CN101193659A - Tunstern particl as x-ray contrast - Google Patents

Abstract

The present invention relates to particles comprising cores of tungsten or tungsten in mixture with other metallic elements as the contrast enhancing material wherein said core are coated, to pharmaceuticals containing such particles, and to the use of such pharmaceuticals specifically as contrast agents in diagnostic imaging, in particular in X-ray imaging.

Description

Tungsten particle as x-ray contrast agent

The present invention relates to particle and contain the medicine of this particle, wherein particle comprises the coating core of metallic element tungsten or comprises tungsten and other coating core of mixture of the metallic element of reinforcing material as a comparison.The invention still further relates to described medicine as diagnostic imaging especially for the contrast Material Injection Protocols in the x-ray imaging, and relate to the contrast medium (contrast media) of the core of the mixture that contains described metallic element tungsten or tungsten and other metallic element.

All diagnostic imagings produce different signal levels based on different structure in body.Therefore, in x-ray imaging, for example for will be in image visible appointment body structure, must be different by the X ray decay that this structure causes with the X ray decay that causes by surrounding tissue.Signal difference between body structure and its surrounding tissue is commonly called contrast, and made a large amount of effort aspect the contrast in strengthening diagnostic imaging, because the contrast between body structure and its surrounding tissue is big more, then the quality of image is high more and their value when diagnosing for the doctor is just big more.In addition, contrast is big more, just can manifest more little body structure in imaging process, that is to say, the contrast increase can produce the spatial resolution of increase.

For given spatial resolution, the quality of diagnosis of image depends on the intrinsic noise level of formation method very much, therefore the ratio of contrast level and noise level can be regarded as the efficient diagnosis qualitative factor of representing diagnostic image.

The improvement that realizes above-mentioned quality of diagnosis factor is for a long time always and remains important target.Various technology such as X ray, nuclear magnetic resonance (MRI) and ultrasonic in, a method improving the quality of diagnosis factor is that contrast reinforcing material, contrast agent are incorporated in the body region of imaging.

Therefore, in X ray, for example the example of contrast agent early is insoluble inorganic barium salt, and they strengthen the X ray decay in the body region of its distribution.In recent years, the iodine compound that contains of solubility is occupied an leading position in the x-ray contrast agent field, for example those that sold with trade name Omnipaque and Visipaque by AmershamHealth AS.

Concentrate on to a great extent on aminopolycanboxylic acid (APCA) chelate of heavy metal ion having the research that heavy metal strengthens the x-ray contrast agent of element as a comparison.Effective image of considering many body parts needs the metal ion of relative high concentration to locate at described body part, and existing suggestion can be used Polychelants (polychelant) for this purpose, promptly has the material that surpasses an independent chelating agen part.Further work concentrates in the application of multi-ring complex, and multi-ring complex strengthens the complex of atoms for the part of complexation wherein itself comprises two or more contrasts, and referring to Yu, S.B. and Watson, A.D. be at Chem.Rev., and 1999, described in the 2353-2377.Therefore, for X ray or ultrasonic, complex should comprise two or more heavy metal atoms, and for MRI, complex should comprise two or more metallic atoms with paramagnetic properties.

Yu, S.B. and Watson, A.D. be at Chem.Rev., and 1999, the application of Metal Substrate X ray contrast medium has been discussed among the 2353-2377.Tungsten powder it is said the X ray comparative additive of using in the embolus agent (embolic agents) that can be used as suberification before euangiotic tumor treatment and art.Yet they find that the heavy metal complex interior application of blood vessel widely may be subjected to the restriction of safety problem and dosage requirement.

Well-known nano crystals tungsten powder spontaneous combustion and spontaneous ignition in air.Because its reactivity, the tungsten nanoparticle is not used as medicine such as x-ray contrast agent.

Heavy metal element gold, silver, platinum and palladic metal conjugated compound and they application as contrast agent such as x-ray contrast agent has also been proposed, as at United States Patent (USP) 5,728, described in 590.In addition, United States Patent (USP) 6,203,778 particles of mentioning the inorganic core of metallic copper with organic coating, nickel, palladium, Jin Heyin can be used for the x-ray imaging method.

WO 03/07961 relates to the metal nanoparticle that is used to strengthen the X ray contrast especially.This patent application concentrated discussion the gold particle in the nanometer range, comprise particle with the antibody covalent attachment.Gold particle is coated with thioglucose, make them have more physiology's toleration, also attempted other coating such as glutathion, but find that toleration is relatively poor.Also mention platinum, palladium, thallium, bismuth, osmium, iridium, silver, tungsten, lead, tantalum and uranium as possible alternative metals.

The purpose that the golden core of the nanoparticle of describing in WO 03/07961 has inert basically surface and has a thioglucose coating is not to make surface passivation.

The thioglucose coating of gold particle is tradable, and a little less than the combination relatively between gold particle surface and the coating.Therefore, these coating gold particle have the long half-life in vivo owing to the exchange of group in part in the coating and the tissue such as protein sulfhydryl.Therefore, the coating gold particle will not be retained in the blood flow, referring to for example Hostetler, M.J., Templeton, A.C., Murray, R.W, " Dynamics of Place-Exchange Reactionson Monolayer-Protected Gold Cluster Molecules ", Langmuir, 1999,15,3782-3789.In vivo the long half-lift be undesirable because this can cause that higher toxicity and long half-life are not advantages usually in X ray research.

As mentioned above, be known in the art the contrast agent of various metals as the core that comprises the element that exists with its metal (O) oxidation state form.Proposed coated nanoparticle as x-ray contrast agent.Preferably the nanoparticle of inert metals like gold, silver, palladium and platinum is used as contrast agent basically.Yet many inert metals cost an arm and a leg as gold, gadolinium, erbium and other rare earth element, and are therefore less feasible as commercial contrast agent.Other metal such as uranium have radioactivity, therefore are not suitable as x-ray contrast agent.Metal makes their uncomfortable fit planted agents use as plumbous, hydrargyrum and thallic toxicity.Bismuth, barium and tungsten are possible material standed fors for this application-specific, yet the X ray attenuation characteristic of bismuth, particularly barium is relatively low.The tungsten of tungsten powder form has pyrophorisity, thereby can not be used as medicine.

Though commercially available solubility contains iodine compound and is considered to as safe as a house and is used for every year surpassing 2,000 ten thousand times X-ray examination in the U.S., still needs to develop new contrast agent.This contrast agent should contain the character that iodine compound has improvement than solubility in following one or more properties ideally: nephrotoxicity, viscosity, injection volume and decay/radiation dose.

Have been found that now and comprise randomly particularly having unexpected and favorable properties with the particle that coating such as polymeric layer or monomer layer apply as medicine as contrast agent with the core of the blended metallic element tungsten of other metallic element and wherein said core.Coating makes the active surface passivation of the sub-core of tungsten particle and the nanoparticle of the safety with favourable character is provided.

It is pointed out that when particle was nanoscale, term particle and nanoparticle used interchangeably, and term core and tungsten core use interchangeably also in following file.In statement, medicine also comprises the particle/nanoparticle that constitutes the pharmaceutically active key element.Other embodiments specify in the claims and describe in text.

Chemical compound of the present invention is the particle that comprises core and coating.The diameter of particle is in nanometer range, so they are called as nanoparticle.Though particle can change to surpassing in the scope of 20nm at about 1.5nm, more preferably 1.5 to 15nm, usually preferably they by renal excretion.Therefore, preferable particle size should be lower than about 6 to the kidney threshold value (Kobayashi, H., Brechbiel, M.W., Molecular Imaging, 2,1 (2003)) of 7nm and preferable particle size should for 1.5nm to 7nm or more preferably 2 to 6nm.

The core of particle comprises the tungsten of metallic forms or the mixture of tungsten and other proper metal element.Preferred W content is 20 to 100 weight %, 50 to 100 weight % more preferably, and more preferably 85 to 100 weight % are preferably 95 to 100 weight % especially.The core of usually preferred about 100% W content.

In the tungsten core, introduce other metallic element the character of improvement can be provided for core, as improve stability, monodispersity, metal-cored synthesizing and/or formation speed.Preferably, be available additive as rhenium, iridium, niobium, tantalum or the molybdenum of 5 to 15 weight % of independent element or element mixture form, most preferably rhenium and iridium.All these elements are mixable with tungsten all, and a spot of rhenium and/or the metal-cored low-temp plastic of iridium improvement.

Importantly, metal-coredly have enough sizes, consider the preferred overall size of nanoparticle for this reason for what particle provided attenuation properties.Therefore, core must comprise the metallic atom of optimised quantity as far as possible, so that required attenuation properties to be provided.When core comprised the tungsten metal of about 100 weight %, core should comprise 15 to 5000 tungsten atoms, preferred 100 to 3000 tungsten atoms, more preferably 200 to 2500 tungsten atoms.Suppose that tungsten atom piles up with body centred cubic crystal, then the core diameter with core of 15 tungsten atoms is about 0.6nm, diameter with core of 100 tungsten atoms is 1.5nm, diameter with core of 1500 tungsten atoms is about 4.2nm, and the core size of 5nm will comprise about 2500 tungsten atoms, and the diameter that comprises the core of 5000 tungsten atoms is about 6.5nm.

More or less have reactivity because contain the core of tungsten, therefore must be with metal-cored coating so that the active surface passivation.The character of coating should provide protection for metal-cored, makes core avoid reaction as igniting, maybe avoid reaction when preparation is used for the body planted agent time spent, maybe avoid reacting when being positioned at internal milieu when being exposed to air following time.Preferably, particle excreted given with the health of this particle before coating should keep its character to arrive such degree, i.e. the tungsten surface of the core activity that can not become.Coating also should provide the nanoparticle of half-life in the body with suitable weak point.If nanoparticle comprises targeting moiety, then can prolong the half-life of particle, but the half-life must be acceptable after considering toxicity.Therefore, importantly coating makes particle have the tendency of low formation aggregation, particularly in vivo.Simultaneously, coating must relative thin so that fully little particle to be provided, the preferred particle size is lower than about 6 to 7nm kidney threshold value, though bigger particle also can be used for this purpose.Combining between metal-cored and the coating also should be enough strong, separates between metal-cored and coating avoiding.

Be used for parenteral when being expelled to vein or intra-arterial when medicine is configured to, the water solublity of nanoparticle must be high.

The viscosity of the medicine of preparation also should be enough low, makes medicine can easily carry out administration.Viscosity is the key factor of parenteral with medicine.For the medicine via the administration of health space outerpace, the importance of viscosity will hang down.The volume fraction of developing agent iopamidol in the aqueous solution of 350mg iodine/ml is 0.26, is 7.6mPas 37 ℃ viscosity.Suppose that for nanoparticle of the present invention, we can use identical volume fraction φ=0.26, wherein aqueous solvent is 37 ℃ viscosities il ₀=0.65310 ^-3Pas, then this solution should be 37 ℃ viscosity:

$\mathrm{\η}={\mathrm{\η}}_0\exp [\frac{5}{2}\mathrm{\φ}/(1-1.43\mathrm{\φ})]\≈1.84\mathrm{mPas}\left(1\right)$

(referring to " The viscosity of a concentrated suspension of sphericalparticles ", Mooney, M.J.Colloid.Sci., vol.6,162 pages, (1951)).This viscosity is low-down for the particle of high concentration like this and depends on the hypothesis that it is a rigid spheres solution.It also is low-down that this viscosity is compared with the viscosity of the x-ray contrast agent that contains iodine.

Tungsten has higher relatively X ray pad value, low toxicity and can acceptable price obtain.

The osmolality of the medicine of preparation is another key factor that influences product toxicity.The osmolality of solution is measured by the dissolved population of per unit solvent (normally water).Preparation with high osmolality is easy to generate more serious adverse, particularly the side effect that is caused by intravenous and intra-arterial injection.Preparation with high osmolality causes that the water transhipment passes semipermeable membrane, produces undesirable physiological effect.Therefore, preparation should be desirably isoosmotic basically, yet to ooze or be hypotonic also be acceptable to slight height.

The concrete form that has been found that coating satisfies the character of discussing, so that the nanoparticle that comprises core and coating that can be used as medicine to be provided, particularly as the contrast agent in the medical imaging, as x-ray contrast agent.

In first embodiment, provide to comprise the metal-cored nanoparticle that applies by charged coating." charged " is meant the chemical entities with band negative or positive electric charge group.The charged coating of each nanoparticle comprises maximum 50 electric charges, preferably maximum 40 electric charges of each nanoparticle, more preferably maximum 25 electric charges of each nanoparticle.Each nanoparticle should comprise and be no less than 4 electric charges, and preferably each particle is no less than 8 electric charges.Charge number depends on the metal-cored size and the size of coated nanoparticle.The coating that comprises the charged group with negative or positive electric charge is that particle is provided in the solution and repels each other, and avoids the formation of nanoparticle aggregate thus basically or partly.Avoid the formation of the aggregate of coated particle to increase the dissolubility of particle.In addition, the viscosity of particle preparation is maintained in the preferred range.

On the other hand, during the preparation of charged particle comprises and counter ion counterionsl gegenions, it causes that osmolality raises.Yet because nanoparticle contains a large amount of tungsten atoms, might obtain with respect to tungsten atom is the solution of 12M, and they typically are 60mM with respect to the number of free particle.Because each electric charge carries counter ion counterionsl gegenions individually, this big edge of generation is used for each particle and accepts some electric charges, oozes preparation because can prepare the grade with the highest 0.5M free particle (comprising counter ion counterionsl gegenions).

Charged group must use therein among the environment pH of chemical compound and be in its ionic species.The most important thing is that they must be charged form at the pH of blood particularly at physiology pH.If medicine is not to be used for parenteral, as pipe and space such as gastrointestinal tract, bladder and uterus administration by the health outside, then coating should be charged form at concrete Target organ pH.

Coating material can comprise the group of band plus or minus electric charge.The anionic group that plays the negative charge effect can be multiple group well known by persons skilled in the art.Acidic-group particularly importantly is as hydroxy-acid group, sulfonic acid group, phosphate group and tart heterocyclic group such as tetrazolium or 5-hydoxyisoxazole.Similarly cation group can be used for this purpose, and multiple group can be used.Can use amino, amidine and guanidine radicals group and the quaternary ammonium or the phosphorio group of alkalescence.

Coating can comprise polymeric material or monomer material.The preferred monomers material coating should comprise the hydrophilic layer of nonmetallic materials, it comprise to the hydrophilic molecule of small part and preferably each molecule have at least one hydrophilic group.Simultaneously, coating should enough cover wicking surface (as, tungsten wicking surface) densely with its passivation.Passivation occurs in wherein on the surface of the core that electron transfer takes place between the surface of metal-complexing group and core.The example of metal-complexing group is with the group A among the following formula An-Lo-Mp.In aspect preferred, coating is a signal layer coating, and it is meant that the thickness of coating has only an one molecule.Monomeric coating has can be made into advantage very thin and coating that have clear and definite character.The effectiveness of nanoparticle depends on the highest possible mark of the tungsten core constituent particle of nanoparticle.Simultaneously, the overall diameter of particle should be little, most preferably is lower than about 6 to 7nm, and it is the renal excretion threshold value that is used for parenteral applications.Directed monolayer also provide improvement to dissolubility and control of Toxicity, because have the outer end of the sharp outline of molecule, wherein hydrophilic group plays as the effect of solubilizing group and can place charged group therein, another end of molecule towards and be incorporated into metal.

In aspect the present invention is preferred, signal layer coating is according to general formula An-Lo-Mp structure, and wherein A is one or more metal-complexing groups, and preferably it is selected from table 1; L is not for existing or exist, and is one or more linking groups when existing, and is preferably selected from table 2; With M be one or more charged and hydrophilic groups, be preferably selected from table 3.Preferred linking group comprises the fragment with any a plurality of tables 2 of the arranged in form of straight chain, side chain or one or more rings.Side chain can be towards A group direction, producing multiple tooth coating, but perhaps its M group branching, to produce higher hydrophilicity.It also is a selection that side chain is all arranged on both direction.The junction fragment of table 2 can be incorporated into the heterocyclic group of phenyl ring or aromatic series or non-aromatic.N is any positive integer, and is preferred 1 to 10, or more preferably 1 to 4.O is zero or any positive integer, and is preferred 1 to 10, more preferably 1 to 2.P is any positive integer, is preferably 1 to 10, more preferably 1 to 4.The indication of the dotted line of group A be connected in W elements key, be connected in the H atom key, be connected in the L-group key, be connected in the key of another A-group or when o is zero, be the key that is connected in the M group.The dotted line of group L represent to be connected in the A group key, be connected in the H atom key, be connected in the key of another L-group or be connected in the key of M-group.The dotted line of group M represent to be connected in the L group key, be connected in the H atom key, be connected in the key of another M-group or when o is zero, be the key that is connected in the A-group.

Table 1. metal-complexing group A:

Table 2. linking group L:

The R-group is independently for being selected from H and C ₁-C ₆Any group of alkyl, wherein C ₁-C ₆Alkyl is randomly replaced by one or more-OH group and wherein one or more C-atoms can be replaced by ether group.

The polymeric material coating comprise be suitable for medicinal application make each nanoparticle comprise the minimal amount charged group and for hydrophilic any polymer material layer.Coating should enough cover the tungsten surface densely with its passivation.The top layer of polymer can be covalently bonded in metal-cored surface or adsorb and maintenance by noncovalent force.As above described for the monomer coating, preferred coatings is thin as far as possible and provide necessary passivation for the tungsten wicking surface simultaneously.Polymer can be natural or synthetic homopolymer or copolymer.Have many polymer to can be used for this purpose, and those skilled in the art can select suitable polymer as known in the art.Useful polymer classes comprises polyethers (as PEG and its randomly by branching), polyacetals, polyvinyl alcohol and polar derivant, polyester, Merlon, polyamide (comprising aliphatic and aromatic polyamide and polypeptide), carbohydrate such as starch and cellulose, polybutylcyanoacrylate and paracyanogen ylmethyl acrylate, and condition is that polymer comprises minimum charged group and is preferably hydrophilic.The certain preferred polymer of making by acrylic monomers.In order to obtain having the layer of charged group number controlled and that be fit to, also preferred wherein copolymer can comprise 2 or the copolymer of more a plurality of monomer or block.At least a in the monomer should provide charged group for polymer coating.Electric charge increases water solublity and reduces the danger of particle accumulation, but also increases the osmolarity of particle.Therefore, should keep carrying the number minimum of the group of electric charge.In preparation, can be provided for the polymer that diameter is 2 to 6nm nanoparticle to be lower than 20: 1, the neutral monomer of preferred 10: 1 to 10: 1.5 mol ratio combination with suitable charge number with charged monomer.Perhaps, this ratio can further increase.The use of monomer F forms crosslinked polymer.

The monomeric example that is fit to that is used to form polymer coating is:

Usually, the preparation of the nanoparticle of polymer-coated is passed through tungsten (O) source as six carbonylation tungsten W (CO) 6 thermal decompositions in the presence of one or more are monomeric in the solvent of high boiling, exsiccant and deoxidation.Monomeric heat-induced aggregation takes place, and covers by tungsten particle that is decomposed to form with polymer coating.When monomer comprise silicon ether protection polar group (OH ,-COOH) time, protecting group ruptures in aqueous solution, obtains the hydrophilic polymer coating particle.

Usually use exsiccant solvent.Hygroscopicity solvent (diethylene glycol dimethyl ether, triethylene glycol dimethyl ether .) should filter and preserve with molecular sieve together by aluminium oxide.All solvents all should be by passing through solvent 25-30 minute deoxidation with the argon gas stream bubbling before they being used for reaction.The choice of Solvent that is used for this method is vital, because need satisfy several standards.One is to dissolve initiation material and keep the final ability of polymer coating particle in solution simultaneously.Polyethers diethylene glycol dimethyl ether and triethylene glycol dimethyl ether. are at this moment particularly useful.Particularly the high boiling point allowable temperature of triethylene glycol dimethyl ether. reaches the level that last carbon monoxide molecule leaves particle.Other useful solvent is diphenyl ether and other inert high boiling point aromatic compound.Also can use trioctyl phosphine oxide (with other alkyl analog), tri octyl phosphine (with other alkyl analog), high boiling amide and ester.

Another important technical parameter leaves the ability of reactant mixture trend for control W (CO) 6 distillations.This can be by mixing fraction low boiling point solvent realize continuously any solid tungsten hexaarbonyl is washed to get back to the reaction from condenser or wall.When using with 5 to 15% volume fractions, cyclooctane and normal heptane are good selections.

Precipitate and suit by adding pentane or other low boiling alkane for the post processing (work-up) of particle.When will be with particle dry, low boiling point solvent be favourable.

Preparation and post-processing approach will further describe in specific embodiment.

In second embodiment, core is applied with the hydrophilic layer that does not contain charged group.Preferred coatings is the monomer material coating and should comprises nonmetallic hydrophilic layer, as mentioned above, nonmetal molecule comprise the hydrophilic molecule of at least a portion and preferably each molecule have at least one hydrophilic group.

Face coat can comprise targeting moiety, as antibody, antibody fragment, peptide, lipid, carbohydrate, nucleic acid, medicine or medicine fragment, maybe can with drug targeting in the checked health concrete organ or any other molecule of structure.By the organ of targeting or example of structure the component of grumeleuse in Intranet (endoreticular) system, blood flow of liver and spleen, component, tumor marker and the macrophage of atherosclerotic speckle.

The common parenteral of contrast medium is as intravenous, intra-arterial or subcutaneous administration.Contrast medium also can be taken orally or the pipe by the outside for example is administered in gastrointestinal tract, bladder or the uterus.The carrier that is fit to is well known in the art, and it is according to for example route of administration and difference.In the limit of power that is chosen in those skilled in the art of carrier.Usually, use aqueous carrier dissolving or suspended drug such as contrast agent, to produce contrast medium.Can use different aqueous carriers, as water, buffered water, saline, glycine, hyaluronic acid, or the like.

Might prepare and comprise about 1.0 solution to the nanoparticle of the present invention of about 4.5g tungsten/ml solution, more specifically be 1.5 to arrive about 3.0g tungsten/ml water, is in particular about 2.2g tungsten/ml water most.This is equivalent to the W content of about 12M.Preferred typical nanoparticle formulation has 200 to 2500 tungsten atoms in core.

For as medicine, the nanoparticle of tungstenic must be sterilized, this can be undertaken by techniques well known in the art.Particle can provide in sterile solution or dispersion, perhaps provides with dried forms such as freeze dried form.

Below further specify the present invention by non-limiting example.

Embodiment 1 to 5 describes the preparation of the tungsten core of monomer layer coating, and embodiment 6 to 10 describes the charged polymer coating of tungsten core.All temperature all are ℃.

The monomer A of Shi Yonging to G is in an embodiment:

The analysis of polymer coating particle mainly by NMR ( ¹³C, ¹H), IR and XRFS (XFS) carry out.In a kind of situation, obtain the TEM microphotograph.

Usually the 1H NMR peak of broadening is finished with the resonance hint polymerization that lacks in two key ranges.Except that the resonances of the aliphatic portion of polymer, ¹³C NMR spectrum shows the resonance of several little spacings (in the 3ppm) in the carbonyl zone.NMR does not detect the resonance of residual metal carbonyl.

IR spectrum shows the strong absorption of polymer carbonyl and residual metal carbonyl in various degree.

W content in the particle is measured by XRFS.

Use UV-Vis spectroscopy (300-800nm) in the triglycine buffer solution of deoxidation, to carry out the particle degradation experiment.

The electrophoresis experiment that carries out in triglycine buffer (pH 7.5) shows the negative charge of the particle that comprises monomer A and D.

The Malvern Zetasizer instrument of use scattered light scattering (DLS) is used to measure the particle diameter of one of them preparation.

By particle being dissolved in the triglycine buffer (0.1M, pH 7.5) and the solution lyophilization being determined at dissolubility in the water.Measure the dissolubility of the powder that obtains then roughly.

Embodiment 1: by reduction preparation tungsten nanoparticle in organic solvent

Be reflected under the noble gas and carry out.With tungsten compound (as, WCI6) and wherein the coating of the protected base protection of active site be dissolved in non-proton property, with the immiscible organic solvent of water in, and add soluble Reducing agent.After reaction is finished, add entry and organic solvent and be separated two.Organic layer washes and is evaporated to little amount with water.Add big excessive ethanol/water and allow solid precipitation.Solid is filtered and dissolve, repeat precipitation process again.With the particle vacuum drying.

Remove protecting group by the method that is fit to.If needed, by dialysis, steric exclusion chromatography or other technology that is fit to the solution desalination.Final products typically obtain by lyophilization.

Embodiment 2: by reduction preparation tungsten nanoparticle in water

Under inert atmosphere with water miscible tungsten compound such as sodium tungstate and coating molecular melting in the water of deoxidation.Regulate pH to expected value.The Reducing agent that then solution is joined vigorous stirring is in the solution of de aerated water.After reduction fully, the amount of solution is reduced, by dialysis desalting, lyophilizing then obtains final products.

Embodiment 3: by reduction preparation tungsten nanoparticle in reversed phase micelle

Be incorporated in the reversed phase micelle in the organic solvent as water by adding aqueous solution that big fractional surfactant will be adjusted to the water solublity tungsten compound of pH of expectation such as sodium tungstate.

The reversed phase micelle preparation that also prepares similar aqueous reducing agent.

The liquid of tungstenic is joined in the Reducing agent.Add the coating molecule.After balance, add entry with breakdown of emulsion.Collect water and with organic facies with the water washing more than two parts.

The amount of the water collected is reduced and passes through dialysis desalting.

With the aqueous solution lyophilizing, obtain final products then.

Embodiment 4: by tungsten (O) complex being decomposed preparation tungsten nanoparticle

In inert, high boiling solvent such as cyclooctane, heat-labile W (O) complex such as W (CO) 6 are decomposed under the coating molecule of the protected base protection of active site therein such as the existence of acrylic acid hexyl ester.After reacting completely, add polar solvent such as ethanol, with the powder filter and the washing of black.

Remove protecting group by for example hydrolysis or other method that is fit to.The amount of solution is reduced and desalination.With the aqueous solution lyophilizing, obtain final products then.

Embodiment 5:N, two (2-hydroxyethyl) the acrylate coatings tungsten nanoparticles of N-synthetic

Be reflected under the airfree condition and carry out.With tungsten carbonyl and N, two (the 2-dimethyl tert-butyl group siloxy ethyl) acrylate of N-are dissolved in the cyclooctane and are heated to backflow, continue 12 hours.Vacuum remove most of solvent and with the residue of black with methanol wash three times.

Remove protecting group by hydrolysis in 10% formic acid.

With the liquid evaporation, residue is dissolved in the water and after drying.Product forms black powder, and its floating coat comprises molecule H ₂C=C-CO-N (CH ₂-CH ₂OH) ₂

Embodiment 6: comprise the preparation of the polymer coating tungsten nanoparticle of monomers B and C

In the round-bottomed flask that is equipped with magnetic stirring apparatus and condenser, add: six carbonylation tungsten W (CO), 6 (500mg; 1.4mmol), glycol monoethyl ether acrylate (C) (390mg; 3.0mmol) and the 2-propyloic acrylic ester (B) of trimethyl silyl protection (120mg, 0.55mmol).For condenser equipment barrier film and apply several vacuum/argon circulation with from flask and condenser air-out.Use syringe to add the diethylene glycol dimethyl ether (30ml) and the heptane (2ml) of deaeration by barrier film.Under argon atmospher, reactant mixture is heated to backflow.After 3 hours, will be reactant mixture cool to room temperature now with dark solution of a small amount of black precipitate, (60ml is last and centrifugal to be poured over the pentane of deaeration.

Precipitate is washed and vacuum drying with pentane.

Yield: 430mg grey black toner end.The XRFS analysis shows that W content is about 60%.

Illustrate: need heptane to prevent the distillation of six carbonylation tungsten, be deposited in the condenser.The spontaneously cracking in aqueous solution of three silicyl protecting groups obtains preferred carboxylate G.

Particle has the core of the crystallinity tungsten that is covered by the C of combined polymerization and B.Particle is about 4 to 5nm.

Embodiment 7: comprise the preparation and the analysis of the polymer coating tungsten nanoparticle of monomers B and D

With six carbonylation tungsten (440mg, 1.2mmol), (970mg, 5.0mmol) (300mg 1.1mmol) joins in the glass flask that is equipped with condenser and magnetic stirring apparatus monomers B with monomer D.Flask and condenser are through several vacuum/argon circulation, to obtain argon gas atmosphere.Add cyclooctane (30ml) by the barrier film on the condenser top with syringe.Reaction solution is stirred and be heated to backflow, continue 18 hours.In first hour process, solution darkens at leisure, finally becomes black (as espresso).After finishing the response time, with the solution cool to room temperature and be poured on the pentane (50ml).The slurry that obtains is centrifugal and precipitate washed and vacuum drying with pentane.

Yield: the powder of 400mg dark color

Analyze

1H NMR: the resonance of broadening appears at (ppm) 4.3,4.1,3.8,3.5,2.8,2.7-2.2,1.8-1.2,0.8,0.1.

IR：1939w，1852w，1731vs，1560m。

XFS：57％W

Dissolubility in water:＞500mg/ml.

Embodiment 8: comprise the preparation and the analysis of the polymer coating tungsten nanoparticle of monomer A and C

According to the method for embodiment 7 with six carbonylation tungsten (500mg, 1.4mmol), (120mg, 0.55mmol) (390mg 3.0mmol) joins in the glass flask monomer A with monomer C.Add diethylene glycol dimethyl ether (30ml) and heptane (2ml) by condenser.The reaction solution stirring is heated to backflow then, continues 3 hours.The dark powder of yield: 410mg.

Analyze:

1H NMR: the resonance of broadening appears at (ppm) 4.1,3.5,3.2,2.5-2.2,1.9-1.3.

IR：1995w，1894w，1727vs，1540s。

XFS：55％W。

TEM: the microphotograph that obtains shows that the core of particle is of a size of 3-4nm.

Degradation experiment: in whole spectrum (300-800nm), absorb and successively decrease with index law.At the most, be absorbed in 4.3 hours and reduce by 22% (at 350nm).

Electrophoresis experiment: the mobile hint of particle is electronegative.

Embodiment 9: comprise the preparation and the analysis of the polymer coating tungsten nanoparticle of monomer E

According to the method for embodiment 7 with six carbonylation tungsten (2.3g, 6.5mmol) and monomer E (7.6g 32mmol) joins in the glass flask.Add cyclooctane (100ml) by condenser.The reaction solution stirring is heated to backflow then, continues 60 hours.

Analyze:

The particle diameter of measuring total particle weight of particle diameter 99% by dynamic light scattering is 5.8-7.8nm.

Embodiment 10: comprise the preparation and the analysis of the polymer coating tungsten nanoparticle of monomer A, C and F

With six carbonylation tungsten (1.0g, 2.8mmol), triethylene glycol dimethyl ether. (45ml) and heptane (3ml) place the glass flask that is equipped with condenser and magnetic stirring apparatus.Flask and condenser are through several vacuum/argon circulation, to obtain argon gas atmosphere.With slurry heating and stir up to dissolving.Solution is heated to 160 ℃ then, thereafter by barrier film with syringe add monomer C (1.8g, 14mmol), monomer A (280mg, 1.3mmol) and monomer F (280mg, mixture 1.4mmol).Solution was stirred 3 hours at 165-170 ℃.After finishing the response time, with the solution cool to room temperature and be poured on the pentane (50ml).The slurry that obtains is centrifugal and precipitate washed and vacuum drying with pentane.The dark powder of yield: 800mg.

Analyze

1H NMR: the resonance of broadening appears at (ppm) 4.2,3.5,3.3,2.3,2.0-1.4.

IR：1921w，1825w，1727vs，1534m。

Claims (53)

1. particle, it comprises randomly the core with other metallic element metallic element tungsten together, the coated coating of wherein said core.

2. the particle of claim 1, its diameter are 1.5 to 20nm.

3. claim 1 and 2 particle, its diameter is 1.5 to 15nm.

4. the particle of claim 1 to 3, its diameter are 1.5 to 7nm.

5. the particle of claim 1 to 4, its diameter are 2 to 6nm.

6. each particle in the aforementioned claim, wherein the core of particle has the W content of 20 to 100 weight % tungstens.

7. each particle in the aforementioned claim, core wherein has the W content of 50 to 100 weight % tungstens.

8. each particle in the aforementioned claim, core wherein has the W content of 85 to 100 weight % tungstens.

9. each particle in the aforementioned claim, core wherein has the W content of 95 to 100 weight % tungstens.

10. each particle in the aforementioned claim, core wherein has the W content of about 100 weight % tungstens.

11. each particle in the aforementioned claim, wherein the core of particle comprises in element rhenium, iridium, niobium, tantalum or the molybdenum of tungsten and metallic forms one or more.

12. each particle in the aforementioned claim, its floating coat comprises charged coating.

13. the particle of claim 12, wherein charged coating provide clean plus or minus electric charge in the pH of the environment of using particle.

14. each particle in the claim 12 to 13, wherein charged coating provides negative charge in the pH of the environment of using particle.

15. each particle in the claim 12 to 14, wherein charged coating provide the clean negative charge of acidic-group such as hydroxy-acid group, sulfonic acid group, phosphate group and acid heterocyclic group.

16. the particle of claim 12 to 13, wherein charged coating provide the clean positive charge of amino, amidine, guanidine, quaternary ammonium and the phosphorio group of alkalescence.

17. each particle in the claim 12 to 16, wherein the charged coating of each particle comprises maximum 50 electric charges.

18. each particle in the claim 12 to 17, wherein the charged coating of each particle comprises maximum 40 electric charges.

19. each medicine in the claim 12 to 18, wherein the charged coating of each particle comprises maximum 25 electric charges.

20. each particle in the claim 12 to 19, wherein the charged coating of each particle comprises at least 8 electric charges.

21. each particle in the claim 12 to 20, wherein the charged coating of each particle comprises at least 4 electric charges.

22. each particle in the claim 12 to 21, wherein this layer comprises the polymeric layer with charged group.

23. the particle of claim 22, wherein polymeric layer comprises hydrophilic polymer.

24. each particle in the claim 22 to 23, wherein polymer comprises homopolymer.

25. each particle in the claim 22 to 24, wherein polymer comprises copolymer.

26. each particle in the claim 22 to 25, wherein polymer is formed by acrylic monomers.

27. each particle in the claim 22 to 26, wherein polymer is formed by at least a monomer that contains charged group.

28. each particle in the claim 22 to 27, wherein polymer is formed by at least a neutral monomer.

29. each particle in the claim 22 to 28, wherein the mol ratio between neutral monomer and the charged monomer is lower than 20: 1.

30. the particle of claim 29, wherein the mol ratio between neutral monomer and the charged monomer is 10: 1 to 10: 1.5.

31. each particle in the claim 1 to 11, its middle level comprises monomer layer.

32. the particle of claim 31, wherein monomer layer comprises hydrophilic monomer layer.

33. the particle of claim 32, wherein said hydrophilic layer comprises the hydrophilic molecule of at least a portion.

34. each particle in claim 31 and 32, wherein said hydrophilic layer comprise that each has the molecule of at least one hydrophilic group.

35. each particle in claim 1 to 11 and 31 to 32, wherein said core applies with signal layer coating.

36. the particle of claim 35, wherein said signal layer coating comprises formula A _n-L _o-M _pChemical compound, wherein A is one or more tungsten coordinating groups, L is not for existing or for one or more linking groups, M is one or more hydrophilic groups, n and p are positive integer, o is zero or positive integer.

37. each particle in the claim 31 to 36, wherein monomer layer comprises charged coating.

38. the particle of claim 37, wherein charged coating comprises the charged group of claim 13 to 21.

39. medicine, it comprises the particle in optional and pharmaceutically useful solvent or the excipient aforementioned claim together.

40. diagnostic medicine, it comprises randomly the particle with solvent or excipient claim 1-38 together.

41.X ray-contrast media, it comprises randomly the particle with solvent or excipient claim 1-38 together.

42. the particle of claim 1 to 38 is as the application of body interimage agent.

43. the particle of claim 1 to 38 is as the application of x-ray contrast agent.

44. diagnostic method, it comprises the particle to the mankind or animal health administration claim 1 to 38, with diagnostic device have a physical examination and edit the data of self-check.

45. formation method is in particular the x-ray imaging method, it comprises the particle to the health administration claim 1 to 38 of the mankind or animal, uses imaging device with body imaging, edit the data and the analytical data randomly of self-check.

46. the method for particle of preparation claim 1 to 30, it is included under one or more monomeric existence in the solvent of high boiling, exsiccant and deoxidation tungsten (0) thereby the source is decomposed and realized thermoinducible monomer polymerization.

47. the method for claim 46, wherein tungsten (0) source is six carbonylation tungsten (W (CO) ₆).

48. the method for claim 46 and 47, wherein solvent comprises diethylene glycol dimethyl ether and triethylene glycol dimethyl ether., diphenyl ether, trialkyl phosphine and trialkyl phosphine.

49. the method for claim 48, wherein solvent comprises trioctyl phosphine oxide and tri octyl phosphine.

50. the method for claim 46 to 49, solvent wherein high boiling, exsiccant and deoxidation comprises a part of lower boiling solvent in addition.

51. the method for claim 50, wherein the fraction of lower boiling solvent comprises cyclooctane and/or the normal heptane of 5 to 15 volume %.

52. the method for claim 46 to 51, its further comprise the particle that will form from lower boiling alkane particularly from the pentane post processing.

53. the method for claim 46 to 52, wherein one or more monomers comprise the polar group of silicon ether protection, and wherein protecting group in aqueous solution cracking to obtain the hydrophilic polymer coating particle.