CN1863866A - Finely particulate composite containing carbon compound encapsulated therein - Google Patents
Finely particulate composite containing carbon compound encapsulated therein Download PDFInfo
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- CN1863866A CN1863866A CNA2004800294828A CN200480029482A CN1863866A CN 1863866 A CN1863866 A CN 1863866A CN A2004800294828 A CNA2004800294828 A CN A2004800294828A CN 200480029482 A CN200480029482 A CN 200480029482A CN 1863866 A CN1863866 A CN 1863866A
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- B82—NANOTECHNOLOGY
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Abstract
This invention provides a finely particulate composite wherein a fine particle of block copolymer having a poly(ethyleneglycol) chain segment and a poly(meth)acrylate ester chain segment containing, on its side chain, a tertiary amino group and/or a secondary amino group has, encapsulated therein, a carbon compound, e.g., fullerene or carbon nanotube which may contains, encapsulated therein, a metal. This composite is water-soluble, and is usable as an active oxygen scavenger. This composite, when it has a metal encapsulated therein, is usable as a contrast medium.
Description
Technical field
The present invention relates to the complex body of fine particle, this complex body is with except that graphite and diamond, and carbonatoms is interior formation of works (or copolymer micelle) that the carbon compound inclosure of the closed shell structure of 30-2000 is formed by segmented copolymer; Be surrounded by the complex body of fine particle of metal ultra micro small-particle and the application of these complex bodys in relating in this fine particle further.
Background technology
The soccerballene and the carbon nanotube that only have the closed shell structure that constitutes by carbon atom, owing to its novel texture is expected to be used for many technical fields, for example medicine, in-vivo diagnostic, makeup etc.
But soccerballene is water-insoluble, uses soccerballene to exist certain restriction in these technical fields.Therefore, the someone provides to making the solvable various Fullerol (for example with reference to Japanese kokai publication hei 7-048302 communique) that imported hydroxyl on the soccerballene carbon atom of soccerballene.In addition, the somebody has proposed to coat on the interior soccerballene surface that belongs to covered with gold leaf the scheme of polyose, and this polyose has functional group's (for example with reference to Japanese kokai publication hei 7-048302 communique) of the sulfo group of being selected from, ketone group, amino and alkyl.
In addition, there is report to show: the acryloyl morpholine oligopolymer or the N of fluoro-alkyl chain that gone up addition endways, add soccerballene and fully stirring in the aqueous solution of N-DMAA oligopolymer etc., the soccerballene amount reaches the thing of group certainly (self-assembly) of about 100 μ g/ml (with reference to Journal of Colloid and Interface Science after can obtaining solubilization, 263, (2003), 1-3 page or leaf).And, also known to forming the following C of containing
60Polymkeric substance make soccerballene possess solubility, this C
60Polymkeric substance is by utilizing soccerballene (soccerballene C for example
60) the Receptive electric charge of electronics move complexingization and form, perhaps for example polyoxyethylene glycol, Polyvinylpyrolidone (PVP), polymethyl acrylic acid (dimethylamino) ethyl ester etc. carry out grafting to soccerballene and form by using hydrophilic polymer; Naturally also to C
60-b-polymethyl acrylic acid (dimethylamino) ethyl ester provide and physical properties has carried out studying (Dai etc., Langmuir 2004, PAGE EST:6.8A-G).And provided such enlightenment: to form in aqueous solvent with the soccerballene be nuclear, be the micella of shell with the polymkeric substance, can make this block polymer possess solubility.
Summary of the invention
Aforesaid prior art makes soccerballene obtain certain success aspect solvable.Journal of Colloid and Interface Science for example, 263, (2003), 1-3 page or leaf report:, can obtain the water-soluble thing of group certainly of bringing up to about 100 μ g/ml by will original water-solublely being the soccerballene of 21.0 μ g/ml and above-mentioned oligopolymer stir about 5 days at room temperature., when using in technical fields such as medicine, in-vivo diagnostic, makeup, the solubleness of described soccerballene can't meet the demands fully.On the other hand, contain C
60Polymkeric substance also can improve the water-soluble of soccerballene, but its preparation is not too easy.So the purpose of the present application is to provide stable, aqueous solution or the dispersion liquid that contains soccerballene, fine particle and the simple method for preparing and the purposes of soccerballene that be provided at the inclosure that has high-dissolvability more in the water simultaneously.
With the people's such as K.Kataoka of the common book of part contriver of the present invention Macromolecules 1999,32, on the 6892-6894 page or leaf, in body, be transferred to the means of transporting effectively of target as DNA etc., DNA and polyoxyethylene glycol-block-polymethyl acrylic acid 2-(N, N-dimethylamino) is provided the polymer micelle complex body of ethyl ester.On the other hand, the inventor finds: by with rerum natura, structure all with the diverse C such as DNA with anionic charge
60Segmented copolymers such as soccerballene and polyoxyethylene glycol-block-polymethyl acrylic acid 2-(N, N-dimethylamino) ethyl ester form complex body in the aqueous solution, can make the effective solubilising of this soccerballene.And, confirmed that also the complex body that the solubilizing method by described improvement forms compares with the complex body that obtains by traditional method, demonstrate higher water-solublely, can keep stable high concentration solution's state.
Also confirm can provide according to the solubilizing method of described improvement the complex body of fine particle, this complex body demonstrates high-dissolvability in water, and can be in aqueous solvent stable existence, described fine particle is not only limited to C
60Soccerballene comprises also that the carbonatoms of vast scope is 30-2000, is preferably the carbon compound of the closed shell structure of 60-120, also comprises the situation that belongs to the ultra micro small-particle covered with gold leaf in this carbon compound.Simultaneously, also confirmed the following fact: only enclosed the works of the segmented copolymer of this carbon compound, had the very strong effect of removing the active oxygen in the aqueous solvent, can extensively be conveniently used in food, medicine and cosmetic field.
Therefore, the invention provides a kind of complex body of fine particle, this complex body is to coat in fact the carbon compound of the closed shell structure that is made of 30-2000 carbon atom and the complex body of the fine particle that forms with polymer chain, it is characterized in that: this fine particle is enclosed carbon compound in works, described works is formed by the segmented copolymer that contains polymer segment and polyoxyethylene glycol segment, and a kind of in the past segment is as kernel, a kind of segment in back contains the repeating unit that possesses uncle's amino and/or secondary amino group on side chain as shell as the polymer segment of kernel.
Invention as other modes, the preparation method of the complex body of above-mentioned fine particle also is provided, it is characterized in that: the carbon compound of the closed shell structure that will be in fact constitutes by 30-2000 carbon atom, the segmented copolymer that contains polymer segment and polyoxyethylene glycol segment dissolves in the bipolarity non-protonic solvent, mix, polymer segment in the wherein said segmented copolymer contains the repeating unit that possesses uncle's amino and/or secondary amino group on side chain, be that the dialysis membrane of 12000-14000 is dialysed to aqueous solvent by molecular weight cut-off subsequently, this carbon compound is sealing in the works that is formed by segmented copolymer, thereby obtains the complex body of fine particle.
As the invention of other modes, it is the active oxygen eliminating agent of effective constituent that the complex body with above-mentioned fine particle also further is provided.
Invention as other modes, a kind of complex body of fine particle also further is provided, this complex body is to coat in fact the carbon compound of the closed shell structure that is made of 30-2000 carbon atom and the complex body of the fine particle that forms with polymer chain, it is characterized in that: this fine particle is enclosed carbon compound in works, described works is formed by the segmented copolymer that contains polymer segment and polyoxyethylene glycol segment, and a kind of in the past segment is as kernel, a kind of segment in back contains the repeating unit that possesses uncle's amino and/or secondary amino group on side chain as shell as the polymer segment of kernel; And be surrounded by the ultra micro small-particle of the metal of metallic element or its ionic forms in the closed shell structure of this carbon compound.
The complex body of the fine particle of making according to the present invention, even preparing after freeze-dried making under pulverous situation, also as easy as rolling off a logly in water, disperse or dissolve, form transparent or homogeneous phase and stable solution, so the present invention also can provide Powdered thing with high density.
The accompanying drawing summary
Fig. 1 is the ESR spectrogram of PBS.
Fig. 2 is the ESR spectrogram of the soccerballene complex body aqueous solution of the present invention.
Fig. 3 is the figure that supplies energy with respect to the active oxygen that the soccerballene concentration of the soccerballene complex body aqueous solution of the present invention is marked and drawed.
Fig. 4 replaces drawing to represent transmission electron microscope (TEM) observations of the soccerballene complex body of interior bag Gd of the present invention with photo.
The preferred forms of invention
" being made of ... carbon atom in fact " meaning that the present invention mentioned is meant so long as in order to realize the object of the invention, then except that carbon atom, can also contain and account for below 10% of carbonatoms, preferred below 5%, the more preferably hydroxyl below 1%, oxo base etc.But the said carbon compound of the present invention especially preferably only contains the carbon compound of carbon atom.In addition, the closed shell structure is not limited to certain structure, except the known structure that can obtain soccerballene or carbon nanotube etc., also comprise the carbon atom close packed grid structure or can folk prescription to or the grid structure of twocouese bending, the structure of putting down in writing in for example international open (WO) No. 93/15768 brochure.But, consider purposes of the present invention, the said carbon compound of the present invention is preferably so-called football shaped structure, especially more preferably those known C own
60, C
84, C
32, C
50, C
66, C
70, C
76, C
78, C
90, C
96And C
120Soccerballene.
On the other hand, can form the segmented copolymer of the works (or polymer micelle) of having enclosed described carbon compound, contain segment from polyoxyethylene glycol as the hydrophilic polymer segment, and contain the polymer segment that is included in the repeating unit that has uncle's amino and/or secondary amino group on the side chain, purpose of the present invention is as long as make for example C
30-C
120Soccerballene or up to C
2000Till carbon nanotube can be dissolved in the water effectively, then can be any molecular species.
But, preferably contain to come monomeric segment shown in the self-drifting (A):
[in the formula, R
1aExpression hydrogen atom or C
1-6Alkyl; R
2aAnd R
3aIndependent expression C
1-6Alkyl, perhaps R
2aAnd R
3aNitrogen-atoms that can be coupled forms 5 or 6 yuan of heterocycles that also can contain 1 or 2 nitrogen-atoms, 1 oxygen or sulphur atom together; X represents-O-or-NH-; And p is the integer of 2-6.]。
As for alkyl that uses in the above-mentioned definition etc., C
1-6Alkyl is the straight or branched alkyl with 1-6 carbon atom, for example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl etc.In addition, work as R
2aAnd R
3aWhen coupled nitrogen-atoms formed 5 or 6 yuan of heterocycles together, its example had following each heterocycle.
Hydrophilic polymer segment that is prepared in advance above-mentioned and the polymer segment polymkeric substance separately that contains the repeating unit that on side chain, has uncle's amino and/or secondary amino group, by using the known method of attachment in present technique field to make it to connect, it can be embedded as the segment in the used segmented copolymer of the present invention.In addition, as the additive method that the segmented copolymer that uses among the present invention can be provided, can the monomer corresponding to another kind of block be increased in an end polymerization of this polymkeric substance by preparing to be equivalent to wherein any segmental polymkeric substance earlier.Preparation method to the segmented copolymer that uses among the present invention is not particularly limited, representative example as described method, the method that records such as above-mentioned Kataoka are for example arranged, and, segmented copolymer shown in the following general formula (A-1) that obtains according to this method, can use expediently in the present invention:
[in the formula, R
1Expression hydrogen atom or C
1-6Alkyl; R
2And R
3Independent expression C
1-6Alkyl, perhaps
R
2And R
3Nitrogen-atoms that can be coupled form together also can contain 1 or 2 nitrogen-atoms,
5 or 6 yuan of heterocycles of 1 oxygen or sulphur atom;
X ' expression-O-or-NH-; And
P ' is the integer of 2-6;
L represents C
1-6Alkylidene group or valence link,
Y represents hydrogen atom, hydroxyl, carboxyl, amino, acetalation formyl radical or formyl (or aldehyde) base;
M is 1-10,000 integer;
N is 10-20,000 integer; And
P ' is the integer of 2-6.]。
The works (or polymer micelle) of having enclosed carbon compound is meant the surface that fully coats this carbon compound by above-mentioned segmented copolymer, thereby makes this carbon compound water soluble and the object that constitutes.Works is not particularly limited, described works preferably in aqueous solvent block copolymer compile the molecule agglomerate that forms, for carbon compound being enclosed wherein as nuclear, the polymer segment that contains the repeating unit that possesses uncle's amino and/or primary amino on side chain with segmented copolymer constitutes inner core or central part, and coat outside (in this manual, described molecule agglomerate be also referred to as polymer micelle) with the polyoxyethylene glycol segment.When in above-mentioned and this specification sheets, using, aqueous solvent can be understood as water, can be with the mixing solutions of water blended organic solvent (for example ethanol, acetone, N, dinethylformamide (DMF), methyl-sulphoxide (DMSO), acetonitrile etc.) and water, in water or this mixing solutions, also can contain the solution of buffer reagent and/or osmotic pressure regulator.
Though be not subjected to theoretic restraining, but can think: water-soluble high polyoxyethylene glycol segment is mobile high in aqueous medium in the said structure thing, can be coated on the works surface with the brush shape, therefore, even in hypothesis water-insoluble carbon compound is enclosed under the inner situation, also can be made works integral body solvable at the water camber.
The complex body of the fine particle that is made of described works can obtain by following method: for example add soccerballene in the aqueous solution that has dissolved segmented copolymer, through long-time stirring method; In addition, also can by with carbon compound and segmented copolymer making for example dissolving in the methylene dichloride etc. of the two dissolved solvent, remove then and desolvate, make the residue polymer micelle that dissolved is general gradually in water prepare employed method subsequently., the inclosure that obtains by these methods the complex body of fine particle of carbon compounds such as soccerballene, as a rule, all be in the water solubleness be subjected to limiting the complex body of (for example, about 100 μ g/ml are following).
The inventor further studies described preparation method, results verification: by the following method in the inefficient method category of the formation that is considered to polymer micelle usually, promptly, make with carbon compound headed by the soccerballene and segmented copolymer and in the bipolarity non-protonic solvent, dissolve, the complex body of the fine particle of obtaining by dialysis treatment subsequently, compare with the complex body of obtaining by aforesaid method, demonstrate solubleness in the obviously high water (more than for example about 500 μ g/ml, for example being about 1mg/ml-4mg/ml).Therefore, as a mode of the present invention, also provide the preparation method of the complex body of above-mentioned fine particle.
As spendable bipolarity non-protonic solvent among the described preparation method, as long as above-mentioned high solubleness can be provided, can not limit its kind to use, but preferred DMF and DMSO.At first, make with carbon compound headed by the soccerballene and segmented copolymer and be dissolved in the described solvent.Dissolved order can be dissolved carbon compound, segmented copolymer subsequently in order respectively, on the contrary, and segmented copolymer, carbon compound or the two is dissolved simultaneously subsequently.During dissolving, can be warming up to the boiling point of solvent as required, also can at room temperature handle.In addition, when dissolving and mixing, can be with the solution ultrasonication.The solution that so obtains as required, by removing by filter insoluble substance, at room temperature static then certain hour (a few hours are to a night).Afterwards, dialyse with respect to water, preferred distilled water via the dialysis membrane of required molecular weight cut-off.Dialysis usually with respect to non-treatment soln be about water more than 10 times carry out 2 hours, more than 3 times, dialyse a whole night at last.Simultaneously, preferably use the dialysis membrane of molecular weight cut-off as 12000-14000, more preferably dialysis membrane makes its abundant swelling with distilled water before use.Above-mentioned operation all can at room temperature be carried out, and (40-80 ℃) carries out under also can or heating up at (for example 0-5 ℃) under the cooling as required.So can efficient is good must make complex body, this complex body is to make carbon compound be enclosed in the complex body of the fine particle in the polymer micelle, in room temperature, for example the solubleness in 25 ℃ of distilled water is more than the 500 μ g/ml.Concentration in mixed solution is not particularly limited to carbon compound and segmented copolymer, as long as can be dissolved in the solvent for use, common volume with respect to solution, the suitable consumption of carbon compound is in the scope of 0.001% weight-10% weight, and segmented copolymer is in the scope of 0.001% weight-2% weight.
So only enclose the complex body of the fine particle of carbon compound, only only carbon compound has been enclosed in the works of segmented copolymer, in aqueous medium, just shown strong active oxygen elimination effect.So, can cause the environment of bad influence at active oxygen, particularly inside and outside body, use as active oxygen eliminating agent.As concrete use object, can use in the field that can advantageously use organic or inorganic antioxidant or superoxide-dismutase (SOD) etc., the oxidative degradation, cosmetic field that field of food for example prevents lipid be the anti-aging skin-protecting agent for example, perhaps aspect medical for example as uses such as carcinostatic agents.
The preparation method of the complex body of the fine particle that provides according to a mode as the invention described above, when even the complex body of the ultra micro small-particle that belongs to covered with gold leaf replaces above-mentioned carbon compound in adopting, also can provide solubleness in the water high or in aqueous medium, can keep stable homodisperse liquid.
So as other modes, the present invention also provides a kind of complex body of fine particle, it is characterized in that: the metal ultra micro small-particle that belongs to element or its ionic forms covered with gold leaf in the closed shell structure of above-mentioned carbon compound.Described metal as long as can for example use in the technical fields such as medical treatment, diagnosis, food improving the technical field of availability by being dissolved in aqueous medium, then can be any metal.Therefore, as the metal that contrast medium adopted that uses in the inspection of any organ injury of disease or body or the diagnosis, for example, be selected from the paramagnetic metal of the element of gadolinium (Gd), europium (Eu), terbium (Tb) and erbium (Er), and the metal etc. of element that the oxide compound of zinc, copper, magnesium, iron, platinum etc. can be provided, can use as the metal that the present invention mentioned.These metals also can be the ionic forms.These metals can be wrapping in the carbon compound in the ultra micro small-particle state, and so-called ultra micro small-particle, be typically its size can in wrap in particle in above-mentioned soccerballene or the carbon nanotube.A soccerballene part that is surrounded by metal like this is commercially available, can directly use; Perhaps can make by itself known method, the method for in above-mentioned Japanese kokai publication hei 8-143478 communique, putting down in writing for example, by with the purpose metal oxide with graphite, under High Temperature High Pressure, its evaporation is waited and obtains with laser.
With the metal ultra micro small-particle that is surrounded by metallic element or its ionic forms in the closed shell structure of carbon compound is the fine particle complex body of feature, to the optimal way of segmented copolymer etc. wherein, be the same with the above-mentioned complex body of only having enclosed carbon compound.
Like this, for example the carbon compound of interior bag paramagnetic metal element is sealing in the works (or polymer micelle) that forms by segmented copolymer and the fine particle complex body that forms, under the aqueous medium middle and high concentration, can keep stable, therefore can be used as and drop into the contrast medium that uses in the blood vessel.
Below, with reference to object lesson the present invention is described in further detail, but the present invention is not subjected to the qualification of these examples.
The preparation example of block polymer
(structural formula of acetal-PEG/PAMA)
Under argon gas, in 200ml eggplant shape beaker, add 50ml distilled tetrahydrofuran (THF) as solvent, (Mw=148 is d=0.941) as initiator to add 157 μ l 3,3 '-diethoxy-1-propyl alcohol.Add 2.73ml potassium naphthalide (K-Naph (c=0.3656mol/l)) then and make its metallization.(EO (Mw=44, d=0.88)) stirred 2 days under water cooling then to add the 5.68ml ethylene oxide subsequently.After 2 days, the sample that takes a morsel is analyzed with GPC, adds 4.29ml methacrylic acid 2-(N, N-dimethylamino) ethyl ester (PAMA then; MW=157.21), stirred 30 minutes down, use the gpc analysis sample ice-cooled.Add the methyl alcohol stopped reaction at last.
After the stopping of reaction, carry out the heavy again hall of Virahol, centrifugation, the freeze-dried back of benzene is reclaimed.
The molecular weight of the polymkeric substance of purifying is PEG/PMAMA=4,500/5,500.
The preparation example 1 of complex body: make the stably dispersing of soccerballene in water by dialysis method
In 25ml solvent dimethyl formamide (DMF), add 1mg soccerballene, 13.8mg segmented copolymer (F: P=1: 1 o'clock), make C
60Soccerballene: the mixing ratio of acetal-PEG/PMAMA segmented copolymer (PEG/PAMA=4,500/5,500) (F: P) be 1: 0,1: 0.5,1: 1, carry out 6 hours ultrasonication after, leave standstill a night.Then this solution is encased in distilled water make its swelling the molecular weight cut-off at one night be in the dialysis membrane of 12000-14000, dialyse (exchanging 3 times water).By the freezing solution drying of the fine particle of bag soccerballene in the 30ml that will so obtain, remove and desolvate, add 5ml distilled water afterwards, make its redispersion.And then carry out DLS and measure.
The concentrated solution that so obtains presents the distinctive chocolate of soccerballene.Can produce turbidity though concentrate when not having segmented copolymer, though the complex body that obtains according to the present invention after freeze-dried also as easy as rolling off a log in water dispersing and dissolving.To ratio of mixture is F: P=1: 1,1: 0.5 solution, and carry out DLS once more and measure, found that: though increased before the photon counting ratio concentrates redispersion, compare, fail to obtain enough photon countings with the value of former mensuration.Can infer thus: the soccerballene particle of making under these conditions like this, disperse with the following molecularity dispersive form that roughly approaches of particle diameter (being about 3nm) that scattering of light can detect.
The preparation example 2 of complex body: make C by the bubbling method
60The stably dispersing of soccerballene in water
The 1mg soccerballene is blended in the 25ml dichloromethane solvent, utilizes ultrasonic wave that it is dissolved in methylene dichloride.Then, 139mg acetal-PEG-PMAMA segmented copolymer (PEG/PMAMA=4,500/5,500) is added in the solvent, ultrasonication left standstill a night after 2 hours.
The dichloromethane solution of making thus is added drop-wise in the distilled water of the decent argon gas bubbling of 40ml.That is so put down in writing in the solution of preparation and the above-mentioned preparation example 1 is the same, and the complex body of the fine particle with light yellow transparent solution is provided.Decentralized stabilization soccerballene complex solution in the water that obtains is carried out DLS measure, it is millimicro particle about 170nm that results verification has formed particle diameter.
The preparation example 3 of complex body: the preparation example of high density fullerene water solution
At room temperature with 100mg C
60Soccerballene is blended in the DMF solution of 150ml, carries out 3 hours ultrasonication.Afterwards, with solution with the hydrophobic filter of 0.45 μ m (manufacturing of ミ リ Port ア society) remove desolvate in not molten material, add acetal-PEG-PMAMA segmented copolymer (PEG/PMAMA=5 subsequently, 000/5,900), make polymer concentration reach 5mg/ml, and make it to leave standstill a night with respect to solvent.Then, the molecular weight cut-off that this solution is encased in one night of in distilled water swelling is in the bag of dialysis membrane system of 12000-14000, with respect to DMF: 2 liters of distilled water (150: 2000) dialyse (exchange 5 times water, exchange in the time of the 2nd, 4,6,8,10 hour was reclaimed after 24 hours).
Afterwards, will be through the freezing solution drying of dialysis treatment, make powder after, use the distilled water of 400 μ l that this sample is dissolved again, carry out ultraviolet visible spectrum and measure, calculate its solubleness from the absorbancy of soccerballene, soccerballene can be dissolved in the water with the high density of 2.9mg/ml as a result.
The complex body of the fine particle of affirmation inclosure soccerballene is to the elimination effect of active oxygen
In container, add the spin trapping agent 5 of 30 μ l in order with 2 times of MilliQ dilutions, 5-dimethyl-1-pyrroline N-oxide compound (DMPO), 50 μ l use through MilliQ and are modulated into 5mM xanthoglobulin (HPX), the 20 μ l 9.625mM diethylenetriamine-N that the phosphate buffer solution (PBS) of 100mM is made, N, N '; N "; N "-pentaacetic acid (DTPA), each 50 μ l sample (1.PBS, 2. soccerballene solution), 50ml 0.4U/ml XOD (XOD), use ESR to carry out spectroscopic measurement after second adding XOD90.
The condition determination of ESR spectrometry is: be input as 9mW, central magnetic field is 339.9mT, scans the width of cloth to be ± 5mT, and the modified tone width of cloth is 79 μ T, and be 1 minute sweep time, and amplification is 630, and the reaction times (time constant) is 0.1 second.
The ESR spectrogram of enclosing soccerballene fine particle solution as the polymer micelle of the PBS of sample and acetal-PEG-PMAMA segmented copolymer (PEG/PMAMA=5,000/5,900) respectively as depicted in figs. 1 and 2.By these spectrograms are carried out integration, compare its area, can compare the inhibition effect of active oxygen.Area with the PBS that uses the effect of non-activity oxygen quenching is 100% o'clock, and the area of fine particle solution is about 30%.
Fig. 3 represents to supply with respect to the active oxygen that soccerballene concentration is marked and drawed the result of energy.Obtain IC from this result
50 soccerballenes=361.76 μ g/ml.
The preparation and the mensuration of water relaxation time of the soccerballene of interior bag gadolinium and the complex body of acetal-PEG-PMAMA segmented copolymer
C with bag Gd in the 1mg
82Soccerballene (Gd@C
82) mix with 10mg DMF, carry out 3 hours ultrasonication.Then, add acetal-PEG-PMAMA segmented copolymer (PEG/PMAMA=5,000/5,900), make its concentration reach 5mg/ml, carry out 1 hour ultrasonication with respect to DMF.Subsequently, the molecular weight cut-off that above-mentioned treatment solution is encased in one night of in distilled water swelling is in the bag of dialysis membrane system of 12000-14000, with respect to 2 liters of distilled water dialyse (exchanged water 3 times, exchange in the time of the 2nd, 5,10 hour is reclaimed after 24 hours then).Replace drawing to represent transmission electron microscope (TEM) observations of made sample with photo, as shown in Figure 4.
With a) Gd@C that makes
82The complex body of/segmented copolymer and b) C
60The complex body of/segmented copolymer is dissolved in H respectively
2O: D
2O=50: in 50 the mixed solvent, make sample.Absorbancy by ultraviolet visible spectrum calculates soccerballene concentration, is respectively (a) 23.36 * 10
-3MM and (b) 31.93 * 10
-3MM.
Relaxation time is measured (T
1Measure) measure by setting condition determination respectively, at first use zero method to obtain T
1Zero point, infer T according to this value
1
The index that the expression relaxation time shortens effect is mitigation degree (or relaxing energy, relaxivility (R)), if C is contrast concentration (mmol/l), and T
10Be the vertical relaxation time before the radiography (the vertical relaxation time of solvent just), T
1pFor giving the relaxation time (relaxation time in the presence of sample) behind the contrast medium, then R is defined as following formula.
Here, the 1/T reciprocal of relaxation time
1Be called as mitigation speed (relaxation rate), as the term suggests be the index that expression relaxes speed.In addition, mitigation degree (R) expression contrast medium distributes in tissue, relaxes what speed up when reaching unit concentration.Promptly the meaning is meant that the mitigation speed facilitation effect (relaxation time shortens effect) of the big more then contrast medium of R value is big more.
According to each sample concentration and T
1, solvent for use relaxation time calculate mitigation degree R, compare research.The result is as shown in table 1.Can be clear and definite from table 1: Gd@C
82The R value of the complex body of/polymkeric substance is significantly high, is expected to use with contrast medium as MRI.
Table 1
| Sample | T 1(second) | R 1 |
| Gd@C 82/ polymkeric substance | 2.726 | 13.36 |
| C 60/ polymkeric substance | 4.402 | 5.4 |
| D 2O+H 2O | 18.271 | 0 |
Industrial applicability
According to the present invention, the complex of the fine particle of fullerene or CNT or the interior fullerene that belongs to covered with gold leaf and block copolymer owing to can make fullerene solubilising in water, therefore can enlarge fullerene in the scope of application in the fields such as medicine, diagnosis medicine. So the present invention can be used for pharmaceutical industry etc.
Claims (14)
1. the complex body of a fine particle, this complex body is that the carbon compound of the closed shell structure that is made of 30-2000 carbon atom in fact is aggregated the complex body that the thing chain coats the fine particle that forms, it is characterized in that: this fine particle is enclosed carbon compound in works, described works is formed by the segmented copolymer that contains polymer segment and polyoxyethylene glycol segment, and a kind of in the past segment as shell, contains the repeating unit that on side chain possess uncle amino and/or secondary amino group as the polymer segment of kernel as kernel, a kind of segment in back.
2. the complex body of the fine particle of claim 1, the solubleness of this complex body in 25 ℃ distilled water is more than the 0.5mg/ml.
3. the complex body of the fine particle of claim 1, the wherein said polymer segment that contains the repeating unit that possesses uncle's amino and/or secondary amino group on side chain comes from monomer shown in the general formula (A), and the solubleness in 25 ℃ distilled water is more than the 0.5mg/ml,
In the formula, R
1aExpression hydrogen atom or C
1-6Alkyl; R
2aAnd R
3aIndependent expression C
1-6Alkyl, perhaps R
2aAnd R
3aCan form 5 or 6 yuan of heterocycles that also can contain 1 or 2 nitrogen-atoms, 1 oxygen or sulphur atom with the nitrogen-atoms that it connected; X represents-O-or-NH-; And p is the integer of 2-6.
4. the complex body of each fine particle among the claim 1-4, wherein said segmented copolymer is represented by general formula (A-1):
In the formula, R
1Expression hydrogen atom or C
1-6Alkyl; R
2And R
3Independent expression C
1-6Alkyl, perhaps R
2And R
3Can form 5 or 6 yuan of heterocycles that also can contain 1 or 2 nitrogen-atoms, 1 oxygen or sulphur atom with the nitrogen-atoms that it connected;
X ' expression-O-or-NH-; And
P ' is the integer of 2-6;
L represents C
1-6Alkylidene group or valence link;
Y represents hydrogen atom, hydroxyl, carboxyl, amino, acetalation formyl radical or formyl (or aldehyde) base;
M is 1-10,000 integer;
N is 10-20,000 integer; And
P ' is the integer of 2-6.
5. the complex body of each fine particle among the claim 1-4, the C of wherein said carbon compound for only constituting by carbon atom
30-120Soccerballene.
6. the preparation method of the complex body of the fine particle of claim 1, it is characterized in that: the carbon compound of the closed shell structure that will be in fact constitutes by 30-2000 carbon atom, the segmented copolymer that contains polymer segment and polyoxyethylene glycol segment dissolves in the bipolarity non-protonic solvent, mix, wherein the polymer segment in the segmented copolymer contains the repeating unit that possesses uncle's amino and/or secondary amino group on side chain, be that the dialysis membrane of 12000-14000 is dialysed to aqueous solvent by molecular weight cut-off subsequently, this carbon compound is sealing in the works that is formed by segmented copolymer, obtains formed fine particle thus.
7. contain the active oxygen eliminating agent of the complex body of each fine particle among the claim 1-5 as effective constituent.
8. the active oxygen eliminating agent of claim 7, this remover uses in food, medical treatment or skin science or cosmetic field.
9. the complex body of a fine particle, this complex body is that the carbon compound of the closed shell structure that is made of 30-2000 carbon atom in fact is aggregated the complex body that the thing chain coats the fine particle that forms, it is characterized in that: this fine particle is enclosed carbon compound in works, described works is formed by the segmented copolymer that contains polymer segment and polyoxyethylene glycol segment, and a kind of in the past segment as shell, contains the repeating unit that on side chain possess uncle amino and/or secondary amino group as the polymer segment of kernel as kernel, a kind of segment in back; And be surrounded by the ultra micro small-particle of the metal of metallic element or its ionic forms in the closed shell structure of this carbon compound.
10. the complex body of the fine particle of claim 9, the metal of wherein said metallic element or its ionic forms is a paramagnetic metal.
11. the complex body of the fine particle of claim 10, wherein said paramagnetic metal is formed by the element that is selected from gadolinium, europium, terbium and erbium.
12. the complex body of each fine particle among the claim 9-11, the wherein said polymer segment that contains the repeating unit that possesses uncle's amino and/or secondary amino group on side chain comes from monomer shown in the general formula (A):
In the formula, R
1aExpression hydrogen atom or C
1-6Alkyl; R
2aAnd R
3aIndependent expression C
1-6Alkyl, perhaps R
2aAnd R
3aCan form 5 or 6 yuan of heterocycles that also can contain 1 or 2 nitrogen-atoms, 1 oxygen or sulphur atom with the nitrogen-atoms that it connected; X represents-O-or-NH-; And p is the integer of 2-6.
13. the complex body of the fine particle of claim 12, wherein said segmented copolymer is represented by general formula (A-1):
In the formula, R
1Expression hydrogen atom or C
1-6Alkyl; R
2And R
3Independent expression C
1-6Alkyl, perhaps R
2And R
3Can form 5 or 6 yuan of heterocycles that also can contain 1 or 2 nitrogen-atoms, 1 oxygen or sulphur atom with the nitrogen-atoms that it connected;
X ' expression-O-or-NH-; And
P ' is the integer of 2-6;
L represents C
1-6Alkylidene group or valence link;
Y represents hydrogen atom, hydroxyl, carboxyl, amino, acetalation formyl radical or formyl (or aldehyde) base;
M is 1-10,000 integer;
N is 10-20,000 integer; And
P ' is the integer of 2-6.
14. the complex body of fine particle that contains claim 11 or 12 is as the contrast medium of effective constituent.
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|---|---|---|---|
| JP2003352666A JP4746834B2 (en) | 2003-10-10 | 2003-10-10 | A complex of fine particles encapsulating carbon compounds |
| JP352666/2003 | 2003-10-10 | ||
| JP033696/2004 | 2004-02-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1863866A true CN1863866A (en) | 2006-11-15 |
| CN100577728C CN100577728C (en) | 2010-01-06 |
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ID=34543531
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Cited By (1)
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| CN101695996B (en) * | 2009-11-09 | 2012-05-30 | 上海交通大学 | Preparation method of carbon nano tube composite material based on amino polyphosphazenes |
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| JPH09235235A (en) * | 1996-02-29 | 1997-09-09 | Res Inst For Prod Dev | Fullerene-binding water-soluble polymer photosensitizer for photodynamic therapy |
| JP2002241307A (en) * | 2001-02-19 | 2002-08-28 | Yasuhiko Tabata | Active oxygen generating agent for ultrasonic therapy containing photosensitizer |
| JP4094277B2 (en) * | 2001-11-09 | 2008-06-04 | 独立行政法人科学技術振興機構 | Preparation of metal nanoparticles using shell-crosslinked micelles as templates |
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| CN101695996B (en) * | 2009-11-09 | 2012-05-30 | 上海交通大学 | Preparation method of carbon nano tube composite material based on amino polyphosphazenes |
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