-mentioned magnetic components or The form that noble metal component constitutes metal carbides exists；O is to be constituted with metal in the first kind, third class or the 4th constituents Metal oxide or in the form of hydroxyl OH existing for particle surface or carboxy CO OH exist, in the preferred hydroxyl OH of particle surface Or carboxy CO OH is made up of the form presence of metal (M) and oxygen covalent bond (M-O) O and metal, and S and Se are mainly with first Class, third class or the 4th metalloid constitute sulfide or the form of selenides exists.

The crystal structure of alloy or compound that above-mentioned each component element is constituted can be amorphous or amorphous state and portion It is the mixing of point crystalline state or being fully crystallized state.

Multicomponent nanocomposite alloy compound particle, size is at 0.2-80 nanometers, and curative effect is relatively good at 0.5-50 nanometers, more preferably At 0.5-20 nanometers, it is best at 1-10 nanometers.Such as CoBPt, FeBPtC, FeSnPtB, Au@of the size at 2-6 nanometers CoFeB、Au@CoFeB@CoFeOOH、Ag@CoFeB、FePt@FeOx、AuAg@FeZn、FeCoAl@Ag@Gp、CoSm@Pt-CNT、 FePt@AgAu-Gp、FePtB@Fe₃O₄、Ag@Pt@CoFeB-Gp、AuPt@CoFeB-Gp。

The preparation method of the present invention, which is characterized in that prepared using Y shape microfluid preparation facilities, which includes Two syringe pumps arranged side by side, a Y shape threeway mixer reactor, three coil pipe preheaters, three thermostats, a product connect Receiving apparatus；Two syringe pumps arranged side by side pass through the first coil pipe preheater (3) and the second coil pipe preheater (4) and Y shape threeway respectively The Liang Ge branches of mixer reactor connect, and the first coil pipe preheater and the second coil pipe preheater are located in thermostat a, Y shape three The third branch of logical mixer reactor is connect by third coil pipe preheater (6) with product reception device, and third coil pipe is pre- Hot device is located in thermostat b, and product reception device is located in thermostat c, product reception device be additionally provided with inert gas import and Inert gas outlet；

Metallic element in first constituents is added in reaction solution in the form of the presoma that metal salt is, by also Original reaction generates simple substance atom, and constitutes nano-particle through being nucleated and growing up；For the B in the second constituents with metal hydroboration The form of object, which is added, is used as reducing agent, if there are Na, Mg in Na, Mg, Li, K, Ca, with the 4th constituents in the 4th constituents, Li, K, Ca form metallic boron hydrides；C is with allotrope (graphene (Gp), carbon nanotube (CNT) or the vitreous carbon of carbon (GC)) or the form of the organic material of carbon (such as polyvinylpyrrolidone, ginsenoside, vitamin C, maleic anhydride) is added , after wherein the allotrope (graphene (Gp), carbon nanotube (CNT) or vitreous carbon (GC)) of carbon is added or form carbon The organic material of allotrope, carbon forms the organic material on surface layer or since high-temperature heating and metal form alloy；

S and Se is introduced there are two types of mode, one is in reduction reaction, by the part water mercaptan of introducing or selenol generation Replace, play effect same with-OH in water, form metal sulfide or selenides in the drying process, be in addition by the moon from Sub- exchange reaction adds sulphite or selenite and reducing agent reacts to be formed after reaction forms metal oxide S^2-Or Se^2-, the sulfide that can be formed with metal ion due to these anion and selenides is more stable, more indissoluble is (smaller Solubility product constant), therefore displacement reaction can occur with oxygen anion, formation is more difficult to stablize and is more easy to be distributed to the metal in water Sulfide or selenides.

Metallic element in third constituents is added in reaction solution in the form of the presoma of metal salt, and reduction is passed through Reaction, which generates simple substance atom or carries out precipitation reaction under conditions of having water and solvent autolysis is aerobic, forms metal oxide, And constitute metal nanometer cluster composition or using metal oxide as multigroup part of nano-particle of outer layer through being nucleated and growing up.Third class Metallic element in ingredient, can be with the first component for being reduced out in reaction solution in the presence of the metal salt of first composition Metallic atom constitute metal alloy nanoparticles, when being reacted under conditions of having water and solvent autolysis is aerobic, due to the Three component metal salts can precipitate generation hydroxide, what which can be generated by third class component Hydroxide or oxide cladding or part are overmolding to nucleocapsid；

Na, Mg, Li, K, Ca in 4th constituents using metallic boron hydrides as reducing agent in the form of be added, pass through choosing Select the content of wash conditions (such as solvent and washing times) control Na, Mg, Li, K, Ca of product；Zr in 4th class component, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La element are added in the form of soluble metallic salt；

It is (usual that the metal nanometer cluster being made of third constituents is added when being reduced in the metal salt of first kind component Less than 5 nanometers), the metal nanometer cluster that third constituents are constituted can grow up to first in the metallic atom nucleation by first kind component Beginning nano-particle (usually less than 5nm) carries out outer nano-particle and merges epitaxial growth, constitutes with first kind multicomponent metallic nanoparticle Son is stratum nucleare, and third constituents metal is the core-shell nano of shell；Contain if had in reaction solution in water and system at this time With the presence of the oxygen of autolysis, the metal hydroxides being made of third multicomponent metallic is had outside shell, the third ingredient The metal hydroxides that metal is constituted can form gold of the outer layer by third constituents in further drying process by dehydration Belong to the metal oxide constituted.

The element of 4th constituents is to be added in two ways, can be with metallic boron hydrides to Na, Mg, Li, K, Ca etc. Form, be added as reduction first, the reducing agent of third constituents metal salt, atom be reduced into the first and third metalloid salt It constitutes Na, Mg, Li, K, Ca in alloy or compound and nucleation to enter wherein as wrappage, according to subsequent It is required that washed, such as need such Na, Mg, Li, K, Ca tenor high, using to such Na, Mg, Li, K, Ca metal from The low washing lotion of sub- solubility (such as alcohols) or washing times reduce and (on 3 times such as common, carry out 1-2 washing), adjust washing Condition makes part continue to remain in the nano-particle to be formed；Such as need removal clean, if using to the Na, Mg, Li, K, There is Ca metalloid ions the solvent (such as water) of highly dissoluble repeatedly to be washed, so that it may have the low content constituents to obtain Nano-particle.To with redox potential ratio Na, Mg, Li, K, Ca metalloid ion it is low as Zr, Nb, Mo, Mn, Zn, Its soluble metallic salt directly can be added to the first kind and/or third metalloid salt is molten by Ti, Sn, Al, Ce, La metalloid In liquid, forms alloy with major metal in nano-particle forming process or form compound with nonmetallic oxygen group elements；

In second constituents, element B essentially from reducing agent metallic boron hydrides, reducing agent decomposition play to metal from It while sub- reduction, has pure boron or boron oxide and generates, pure boron can be added in the form of alloying element to be formed In metal alloy；S and Se is introduced there are two types of mode, one is in reduction reaction, by the part water mercaptan or selenol of introducing Instead of playing effect same with-OH in water, forming metal sulfide or selenides in the drying process, be in addition to pass through the moon Ion-exchange reactions adds sulphite or selenite and reducing agent reaction shape after reaction forms metal oxide At S^2-Or Se^2-, the sulfide that can be formed with metal ion due to these anion and selenides is more stable, more indissoluble (smaller Solubility product constant), therefore displacement reaction can occur with oxygen anion, be formed and more stable, indissoluble but be more easy to be distributed in water Metal sulfide or selenides.

In the present invention in alloy particle when that need not contain B, then reducing agent cannot contain the reduction of B using others Agent, such as hydrazine hydrate.

If such nanoparticle surface contains polyhydroxy or other specific functional groups (organic material existing for the form of C) Such as glycine, alanine, cysteine, phenylalanine amino acid, grape sodium carbonate, sodium citrate, sulfydryl dodecanoic acid, the moon Cinnamic acid etc.) compound (such as ginsenoside, anthocyanidin, beet soda acid, vitamin C, the vitamin B12 compatible with organism Deng), you can to improve its biocompatibility and body fluid stability, and there is protective effect to normal cell, and has to cancer cell hidden Body can enter inside cancer cell, and destroying its nucleus makes its apoptosis, or guide its interior inhereditary material (such as DNA, RNA) It revert to the duplication production function to biomolecule such as protein of normal cell.

The other medicines ratio developed at present, such multicomponent nanocomposite complex anticancer drug of invention is with following excellent Point：(1) ferromagnetism ingredient can use the magnetic resonance imaging method employing of medicine to pharmaceutical indications in such drug, while such medicine Object to liver, spleen, lung, marrow etc. have autonomous target function, can also under induced by magnetic field can to other body parts (as breast Gland, rectum) cancer cell carry out targeted therapy；(2) noble metal component in drug (such as Au, Ag, Pt, Cu, Ru, Pd, Rh, Re, Os, Ir) there is optical effect, the method and X-ray tomoscan of visible light wave range laser to infrared light tracer can be passed through Means (PET-CT) etc. to pharmaceutical indications；(3) the third constituents contained can be as the carrier of the first and second constituents It (such as graphene and carbon nanotube) or forms compound with magnetic or/and noble metal component (such as iron and oxygen is in nano grain surface Form iron oxide, manganese and oxygen and form manganese oxide in nano grain surface) or alloy (such as boron and iron formation iron boron non-crystaline amorphous metal, silicon Gold silicon non-crystaline amorphous metal is formed with gold) or itself formation oxide (such as titanium and oxygen formation titanium oxide, aluminium and oxygen formation aluminium oxide, zinc Zinc selenide is formed with zinc oxide, zinc and selenium is formed) Nanoalloy or complex are constructed, it plays and stablizes magnetic and noble metal component simultaneously Its biocompatibility is improved, the oxide especially formed may be constructed surface layer polyhydroxy base, make its rejection work(to organism There can be stealthy effect, reduce organism to its rejection, improve the persistence of its curative effect and drug effect；(4) due on cell membrane Normal transport of substances channel size (such as aquaporin, ion channel, protein channel) is substantially at 80 nanometers hereinafter, much 50 Nanometer or less.Therefore, the aerodynamic particle size of the Nano medication of preparation must at 80 nanometers hereinafter, it is preferable to 50 nanometers with Under, more excellent grain size is at 20 nanometers hereinafter, passing in and out the degree of freedom of cell, root in order not to block cell aquaporin, improve it According to Hydrodynamics Theory, aerodynamic size should be less than the one third of channel internal diameter, its aerodynamic size is preferably 10 in this way Nanometer or less；(6) in order to improve its Stealth and curative effect, such particle often coat one layer it is good with organic compatability Macromolecule or organic matter (such as polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, citric acid, maleic anhydride, vitamin C, dimension Raw element B12, various amino acid, grape sodium carbonate, sodium citrate, sulfydryl dodecanoic acid, lauric acid, ginsenoside, ginkgoic acid, silver Flavone, ginkgol, tea polyphenols, anthocyanidin oligomer (Proantho Cyanidins), beet soda acid (SB12), or directly by Polyhydroxy decorative layer (Fe-O (OH) is constituted in the oxidation effect of surface-element_x、Au-O(OH)_x), general 0.2~3 nanometer of the layer, Although the layer improves its aerodynamic size, but the biocompatibility that can improve drug entirety and the dispersibility in body fluid, but Preferably still make the overall dimensions of multicomponent nanocomposite complex particles be maintained at 10 nanometers hereinafter, it is optimal at 5 nanometers hereinafter, curative effect It is best.

For the above multicomponent nanocomposite alloy complex of prepare with scale, ultra micro hybrid particle work is prepared in microfluid On the basis of skill, the present invention will be coupling in emulative reduction reaction nucleation and precipitation reaction in multi-step sequence microfluid Method prepares the above multicomponent heterogeneous structural nano complex.All chemicals are all the pure above purity of chemistry or market purchase Buy direct use.Entire reaction carries out under the protection of nitrogen, carbon dioxide or argon gas atmosphere.

Fig. 1 is the program miniflow volume primitive process composition schematic diagram of the multi-step sequence microfluidic methods.

Main processes include using syringe pump (1) and (2), the prepared all kinds of reaction solutions of transport (such as reducing agent/ Stabiliser solution and metal salt solution) it is heated to the preheating fluid channel (3) heated respectively through thermostat a (8) and (4) are interior Temperature before the hybrid reaction of setting；Then into reaction in Y types mixing reactor (5)；Later, it enters by thermostat b (9) It controls and carries out moment nucleation and controllable growth specific time in the fluid channel (6) of temperature；Enter finally by thermostat c temperature controls and Growing up for particle is terminated in the product collector of inert gas shielding, and collects product.The temperature of thermostat a and b can control At 25 DEG C to 200 DEG C；The temperature of thermostat c (10) can be by refrigeration machine or dry ice control at -40 DEG C to 15 DEG C.

The program miniflow volume primitive process includes following steps.

Step 1：First kind component and third class component or/and the 4th class component are removed to the precursor of Na, Mg, Li, K, Ca Be dissolved in obtained in solvent (organic solvent or ultra-pure water) macromolecule dispersing agent dispersion mixing salt solution be additionally added if containing C The allotrope or organic material of carbon；Wherein solvent be N-Methyl pyrrolidone, dimethylformamide, dimethyl sulfoxide (DMSO), Tetrahydrofuran, dimethylacetylamide or water；Organic material is the macromolecule organic or biochemical reagents for being dissolved in the above solvent, such as Polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, citric acid, maleic anhydride, vitamin C, vitamin B12, amino acid, Portugal Grape sodium carbonate, sodium citrate, sulfydryl dodecanoic acid, lauric acid, ginsenoside, ginkgoic acid, GINKGO BILOBA EXTRACT, ginkgol, tea polyphenols, 6- sulfydryl 1- ethyl alcohol, anthocyanidin oligomer (Proantho Cyanidins), beet soda acid etc..Organic material and metal salt with The ratio of solvent is：Mole/solvent volume of organic material quality/metal salt or its compound be (0.05~4.0g)/ 0.5~15mmol)/50ml.

Step 2：Dissolve reduce agent in N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), dimethylformamide, tetrahydrofuran or Dimethylacetylamide obtains reducing agent solution；Wherein 50ml solvents are corresponded to per 0.03g-3g reducing agents；The dosage of general reducing agent It it is 1.5-2 times of metal salt equivalent, reducing agent is the reducing agent containing B if containing B, and reducing agent can be solid NaBH₄、 KBH₄、LiBH₄、Ca(BH₄)₂、Zn(BH₄)₂Or Al (BH₄)₃, can also be Li [B (C₂H₅)₃H] tetrahydrofuran solution；If product In without containing B then use the reducing agents such as hydrazine hydrate.

Step 3：It extracts the reaction solution configured by step 1 and step 2 respectively with syringe and is respectively placed in two simultaneously In the syringe pump (1) of row and (2), the flow velocity of syringe pump is adjusted to：0.01ml/min~20ml/min respectively flows through leaching Enter after being preheating to certain temperature (40-200 DEG C) to the coil pipe preheater (3) of thermostat a (8) and (4), into the threeway in Fig. 1 Mixer hybrid concurrency life reaction nucleation, for a period of time subsequently into nucleation and growth process in third coil pipe preheater, final reaction production Object enters in the product reception device (controlling temperature by thermostat c (10)) of the lower temperature of inertia protection, and product is frozen Knot obtains the solution of evenly dispersed extra small nano particle in specific growth phase；Inert gas can be nitrogen, argon gas and Carbon dioxide gas.

In the preparation method step of the present invention, following methods can also be used directly to prepare with metal alloy core and metallization Close the core-shell nano that object is shell.By controlling the type of two or more metal salt (as electrochemical potential differs greatly The metal salt of two kinds of metals, such as FeCl₂And H₂PtCl₆) and concentration difference and reducing agent dosage, obtain nucleocapsid (such as FeCl₂Amount Much larger than H₂PtCl₆Amount, FeCl₂/H₂PtCl₆>Or part nucleocapsid (FeCl 4)₂/H₂PtCl₆<4) nano-particle；Wherein Na, K, Ca, Li et al. metallic element are added in step 2, in nano-particle fast nucleation growth process in step 3 It is too late to be diffused into solution, and be introduced directly into nano-particle with dopant；

Using extra small nano particle be seed and the entirely different other materials of ingredient jointly structure with heterojunction structure Using such nano-particle as seed, and the reduction dose construction shape of needs is added in its solution in multicomponent nanocomposite particle Nano-particle seed-the reducing agent needed at heterojunction structure；The solution of the raw material of the other component of heterojunction structure needs is built again As another feed liquid；Using above-mentioned same reaction unit, step 3 is repeated, adjusts reaction process parameter, is obtained with different The solution of obtained nano-particle product is centrifuged, it is made to be settled from mother solution by the multicomponent nanocomposite particle of matter structure Get off, outwell supernatant, obtain sediment, the cleaning solution of volume same as supernatant (is added in sediment, ultrasound is shaken It swings, centrifugal sedimentation；Repeatedly after 2-3 times, the multicomponent nanocomposite particle slurry class sediment of heterojunction structure is obtained, at this time inside shell Third constituents metal exists in the form of MOx, and surface layer third constituents metal and oxygen are with M-O (OH)_xForm exists.If It is dried for standby in 40-100 DEG C of vacuum drying oven, at this time nanoparticle surface M-O (OH)_xLargely dehydration it can be transformed into MO_xIngredient.

The metal nanometer cluster being made of third constituents, third is added when being reduced in the metal salt of first kind component The initial nano-particle that the metal nanometer cluster that constituents are constituted can grow up in the metallic atom nucleation by first kind component carries out Outer nano-particle merges epitaxial growth, constitutes using first kind multicomponent metallic nano-particle as stratum nucleare, and third constituents metal is shell The core-shell nano of layer；If at this time with the presence of the oxygen containing autolysis in water and system in reaction solution, in shell The metal hydroxides being made of third multicomponent metallic is had outside, the metal hydroxides that further the third multicomponent metallic is constituted The metal oxide that outer layer is made of the metal of third constituents can be formed during drying by dehydration；

And nonmetallic carbon enters nano-particle there are two types of form when using organic material, one is when reaction temperature very When high (generally higher than 120 DEG C), realized by adjusting temperature, making, which has partial organic substances to decompose, generates simple substance carbon or carbon radicals, The carbon vivaciously can form metal-carbon alloy (such as Fe very with metal₃C), to enter metal alloy in a manner of alloying element In；In addition most of there are still in the skeleton carbochain of organic matter, it is coated on outside particle in the form of surface stabilizer.When reaction temperature Spend it is low, when organic matter cannot decompose, then to be coated on particle outer layer.

The multicomponent nanocomposite particle slurry of the clean undried heterojunction structure of acquisition is re-dissolved into the life prepared It manages in brine nutrient solution, after ultraviolet disinfection, so that it may survey its poison to each quasi-cancer cell to be tested by vitro cytotoxicity Property；And then be implanted in the laboratory mice or white rabbit body of all kinds of cancer cells by being injected intravenously into kind, it is thin to all kinds of cancers to survey it The therapeutic effect of born of the same parents.

The nano-particle of the present invention can be continuing with the carbon Asia two used in granted patent (ZL 200910085973.9) Amine (EDC) coupled reaction is to its surface modification and functionalization, first using with carboxyl-functional in the preparation of above-mentioned nano-particle Organic material (such as sulfydryl dodecanoic acid of group's ingredient：12-MUA；Gluconic acid, citric acid, maleic acid glycosides etc.), surface is repaiied It is decorated with the surface organic matter material activation with carboxyl functional group and passes through patent after the activation of such nano-particle The special medicaments or insighted to certain disease that reaction (2) and (3) in ZL200910085973.9 need in the coupling of its surface The organic or biomolecule of other function.Specifically, EDC first and carboxyl react to be formed a urea ester reactive intermediate (reaction 1, see Attached drawing 15)；The reactive intermediate reacts to form amido bond by the life with a primary amine group in added biomolecule quickly Object molecule and nano particle coupling (reaction 2, see attached drawing 15).A kind of nanometer of surface modification and functionalization is thus prepared Drug.

The nano-particle for having amido for surface modification passes through the similar reaction in patent ZL 200910085973.9 (4), the extraordinary medicine needed in the coupling of its surface using disuccinimidyl suberate coupled reaction (reaction 3, see attached drawing 15) Object or the organic or biomolecule for having identification function to certain disease.

The advantage of the invention is that：

1, the advantage of ingredient, hierarchical structure, size, physical and chemical performance, biocompatibility, drug effect of anticancer drug prepared etc. See and is discussed above：The advantages of such multicomponent nanocomposite complex anticancer drug.

2, the multi-step sequence miniflow preparation started can linearly open up the growth course of nano-particle along microchannel It opens, realizes that time-space resolution controls particle formation, there is medicinal property that can be as needed, Nano medication can be controlled In the stage that needs of growth course, the fine composition of online such drug of flexible modulation is (metal, metallic compound, non-metallic Close object, high polymer, biomolecule), hierarchical structure (multi-layer core-shell structure), micro structure is (again to more from amorphous phase to monocrystalline It is brilliant adjustable), surface modification, autonomous targeting and specific targeting, biocompatibility etc..

3, both there is the multilayer shell structurre built the biocompatibility for improving itself and cancer cell (such as to avoid all kinds of in vivo exempt from Epidemic disease body or macrophage find and destroy to it and have from stealthy function) and enter (such as surface tool of the ability in cancer cell Have the elements such as iron, cobalt, nickel, potassium, zinc, calcium, sulphur, the selenium that a large amount of cancer cells like), while its shell composition can be adjusted (such as gold Belong to oxide and polyhydroxy primary surface) and crystal structure (such as structure amorphous state or crystalline state and amorphous mixed state) with into cancer DNA, the RNA or S, Se, P element in functional protein for dissolving out stratum nucleare functional element (such as Pt, Au, Ag) and cancer cell after cell In conjunction with ability, and then change the function of its DNA, RNA or functional protein or make its denaturation.

4, the molecule of the outmost organic coating layer of the multilayer shell built is known in addition to that can be coupled to have cancer cell Outside the biomolecule of other function or treatment function, it can also be coupled Chinese medicine class organic molecule (such as ginsenoside), have and improve The activity of normal cell, the immunity to improving body have certain effect, and common chemotherapeutics kills organism normal cell Dead effect is on the contrary, greatly improve the general level of the health of patient.

Description of the drawings

Program miniflow volume primitive process in Fig. 1 multi-step sequence miniflow preparations constitutes schematic diagram.

(1) and (2) syringe, (3) first coil pipe preheaters, (4) second coil pipe preheaters, (5) Y shape threeway hybrid reaction Device, (6) third coil pipe preheater, (7) product reception device, (8) thermostat a, (9) thermostat b, (10) thermostat c.

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

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

Au@CoFeB@(CoFe)-O (OH) prepared by Fig. 4_xTransmission electron microscope photo (a), high-resolution transmitted electron are aobvious Micro mirror photo (upper right illustration in a) and (b) particle size distribution count block diagram

Single Au@CoFeB@(the CoFe)-O (OH) of Fig. 5_x(a) and (b) EDX spectrograms at shell layer surface at nano-particle core.

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

The drug of all kinds of Nano medications and non-coupled nanosecond particle prepared by Fig. 7 is thin to normal cell (TM4) and breast cancer The growth inhibitory effect of born of the same parents' line (MDA-MB-435S) cell.

Fig. 8 Fe/Pt salt mole dosage ratios are 11:The FePtB@Fe prepared when 1₃O₄The wide field of alloy nano particle transmits Electromicroscopic photograph (a) and high-resolution-ration transmission electric-lens photo (b)

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

Figure 10 is injected intravenously FePtB@Fe-O (OH)_xThe T2WI shadows of (a) (b) liver tissues of rats afterwards before@(PVP-GS) drug Picture.

NiPtB@Ni-O (OH) prepared by Figure 11_xThe transmission electron microscope photo of class nano-particle drug.

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

The Gp-AlPt@Mg that graphene prepared by Figure 13 is stablized_xAl_ySi_zO@PVP (2x+3y+4z=2) nano-particle it is saturating The element power dissipation wave spectrum (b) penetrated electromicroscopic photograph (a) and its ingredient is done.

Figure 14 Ag@AlPt@Mg_xAl_ySi_zCa_jThe multi-layer core-shell structure nano-particle of O@PVP (2x+3y+4z+2j=2) Element power dissipation wave spectrum.

Reaction structure schematic diagram in Figure 15 embodiments 1.

Specific implementation mode

With reference to embodiment, the present invention will be further described, but the present invention is not limited to following embodiments.

Embodiment 1

Below with Au@CoFeB@(CoFe)-O (OH)_x@(LHRH-HECATE)(LHRH：Promote sex hormone secreting hormone； HECATE：Cell membrane lysin peptide) for come illustrate its preparation process and cancer cell treatment on application effect.

(1) by a certain amount of metal salt FeCl in there-necked flask₂·4H₂O(0.07g(0.35mmol)、CoCl₂·6H₂O (0.0833g, 0.35mmol) and a certain amount of stabilizer PVP (0.42g, Mw=10000) are dissolved into N-Methyl pyrrolidone In (50mL, NMP), keep having nitrogen protection in bottle.(2) by a certain amount of reducing agent NaBH₄(0.4g, 10.25mmol) dissolves Into the NMP of 50mL in the there-necked flask for have nitrogen protection.(3) reacted in tubular type micro-fluid reactor, set reaction speed as 3.0ml/min, reaction temperature are 100 DEG C (thermostat a and b), and (thermostat c) prepares stable structure and property to 4 DEG C of collection products The excellent monodisperse CoFeB nano particles of energy, shown in reaction equation such as formula (4)：

CoCl₂+FeCl₂+NaBH₄+H₂O→CoFeB+NaCl+NaBO₂+H₂ (4)

(4)Au@CoFeB@(CoFe)-O(OH)_xThe preparation of Core-shell Structure Nanoparticles.To the end of above-mentioned reaction, take out immediately Take 50mLCoFeB nano-particle solutions, and by 0.2g (5.13mmol) NaBH₄The product for being dissolved in the CoFeB nano-particles is molten In liquid, then by appropriate HAuCl₄·4H₂O (2.5ml, gold content 0.36mmol) is dissolved into other 50mLNMP, with injection Device extracts the 50mLHAuCl₄Two pipe solution are placed in tubular type micro fluid reaction system, are reacted immediately, Jin Eryong by solution NaBH₄Restore HAuCl₄·4H₂O sets reaction speed as 3.0ml/min, and reaction temperature is 80 DEG C, and product is collected under room temperature.By It is easy to quickly be reduced into gold atom in gold salt, and gold atom is by being readily generated ultra micro gold nanoparticle, therefore pre- Mr. At CoFeB in its surface aggregation and can be merged and extension generates Au@CoFeB nano-particles, while table using gold particle as core The hydrone that some Co and Fe atoms in face can be introduced into is oxidized to metal oxide and simultaneously constitutes polyhydroxy with the hydroxyl of solution and satisfy The Surface Fe of sum and the oxide surface layer of cobalt obtain hierarchical structure such as Au@CoFeB@(CoFe)-O (OH)_xMulti-layer core-shell structure Type nano particle, its certain outermost layer are still stablized by surfactant PVP claddings.

Shown in the specific reaction mechanism of nano particle such as chemical equation (5), nucleocapsid formation basic theory such as reaction schematic diagram is such as (15) shown in：

HAuCl₄+NaBH₄+CoFeB+H₂O→Au@CoFeB@(CoFe)-O(OH)_x+NaCl+BO₂+H₂ (5)

(5) according to reaction equation (1) and (2), by s-NHS (the N- hydroxy ambers of the EDC and 0.36mmol of 0.27 μm of ol Acid imide) it is added in the aqueous solution of the modified core-shell magnetic nano particle in the surfaces 30mL (80nM), form s-NHS couplings Magnetic nanoparticle with magnetic method desalination and removes excessive EDC and s-NHS, then by nanometer after stirring half an hour at room temperature Particle is dissolved in PBS buffer solution (pH=7.4), and the polyvinyl alcohol (PVA) or polyethylene glycol (PEG) that 0.05%w/v is added block Possible non-specific bonding.Then ligand is added to the ratio for being 0.97 with nano particle ratio and is dissolved in PBS buffer solution In solution of magnetic nanoparticles, by the mixed liquor at 4 DEG C, mixed 12 hours with rotary shaker.Then it is detached with magnetic method The good magnetic nanoparticle of functionalization is used in combination PBS buffer solution to wash 2 to 3 times.The magnetism of the good nucleocapsid of the functionalization of gained Nano particle is again dissolved in the PBS buffer solution containing 0.05%w/v PEG (polyethylene glycol), is stored for future use at 4 DEG C.

(6) and then by luteinizing hormone-releasing hormone (LHRH) receptor, cell membrane lysin peptide (HECATE) and nanometer The ratio that grain mass ratio is 2/10/1 to 5/50/1 is added in the nanoparticles solution for being dissolved in PBS buffer solution, by the mixed liquor At 4 DEG C, mixed 12 hours with rotary shaker.Then the magnetic nanoparticle for using magnetic method separation functionization good, is used in combination PBS Buffer solution washs 2 to 3 times.What is obtained functionally has breast cancer cell the multilayer of the LHRH and kill effect of specific recognition Nuclear-shell structure type nanoparticulate drug.The nano biological molecular drug is put into the PBS buffer solution containing 0.05%w/v PEG It is interior, it is stored for future use at 4 DEG C.

Attached drawing 2a is the transmission electron microscope image of the CoFe nano-particles for building shell prepared.Its size point Cloth is shown in Fig. 2 b, is 2.4 ± 0.3nm according to the grain size of statistical result its particle.Crystalline substance of the high-resolution-ration transmission electric-lens to its single particle Body structure (Fig. 2 a upper rights illustration) characterize and to the x-ray diffractions (attached drawing 3) of integral particles the result shows that：Its for crystallinity very High body-centered cubic (bcc) crystal structure.

Attached drawing 4a is Au@CoFeB@(the CoFe)-O (OH) prepared_xTransmission electron microscope photo, Size Distribution are shown in figure 4b is 5.6 ± 0.4nm according to the grain size of statistical result its particle.Crystal structure of the high-resolution-ration transmission electric-lens to its single particle (Fig. 2 a upper rights illustration) characterizes, and is analyzed in conjunction with the lattice constant of face-centered cubic (fcc) gold and body-centered cubic crystal structure, coreCorrespond to fcc-Au (JCPDS:(200) crystal face 04-0784)；Casing part,Lattice is normal Corresponding number is bcc-CoFe (JCPDS:(100) crystal face 44-1433) tentatively judges obtained structure for Au@CoFe.

To further determine that its nucleocapsid and the CoFe layer of surface portion oxidation may be constructed (CoFe)-O (OH)_xIt is outermost Layer composition, characterizes the core and outer layer of multiple single nano-particles using element power dissipation wave spectrum (EDX), wherein An EDX characterization result it is as shown in Figure 5.The result shows that the content of the Au at its kernel is obviously than particle shell surface layer Au contents It is much higher, and the content of particle shell surface layer Co, Fe and oxygen is more much higher than core place.In addition, due to the original in reaction Contain water in material in itself, along with the water etc. in washing process, as NiFePt class core-shell nanos, shell outer surface Place part CoFe can be formed the compound state of Fe-OOH and Co-OOH by oxidation, to constitute the Au@with hydrophilic outer layer CoFeB@(CoFe)-O(OH)_xThree-decker has good biocompatibility and is further coupled biological or drug molecule Ability.

Fig. 6 is Au@CoFeB@(the CoFe)-O (OH) prepared_x@(HECATE) and Au@CoFeB@(CoFe)-O (OH)_x@ (LHRH-HECATE) nano anti-cancer medicines structure schematic diagram.

By the various kinds of drug of preparation and nano-particle to the function and effect (such as Fig. 7) of normal cell core cancer cell as it can be seen that TM4 cell lines (non-cancerous) only generate reaction, the functionally nano-particle of recognition group and cytolysin peptide biology to Hecate Molecular probe and drug (LHRH+Hecate+ nano-particles:Molecular structure mimics figure is shown in Fig. 6 b), kill breast cancer cell (MDA-MB-435S) efficient 85 times of efficiency than kill normal cell (TM4)；And nano-particle itself is to the quasi-cancer cell Also there is very high kill rate (65%), it is more slightly lower than HECATE (25%), and can more effectively kill cancer after the two cooperation Cell (85%)；No matter nano-particle or HECATE, by being coupled with LHRH, the kill rate of cancer cell is significantly improved again (about 5%).

Embodiment 2

This example is illustrated through mixed salt method using a program microfluid base in multi-step sequence miniflow preparation First process is adjusted by reactant ratio and prepares the FePtB@Fe with different-shape (nucleocapsid or crystal structure of alloy)₃O₄Nanometer Particle, and compare with the anticancer effect of the iron containing only single component or Pt particles.

Single program miniflow volume primitive process prepares FePtB Fe₃O₄The instance method of nano-particle is as follows.

(1) by the FeCl of 0.07g (0.35mmol)₂·4H₂O, the PVP (Mw=10000) and 0.017g of 0.3g The H of (0.032mmol)₂PtCl₆·6H₂O, which is dissolved in the nmp solvent of 50mL, forms mixed salt solution, and passes through pump (1) The mixed salt solution is pumped into micro- preheating channel (3) by thermostat a temperature controls and is preheating to 120 DEG C, preheating channel internal diameter For 127 μm, long 15cm；

(2) 0.3g (7.9mmol) NaBH4 is dissolved in formation reducing solution system in the nmp solvent of 50mL, and passes through pump (2) reducing agent solution is pumped into micro- preheating channel (4) by thermostat a temperature controls and is preheating to 120 DEG C of suckings, in preheating channel Diameter is 127 μm, long 15cm；

(3) two kinds of solution are 250 μm, are mixed in the Y types mixer (5) of long 4~10 ㎜ that is coupled has in internal diameter The reaction of emulative mixed metal salt reduction nucleation and molysite deposition shelling, forms reduction reaction and forms alloy core and precipitation Form the process of shell presoma；

(4) particle being initially formed is being placed in thermostat b (temperature：30 DEG C) in one section of microchannel (μ of internal diameter=250 M, long=30 ㎝) in enter in the collector (7) by thermostat c control temperature (2 DEG C) after growth a period of time and collect, and pass through Low temperature terminates growth.

It by product centrifugation, precipitates and with after pure water washing 4 times, is dried in vacuo at a temperature of 60 DEG C, obtain FePtB Fe₃O₄Nano-particle powder.Attached drawing 8a be prepare using FePtB alloys as sandwich layer, with Fe₃O₄For the nano-particle of shell, from it It is amorphous state that high-resolution-ration transmission electric-lens photo Fig. 8 a, which can be seen that its stratum nucleare and shell,.Its stratum nucleare size is about 1.3 ± 0.2nm, about 2.1 ± 0.4 nanometers of shell thickness.Such nano-particle is re-dispersed into for the water-soluble of cytotoxicity detection In liquid, contrast experiment's (normal cell and liver cancer cells) that 3 anticancers are carried out to such nano-particle shows：Such particle is same 70% (Percent mortality) can averagely be reached under sample condition of culture to the kill rate of liver cancer cells, and do not had substantially to normal cell There is kill rate (being less than 3%).

Embodiment 3

By the H in embodiment 2₂PtCl₆·6H₂O dosages are promoted to 0.061g (0.117mmol)；And by growth phase Thermostat b temperature is increased to 85 DEG C, remaining reaction condition is constant.The transmission electron microscope photo of the nano-particle of preparation such as Fig. 9 a, Statistical result shows that its grain size is 2.1 ± 0.4nm.Although there is segregation phenomena when shell formation, from the high-resolution of its single particle The contrast on transmission electron microscope photo internal layer and surface layer is this it appears that its nucleocapsid pattern, the deeper core of color close for FePtB Golden sandwich layer (intermediate dotted line is enclosed), lattice constant are face-centered cubic FePtB (111) faces for 0.211nm's, and color is shallower The shell (ring part that two circle of dotted lines enclose) that part is made of the oxide of Fe and Fe.Simultaneously it can also be seen that core The crystalline state quality of layer is relatively good, and the blending constituent that shell is constituted due to two kinds of ingredients, essentially amorphous state.With such nanoparticle Contrast experiment's (normal cell and liver cancer cells) that son carries out 3 anticancers shows：Such particle is under same condition of culture to liver The kill rate of cancer cell can averagely reach 77% (than high 7%) of Fe/Pt=11/1 in example 2, and basic to normal cell There is no kill rate (being less than 5%).

Embodiment 4

Change the gold chloride in embodiment 1 into H₂PtCl₆·6H₂O, remaining composition and preparation process are constant, can prepare class As grain size be 5.2 ± 0.4nm Pt@CoFeB@(CoFe)-O (OH)_xIt is 6.0 ± 0.5nm Pt@CoFeB@with grain size (CoFe)-O(OH)_xThe Nano medications such as@(LHRH-HECATE).The type nano granular can be stabilized in physiological saline 2 years with On, occur without apparent sedimentation.Pt@CoFeB@(CoFe)-O(OH)_x@(LHRH-HECATE) is to breast cancer cell line (MDA-MB- Killing rate 435S) is up to 90% or more, while the mouse mainline effect highly significant by there is such tumour to termination, It after 3 (once every other day) treatments, was observed by 1 week, the breast cancer cell heading line off, by 6 months trace detections, without again The phenomenon that secondary recurrence.In addition, it was also found that Pt@CoFeB@(CoFe)-O (OH)_xNano-particle itself is also to breast cancer cell line (MDA-MB-435S) have killing rate up to 75% or more.

We also studied Pt@CoFeB@(CoFe)-O (OH)_xThe effect of to liver cancer cells, arrives mouse by intravenous injection In vivo, magnetic resonance imaging shows that such particle has an apparent concentration effect in mouse liver, while a shot, 3 filling out observation It was found that reaching 75% or more to the kill rate of all kinds of liver cancer cells, by 3 magnetic treatments in one week, the death rate of liver cancer cells reaches Show to can't detect all kinds of liver cancer cells planted on mouse, reinspection in 6 months to 99% or more, month review result Also without the rebound phenomenon for such liver cancer cells for finding to have plantation.We also so as in various-advanced liver cancer patient uses, The clinical research (patient is voluntary user) for passing through 30 multiple-cases at present, finding all kinds of patients, (one day quiet within a month by 3-4 Arteries and veins injects 10mL and contains such nano-particle, and effective dose is 20 micrograms) the course for the treatment of after, liver cancer cells drop to normal level, Repetition measurement after half a year, to find to have the recurrent cases of such liver cancer cells.

Embodiment 5

Molysite in embodiment 2 is changed into the CoCl of 0.0833g (0.35mmol)₂·6H₂O；And by the perseverance of growth phase Warm slot b temperature is increased to 150 DEG C, remaining reaction condition is constant.Since reaction temperature is very high at this time, part PVP can generated The catalysis of Co simple substance it is lower decompose, generate some free C atoms, which can form CoPtC alloys with Pt together with Co, right CoPtCB@Co-Co are prepared after the slurry product of acquisition is dry in 120 DEG C of vacuum drying ovens₃O₄Class nano-particle, particle diameter For 3.5 ± 0.4nm.The crystal quality of its stratum nucleare and shell is all relatively good at this point in the reaction.3 are carried out with such nano-particle Contrast experiment's (normal cell and liver cancer cells) of secondary anticancer shows：Such particle is under same condition of culture to liver cancer cells Kill rate can averagely reach 80% and (than high 10%) of Fe/Pt=11/1 in example 2, and not killed substantially to normal cell Rate (is less than 5%).

Embodiment 6

Ginsenoside (Rg3 and the Rh2 matter in GS, GS of 0.2g will be added in the metal salt solution of step (1) in embodiment 3 Degree is measured not less than 10%), reaction temperature is adjusted to 50 DEG C, prepares the FePtB@Fe-O of ginsenoside modification (OH)_x@(PVP-GS).Such Nano medication is used for the treatment of breast cancer, is found to breast cancer cell line (MDA-MB-435S) There is high inhibition effect, cell mortality to reach 80% or more for the growth of cell, and to normal cell growth not only unrestraint Effect, also value-added effect, its cell quantity can improve 7% or more under similarity condition.Liver cancer is killed to such Nano medication The research structure of cell shows to compare with exclusive use ginsenoside, and the kill rate of liver cancer cells is enhanced about more than once, ginseng Saponin(e is 30-40% to the kill rate of liver cancer cells, and such drug is 80-85%, also the same to find to normal cell not only Without effect is killed, there is value-added effect instead, its cell quantity can improve 5% or more under similarity condition.Such drug can simultaneously It is observed in real time with the target hepatic tissue for using nmr molecular image method to reach drug after vein or stomach perfusion.Figure 10 be to change compares figure, Ke Yiguan by the T2WI shades of murine liver tissue before and after intravenous injection (drug 5mg metals/kg mouse) It measures after injecting after 3-5 minutes, the image contrast of murine liver tissue before injection drug obviously than without being more clear.

Embodiment 7

Molysite in embodiment 2 is changed into the nickel acetate (Ni (CH of 0.0566g₃COO)₂·4H₂O Mw=176.78； 0.32mmol)；And the thermostat b temperature of growth phase is increased to 200 DEG C, remaining reaction condition is constant.Due at this time Reaction temperature is very high, and part PVP can be decomposed under the catalysis of the Ni simple substance of generation, generate some free C atoms, which can be with NiPtBC alloys are formed together with the B in the Ni and Pt and reducing agent that restore, and the slurry product of acquisition is dried in 100 DEG C of vacuum Preparing NiPtBC@NiO classes nano-particle after drying in case (has B, but does not have body in this embodiment product in embodiment 2 Existing B),Nano particle diameter is 26.0Appended Figure 11 a are had apparent nucleocapsid knot by ± 9.0nm, representative transmission electron microscope Structure；Its stratum nucleare and shell at this point in the reaction are shown to the high-resolution-ration transmission electric-lens photo (Figure 11 b) of its single particle Crystal quality it is all relatively good.Contrast experiment (normal cell and liver cancer cells) table of 5 anticancers is carried out with such nano-particle It is bright：Such particle can also averagely reach the kill rate of liver cancer cells under same condition of culture 80% (than Fe/ in example 2 Pt=11/1 it is high 10%), and to the kill rate very little of normal cell (about 6%).

Embodiment 8

Change the ferrous salt in embodiment 3 into gadolinium salt (GdCl₃), while 0.3g pentoses being added in mixing salt solution (Pts, pentose), remaining reaction condition is constant, is prepared after drying in 40 DEG C of vacuum drying ovens to the slurry product of acquisition GdPtB@Gd₂O₃@(PVP-PTs) Nano medication, grain size is in 3.8 ± 0.4nm.Although the type nano granular magnetism is very strong, but still have There is very excellent water solubility, can be stabilized in water phase 1.5 years or more, is occurred without apparent sedimentation, the reason is that surface modification Pentose have very high water solubility.Carrying out the contrast experiments of 3 anticancers with such nano-particle, (normal cell and liver cancer are thin Born of the same parents) show：Such particle can also averagely reach 85% under same condition of culture to the kill rate of liver cancer cells, and to normal The kill rate very little (about 3%) of cell.

Embodiment 9

By the gadolinium salt (GdCl in embodiment 8₃) change europium salt (EuCl into₃), grain size can be prepared in 2.6 ± 0.3nm EuPtB@Eu₂O₃@(PVP-PTs) Nano medication has and 8 same anticancer effect of example.

Embodiment 10

By the gadolinium salt (GdCl in embodiment 8₃) change neodymium salt (NdCl into₃), grain size can be prepared in 1.5 ± 0.2nm NdPtB@Nd₂O₃@(PVP-PTs) Nano medication has and 8 same anticancer effect of example.

Embodiment 11

By the gadolinium salt (GdCl in embodiment 8₃) change samarium salt (SmCl into₃), grain size can be prepared in 1.0 ± 0.2nm SmPtB@Sm₂O₃@(PVP-PTs) Nano medication has and 8 same anticancer effect of example.

Embodiment 12

By the gadolinium salt (GdCl in embodiment 8₃) change acetic acid terbium (Tb (CH3COO) into₃), can prepare grain size 2.5 ± 0.3nm TbPtB@Tb₂O₃@(PVP-PTs) Nano medication has and 8 same anticancer effect of example.

Embodiment 13

Scheme that CoFeB seed grains are prepared in (1) the multi-step sequence miniflow preparation of embodiment 1 the step of is changed At the following method for preparing Ag seed grains.By 0.25gAgNO₃, 0.75g sodium citrates (STC) 1.0mL a concentration of 30% mistake Hydrogen peroxide solution, 0.35gPVP are dissolved in 50mL water, as metal salt solution；By the hydrazine hydrate of 0.046mL a concentration of 85% (N₂H₄·H₂O it) is dissolved in 50mL water, as reducing agent solution.By in the program micro fluid reaction unit of the two in Fig. 1, Each syringe pump flow velocity is 1.0mL, and each elementary reaction temperature is to be carried out at 25 DEG C, prepares the seed as shell The Ag nano particles of particle, transmission electron microscope photo are as shown in figure 12.Its grain size, which is, to be shown to the statistics of grain diameter 2.5 ± 0.3nm characterizes explanation, with good crystallinity to the high resolution electron microscopy (illustration in Figure 12) of single particle.

Remaining step in embodiment 1 is then proceeded by, the Au@Ag@Ag that grain size is 6.2 ± 0.5nm are prepared₂O receives Rice corpuscles.Contrast experiment's (normal cell and liver cancer cells) that 3 anticancers are carried out with such nano-particle shows：Such particle exists 70% can also averagely be reached to the kill rate of liver cancer cells under same condition of culture, and do not have kill rate to normal cell.

Embodiment 14

(1) by embodiment 13 prepare Ag nano-particles, and by centrifugal sedimentation after, bottom slurry is redissolved in In the nmp solvent of 50mL.

(2) and then by the FeCl of 0.07g (0.35mmol)₂·4H₂O, the PEG (Mw=2000) and 0.017g of 0.3g The H of (0.032mmol)₂PtCl₆·6H₂O, which is dissolved in the nmp solution of the Ag nano-particles of the 50mL, forms nano-particle mixing Metal salt solution, and the mixed salt solution is pumped into micro- preheating channel (3) by thermostat a temperature controls by pump (1) 120 DEG C are preheating to, preheating channel internal diameter is 127 μm, long 15cm；

(3) by 0.3g (7.9mmol) NaBH₄It is dissolved in formation reducing solution system in the nmp solvent of 50mL, and passes through pump (2) reducing agent solution is pumped into micro- preheating channel (4) by thermostat a temperature controls and is preheating to 120 DEG C of suckings, in preheating channel Diameter is 127 μm, long 15cm；

(4) two kinds of solution are 250 μm, are mixed in the Y types mixer (5) of long 4~10 ㎜ that is coupled has in internal diameter The reaction of emulative mixed metal salt reduction nucleation and molysite deposition shelling, forms reduction reaction and forms alloy core (FePtB Alloy) and precipitation form the process of shell presoma (iron and iron hydroxide mixture)；

(5) particle being initially formed is being placed in thermostat b (temperature：30 DEG C) in one section of microchannel (μ of internal diameter=250 M, long=30 ㎝) in enter in the collector (7) by thermostat c control temperature (2 DEG C) after growth a period of time and collect, and pass through Low temperature terminates growth.

By centrifugal sedimentation, bottom slurry is obtained, then redisperse to 20mL pure water；Centrifugal sedimentation is re-dispersed into again It is secondary in pure water, obtain Ag@FePtB@Fe₃O₄@(PEG-STC) nano-particle.Ag@FePtB@can be prepared by crossing this method Fe₃O₄Nano-particle.The type nano granular can be stabilized 1 year or more in water phase, be occurred without apparent sedimentation.

Contrast experiment's (normal cell and liver cancer cells) that 5 anti-liver cancer and anti-cells are carried out with such nano-particle shows：It should Class particle can also averagely reach 85% under same condition of culture to the kill rate of liver cancer cells, and not killed to normal cell Dead rate.

Also with such drug to Small Cell Lung Cancer NCIH446 cell strains, 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 leaching Fawn on transfevent lung carcinoma cell NCI-H292 and carry out inhibiting tumor cell performance test, find its to such lung carcinoma cell have 75% with On kill rate.By the using effect to 10 middle and advanced stage patients with Small Cell Lung Cancer NCIH446, show by daily The 250mL glucose injections of Neulized inhalation agent containing 10mL/ twice (20 μ g of effective content), 1-2 months as a treatment course, passes through After the 2-3 course for the treatment of, 9 patient symptoms disappear substantially, and 1 mid-term patient symptom is suppressed, and no longer deteriorates.Turn to suffering from height Move maxicell lung cancer cell line L9981 and NL9980 and people's squamous lung carcinoma cell SK-MES-1, human A549 cell lines Patient does same experiment, shows that treated effect also reaches 80% or more, and to lymphatic metastasis type lung cancer NCI-H292's Patient's effective percentage is 70%.

Embodiment 15

By the FeCl of the 0.07g (0.35mmol) of (2) in 14 step of embodiment₂·4H₂O change into 0.025g cupric sulfate pentahydrates, The PEG (Mw=2000) of 0.3g changes the beet soda acid (SB12) and 0.2gPVP of 0.3g into, can prepare Ag@CuPtB@Cu₂O@ (STC-PVP-SB12) nano-particle, the particle can be also stabilized 1 year or more in water phase, be occurred without apparent sedimentation.With this Class drug shows the kill Contrast on effect experiment (normal cell and liver cancer cells) of liver cancer cells：Such particle is equally being cultivated Under the conditions of 85% can also averagely be reached to the kill rate of liver cancer cells, and normal cell (is less than without kill rate substantially 5%).Such drug is to human lung carcinoma cell H125 and 95D, human lung adenocarcinoma cell SPC-A-1, people's classics small cell lung cancer cell H1688, 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 cancer Cell NCI-H292 carries out inhibiting tumor cell performance test, it is found that it has such lung carcinoma cell 80% or more kill rate, but Also there is certain kill effect (about 6%) to normal cell.By to 10 middle and advanced stage diseases with the above cell type strain lung cancer The using effect of people shows the 250mL glucose injections by Neulized inhalation agent containing 10mL/ twice daily (20 μ g of effective content) Liquid or normal saline solution, 1-2 months as a treatment course, and after the 2-3 course for the treatment of, 9 patient symptoms disappear substantially, 1 Mid-term patient symptom is suppressed, and no longer deteriorates.To suffer from height transfer maxicell lung cancer cell line L9981 and NL9980 and People's squamous lung carcinoma cell SK-MES-1, human A549 cell lines patient do same experiment, show that treated effect also reaches To 85% or more, and it is 80% to patient's effective percentage of lymphatic metastasis type lung cancer NCI-H292.

Embodiment 16

By the FeCl of the 0.07g (0.35mmol) of (2) in 14 step of embodiment₂·4H₂O changes the Zr of 0.040g into (NO₃)₄·5H₂O, the PEG (Mw=2000) of 0.3g changes the ginkgoic acid (GA) of 0.3g into, by 0.3g (7.9mmol) NaBH₄It changes into Ca (the BH of 0.44g₄)₄, Ag@ZrPtB@Zr can be prepared_1-xCa_xO@(GA-STC-PVP) nano-particle, the particle also can be It is stabilized in water phase 1 year or more, occurs without apparent sedimentation.Experiment shows such nano-particle drug and Ag@CuPtB@ Cu₂O@(STC-PVP-SB12) nano-particle has same anticancer effect, but it is less than 4% to the kill rate of normal cell.

Embodiment 17

By the FeCl of the 0.07g (0.35mmol) of (2) in 14 step of embodiment₂·4H₂O changes the Ru (NO of 0.03g into₃)₃、 The PEG (Mw=2000) of 0.3g changes the GINKGO BILOBA EXTRACT (Gbb) of 0.3g into, by 0.3g (7.9mmol) NaBH₄Change 0.44g's into LiBH₄, Ag@RuPtB@Ru can be prepared_1-xLi_xO@(Gbb-STC-PVP).Such drug and Ag@ZrPtB@Zr_1-xCa_xO@ (GA-STC-PVP) nano-particle equally has same curative effect to liver cancer and lung cancer.

Embodiment 18

By the H in embodiment 14₂PtCl₆·6H₂O replaces with the H of 0.054g₂IrCl₆·3H₂O、0.07g(0.35mmol) FeCl₂·4H₂O changes the prochloraz-manganese chloride complex ([C of 0.57g into₁₅H₁₆Cl₃N₃O₂]₄MnCl₂)；The PVP of (2) changes 0.3g into step Ginkgolides (Ggl), by 0.3g (7.9mmol) NaBH₄Change the Al (BH of 0.44g into₄)₃, Ag@AlMn (IrB@can be prepared Mn_1-xAl_xO@(Ggl-STC-PVP).Such drug and Ag@ZrPtB@Zr_1-xCa_xO@(GA-STC-PVP) nano-particle is equally right Liver cancer and lung cancer have same curative effect.

Embodiment 19

By the FeCl in embodiment 2₂Change 0.05g cupric sulfate pentahydrates and 0.02gAl (NO into₃)；PVP changes the ginkgo of 0.3g into Lactone (Ggl)；By 0.3g (7.9mmol) NaBH₄Change the Mg (BH of 0.44g into₄)₃, and 0.1g organo-silicon compound (such as silicon is added Alkane etc.) nmp solution in, Gp-AlPtCuB@Mg can be prepared_xySi_zO@Ggl (2x+3y+4z=2).Such nano-particle can It is stabilized in water phase 1 year or more, occurs without apparent sedimentation.Figure 13 a are the transmission electron microscope photos of such nano-particle drug, It can be seen that disperseing on graphene very uniformly at the nano-particle of particle, element energy level dispersion wave spectrum (Figure 13 b) also indicates 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 drug and Ag@ZrPtB@Zr_1-xCa_xO@(GA-STC-PVP) nano-particle equally has liver cancer and lung cancer Same curative effect.

Embodiment 20

With a small amount of Ag nano-particles (about 10mg solid powders) for being prepared in embodiment 13 for seed, and it is distributed to embodiment Al (the NO of 0.04g cupric sulfate pentahydrates and 0.02g in 19₃) nmp solution in；In the Mg (BH containing 0.6g₄)₂Reducing agent It is middle that a small amount of (~0.05g) Ca (BH are added₄)₂, remaining condition and embodiment 19 are identical, can prepare Ag@AlPtCuB@ Mg_xAl_ySi_zCa_jThe multi-layer core-shell structure nano-particle of O@PVP (2x+3y+4z+2j=2), appended Figure 14 are to such nanoparticle The element energy level dispersion wave spectrum (note that son is done：Gold element is to think to add), 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 drug and Ag@ZrPtB@Zr_1-xCa_xO@(GA- STC-PVP) nano-particle equally has same curative effect to liver cancer and lung cancer.

Embodiment 21

With the FePtB@Fe prepared in embodiment 2₃O₄For seed particles, continue following reaction.(1) by the nanometer Particle is dissolved in containing 0.165g zinc gluconates, 0.162g zincium selenious acids, 0.3g anthocyanidin oligomer and 0.15g maleic anhydrides Aqueous solution in, formed nano-particle and metal salt mixed solution；(2) 0.24 gram of Li [B (C will be contained₂H₅)₃H] tetrahydrochysene furan Solution of muttering is dissolved in nmp solution, forms reducing agent solution；By being preheating to 100 in (3) two kinds of solution devices shown in Fig. 1 Enter internal diameter after DEG C to be 250 μm, mix in the Y types mixer of long 4~10 ㎜, Zn salt and part Fe occurs₃O₄Reduction reaction, In FePtB@Fe₃O₄Outer composition Zn_(1-x)Fe_xThe second layer shell of Se；(4) multi-layer core-shell structure nano-particle is initially formed to set In thermostat b (temperature：30 DEG C) in one section of microchannel (internal diameter=250 μm, long=30 ㎝) in growth a period of time it is laggard Enter and collected in the collector by thermostat c control temperature (2 DEG C), and is terminated and grown by low temperature.

After centrifugal sedimentation, milli-Q water 2-3 times, the FePtB@that anthocyanidin oligomer and maleic anhydride are stablized are obtained Fe₃O₄@Zn_(1-x)Fe_xSe slurry is then dissolved in the aqueous solution containing 0.1g ginsenosides, is preserved at 4 DEG C.

Such nano-particle, which has, to be shown to the therapeutic effect of liver cancer and lung cancer in embodiment 14 and 15 to the nano-particle Have the function being enriched with automatically in liver cancer and lung cancer affected area, to the kill rate of liver cancer cells and all kinds of lung carcinoma cells reach 90% with On.Shown by the using effect to 20 middle and advanced stage patients with the above type lung cancer or liver cancer：By mist twice daily Change the 250mL glucose injections or normal saline solution of sucking agent containing 10mL/ (20 μ g of effective content), 1-2 months are one A course for the treatment of, after the 2-3 course for the treatment of, 19 patient symptoms disappear substantially, and 1 mid-term patients with lung cancer symptom is suppressed, no longer Deteriorate.

Embodiment 22

The nano-particle that embodiment 21 obtains is continued such as the 5th step of example 1 and the 6th step to react, idol can be obtained LHRH and Hecate biomolecule has the targeted nano-particle drug for identifying and killing function to breast cancer cell on connection FePtB@Fe₃O₄@Zn_(1-x)Fe_xSe@(LHRH+HECATE).Kill rate of the drug to breast cancer cell line (MDA-MB-435S) Can reach 96% or more, and to normal cell TM4 without it is apparent kill effect (<3%).

Embodiment 23

The zinc sulfite that 0.162g zincium selenious acids in embodiment 21 are changed into 0.129g, can be prepared FePtB@ Fe₃O₄@Zn_(1-x)Fe_xS nano-particles and FePtB@Fe₃O₄@Zn_(1-x)Fe_xSe particles have same anticancer effect.

Embodiment 24

Substantially with CNT-AlPtB@Mg in embodiment 19, can be prepared_xAl_ySi_zO@PVP (2x+3y+4z=2), and Gp-AlPtB@Mg_xAl_ySi_zO@PVP particles have same anticancer effect.

Embodiment 25

Preheating temperature in step 1 and 2 in embodiment 2 is increased to 180 DEG C, since reaction temperature is very high at this time, portion Point PVP can be decomposed under the catalysis of the Fe simple substance of generation, generate some free C atoms, the atom can with Fe together with Pt shapes At FePtCB alloys, FePtCB@Fe are prepared₃O₄Nano-particle.Since reaction temperature improves, shell crystal structure improves, and The carbon of stratum nucleare exists, and Pt is made to be more easy to the FePtB@Fe prepared from stratum nucleare separate out and embodiment 2₃O₄Particle is compared, and drug effect can To be improved significantly, it is (dead that such particle can averagely reach the kill rate of liver cancer cells under same condition of culture 80% Die percentage), and to normal cell substantially without kill rate.

Embodiment 26

Change the ginsenoside for the 0.2g being added in the metal salt solution of step (1) in embodiment 6 into various amino acid (amac) (such as glycine, alanine, cysteine, phenylalanine), other conditions are constant, prepare amino acid surface modification FePtB@Fe-O (OH)_x@(PVP-amac) has the curative effect same with product in example 6.

Embodiment 27

The ginsenoside for the 0.2g being added in the metal salt solution of step (1) in embodiment 6 is changed into various carboxylic Multifunctional organic matter (MFG) (such as grape sodium carbonate, sodium citrate, sulfydryl dodecanoic acid, lauric acid, maleic acid glycosides, grape carbon Acid, citric acid etc.), other conditions are constant, prepare the FePtB@Fe-O (OH) of polyfunctional group surface modification_x@(PVP-MFG), With the curative effect same with product in example 6.

Embodiment 28

Molysite in embodiment 2 is changed into the nickel acetate (Ni (CH of 0.0283g₃COO)₂·4H₂O Mw=176.78； 0.16mmol), the Zr (NO of 0.034g₃)₄·5H₂O (Mw=429.39；0.08mmol), the dibutyitin maleate of 0.014g (Mw=346.99；0.04mmol)；Use KBH₄Instead of NaBH₄Reducing agent is made, and the thermostat b temperature of growth phase is carried For height to 180 DEG C, remaining reaction condition is constant.Since reaction temperature is very high at this time, part PVP can be single in Ni, Sn of generation etc. Matter catalysis is lower to decompose, and generates some free C atoms, which can form NiPtC alloys together with Ni, Sn, Zr with Pt, right PtNiSnZrBC@(Ni are prepared after the slurry product of acquisition is dry in 120 DEG C of vacuum drying ovens_1-x-ySn_xZr_y)O-K₂O class nanometers Particle.Contrast experiment's (normal cell and liver cancer cells) that 3 anticancers are carried out with such nano-particle shows：Such particle is same Can also averagely reach 80% under sample condition of culture to the kill rate of liver cancer cells (than in example 2 Fe/Pt=11/1 it is high 10%), and to the kill rate very little of normal cell (about 3%).

Embodiment 29

Sm, Nd, Tb, referred to as the first constituents；(2) one or more in following noble metal component must be contained： Au、Ag、Pt、Cu、Ru、Pd、Rh、Re、Os、Ir；Referred to as the second constituents (3) must be in above-mentioned magnetic components or noble metal component In the ingredient containing the three kinds or more in following element, Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La, Na, Mg, Li、K、Ca。

Molysite part in embodiment 2 is changed into the lithium niobate (Mw=147.85 of 0.006g；0.04mmol), 0.014g Acetic acid terbium hydrate (Mw=354.07；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) Instead of part chloroplatinic acid；Use LiBH₄Instead of the NaBH of same amount₄Make reducing agent, and by the thermostat b temperature of growth phase 150 DEG C are increased to, remaining reaction condition is constant.Since reaction temperature is very high at this time, part PVP can generation Nb, Fe, The catalysis of the simple substance such as Pt, Ir is lower to decompose, and generates some free C atoms, which can contain with formation such as Nb, Fe, Pt, Ir The FePtBC alloys of Nb, Ir, Ru, Tb prepare the slurry product of acquisition in 120 DEG C of vacuum drying ovens after drying (NbIrRuTb)FePtBC@(NbIrRuTbFe)O_x-Li₂O class nano-particles.The comparison of 5 anticancers is carried out with such nano-particle Experiment (normal cell and liver cancer cells) shows：Such particle is average to the kill rate of liver cancer cells under same condition of culture 85% can be reached (than high 15%) of Fe/Pt=11/1 in example 2, and to the kill rate very little of normal cell (about 7%).

Claims (9)

1. a kind of multicomponent nanocomposite alloy compound particle anticancer drug, which is characterized in that multicomponent nanocomposite alloy compound particle by Metal and nonmetallic composition, wherein (1) metal must at least contain one kind in following noble metal component：Au、Ag、Pt、Cu、 Ru, Pd, Rh, Re, Os, Ir, referred to as the first constituents；(2) it is nonmetallic must be at least following nonmetalloid B, C, Si, O, S, One kind in Se, referred to as the second constituents；

Or the metal further includes one or more of following magnetic components：Fe, Co, Ni, Gd, Sm, Eu, Nd, Tb, referred to as Three constituents；

Or further include one or more kinds of ingredients in following element in the metal, Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La, Na, Mg, Li, K, Ca, referred to as the 4th constituents；

If multicomponent nanocomposite alloy compound particle anticancer drug contains only two class of above-mentioned first constituents and referred to as the second constituents Ingredient, then multicomponent nanocomposite alloy compound particle is nucleocapsid, and the first constituents noble metal belongs to stratum nucleare, the second constituents category In shell；O is to be constituted metal oxide with the metal or with the shape of hydroxyl OH or carboxy CO OH existing for particle surface Formula exists, and S and Se exists in the form of being constituted sulfide or selenides with metal, and B and Si are that doping constitutes conjunction in a metal Gold, C are to exist by the allotrope of carbon or in the form of the organic carbon that surface coats or constituted metal carbides with the metal Form exist；

If multicomponent nanocomposite alloy compound particle anticancer drug includes the first constituents, the second constituents, third constituents or packet The first constituents, the second constituents, third constituents, the 4th constituents are included, then multicomponent nanocomposite alloy compound particle is alloy The form of structure or hetero-junctions；The form of hetero-junctions is the nucleocapsid that part coats or coats completely；If the shape of hetero-junctions Formula, then first and third or/and the 4th ingredient constitute alloy or the heterogeneous hetero-junctions for becoming multicomponent nanocomposite alloy compound particle Inside stratum nucleare；Second constituents and third class or/and the 4th constituents compound are shell, and shell is single layer or multilayer； B and Si in second constituents are to be entrained in the alloy of the first kind or/and third constituents composition, and C is different with the homoatomic of carbon Body or by surface coating organic carbon in the form of exist or to be constituted metallic carbide with above-mentioned magnetic components or noble metal component The form of object exists；O is metal oxide to be constituted with metal in the first kind, third class or the 4th constituents or with particle table The form of hydroxyl OH or carboxy CO OH existing for face exist, and are made up of O and metal in particle surface hydroxyl OH or carboxy CO OH The form of metal (M) and oxygen covalent bond (M-O) exists, and S and Se with the first kind, third class or the 4th metalloid to be constituted vulcanization The form of object or selenides exists；Multicomponent nanocomposite alloy compound particle, size are 0.2-80 nanometers.

2. according to the multicomponent nanocomposite alloy compound particle anticancer drug of claim 1, which is characterized in that multicomponent nanocomposite alloy Compound particle, size are 0.5-20 nanometers.

3. according to the multicomponent nanocomposite alloy compound particle anticancer drug of claim 1, which is characterized in that multicomponent nanocomposite alloy Compound particle, size are 1-6 nanometers.

4. the method for preparing multicomponent nanocomposite alloy compound particle anticancer drug described in claim 1, which is characterized in that use It is prepared by Y shape microfluid preparation facilities, the device include two syringe pumps arranged side by side, a Y shape threeway mixer reactor, Three coil pipe preheaters, three thermostats, a product reception device；Two syringe pumps arranged side by side are pre- by the first coil pipe respectively Hot device (3) and the second coil pipe preheater (4) are connect with the Liang Ge branches of Y shape threeway mixer reactor, the first coil pipe preheater (3) it is located in thermostat a (8) with the second coil pipe preheater (4), the third branch of Y shape threeway mixer reactor passes through Three coil pipe preheaters (6) are connect with product reception device, and third coil pipe preheater (6) is located in thermostat b, product reception device In thermostat c, product reception device is additionally provided with inert gas import and inert gas outlet；

Step 1：By first kind component or first kind component and third class component or/and the 4th class component except Na, Mg, Li, K, The precursor of Ca be dissolved in obtained in solvent macromolecule dispersing agent dispersion mixing salt solution be additionally added the homoatomic of carbon if containing C Obform body or organic material；Wherein solvent be N-Methyl pyrrolidone, dimethylformamide, dimethyl sulfoxide (DMSO), tetrahydrofuran, Dimethylacetylamide or water；Organic material is the macromolecule organic or biochemical reagents for being dissolved in the above solvent；

Step 2：Dissolve reduce agent in N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), dimethylformamide, tetrahydrofuran or diformazan Yl acetamide obtains reducing agent solution；Wherein 50ml solvents are corresponded to per 0.03g-3g reducing agents；The dosage of reducing agent is metal salt 1.5-2 times of equivalent, reducing agent are the reducing agent containing B if containing B；Hydrazine hydrate is used if not containing B in product；

Step 3：Extracted respectively with syringe by step 1 and the prepared reaction solution of step 2 and be respectively placed in two it is arranged side by side In syringe pump (1) and (2), the flow velocity of syringe pump is adjusted to：0.01ml/min~20ml/min is respectively flowed through and is immersed in After the coil pipe preheater of thermostat a (8) is preheating to 40-200 DEG C of certain temperature, into threeway mixer hybrid concurrency life reaction at Core, for a period of time subsequently into third coil pipe preheater (6) interior nucleation and growth process, final reaction product has entered inert gas guarantor In the product reception device of the lower temperature of shield, product is freezed into specific growth phase herein, is obtained evenly dispersed extra small The solution of nano particle；Inert gas is nitrogen, argon gas and carbon dioxide gas.

5. according to the method for claim 4, which is characterized in that the metallic element in the first constituents is the presoma with metal salt Form be added reaction solution in, by reduction reaction generate simple substance atom, and through be nucleated and grow up constitute nano-particle；For B in second constituents is added in the form of metallic boron hydrides as reducing agent, if there are Na, Mg in the 4th constituents, Li, K, Ca then forms metallic boron hydrides with Na, Mg, Li, K, Ca in the 4th constituents；C has with the allotrope of carbon or carbon What the form of machine material was added, wherein the allotrope of carbon still forms the allotrope of carbon, organic material of carbon after being added Material forms the organic material on surface layer or since high-temperature heating and metal forms alloy；S and Se is introduced there are two types of mode, one is In reduction reaction, the part water of introducing is replaced with mercaptan or selenol, effect same with-OH in water is played, in drying process Middle formation metal sulfide or selenides, be in addition by anion exchange reaction, after reaction forms metal oxide, then Sulphite or selenite is added and reducing agent reacts to form S^2-Or Se^2-, since these anion can be with metal ion shape At sulfide and selenides is more stable, more indissoluble, therefore displacement reaction can occur with oxygen anion, formation be more difficult to stablize and It is more easy to be distributed to metal sulfide or selenides in water；

Metallic element in third constituents is added in reaction solution in the form of the presoma of metal salt, and reduction reaction is passed through It generates simple substance atom or carries out precipitation reaction under conditions of having water and solvent autolysis is aerobic and form metal oxide, and pass through It is nucleated and grows up and constitute metal nanometer cluster or using metal oxide as the multicomponent nanocomposite particle of outer layer；

Metallic element in third constituents in reaction solution in the presence of the metal salt of first composition, and be reduced out The metallic atom of one component constitutes metal alloy nanoparticles；When being reacted under conditions of having water and solvent autolysis is aerobic, Since third component metal salt can precipitate generation hydroxide, which can be by third class component The hydroxide or oxide of generation coat or part is overmolding to nucleocapsid；

Na, Mg, Li, K, Ca in 4th constituents using metallic boron hydrides as reducing agent in the form of be added, pass through and select production The content of wash conditions control Na, Mg, Li, K, Ca of product；Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce in 4th class component, La elements are added in the form of soluble metallic salt.

6. according to the method for claim 4, which is characterized in that using extra small nano particle be seed and entirely different its of ingredient Its material builds the multicomponent nanocomposite particle with heterojunction structure jointly, using such nano-particle as seed, and it is molten at its The reduction dose construction needed is added in liquid and forms nano-particle seed-reducing agent that heterojunction structure needs；Hetero-junctions is built again The solution of the raw material for the other component that structure needs is as another feed liquid；Using above-mentioned same reaction unit, step 3 is repeated, Reaction process parameter is adjusted, the multicomponent nanocomposite particle with heterojunction structure is obtained, by the solution of obtained nano-particle product It centrifuges, so that it is settled down from mother solution, outwell supernatant, obtain sediment, by washing for volume same as supernatant It washs liquid to be added in sediment, sonic oscillation, centrifugal sedimentation；Repeatedly after 2-3 times, the multicomponent nanocomposite particle of heterojunction structure is obtained Slurry class sediment, third constituents metal exists in the form of MOx inside shell at this time, surface layer third constituents metal and oxygen With M-O (OH)_xForm exists；If be dried for standby in 40-100 DEG C of vacuum drying oven, nanoparticle surface M-O (OH) at this time_x Largely dehydration it can be transformed into MO_xIngredient；

Or the metal nanometer cluster being made of third constituents, third class is added when being reduced in the metal salt of first kind component The initial nano-particle that the metal nanometer cluster that ingredient is constituted can grow up in the metallic atom nucleation by first kind component carries out outer Nano-particle merges epitaxial growth, constitutes using first kind multicomponent metallic nano-particle as stratum nucleare, and third constituents metal is shell Core-shell nano；If at this time with the presence of the oxygen containing autolysis in water and system in reaction solution, outside shell The metal hydroxides being made of third multicomponent metallic is had, the metal hydroxides meeting that further the third multicomponent metallic is constituted By dehydration during drying, the metal oxide that outer layer is made of the metal of third constituents is formed.

7. according to the either method of claim 4-6, which is characterized in that the element of the 4th constituents is to be added in two ways, To Na, Mg, Li, K, Ca in the form of metallic boron hydrides, the reducing agent as reduction first, third constituents metal salt adds Enter, the first and third metalloid salt be reduced into atomic building alloy or compound and nucleation Na, Mg, Li, K, Ca at It enters wherein for wrappage, is washed according to subsequent requirement；To with redox potential ratio Na, Mg, Li, K, Ca class Low Zr, Nb, Mo, Mn, Zn, Ti, Sn, Al, Ce, La metalloid of metal ion, directly by it in the form of soluble metallic salt It is added in the first kind and/or third metalloid salting liquid.

8. according to the method for claim 4, which is characterized in that do not contain B in alloy particle, then reducing agent cannot using others Reducing agent containing B.

9. according to the method for claim 4, which is characterized in that there are two types of forms to enter using when organic material for non-metal carbon element Nano-particle realizes that making, which has partial organic substances to decompose, generates simple substance carbon one is when reaction temperature is very high by adjusting temperature Or carbon radicals, such active carbon can form metal-carbon alloy with metal, to enter metal conjunction in a manner of alloying element Jin Zhong；In addition most of to be still in the skeleton carbochain of organic matter, it is coated on outside particle in the form of surface stabilizer；When anti- Answer temperature low, when organic matter cannot decompose, then to be coated on particle outer layer.