CN103893128A - Tumor-therapy composite nano material and preparation method thereof - Google Patents
Tumor-therapy composite nano material and preparation method thereof Download PDFInfo
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- CN103893128A CN103893128A CN201410175018.5A CN201410175018A CN103893128A CN 103893128 A CN103893128 A CN 103893128A CN 201410175018 A CN201410175018 A CN 201410175018A CN 103893128 A CN103893128 A CN 103893128A
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Abstract
The invention provides a tumor-therapy composite nano material and a preparation method thereof, and specifically provides a composite nano material. The nano composite material comprises a core material A-stabilizer B composite, wherein the core material A is a hydrogenated metal oxide semiconductor nano material, or a composite material compounded by a hydrogenated metal oxide semiconductor nano material and other materials. The composite nano material can be used for tumor photothermal therapy, or can be used as a carrier of a tumor drug, and the like.
Description
Technical Field
The invention relates to a composite nano material. Specifically, the invention provides a composite nano material capable of realizing the treatment or diagnosis of malignant tumors, in particular the tumor treatment by the cooperation of photothermal and chemical drugs, and a preparation method thereof.
Background
Photothermal Therapy (PTT) is a new tumor treatment modality. The basic principle is that a photothermal reagent is accumulated at a tumor part, and the photothermal reagent converts light energy into heat energy through local near-infrared laser irradiation and kills the tumor through high temperature. The method has high selectivity and minimal invasion, and can avoid side effects brought by the traditional tumor treatment method, thereby being a hot research field of tumor treatment. Based on the principle of tumor photothermal therapy, finding out photothermal therapy materials with good biocompatibility, strong near-infrared absorption, high photothermal conversion efficiency and good thermal stability is the key research direction of tumor photothermal therapy, and developing multifunctional and multi-mode tumor photothermal therapy materials is the development trend in the field. Photothermal therapy is a non-invasive tumor local treatment technology, and is one of important factors for photothermal effective tumor treatment by means of medical imaging means and accurate imaging positioning of tumors. Therefore, a photothermal therapy material with the function of enhancing medical imaging signals of tumor tissues is developed, the imaging sensitivity of tumor parts is improved, and the effect of photothermal therapy on malignant tumors can be certainly improved. In addition, the multi-mode treatment agent formed by anti-tumor chemotherapeutic drugs is carried by taking the photo-thermal treatment material as a carrier, so that the targeted delivery and the light-operated release of the chemotherapeutic drugs can be realized, the side effects of the drugs can be reduced, the tumor cells are increasingly sensitive to the chemotherapeutic drugs due to the thermal ablation effect, the synergistic sensitization effect of chemotherapy and photo-thermal treatment is shown, the incomplete tumor ablation caused by the limited penetration depth of near infrared light is overcome, and the treatment effect of malignant tumors is greatly improved.
Therefore, the photo-thermal treatment material which has good stability in biological environment, is not easy to agglomerate and has biological application value is urgently needed in the field.
Disclosure of Invention
The invention aims to provide a photothermal therapy material which has good stability in a biological environment, is not easy to agglomerate and has biological application value.
In a first aspect of the present invention, there is provided a composite nanomaterial comprising a core material a-stabilizer B complex: wherein,
the core material A is a metal oxide semiconductor nano material subjected to hydrogenation treatment, or a composite material formed by compounding the metal oxide semiconductor nano material subjected to hydrogenation treatment and a material selected from the following group: magnetic nanomaterials, upconversion luminescent nanomaterials, noble metal nanomaterials, quantum dots, fluorescent materials, or a combination thereof;
the stabilizer B is selected from the following group: organic high molecular polymer, liposome, microbubble, albumin nanosphere, or combination thereof, wherein the polymeric monomer of the organic high molecular polymer is selected from the following group: an unsaturated alcohol, acid or amine from C2 to C10, a polyol from C2 to C12, lactic acid, glycolic acid, or combinations thereof.
In another preferred embodiment, the complexing is physical loading and/or chemical modification.
In another preferred embodiment, said stabilizer B substantially coats said core material a, or said stabilizer B embeds said core material a.
In another preferred embodiment, the stabilizer B contains a functional group for further modification or reaction.
In another preferred embodiment, the particle size of the composite nano-material is 5-50nm, preferably 10-40 nm.
In another preferred embodiment, the average hydrated particle size of the composite nanomaterial is 10-500nm, preferably 50-200 nm.
In another preferred embodiment, the composite nanomaterial is stable in an aqueous solution or a physiological solution (such as phosphate buffer, serum, physiological saline), wherein the stability means that the composite nanomaterial does not undergo significant agglomeration in the aqueous solution.
In another preferred embodiment, the phrase "no significant agglomeration" means that the composite nanomaterial does not undergo agglomeration detectable by transmission electron microscopy in an aqueous solution.
In another preferred embodiment, the composite nanomaterial has an average hydrated particle size of 1 μm or less in an aqueous solution or physiological solution (e.g., phosphate buffer, serum, physiological saline), preferably 500nm or less, and more preferably 300nm or less.
In another preferred embodiment, the composite nano material has light absorption in visible light and near infrared regions.
In another preferred embodiment, the composite nano material can convert absorbed light energy into heat energy; preferably, the photothermal conversion efficiency of the composite nanomaterial is greater than or equal to 20%, preferably greater than or equal to 30%, and more preferably greater than or equal to 35%.
In another preferred embodiment, the composite nanomaterial has low cytotoxicity.
In another preferred embodiment, the composite nanomaterial has no significant inhibition on cell activity at a concentration of 200 μ g/mL or more, preferably 300 μ g/mL or more, and more preferably 500 μ g/mL or more.
In another preferred embodiment, the expression "without significant inhibition" means that the inhibition rate is less than or equal to 20%, preferably less than or equal to 15%.
In another preferred embodiment, the composite nano material has better biocompatibility.
In another preferred embodiment, the composite nano material has the following characteristics: after the organism is intravenously administrated for 24 hours, the organic function and/or physical index of the organism are not obviously influenced.
In another preferred embodiment, the composite nanomaterial further comprises: a tumor targeting molecule C coupled to the core material A-stabilizer B complex.
In another preferred embodiment, the composite nanomaterial further comprises: an active pharmaceutical ingredient D loaded on the core material A-stabilizer B compound.
In a further preferred embodiment of the method,
the hydrotreated metal oxide semiconductor nanomaterial is selected from the group consisting of: hydrogenated TiO2Nanomaterial, hydrogenated ZrO2Nanomaterials, hydrogenated ZnO nanomaterials, or combinations thereof; and/or
The magnetic nanomaterial is selected from the group consisting of: fe3O4Nano material、CoFe2O4Nanomaterial, ZnFe2O4Nanomaterial, NiFe2O4Nanomaterial, MnFe2O4Nanomaterial, Gd2O3Nanomaterials, or combinations thereof; and/or
The up-converting luminescent nanomaterial is selected from the group consisting of: NaYF4:Er3+/Yb3+Nanomaterial, NaYF4:Yb3+/Tm3+Nanomaterial, NaYF4:Tm3+/Er3+Nanomaterial, NaYF4:Yb3+/Tm3+/Er3+、NaGdF4:Yb3+/Tm3+/Er3+Nanomaterials, or combinations thereof; and/or
The noble metal nano material is selected from the following group: au nanomaterial, Ag nanomaterial, Pt nanomaterial, Pd nanomaterial, or a combination thereof; and/or
The quantum dots are selected from the group consisting of: quantum dots CdSe, CdS, CdTe, ZnS, ZnSe, or combinations thereof; and/or
The fluorescent material is selected from the group consisting of: organic fluorescent dye molecules (such as alizarin red, rhodamine, indocyanine green, anthocyanin Cy5.5 and Cy7), inorganic fluorescent mesoporous materials, noble metal fluorescent nano materials (such as small-particle-size gold and small-particle-size silver), or combinations thereof.
In another preferred embodiment, the stabilizer B is selected from the group consisting of: polyethylene glycol, polyacrylic acid, dextran, polyethyleneimine, polyvinylamine, polymaleic acid, carboxymethyl chitosan, carboxymethyl starch, carboxymethyl dextran, polylactic acid, polylactic-co-glycolic acid, liposomes, albumin nanospheres, or combinations thereof.
In another preferred embodiment, the tumor targeting molecule C is selected from the group consisting of: folic acid, methotrexate, aminopterin, RGD peptide (arginyl-glycyl-aspartic acid), Vascular Endothelial Growth Factor (VEGF), Neuropeptide (NPY), tumor specific antibodies, or combinations thereof.
In another preferred embodiment, the active pharmaceutical ingredient D is selected from the group consisting of: one or more of adriamycin and paclitaxel.
In a second aspect of the present invention, there is provided a method of preparing a composite nanomaterial according to the first aspect of the present invention, the method comprising the steps of:
(1) providing a metal oxide semiconductor nano material A subjected to hydrogenation treatment;
(2) the metal oxide semiconductor nano material A subjected to hydrogenation treatment reacts with a stabilizer B to obtain a core material A-stabilizer B compound.
In another preferred embodiment, the preparation method further comprises the steps of: and carrying out coupling reaction on the core material A-stabilizer B compound and the tumor targeting molecule C to obtain the core material A-stabilizer B-tumor targeting molecule C compound.
In another preferred embodiment, the preparation method further comprises the steps of: loading the core material A-stabilizer B compound and the active pharmaceutical ingredient D to obtain the core material A-stabilizer B-active pharmaceutical ingredient D compound.
In another preferred embodiment, the preparation method further comprises the steps of: and carrying out coupling reaction on the core material A-stabilizer B-tumor targeting molecule C compound and the active pharmaceutical ingredient D to obtain the core material A-stabilizer B-tumor targeting molecule C-active pharmaceutical ingredient D compound.
In a third aspect of the invention there is provided the use of a composite nanomaterial as described in the first aspect of the invention, the material being for:
(a) preparing a tumor photothermal treatment pharmaceutical composition;
(b) for preparing a tumor imaging contrast agent;
(c) for non-therapeutically inhibiting tumor cell activity in vitro;
(d) for non-therapeutic induction of tumor cell apoptosis in vitro.
In another preferred embodiment, when used for non-therapeutic inhibition of tumor cell activity in vitro, the composite nanomaterial is applied to a tumor cell to be inhibited, and then the tumor cell to be inhibited is irradiated with infrared light.
In another preferred embodiment, when used for non-therapeutic inhibition of tumor cell activity in vitro, the action time of the composite nano material is 2-96 h, preferably 5-48 h.
In another preferred embodiment, the composite nanomaterial has an effective concentration of 20-500 μ g/mL, preferably 50-300 μ g/mL, when used for non-therapeutic inhibition of tumor cell activity in vitro.
In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a composite nanomaterial according to the first aspect of the invention; and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition is used for treating tumors; preferably, the treatment is photothermal therapy or photothermal/drug co-therapy.
In another preferred embodiment, the pharmaceutical composition is an injection; preferably, the medicine injection is intravenous injection.
In another preferred embodiment, the pharmaceutically acceptable carrier is physiological saline.
In another preferred embodiment, the tumor is a liver tumor or a spleen tumor.
In another preferred embodiment, the tumor is a breast tumor.
In another preferred embodiment, the pharmaceutical composition further comprises other tumor treatment drugs; preferably, the other tumor treatment drug is selected from the group consisting of: adriamycin and paclitaxel.
In another preferred embodiment, when the pharmaceutical composition comprises other tumor treatment drugs, the other tumor treatment drugs are released in an acidic environment; preferably, the release is carried out in an acidic environment with a pH value of 1-6.
In another preferred embodiment, the release of said other therapeutic agent for tumors is 60 or more, preferably 70 or more, more preferably 80 or more, in an acidic environment at pH 1-6 for 48 hours.
In a fifth aspect of the invention, there is provided a method of tumour therapy, the method comprising: administering to the subject a therapeutically effective amount of a composite nanomaterial according to the first aspect of the invention.
In another preferred example, the method further comprises: irradiating the tumor part of the treated object with infrared light.
In another preferred example, the method further comprises: administering to the subject an additional tumor treatment drug; preferably, the other tumor treatment drug is selected from the group consisting of: adriamycin and paclitaxel.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows black TiO compounds prepared in examples 1 and 22Black TiO22-PEG, Black TiO2TEM results of PEG-FA composite nanomaterial (example 19).
FIG. 2 shows black TiO compounds prepared in examples 1 and 22Black TiO22-PEG, Black TiO2-dynamic light scattering hydrated particle size distribution of PEG-FA in water.
FIG. 3 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2-PEG-FA composite nanomaterial and white TiO2Ultraviolet-visible absorption spectrum (example 19).
FIG. 4 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2-PEG-FA composite nano material and intermediate black TiO thereof2-PEG-NH2Zeta potential (example 19).
FIG. 5 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2the-PEG-FA composite nano material is at 808nm and 2W/cm2Temperature rise curve under near-infrared light irradiation (example 19).
FIG. 6 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2-cytotoxicity of PEG-FA composite nanomaterial on human breast cancer cells MCF-7 (example 20).
FIG. 7 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2the-PEG-FA composite nano material is at 808nm and 2W/cm2The photothermal therapeutic effect of MCF-7 on human breast cancer cells (example 21, MTT results).
FIG. 8 is a black TiO prepared in example 12the-PEG composite nano material is at 808nm and 2W/cm2The photothermal therapeutic effect of MCF-7 on human breast cancer cells (example 21, calcein/propidium iodide staining).
FIG. 9 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2Effect of PEG-FA composite nanomaterial on liver and kidney-related serum biochemical markers in healthy mice (example 22).
FIG. 10 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2Distribution of-PEG-FA composite nanomaterial in heart, liver, spleen, kidney, lung and tumor of human breast cancer cell-bearing mice injected via tail vein (example 23).
FIG. 11 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2the-PEG-FA composite nano material is at 808nm and 2W/cm2Under the irradiation of near infrared lightPhotothermal therapeutic effect on human breast cancer cell-bearing mice (example 23).
Detailed Description
The inventor of the present invention has conducted extensive and intensive studies for a long time, and unexpectedly found that a novel tumor photothermal therapy drug (or material) can be obtained by modifying the surface of a metal oxide semiconductor nanomaterial, which is subjected to hydrogenation treatment, of an existing energy-producing material (in the field of photocatalytic degradation of hydrogen produced by water) with a stabilizer. The medicine (or material) has high bioavailability, good stability and dispersibility in water, and is suitable for being applied to the field of tumor photothermal therapy to prepare tumor treatment medicines or adjuvant treatment medicines. Based on the above findings, the inventors have completed the present invention.
Term(s) for
As used herein, the term "composite" refers to the combination of two materials in any method known in the art, such as physical loading (or mounting), or chemical coupling, among others.
The terms "core material a-stabilizer B composite", "core material-stabilizer composite" or "a-B composite" are used interchangeably and all refer to a core material (a) modified with a stabilizer (B). Wherein the core material is as defined herein. In a preferred aspect, the above term refers to the core material-stabilizer composite without other composite materials (e.g., the tumor targeting molecule and active pharmaceutical ingredient of the present invention).
The term "C2-C10 unsaturated alcohol, acid or amine" refers to an alcohol, acid or amine having 2-10 carbon atoms and a C-C double bond in the structure, such as acrylic acid, ethyleneimine, ethyleneamine, maleic acid, or the like.
The term "C2-C12 polyol" refers to compounds having 2-12 carbon atoms and more than one hydroxyl group in the structure, such as ethylene glycol, glycerol, saccharides, and the like.
After extensive literature research, the invention provides a composite nano material formed by taking a metal oxide semiconductor nano material subjected to hydrogenation treatment as a core material or compounding a nano material with a function of enhancing a medical imaging signal and carrying a tumor chemotherapeutic drug, and the composite nano material is used for photothermal therapy or photothermal and chemical drug synergistic therapy of malignant tumors. In addition, the composite nano material prepared by the invention can also be used for diagnosis and visual treatment of malignant tumors.
Core material
Hydrotreated metal oxide semiconductor nanomaterials (Scientific Reports2014, doi:10.1038/srep03986.), such as high temperature, high pressure hydrotreated black TiO2Nanoparticles (Angew. chem. int. Ed.2012,51,12410-2Compared with the nanometer material, the nanometer material has disordered surface, a large amount of oxygen defects in the interior, strong absorption in a near infrared region and excellent photo-thermal conversion efficiency, and has the potential to be further developed into a tumor photo-thermal treatment material. However, the metal oxide semiconductor nano-material subjected to hydrogenation treatment is easy to agglomerate in bionic environments such as physiological saline, and the like, so that the application of the metal oxide semiconductor nano-material in tumor treatment is hindered.
The composite material comprises a core material A and a stabilizer B, wherein the core material A is a metal oxide semiconductor nano material subjected to hydrogenation treatment or a composite material containing the metal oxide semiconductor nano material subjected to hydrogenation treatment.
With conventional white TiO2Compared with the nanomaterial, the metal oxide semiconductor nanomaterial subjected to hydrogenation treatment has disordered surface, a large number of oxygen defects in the nanomaterial, strong absorption in a near infrared region, excellent photothermal conversion efficiency and potential to be further developed. However, the biological application performance of the hydrotreated metal oxide semiconductor nano-material is poor, which hinders the application thereof in tumor treatment.
In another preferred embodiment, the hydrotreated metal oxygenThe compound semiconductor nano-material is selected from the following group: hydrogenated TiO2Nanomaterial (i.e. black TiO)2) Hydrogenated ZrO2Nanomaterial (i.e. black ZrO)2) Hydrogenated ZnO nanomaterials (i.e., black ZnO), or combinations thereof.
In the present invention, the metal oxide semiconductor nanomaterial subjected to hydrogenation treatment can be combined with other nanomaterials to form a composite material containing the metal oxide semiconductor nanomaterial subjected to hydrogenation treatment. Among them, the preferable nano-materials to be compounded are selected from the following group: magnetic nanomaterials, upconversion luminescent nanomaterials, noble metal nanomaterials, quantum dots, fluorescent materials, or combinations thereof.
In a preferred embodiment of the present invention, the magnetic nanomaterial is selected from the group consisting of: fe3O4Nanomaterial, CoFe2O4Nanomaterial, ZnFe2O4Nanomaterial, NiFe2O4Nanomaterial, MnFe2O4Nanomaterial, Gd2O3Nanomaterials, or combinations thereof.
In a preferred embodiment of the present invention, the up-conversion luminescent nanomaterial is selected from the group consisting of: NaYF4:Er3+/Yb3+Nanomaterial, NaYF4:Yb3+/Tm3+Nanomaterial, NaYF4:Tm3+/Er3+Nanomaterial, NaYF4:Yb3+/Tm3+/Er3+、NaGdF4:Yb3+/Tm3+/Er3+Nanomaterials, or combinations thereof.
In a preferred embodiment of the present invention, the noble metal nanomaterial is selected from the group consisting of: au nanomaterial, Ag nanomaterial, Pt nanomaterial, Pd nanomaterial, or a combination thereof.
In a preferred embodiment of the present invention, the quantum dots are selected from the group consisting of: quantum dots CdSe, CdS, CdTe, ZnS, ZnSe, or combinations thereof.
In a preferred embodiment of the present invention, the fluorescent material is selected from the group consisting of: organic fluorescent dye molecules (such as alizarin red, rhodamine, indocyanine green (ICG), anthocyanidin cy5.5, Cy7), inorganic fluorescent mesoporous materials, noble metal fluorescent nano materials (such as small-particle-size gold and small-particle-size silver), or combinations thereof.
Stabilizer
In the invention, the core material A is modified by the stabilizing agent B to improve the biological application performance of the core material A.
The stabilizer B may be a stabilizer selected from the group consisting of: organic high molecular polymer, liposome, microbubble, albumin nanosphere, or a combination thereof, preferably one of the four.
Wherein, the polymeric monomer of the organic high molecular polymer is selected from the following group: unsaturated alcohol, acid or amine of C2-C10, polyhydroxy compound of C2-C12, lactic acid, glycolic acid, or their combination, preferably the organic high molecular polymer can be one or more of polyethylene glycol, polyacrylic acid, dextran, polyethylene imine, polyethylene amine, polymaleic acid, carboxymethyl chitosan, carboxymethyl starch, carboxymethyl dextran.
Wherein, the micro-bubble refers to a micron-sized spherical hollow structure. In a preferred embodiment of the present invention, the shell material of the microbubble can be one or more of polylactic acid and polylactic-co-glycolic acid.
Tumor targeting molecules and active pharmaceutical ingredients
In the present invention, the core material a-stabilizer B composite material may optionally be compounded with other tumor treatment related materials, such as tumor targeting molecules, or active pharmaceutical ingredients, to improve its targeting or therapeutic effect. The complex form is not particularly limited, and may be a form of physical loading (or loading), chemical coupling, or the like.
In the present invention, the tumor targeting molecule is not particularly limited, and may be any molecule known in the art to have tumor targeting properties and to be conjugated to a-B. In a preferred embodiment, the tumor targeting molecule C is selected from the group consisting of: folic acid, methotrexate, aminopterin, RGD peptide (arginyl-glycyl-aspartic acid), Vascular Endothelial Growth Factor (VEGF), Neuropeptide (NPY), tumor specific antibodies, or combinations thereof.
The active pharmaceutical ingredient is not particularly limited, and may be any drug known in the art that can be used for tumor therapy, or adjuvant therapy for tumor therapy. In a preferred embodiment of the present invention, the active pharmaceutical ingredient D is selected from the group consisting of: one or more of adriamycin and paclitaxel.
Tumor photothermal treatment pharmaceutical composition
Photothermal Therapy (PTT) is a new tumor treatment modality. The basic principle is that a photothermal reagent is accumulated at a tumor part, and the photothermal reagent converts light energy into heat energy through local near-infrared laser irradiation and kills the tumor through high temperature. The precise imaging and positioning of the tumor by means of medical imaging means is one of the important factors for the photothermal effective treatment of the tumor. Therefore, a photothermal therapy material with the function of enhancing medical imaging signals of tumor tissues is developed, the imaging sensitivity of tumor parts is improved, and the effect of photothermal therapy on malignant tumors can be certainly improved.
Based on the above, the invention provides a tumor photothermal treatment pharmaceutical composition. The composition comprises a composite material of the invention, namely a core material A-stabilizer B composite material, or a composite material formed by compounding the core material A-stabilizer B with a tumor targeting molecule C and/or an active medicine component D, with a therapeutically effective amount.
The composite material modified by the stabilizer B has a series of characteristics suitable for biological application, for example, the core material A modified by the stabilizer B-the stabilizer B composite material has better stability in water; the light absorption is realized in visible light and near infrared regions, and the photo-thermal conversion efficiency is high, so that the tumor photo-thermal treatment device is suitable for tumor photo-thermal treatment; low cytotoxicity, good biocompatibility, and the like.
Preferably, the composite material further comprises a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier comprises: injection carrier such as distilled water, physiological saline, glycerol, etc.
The main beneficial effects of the invention include:
(1) the invention provides a preparation method of a composite nano material for treating malignant tumors, which is simple and easy to implement, has low cost and is beneficial to industrial production and market popularization.
(2) When the composite nano material provided by the invention is applied to a tumor part, near-infrared light-excited tumor photothermal treatment can be realized, and near-infrared light-excited photothermal and chemotherapeutic drugs can be used for cooperatively treating tumors.
(3) The composite nano material provided by the invention can enhance medical contrast signals such as magnetic resonance imaging, ultrasonic imaging, photoacoustic imaging, fluorescence imaging and the like, and can be used for diagnosis and visual treatment of malignant tumors.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1: black TiO22Preparation of-PEG composite nano material
0.2mol/L titanium tetrachloride (TiCl) is taken4)10 mL of hydrochloric acid solution was added dropwise to 90mL of ultrapure water, and the mixture was stirred and hydrolyzed for 5 hours under ice bath conditions. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every two hours for 5 times, and TiO is obtained2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 10 hours at 240 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 80 ℃ to obtain TiO2And (3) nanoparticle powder. Taking the prepared TiO250mg of nano particle powder is placed in a high-pressure hydrogen system, and the following reaction conditions are set: the pressure was 20.0bar, the temperature was 200 ℃ and the hydrogenation time was 5 days. After the reaction is finished, hydrogenated black TiO is obtained2Nanoparticles. Get black TiO2100mg of nanoparticles are dispersed in 200mL of ethanol, and 200W of the solution is ultrasonically dispersed for 30 minutes. 7500mg of polyethylene glycol (PEG, molecular weight 2000) was dissolved in 300mL of ethanol. Will contain black TiO2Adding ethanol of the nano material into PEG ethanol solution drop by drop, stirring and reacting for 24 hours to ensure that the PEG is fully wrapped in the black TiO2And (4) the surface of the nano material. After the reaction is finished, centrifuging for 30 minutes at 12000 r/min, removing redundant PEG in supernate to obtain black TiO2-PEG composite nanomaterial.
Example 2: black TiO22Preparation of (E) -PEG-FA composite nano material
The black TiO prepared in example 1 was taken2-50 mg of PEG composite nanomaterial dispersed in 100mL ethanol. 600. mu.L of 3-Aminopropyltriethoxysilane (APTES) was dissolved in 200mL of ethanol. The ethanol solution of APTES was added dropwise to the black TiO containing solution2Stirring and reacting in ethanol of the PEG composite nano material for 24 hours to ensure that the black TiO is2The PEG end on the surface of the PEG composite nano material is modified with amino. After the reaction is finished, centrifuging for 30 minutes at 12000 r/min, removing redundant reaction byproducts in the supernatant fluid to obtain the black TiO2-PEG-NH2The nanomaterial intermediate was compounded and dispersed in 100mL of pure water. Adding 20mg of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) into 100mL of 0.1mg/mL Folic Acid (FA) solution to activate the carboxyl group of folic acid, and rapidly adding the mixed solution of EDC and FA into the solution containing black TiO2-PEG-NH2The reaction is carried out for 24 hours in pure water of the composite nano material by stirring. After the reaction is finished, centrifuging for 30 minutes at 12000 r/min, removing redundant by-products in supernatant fluid to obtain black TiO2-PEG-FA composite nanomaterial.
Example 3: black TiO22Preparation of (E) -PEG-DOX composite nano material
The black TiO prepared in example 1 was taken250mg of PEG composite nano material is dispersed in 250mL of pure water and is used after high-temperature sterilization. 4mg of antitumor drug Doxorubicin (DOX) is dissolved in 250mL of pure water, and filtered through a 0.22-micron filter membrane for sterilization. Under aseptic condition, adding DOX solution dropwise into black TiO sterilized at high temperature2And (3) stirring and reacting the-PEG composite nano material dispersion liquid for 24 hours. After the reaction is finished, centrifuging for 30 minutes at 10000 r/min, removing redundant DOX in supernatant fluid to obtain black TiO2-PEG-DOX composite nanomaterial.
Example 4: black TiO22Preparation of (E) -PEG-FA-DOX composite nano material
Black TiO prepared in example 22100mg of-PEG-FA composite nano-material dispersed in 200mL of pure water. 5mg DOX was dissolved in 200mL of purified water. The DOX solution was added drop-wise to the black TiO2And (4) stirring and reacting the-PEG-FA composite nano material dispersion liquid for 18 hours. After the reaction is finished, centrifuging for 30 minutes at 10000 r/min, removing redundant DOX in supernatant fluid to obtain black TiO2-PEG-FA-DOX composite nanomaterial.
Example 5: hydrogenated ZrO2Preparation of-PAA composite nano material
6mL of tetrabutyl zirconate was dissolved in 40mL of isopropanol to obtain a solution A. 2mL of ultrapure water and 2mL of concentrated nitric acid were dissolved in 40mL of isopropanol to obtain a solution B. Dropwise adding the solution A into the solution B, stirring for 1 hour, placing the reaction solution into a reaction kettle, and reacting for 24 hours at 180 ℃. After the reaction is finished, the reactant is heated and dried at 60 ℃ to obtain ZrO2And (3) precursor. ZrO 2 is mixed with2Grinding the precursor into powder, and calcining at 600 ℃ for 5 hours to obtain ZrO2Nanoparticles. Taking out the above ZrO2Placing the nano particle powder in a high-pressure hydrogen system, hydrogenating for 5 days at the pressure of 20.0bar and the temperature of 220 ℃ to obtain hydrogenated ZrO2Nanoparticles. Taking the hydrogenated ZrO prepared above250mg of nano particles are dispersed in 200mL of ethanol and ultrasonically dispersed for 0.5 hour. Polyacrylic acid (PAA, molecular weight 2000)2000mg was dissolved in 300mL of ethanol. Will contain hydrogenated ZrO2Adding ethanol of the nano material into the PAA ethanol solution drop by drop, stirring and reacting for 24 hours to ensure that the PAA is fully coated on the hydrogenated ZrO2And (4) the surface of the nano material. After the reaction is finished, centrifuging for 30 minutes at 12000 r/min, removing redundant PAA in the supernatant fluid to obtain hydrogenated ZrO2-PAA composite nanomaterial.
Example 6: preparation of hydrogenated ZnO-PEI composite nano material
Taking 2mol/L sodium carbonate solution (Na)2CO3)20mL, heat to 80 ℃ with stirring. Taking 1mol/L zinc sulfate (ZnSO)4)10 mL of the solution was added dropwise to Na2CO3After the reaction was stirred for 1 hour in the solution, it was cooled and filtered under suction. And drying the reactant at 80 ℃, and placing the reactant in a reaction kettle for reaction at 400 ℃ for 3 hours to obtain ZnO nano particle powder. Placing the ZnO nanoparticles in a high-pressure hydrogen system at a pressure of 20.0bar, hydrogenation at 200 ℃ for 4 days to obtain the hydrogenated ZnO nanoparticles. 20mg of the hydrogenated ZnO nanoparticles were dispersed in 200mL of ethanol, and ultrasonically dispersed for 0.5 hour. Polyethyleneimine (PEI, molecular weight 5000)400mg was dissolved in 100mL of ethanol. And dropwise adding ethanol containing the hydrogenated ZnO nano material into the PEI ethanol solution, and stirring and reacting for 24 hours to fully wrap the PEI on the surface of the hydrogenated ZnO nano material. And after the reaction is finished, centrifuging at 12000 r/min for 30 min, and removing redundant PEI in the supernatant to obtain the hydrogenated ZnO-PEI composite nano material.
Example 7: black TiO22-Fe3O4Preparation of-PEG composite nano material
0.1mol/L titanium tetrachloride (TiCl) is taken4)10 mL of hydrochloric acid solution was added dropwise to 90mL of ultrapure water, and the mixture was stirred and hydrolyzed under ice-bath conditions for 4 hours. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every 3 hours for 5 times, and TiO is obtained2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 12 hours at 180 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 60 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO2100mg of the nano-particle powder is put into a high-pressure hydrogen system, the pressure is 22.0bar, the temperature is 220 ℃, and the hydrogenation is carried out for 3 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Get black TiO2Dispersing 100mg of nano material in 200mL of ethanol, carrying out ultrasonic dispersion for 0.5 hour, dropwise adding the nano material into 100mL of n-hexane, and uniformly stirring. 200mg of iron acetylacetonate [ Fe (acac) ]3]Dissolved in a mixed solution of 40mL of oleylamine and 120mL of n-octanol. Mixing black TiO2Adding the dispersion into the above mixed solution, stirring, heating to 80 deg.C, and evaporating ethanol and n-hexane. Then, the solution is placed in a reaction kettle and reacted for 2 hours at 240 ℃. After the reaction is finished, the oleylamine and the n-octanol are removed by centrifugation, and the mixture is washed for a plurality of times by ethanol to obtain the black TiO2-Fe3O4A composite nanomaterial. Mixing the above black TiO2-Fe3O4The composite nano material is dispersed in 200mL of ethanol and ultrasonically dispersed for 30 minutes. Dissolving PEG (molecular weight 1500)5000mg in 300mL ethanol. Will contain black TiO2-Fe3O4The ethanol dispersion liquid of the composite nano material is dropwise added into the PEG ethanol solution, and the mixture is stirred and reacted for 18 hours, so that the PEG is fully wrapped on the black TiO2-Fe3O4And (3) compounding the surface of the nano material. After the reaction is finished, centrifuging the mixture for 30 minutes at 12000 r/min, removing excessive PEG in supernate and obtaining black TiO2-Fe3O4-PEG composite nanomaterial.
Example 8: black TiO22-Gd2O3Preparation of-PEG composite nano material
Taking gadolinium nitrate hexahydrate [ Gd (NO)3)3·6H2O]Dissolving 100mg and 1mg of sodium hydroxide in 200mL of diethylene glycol, magnetically stirring the solution at 180 ℃ for reaction for 5 hours, and dialyzing the reaction solution to obtain a dialysate. 0.1mol/L titanium tetrachloride (TiCl) is taken4) 7mL of hydrochloric acid solution was slowly added dropwise to 93mL of ultrapure water, and the mixture was stirred and hydrolyzed for 3 hours under ice bath conditions. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every 3 hours for 4 times to obtain TiO2And (3) precursor solution. Adding TiO into the mixture2The precursor is placed in a reaction kettle and heated for 10 hours at 180 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 60 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO2100mg of the nano-particle powder is put into a high-pressure hydrogen system, the pressure is 20.0bar, the temperature is 220 ℃, and the hydrogenation is carried out for 5 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Get black TiO2Dispersing 100mg of nano material into 200mL of ethanol, ultrasonically scattering for 30 minutes, dropwise adding the gadolinium nitrate hexahydrate dialysate, and stirring; after 8 hours of reaction, aging is carried out for 24 hours at room temperature; centrifuging at 12000 r/min for 30 min, removing excessive reactant to obtain black TiO2-Gd2O3A composite nanomaterial. Mixing black TiO2-Gd2O3The composite nano material is dispersed in 200mL ethanol, ultrasonic treatment is carried out for 30 minutes, PEG (molecular weight 1500)4000mg is taken, and the PEG is dissolved in 300mL ethanol. Will contain black TiO2-Gd2O3The ethanol dispersion liquid of the composite nano material is dropwise added into the PEG ethanol solution, and the mixture is stirred and reacted for 24 hours, so that the PEG is fully wrapped on the black TiO2-Gd2O3And (3) compounding the surface of the nano material. After the reaction is finished, centrifuging the mixture for 30 minutes at 12000 r/min, removing excessive PEG in supernate and obtaining black TiO2-Gd2O3-PEG composite nanomaterial.
Example 9: black TiO22-NaYF4:Yb3+/Tm3+Preparation of-PEG composite nano material
0.2mol/L titanium tetrachloride (TiCl) is taken4)10 mL of hydrochloric acid solution was added dropwise to 90mL of ultrapure water, and the mixture was stirred and hydrolyzed for 5 hours under ice bath conditions. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every 3 hours for 4 times to obtain TiO2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 10 hours at 180 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 60 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO2100mg of the nano-particle powder is put into a high-pressure hydrogen system, the pressure is 20.0bar, the temperature is 220 ℃, and the hydrogenation is carried out for 3 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Get black TiO250mg of the nano material is dispersed in 100mL of water, and ultrasonic dispersion is carried out for 30 minutes. Then 20mg/mL yttrium chloride (YCl) is added in turn3)8.9mL of ytterbium chloride (YbCl)3)1mL of thulium chloride (TmCl)3)0.1 mL. A further 10mL of 20mg/mL aqueous sodium citrate solution and 40mL of 10mg/mL aqueous sodium fluoride (NaF) solution were added, and the mixture was stirred for 1 hour. Then the mixed solution is put into a reaction kettle and undergoes hydrothermal reaction for 2 hours at 120 ℃. After the reaction is finished, centrifugally washing the product for a plurality of times to obtain the black TiO2-NaYF4:Yb3+/Tm3+A composite nanomaterial. The prepared black TiO2-NaYF4:Yb3+/Tm3+Composite nanomaterial 50mgAnd dispersing in 100mL of ethanol. PEG (molecular weight 1500)2000mg was dissolved in 300mL of ethanol. Will contain black TiO2-NaYF4:Yb3+/Tm3+The ethanol dispersion liquid of the composite nano material is dropwise added into the PEG ethanol solution, and the mixture is stirred and reacted for 24 hours, so that the PEG is fully wrapped on the black TiO2-NaYF4:Yb3+/Tm3+And (3) compounding the surface of the nano material. After the reaction is finished, centrifuging the mixture for 30 minutes at 12000 r/min, removing excessive PEG to obtain black TiO2-NaYF4:Yb3+/Tm3+-PEG composite nanomaterial.
Example 10: black TiO22-NaYF4:Yb3+/Tm3+Preparation of-PEG-VEGF composite nanomaterial
Black TiO prepared in example 92-NaYF4:Yb3+/Tm3+-10 mg of PEG composite nanomaterial dispersed in 100mL ethanol. 50. mu.L of 3-Aminopropyltriethoxysilane (APTES) was dissolved in 100mL of ethanol. The ethanol solution of APTES was added dropwise to the black TiO containing solution2-NaYF4:Yb3+/Tm3+Stirring and reacting in ethanol of the PEG composite nano material for 24 hours to ensure that the black TiO is2-NaYF4:Yb3+/Tm3+-PAnd modifying the PEG tail end on the surface of the EG composite nano material with amino. After the reaction is finished, centrifuging the mixture for 30 minutes at 13000 r/min, removing redundant 3-aminopropyl triethoxysilane, and collecting the prepared black TiO2-NaYF4:Yb3+/Tm3+-PEG-NH2The nanomaterial was compounded and dispersed in 100mL of pure water. Adding 1mL of a 0.1mg/mL Vascular Endothelial Growth Factor (VEGF) solution activated by 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) to the solution containing black TiO2-NaYF4:Yb3+/Tm3+-PEG-NH2The reaction was carried out for 18 hours with stirring in pure water containing the composite nanomaterial. After the reaction is finished, centrifuging for 30 minutes at 12000 r/min, removing redundant VEGF, and obtaining black TiO2-NaYF4:Yb3+/Tm3+-PEG-VEGF composite nanomaterial.
Example 11: black TiO22Preparation of-Au-PEG composite nano material
0.1mol/L titanium tetrachloride (TiCl) is taken4) 5mL of hydrochloric acid solution was slowly added dropwise to 95mL of ultrapure water, and the mixture was stirred and hydrolyzed for 3 hours under ice bath conditions. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every 2 hours for 5 times, and TiO is obtained2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 10 hours at 180 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 60 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO2100mg of the nano-particle powder is put into a high-pressure hydrogen system, the pressure is 20.0bar, the temperature is 220 ℃, and the hydrogenation is carried out for 3 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Get black TiO250mg of nano material is dispersed in 100mL of ethanol, and ultrasonic dispersion is carried out for 30 minutes. The solution was added to 100mL of an aqueous glucose (10mmol/mL) solution and stirred to adsorb glucose to the black TiO2The surface of the particles. Then 1mL of chloroauric acid (AuCl) with a concentration of 1mmol/mL is added4) The solution, 10mg of sodium citrate and heated with stirring for 16 hours to obtain black TiO2-an Au composite nanomaterial. The black TiO obtained above is mixed2-Au composite nanomaterialThe material was dispersed in 100mL of pure water and dispersed by ultrasonic for 30 minutes. 1000mg of PEG (molecular weight 1500) is taken and dissolved in 300mL of pure water. Will contain black TiO2Dropwise adding the dispersion liquid of the Au nano material into the PEG aqueous solution, and stirring and reacting for 24 hours to ensure that the PEG is fully wrapped in the black TiO2-Au composite nanomaterial surface. After the reaction is finished, centrifuging for 30 minutes at 12000 r/min, removing redundant PEG, and obtaining black TiO2-Au-PEG composite nanomaterial.
Example 12: black TiO22Preparation of-CdSe-PEG composite nano material
0.1mol/L titanium tetrachloride (TiCl) is taken4)10 mL of hydrochloric acid solution was added dropwise to 90mL of ultrapure water, and the mixture was stirred and hydrolyzed for 3 hours under ice bath conditions. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every 2 hours for 4 times to obtain TiO2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 12 hours at 180 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 60 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO250mg of nano particle powder is put into a high-pressure hydrogen system, the pressure is 20.0bar, the temperature is 220 ℃, and the hydrogenation is carried out for 5 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Get black TiO250mg of nano material is dispersed in 100mL of pure water and is dispersed for 30 minutes by ultrasonic waves. Then adjusting the pH value of the solution to 3.0 with 0.1mol/L hydrochloric acid aqueous solution, adding 100 μ L sodium selenosulfate (Na) with concentration of 10mmol/L2SeSO3) Adding 1mL of 5mmol/L cadmium chloride (CdCl)2) Stirring the aqueous solution for reaction for 24 hours, and obtaining black TiO by high-speed centrifugation2-CdSe composite nanomaterials. The obtained black TiO2And dispersing the-CdSe composite nano material in 300mL of pure water, and performing ultrasonic dispersion for 30 minutes. 2000mg of PEG (molecular weight 2000) was dissolved in 200mL of purified water. Will contain black TiO2Adding pure water of the CdSe nano material into the PEG water solution drop by drop, stirring and reacting for 24 hours to ensure that the PEG is fully wrapped in the black TiO2-CdSe composite nanomaterial surface. After the reaction is complete, 1Centrifuging at 2000 rpm for 30 min to remove excessive PEG to obtain black TiO2-CdSe-PEG composite nanomaterial.
Example 13: black TiO22Preparation of-ICG-PEG composite nano material
0.1mol/L titanium tetrachloride (TiCl) is taken4)10 mL of hydrochloric acid solution was added dropwise to 90mL of ultrapure water, and the mixture was stirred and hydrolyzed for 5 hours under ice bath conditions. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every 2 hours for 5 times, and TiO is obtained2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 12 hours at 220 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 60 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO250mg of nano particle powder is put into a high-pressure hydrogen system, the pressure is 20.0bar, the temperature is 220 ℃, and the hydrogenation is carried out for 5 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Taking the prepared black TiO250mg of nano material is dispersed in 90mL of pure water and is dispersed for 30 minutes by ultrasonic waves. Then, 10mL of a solution of indocyanine green (ICG) of 0.1mg/mL was added thereto, and the reaction was stirred with exclusion of light for 16 hours. After the reaction was completed, excess ICG was removed by centrifugation to obtain black TiO2-ICG composite nanomaterial. The composite nanomaterial is dispersed in 100mL of ultrapure water. 1000mg of PEG (molecular weight 1500) is dissolved in 200mL of pure water. Will contain black TiO2Dropwise adding the dispersion liquid of the ICG nano material into the PEG aqueous solution, stirring in the dark for 24 hours for reaction, and fully wrapping the PEG in the black TiO2-ICG composite nanomaterial surface. After the reaction is finished, centrifuging for 30 minutes at 12000 r/min, removing redundant PEG, and obtaining black TiO2-ICG-PEG composite nanomaterial.
Example 14: black TiO22Preparation of-fluorescent mesoporous silicon-PEG composite nano material
0.1mol/L titanium tetrachloride (TiCl) is taken4)10 mL of hydrochloric acid solution was added dropwise to 90mL of ultrapure water, and the mixture was stirred and hydrolyzed for 3 hours under ice bath conditions. After the hydrolysis is finished, the reaction solution is dialyzedDialyzing in ultrapure water, changing fresh water every 1 hr for 5 times to obtain TiO2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 10 hours at 200 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 80 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO250mg of nano particle powder is put into a high-pressure hydrogen system, the pressure is 20.0bar, the temperature is 200 ℃, and the hydrogenation is carried out for 6 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Taking the prepared black TiO2Dissolving 50mg of nano material in 100mL of ethanol, ultrasonically dispersing for 30 minutes, adding 100mL of pure water, and uniformly stirring to obtain a solution A. To solution A, 300mg of cetyltrimethylammonium bromide (CTAB), 1mL of ammonia (NH) was added3·H2O), stirring and heating at 40 ℃ for 30 minutes to dissolve CTAB. After CTAB is dissolved, 400 mu L of Tetraethoxysilane (TEOS) is added into the reaction solution, the mixture is stirred and reacted for 8 hours, and after multiple times of centrifugal water washing, black TiO is obtained2-a mesoporous silicon composite. Get black TiO2Dispersing 50mg of mesoporous silicon composite material into 100mL of water, and then sequentially adding 20mg/mL of yttrium chloride (YCl)3)8.9mL of ytterbium chloride (YbCl)3)1mL of thulium chloride (TmCl)3)0.1 mL. Further, 10mL of a 20mg/mL aqueous solution of sodium citrate and 20mL of a 20mg/mL aqueous solution of sodium fluoride were added, and the mixture was stirred for 1 hour. Then, the mixed solution was put into a reaction vessel and subjected to hydrothermal reaction at 130 ℃ for 2 hours. After the reaction is finished, centrifugally washing the product for a plurality of times to obtain the black TiO2-fluorescent mesoporous silicon composite. The prepared black TiO250mg of the/fluorescent mesoporous silicon composite material is dispersed in 200mL of water. 3000mg of PEG (molecular weight 2000) was dissolved in 300mL of water. Will contain black TiO2Dropwise adding the dispersion liquid of the fluorescent mesoporous silicon composite material into the PEG aqueous solution, and stirring for reacting for 24 hours to ensure that the PEG is fully wrapped in the black TiO2-fluorescent mesoporous silicon composite surface. After the reaction was completed, excess PEG was removed by centrifugation to obtain black TiO2-fluorescent mesoporous silicon-PEG composite nanomaterial.
Example 15: black TiO22Preparation of-fluorescent Au-PEG composite nano material
0.2mol/L titanium tetrachloride (TiCl) is taken4)10 mL of hydrochloric acid solution was added dropwise to 90mL of ultrapure water, and the mixture was stirred and hydrolyzed under ice-bath conditions for 6 hours. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every 1 hour, and the water is replaced for 5 times to obtain TiO2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 12 hours at 240 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 80 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO250mg of nano particle powder is put into a high-pressure hydrogen system, the pressure is 20.0bar, the temperature is 220 ℃, and the hydrogenation is carried out for 3 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Taking the prepared black TiO25mg of nano particles are dispersed in 5mL of ultrapure water and ultrasonically dispersed for 30 minutes. 5mL of 4mg/mL chloroauric acid (HAuCl)4) 5mL of 20mg/mL Bovine Serum Albumin (BSA) solution was added to the stirred black TiO2In the nanoparticle dispersion. Adding 50 mu L of 0.3mg/mL ascorbic acid solution at 37 ℃, adjusting the pH of the solution to 11 by using sodium hydroxide solution, and stirring for reaction for 5 hours to obtain black TiO2-fluorescent Au complex nanoclusters. The obtained black TiO2-fluorescent Au complex nanoclusters are dispersed in 50mL of water. PEG (molecular weight 2000)500mg was dissolved in 200mL of water. Will contain black TiO2Dropwise adding the aqueous solution of the-fluorescent Au composite nano cluster into the aqueous solution of PEG, stirring and reacting for 24 hours to ensure that the PEG is fully wrapped in the black TiO2-fluorescent Au complex nanocluster surface. After the reaction was completed, excess PEG was removed by centrifugation to obtain black TiO2-fluorescent Au-PEG composite nanomaterial.
Example 16: black TiO22Preparation of-liposome-PEG composite nanomaterial
0.1mol/L titanium tetrachloride (TiCl) is taken4) 5mL of hydrochloric acid solution was slowly added dropwise to 95mL of ultrapure water, and the mixture was stirred and hydrolyzed for 2 hours under ice bath conditions. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every 1 hour for 6 times,obtaining TiO2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 16 hours at 200 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 80 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO250mg of nano particle powder is put into a high-pressure hydrogen system, the pressure is 20.0bar, the temperature is 200 ℃, and the hydrogenation is carried out for 4 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Taking the prepared black TiO210mg of nano material, 40mg of hydrogenated soybean phospholipid, 20mg of cholesterol and 50mg of distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 monomethoxylate, dispersing or dissolving the materials in 10mL of chloroform-n-hexane (1:1, volume ratio), ultrasonically dispersing to form milk, and performing reduced pressure rotary evaporation to about 2mL of thick milk to obtain emulsion A. 40mg of hydrogenated soybean phospholipid, 20mg of cholesterol and 50mg of distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000 monomethoxy ether are dissolved in 5mL of chloroform-n-hexane (1:1, volume ratio) to obtain emulsion B. Adding the emulsion B into the concentrated emulsion A, uniformly mixing, adding 10mL of lysine buffer solution (0.02mol/L), fully oscillating, evaporating the emulsion under reduced pressure until no bubbles are generated, blowing nitrogen to evaporate the organic solvent, and performing ultrasonic treatment at room temperature for 5 minutes to obtain the black TiO2-liposome-PEG composite nanomaterial.
Example 17: black TiO22Preparation of-BSA composite nanomaterial
0.1mol/L titanium tetrachloride (TiCl) is taken4)10 mL of hydrochloric acid solution was added dropwise to 90mL of ultrapure water, and the mixture was stirred and hydrolyzed for 3 hours under ice bath conditions. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every 2 hours for 5 times, and TiO is obtained2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 10 hours at 220 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 80 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO250mg of nano particle powder is put into a high-pressure hydrogen system, the pressure is 20.0bar, the temperature is 200 ℃, and the hydrogenation is carried out for 4 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Taking the prepared blackTiO250mg of nano material is dissolved in 100mL of ultrapure water and is subjected to ultrasonic dispersion for 30 minutes. 50mg of Bovine Serum Albumin (BSA) was dissolved in 50mL of a 10 pH sodium chloride solution (0.8 mg/mL). Mixing black TiO2The dispersion was added dropwise to the BSA solution while stirring, 5mL of ethanol was added dropwise, 50. mu.L of a 10% glutaraldehyde solution was added dropwise, the reaction was stirred for 24 hours, 1mL of a 50mg/mL lysine solution was added, and the mixture was stirred for 2 hours. Dialyzing the reaction solution in ultrapure water for 5 times to obtain black TiO2-BSA composite nanomaterial.
Example 18: black TiO22Preparation of-PLA composite materials
0.1mol/L titanium tetrachloride (TiCl) is taken4) 5mL of hydrochloric acid solution was slowly added dropwise to 95mL of ultrapure water, and the mixture was stirred and hydrolyzed under ice-bath conditions for 4 hours. After the hydrolysis is finished, the reaction solution is placed in a dialysis bag and dialyzed in ultrapure water, fresh water is replaced every 2 hours for 4 times to obtain TiO2And (3) precursor solution. Taking TiO2Putting 100mL of precursor solution into a reaction kettle, and heating for 12 hours at 240 ℃ to obtain TiO2Nanoparticles. TiO22Drying the nano particles at a high temperature of 80 ℃ to obtain TiO2And (3) nanoparticle powder. Taking TiO250mg of nano particle powder is put into a high-pressure hydrogen system, the pressure is 20.0bar, the temperature is 200 ℃, and the hydrogenation is carried out for 5 days. After the reaction is finished, hydrogenated black TiO is obtained2And (3) nano materials. Taking the prepared black TiO25mg, added to 2mL of chloroform containing 0.1g of polylactic acid (PLA), 0.05g of Span80 (Span80) and sonicated for 1 minute to give homogeneous colostrum. The colostrum is added to 20mL of polyvinyl alcohol solution (30mg/mL) and stirred vigorously for 6 hours to obtain microbubbles, and dichloromethane is completely volatilized. Washing the microbubbles with water for 3 times, dispersing the microbubbles in pure water again, and freeze-drying to obtain black TiO2-a PLA composite.
Example 19: characterization of composite nanomaterials
Comprehensive physical properties: the composite nanomaterials prepared in examples 1 to 18 were taken and characterized with respect to their micro-morphology, crystal form, hydrated particle size, chemical bond, near-infrared absorption, etc. by means of a Transmission Electron Microscope (TEM), an X-ray diffractometer (XRD), a dynamic light scattering nano-particle size analyzer (DLS), a fourier transform infrared spectrometer (FT-IR), an ultraviolet-visible spectroscopy (UV-VIS), etc.
Taking the characterization results of the composite nano-materials prepared in the examples 1 and 2 as examples, the black TiO prepared in the examples 1 and 22Black TiO22-PEG, Black TiO2The transmission electron microscope result of the-PEG-FA composite nano material is shown in figure 1, and the characterization result shows that the prepared black TiO is2The particle size of the base composite nano material is about 20nm, however, the black TiO2Significant agglomeration occurred, while black TiO2-PEG, Black TiO2The dispersibility of the-PEG-FA composite nano material is good.
Black TiO prepared in examples 1 and 22Black TiO22-PEG, Black TiO2The dynamic light scattering hydrated particle size distribution of the-PEG-FA composite nano material is shown in figure 2, and the experimental result shows that the black TiO is2Is easy to agglomerate in water, the average hydrated particle size of the agglomerate is about 3 mu m, and the black TiO2After being wrapped by stabilizer PEG (Black TiO)2-PEG, Black TiO2PEG-FA) with a significantly improved stability in water and an average hydrated particle size of about 200 nm.
Black TiO prepared in examples 1 and 22-PEG, Black TiO2-PEG-FA composite nanomaterial and white TiO2The ultraviolet-visible absorption spectrum result is shown in figure 3, and the characterization result shows that the prepared black TiO2The composite nano material has obvious light absorption in visible light and near infrared regions, and has the basic characteristics of tumor photothermal treatment reagents. While white TiO of the same concentration2The light absorption in the near infrared region is very weak.
Black TiO prepared in examples 1 and 22-PEG, Black TiO2The Zeta potential results of the-PEG-FA composite nano material and the intermediate black TiO2-PEG-NH2 are shown in figure 4, and the characterization results show that in a neutral aqueous solution with the pH value of 7, the black TiO is2-PEG surface has negative charge (-33.9)) After the surface of the black TiO is subjected to amino modification by APTES2-PEG-NH2Positively charged on the surface (7.16) coupling folic acid to Black TiO2-PEG-NH2After the surface, black TiO is formed2PEG-FA has negative charge (-20.77), which indicates that folic acid is successfully coupled to the surface of the composite nano material.
Photothermal conversion performance: 1mg of the composite nanomaterial prepared in examples 1 to 18, and 1mg of white TiO were separately used2As a control, the dispersion was made up in 10mL of pure water. Irradiating the dispersion containing the composite nanomaterial with a 808nm laser system at a laser power density of 2W/cm for 10 minutes2. And measuring the liquid temperature at each minute time point, drawing a temperature rise curve, and calculating the photothermal conversion efficiency of the material. Black TiO prepared as in examples 1 and 22-PEG, Black TiO2PEG-FA composite nanomaterial. The experimental result is shown in fig. 5, the composite nanomaterial has excellent photothermal conversion efficiency and can rapidly convert absorbed light energy into heat energy, wherein the black TiO2The photothermal conversion efficiency of PEG reaches 38%. The results show that the prepared composite nano material has the basic characteristics of the tumor photothermal treatment nano material.
Stability under physiological conditions: 1mg of the composite nanomaterial prepared in examples 1 to 18 was dispersed in 10mL of 0.1mol/L Phosphate Buffered Saline (PBS), 10% Fetal Bovine Serum (FBS), and 0.9% physiological saline (NaCl), and the dispersion was placed in a 37 ℃ incubator for 30 days, and the particle size of the composite nanomaterial was measured by a dynamic light scattering nanometer particle size analyzer (DLS) every day. The experimental result shows that the particle size of the prepared composite nano material is stably kept between 10 nm and 300nm in solutions of PBS, 10% FBS, 0.9% NaCl and the like. The result shows that the prepared composite nano material has good stability and dispersibility in physiological solution and has the basic condition of in vivo injection.
pH controlled drug release properties: the black TiO prepared in examples 3 and 4 was used2-PEG-DOX, Black TiO210mg of PEG-FA-DOX composite nano material is dispersed in 10mL of buffer solution with pH values of 3, 5 and 7, the buffer solution is filled into a dialysis bag,dialyzing in 90mL of the same buffer solution at the same pH for 2 days, collecting 1mL of the dialysate every 2 hours (with 1mL of fresh buffer solution being replenished), and quantitatively analyzing DOX in the dialysate by High Performance Liquid Chromatography (HPLC) to plot a drug release curve. The experimental results show that DOX is released more easily in an acidic environment at pH 3, with a release of 80% for 48 hours, and 20% in a neutral environment at pH 7. The results show that the prepared composite nano material has the basic characteristics of a tumor drug delivery system and can be used for delivering anti-tumor chemotherapeutic drugs.
Magnetic Resonance Imaging (MRI) performance: black TiO prepared in examples 7 and 82-Fe3O4-PEG, Black TiO2-Gd2O3-PEG composite nanomaterial, dispersed in ultrapure water, formulated into solutions of concentrations of 0.01mg/mL, 0.02mg/mL, 0.04mg/mL, 0.08mg/mL, 0.16mg/mL, 0.32mg/mL each 2 mL. The composite nanomaterial was characterized by Nuclear Magnetic Resonance (NMR) for T2 or T1 weighted MRI signals. The experimental result shows that the prepared composite nano material has good T2 (black TiO)2-Fe3O4PEG) or T1 (Black TiO)2-Gd2O3PEG), and can be used for MRI diagnosis of tumors and for evaluation of therapeutic efficacy.
Computed Tomography (CT) imaging: properties of Black TiO prepared in example 112-Au-PEG composite nanomaterial, dispersed in ultrapure water, to prepare solutions of concentrations of 0.01mg/mL, 0.02mg/mL, 0.04mg/mL, 0.08mg/mL, 0.16mg/mL each of 2 mL. The X-ray imaging performance of the composite nanomaterial was characterized by an electronic computer tomography scanner. Experimental results show that the prepared composite nano material has good CT signals and can be used for CT diagnosis and treatment effect evaluation of tumors.
Fluorescence emission performance: black TiO prepared in examples 9, 10, 12, 13 and 14 was used2-NaYF4:Yb3+/Tm3+-PEG, Black TiO2-NaYF4:Yb3+/Tm3+-PEG-VEGF, Black TiO2-CdSe-PEG, black TiO2-ICG-PEG, BlackTiO2The fluorescent mesoporous silicon-PEG composite nano materials are respectively 1mg, dispersed in 10mL of pure water and prepared into 0.1 mg/mL. And testing the fluorescence luminescence property of the composite nano material by a fluorescence spectrometer. The experimental result shows that the composite nano material has good fluorescence luminescent property and can be used for diagnosis and visual treatment of tumors.
Two-photon luminescence property: black TiO prepared in example 1521mg of-fluorescent Au-PEG composite nano material is dispersed in 10mL of ultrapure water. The luminescent properties of the composite nanomaterial were observed by two-photon microscopy. The results show that the prepared black TiO2The fluorescent Au-PEG composite nano material has good two-photon excitation fluorescence performance and can be used for diagnosis and visual treatment of tumors.
Ultrasonic imaging performance: black TiO prepared in example 1822mg of PLA composite, dispersed in 20mL of ultrapure water. And injecting the composite material into an agarose simulation ultrasonic imaging hose, and detecting an ultrasonic signal of the composite material through an ultrasonic imager. The experimental result shows that the composite material has good ultrasonic signals and can be used for diagnosis and visual treatment of tumors.
Example 20: cytotoxicity of composite nanomaterials
The composite nano-materials prepared in the examples 1 to 18 are taken, sterilized at high temperature, dispersed in culture solution and prepared into 50, 100, 200, 300, 400 and 500 mu g/mL respectively for standby. Taking human breast cancer cells MCF-7 in logarithmic growth phase, and adjusting cell concentration to 1 × 105one/mL, 100. mu.L per well in 96-well cell culture plates in 5% CO2And cultured in a cell culture box at 37 ℃ and saturated humidity for 24 hours. After 24 hours, the medium in the plate was discarded, and fresh medium and medium containing the composite nanomaterial were added to the plate in 5% CO2Incubated at 37 ℃ for 24 hours in a cell incubator saturated with humidity. After 24 hours, 10. mu.L of thiazole blue (MTT,5mg/mL) was added to the culture wells and the cells were incubated for 4 hours. After 4 hours, the culture medium was aspirated, 100. mu.L of dimethyl sulfoxide (DMSO) was added to each well,after dissolving for 10 minutes, measuring the OD value of each hole on a microplate reader at 550nm, and calculating the cytotoxicity of the composite nano material. Taking the characterization results of the composite nano-materials prepared in the examples 1 and 2 as examples, the black TiO prepared in the examples 1 and 22-PEG, Black TiO2The cytotoxicity of the-PEG-FA composite nano material on human breast cancer cells MCF-7 is shown in figure 6, and the result shows that the cell activity is not obviously reduced after the composite nano material with the concentration as high as 500 mug/mL acts on the cells for 24 hours, which indicates that the prepared black TiO2-PEG, Black TiO2The PEG-FA composite nano material has low cytotoxicity and good biocompatibility.
Example 21: photothermal therapy of tumor cells by composite nano material
The composite nano-materials prepared in the examples 1 to 18 are taken, sterilized at high temperature, dispersed in a culture solution and prepared into 100 mu g/mL for standby. Taking human breast cancer cells MCF-7 in logarithmic growth phase, and adjusting cell concentration to 1 × 105one/mL, 100. mu.L per well in 96-well cell culture plates in 5% CO2And cultured in a cell culture box at 37 ℃ and saturated humidity for 24 hours. After 24 hours, the culture medium in the culture well plate is discarded, and fresh culture solution and culture solution containing composite nano material are respectively added into the culture plate and are added in 5% CO2Incubated at 37 ℃ for 4 hours in a cell incubator saturated with humidity. The stock solution was discarded and the culture medium was added. Irradiating cells with 808nm laser system with laser power density of 2W/cm2. After irradiation, a part of the cells are taken, stained by calcein/propylidine bromide, and observed under a fluorescence microscope; another part of the cells were in 5% CO2Incubation was continued for 24 hours in a cell incubator at 37 ℃ and saturated humidity. After 24 hours, 10. mu.L of thiazole blue (MTT,5mg/mL) was added to the culture wells and the cells were incubated for 4 hours. And (3) after 4 hours, removing the culture solution by suction, adding 100 mu L of dimethyl sulfoxide (DMSO) into each hole, dissolving for 10 minutes, measuring the OD value of each hole on a microplate reader at 550nm, and calculating the photothermal treatment effect of the composite nanomaterial on the breast cancer cells.
Composite nanomaterials prepared in examples 1 and 2Characterization results of (1) and (2) are black TiO prepared in examples2-PEG, Black TiO2the-PEG-FA composite nano material is at 808nm and 2W/cm2The MTT results of the photothermal therapeutic effect on human breast cancer cells MCF-7 under near-infrared light irradiation are shown in FIG. 7, and the results show that 2W/cm was used 4 hours after the cells were exposed to 100. mu.g/mL of the composite nanomaterial2After the cells were irradiated with 808nm near-infrared light for 5 minutes, the cells were cultured for 24 hours, and all the irradiated tumor cells were dead.
FIG. 8 is a black TiO prepared in example 12the-PEG composite nano material is at 808nm and 2W/cm2The result of calcein/propylidine bromide staining for the photothermal therapeutic effect on human breast cancer cells MCF-7 under near-infrared light irradiation. The results show that 100. mu.g/mL of black TiO 24 hours after PEG-action on the cells, 2W/cm was used2The 808nm near infrared light irradiates the cells for 5 minutes, the tumor cells are subjected to massive death, and the death rate can reach 95 percent or higher.
Example 22: acute toxicity of animals by composite nano material
The composite nano-materials prepared in the examples 1 to 18 are dispersed in physiological saline to be prepared into 200 mu g/mL, and are sterilized at high temperature for standby. Healthy mice were taken and 100 μ L of the composite nanomaterial and physiological saline was administered via the tail vein. The symptoms and extent of toxicity within 24 hours after administration were observed and recorded. After 24 hours, the mice were sacrificed, serum biochemical markers related to liver and kidney functions were measured, and tissue section analysis was performed on major organs such as heart, liver, spleen, kidney, and lung.
FIG. 9 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2Experimental results of the effect of the-PEG-FA composite nano material on serum biochemical indexes related to liver and kidney of healthy mice. The results show that the prepared black TiO2-PEG, Black TiO2The PEG-FA composite nano material has good biocompatibility, and does not obviously influence the functions of liver and kidney organs of a mouse after the PEG-FA composite nano material acts on the mouse for 24 hours.
Example 23: photothermal therapy of solid tumor of tumor-bearing mouse by using composite nano material
The composite nano-materials prepared in the examples 1 to 18 are dispersed in physiological saline to be prepared into 200 mu g/mL, and are sterilized at high temperature for standby. Taking MCF-7 cell tumor-bearing mice, and administering 200 μ L of composite nanometer material and normal saline at a dose of 2W/cm2808nm laser of (1) irradiating the tumor part. After the irradiation, half of the mice were sacrificed, and the tumors were analyzed by hematoxylin/eosin-stained tissue sections to evaluate the tumor damage of the mice, and the heart, liver, spleen, kidney, lung and tumor contents of the sacrificed mice were analyzed by ICP-MS. The remaining mice were analyzed for treatment effect by measuring tumor size and body weight daily over a two week period. After two weeks all mice were sacrificed and solid tumors were dissected, their volume, weight were recorded and the effect of composite nanomaterials on treating solid tumors in mice was evaluated.
FIG. 10 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2After the PEG-FA composite nano material is injected into a human breast cancer cell tumor-bearing mouse through tail vein, the distribution of the PEG-FA composite nano material in the heart, the liver, the spleen, the kidney, the lung and the tumor is realized. The results show that black TiO2-PEG, Black TiO2the-PEG-FA composite nano material is mainly distributed in organs such as liver, spleen and the like, and has a certain amount of distribution at tumor parts.
FIG. 11 shows black TiO compounds prepared in examples 1 and 22-PEG, Black TiO2the-PEG-FA composite nano material is at 808nm and 2W/cm2Under the irradiation of near infrared light, the photo-thermal treatment effect on human breast cancer cell tumor-bearing mice is achieved. The results showed that the samples were compared with the control group (saline, laser, black TiO)2-PEG, Black TiO2PEG-FA, etc.), Black TiO2-PEG, Black TiO2Under the action of near infrared light of 808nm, the PEG-FA composite nano material can obviously cause tumor ablation, which indicates that the prepared composite nano material is an excellent tumor photothermal treatment agent.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A composite nanomaterial, wherein the composite nanomaterial comprises a core material a-stabilizer B complex: wherein,
the core material A is a metal oxide semiconductor nano material subjected to hydrogenation treatment, or a composite material formed by compounding the metal oxide semiconductor nano material subjected to hydrogenation treatment and a material selected from the following group: magnetic nanomaterials, upconversion luminescent nanomaterials, noble metal nanomaterials, quantum dots, fluorescent materials, or a combination thereof;
the stabilizer B is selected from the following group: organic high molecular polymer, liposome, microbubble, albumin nanosphere, or combination thereof, wherein the polymeric monomer of the organic high molecular polymer is selected from the following group: an unsaturated alcohol, acid or amine from C2 to C10, a polyol from C2 to C12, lactic acid, glycolic acid, or combinations thereof.
2. The composite nanomaterial of claim 1, wherein the composite nanomaterial further comprises: a tumor targeting molecule C coupled to the core material A-stabilizer B complex.
3. The composite nanomaterial of claim 1, wherein the composite nanomaterial further comprises: an active pharmaceutical ingredient D loaded on the core material A-stabilizer B compound.
4. The composite nanomaterial of claim 1,
the hydrotreated metal oxide semiconductor nanomaterial is selected from the group consisting of: hydrogenated TiO2Nanomaterial, hydrogenated ZrO2Nanomaterials, hydrogenated ZnO nanomaterials, or combinations thereof; and/or
The magnetic nanomaterial is selected from the group consisting of: fe3O4Nanomaterial, CoFe2O4Nanomaterial, ZnFe2O4Nanomaterial, NiFe2O4Nanomaterial, MnFe2O4Nanomaterial, Gd2O3Nanomaterials, or combinations thereof; and/or
The up-converting luminescent nanomaterial is selected from the group consisting of: NaYF4:Er3+/Yb3+Nanomaterial, NaYF4:Yb3+/Tm3+Nanomaterial, NaYF4:Tm3+/Er3+Nanomaterial, NaYF4:Yb3+/Tm3+/Er3+、NaGdF4:Yb3+/Tm3+/Er3+Nanomaterials, or combinations thereof; and/or
The noble metal nano material is selected from the following group: au nanomaterial, Ag nanomaterial, Pt nanomaterial, Pd nanomaterial, or a combination thereof; and/or
The quantum dots are selected from the group consisting of: quantum dots CdSe, CdS, CdTe, ZnS, ZnSe, or combinations thereof; and/or
The fluorescent material is selected from the group consisting of: organic fluorescent dye molecules (such as alizarin red, rhodamine, indocyanine green, anthocyanin Cy5.5 and Cy7), inorganic fluorescent mesoporous materials, noble metal fluorescent nano materials (such as small-particle-size gold and small-particle-size silver), or combinations thereof.
5. The composite nanomaterial of claim 1, wherein the stabilizer B is selected from the group consisting of: polyethylene glycol, polyacrylic acid, dextran, polyethyleneimine, polyvinylamine, polymaleic acid, carboxymethyl chitosan, carboxymethyl starch, carboxymethyl dextran, polylactic acid, polylactic-co-glycolic acid, liposomes, albumin nanospheres, or combinations thereof.
6. The composite nanomaterial of claim 2, wherein the tumor targeting molecule C is selected from the group consisting of: folic acid, methotrexate, aminopterin, RGD peptide (arginyl-glycyl-aspartic acid), Vascular Endothelial Growth Factor (VEGF), Neuropeptide (NPY), tumor specific antibodies, or combinations thereof.
7. The composite nanomaterial of claim 3, wherein the active pharmaceutical ingredient D is selected from the group consisting of: one or more of adriamycin and paclitaxel.
8. The method of preparing a composite nanomaterial of claim 1, comprising the steps of:
(1) providing a metal oxide semiconductor nano material A subjected to hydrogenation treatment;
(2) the metal oxide semiconductor nano material A subjected to hydrogenation treatment reacts with a stabilizer B to obtain a core material A-stabilizer B compound.
9. Use of a composite nanomaterial as claimed in any of claims 1 to 7, for:
(a) preparing a tumor photothermal treatment pharmaceutical composition;
(b) for preparing a tumor imaging contrast agent;
(c) for non-therapeutically inhibiting tumor cell activity in vitro;
(d) for non-therapeutic induction of tumor cell apoptosis in vitro.
10. A pharmaceutical composition comprising a therapeutically effective amount of the composite nanomaterial of any of claims 1 to 7; and a pharmaceutically acceptable carrier.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100260686A1 (en) * | 2009-04-09 | 2010-10-14 | Washington, University Of | Nanoparticles for brain tumor imaging |
| CN102743752A (en) * | 2012-05-25 | 2012-10-24 | 中国科学院宁波材料技术与工程研究所 | Composite nano-particles used in inorganic photodynamic therapy, and preparation method thereof |
-
2014
- 2014-04-28 CN CN201410175018.5A patent/CN103893128B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100260686A1 (en) * | 2009-04-09 | 2010-10-14 | Washington, University Of | Nanoparticles for brain tumor imaging |
| CN102743752A (en) * | 2012-05-25 | 2012-10-24 | 中国科学院宁波材料技术与工程研究所 | Composite nano-particles used in inorganic photodynamic therapy, and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| CHEN XB,ET AL.: "increasing Solar Absorption for Photocatalysis with Black Hydrogenated Titanium Dioxide Nanocrystals", 《SCIENCE》 * |
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