CN104771756A - Preparation method and application of rare earth up-conversion drug-delivery nano-carrier - Google Patents
Preparation method and application of rare earth up-conversion drug-delivery nano-carrier Download PDFInfo
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Abstract
The invention relates to a preparation method and application of a rare earth up-conversion light-operated drug-delivery nano-carrier. The preparation method comprises the following steps: with a variety of rare earth salts as raw materials, preparing a rare earth up-conversion nanoparticle through a solvothermal process; synthesizing meso-porous silicon via a template process and carrying out coating; connecting a silane reagent to the surface of a meso-porous silicon shell layer; and finally, embedding a drug into meso pores. The nano-carrier prepared in the invention has a targeted aggregation effect and can realize precise positioning at a tumor site. The nano-carrier has a light-operated release effect; the drug is stored in the nano-carrier under the condition of no external near infrared laser (with wavelength of 980 nm) irradiation; the chemotherapy drug can only be released when a near infrared excitation source irradiates tumor tissue; thus, precise, timed and quantitative release of the nano-carrier at a tumor site can be realized. The nano-carrier has a fluorescence imaging function, can realize visualization of chemotherapy process and has the advantages of simple operation, good applicability, low cost and good dispersibility in water.
Description
Technical field
The present invention relates to the preparation method and application of a kind of rare earth being changed light-operated drug release nano-carrier, belong to medical art.
Background technology
Chemotherapy is one for the treatment of malignant tumor important means.Three large treatment meanss are become side by side with operation, radiotherapy.Chemotherapy of tumors specifically refers to that malignant tumor treated by applied chemistry medicine (comprising endocrine agents).Cancer therapy drug enters after in body and is distributed to whole body very soon, and the tumor both can having killed local also can kill the tumor of metastasis, and therefore chemotherapy is a kind of whole body therapeutic.
But the defect that due in classic chemotherapy process, drug release exists " time is uncertain, and the uncertain and position of total amount is uncertain ", causes clinical application can only reach therapeutic effect by " altofrequency, heavy dose and whole body to mode ".This Therapeutic Method, while killing tumor cell, produces toxic and side effects to the normal organ of human body, tissue, cell, especially to division, propagation, than cell faster as myeloid element, gastrointestinal tract mucous epithelial cell etc.Therefore the chemotheraping preparation of development of new, realizes the timing of medicine, quantitatively, locates release, reduce toxic and side effects, have important clinical value.
The development of current new medicinal preparation, mainly concentrates on the location release how effectively realizing medicine.Concrete solution is as 1) utilize nanoscopic drug carriers system, conduct drugs to tumor locus by passive target effect; 2) utilize the target function on medicament carrier system surface to modify, conduct drugs to tumor locus by active targeting effect.But side by side can realize the pharmaceutical preparation of " medicine timing, quantitative, location release, reduce toxic and side effects ", not yet find the report of related article and patent at present.
Summary of the invention
In view of structure new medicinal preparation realize medicine timing, quantitatively, there is important clinical meaning in location release.The invention provides the preparation method a kind of rare earth being changed light-operated drug release nano-carrier.The main component of this nanometer formulation comprises three aspects:
1) rare earth upconversion nano particle core: it act as and external near-infrared excitation light is converted to ultraviolet light.
2) mesoporous silicon oxide shell: it act as medicament-carried, improves the stability of whole carrier granular.
3) surface light sensitive molecule diphenyl diimide and targeted molecular modified with folic acid: surface light sensitive molecule diphenyl diimide, as sealing of hole molecule, prevents medicine from revealing in pharmaceutical carrier transportation; When arrival tumor locus, under the illuminate condition of ultraviolet light, its conformation changes, thus by the drug release in hole out.Surface targeted molecular modified with folic acid, can improve the targeting positioning function of whole nano-carrier, make it optionally gather tumor locus.
The ultimate principle that this nanometer formulation realizes " regularly, quantitatively, locating chemotherapy " is:
1) will the rare earth prepared be changed the mode administration of light-operated drug release nanometer formulation by intravenous injection or local injection;
2) after preparation gathers tumor locus under the effect of targeted molecular folic acid, near-infrared (wavelength 980nm) the laser direct irradiation target site enough penetrating deep tissue is used at specific position;
3) first the laser penetrating deep tissue absorbed by upper conversion nano core, thus produce corresponding ultraviolet light;
4) ultraviolet light is absorbed by the photosensitive micromolecule diphenyl diimide in surface, and its structure changes, thus Drug controlled release out.
This nanometer formulation passes through the irradiation time of regulating near-infrared laser, exposure rate, irradiation position, thus effectively can realize medicine timing, quantitative, location release, reduction toxic and side effects.Rare earth is changed light-operated drug release nanometer chemotheraping preparation mechanism of action figure as shown in Figure 1.
Compare relative to traditional chemotheraping preparation, utilize and this rare earth changes light-operated drug release nanometer formulation there is many advantages:
1) said preparation has targeting aggregation, can realize the precise positioning at tumor locus.
2) said preparation has light-operated release action, under there is no extraneous near-infrared (wavelength 980nm) laser irradiation condition, medicine is stored in preparation, only have and when near-infrared excitaton source irradiates tumor tissues be, chemotherapeutics just can be released, can realize tumor locus accurate timing, quantitatively discharge.
3) in addition, this nanometer formulation has fluorescence imaging function, can realize the visual of chemotherapy process.
The invention provides the preparation method a kind of rare earth being changed light-operated drug release nano-carrier.Be specifically related to three partial contents that is 1) synthesis of rare earth upconversion nano grain; 2) the coating mesoporous silicon shell of rare earth upconversion nano grain and the modification of surface light sensitive molecule and targeted molecular and the embedding of chemotherapeutic drugs Doxorubicin.The rare earth that assembling obtains changes light-operated drug release nanometer chemotheraping preparation and there is Stability Analysis of Structures, uniform particle diameter, there is targeting location, the advantages such as light-operated drug release.Not yet be found in the report of this relevant nanometer formulation article and patent at present.
The present invention first, as Fig. 3 projects the display of Electronic Speculum test result, utilize solvent-thermal method to prepare rare earth upconversion nano grain (left figure) particle diameter and be less than 50nm, even particle size distribution, the rare earth of preparation changes light-operated drug release nanometer chemotherapy preparation granules (right figure) particle diameter and is less than 100nm, even particle size distribution.As Fig. 4 granularmetric analysis shows, the rare earth prepared is changed light-operated drug release nanometer chemotherapy preparation granules and be of a size of 98.3nm.As shown in the analysis of Fig. 5 fluorescence emission analysis of spectrum, the rare earth of preparation is changed light-operated drug release nanometer formulation granule and under near infrared light exciter irradiates, the light of multiple color can be sent as ultraviolet light, green glow, HONGGUANG etc.As photo display under Fig. 6 light field and dark fieid conditions, rare earth is changed the fluorescence photo (dark fieid conditions) under the photomacrograph (light field condition) of light-operated drug release nanometer formulation and near infrared laser illuminate condition.Show as Fig. 8 carries out drug release experiment, the irradiating laser by whether, can Drug controlled release effectively.
Rare earth of the present invention is changed light-operated drug release chemotheraping preparation preparation method, as shown in Figure 2:
1), the synthesis of rare earth upconversion nano grain: first utilize various rare-earth salts for raw material, prepare rare earth upconversion nano grain by solvent thermal.
2), rare earth upconversion nano grain coating mesoporous silicon shell and the modification of surface light sensitive molecule and targeted molecular and the embedding of chemotherapeutic drugs Doxorubicin: adopt Template synthesis mesoporous silicon coated, then silane reagent is connected to the surface of mesoporous silicon shell, finally medicine is embedded into mesoporous in.
Concrete preparation method is as follows:
A kind of rare earth is changed the preparation method of light-operated drug release nano-carrier; Its step is as follows:
The synthesis of rare earth upconversion nano grain:
(1) be Ytterbium trichloride according to ratio of quality and the number of copies: Yttrium chloride(Y2Cl6): Erbium trichloride=(20 ~ 50): (20 ~ 70): raw material joins in reactor by 1, then adds aqueous solvent and above-mentioned substance is dissolved completely in reactor; In magnetic agitation condition, be heated to boiling until rare earths salt becomes white solid;
(2) after water evaporate to dryness, cooling 50 ~ 80 DEG C, is oleic acid according to volume ratio: the two adds in reactor by octadecylene=2 ~ 6:1 makes white solid dissolve completely;
(3) be NaOH according to mass number: add methanol in the reactor that the two adds by ammonium fluoride=1 ~ 6:3 and make it dissolve completely, the mass ratio=3:1 of ammonium fluoride and above-mentioned Erbium trichloride; Regulate temperature to 100 ~ 150 DEG C, evacuation 10 ~ 40min, logical argon; Rapid temperature increases, to 250 ~ 300 DEG C, maintains reaction 1 ~ 3 hour; Add acetone centrifugal purification after end, after vacuum drying treatment, obtain rare earth upconversion nano grain;
The coating mesoporous silicon shell of rare earth upconversion nano grain and the modification of surface light sensitive molecule and targeted molecular and the embedding of chemotherapeutic drugs Doxorubicin:
(1) be rare earth upconversion nano grain according to the ratio of quality and the number of copies of material: cetyl trimethyl ammonium bromide: sodium hydroxide=1:(50 ~ 200): raw material joins in reactor by (5 ~ 20), then in reactor, add aqueous solvent makes above-mentioned substance dissolve completely, be heated to 30 ~ 70 DEG C under magnetic agitation condition, stir 1 ~ 3 hour;
(2) then ethyl orthosilicate is added, wherein mass ratio=0.01 ~ the 0.5:1 of ethyl orthosilicate and rare earth upconversion nano grain; React after 1 ~ 5 hour, centrifugal purification;
(3) then the nanoparticle after centrifugal is re-dispersed in ethanol, add sodium chloride as template agent removing, wherein mass ratio=10 ~ the 50:1 of sodium chloride and above-mentioned rare earth upconversion nano grain, is heated to 30 ~ 70 DEG C under magnetic agitation condition, stirs 1 ~ 3 hour; Centrifugal purification after reacting completely, obtains rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle after product vacuum dried;
(4) be then 4-benzene-azo-benzene formyl chloride according to the ratio of quality and the number of copies of material: folic acid: 3-aminopropyl triethoxysilane=1:(1 ~ 50): raw material joins in reactor by (1 ~ 6), then in reactor, add solvents tetrahydrofurane above-mentioned substance is dissolved completely, stir 5 ~ 10 hours under lucifuge condition;
(5) then add according to ratio of quality and the number of copies carbodiimide: N-hydroxy-succinamide=0.4:0.4 ~ 0.8, wherein the ratio of quality and the number of copies of carbodiimide and 4-benzene-azo-benzene formyl chloride is 0.4:1, continues stirring 0.5 ~ 3 hour;
(6) rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle is then added, wherein mass ratio=10 ~ the 50:1 of rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle and 4-benzene-azo-benzene formyl chloride, react centrifugal purification after spending the night, obtain rare earth being changed light-operated drug release nano-carrier.
(7) be then rare earth is changed light-operated drug release nano-carrier according to the ratio of quality and the number of copies of material: raw material joins in reactor by drug adriamycin=1 ~ 10:1, in reactor, then adds solvent dimethyl sulphoxide solution disperseed completely by above-mentioned substance;
(8) under magnetic agitation condition, 30 ~ 60 DEG C are heated to, stir 5 ~ 12 hours, react centrifugal purification after spending the night, finally obtain rare earth being changed light-operated drug release nanometer chemotheraping preparation, product vacuum dried, obtains the nanometer formulation that particle size is 80-150nm.
The quality taking material in above-mentioned steps is milligram level (mg), and the volume taken is milliliter level (mL).
Carrier of the present invention is preferably applied to the medicament of the light-operated drug release of chemotherapy of tumors.
Beneficial effect of the present invention:
1) main advantage rare earth that the present invention relates to being changed light-operated drug release nanometer chemotheraping preparation comprises: easy and simple to handle, the suitability is strong, cost is low, has good dispersibility in water, can realize the timing of chemotherapeutics at tumor tissues place simultaneously, quantitatively, locate release.
2) main performance index rare earth that the present invention relates to being changed light-operated drug release nanometer chemotheraping preparation comprises: a) effective grain size is between 80 ~ 150nm, particle diameter evenly, and can according to the constituent of preparation, experiment conditions etc. regulate; B) good stability, can preserve more than at least 2 months in aqueous; C) surface is containing a large amount of targeted molecular folic acid, is easy to preparation and assembles at tumor tissues place; D) whole preparation process simple and fast, manufacturing cycle is short, and productive rate is high, is applicable to producing in enormous quantities.
The present invention compares with traditional chemotheraping preparation has following advantage:
Accompanying drawing explanation
Fig. 1: rare earth is changed light-operated drug release nanometer chemotheraping preparation mechanism of action figure.
Fig. 2: rare earth is changed light-operated drug release chemotheraping preparation technology of preparing scheme.
Fig. 3: the rare earth upconversion nano grain (left side) synthesized according to embodiment 1 and prepare on light rare earth according to embodiment 4 and change light-operated drug release nanometer chemotherapy preparation granules (right side) projection electron microscope photo (morphology analysis).
Fig. 4: the grain size distribution (dimension analysis) rare earth prepared according to embodiment 4 being changed light-operated drug release nanometer chemotherapy preparation granules.
Fig. 5: rare earth is changed light-operated drug release nanometer chemotheraping preparation fluorescence emission analysis of spectrum.
Fig. 6: rare earth is changed the fluorescence photo (right figure) under the photomacrograph (left figure) of light-operated drug release nanometer formulation and near infrared laser illuminate condition.
Fig. 7: rare earth is changed light-operated drug release nanometer formulation cytotoxicity analysis (left figure) and cell endocytic experimental result (right figure).
Fig. 8: rare earth is changed light-operated drug release nanometer formulation drug release patterns at different conditions.
Detailed description of the invention
In the following examples, the invention will be further elaborated, but the present invention is not limited thereto.
Embodiment 1:
One, the synthesis of rare earth upconversion nano grain (UCN):
(1) take 200mg Ytterbium trichloride, 700mg Yttrium chloride(Y2Cl6) and 10mg Erbium trichloride, above-mentioned three kinds of materials are joined in four ml waters, in magnetic agitation condition, be heated to boiling until rare earths salt becomes white solid.
(2), after water evaporate to dryness, slightly cool (less than 50 DEG C) and add 10mL oleic acid ligand solution with pipet and 5mL octadecylene ligand solution makes white solid dissolve completely;
(3) then add 60mgNaOH, 30mg ammonium fluoride, dissolve by five ml methanol; Regulate temperature to 150 DEG C, adopt oil pump evacuation 15min, logical argon; Rapid temperature increases, to 250 DEG C, maintains reaction 2 hours; Add acetone centrifugal purification after end, preserve after end product vacuum drying treatment.The rare earth upconversion nano grain particle diameter of preparation is 20nm.Fig. 3: the rare earth upconversion nano grain (left side) synthesized according to embodiment 1.
Two, the coating mesoporous silicon shell of rare earth upconversion nano grain and the modification of surface light sensitive molecule and targeted molecular and the embedding of chemotherapeutic drugs Doxorubicin:
(1) according to the quality of material, take 20mg rare earth upconversion nano grain respectively, 1000mg cetyl trimethyl ammonium bromide (CTAB) and 400mg sodium hydroxide join in reactor, then in reactor, add aqueous solvent 30mL makes above-mentioned substance dissolve completely, be heated to 70 DEG C under magnetic agitation condition, stir 2 hours.
(2) finally add 0.2mg ethyl orthosilicate (TEOS), react after 3 hours, centrifugal purification.
(3) nanoparticle after centrifugal is re-dispersed in 20mL ethanol, then adds 1000mg sodium chloride template agent removing, under magnetic agitation condition, be heated to 30 DEG C, stir 3 hours.Centrifugal purification after reacting completely, preserves after product rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment.
(4) 5mg4-benzene-azo-benzene formyl chloride is taken respectively, raw material joins in reactor by 150mg folic acid and 30mg3-aminopropyl triethoxysilane, then in reactor, add 5mL solvents tetrahydrofurane above-mentioned substance is dissolved completely, stir 8 hours under lucifuge condition.
(5) 2mg carbodiimide (EDC) and 2mgN-N-Hydroxysuccinimide (NHS) is then added respectively.Continue stirring after 2 hours.
(6) the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle that 250mg prepares is added, react centrifugal purification after spending the night, obtain the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle of surface-functionalized modification, preserve after the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment of its surface functional modification.
(7) take rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle and the 50mg drug adriamycin of the surface-functionalized modification of 50mg, above-mentioned two kinds of raw materials are added in five milliliters of dimethyl sulfoxide (DMSO) solution.
(8) be heated to 45 DEG C under magnetic agitation condition, stir 5 hours, react centrifugal purification after spending the night, finally obtain rare earth being changed light-operated drug release nanometer chemotheraping preparation, preserve after product vacuum dried.In nanometer formulation, particle size is 98nm.Fig. 3: prepare on light rare earth according to embodiment 1 and change light-operated drug release nanometer chemotherapy preparation granules (right side) projection electron microscope photo (morphology analysis).Fig. 4: the grain size distribution (dimension analysis) rare earth prepared according to embodiment 1 being changed light-operated drug release nanometer chemotherapy preparation granules.
Embodiment 2:
One, the synthesis of rare earth upconversion nano grain (UCN):
A) above-mentioned up-conversion nanoparticles adopts solvent-thermal method to prepare:
(1) take 250mg Ytterbium trichloride, 100mg Yttrium chloride(Y2Cl6) and 5mg Erbium trichloride, above-mentioned three kinds of materials are joined in four ml waters, in magnetic agitation condition, be heated to boiling until rare earths salt becomes white solid.
(2), after water evaporate to dryness, slightly cool (less than 80 DEG C) and add 60mL oleic acid ligand solution with pipet and 10mL octadecylene ligand solution makes white solid dissolve completely;
(3) then add 15mgNaOH, 15mg ammonium fluoride, dissolve by five ml methanol; Regulate temperature to 100 DEG C, adopt oil pump evacuation 10min, logical argon; Rapid temperature increases, to 270 DEG C, maintains reaction 1 hour; Add acetone centrifugal purification after end, preserve after end product vacuum drying treatment.The rare earth upconversion nano grain particle diameter of preparation is 45nm.
Two, the coating mesoporous silicon shell of rare earth upconversion nano grain and the modification of surface light sensitive molecule and targeted molecular and the embedding of chemotherapeutic drugs Doxorubicin:
(1) according to the quality of material, take 10mg rare earth upconversion nano grain respectively, 2000mg cetyl trimethyl ammonium bromide (CTAB) and 50mg sodium hydroxide join in reactor, then in reactor, add aqueous solvent 30mL makes above-mentioned substance dissolve completely, be heated to 30 DEG C under magnetic agitation condition, stir 3 hours.
(2) finally add 5mg ethyl orthosilicate (TEOS), react after 1 hour, centrifugal purification.
(3) nanoparticle after centrifugal is re-dispersed in 40mL ethanol, then adds 100mg sodium chloride template agent removing, under magnetic agitation condition, be heated to 50 DEG C, stir 1 hour.Centrifugal purification after reacting completely, preserves after product rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment.
(4) 50mg4-benzene-azo-benzene formyl chloride is taken respectively, raw material joins in reactor by 50mg folic acid and 50mg3-aminopropyl triethoxysilane, then in reactor, add 5mL solvents tetrahydrofurane above-mentioned substance is dissolved completely, stir 5 hours under lucifuge condition.
(5) 20mg carbodiimide (EDC) and 30mgN-N-Hydroxysuccinimide (NHS) is then added respectively.Continue stirring after 3 hours.
(6) the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle that 500mg prepares is added, react centrifugal purification after spending the night, obtain the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle of surface-functionalized modification, preserve after the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment of its surface functional modification.
(7) take rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle and the 10mg drug adriamycin of the surface-functionalized modification of 50mg, above-mentioned two kinds of raw materials are added in five milliliters of dimethyl sulfoxide (DMSO) solution.
(8) be heated to 30 DEG C under magnetic agitation condition, stir 12 hours, react centrifugal purification after spending the night, finally obtain rare earth being changed light-operated drug release nanometer chemotheraping preparation, preserve after product vacuum dried.In nanometer formulation, particle size is 80nm.Fig. 5: rare earth is changed light-operated drug release nanometer chemotheraping preparation fluorescence emission analysis of spectrum.Fig. 6: rare earth is changed the fluorescence photo (right figure) under the photomacrograph (left figure) of light-operated drug release nanometer formulation and near infrared laser illuminate condition.
Embodiment 3:
One, the synthesis of rare earth upconversion nano grain (UCN):
(1) above-mentioned up-conversion nanoparticles adopts solvent-thermal method to prepare: take 30mg Ytterbium trichloride, 50mg Yttrium chloride(Y2Cl6) and 1mg Erbium trichloride, above-mentioned three kinds of materials are joined in four ml waters, in magnetic agitation condition, is heated to boiling until rare earths salt becomes white solid.
(2), after water evaporate to dryness, slightly cool (less than 60 DEG C) and add 20mL oleic acid ligand solution with pipet and 5mL octadecylene ligand solution makes white solid dissolve completely;
(3) then add 1mgNaOH, 3mg ammonium fluoride, dissolve by five ml methanol; Regulate temperature to 120 DEG C, adopt oil pump evacuation 40min, logical argon; Rapid temperature increases, to 300 DEG C, maintains reaction 3 hours; Add acetone centrifugal purification after end, preserve after end product vacuum drying treatment.The rare earth upconversion nano grain particle diameter of preparation is 60nm.
Two, the coating mesoporous silicon shell of rare earth upconversion nano grain and the modification of surface light sensitive molecule and targeted molecular and the embedding of chemotherapeutic drugs Doxorubicin:
(1) according to the quality of material, take 10mg rare earth upconversion nano grain respectively, 1000mg cetyl trimethyl ammonium bromide (CTAB) and 100mg sodium hydroxide join in reactor, then in reactor, add aqueous solvent 30mL makes above-mentioned substance dissolve completely, be heated to 45 DEG C under magnetic agitation condition, stir 1 hour.
(2) finally add 2mg ethyl orthosilicate (TEOS), react after 5 hours, centrifugal purification.
(3) nanoparticle after centrifugal is re-dispersed in 60mL ethanol, then adds 300mg sodium chloride template agent removing, under magnetic agitation condition, be heated to 70 DEG C, stir 2 hours.Centrifugal purification after reacting completely, preserves after product rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment.
(4) 10mg4-benzene-azo-benzene formyl chloride is taken respectively, raw material joins in reactor by 500mg folic acid and 40mg3-aminopropyl triethoxysilane, then in reactor, add 5mL solvents tetrahydrofurane above-mentioned substance is dissolved completely, stir 10 hours under lucifuge condition.
(5) 4mg carbodiimide (EDC) and 8mgN-N-Hydroxysuccinimide (NHS) is then added respectively.Continue stirring after 0.5 hour.
(6) the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle that 200mg prepares is added, react centrifugal purification after spending the night, obtain the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle of surface-functionalized modification, preserve after the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment of its surface functional modification.
(7) take rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle and the 5mg drug adriamycin of the surface-functionalized modification of 50mg, above-mentioned two kinds of raw materials are added in five milliliters of dimethyl sulfoxide (DMSO) solution.
(8) be heated to 60 DEG C under magnetic agitation condition, stir 8 hours, react centrifugal purification after spending the night, finally obtain rare earth being changed light-operated drug release nanometer chemotheraping preparation, preserve after product vacuum dried.In nanometer formulation, particle size is 150nm.
Embodiment 4:
One, the synthesis of rare earth upconversion nano grain (UCN):
(1) above-mentioned up-conversion nanoparticles adopts solvent-thermal method to prepare: take 25mg Ytterbium trichloride, 45mg Yttrium chloride(Y2Cl6) and 1mg Erbium trichloride, above-mentioned three kinds of materials are joined in four ml waters, in magnetic agitation condition, is heated to boiling until rare earths salt becomes white solid.
(2), after water evaporate to dryness, slightly cool (less than 65 DEG C) and add 60mL oleic acid ligand solution with pipet and 15mL octadecylene ligand solution makes white solid dissolve completely;
(3) then add 4.5mgNaOH, 3mg ammonium fluoride, dissolve by five ml methanol; Regulate temperature to 125 DEG C, adopt oil pump evacuation 35min, logical argon; Rapid temperature increases, to 275 DEG C, maintains reaction 2.5 hours; Add acetone centrifugal purification after end, preserve after end product vacuum drying treatment.The rare earth upconversion nano grain particle diameter of preparation is 43nm.
Two, the coating mesoporous silicon shell of rare earth upconversion nano grain and the modification of surface light sensitive molecule and targeted molecular and the embedding of chemotherapeutic drugs Doxorubicin:
(1) according to the quality of material, take 5mg rare earth upconversion nano grain respectively, 750mg cetyl trimethyl ammonium bromide (CTAB) and 75mg sodium hydroxide join in reactor, then in reactor, add aqueous solvent 30mL makes above-mentioned substance dissolve completely, be heated to 55 DEG C under magnetic agitation condition, stir 2.5 hours.
(2) finally add 1.5mg ethyl orthosilicate (TEOS), react after 3.5 hours, centrifugal purification.
(3) nanoparticle after centrifugal is re-dispersed in 60mL ethanol, then adds 120mg sodium chloride template agent removing, under magnetic agitation condition, be heated to 45 DEG C, stir 2.5 hours.Centrifugal purification after reacting completely, preserves after product rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment.
(4) 5mg4-benzene-azo-benzene formyl chloride is taken respectively, raw material joins in reactor by 120mg folic acid and 21mg3-aminopropyl triethoxysilane, then in reactor, add 5mL solvents tetrahydrofurane above-mentioned substance is dissolved completely, stir 6.5 hours under lucifuge condition.
(5) 2mg carbodiimide (EDC) and 3mgN-N-Hydroxysuccinimide (NHS) is then added respectively.Continue stirring after 2.5 hours.
(6) the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle that 160mg prepares is added, react centrifugal purification after spending the night, obtain the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle of surface-functionalized modification, preserve after the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment of its surface functional modification.
(7) take rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle and the 1mg drug adriamycin of the surface-functionalized modification of 8mg, above-mentioned two kinds of raw materials are added in five milliliters of dimethyl sulfoxide (DMSO) solution.
(8) be heated to 45 DEG C under magnetic agitation condition, stir 6.5 hours, react centrifugal purification after spending the night, finally obtain rare earth being changed light-operated drug release nanometer chemotheraping preparation, preserve after product vacuum dried.In nanometer formulation, particle size is 105nm.
Embodiment 5:
One, the synthesis of rare earth upconversion nano grain (UCN):
(1) above-mentioned up-conversion nanoparticles adopts solvent-thermal method to prepare: take 30mg Ytterbium trichloride, 50mg Yttrium chloride(Y2Cl6) and 1mg Erbium trichloride, above-mentioned three kinds of materials are joined in four ml waters, in magnetic agitation condition, is heated to boiling until rare earths salt becomes white solid.
(2), after water evaporate to dryness, slightly cool (less than 75 DEG C) and add 20mL oleic acid ligand solution with pipet and 4mL octadecylene ligand solution makes white solid dissolve completely;
(3) then add 1mgNaOH, 3mg ammonium fluoride, dissolve by five ml methanol; Regulate temperature to 105 DEG C, adopt oil pump evacuation 35min, logical argon; Rapid temperature increases, to 280 DEG C, maintains reaction 2.5 hours; Add acetone centrifugal purification after end, preserve after end product vacuum drying treatment.The rare earth upconversion nano grain particle diameter of preparation is 48nm.
Two, the coating mesoporous silicon shell of rare earth upconversion nano grain and the modification of surface light sensitive molecule and targeted molecular and the embedding of chemotherapeutic drugs Doxorubicin:
(1) according to the quality of material, take 10mg rare earth upconversion nano grain respectively, 2000mg cetyl trimethyl ammonium bromide (CTAB) and 50mg sodium hydroxide join in reactor, then in reactor, add aqueous solvent 30mL makes above-mentioned substance dissolve completely, be heated to 65 DEG C under magnetic agitation condition, stir 2 hours.
(2) finally add 5mg ethyl orthosilicate (TEOS), react after 4.5 hours, centrifugal purification.
(3) nanoparticle after centrifugal is re-dispersed in 60mL ethanol, then adds 100mg sodium chloride template agent removing, under magnetic agitation condition, be heated to 45 DEG C, stir 3 hours.Centrifugal purification after reacting completely, preserves after product rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment.
(4) 5mg4-benzene-azo-benzene formyl chloride is taken respectively, raw material joins in reactor by 150mg folic acid and 30mg3-aminopropyl triethoxysilane, then in reactor, add 5mL solvents tetrahydrofurane above-mentioned substance is dissolved completely, stir 7 hours under lucifuge condition.
(5) 2mg carbodiimide (EDC) and 2mgN-N-Hydroxysuccinimide (NHS) is then added respectively.Continue stirring after 2 hours.
(6) the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle that 250mg prepares is added, react centrifugal purification after spending the night, obtain the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle of surface-functionalized modification, preserve after the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment of its surface functional modification.
(7) take rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle and the 1mg drug adriamycin of the surface-functionalized modification of 8mg, above-mentioned two kinds of raw materials are added in five milliliters of dimethyl sulfoxide (DMSO) solution.
(8) be heated to 45 DEG C under magnetic agitation condition, stir 8 hours, react centrifugal purification after spending the night, finally obtain rare earth being changed light-operated drug release nanometer chemotheraping preparation, preserve after product vacuum dried.In nanometer formulation, particle size is 125nm.
Embodiment 6:
One, the synthesis of rare earth upconversion nano grain (UCN):
(1) above-mentioned up-conversion nanoparticles adopts solvent-thermal method to prepare: take 200mg Ytterbium trichloride, 700mg Yttrium chloride(Y2Cl6) and 10mg Erbium trichloride, above-mentioned three kinds of materials are joined in four ml waters, in magnetic agitation condition, is heated to boiling until rare earths salt becomes white solid.
(2), after water evaporate to dryness, slightly cool (less than 55 DEG C) and add 30mL oleic acid ligand solution with pipet and 10mL octadecylene ligand solution makes white solid dissolve completely;
(3) then add 60mgNaOH, 30mg ammonium fluoride, dissolve by five ml methanol; Regulate temperature to 140 DEG C, adopt oil pump evacuation 30min, logical argon; Rapid temperature increases, to 280 DEG C, maintains reaction 3 hours; Add acetone centrifugal purification after end, preserve after end product vacuum drying treatment.The rare earth upconversion nano grain particle diameter of preparation is 55nm.
Two, the coating mesoporous silicon shell of rare earth upconversion nano grain and the modification of surface light sensitive molecule and targeted molecular and the embedding of chemotherapeutic drugs Doxorubicin:
(1) according to the quality of material, take 10mg rare earth upconversion nano grain respectively, 1000mg cetyl trimethyl ammonium bromide (CTAB) and 100mg sodium hydroxide join in reactor, then in reactor, add aqueous solvent 30mL makes above-mentioned substance dissolve completely, be heated to 65 DEG C under magnetic agitation condition, stir 2.5 hours.
(2) finally add 2mg ethyl orthosilicate (TEOS), react after 4.5 hours, centrifugal purification.
(3) nanoparticle after centrifugal is re-dispersed in 60mL ethanol, then adds 300mg sodium chloride template agent removing, under magnetic agitation condition, be heated to 45 DEG C, stir 2 hours.Centrifugal purification after reacting completely, preserves after product rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment.
(4) 50mg4-benzene-azo-benzene formyl chloride is taken respectively, raw material joins in reactor by 50mg folic acid and 50mg3-aminopropyl triethoxysilane, then in reactor, add 5mL solvents tetrahydrofurane above-mentioned substance is dissolved completely, stir 6 hours under lucifuge condition.
(5) 20mg carbodiimide (EDC) and 30mgN-N-Hydroxysuccinimide (NHS) is then added respectively.Continue stirring after 2 hours.
(6) the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle that 500mg prepares is added, react centrifugal purification after spending the night, obtain the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle of surface-functionalized modification, preserve after the rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle vacuum drying treatment of its surface functional modification.
(7) take rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle and the 1mg drug adriamycin of the surface-functionalized modification of 8mg, above-mentioned two kinds of raw materials are added in five milliliters of dimethyl sulfoxide (DMSO) solution.
(8) be heated to 40 DEG C under magnetic agitation condition, stir 8 hours, react centrifugal purification after spending the night, finally obtain rare earth being changed light-operated drug release nanometer chemotheraping preparation, preserve after product vacuum dried.In nanometer formulation, particle size is 120nm.
Morphologic observation, particles size and distribution measure:
Extracting sample solution is after ultracentrifugation is separated, and take out precipitate, adding distil water makes dispersion on a small quantity, drips sample preparation on carbon supporting film, observes its pattern state and take pictures under transmission electron microscope.Observe under transmission electron microscope on rare earth and change light-operated drug release nanometer chemotherapy preparation granules in evenly regular spheroidal particle.The rare earth that experiment records changes light-operated drug release nanometer chemotheraping preparation even particle size distribution, controlled within the scope of 80-150nm.Obtained nanoparticle as shown in Figure 1.
Mtt assay tests the cytotoxicity light-operated thermotherapy targeting rare earth being changed-Jin core-shell nano preparation:
1) get the l cell being in exponential phase, fully blow and beat into single cell suspension after 0.125% trypsinization, after counting, adjustment cell concentration is 5 × 10
4/ m1.
2) in every hole of 96 orifice plates, 100 μ l cell suspension are added, at 37 DEG C, 5%CO
224h is cultivated in incubator.
3) 120 μ l are contained and certain density rare earth changes light-operated drug release nanometer chemotherapy formulation soln join in fresh culture, and at 37 DEG C, 5%CO
2logical co-culture of cells 24h in incubator.
4) culture plate is taken out after 24h, 10 μ l MTT solution are added in each hole, at 37 DEG C, after continuing to cultivate 4h in 5%CO2 incubator, culture medium in careful absorption culture hole, in each hole, add 200 μ l DMSO (dimethyl sulfoxide) solution, shaking table shakes 20min, make DMSO solution dissolve Formazan crystal fully.
5) use enzyme-linked immunosorbent assay instrument at 570nm wavelength place, with blank tube zeroing, measure the light absorption value A in each hole, be calculated as follows cell survival rate.Often group establish 8 parallel, calculate its meansigma methods.
Cell survival rate (%)=experimental cell group light absorption value (A2)/blanc cell group light absorption value (A1) * 100%
Fig. 7: rare earth is changed light-operated drug release nanometer formulation cytotoxicity analysis (left figure) and cell endocytic experimental result (right figure).
The drafting of light-operated drug release patterns:
1) get the Doxorubicin solution of concentration known (C), go out to record light absorption value (A) at characteristic wavelength 480nm, obtain the relational expression of concentration (C) and light absorption value (A) according to software matching.
2) be divided into two parts of equivalent and join by the rare earth prepared being changed light-operated drug release nanometer chemotheraping preparation and be equipped with in the cuvette of dialyzer, wherein one group irradiates at special time with 980nm near infrared light, the change of light absorption value in test cuvette, thus release amount of medicine of seizing back confiscated property out.
Fig. 8 display be that the rare earth for preparing according to example 1 changes light-operated drug release nanometer chemotheraping preparation drug release patterns at different conditions.
Claims (4)
1. a rare earth is changed the preparation method of drug release nano-carrier; It is characterized in that step is as follows:
1), first utilize various rare-earth salts for raw material, prepare rare earth upconversion nano grain by solvent thermal;
2), adopt Template synthesis mesoporous silicon coated, silane reagent be connected to the surface of mesoporous silicon shell, finally medicine is embedded into mesoporous in.
2. the method for claim 1, is characterized in that described step 1) method is as follows:
(1) be Ytterbium trichloride according to ratio of quality and the number of copies: Yttrium chloride(Y2Cl6): Erbium trichloride=(20 ~ 50): (20 ~ 70): raw material joins in reactor by 1, then adds aqueous solvent and above-mentioned substance is dissolved completely in reactor; In magnetic agitation condition, be heated to boiling until rare earths salt becomes white solid;
(2) after water evaporate to dryness, cooling 50 ~ 80 DEG C, is oleic acid according to volume ratio: the two adds in reactor by octadecylene=2 ~ 6:1 makes white solid dissolve completely;
(3) be NaOH according to mass number: add methanol in the reactor that the two adds by ammonium fluoride=1 ~ 6:3 and make it dissolve completely, the mass ratio=3:1 of ammonium fluoride and above-mentioned Erbium trichloride; Regulate temperature to 100 ~ 150 DEG C, evacuation 10 ~ 40min, logical argon; Rapid temperature increases, to 250 ~ 300 DEG C, maintains reaction 1 ~ 3 hour; Add acetone centrifugal purification after end, after vacuum drying treatment, obtain rare earth upconversion nano grain.
3. the method for claim 1, is characterized in that described step 2) method is as follows:
(1) be rare earth upconversion nano grain according to the ratio of quality and the number of copies of material: cetyl trimethyl ammonium bromide: sodium hydroxide=1:(50 ~ 200): raw material joins in reactor by (5 ~ 20), then in reactor, add aqueous solvent makes above-mentioned substance dissolve completely, be heated to 30 ~ 70 DEG C under magnetic agitation condition, stir 1 ~ 3 hour;
(2) ethyl orthosilicate is added, wherein mass ratio=0.01 ~ the 0.5:1 of ethyl orthosilicate and rare earth upconversion nano grain; React after 1 ~ 5 hour, centrifugal purification;
(3) nanoparticle after centrifugal is re-dispersed in ethanol, add sodium chloride as template agent removing, wherein mass ratio=10 ~ the 50:1 of sodium chloride and above-mentioned rare earth upconversion nano grain, is heated to 30 ~ 70 DEG C under magnetic agitation condition, stirs 1 ~ 3 hour; Centrifugal purification after reacting completely, obtains rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle after product vacuum dried;
(4) be 4-benzene-azo-benzene formyl chloride according to the ratio of quality and the number of copies of material: folic acid: 3-aminopropyl triethoxysilane=1:(1 ~ 50): raw material joins in reactor by (1 ~ 6), then in reactor, solvents tetrahydrofurane is added, above-mentioned substance is dissolved completely, stirs 5 ~ 10 hours under lucifuge condition;
(5) add according to ratio of quality and the number of copies carbodiimide: N-hydroxy-succinamide=0.4:0.4 ~ 0.8, wherein the ratio of quality and the number of copies of carbodiimide and 4-benzene-azo-benzene formyl chloride is 0.4:1, continues stirring 0.5 ~ 3 hour;
(6) rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle is added, wherein mass ratio=10 ~ the 50:1 of rare earth upconversion nano grain coating mesoporous silicon shell nanoparticle and 4-benzene-azo-benzene formyl chloride, react centrifugal purification after spending the night, obtain rare earth being changed light-operated drug release nano-carrier.
(7) be rare earth is changed light-operated drug release nano-carrier according to the ratio of quality and the number of copies of material: raw material joins in reactor by drug adriamycin=1 ~ 10:1, in reactor, then adds solvent dimethyl sulphoxide solution disperseed completely by above-mentioned substance;
(8) under magnetic agitation condition, 30 ~ 60 DEG C are heated to, stir 5 ~ 12 hours, react centrifugal purification after spending the night, finally obtain rare earth being changed light-operated drug release nanometer chemotheraping preparation, product vacuum dried, obtains the nanometer formulation that particle size is 80-150nm.
4. carrier of the present invention is applied to the medicament of the light-operated drug release of chemotherapy of tumors.
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