CN101284161A - Microparticle with double function of radiotheraphy and thermotherapy and preparation method thereof - Google Patents
Microparticle with double function of radiotheraphy and thermotherapy and preparation method thereof Download PDFInfo
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- CN101284161A CN101284161A CNA2008100380823A CN200810038082A CN101284161A CN 101284161 A CN101284161 A CN 101284161A CN A2008100380823 A CNA2008100380823 A CN A2008100380823A CN 200810038082 A CN200810038082 A CN 200810038082A CN 101284161 A CN101284161 A CN 101284161A
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Abstract
The invention discloses particulates with double functions of internal radiotherapy and thermal therapy, and a preparation method thereof. The particulates are mainly compounded and formed by glass containing radioactive species yttrium-90 or/and phosphorus-32, and solid ferrite with magnetocaloric effect. When the particulates intervene in vivo, the radioactive species yttrium-90 or/and the phosphorus-32 contained in the glass can release Beta rays in vivo to kill cancer cells intervening in surrounding tissues without damaging the distant healthy tissues; the solid ferrite has good hysteresis exothermicity and can transform exosomatic magnetic energy into heat energy so as to release heat under the action of an external alternating magnetic field, so that the temperature around the tumor area can raise to 43 to 47 DEG C within a short time, and tumour cells intervening in the surrounding tissues are burnt and killed without influencing normal cells with better heat tolerance, thereby realizing the purpose of treating tumor by combining the internal radiotherapy and the thermotherapy, and having double lethality to cancer cells. The method for combining the radiation treatment and the heat treatment is an indispensable supplementary therapy means to treat the malignant tumor with chemical drug resistance. In addition, the particulates have good chemical stability and biocompatibility, and have great application prospect in the aspect of treating the malignant tumor.
Description
Technical field
The invention belongs to technical field of biological material, relate to microgranule with body internal radiotherapy and thermotherapy dual-use function and preparation method thereof.Mentioned microgranule can be launched the β ray that range is short, energy is low in vivo as the body internal source, and cancerous cell is carried out direct radiation, kill cancer cell but can not damage near normal tissue cell; Can add under the action of alternating magnetic field simultaneously, become the body endogenous pyrogen, the heating tumor cell makes the tumor region temperature reach 43～47 ℃, thus kill cancer cell, and normal cell is unaffected.
Background technology
Tumor is the maximum killer who threatens human life's health, and according to World Health Organization's statistics, the whole world has 6,350,000 people to die from malignant tumor every year approximately, and being equivalent to just had people's death in per 5～6 seconds.The method of treatment tumor has chemical medicinal treatment, actinotherapy, excision and heating therapy, yet these methods all have certain limitation, lacks specificity as common chemical medicinal treatment, does not also treat the specific medicament of tumor at present; And after using chemotherapy for several times, tumor cell has improved drug resistance, continue after the Drug therapy curative effect fall sharply.And traditional external beam radiation therapy and whole body radio-frequency (RF) thermotherapeutic have also caused injury to normal cell in the kill tumor cell; Excision then brings on the physiology and psychological misery to patient.Therefore, kill tumor cell and, be the target that scientist pursues for many years always how optionally to the not damage of normal cellular machine soma.
Interior radiation microsphere is used for treatment of cancer starts from the seventies in last century.So-called microsphere is the microgranule that a class contains radionuclide, and its diameter is the carrier of radioactive source between 15～100 μ m.The ray that microsphere sends only kills and wounds cancerous cell, and can not damage normal histiocyte.Through a series of test, scientist just considers with glass microsphere as the radiation source carrier up to the beginning of the eighties, and first patent (U.S. Pat P4,789,501) occurred in 1984, has made to contain yttric glass microsphere.Radiation source 90Y nucleic and glass microsphere are closely linked, can prevent effectively that nucleic from leaking in vivo, after zoopery, enter the human clinical in Canada and try out, demonstrate good curative effect, later period of hepatocarcinoma patient's three annual survival rates are reached more than 50% in beginning in 1989.And begin to be listed in formal use medicine in 2000 by Food and Drug Administration in U.S. test in nineteen ninety-five.After this, this single radiation is controlled cancer the cure rate of cancer is further improved.
The magnetic heating therapy of tumor is to utilize tumor cell different to the sensitivity of heat with normal cell, by magnetic nano-particle is injected or the implantation tumour tissue, under the effect of externally-applied magnetic field, produce heat then, again the heat that produces is discharged to tumor tissues, because the blood supply in the tumor is not as the normal structure abundance, cause in the tumor cell heat diffusion slower, the result causes local temperature to raise (generally being controlled between 42～47 ℃), thereby reaches the purpose of kill tumor cell.In recent years, adopt the research of the magnetothermal effect treatment tumor of magnetic nano powder to cause people's extensive concern, the nano-powder that is adopted mostly is Fe
3O
4Or γ-Fe
2O
3Magnetic powder.As Chinese patent CN200310106498.1, CN200510041048, U.S. Pat 7,282,479 B2, US 6,074, and 337 grades disclose the tumor magnetic thermotherapy iron oxide magnetic powder and preparation method thereof with high magnetic hysteresis caloricity.This kind powder body has higher magnetic hysteresis and gives birth to heat, has excellent biological compatibility, can not discharge poisonous element in the body fluid environment, no teratogenesis, mutagenic action; Also have good non-oxidizability and heat stability simultaneously, be applied gradually in the thermotherapy field.But this single hot Procarbazium also can't make the cure rate of cancer further improve.
Clinical research shows, the X-ray therapy treatment malignant tumor that combines with thermotherapy can be obtained better effects.Therefore, according to radiotherapy and thermotherapy characteristics and complementarity, prepare a kind of material that can be simultaneously malignant tumor be carried out radiotherapy and thermotherapy and obviously will have good application prospects.
Summary of the invention
The object of the present invention is to provide a kind of microgranule that has interior radiotherapy of body and thermotherapy dual-use function simultaneously and preparation method thereof.Microgranule with this method preparation has the function of body internal radiotherapy function and thermotherapy, can in patient's body, continue emission β ray within a certain period of time, and release heat under the effect that adds alternating magnetic field utilizes lonizing radiation and thermotherapy to work along both lines kill cancer cell; This microgranule also has good chemical stability and biological safety in addition, can not damage patient's normal structure.
In order to achieve the above object, solution of the present invention is:
A kind of novel composite particles has the interior radiation function of emission β ray kill cancer cell, also has heating under the action of alternating magnetic field, the thermotherapy function of high temperature killing tumor cells adding.
Radiation function is meant that this microgranule can be at radionuclide (90Y in described, phosphorus-32, iodine-125, rhenium-188) continues the definite β ray of tumor region emitted energy towards periphery in half-life, disturb the reproduction process of DNA in the tumor cell, thereby kill near the cancerous cell of microgranule or the merisis of anticancer.
Described thermotherapy function is meant under the effect that adds alternating magnetic field, the ferrite particle that contains in this particle is because the magnetic hystersis loss release heat, but make within a short period of time the tumor region temperature be increased to 42～47 ℃, tumor cell is heated, utilize the characteristic of tumor cell heat-transfer capability than normal tissue cell difference, tumor is carried out local heat, thus the kill tumor cell, but can not influence the Normocellular preferably function of heat resistance.
This microgranule by the glassy phase that contains yttrium-89 and/or phosphorus-31 nucleic or contain iodine, rhenium isotope and the ferrite ceramics that contains low Curie temperature mutually, the composite particles of making by biphase surface active.After will containing glass microsphere, granule or the modification of columnar-shaped particle usefulness surface modifier of yttrium-89 and/or phosphorus-31 nucleic, bond mutually, promptly obtain to have the compound system of thermotherapy and internal radiotherapy double effects under the high temperature behind the heat treatment with the ferrite ceramics powder.
Above-mentioned preparation method with microgranule of radiotherapy and warm treatment dual-use function comprises:
(1) prepares the glassy phase that contains yttrium-89 and/or phosphorus-31 nucleic or contain iodine, rhenium isotope
1. fusion method prepares the glassy phase that contains yttrium-89 nucleic and phosphorus-31 nucleic respectively: the composition of two kinds of glass is respectively: 40%Y
2O
3, 40%SiO
2, 20%Al
2O
3And 20%MgO, 60%P
2O
5, 20%Al
2O
3, according to its corresponding composition, respectively 1550-1650 ℃ with 1350-1450 ℃ of condition under frit melted became glass melt in 4-6 hour, must not have the clear glass piece of crystallize behind the quenching.
With the glass blocks of above-mentioned two kinds of quenchings pulverize, behind the ball milling, screening obtains the small glass particle that particle diameter is 20～40 μ m.And can further make the glass microsphere that particle diameter is 20～40 μ m by the flame floating method, or before glass quenching, glass melt is adopted czochralski method, above-mentioned pyritous glass melt is lifted into diameter be about the 0.4-0.7mm glass fibre, after the cooling glass fibre is blocked into the cylindric particle of the about 2-6mm of length.
2. above-mentioned glass also can make with sol-gel process.Respectively with the alkoxide or the inorganic salt primary raw material of corresponding metal, obtain the precursor sol of glass through hydrolysis, polycondensation, by the reverse microemulsion method this precursor sol is made the colloidal sol microsphere then, promptly obtain the glass microsphere of particle diameter 10～40 μ m behind the heat treatment.In addition, the fiber that can utilize extrusion molding that colloidal sol is made also, heat treatment obtains diameter and is about 0.4～0.7mm glass fibre, after the cooling glass fibre is blocked into the cylindric particle of the about 2～6mm of length.
(2) preparation ferrite particle
The ferrite particle that microgranule adopted of radiation and thermotherapy dual-use function can be the manganese-zinc ferrite of low Curie temperature in having, and also can be Fe
3O
4Or γ-Fe
2O
3
1. the preparation method of manganese-zinc ferrite: with MnSO
47H
2O, ZnSO
47H
2O, FeSO
47H
2The O pressed powder is a raw material, press the molecular mixed of manganese-zinc ferrite evenly after, join in the sodium hydrate aqueous solution rapidly, and add quantitative sodium carbonate powdery solid and stir, make the subcarbonate presoma, obtain being of a size of the manganese-zinc-ferrite powder of 10～100nm behind the high temperature sintering.
2. Fe
3O
4Nanometer particle process method: utilize chemical coprecipitation, at Ar
2Under the protective atmosphere to FeCl
3And FeSO
4Mixed solution in add strong aqua ammonia, constant temperature stirs the Fe make particle diameter 10～50nm
3O
4Nanoparticle.
3. γ-Fe
2O
3Nanometer particle process method: the Fe that 2. above-mentioned steps is made
3O
4Nanoparticle is dispersed in the deionized water, makes suspension, with Fe (NO
3)
3Solution mixes, and 90 ℃ of ageings obtain γ-Fe that particle diameter is about 10～100nm
2O
3
(3) preparation surface modifier:
Surface modifier can be siliceous surfactant, as the gel of silicon or the coupling agent of silane series; Also can be phosphorated surface modifier, as the gel of phosphorus or the inorganic high polymer fluid of phosphoric acid and its esters series:
1. the preparation method of silicon gel: ethyl orthosilicate (TEOS), ethanol, water are mixed, make catalyst with dilute hydrochloric acid, room temperature stirs down, make water white silicon gel after the ageing, or directly adopts the commodity silane coupler.
2. the preparation method of the inorganic high polymeric liquid of phosphoric acid and its esters series: under the high temperature with H
3PO
4Mix with metal oxide powder (, it is complete to be stirred well to oxide dissolution, obtains the high polymeric liquid of thickness phosphate.
(4) preparation of whole composite particles
Composite particles with dual-use function can be made complex microsphere, also can make cylindric compound particle:
1. the preparation method of complex microsphere: will contain the glass microsphere of yttrium-89 and/or phosphorus-31 nucleic, and handle and dry with siliceous surface modifier.Under argon or nitrogen protection atmosphere, apply and to contain the silicon gel of ferrite powder or the inorganic high polymer fluid that coating contains ferrite powder, obtain having the spherical particle of interior radiotherapy and thermotherapy dual-use function behind 400～500 ℃ of heat treatments.Its structure as shown in Figure 1, spheroid is the glass microsphere that contains yttrium-89 or phosphorus-31 nucleic in the middle of among the figure, the spherical small-particle of dense distribution is a ferrite particle around the microsphere, the silicon after being heat treatment between ferrite particle and the glass microsphere or the remaining inorganic matter of phosphorus.
2. the preparation method of composite cylindrical shape particle:
(a.) adopt the glass particle of columned yttrium-89 and/or phosphorus-31 nucleic, use and 1. identical method, make cylindric shape particle with interior radiotherapy and thermotherapy dual-use function.Its structure as shown in Figure 2, intermediate cylindrical is the glass particle that contains yttrium-89 or phosphorus-31 nucleic among the figure, coccode that is dispersed in around it is ferrite particle, is the silicon behind the heat treatment or the remaining inorganic matter of phosphorus between them.
(b.) adopt the glass particle of erose yttrium-89 and/or phosphorus-31 nucleic, with with 1. identical method, before 400～500 ℃ of heat treatments, to contain glass particle and ferritic slurry, inject mould molding, heat treatment obtains having the cylindric shape particle of interior radiotherapy and thermotherapy dual-use function then.Its structure as shown in Figure 3, irregularly shaped particle is the glass particle that contains yttrium-89 and/or phosphorus-31 nucleic among the figure, coccode is a ferrite particle, is the silicon behind the heat treatment or the remaining inorganic matter of phosphorus between two kinds of particles.
In addition, for the microgranule that adopts the distinct methods preparation,, should take different vivo inserted methods according to the difference on its form and the size.Particle for the microsphere form, because its size less (particle diameter 20～40 μ m), have and to flow in moving/vein blood vessel with blood, and the characteristics of thromboembolism in blood capillary, therefore can take the tremulous pulse injection mode, an amount of microsphere is injected specific arteries, make its with blood flow to tumor region, and near the final blood capillary of thromboembolism tumor tissues.Simultaneously,, therefore can also add outside under the effect of high-intensity magnetic field microsphere is carried out external guiding, make it can be positioned at tumor region more accurately because microsphere has good magnetic responsiveness; (the subcutaneous puncture operation is taked in diameter * height=0.5 * 2mm), gets involved in the body for cylindric particle.In surgical procedures, after tangible tumor tissues excision, utilize puncture needle with cylindric particle, thrust the suspected tumor zone by grain.
The microgranule with interior radiation and thermotherapy dual-use function that the present invention is mentioned can be by behind the operation implantation tumour position, and at the external alternating magnetic field that applies, microgranule is because magnetic hystersis loss effect release heat.Because tumor tissues medium vessels quantity is few with respect to normal structure, thus its heat-conductive characteristic than normal cell a little less than, the heat that microgranule produces is collected at tumor tissues, be difficult to heat loss through conduction, cause the tumor tissues temperature to raise, when temperature reached 42～47 ℃, tumor cell was dead rapidly.This moment, the manganese-zinc ferrite particle reached its Curie temperature, and by the ferromagnetic paramagnetic phase that changes into mutually, microgranule stops heating.Normal tissue cell is because blood supplies abundance, and heat conductivity is better, and thermostability is better than tumor cell, thereby can not influence its normal physiological function owing to temperature is too high.Simultaneously microgranule is launched the β ray towards periphery, disturbs the reproduction process of DNA in the tumor cell, thus final kill tumor cell or suppress it and continue division.Because the β ray energy is less, and range is short (about 0.5～2mm), so the β ray coverage that microgranule discharges less relatively (only limit to microgranule around about 2mm diameter range), thereby can not cause excessive damage by near the normal cell of tumor.This microgranule also has good chemical stability and biocompatibility in addition; elements such as the yttrium that contains in the microgranule, phosphorus, ferrum are difficult for stripping in the body fluid environment; human body cell is not had obvious toxic and side effects, and do not have teratogenesis, mutagenicity, thereby can be widely used in field of cancer.
Description of drawings
Fig. 1 is the spherical compound particle sketch map of the embodiment of the invention, and among the figure: 1-contains the glass microsphere of yttrium-89 or phosphorus-31 nucleic, the coccoid ferrite particle of 2-, remaining inorganic matter behind the 3-heat treatment.
Fig. 2 is the cylindric compound particle sketch map one of the embodiment of the invention, and among the figure: 1-contains the cylindric glass particle of yttrium-89 or phosphorus-31 nucleic, the coccoid ferrite particle of 2-, remaining inorganic matter behind the 3-heat treatment.
Fig. 3 is the cylindric compound particle sketch map two of the embodiment of the invention, among the figure: the 1-glass particle that contains yttrium-89 or phosphorus-31 nucleic in irregular shape, the coccoid ferrite particle of 2-, remaining inorganic matter behind the 3-heat treatment.
Fig. 4 contains the glass particle and the γ-Fe of yttrium-89 nucleic for the usefulness of the embodiment of the invention
2O
3The accumulation weight loss that the cylindric compound particle of preparation is immersed in the normal saline changes sketch map.
Fig. 5 contains the glass microsphere and the γ-Fe of phosphorus-32 nucleic for the usefulness of the embodiment of the invention
2O
3The accumulation weight loss that the spherical compound particle of preparation is immersed in the normal saline changes sketch map.
Fig. 6 contains the glass particle of yttrium-89 nucleic and the cylindric compound particle magnetic hysteresis caloricity test result sketch map of manganese-zinc ferrite preparation for the usefulness of the different quality of the embodiment of the invention.
The specific embodiment
The present invention is further illustrated below in conjunction with the accompanying drawing illustrated embodiment.
Embodiment 1. usefulness contain the glass particle and the γ-Fe of yttrium-89 nucleic
2O
3Preparation has the particle of radiotherapy and thermotherapy dual-use function and measures its chemical stability:
The glass particle and the γ-Fe that contain yttrium-89 nucleic with particle diameter 20～40 μ m
2O
3Powder mixes is ground, and wherein the content of glass particle is 75%, γ-Fe
2O
3The content of powder is 25% (mass percent).Measure 10ml concentration and be 85% phosphoric acid, add the 5ml deionized water, 100 ℃ are stirred fast; Take by weighing 2.49gAl
2O
3Powder slowly adds H
3PO
4Aqueous solution in, continued stir about 15 minutes, treat Al
2O
3Dissolving obtains white thickness aluminum phosphate high polymer fully.Get 20g glass particle and γ-Fe
2O
3Mixed powder, mix with the aluminum phosphate high polymer that makes, stirred 1～2 minute under 100 ℃ of conditions, inject mould molding, 500 ℃ of heat treatments 1 hour promptly obtain being of a size of diameter * height=0.5 * 2mm, and the higher compound particle of intensity.
Under 37 ℃ of conditions, be the ratio of 1g: 100ml, microgranule is immersed in the normal saline according to particle mass and normal saline volume ratio.Every 24 hours microgranule is removed, done, measure and soak back particle mass m with the deionized water wash after bake
2, with the quality m that soaks preceding microgranule
1Difference be the amount of stripping in the immersion process, then the weight-loss ratio of microgranule in the unit interval is:
(the results are shown in Table 1, Fig. 4)
Table 1 normal saline soaks particle mass to be changed
| Time/day | 3 | 7 | 14 | 28 |
| Weight loss/％ | 0.090 | 0.145 | 0.190 | 0.235 |
As can be seen, particle is after soaking 28 days from chart, and the accumulative total weight-loss ratio is very low, is 0.235% only, and illustrating only has trace substance stripping from particle, shows that this particle has better chemical stability.
With the 1g glass microsphere: the ratio of 100ml NaOH solution, the glass microsphere that will contain the phosphorus-31 nucleic is dispersed in the NaOH solution of 5mol/L magnetic stirrer 48 hours.Subsequently microsphere is separated with the NaOH solution centrifugal, with microsphere washing three times, thoroughly remove the residual NaOH of microsphere surface, 80 degree oven dryings 12 hours with deionized water.Getting the dry good glass microsphere of 2g is dispersed in the mixed solution of 100ml ethanol and 40ml deionized water, add 0.11ml KH550, after the magnetic stirrer 12 hours, with ethanol, deionized water glass microsphere is washed three times respectively, thoroughly remove microsphere surface unreacted KH550 completely, 80 degree oven dryings 10 hours.
2ml ethyl orthosilicate (TEOS), 30ml ethanol, 5ml water are mixed, drip a small amount of 1mol/L dilute hydrochloric acid, the control pH value stirred 12 hours under 25 ℃ of conditions in 4～5 scopes, and water white silicon gel was made in ageing in 12 hours.The 5g ferrite powder is dispersed in the above-mentioned silicon gel of 50ml, stirred fast 30 minutes, make the silicon gel that contains the ferrite decentralized photo.Getting 2.5g mixes with above-mentioned silicon gel with the glass microsphere that contains the phosphorus-31 nucleic that NaOH and KH550 handled; 25 ℃ of condition lower magnetic force agitators stirred 12 hours; after the glass microsphere centrifugalize that makes; use ethanol and deionized water wash three times respectively; 500 ℃ of heat treatments are 2 hours under argon or nitrogen protection atmosphere, obtain having the complex microsphere of interior radiotherapy and thermotherapy dual-use function
Under 37 ℃ of conditions, be the ratio of 1g: 100ml according to particle mass and normal saline volume ratio, microgranule is immersed in the normal saline.Every 24 hours microgranule is removed, done, measure and soak back particle mass m with the deionized water wash after bake
2, with the quality m that soaks preceding microgranule
1Difference be the amount of stripping in the immersion process, then the weight-loss ratio of microgranule in the unit interval is:
(the results are shown in Table 2, Fig. 5)
Table 2 normal saline soaks microspheres quality to be changed
| Time/day | 3 | 7 | 14 | 28 |
| Weight loss/％ | 0.220 | 0.365 | 0.480 | 0.535 |
As can be seen, microsphere is after soaking 28 days from chart, and the accumulative total weight-loss ratio is very low, is 0.535% only, and illustrating only has trace substance stripping from microsphere, shows that this microsphere has better chemical stability.
Embodiment 3. usefulness contain the glass particle of yttrium-89 nucleic and the manganese-zinc ferrite preparation of low Curie temperature has the microgranule of radiotherapy and thermotherapy dual-use function and measures its magnetic hysteresis exothermicity
With the glass particle that contains yttrium-89 nucleic of particle diameter 20～40 μ m and manganese-zinc ferrite powder according to 1: 1 quality than mixed grinding, the powder body that is uniformly mixed.Measure 10ml concentration and be 85% phosphoric acid, add the 5ml deionized water, 100 ℃ are stirred fast; Take by weighing 2.49gAl
2O
3Powder slowly adds H
3PO
4Aqueous solution in, continued stir about 15 minutes, treat Al
2O
3Dissolving obtains white thickness aluminum phosphate high polymer fully.Get 20g glass particle and γ-Fe
2O
3Mixed powder, mix with the aluminum phosphate high polymer that makes, stirred 1～2 minute under 100 ℃ of conditions, inject mould molding, 500 ℃ of heat treatments 1 hour promptly obtain being of a size of diameter * height=0.5 * 2mm, compound particle.
The intermediate frequency alternating magnetic field generator that the mensuration of the magnetic hysteresis caloricity of sample adopts Nanjing Univ. Instrument Factory to produce, its rated power is 8kW, and operating frequency is 55～65kHz, and maximum magnetic field strength is about 7kA/m.It is last that microgranule is pulverized, getting the different quality sample places in the sealing device that fills the 1ml distilled water, be placed on the water temperature of measuring in the different time with alcohol thermometer in the coil then and change (as shown in Figure 6), the result shows, when the heating of composite particles and environment heat radiation towards periphery reached balance, temperature remained on the designed temperature spot.
The above-mentioned description to embodiment is can understand and apply the invention for ease of those skilled in the art.The person skilled in the art obviously can easily make various modifications to these embodiment, and needn't pass through performing creative labour being applied in the General Principle of this explanation among other embodiment.Therefore, the invention is not restricted to the embodiment here, those skilled in the art should be within protection scope of the present invention for improvement and modification that the present invention makes according to announcement of the present invention.
Claims (14)
1. novel composite particles, it is characterized in that: this microgranule has can discharge Beta-ray ability; Adding under the action of alternating magnetic field, this microgranule can change extraneous magnetic energy into heat energy and release heat.
2. novel composite particles according to claim 1 is characterized in that: described " can discharge Beta-ray ability " is meant that this microgranule can continue the β ray that regional towards periphery emitted energy is determined in the half-life of radionuclide; Described " changing extraneous magnetic energy into heat energy and release heat " is meant under the effect that adds alternating magnetic field, and this particle is because the magnetic hystersis loss release heat can make particle peripheral region temperature be increased to 42-47 ℃ in 10-40 minute.
3. novel composite particles according to claim 1 is characterized in that: this microgranule has good chemical stability and biocompatibility, soaks in external physiology simulated solution after 28 days, and the accumulation weight-loss ratio is 2.35～5.35 * 10
-3G/g, per day dissolution rate are 0.84～1.91 * 10
-4G/gd, the trace element stripping quantity reaches the requirement of safe handling in the microgranule; Excellent biological compatibility does not produce rejection phenomenon in vivo.
4. novel composite particles according to claim 2, it is characterized in that: this radionuclide comprises 90Y, phosphorus-32, iodine-125, rhenium-188 contains yttrium-89 and/or phosphorus-31 nucleic or isotopes such as iodine or rhenium in the glassy phase of this microgranule, these yttriums-89 in the glass and/or phosphorus-31 nucleic or iodine or rhenium isotope are activated into 90Y and/or phosphorus-32 nucleic or iodine-125 under neutron bombardment, rhenium-188 can discharge the β ray.
5. novel composite particles according to claim 1, it is characterized in that: contain Curie temperature in this microgranule and be 42-47 ℃ ferrite ceramics phase material, be ferromagnet at normal temperatures, the magnetic hysteresis heating effect is arranged, can add release heat under the action of alternating magnetic field, make particle peripheral region temperature be increased to Curie temperature; When temperature is higher than Curie temperature, ferrite changes paramagnet into by ferromagnet, and no hysteresis effect stops heating, therefore can control the heating temp of particle automatically between 42-47 ℃.This microgranule also can be to contain the ferrite ceramics phase material that Curie temperature is higher than 47 ℃, and the heating temp of controlling particle by the length that adds the action of alternating magnetic field time is between 42-47 ℃.
6. according to arbitrary described novel composite particles in the claim 1 to 5, it is characterized in that: this microgranule by the glassy phase material that contains yttrium-89 and/or phosphorus-31 nucleic or iodine or rhenium isotope with contain ferrite ceramics material mutually, by surfactant, two kinds of materials are composited get involved the microgranule of interior therapeutic; Complex method be adopt surfactant to glassy phase material and ferrite ceramics mutually material carry out surface modification, the two can be bondd mutually, thereby makes composite particles; Usually the surface modifier that is adopted comprises siliceous or/and phosphorated macromole organic or inorganic gel; Wherein, the gel of silicon can be the surfactant of silane series, and the gel of phosphorus can be the inorganic high polymeric liquid of phosphoric acid and its esters series.
7. novel composite particles according to claim 6 is characterized in that: contain the glassy phase material of yttrium-89 nucleic in this microgranule, its compositing range is: Y
2O
35-50%, SiO
220-70%, Al
2O
35-40%; As containing the glassy phase of phosphorus-31 nucleic in this microgranule, its main compositing range is P
2O
520-75%, MgO 5-20%, Al
2O
35-40%, as contain or when iodine or rhenium isotope, its content is not more than 10% is added to during glass forms the above-mentioned mass percent wt% that is as doping; This glassy phase material can be obtained by the high-temperature melting method quenching, also can make by sol-gel process low temperature is synthetic.
8. novel composite particles according to claim 6 is characterized in that: the ferrite ceramics phase material in this microgranule can be a manganese-zinc ferrite, or Fe
3O
4Or γ-Fe
2O
3In the chemical constituent of ferrite ceramics phase material, iron oxide content is 30-100%, and zinc oxide content is 0-60%, manganese oxide content is 0-60%, particle diameter is 10～50nm to 1-5 μ m, the above-mentioned mass percent wt% that is, and its Curie temperature can be regulated composition as required; Its Curie temperature of ferrite that is used for spontaneously controlling self temperature is chosen for 42～47 ℃; The form of this ferrite ceramics phase material is a powdery, and its size can be from nanoscale to micron order.
9. novel composite particles according to claim 1 is characterized in that: utilize the form of the microgranule with interior radiotherapy and warm treatment dual-use function that distinct methods prepares to have nothing in common with each other, be applicable to different interventional methods; Be shaped as microsphericly, diameter is the particle of 20-40 micron, can be expelled to lesions position by arterial cannulation; Be shaped as cylindricly, diameter is the 0.4-0.7 millimeter, and height is the particle of 2-6 millimeter, and subcutaneous puncture is got involved in lesions position in operation.
10. the preparation method of the described novel composite particles of claim 1 is characterized in that: may further comprise the steps:
(1) contains the preparation of the glassy phase of yttrium-89 and/or phosphorus-31 nucleic;
(2) preparation of ferrite ceramics phase;
(3) preparation of surface modifier;
(4) preparation of dual-use function compound particle.
11. the preparation method of novel composite particles according to claim 10 is characterized in that:
In the step (1):
1. available fusion method prepares the glass that contains yttrium-89 nucleic and phosphorus-31 nucleic respectively, or contains iodine, rhenium isotope doped-glass, makes the glass microsphere that particle diameter is 20～40 μ m by the flame floating method then; In addition, can also adopt czochralski method, above-mentioned pyritous glass melt be lifted into diameter be about the 0.4-0.7mm glass fibre, after the cooling glass fibre that is drawn into be blocked into the cylindric particle of the about 2-6mm of length;
2. available sol-gel process prepares the glass colloidal sol that contains yttrium-89 nucleic and phosphorus-31 nucleic respectively, or contains iodine, rhenium isotope doped-glass colloidal sol, obtains the glass microsphere of particle diameter 20～40 μ m by the reverse microemulsion method; In addition, also heavy-gravity gel can be drawn into fiber, can process behind the heat treatment and obtain the cylindric particle that diameter is 0.4～0.7mm height, 2～6mm.
12. the preparation method of novel composite particles according to claim 10,, it is characterized in that: the ferrite ceramics that is adopted in the step (2) is to can being manganese-zinc ferrite, Fe along with the content difference of Fe2O3
3O
4Nanoparticle and γ-Fe
2O
3Deng nanoparticle:
1. the preparation method of manganese-zinc ferrite: with MnSO
47H
2O, ZnSO
47H
2O, FeSO
47H
2The O pressed powder is a raw material, behind the mix homogeneously, joins in the sodium hydrate aqueous solution according to a certain percentage, and adds quantitative sodium carbonate powdery solid and stir, and makes the subcarbonate presoma, obtains manganese-zinc-ferrite powder behind the high temperature sintering;
2. Fe
3O
4Nanometer particle process method: utilize chemical coprecipitation, at Ar
2Under the protective atmosphere to FeCl
3And FeSO
4Mixed solution in add strong aqua ammonia, constant temperature stirred 60～90 minutes, made the Fe of particle diameter 10～50nm
3O
4Nanoparticle;
3. γ-Fe
2O
3Nanometer particle process method: the Fe that 2. above-mentioned steps is made
3O
4Nanoparticle is dispersed in the deionized water, and being mixed with concentration is 1g γ-Fe
2O
3/ 100ml H
2The suspension of O is with Fe (NO
3)
3Solution mixes, and 90 ℃ of ageings obtain γ-Fe that particle diameter is about 10～100nm
2O
3
13. the preparation method of novel composite particles according to claim 10 is characterized in that:
Surface modifier described in the step (3) can be siliceous surfactant, as the coupling agent of silicon gel or silane series; Also can be phosphorated surface modifier, as the gel of phosphorus or the inorganic high polymer fluid of phosphoric acid and its esters series;
The preparation method of 1. siliceous surfactant: 2ml ethyl orthosilicate (TEOS), 30ml ethanol, 10ml water are mixed, a small amount of dilute hydrochloric acid is made catalyst, room temperature is made water white silicon gel after stirring, the ageing down, compound more required functional group, or directly adopt the commodity silane coupler;
2. the preparation method of the inorganic high polymeric liquid of phosphoric acid and its esters series: according to the 1mol metal-oxide: 3mol H
3PO
4Ratio, with H
3PO
4High temperature mixes with metal oxide powder down, and it is complete to be stirred well to oxide dissolution, obtains the high polymeric liquid of thickness phosphate.
14. the preparation method of novel composite particles according to claim 10 is characterized in that:
The described composite particles with dual-use function of step (4) can be made complex microsphere, also can make bar-shaped compound particle:
1. the preparation method of complex microsphere particle:, handle and dry with siliceous surface modifier with glass microsphere; Under argon or nitrogen protection atmosphere, apply and contain the silicon gel of ferrite powder or the inorganic high polymer fluid that coating contains ferrite powder, behind the heat treatment, obtain having the spherical particle of interior radiotherapy and thermotherapy dual-use function;
2. the preparation method of composite cylindrical shape particle:
(a.) adopt columned glass particle, use and 1. identical method, make cylindric particle with interior radiotherapy and thermotherapy dual-use function;
(b.) adopt irregular glass particle, use and 1. identical method, before heat treatment,, inject mould molding, and then heat treatment obtains having the cylindric particle of interior radiotherapy and thermotherapy dual-use function the raw material mixture slurry.
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