CN104888216B - Delay the zirconium dioxide composite nano materials and preparation method and application of controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics - Google Patents
Delay the zirconium dioxide composite nano materials and preparation method and application of controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics Download PDFInfo
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Abstract
The present invention discloses a kind of zirconium dioxide composite nano materials for delaying controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics, and the zirconium dioxide composite nano materials include Ions in nanocrystalline zirconia and Huai Er；The Ions in nanocrystalline zirconia is hollow Ions in nanocrystalline zirconia, and the zirconium dioxide composite nano materials are filled with Huai Er for the boring of Ions in nanocrystalline zirconia；The particle diameter of the zirconium dioxide composite nano materials is 50 500nm, and shell thickness is 10 100nm.Zirconium dioxide composite nano materials favorable dispersibility, size and shell thickness prepared by the present invention can regulate and control on demand；The Chinese medicine Huai Er with chemotherapy effect is filled in inside hollow zirconium dioxide first in the present invention, microwave enhanced sensitivity can be applied to simultaneously, chemotherapeutics delays controlled release and CT technical field of imaging, realize that diagnosis and treatment integration and targeting thermochemotherapy are combined the target for the treatment of tumour, there is good potential applicability in clinical practice.
Description
Technical field
The present invention relates to the application of zirconium dioxide composite nano materials and technology in cancer diagnosis and treatment.More specifically
Ground, it is related to a kind of zirconium dioxide composite nano materials and system for delaying controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics
Preparation Method and application.
Background technology
Cancer has become global first fatal disease.According to the World Health Organization《World's cancer report in 2014》It is aobvious
Show, global cancer new cases reach more than 1,400 ten thousand within 2012, and 19,000,000 people were up to 2025, will break through within 2035
24000000 people.Report also shows that developing country's pathogenesis of cancer situation in Africa, Asia and Central and South America is the severeest.China
Cancer Mortality is also constantly to rise, and newly-increased 3,070,000 cancer patients in 2012, there are about 2,200,000 people and dies from cancer, account for respectively
The 21.9% of global total amount and 26.8%.Cancer turns into the first big cause of the death of China resident, is brought to society, family and individual huge
Big burden and pain (Cell Death Dis., 2013,4,596, Chem.Soc.Rev., 2012,41,4306-4334).
At present, chemotherapy, radiotherapy, operation are still the Main Means in clinical cancer therapy, but operative treatment can only be directed to
Local knurl, primary lesion can be quickly cut off, not be suitable for the tumour at difficult excision position；Radiotherapy is preferable in cancer early efficacy,
Specific poor, easy injuring normal cell；Chemotherapeutics also has very big poison secondary while tumour cell is killed to human body
Effect.Microwave heat therapeutic technology has that noninvasive or minimally invasive, security is preferable, heating-up temperature is higher inside linked groups, ablated volume
It is bigger, ablation time faster with heat flux distribution it is more uniform the advantages of, everybody concern is gradually caused in the treatment of tumour
(Nature Reviews,2014,199-208).As a kind of non-invasion and attack formula local heating, the mechanism of microwave heat therapeutic is using micro-
The fuel factor of ripple carries out the thermotherapy of tumour.When microwave enters biological tissue, the transmission of microwave and the absorption of energy can be produced, from
And certain temperature rise is formed in tissue.When temperature reaches more than 43 DEG C, tumour cell can be effectively killed, and then
Realize thermotherapy purpose (Cardiovasc.Inter.Rad.2010,33 (4), 818-827, Phys.Med.Biol.2012,57
(8),2309-2327,Nat.Rev.Drug.Discov.2010,615-27)。
Clinically, to tumour can Precise Diagnosis be to realize the deciding factor accurately treated, CT imaging technique conducts
A kind of ripe medical imaging diagnostic means, with sweep speed is fast, image inorganization structure is overlapping, anatomy relationship is clear and definite, figure
As it is clear, density resolution is high, hurtless measure and it is painful the advantages that (J.Nucl.Med.2013,54 (11), 1938-1945, JACC-
Cardiovasc.Imag.2013,6(12),1229-1238,Clin.Oral Implant.Res.2013,24(7),746-
749)。
The Chinese patent that number of patent application is 201410453049.2 is filled with tool using hollow Ions in nanocrystalline zirconia
There is the ionic liquid of microwave enhanced sensitivity performance, the composite is successfully applied to tumour CT diagnosis simultaneously and led with microwave heat therapeutic technology
Domain, and achieve satisfied therapeutic effect.But the kernel ionic liquid biological safety that is utilized of the patent need into
One step is demonstrate,proved, and the composite construction has CT imagings and two kinds of functions of microwave heat therapeutic, without chemotherapy function；And Huai Er conduct
A kind of Chinese medicine, the research in terms of being acted on for chemotherapy of tumors with mechanism is also seldom, and the function that particularly microwave enhanced sensitivity, CT strengthen is also
Have no report.
Therefore, the present invention develops that a kind of biological safety is higher, and CT enhancing effects are more notable, collection chemotherapy, microwave
Thermotherapy, CT are imaged, the more rich material of function；Realize that the lower accurate microwave heat therapeutic of tumour of CT imagings guiding is combined with chemotherapy
Treatment, realize the diagnosis and treatment integration of tumour.
The content of the invention
First technical problem to be solved by this invention is that providing one kind, there is microwave enhanced sensitivity, chemotherapeutics to delay controlled release
And the zirconium dioxide composite nano materials of CT imaging functions, the zirconium dioxide composite nano materials biocompatibility is good, and poison is secondary
Act on relatively low, be applied to tumor microwave heat treatment auxiliary targeted chemotherapy and CT Tomographic Diagnosis Technologies, have clinical well
Diagnosis and treatment application value.
Second technical problem to be solved by this invention is to provide a kind of zirconium dioxide composite nano materials
Preparation method.
3rd technical problem to be solved by this invention is the application for providing the zirconium dioxide composite nano materials.
To solve above-mentioned first technical problem, the present invention uses following technical proposals：
A kind of zirconium dioxide composite nano materials for delaying controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics, institute
State zirconium dioxide composite nano materials and include Ions in nanocrystalline zirconia and Huai Er；The Ions in nanocrystalline zirconia is sky
Heart Ions in nanocrystalline zirconia, the material use sacrifice template method and prepare gained, and the zirconium dioxide composite nano materials are two
The boring of nanometer zirconium oxide is filled with Huai Er；The particle diameter of the zirconium dioxide composite nano materials is 50-
500nm, shell thickness 10-100nm.
Preferably, the particle diameter of the zirconium dioxide composite nano materials is 120-250nm, shell thickness 20-50nm.
Second technical problem to be solved by this invention is the preparation method of the zirconium dioxide composite nano materials, institute
The method of stating comprises the following steps：
1) Huai Er is scattered in the mixed liquor of water and organic solvent composition, ultrasound or is dispersed with stirring and is formed uniformly Chinese scholartree
Fungus polysaccharides solution, the quality volume fraction of the Huai Er solution is 1-30%；
2) hollow Ions in nanocrystalline zirconia, concentration 1-200mg are added in the Huai Er solution obtained to step 1)
mL-1, Huai Er is filled in hollow Ions in nanocrystalline zirconia by Vessel in Negative Pressure Filling method；
3) Ions in nanocrystalline zirconia for being filled with Huai Er for obtaining step 2) is washed with deionized, until upper
Clear liquid clear, that is, obtain that there is microwave enhanced sensitivity, chemotherapeutics to delay the zirconium dioxide composite Nano of controlled release and CT imaging functions
Material.
Preferably, the solvent described in step 1) be selected from water-soluble absolute ethyl alcohol, acetonitrile, DMSO, Isosorbide-5-Nitrae-dioxane,
One or more in acetone and isopropanol.
3rd technical problem to be solved by this invention is the application of the zirconium dioxide composite nano materials.
The zirconium dioxide composite nano materials for delaying controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics are answered
With, the Ions in nanocrystalline zirconia for being filled with Huai Er is dispersed in PBS, the pH value of PBS is 7.2,
Compound concentration scope is 0-50mg mL-1Dispersion liquid, be respectively placed in external microwave heating device, microwave irradiation processing；Or will
The Ions in nanocrystalline zirconia for being filled with Huai Er is dispersed in PBS, and the pH value of PBS is 7.2, is prepared dense
Spend for 5-20mg mL-1Dispersion liquid, by tail vein injection in the Mice Body of inoculated tumour, microwave irradiation after 12 hours
Processing；
Or the Ions in nanocrystalline zirconia for being filled with Huai Er is dispersed in PBS, the pH value of PBS
For 7.2, different gradient concentration dispersion liquids are formulated as, concentration range is 0-50mg mL-1, external CT imagings are carried out respectively；Or it will fill
The Ions in nanocrystalline zirconia for being filled with Huai Er is dispersed in PBS, and the pH value of PBS is 7.2, compound concentration
For 5-20mg mL-1Dispersion liquid, by tail vein injection in the Mice Body of inoculated tumour, different time sections carry out internal CT
Imaging.
Beneficial effects of the present invention are as follows：
1st, it is of the invention dramatically different with prior art, utilize hollow zirconium dioxide composite nano materials in the present invention
Huai Er of the parcel with chemotherapy effect, it can realize that microwave enhanced sensitivity, chemotherapeutics delay controlled release and CT imaging functions simultaneously
Target, diagnoses and treatment efficiency is substantially increased, there is good clinical value.
2nd, the parcel Huai Er of the present invention for delaying controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics
Hollow zirconium dioxide composite nano materials, its shell zirconium dioxide material are respectively provided with CT images enhancement with kernel Huai Er
Can, after being compound in together, further CT images effect can be strengthened, can be as good CT contrast agent.
3rd, the parcel Huai Er of the present invention for delaying controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics
Hollow zirconium dioxide composite nano materials, its kernel Huai Er are a kind of chemotherapy Chinese medicine, have anti-cancer properties, while have good
Good microwave enhanced sensitivity performance, under microwave field radiation, good temperature rise model can be shown, it is possible to achieve tumor microwave heat treatment
With the effect of chemotherapy combined treatment tumour.
4th, the parcel Huai Er of the present invention for delaying controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics
Hollow zirconium dioxide composite nano materials, because its size is smaller, there is EPR passive target performances, can accurate realization
Treat drug targeting and delay controlled release, the accurate effect for treating tumour.
Brief description of the drawings
The embodiment of the present invention is described in further detail below in conjunction with the accompanying drawings.
Fig. 1 shows there is microwave enhanced sensitivity, chemotherapeutics to delay controlled release and CT imaging functions obtained by the embodiment of the present invention 1
The electron scanning micrograph of zirconium dioxide composite nano materials；
Fig. 2 shows there is microwave enhanced sensitivity, chemotherapeutics to delay controlled release and CT imaging functions obtained by the embodiment of the present invention 1
The transmission electron microscope photo of zirconium dioxide composite nano materials；
Fig. 3 shows there is microwave enhanced sensitivity, chemotherapeutics to delay controlled release and CT imaging functions obtained by the embodiment of the present invention 1
Dynamic light scattering (DLS) collection of illustrative plates of zirconium dioxide composite nano materials, shows its monodispersity；
Fig. 4 shows there is microwave enhanced sensitivity, chemotherapeutics to delay controlled release and CT imaging functions obtained by the embodiment of the present invention 1
The external microwave temperature rise effect of zirconium dioxide composite nano materials；
Fig. 5 shows there is microwave enhanced sensitivity, chemotherapeutics to delay controlled release and CT imaging functions obtained by the embodiment of the present invention 1
The external CT imaging effects of hollow zirconium dioxide material of the zirconium dioxide composite nano materials with being mounted with ionic liquid.
Embodiment
In order to illustrate more clearly of the present invention, the present invention is done further with reference to preferred embodiments and drawings
It is bright.Similar part is indicated with identical reference in accompanying drawing.It will be appreciated by those skilled in the art that institute is specific below
The content of description is illustrative and be not restrictive, and should not be limited the scope of the invention with this.
Embodiment 1
(1) Huai Er is scattered in deionized water and absolute ethyl alcohol mixed liquor (volume ratio 1:1) in, quality volume fraction
For 1%, ultrasound or it is dispersed with stirring uniformly；
(2) hollow zirconium dioxide composite nano materials are added in the Huai Er aqueous solution obtained to step 1), concentration is
5mg mL-1, realize that Huai Er wraps up by Vessel in Negative Pressure Filling method；
(3) the hollow zirconium dioxide composite nano materials for the parcel Huai Er that step 2) obtains are washed with deionized water
Wash, until supernatant clear, that is, obtain that there is microwave enhanced sensitivity, chemotherapeutics to delay the parcel trametes robinioplila of controlled release and CT imaging functions
The hollow zirconium dioxide composite nano materials of polysaccharide.
Can be with clear view to the hollow zirconium dioxide composite nano materials of gained are uniformly distributed, particle diameter distribution from Fig. 1-3
It is narrower, a diameter of 165nm, shell thickness 25nm, and also it is obvious with transmission electron microscope image by SEM
It can be seen that resulting materials are hollow-core construction.
It is micro- that the hollow zirconium dioxide composite nano materials for the parcel Huai Er that the present embodiment is prepared are used for tumour
Ripple technique for hyperthermia, its external and internal microwave heating experiment are as follows with tumor thermotherapy effect：
The hollow zirconium dioxide composite nano materials for wrapping up Huai Er are dispersed in PBS (pH=7.2), matched somebody with somebody
Concentration processed is 20mg mL-1Dispersion liquid, be placed in external microwave heating device, microwave irradiation processing, control group is with isometric
PBS (pH=7.2), heating result is as shown in figure 4, work well.Heating experiment is as follows in animal body：Trametes robinioplila will be wrapped up
The hollow zirconium dioxide composite nano materials of polysaccharide are dispersed in PBS (pH=7.2), and compound concentration is 5mg mL-1's
Dispersion liquid, by tail vein injection in the ICR Mice Bodies of inoculation H22 tumours, injection dosage is 40mg kg-1, after 12 hours
Microwave irradiation knub position, due to wrapping up the hollow zirconium dioxide composite nano materials of Huai Er due to EPR effect quilts
Move targeted to knub position, and realize the slow controlled release of Huai Er, tumor by local temperature can be rapidly reached more than 43 DEG C, the temperature
Degree is enough to kill tumour cell.Or so two weeks knub position returns to one's perfect health and recovers normal.
The hollow zirconium dioxide composite nano materials for the parcel Huai Er that the present embodiment is prepared are imaged for CT
Technology, its external and in-vivo imaging process and effect are as follows：
The hollow zirconium dioxide composite nano materials for wrapping up Huai Er are dispersed in PBS (pH=7.2), matched somebody with somebody
Different gradient concentration dispersion liquids are made as, concentration range is 0~50mg mL-1, external CT imagings are carried out respectively, and CT values have concentration
Dependence, imaging effect and linear relationship are as shown in Figure 5.CT imaging experiments process is as follows in animal body：It is more trametes robinioplila will to be wrapped up
The hollow zirconium dioxide composite nano materials of sugar are dispersed in PBS (pH=7.2), and compound concentration is 5mg mL-1Point
Dispersion liquid, by tail vein injection in the ICR Mice Bodies of inoculation H22 tumours, injection dosage is 40mg kg-1, different time sections enter
The internal CT imagings of row, knub position have CT enhancement effects.
Embodiment 2
(1) Huai Er is scattered in deionized water and 1,4- dioxane mixed liquor (volume ratio 1:1) in, quality volume
Fraction is 10%, ultrasound or be dispersed with stirring uniformly；
(2) hollow zirconium dioxide composite nano materials are added in the Huai Er aqueous solution obtained to step 1), concentration is
10mg mL-1, realize that Huai Er wraps up by Vessel in Negative Pressure Filling method；
(3) the hollow zirconium dioxide composite nano materials for the parcel Huai Er that step 2) obtains are washed with deionized water
Wash, until supernatant clear, that is, obtain that there is microwave enhanced sensitivity, chemotherapeutics to delay the parcel trametes robinioplila of controlled release and CT imaging functions
The hollow zirconium dioxide composite nano materials of polysaccharide.
It is micro- that the hollow zirconium dioxide composite nano materials for the parcel Huai Er that the present embodiment is prepared are used for tumour
Ripple technique for hyperthermia, its external and internal microwave heating experiment are as follows with tumor thermotherapy effect：
The hollow zirconium dioxide composite nano materials for wrapping up Huai Er are dispersed in PBS (pH=7.2), matched somebody with somebody
Concentration processed is 20mg mL-1Dispersion liquid, be placed in external microwave heating device, microwave irradiation processing, control group is with isometric
PBS (pH=7.2), temperature rise effect is good.Heating experiment is as follows in animal body：The hollow dioxy of Huai Er will be wrapped up
Change zirconium composite nano materials to be dispersed in PBS (pH=7.2), compound concentration is 5mg mL-1Dispersion liquid, it is quiet by tail
Arteries and veins is injected in the ICR Mice Bodies of inoculation H22 tumours, and injection dosage is 40mg kg-1, microwave irradiation tumour position after 12 hours
Put, due to wrapping up the hollow zirconium dioxide composite nano materials of Huai Er due to EPR effects passive target to tumour position
Put, and realize the slow controlled release of Huai Er, tumor by local temperature can be rapidly reached more than 43 DEG C, and the temperature is enough to kill tumour
Cell.Or so two weeks knub position returns to one's perfect health and recovers normal
The hollow zirconium dioxide composite nano materials for the parcel Huai Er that the present embodiment is prepared are imaged for CT
Technology, its external and in-vivo imaging process and effect are as follows：
The hollow zirconium dioxide composite nano materials for wrapping up Huai Er are dispersed in PBS (pH=7.2), matched somebody with somebody
Different gradient concentration dispersion liquids are made as, concentration range is 0~50mg mL-1, external CT imagings are carried out respectively, and CT values have concentration
Dependence.CT imaging experiments process is as follows in animal body：The hollow zirconium dioxide composite nano materials point of Huai Er will be wrapped up
It is dispersed in PBS (pH=7.2), compound concentration is 5mg mL-1Dispersion liquid, by tail vein injection in inoculation H22 swell
In the ICR Mice Bodies of knurl, injection dosage is 40mg kg-1, different time sections carry out internal CT imagings, and knub position has CT increasings
It is potent to answer.
Embodiment 3
(1) Huai Er is scattered in deionized water, quality volume fraction be 30%, ultrasound or be dispersed with stirring uniformly；
(2) hollow zirconium dioxide composite nano materials are added in the Huai Er aqueous solution obtained to step 1), concentration is
100mg mL-1, realize that Huai Er wraps up by Vessel in Negative Pressure Filling method；
(3) the hollow zirconium dioxide composite nano materials for the parcel Huai Er that step 2) obtains are washed with deionized water
Wash, until supernatant clear, that is, obtain that there is microwave enhanced sensitivity, chemotherapeutics to delay the parcel trametes robinioplila of controlled release and CT imaging functions
The hollow zirconium dioxide composite nano materials of polysaccharide.
It is micro- that the hollow zirconium dioxide composite nano materials for the parcel Huai Er that the present embodiment is prepared are used for tumour
Ripple technique for hyperthermia, its external and internal microwave heating experiment are as follows with tumor thermotherapy effect：
The hollow zirconium dioxide composite nano materials for wrapping up Huai Er are dispersed in PBS (pH=7.2), matched somebody with somebody
Concentration processed is 20mg mL-1Dispersion liquid, be placed in external microwave heating device, microwave irradiation processing, control group is with isometric
PBS (pH=7.2), temperature rise effect is good.Heating experiment is as follows in animal body：The hollow dioxy of Huai Er will be wrapped up
Change zirconium composite nano materials to be dispersed in PBS (pH=7.2), compound concentration is 5mg mL-1Dispersion liquid, it is quiet by tail
Arteries and veins is injected in the ICR Mice Bodies of inoculation H22 tumours, and injection dosage is 40mg kg-1, microwave irradiation tumour position after 12 hours
Put, due to wrapping up the hollow zirconium dioxide composite nano materials of Huai Er due to EPR effects passive target to tumour position
Put, and realize the slow controlled release of Huai Er, tumor by local temperature can be rapidly reached more than 43 DEG C, and the temperature is enough to kill tumour
Cell.Or so two weeks knub position returns to one's perfect health and recovers normal
The hollow zirconium dioxide composite nano materials for the parcel Huai Er that the present embodiment is prepared are imaged for CT
Technology, its external and in-vivo imaging process and effect are as follows：
The hollow zirconium dioxide composite nano materials for wrapping up Huai Er are dispersed in PBS (pH=7.2), matched somebody with somebody
Different gradient concentration dispersion liquids are made as, concentration range is 0~50mg mL-1, external CT imagings are carried out respectively, and CT values have concentration
Dependence.CT imaging experiments process is as follows in animal body：The hollow zirconium dioxide composite nano materials point of Huai Er will be wrapped up
It is dispersed in PBS (pH=7.2), compound concentration is 5mg mL-1Dispersion liquid, by tail vein injection in inoculation H22 swell
In the ICR Mice Bodies of knurl, injection dosage is 40mg kg-1, different time sections carry out internal CT imagings, and knub position has CT increasings
It is potent to answer.
Embodiment 4
(1) Huai Er is scattered in deionized water and acetone mixture, quality volume fraction be 20%, ultrasound or stir
Mix and be uniformly dispersed；
(2) hollow zirconium dioxide composite nano materials are added in the Huai Er aqueous solution obtained to step 1), concentration is
200mg mL-1, realize that Huai Er wraps up by Vessel in Negative Pressure Filling method；
(3) the hollow zirconium dioxide composite nano materials for the parcel Huai Er that step 2) obtains are washed with deionized water
Wash, until supernatant clear, that is, obtain that there is microwave enhanced sensitivity, chemotherapeutics to delay the parcel trametes robinioplila of controlled release and CT imaging functions
The hollow zirconium dioxide composite nano materials of polysaccharide.
It is micro- that the hollow zirconium dioxide composite nano materials for the parcel Huai Er that the present embodiment is prepared are used for tumour
Ripple technique for hyperthermia, its external and internal microwave heating experiment are as follows with tumor thermotherapy effect：
The hollow zirconium dioxide composite nano materials for wrapping up Huai Er are dispersed in PBS (pH=7.2), matched somebody with somebody
Concentration processed is 20mg mL-1Dispersion liquid, be placed in external microwave heating device, microwave irradiation processing, control group is with isometric
PBS (pH=7.2), temperature rise effect is good.Heating experiment is as follows in animal body：The hollow dioxy of Huai Er will be wrapped up
Change zirconium composite nano materials to be dispersed in PBS (pH=7.2), compound concentration is 5mg mL-1Dispersion liquid, it is quiet by tail
Arteries and veins is injected in the ICR Mice Bodies of inoculation H22 tumours, and injection dosage is 40mg kg-1, microwave irradiation tumour position after 12 hours
Put, due to wrapping up the hollow zirconium dioxide composite nano materials of Huai Er due to EPR effects passive target to tumour position
Put, and realize the slow controlled release of Huai Er, tumor by local temperature can be rapidly reached more than 43 DEG C, and the temperature is enough to kill tumour
Cell.Or so two weeks knub position returns to one's perfect health and recovers normal
The hollow zirconium dioxide composite nano materials for the parcel Huai Er that the present embodiment is prepared are imaged for CT
Technology, its external and in-vivo imaging process and effect are as follows：
The hollow zirconium dioxide composite nano materials for wrapping up Huai Er are dispersed in PBS (pH=7.2), matched somebody with somebody
Different gradient concentration dispersion liquids are made as, concentration range is 0~50mg mL-1, external CT imagings are carried out respectively, and CT values have concentration
Dependence.CT imaging experiments process is as follows in animal body：The hollow zirconium dioxide composite nano materials point of Huai Er will be wrapped up
It is dispersed in PBS (pH=7.2), compound concentration is 5mg mL-1Dispersion liquid, by tail vein injection in inoculation H22 swell
In the ICR Mice Bodies of knurl, injection dosage is 40mg kg-1, different time sections carry out internal CT imagings, and knub position has CT increasings
It is potent to answer.
Embodiment 5
(1) Huai Er is scattered in deionized water and isopropanol mixed liquor, quality volume fraction be 15%, ultrasound or
It is dispersed with stirring uniformly；
(2) hollow zirconium dioxide composite nano materials are added in the Huai Er aqueous solution obtained to step 1), concentration is
50mg mL-1, realize that Huai Er wraps up by Vessel in Negative Pressure Filling method；
(3) the hollow zirconium dioxide composite nano materials for the parcel Huai Er that step 2) obtains are washed with deionized water
Wash, until supernatant clear, that is, obtain that there is microwave enhanced sensitivity, chemotherapeutics to delay the parcel trametes robinioplila of controlled release and CT imaging functions
The hollow zirconium dioxide composite nano materials of polysaccharide.
It is micro- that the hollow zirconium dioxide composite nano materials for the parcel Huai Er that the present embodiment is prepared are used for tumour
Ripple technique for hyperthermia, its external and internal microwave heating experiment are as follows with tumor thermotherapy effect：
The hollow zirconium dioxide composite nano materials for wrapping up Huai Er are dispersed in PBS (pH=7.2), matched somebody with somebody
Concentration processed is 20mg mL-1Dispersion liquid, be placed in external microwave heating device, microwave irradiation processing, control group is with isometric
PBS (pH=7.2), temperature rise effect is good.Heating experiment is as follows in animal body：The hollow dioxy of Huai Er will be wrapped up
Change zirconium composite nano materials to be dispersed in PBS (pH=7.2), compound concentration is 5mg mL-1Dispersion liquid, it is quiet by tail
Arteries and veins is injected in the ICR Mice Bodies of inoculation H22 tumours, and injection dosage is 40mg kg-1, microwave irradiation tumour position after 12 hours
Put, due to wrapping up the hollow zirconium dioxide composite nano materials of Huai Er due to EPR effects passive target to tumour position
Put, and realize the slow controlled release of Huai Er, tumor by local temperature can be rapidly reached more than 43 DEG C, and the temperature is enough to kill tumour
Cell.Or so two weeks knub position returns to one's perfect health and recovers normal
The hollow zirconium dioxide composite nano materials for the parcel Huai Er that the present embodiment is prepared are imaged for CT
Technology, its external and in-vivo imaging process and effect are as follows：
The hollow zirconium dioxide composite nano materials for wrapping up Huai Er are dispersed in PBS (pH=7.2), matched somebody with somebody
Different gradient concentration dispersion liquids are made as, concentration range is 0~50mg mL-1, external CT imagings are carried out respectively, and CT values have concentration
Dependence.CT imaging experiments process is as follows in animal body：The hollow zirconium dioxide composite nano materials point of Huai Er will be wrapped up
It is dispersed in PBS (pH=7.2), compound concentration is 5mg mL-1Dispersion liquid, by tail vein injection in inoculation H22 swell
In the ICR Mice Bodies of knurl, injection dosage is 40mg kg-1, different time sections carry out internal CT imagings, and knub position has CT increasings
It is potent to answer.
Embodiment 6-10
With embodiment 1, it the difference is that only, absolute ethyl alcohol acetonitrile, DMSO, Isosorbide-5-Nitrae-dioxy used in step (1)
One or more of mixtures in six rings, acetone, isopropanol replace, as a result similar.
Comparative example 1
Fig. 5 is the external CT imaging effects and the embodiment of the present invention 1 for the hollow zirconium dioxide material for being mounted with ionic liquid
The contrast of the external CT imaging effects of zirconium dioxide composite nano materials of synthesis.
The present invention has found that hollow zirconium dioxide material itself has good CT enhancing performances, can conduct under study for action
Good CT contrast agent, meanwhile, the Huai Er as chemotherapeutics also has good CT enhancing performances, and two kinds of materials are answered
After together, CT images effect further enhancing；Secondly the Huai Er as chemotherapeutics is wrapped in hollow dioxy
After changing inside zirconium, there is the microwave enhanced sensitivity performance more excellent than wrapping up the hollow zirconium dioxide of ionic liquid, therefore can answer
For tumor microwave heat treatment field；Furthermore because Huai Er itself is a kind of excellent cancer therapy drug, there is chemotherapy performance, because
After Huai Er is wrapped in inside hollow zirconium dioxide by this present invention, it is possible to achieve chemotherapy swells with microwave heat therapeutic combined treatment
The target of knurl, for killing microwave heat therapeutic residual tumor cells, reduce tumor recurrence and play an important roll.Therefore by Huai Er
Combined with hollow Ions in nanocrystalline zirconia, prepare that biological safety is higher, and CT enhancing effects are more notable, collection chemotherapy, microwave
Thermotherapy, CT are imaged, the more rich material of function.
Obviously, the above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and is not pair
The restriction of embodiments of the present invention, for those of ordinary skill in the field, may be used also on the basis of the above description
To make other changes in different forms, all embodiments can not be exhaustive here, it is every to belong to this hair
Row of the obvious changes or variations that bright technical scheme is extended out still in protection scope of the present invention.
Claims (4)
1. a kind of zirconium dioxide composite nano materials for delaying controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics, it is special
Sign is：The zirconium dioxide composite nano materials include Ions in nanocrystalline zirconia and Huai Er；The zirconium dioxide is received
Rice material is hollow Ions in nanocrystalline zirconia, and the zirconium dioxide composite nano materials are the inside of Ions in nanocrystalline zirconia
It is hollow to be filled with Huai Er；The particle diameter of the zirconium dioxide composite nano materials is 50-500nm, shell thickness 10-
100nm。
2. zirconium dioxide composite nano materials according to claim 1, it is characterised in that：The zirconium dioxide composite Nano
The particle diameter of material is 120-250nm, shell thickness 20-50nm.
3. the zirconium dioxide according to claim 1 or 2 for delaying controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics
The preparation method of composite nano materials, it is characterised in that comprise the following steps：
1) Huai Er is scattered in the mixed liquor of water and organic solvent composition, ultrasound or is dispersed with stirring that to be formed uniformly trametes robinioplila more
Sugar juice, the quality volume fraction of the Huai Er solution is 1-30%；
2) hollow Ions in nanocrystalline zirconia is added in the Huai Er solution obtained to step 1), concentration is 1-200mg mL-1,
Huai Er is filled in hollow Ions in nanocrystalline zirconia by Vessel in Negative Pressure Filling method；
3) Ions in nanocrystalline zirconia for being filled with Huai Er for obtaining step 2) is washed with deionized, until supernatant
Clear, that is, obtain that there is microwave enhanced sensitivity, chemotherapeutics to delay the zirconium dioxide composite nano materials of controlled release and CT imaging functions.
4. according to the method for claim 3, it is characterised in that：Solvent described in step 1) is selected from water-soluble anhydrous second
One or more in alcohol, acetonitrile, DMSO, 1,4- dioxane, acetone and isopropanol.
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| CN201510076388.8A CN104888216B (en) | 2015-02-12 | 2015-02-12 | Delay the zirconium dioxide composite nano materials and preparation method and application of controlled release and CT imaging functions with microwave enhanced sensitivity, chemotherapeutics |
| CN201711177402.9A CN107670041B (en) | 2015-02-12 | 2015-02-12 | Method for preparing zirconium dioxide composite nano material dispersion liquid |
| CN201711177403.3A CN107812191B (en) | 2015-02-12 | 2015-02-12 | A dispersion for chemotherapy, microwave thermotherapy and CT imaging |
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| CN109806400B (en) * | 2019-03-18 | 2022-03-18 | 中国医科大学附属第一医院 | Mesoporous nano zirconium dioxide drug-loaded material, preparation method thereof and sustained and controlled release drug |
| CN110257070B (en) * | 2019-04-28 | 2022-03-04 | 中国科学院理化技术研究所 | Hollow zirconia @ quantum dot composite ball and preparation method and application thereof |
| CN110548173B (en) * | 2019-08-26 | 2021-10-26 | 苏州恒瑞迦俐生生物医药科技有限公司 | Preparation method of chemoembolization microsphere with microwave sensitization effect |
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| CN104119428A (en) * | 2013-04-24 | 2014-10-29 | 启东盖天力药业有限公司 | Trametes robiniophia Murr. proteoglycan protein, and preparation method and use thereof |
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| CN104888216A (en) | 2015-09-09 |
| CN107812191A (en) | 2018-03-20 |
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