CN108096586A - Double-bang firecracker based on manganese dioxide modification answers preparation method, product and the application of drug delivery system - Google Patents

Double-bang firecracker based on manganese dioxide modification answers preparation method, product and the application of drug delivery system Download PDF

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Publication number
CN108096586A
CN108096586A CN201711267852.7A CN201711267852A CN108096586A CN 108096586 A CN108096586 A CN 108096586A CN 201711267852 A CN201711267852 A CN 201711267852A CN 108096586 A CN108096586 A CN 108096586A
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manganese dioxide
dispersion liquid
double
delivery system
drug delivery
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孙丽宁
施利毅
赵磊
葛笑千
赵慧君
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University of Shanghai for Science and Technology
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University of Shanghai for Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The invention discloses a kind of double-bang firecrackers based on manganese dioxide modification to answer the preparation method of drug delivery system and product and application, by modifying amino on the up-conversion luminescence nanometer crystal of the coating mesoporous silicon dioxide layer in surface, carrying medicament again finally coats sheet manganese dioxide and is made.It is nucleocapsid that the obtained double-bang firecracker based on manganese dioxide modification, which answers drug delivery system, core is up-conversion luminescence nanometer crystal, shell is mesoporous silicon oxide, and being loaded in the mesoporous passage of mesoporous silicon oxide has drug, and mesoporous passage is coated with sheet manganese dioxide.Preparation method of the present invention has simple for process, easy to operate, easy control of structure advantage.Product has many advantages, such as that good biocompatibility, double-bang firecracker answer controlled drug release, can be applied to the chemotherapy that magnetic resonance imaging and up-conversion luminescence imaging guide, and can simultaneously be effectively loads a variety of anticancer drugs, for biomedical sectors such as the diagnose and treats of tumour.

Description

Double-bang firecracker based on manganese dioxide modification answers the preparation method of drug delivery system, product With application
Technical field
The present invention relates to a kind of drug delivery system technical field more particularly to a kind of double-bang firecrackers based on manganese dioxide modification Answer the preparation method of drug delivery system and product and application.
Background technology
In recent years, rear-earth-doped up-conversion luminescence nanomaterial causes the wide of people as a kind of emerging fluorescent material Because it is typically using low energy light excitation (be typically near infrared light 980nm), it is (feux rouges, green to launch high energy light for general concern Light, near infrared light 800nm), these advantages can eliminate the interference of biological context fluorescence and low signal-to-noise ratio so that it can extensively A series of bio-imaging fields are used in, as above convert luminescence imaging, magnetic resonance imaging etc., but for tumour cell detection Sensitivity still needs raising.
Cancer remains as a great problem of puzzlement medical field, and anticancer drug causes therapeutic effect due to its serious side effect It is barely satisfactory.Therefore how to reduce the side effect of anticancer drug becomes the hot spot of research.Most of research concentrates on solely Detection or treating cancer, this cannot realize the diagnosis and treatment integration for cancer well, so as to influence therapeutic effect.
Publication No. is that the patent of CN107224588A discloses a kind of preparation for the pharmaceutical carrier answered with magnetic-pH value double-bang firecracker Method is prepared for FeO4@SiO2Composite nanoparticle, and be modified using β-CD, pharmaceutical carrier is made.But it is only capable of reality The treatment of existing drug, can not realize the detection of cancer simultaneously, and need externally-applied magnetic field that can just realize the Targeting delivery of drug, and It is not very convenient.
Therefore, research and develop a kind of double-bang firecracker for the detection and treatment that can take into account cancer and answer drug delivery system, just become more Urgently.
The content of the invention
Against the above deficiency, it is an object of the invention to provide a kind of double-bang firecrackers based on manganese dioxide modification to answer drug release The preparation method and product of system and application are improved rear-earth-doped up-conversion luminescence nanomaterial so that it can be same Shi Shixian bio-imagings and carrying medicament are realized the controlled drug release that pH/ glutathione (GSH) double-bang firecracker is answered, and are realized Magnetic resonance imaging and the chemotherapy of up-conversion luminescence imaging double mode guiding, improve image sensitivity.
The used in order to achieve the above objectives technical solution of the present invention is：
A kind of double-bang firecracker based on manganese dioxide modification answers the preparation method of drug delivery system, comprises the following steps：
(1) rare earth upconversion nano crystal of the coating mesoporous silicon dioxide layer in surface is taken, disperses to form first point in ethanol Dispersion liquid；
(2) by step (1) obtained by the first dispersion liquid, with 3- aminopropyl triethoxysilanes modify, take solid centrifugation, wash After washing, it is scattered in ethyl alcohol and forms the second dispersion liquid；
(3) step (2) is added in into drug in the second dispersion liquid, after being sufficiently stirred, takes solid centrifugation, washing, be dispersed in The 3rd dispersion liquid is formed in water；
(4) 2-N- morphines is taken to mix the two for alkyl sulfonic acid and potassium permanganate, after carrying out ultrasound and crushing, be dispersed in The 4th dispersion liquid is formed in water；
(5) after the 3rd dispersion liquid obtained by step (3) and the 4th dispersion liquid obtained by step (4) being mixed from The heart is dispersed in water again, and the double-bang firecracker based on manganese dioxide modification is made and answers drug delivery system.
As a further improvement on the present invention, the step (2) specifically includes following steps：
(2.1) in the surface modification amino of meso-porous titanium dioxide silicon layer：Take 10~15mg/ obtained by 15~30mL steps (1) The first dispersion liquids of mL add in 150~300 μ L3- aminopropyl triethoxysilanes, when stirring 24 is small under room temperature,；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, disperses in ethanol, to obtain concentration as 10 after washing The second dispersion liquid of~15mg/mL.
As a further improvement on the present invention, the step (3) specifically includes following steps：
(3.1) carrying medicament in the mesoporous passage of meso-porous titanium dioxide silicon layer：The second dispersion liquid obtained by step (2) is taken, Add in doxorubicin hydrochloride aqueous solution or cisplatin medicine aqueous solution that 5~10mL concentration is 1~2mg/mL or curcumin aqueous solution, Or Japanese yew alcohol solution, when stirring 24 is small under room temperature,；
(3.2) solid will be taken after the centrifugation of step (3.1) products therefrom, be dispersed in water after washing, obtain concentration for 5~ The 3rd dispersion liquid of 10mg/mL.
As a further improvement on the present invention, the step (4) specifically includes following steps：
(4.1) manganese dioxide nano-plates are prepared：The 2-N- morphines that 50~100 μ L concentration are 200~300mmol/L are taken for alkane Sulfonic acid solutions and the liquor potassic permanganate that 50~100 μ L concentration are 200~300mmol/L, the two is mixed, ultrasonic under room temperature 0.5~1 it is small when, then with clasmatosis crusher machine 0.5~2 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after as washing, obtains Mn4+Concentration is 5 The 4th dispersion liquid of~10mg/mL.
As a further improvement on the present invention, the step (5) specifically includes following steps：
(5.1) in meso-porous titanium dioxide silicon layer outer cladding sheet manganese dioxide：By the 3rd dispersion liquid 10 obtained by step (3)~ 20mL and the 4th 5~10mL of dispersion liquid mixing obtained by step (4), stirred under room temperature 24 it is small when；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing by 15~30mg/mL of concentration, It obtains the double-bang firecracker based on manganese dioxide modification and answers drug delivery system.
As a further improvement on the present invention, the rare earth upconversion nano crystal bag of the coating mesoporous silicon dioxide layer in the surface It includes：NaYF4:Yb3+,Er3+@mSiO2、NaYF4:Yb3+,Tm3+@mSiO2、NaGdF4:Yb3+,Tm3+@mSiO2、NaGdF4:Yb3+, Er3+@mSiO2、NaYF4:Yb3+,Er3+,Tm3+@mSiO2、NaYF4:Yb3+,Er3+@NaGdF4@mSiO2、NaYF4:Yb3+,Er3+@ NaYF4@mSiO2。
A kind of double-bang firecracker based on manganese dioxide modification answers drug delivery system, and hydration grain size is 100-300nm, and is core Shell structure, the meso-porous titanium dioxide silicon layer including the rare earth upconversion nano crystal as core and as shell, the mesoporous dioxy Load has doxorubicin hydrochloride or cisplatin medicine or curcumin or taxol in the mesopore orbit of SiClx layer, the meso-porous titanium dioxide Silicon layer outer surface is modified with sheet manganese dioxide, which is also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer On.
As a further improvement on the present invention, the rare earth upconversion nano crystal includes：NaYF4:Yb3+,Er3+、NaYF4: Yb3+,Tm3+、NaGdF4:Yb3+,Tm3+、NaGdF4:Yb3+,Er3+、NaYF4:Yb3+,Er3+,Tm3+、NaYF4:Yb3+,Er3+@ NaGdF4、NaYF4:Yb3+,Er3+@NaYF4。
A kind of double-bang firecracker based on manganese dioxide modification answers the application of drug delivery system, is applied to controlled drug and releases It puts.
A kind of double-bang firecracker based on manganese dioxide modification answers the application of drug delivery system, is applied to being total to for HeLa cells Focal imaging.
A kind of double-bang firecracker based on manganese dioxide modification answers the application of drug delivery system, is applied to magnetic resonance imaging.
Beneficial effects of the present invention are：
(1) double-bang firecracker based on manganese dioxide modification answers the preparation method of drug delivery system simple and practicable, has high repeat Property, structure can be controlled simply according to actual needs；
(2) double-bang firecracker based on manganese dioxide modification answers drug delivery system can effectively carrying medicament, and using sheet The coating mesoporous duct of manganese dioxide, further improves load capacity and load stability；
(3) double-bang firecracker based on manganese dioxide modification answers drug delivery system monodispersity good, has the controllable medicine that double-bang firecracker is answered Object releasability, good biocompatibility；
(4) double-bang firecracker based on manganese dioxide modification answers effect of the drug delivery system due to manganese ion, and magnetic resonance signal is bright Aobvious enhancing, so as to achieve the effect that improve magnetic resonance imaging sensitivity, imaging effect is than existing rear-earth-doped up-conversion luminescence Nano material is more preferable, the biomedical sectors such as diagnose and treat available for tumour, particularly for magnetic resonance imaging and upper turn Change the chemotherapy of luminescence imaging guiding.
Above-mentioned is the general introduction of inventive technique scheme, and below in conjunction with specific embodiment, the present invention will be further described.
Description of the drawings
Fig. 1 is the TEM photos of 1 gained sample of the embodiment of the present invention；
Fig. 2 is the fluorescence spectra under the excitations of 980nm at different conditions of 1 gained sample of the embodiment of the present invention；
Fig. 3 is the drug release rate contrast schematic diagram under 7 gained sample different condition of the embodiment of the present invention；
Fig. 4 is the co-focusing imaging figure that 8 gained sample of the embodiment of the present invention is used for HeLa cells；
Fig. 5 is the magnetic resonance imaging figure at different conditions of 9 gained sample of the embodiment of the present invention.
Specific embodiment
Further to illustrate the present invention to reach the technological means and effect that predetermined purpose is taken, below in conjunction with attached drawing And preferred embodiment, the specific embodiment of the present invention is described in detail.
Embodiment 1
The double-bang firecracker of load doxorubicin hydrochloride provided in this embodiment based on manganese dioxide modification answers drug delivery system Preparation method comprises the following steps：
(1) NaYF is taken4:Yb3+,Er3+@mSiO2, it is dispersed in ethyl alcohol, form that concentration is 13mg/mL first is scattered Liquid；
(2.1) the first dispersion liquid obtained by 23mL steps (1) is taken, adds in 230 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 13mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, adds in the doxorubicin hydrochloride water that 7.5mL concentration is 1.5mg/mL Solution, when stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 13mg/ The 3rd dispersion liquid of mL；
(4.1) it for alkyl sulfonic acid solution and 75 μ L concentration is 250mmol/L to take 2-N- morphines that 75 μ L concentration are 250mmol/L Liquor potassic permanganate, the two is mixed, under room temperature ultrasound 0.75 it is small when, then with clasmatosis crusher machine 1 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 5mg/mL The 4th dispersion liquid.
(5.1) the 3rd dispersion liquid obtained by 12mL steps (3) and the 4th dispersion liquid obtained by 6mL steps (4) are mixed, When stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 18mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
Pair of load doxorubicin hydrochloride being prepared using the above method, based on manganese dioxide modification provided in this embodiment Response medicine delivery systme is nucleocapsid, including the NaYF as core4:Yb3+,Er3+And as the mesoporous of shell Silicon dioxide layer, the interior load of mesopore orbit of the meso-porous titanium dioxide silicon layer have doxorubicin hydrochloride, the meso-porous titanium dioxide silicon layer appearance Face is modified with sheet manganese dioxide, which is also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
The double-bang firecracker for the load doxorubicin hydrochloride that Fig. 1, which is 1 gained sample of the embodiment of the present invention, to be modified based on manganese dioxide answers medicine The TEM photos of object delivery systme, as can be seen from the figure nano particle diameter be evenly distributed, can be clearly in external mesoporous layer Observe hole path, can effectively carrying medicament, manganese dioxide nano-plates are uniform must to be distributed in mesoporous silicon face, illustrate the party Method can obtain that pattern is good, nucleocapsid is apparent, and the nano-medicament carrier that manganese dioxide nano-plates uniformly wrap up can be effectively Load and controlled drug release applied to tumour medicine, realize the diagnosis and treatment integration to cancer.
The double-bang firecracker for the load doxorubicin hydrochloride that Fig. 2, which is 1 gained sample of the embodiment of the present invention, to be modified based on manganese dioxide answers medicine Fluorescence spectra of the object delivery systme (UCDMs) before and after glutathione (GSH) is added in, due to titanium dioxide after GSH is added in Manganese nanometer sheet is reduced to manganese ion, and up-conversion fluorescence is restored, and enhances so as to reach the up-conversion luminescence in tumour cell Imaging effect.
Embodiment 2
The double-bang firecracker of load doxorubicin hydrochloride provided in this embodiment based on manganese dioxide modification answers drug delivery system Preparation method comprises the following steps：
(1) NaYF is taken4:Yb3+,Tm3+@mSiO2, it is dispersed in ethyl alcohol, form that concentration is 11mg/mL first is scattered Liquid；
(2.1) the first dispersion liquid obtained by 30mL steps (1) is taken, adds in 300 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 11mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, adds in the doxorubicin hydrochloride aqueous solution that 5mL concentration is 1mg/mL, When stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 11mg/ The 3rd dispersion liquid of mL；
(4.1) it for alkyl sulfonic acid solution and 50 μ L concentration is 300mmol/L to take 2-N- morphines that 50 μ L concentration are 300mmol/L Liquor potassic permanganate, the two is mixed, under room temperature ultrasound 0.5 it is small when, then with clasmatosis crusher machine 0.5 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 6mg/mL The 4th dispersion liquid.
(5.1) the 3rd dispersion liquid obtained by 13mL steps (3) and the 4th dispersion liquid obtained by 7mL steps (4) are mixed, When stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 20mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
The present embodiment also provides a kind of double-bang firecracker of the load doxorubicin hydrochloride based on manganese dioxide modification and answers drug release body System, is nucleocapsid, including the NaYF as core4:Yb3+,Tm3+And the meso-porous titanium dioxide silicon layer as shell, Jie Load has doxorubicin hydrochloride in the mesopore orbit of hole silicon dioxide layer, which is modified with sheet dioxy Change manganese, which is also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
Embodiment 3
The present embodiment provides a kind of double-bang firecrackers of the load doxorubicin hydrochloride based on manganese dioxide modification to answer drug delivery system Preparation method, comprise the following steps：
(1) NaGdF is taken4:Yb3+,Er3+@mSiO2, it is dispersed in ethyl alcohol, it is first point of 15mg/mL to form concentration Dispersion liquid；
(2.1) the first dispersion liquid obtained by 15mL steps (1) is taken, adds in 150 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 15mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, it is water-soluble to add in the doxorubicin hydrochloride that 10mL concentration is 2mg/mL Liquid, when stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 15mg/ The 3rd dispersion liquid of mL；
(4.1) the 2-N- morphines that 100 μ L concentration are 200mmol/L are taken to be for alkyl sulfonic acid solution and 100 μ L concentration The liquor potassic permanganate of 200mmol/L, the two is mixed, under room temperature ultrasound 1 it is small when, then with clasmatosis crusher machine 2 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 7mg/mL The 4th dispersion liquid.
(5.1) the 3rd dispersion liquid obtained by 14mL steps (3) and the 4th dispersion liquid obtained by 8mL steps (4) are mixed, When stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 15mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
The present embodiment also provides a kind of double-bang firecracker of the load doxorubicin hydrochloride based on manganese dioxide modification and answers drug release body System, is nucleocapsid, including the NaGdF as core4:Yb3+,Er3+And the meso-porous titanium dioxide silicon layer as shell, it should Load has doxorubicin hydrochloride in the mesopore orbit of meso-porous titanium dioxide silicon layer, which is modified with sheet two Manganese oxide, the sheet manganese dioxide are also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
Embodiment 4
The present embodiment provides a kind of double-bang firecrackers of the load doxorubicin hydrochloride based on manganese dioxide modification to answer drug delivery system Preparation method, comprise the following steps：
(1) NaGdF is taken4:Yb3+,Tm3+@mSiO2, it is dispersed in ethyl alcohol, it is first point of 12mg/mL to form concentration Dispersion liquid；
(2.1) the first dispersion liquid obtained by 20mL steps (1) is taken, adds in 200 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 12mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, adds in the doxorubicin hydrochloride aqueous solution that 8mL concentration is 3mg/mL, When stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 12mg/ The 3rd dispersion liquid of mL；
(4.1) it for alkyl sulfonic acid solution and 60 μ L concentration is 230mmol/L to take 2-N- morphines that 60 μ L concentration are 230mmol/L Liquor potassic permanganate, the two is mixed, under room temperature ultrasound 0.5 it is small when, then with clasmatosis crusher machine 1.5 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 8mg/mL The 4th dispersion liquid.
(5.1) the 3rd dispersion liquid obtained by 15mL steps (3) and the 4th dispersion liquid obtained by 8mL steps (4) are mixed, When stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 21mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
The present embodiment also provides a kind of double-bang firecracker of the load doxorubicin hydrochloride based on manganese dioxide modification and answers drug release body System, is nucleocapsid, including the NaGdF as core4:Yb3+,Tm3+And the meso-porous titanium dioxide silicon layer as shell, it should Load has doxorubicin hydrochloride in the mesopore orbit of meso-porous titanium dioxide silicon layer, which is modified with sheet two Manganese oxide, the sheet manganese dioxide are also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
Embodiment 5
The present embodiment provides a kind of double-bang firecrackers of the load cisplatin medicine based on manganese dioxide modification to answer drug delivery system Preparation method comprises the following steps：
(1) NaYF is taken4:Yb3+,Er3+@mSiO2, it is dispersed in ethyl alcohol, form that concentration is 12mg/mL first is scattered Liquid；
(2.1) the first dispersion liquid obtained by 23mL steps (1) is taken, adds in 230 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 13mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, it is water-soluble to add in the cisplatin medicine that 7.5mL concentration is 1.5mg/mL Liquid, when stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 13mg/ The 3rd dispersion liquid of mL；
(4.1) it for alkyl sulfonic acid solution and 75 μ L concentration is 250mmol/L to take 2-N- morphines that 75 μ L concentration are 250mmol/L Liquor potassic permanganate, the two is mixed, under room temperature ultrasound 0.75 it is small when, then with clasmatosis crusher machine 1 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 8mg/mL The 4th dispersion liquid.
(5.1) the 3rd dispersion liquid obtained by 15mL steps (3) and the 4th dispersion liquid obtained by 8mL steps (4) are mixed, When stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 25mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
The present embodiment also provides a kind of double-bang firecracker of the load cisplatin medicine based on manganese dioxide modification and answers drug delivery system, It is nucleocapsid, including the NaYF as core4:Yb3+,Er3+And the meso-porous titanium dioxide silicon layer as shell, this is mesoporous Load has cisplatin medicine in the mesopore orbit of silicon dioxide layer, which is modified with sheet titanium dioxide Manganese, the sheet manganese dioxide are also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
Embodiment 6
The present embodiment provides the systems that a kind of double-bang firecracker of the load curcumin based on manganese dioxide modification answers drug delivery system Preparation Method comprises the following steps：
(1) NaYF is taken4:Yb3+,Er3+@mSiO2, it is dispersed in ethyl alcohol, form that concentration is 12mg/mL first is scattered Liquid；
(2.1) the first dispersion liquid obtained by 23mL steps (1) is taken, adds in 230 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 13mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, adds in the curcumin aqueous solution that 7.5mL concentration is 1.5mg/mL, When stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 13mg/ The 3rd dispersion liquid of mL；
(4.1) it for alkyl sulfonic acid solution and 75 μ L concentration is 250mmol/L to take 2-N- morphines that 75 μ L concentration are 250mmol/L Liquor potassic permanganate, the two is mixed, under room temperature ultrasound 0.75 it is small when, then with clasmatosis crusher machine 1 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 8mg/mL The 4th dispersion liquid.
(5.1) the 3rd dispersion liquid obtained by 10mL steps (3) and the 4th dispersion liquid obtained by 5mL steps (4) are mixed, When stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 23mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
The present embodiment also provides a kind of double-bang firecracker of the load curcumin based on manganese dioxide modification and answers drug delivery system, For nucleocapsid, including the NaYF as core4:Yb3+,Er3+And the meso-porous titanium dioxide silicon layer as shell, this mesoporous two Load has curcumin in the mesopore orbit of silicon oxide layer, which is modified with sheet manganese dioxide, should Sheet manganese dioxide is also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
Embodiment 7
The present embodiment provides the systems that a kind of paclitaxel loaded double-bang firecracker based on manganese dioxide modification answers drug delivery system Preparation Method comprises the following steps：
(1) NaYF is taken4:Yb3+,Er3+@mSiO2, it is dispersed in ethyl alcohol, form that concentration is 12mg/mL first is scattered Liquid；
(2.1) the first dispersion liquid obtained by 23mL steps (1) is taken, adds in 230 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 13mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, adds in the Japanese yew alcohol solution that 7.5mL concentration is 1.5mg/mL, When stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 13mg/ The 3rd dispersion liquid of mL；
(4.1) it for alkyl sulfonic acid solution and 75 μ L concentration is 250mmol/L to take 2-N- morphines that 75 μ L concentration are 250mmol/L Liquor potassic permanganate, the two is mixed, under room temperature ultrasound 0.75 it is small when, then with clasmatosis crusher machine 1 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 9mg/mL The 4th dispersion liquid.
(5.1) the 3rd dispersion liquid obtained by 15mL steps (3) and the 4th dispersion liquid obtained by 7mL steps (4) are mixed, When stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 26mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
The present embodiment also provides a kind of paclitaxel loaded double-bang firecracker based on manganese dioxide modification and answers drug delivery system, For nucleocapsid, including the NaYF as core4:Yb3+,Er3+And the meso-porous titanium dioxide silicon layer as shell, this mesoporous two Load has taxol in the mesopore orbit of silicon oxide layer, which is modified with sheet manganese dioxide, should Sheet manganese dioxide is also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer
Embodiment 8
The present embodiment provides a kind of double-bang firecrackers of the load doxorubicin hydrochloride based on manganese dioxide modification to answer drug delivery system Preparation method, comprise the following steps：
(1) NaGdF is taken4:Yb3+,Er3+@mSiO2, it is dispersed in ethyl alcohol, it is first point of 14mg/mL to form concentration Dispersion liquid；
(2.1) the first dispersion liquid obtained by 25mL steps (1) is taken, adds in 150 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 14mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, adds in the doxorubicin hydrochloride aqueous solution that 6mL concentration is 2mg/mL, When stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 14mg/ The 3rd dispersion liquid of mL；
(4.1) it for alkyl sulfonic acid solution and 90 μ L concentration is 300mmol/L to take 2-N- morphines that 80 μ L concentration are 270mmol/L Liquor potassic permanganate, the two is mixed, under room temperature ultrasound 0.8 it is small when, then with clasmatosis crusher machine 1.5 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 8mg/mL The 4th dispersion liquid.
(5.1) the 3rd dispersion liquid obtained by 16mL steps (3) and the 4th dispersion liquid obtained by 9mL steps (4) are mixed, When stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 28mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
The present embodiment also provides a kind of double-bang firecracker of the load doxorubicin hydrochloride based on manganese dioxide modification and answers drug release body System, is nucleocapsid, including the NaGdF as core4:Yb3+,Er3+And the meso-porous titanium dioxide silicon layer as shell, it should Load has doxorubicin hydrochloride in the mesopore orbit of meso-porous titanium dioxide silicon layer, which is modified with sheet two Manganese oxide, the sheet manganese dioxide are also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
Embodiment 9
The present embodiment provides the systems that a kind of double-bang firecracker of the load curcumin based on manganese dioxide modification answers drug delivery system Preparation Method comprises the following steps：
(1) NaYF is taken4:Yb3+,Er3+,Tm3+@mSiO2, it is dispersed in ethyl alcohol, forms concentration as the first of 13mg/mL Dispersion liquid；
(2.1) the first dispersion liquid obtained by 15mL steps (1) is taken, adds in 300 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 13mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, adds in the curcumin aqueous solution that 10mL concentration is 1.5mg/mL, When stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 13mg/ The 3rd dispersion liquid of mL；
(4.1) it for alkyl sulfonic acid solution and 80 μ L concentration is 270mmol/L to take 2-N- morphines that 90 μ L concentration are 300mmol/L Liquor potassic permanganate, the two is mixed, under room temperature ultrasound 0.8 it is small when, then with clasmatosis crusher machine 1.5 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 9mg/mL The 4th dispersion liquid.
(5.1) the 3rd dispersion liquid obtained by 15mL steps (3) and the 4th dispersion liquid obtained by 8mL steps (4) are mixed, When stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 27mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
The present embodiment also provides a kind of double-bang firecracker of the load curcumin based on manganese dioxide modification and answers drug delivery system, For nucleocapsid, including the NaYF as core4:Yb3+,Er3+,Tm3+And the meso-porous titanium dioxide silicon layer as shell, Jie Load has curcumin in the mesopore orbit of hole silicon dioxide layer, which is modified with sheet titanium dioxide Manganese, the sheet manganese dioxide are also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
Embodiment 10
The present embodiment provides the systems that a kind of paclitaxel loaded double-bang firecracker based on manganese dioxide modification answers drug delivery system Preparation Method comprises the following steps：
(1) NaYF is taken4:Yb3+,Er3+@NaGdF4@mSiO2, it is dispersed in ethyl alcohol, it is 12mg/mL's to form concentration First dispersion liquid；
(2.1) the first dispersion liquid obtained by 20mL steps (1) is taken, adds in 200 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 12mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, adds in the Japanese yew alcohol solution that 7mL concentration is 1mg/mL, Yu Chang When the lower stirring 24 of temperature is small；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 12mg/ The 3rd dispersion liquid of mL；
(4.1) it for alkyl sulfonic acid solution and 60 μ L concentration is 230mmol/L to take 2-N- morphines that 65 μ L concentration are 250mmol/L Liquor potassic permanganate, the two is mixed, under room temperature ultrasound 0.5 it is small when, then with clasmatosis crusher machine 1 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 10mg/ The 4th dispersion liquid of mL.
(5.1) the 3rd dispersion liquid obtained by 17mL steps (3) and the 4th dispersion liquid obtained by 10mL steps (4) are mixed It closes, when stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 28mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
The present embodiment also provides a kind of paclitaxel loaded double-bang firecracker based on manganese dioxide modification and answers drug delivery system, For nucleocapsid, including the NaYF as core4:Yb3+,Er3+@NaGdF4And the meso-porous titanium dioxide silicon layer as shell, it should Load has taxol in the mesopore orbit of meso-porous titanium dioxide silicon layer, which is modified with sheet titanium dioxide Manganese, the sheet manganese dioxide are also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
Embodiment 11
The present embodiment provides a kind of double-bang firecrackers of the load cisplatin medicine based on manganese dioxide modification to answer drug delivery system Preparation method comprises the following steps：
(1)NaYF4:Yb3+,Er3+@NaYF4@mSiO2, it is dispersed in ethyl alcohol, forms concentration as the first of 11mg/mL Dispersion liquid；
(2.1) the first dispersion liquid obtained by 30mL steps (1) is taken, adds in 250 μ L3- aminopropyl triethoxysilanes, Yu Chang When the lower stirring 24 of temperature is small；
(2.2) solid is taken after step (2.1) products therefrom is centrifuged, is disperseed in ethanol after washing, obtaining concentration is The second dispersion liquid of 11mg/mL；
(3.1) the second dispersion liquid obtained by step (2) is taken, adds in the cisplatin medicine aqueous solution that 5mL concentration is 1.5mg/mL, When stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 11mg/ The 3rd dispersion liquid of mL；
(4.1) it for alkyl sulfonic acid solution and 85 μ L concentration is 200mmol/L to take 2-N- morphines that 85 μ L concentration are 200mmol/L Liquor potassic permanganate, the two is mixed, under room temperature ultrasound 1 it is small when, then with clasmatosis crusher machine 0.5 it is small when；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 8mg/mL The 4th dispersion liquid.
(5.1) the 3rd dispersion liquid obtained by 20mL steps (3) and the 4th dispersion liquid obtained by 8mL steps (4) are mixed, When stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with concentration 30mg/mL, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
The present embodiment also provides a kind of double-bang firecracker of the load cisplatin medicine based on manganese dioxide modification and answers drug delivery system, It is nucleocapsid, including the NaYF as core4:Yb3+,Er3+@NaYF4And the meso-porous titanium dioxide silicon layer as shell, Load has cisplatin medicine in the mesopore orbit of the meso-porous titanium dioxide silicon layer, which is modified with sheet two Manganese oxide, the sheet manganese dioxide are also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
Embodiment 12
Based on the double-bang firecracker that manganese dioxide is modified drug delivery system will be answered to be released for controlled drug the present embodiment provides a kind of The method put, comprises the following steps：
(1) preparation pH value is respectively 7.4 and 5.0 phosphate buffer (PBS)；
(2) glutathione solution of 10mmol/L is configured with the phosphate buffer (PBS) that pH value is 7.4 and 5.0 respectively；
(3) it is obtained based on the double of manganese dioxide modification that 3mL embodiments 1 are added in the bag filter for being 12000 in molecular weight Response medicine delivery systme inserts the phosphate buffer (PBS) under the conditions of tetra- kinds of 15mL；
(4) absorbance of the doxorubicin hydrochloride under 488nm in dialyzate is monitored under different time respectively.
Fig. 3 is the drug delivery system (UCDMs) of the load doxorubicin hydrochloride based on manganese dioxide modification in varying environment The release rate of lower doxorubicin hydrochloride, it is as can be seen from the figure only relatively low in pH and also there are GSH under conditions of doxorubicin hydrochloride It can just be released out of mesopore orbit, and release rate is up to 80%.It is double to show that the platform can be efficiently used for pH/GSH The controlled drug release of response, reduces the side effect of antitumor drug.
Embodiment 13
Based on the double-bang firecracker that manganese dioxide is modified drug delivery system will be answered to be total to for intracellular the present embodiment provides a kind of The method of focal imaging, specifically includes following steps：
(1) double-bang firecracker obtained based on manganese dioxide modification of Preparative Example 1 answers controlled drug delivery systme 15mg, cell Culture medium, the HeLa cells of 96 orifice plate cultures；
(2) cell is used into 4' in advance, 6- diamidinos -2-phenylindone (DAPI) is incubated, is washed afterwards with new culture medium Cell；
(3) by prepared drug delivery system and cell culture medium with 1:9 ratio mixing, forms the 5th dispersion liquid；
(4) the 5th dispersion liquid is taken to add in 96 orifice plates, is subsequently placed at after cultivating 3h in constant temperature and humidity cabinet, it is burnt in copolymerization Micro- Microscopic observation.
Fig. 4 is that the double-bang firecracker of the load doxorubicin hydrochloride based on manganese dioxide modification answers drug delivery system in tumour cell Co-focusing imaging, as time went on, sample are constantly swallowed and accumulated by cell, and up-conversion luminescence (UCL) is located in cytoplasm, Doxorubicin hydrochloride is released in the environment of acid and high concentration glutathione in tumour cell, into nucleus so that cell Apoptosis achievees the effect that treat tumour.
Embodiment 14
To drug delivery system be answered for magnetic resonance imaging based on the double-bang firecracker that manganese dioxide is modified the present embodiment provides a kind of Method, specifically include following steps：
(1) the drug delivery system phosphate-buffered for answering the double-bang firecracker obtained based on manganese dioxide modification of embodiment 1 Liquid (PBS) is configured to the 6th dispersion liquid of 1.5mg/mL；
(2) glutathione is added in the concentration of 10mmol/L in the 6th dispersion liquid of 2.5mL, the is formed after ultrasonic dissolution Seven dispersion liquids.
(3) the 6th dispersion liquid and the 7th dispersion liquid are subjected to Magnetic Resonance Imaging respectively.
Fig. 5, which is that the present invention is based on the double-bang firecrackers of the load doxorubicin hydrochloride of manganese dioxide modification, to answer drug delivery system adding in Magnetic resonance imaging before and after glutathione, by the figure, due to the effect of manganese ion after glutathione is added in, magnetic is common The signal that shakes is remarkably reinforced, so as to achieve the effect that improve magnetic resonance imaging sensitivity.
The emphasis of the present invention essentially consists in, according to preparation method provided by the present invention, obtained product biocompatibility Good, stable structure, and there is the controlled drug release that double-bang firecracker is answered, particularly gained nano material is in tumour cell ring It can achieve the effect that Up-conversion Intensity and magnetic resonance signal enhancing under border, can reach the integrated effect of tumour diagnosis and treatment. And preparation method has mild, simple for process, the easy to operate advantage of reaction condition.
The various raw materials used in the present invention all can be from directly buying on the market, and wherein rare earth upconversion nano crystal may be used also To be prepared with reference to following method：
(1) using solvent-thermal method, with YCl3·6H2O、YbCl3·6H2O and ErCl3·6H2O is raw material, be scattered in oleic acid/ In the mixed solution of 1- octadecenes, after stirring 1h at 150 DEG C, NaOH and NH is added in4The methanol solution of F, in 300 DEG C and argon 1h is stirred under gas shielded, postcooling is completed in reaction, is added in acetone and is carried out centrifugation acquisition NaYF4:Yb3+,Er3+, and use hexamethylene It is washed twice with acetone, NaYF is made4:Yb3+,Er3+, and be scattered in cyclohexane solution, obtain NaYF4:Yb3+,Er3+ Cyclohexane solution；
(2) by GdCl3It is added in three neck round bottom, and is heated to 110 DEG C and water is removed with evaporation.Then at 150 DEG C The lower composite solution for adding in oleic acid and octadecane, treats GdCl3Postcooling is completely dissolved to 60 DEG C.Then, NaYF is added in4:Yb3+, Er3+, NaOH and NH4The methanol solution of F heats solution 30 minutes at 110 DEG C, to remove methanol, hexamethylene.By acquired solution When reaction 1 is small under 300 DEG C of argon gas.After the completion of reaction, NaYF is obtained by being centrifuged in acetone is added in4:Yb3+,Er3+@ NaGdF4Crude product, and after being washed twice with hexamethylene and acetone, obtain NaYF4:Yb3+,Er3+@NaGdF4Finished product；
(3) by NaYF4:Yb3+,Er3+@NaGdF4It is scattered in deionized water, is mixed with CTAB, stirred under the conditions of 50~80 DEG C 0.5~1h is mixed, sodium hydroxide and absolute ethyl alcohol is added in thereafter, TEOS is added in after being warming up to 50~80 DEG C, reacts 2 under reflux state ~4h, centrifuge washing disperse product in ethanol, to add ammonium nitrate ethanol solution, at 50~80 DEG C back flow reaction 2~ 4h, removes CTAB, and centrifuge washing obtains NaYF4:Yb3+,Er3+@NaGdF4@mSiO2。
NaYF4:Yb3+,Er3+@NaYF4@mSiO2Preparation, according to method made above, choose corresponding rare-earth chlorination Object is prepared as raw material.
NaYF4:Yb3+,Er3+@mSiO2、NaYF4:Yb3+,Tm3+@mSiO2、NaGdF4:Yb3+,Tm3+@mSiO2、NaGdF4: Yb3+,Er3+@mSiO2、NaYF4:Yb3+,Er3+,Tm3+@mSiO2、NaYF4:Yb3+,Er3+@NaGdF4@mSiO2Preparation only need to walk Suddenly (1) and (3) according to method made above, is chosen corresponding rare earth-iron-boron and is prepared as raw material.
The preparation method of rare earth upconversion nano crystal is not limited to above-mentioned preparation method, and also can refer to other can be made grain size phase Like and with nucleocapsid and meso-hole structure rare earth upconversion nano crystal preparation method.The above is only the present invention Preferred embodiment, be not intended to limit the scope of the present invention, thus use and the above embodiment of the present invention phase Same or approximate technical characteristic, such as different upper conversion nano crystalline substance (NaYF4:Yb,Er；NaYF4:Yb,Er,Tm；NaYF4:Yb, Ho；NaYF4:Yb,Er@NaGdF4；NaYF4:Yb,Er@NaYF4Deng), in mesoporous silicon dioxide modified different functional groups (sulfydryl Deng), within protection scope of the present invention.

Claims (11)

1. a kind of double-bang firecracker based on manganese dioxide modification answers the preparation method of drug delivery system, which is characterized in that including following Step：
(1) rare earth upconversion nano crystal of the coating mesoporous silicon dioxide layer in surface is taken, it is scattered to form the first dispersion liquid in ethanol；
(2) by step (1) obtained by the first dispersion liquid, with 3- aminopropyl triethoxysilanes modify, take solid centrifugation, wash it Afterwards, it is scattered in ethyl alcohol and forms the second dispersion liquid；
(3) step (2) is added in into drug in the second dispersion liquid, after being sufficiently stirred, takes solid centrifugation, washing, be dispersed in water Form the 3rd dispersion liquid；
(4) 2-N- morphines is taken to mix the two for alkyl sulfonic acid and potassium permanganate, after carrying out ultrasound and crushing, be dispersed in water Form the 4th dispersion liquid；
(5) centrifuged after the 3rd dispersion liquid obtained by step (3) and the 4th dispersion liquid obtained by step (4) being mixed, weight It is newly dispersed in water, the double-bang firecracker based on manganese dioxide modification is made and answers drug delivery system.
2. the double-bang firecracker as described in claim 1 based on manganese dioxide modification answers the preparation method of drug delivery system, feature It is, the step (2) specifically includes following steps：
(2.1) the first dispersion liquids of 10~15mg/mL obtained by 15~30mL steps (1) are taken, add in 150~300 μ L 3- aminopropyls Triethoxysilane, when stirring 24 is small under room temperature；
(2.2) solid will be taken after the centrifugation of step (2.1) products therefrom, disperse after washing in ethanol, obtain concentration for 10~ The second dispersion liquid of 15mg/mL.
3. the double-bang firecracker as described in claim 1 based on manganese dioxide modification answers the preparation method of drug delivery system, feature It is, the step (3) specifically includes following steps：
(3.1) the second dispersion liquid obtained by step (2) is taken, it is water-soluble to add in the doxorubicin hydrochloride that 5~10mL concentration is 1~2mg/mL Liquid or cisplatin medicine aqueous solution or curcumin aqueous solution or Japanese yew alcohol solution, when stirring 24 is small under room temperature；
(3.2) solid is taken after step (3.1) products therefrom is centrifuged, is dispersed in water after washing, obtains concentration as 5~10mg/ The 3rd dispersion liquid of mL.
4. the double-bang firecracker as described in claim 1 based on manganese dioxide modification answers the preparation method of drug delivery system, feature It is, the step (4) specifically includes following steps：
(4.1) the 2-N- morphines that 50~100 μ L concentration are 200~300mmol/L are taken for alkyl sulfonic acid solution and 50~100 μ L concentration For the liquor potassic permanganate of 200~300mmol/L, the two is mixed, when ultrasound 0.5~1 is small under room temperature, then uses clasmatosis When crusher machine 0.5~2 is small；
(4.2) solid is taken after (4.1) products therefrom is centrifuged, is dispersed in water after washing, obtains Mn4+Concentration is 5~10mg/mL The 4th dispersion liquid.
5. the double-bang firecracker as described in claim 1 based on manganese dioxide modification answers the preparation method of drug delivery system, feature It is, the step (5) specifically includes following steps：
(5.1) by the 3rd 10~20mL of dispersion liquid obtained by step (3) and the 4th 5~10mL of dispersion liquid obtained by step (4) Mixing, when stirring 24 is small under room temperature；
(5.2) solid is taken after (5.1) products therefrom is centrifuged, is dispersed in water after washing with 15~30mg/mL of concentration, obtains base Drug delivery system is answered in the double-bang firecracker of manganese dioxide modification.
6. the double-bang firecracker as described in claim 1 based on manganese dioxide modification answers the preparation method of drug delivery system, feature It is, the rare earth upconversion nano crystal of the coating mesoporous silicon dioxide layer in surface includes：NaYF4:Yb3+,Er3+@mSiO2、 NaYF4:Yb3+,Tm3+@mSiO2、NaGdF4:Yb3+,Tm3+@mSiO2、NaGdF4:Yb3+,Er3+@mSiO2、NaYF4:Yb3+,Er3+, Tm3+@mSiO2、NaYF4:Yb3+,Er3+@NaGdF4@mSiO2、NaYF4:Yb3+,Er3+@NaYF4@mSiO2。
7. a kind of double-bang firecracker based on manganese dioxide modification prepared such as any one of claim 1-6 method answers drug delivery system, It is characterized in that, it is 100-300nm that it, which is hydrated grain size, and for nucleocapsid, including the rare earth upconversion nano crystal as core, And the meso-porous titanium dioxide silicon layer as shell, in the mesopore orbit of the meso-porous titanium dioxide silicon layer load have doxorubicin hydrochloride or Cisplatin medicine or curcumin or taxol, the meso-porous titanium dioxide silicon layer outer surface are modified with sheet manganese dioxide, the sheet two Manganese oxide is also coated on the mesopore orbit of meso-porous titanium dioxide silicon layer.
8. the double-bang firecracker as claimed in claim 7 based on manganese dioxide modification answers drug delivery system, which is characterized in that described dilute Conversion nano crystalline substance includes on soil：NaYF4:Yb3+,Er3+、NaYF4:Yb3+,Tm3+、NaGdF4:Yb3+,Er3+、NaGdF4:Yb3+,Tm3 +、NaYF4:Yb3+,Er3+,Tm3+、NaYF4:Yb3+,Er3+@NaGdF4、NaYF4:Yb3+,Er3+@NaYF4。
9. a kind of double-bang firecracker as claimed in claim 7 based on manganese dioxide modification answers the application of drug delivery system, feature It is, is applied to controlled drug release.
10. a kind of double-bang firecracker as claimed in claim 7 based on manganese dioxide modification answers the application of drug delivery system, feature It is, is applied to the co-focusing imaging of HeLa cells.
11. a kind of double-bang firecracker as claimed in claim 7 based on manganese dioxide modification answers the application of drug delivery system, feature It is, is applied to magnetic resonance imaging.
CN201711267852.7A 2017-12-05 2017-12-05 Double-bang firecracker based on manganese dioxide modification answers preparation method, product and the application of drug delivery system Pending CN108096586A (en)

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CN112494666A (en) * 2020-12-08 2021-03-16 南方科技大学 T1-T2 dual-activation magnetic resonance imaging contrast agent and preparation method and application thereof
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