CN113730574A - Composite nano material, preparation method and application - Google Patents
Composite nano material, preparation method and application Download PDFInfo
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- CN113730574A CN113730574A CN202010479043.8A CN202010479043A CN113730574A CN 113730574 A CN113730574 A CN 113730574A CN 202010479043 A CN202010479043 A CN 202010479043A CN 113730574 A CN113730574 A CN 113730574A
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- 239000002131 composite material Substances 0.000 title claims abstract description 86
- 239000002086 nanomaterial Substances 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims abstract description 109
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- 239000002105 nanoparticle Substances 0.000 claims abstract description 91
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- 238000000034 method Methods 0.000 claims abstract description 17
- 238000003745 diagnosis Methods 0.000 claims abstract description 15
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- 239000000463 material Substances 0.000 claims description 188
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 120
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 108
- 238000003384 imaging method Methods 0.000 claims description 54
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- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 51
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 33
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- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 17
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 14
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Images
Classifications
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
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- A—HUMAN NECESSITIES
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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Abstract
The present application discloses a composite nano materialMaterials, preparation method and application. A composite nanomaterial comprising magnetic resonance imaging nanoparticles and reduced titanium dioxide nanoparticles; the particle size of the magnetic resonance imaging nano particles is smaller than that of the reduced titanium dioxide nano particles; the magnetic resonance imaging nano particles are attached to the surfaces of the reduced titanium dioxide nano particles; wherein the reduced titanium dioxide nanoparticles are titanium dioxide nanoparticles subjected to reduction treatment. Magnetic resonance imaging nanoparticles (e.g., Gd)2O3) T1 magnetic resonance imaging and bTiO2The photo-thermal treatment is integrated together to obtain the nano composite for diagnosis and treatment. Is expected to realize early diagnosis, accurate positioning and in-situ treatment of the tumor, real-time tracking and prognosis monitoring in the treatment process, and can be better applied to tumor treatment.
Description
Technical Field
The application relates to a composite nano material, a preparation method and application thereof, belonging to the field of functional materials.
Background
The molecular imaging technology of non-invasive visualization not only can reduce the damage to the human body, but also can provide effective diagnostic information for various diseases, and MRI is taken as a popular molecular diagnostic imaging technology in medicine, and the MRI technology is usually taken as a preferred diagnostic means because the MRI technology has less damage to the human body and less hidden danger.
In MRI clinical examination, it is necessary to use an MRI contrast agent for disease diagnosis, mainly because introduction of the contrast agent can change the hydrogen proton relaxation rate in local tissues, improve the signal difference between healthy and diseased sites, and further obtain clear images with different contrasts. MRI contrast agents can now be divided into two classes according to their mechanism of action: t1 weighted contrast, the commonly used T1 contrast agent contains coordination compound materials containing gadolinium, manganese and the like, and can increase the signal intensity of tissues on a T1 weighted image; the other type is T2 weighted contrast, and a common T2 contrast agent is superparamagnetic iron oxide nanomaterial (SPION), which can reduce the signal intensity of tissues substantially on a T2 weighted image.
The rare earth element Gd has seven unpaired electrons, has the advantages of large electron spin magnetic moment, high relaxation efficiency and the like, and becomes the best choice for developing contrast agents. Currently, contrast agents widely used in clinical applications are mainly Gd-based complexes, such as gadolinium-diethylenediamine pentaacetic acid (Gd-DTPA), gadolinium- [1, 4, 7, 10-tetraacetic acid ] (Gd-DOTA), and the like. However, there are problems in using Gd-based complex as a contrast agent, for example, gadolinium-based complex is an ionic contrast agent, gadolinium ions are easily dissociated into blood, and Gd and Ca have similar ionic radii, form a stable complex with biological ligands of Ca ions in the body, destroy normal Ca-mediated signals or deposit in certain specific organs, thereby causing damage to the liver and spleen.
In the aspect of tumor treatment, surgical resection combined with radiotherapy and chemotherapy is one of the current common means. The method can effectively improve the local control rate of the tumor, but is difficult to remove peripheral tiny residual focuses, so that the tumor is easy to relapse and transfer; meanwhile, although the radiotherapy and chemotherapy can effectively kill tumor cells, the radiotherapy and chemotherapy also have a killing effect on normal cells of a human body, certain harm can be caused to the human body, and patients need to bear the pain caused by treatment, and the curative effect is not very ideal. The Photothermal Therapy (PTT) utilizes the difference between the temperature tolerance of normal tissue and tumor tissue to kill tumor cells without damaging normal tissue, and is gradually another tumor treatment means after surgery, radiotherapy and chemotherapy because of its safety and high efficiency.
Black titanium dioxide (Black-titanium oxide, bTiO2) made of TiO2The surface of the material is reduced to form a disordered layer, and the absorption is red-shifted from the initial ultraviolet region to the near infrared region, so that the material has wide spectrum absorption which is expanded to the near infrared range, has good tumor photo-thermal treatment activity, completely overcomes the side effect on a human body caused by ultraviolet excitation, and has the advantages of high photo-thermal conversion efficiency and good biocompatibility.
However, the black titanium dioxide alone only has photothermal therapy effect and cannot diagnose tumors, so that other tumor diagnosis technologies are needed in use, the purpose of efficient treatment is difficult to achieve, and time and labor are wasted.
Disclosure of Invention
According to one aspect of the present application, there is provided a composite nanomaterial that is useful for magnetic resonance imagingRice grains (e.g. Gd)2O3) T1 magnetic resonance imaging and bTiO2The photo-thermal treatment is integrated together to obtain the nano composite for diagnosis and treatment. Is expected to realize early diagnosis, accurate positioning and in-situ treatment of the tumor, real-time tracking and prognosis monitoring in the treatment process, and can be better applied to tumor treatment.
A composite nanomaterial comprising magnetic resonance imaging nanoparticles and reduced titanium dioxide nanoparticles;
the particle size of the magnetic resonance imaging nano particles is smaller than that of the reduced titanium dioxide nano particles;
the magnetic resonance imaging nano particles are attached to the surfaces of the reduced titanium dioxide nano particles;
wherein the reduced titanium dioxide nanoparticles are titanium dioxide nanoparticles subjected to reduction treatment.
Optionally, the magnetic resonance imaging nanoparticles are imaging metal oxide nanoparticles;
the imaging metal oxide contains magnetic resonance imaging metal elements;
the magnetic resonance imaging metal element is selected from any one of gadolinium, manganese and iron.
For example, the magnetic resonance imaging nanoparticles comprise any one of gadolinium oxide, manganese oxide, iron oxide.
Optionally, the particle size of the reduced titanium dioxide nanoparticles is 20-50 nm;
the particle size of the magnetic resonance imaging nanoparticles is 1-2 nm.
Optionally, in the composite nanomaterial, the mass content of Ti element is 50% to 90%.
Optionally, in the composite nanomaterial, the mass content of the magnetic resonance imaging metal element is 10% to 50%.
Specifically, in the composite nano material, the mass content of Ti element is 50-90%;
in the composite nano material, the mass content of Gd element is 10-50%.
Preferably, in the composite nano material, the mass content of Ti element is 56-85%;
in the composite nano material, the mass content of Gd element is 15-44%.
Preferably, the reduced titania nanoparticles have any one of a rod-like shape, a spherical shape, an approximately spherical shape, and an irregular shape.
Preferably, the particle size of the composite nano material is 50-300 nm.
Optionally, the composite nanomaterial is a gadolinium-titanium composite nanomaterial; the gadolinium-titanium composite nanomaterial comprises Gd2O3Nanoparticles and reduced titania nanoparticles; the Gd2O3The nanoparticles are attached to the surface of the reduced titania nanoparticles.
According to a second aspect of the present application, there is also provided a method of preparing a composite nanomaterial of any of the above, the method of preparing comprising at least:
a) obtaining reduced titanium dioxide nanoparticles;
b) and reacting the mixture containing the magnetic resonance imaging nanoparticle source and the reduced titanium dioxide nanoparticles under an alkaline condition to obtain the composite nanomaterial.
Optionally, in the step a), the solid phase mixture containing the titanium dioxide nanoparticles and the reducing agent is calcined for 1-4 hours at 200-400 ℃ to obtain the reduced titanium dioxide nanoparticles.
Alternatively, the reducing agent in step a) may be NaBH4、H2And a reducing metal (e.g., Mg, Al, etc.).
Optionally, the mass ratio of the titanium dioxide nanoparticles to the reducing agent is 4: 1-1: 1, preferably 2: 1-1: 1, and more preferably 1: 1.
Optionally, in step b), the magnetic resonance imaging nanoparticle source comprises any one of gadolinium source, manganese source, iron source; the gadolinium source is gadolinium salt; the manganese source is manganese salt; the iron source is iron salt.
In particular, in the present application, the source of gadolinium is hydrolyzed under alkaline conditionsReacting to obtain Gd2O3(ii) a The manganese source is oxidized and reduced under the alkaline condition to obtain MnO2(ii) a The iron source is hydrolyzed to obtain Fe under the alkaline condition2O3。
Optionally, the gadolinium salt is selected from Gd (NO)3)3·6H2O、GdCl3·6H2O、Gd(SO4)3·6H2Any one of O;
the manganese salt is selected from MnCl2、Mn(NO3)2、Mn(SO4)2Any one of the above.
Said iron salt is selected from Fe (NO)3)3·6H2O、FeCl3·6H2O、Fe(SO4)3·6H2O
Optionally, in the step b), the molar ratio of the reduced titanium dioxide nanoparticles to the magnetic resonance imaging nanoparticle source is 5: 1-1: 5;
wherein the moles of the reduced titania nanoparticles are based on the moles of titania;
the number of moles of the magnetic resonance imaging nanoparticle source is calculated as the number of moles of the magnetic resonance imaging nanoparticle source itself.
Preferably, the molar ratio of the reduced titanium dioxide nanoparticles to the magnetic resonance imaging nanoparticle source is 2.5: 1-1: 2.5, and more preferably 2.5: 1.
In one example, the molar ratio of the reduced titania nanoparticles to the Gd source is 5:1 to 1:5, preferably 2.5:1 to 1:2.5, more preferably 2.5: 1.
Optionally, in the step b), the mixture further contains a solvent, and the solvent is any one of DEG (diethylene glycol) and EG (ethylene glycol) TEG (triethylene glycol).
Optionally, in the step b), the pH of the mixture containing the magnetic resonance imaging nanoparticle source and the reduced titanium dioxide nanoparticles is 8-10.
Optionally, in step b), the alkaline conditions are conditions containing alkaline substances;
the alkaline substance is selected from NaOH, KOH and NH3·H2Any one of O.
Optionally, in step b), the reaction comprises a stage i, a stage ii and a stage iii which are continuously performed in sequence;
the stage I comprises the following steps: heating to 95-105 ℃, and preserving heat for 10-30 min;
the stage II comprises the following steps: heating to 130-150 ℃, and keeping the temperature for 0.5-2 h;
the stage III comprises: heating to 170-180 ℃, and preserving heat for 2-6 h.
For a gadolinium source, said step b) comprises:
b-1) obtaining a solution I containing an alkaline substance and a gadolinium source;
b-2) obtaining a dispersion containing reduced titanium dioxide nanoparticles;
b-3) dropwise adding the dispersion liquid into the solution I, fixing the volume, heating to 90-100 ℃, and keeping the temperature for 5-15 min; then, continuously heating to 130-150 ℃, and preserving heat for 0.5-2 h; then, continuously heating to 170-180 ℃, and preserving heat for 3-5 hours to obtain the composite nano material Gd2O3-bTiO2。
Optionally, in the step b-1), the content of the alkaline substance in the solution I is 8-12 mg/ml;
the content of the gadolinium source in the solution I is 0.008-0.03 mmol/ml.
Optionally, in the step b-2), the content of the reduced titanium dioxide nanoparticles in the dispersion liquid is 0.05-0.1 mmol/ml.
For a manganese source, step b) comprises:
b-I) obtaining a solution I containing an alkaline substance and a manganese source;
b-II) obtaining a dispersion containing reduced titanium dioxide nanoparticles;
b-III) dropwise adding the dispersion liquid into the solution I, fixing the volume, and reacting for 1-3 h to obtain the composite nano material MnO2-bTiO2。
For an iron source, step b) comprises:
b-i) obtaining a solution I containing sodium citrate dihydrate and an iron source;
b-ii) obtaining a dispersion containing reduced titania nanoparticles;
b-iii) dropwise adding the dispersion liquid into the solution I, fixing the volume, adjusting the pH to 5-6 by using an alkaline substance, adding urea, and reacting at the temperature of 90-110 ℃ for 20-26 h to obtain the composite nano material Fe2O3-bTiO2。
According to a third aspect of the present application, there is provided a composite contrast/photothermal therapy agent prepared from the composite nanomaterial described in any one of the above and the composite nanomaterial obtained by the preparation method described in any one of the above.
According to a fourth aspect of the present application, there is provided a method for preparing a complex contrast/photothermal therapy agent, the method comprising the steps of:
i) carrying out modification macromolecule treatment on the composite nano material to obtain a modified composite nano material;
II) reacting the solution containing the modified composite nano material and the targeting molecule in the presence of an activating agent to obtain the contrast/photothermal therapy compound agent.
The modified polymer in the present application is not limited to the following polymers, and any polymer containing a dicarboxyl group and having good biocompatibility may be used.
Optionally, in step i), the modifying polymer is selected from any one of COOH-PEG-COOH, COOH-PDMS-COOH, and polyacrylic acid (PAA).
In the step I), the modified macromolecule contains negative charges, the surface of the composite nanometer material has positive charges, and one end (for example COOH-) of the modified macromolecule is adsorbed to the surface of the composite nanometer material through electrostatic adsorption, so that the modified composite nanometer material is obtained.
Optionally, in step i), the mass ratio of the composite nanomaterial to the modifying polymer is 1: 1-10; wherein the mass of the composite nanomaterial is based on the mass of the reduced titanium dioxide nanoparticles.
Optionally, the mass ratio of the composite nanomaterial to the modifying macromolecule is 1: preferably, the mass ratio of the composite nano material to the modifying macromolecule is 1: 8; more preferably, the mass ratio of the composite nanomaterial to the modifying polymer is 1: 5.
optionally, in step ii), the targeting molecule is selected from any one of GE11, Folate (FA), Hyaluronic Acid (HA).
In this application, the structure of the targeting molecule is illustrated: the molecular structure contains amino functional group, and polysaccharide, polypeptide and their derivatives can be obtained by carboxyl and amino dehydration reaction. Description of the function: GE11 can target tumor cells such as esophageal cancer and pancreatic cancer; FA can target tumor cells such as ovarian cancer, lung cancer and the like, HA can target macrophages, and the macrophages are related to the formation of various tumor cells.
Optionally, in the step II), the activator is selected from any one of an activator I, an activator II and an activator III;
wherein the activating agent I is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide;
the activating agent II is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole;
the activating agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxy-7-azobenzotriazole.
Specifically, in the step ii), the activating agent is selected from any one of combinations of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) + N-hydroxysuccinimide (NHS), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) + 1-Hydroxybenzotriazole (HOBT), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) + 1-hydroxy-7-azobenzotriazol (HOAT).
Preferably, the activator consists of EDC and NHS.
Alternatively, the molar ratio relationship between EDC and NHS is 1: 0.5 to 2; preferably, the molar ratio relationship between EDC and NHS is 1: 1.
optionally, in step ii), the ratio of the modified composite nanomaterial to the targeting molecule is 0.01: 3-5 mmol/mg.
Optionally, in the step II), the content of the modified composite nano material in the solution is 0.0005-0.002 mmol/ml; the content of the targeting molecule in the solution is 0.2-0.6 mg/ml; wherein the moles of the modified composite nanomaterial are based on the moles of reduced titanium dioxide.
Optionally, in the step II), the content of the activating agent in the solution is 0.004-0.008 mmol/ml.
In one example, the content of the activating agent EDC in the solution is 0.001-0.003 mmol/ml; the content of the activating agent NHS in the solution is 0.001-0.003 mmol/ml.
Optionally, in the step II), the reaction condition is 2-6 ℃; the reaction time is 12-24 h;
preferably, in step II), the reaction conditions are 4 ℃; the reaction time was 16 h.
Optionally, step ii) comprises:
II-1) obtaining a solution A containing the modified composite nano material, EDC and NHS;
II-2) obtaining a solution B containing the target molecules;
II-3) dropwise adding the solution B into the solution A;
II-4) stirring and reacting for 12-24 h at the temperature of 2-6 ℃ to obtain the contrast/photothermal treatment complexing agent.
Optionally, in the step II-2), the content of the targeting molecule in the solution B is 45-65 mg/ml.
In step ii), activating-COOH (i.e., the other end of the modified polymer) on the surface of the obtained modified composite nanomaterial with an activating agent, and dehydrating and condensing the targeting molecule and-COOH to form an amide bond.
According to the fifth aspect of the present application, there is also provided the use of the above contrast/photothermal therapy composite agent and the contrast/photothermal therapy composite agent according to any one of the above claims in the fields of MRI contrast material, disease diagnosis material, photothermal therapy material, and diagnosis and treatment integrated nanomaterial.
In the present application, the term "Gd2O3-bTiO2"represents Gd2O3With bTiO2The formed composite nanomaterial does not represent Gd2O3With bTiO2The molar relationship between them is 1: 1.
The term "Gd2O3-bTiO2-PEG "represents Gd modified by a modified PEG2O3-bTiO2I.e. modifying the composite nanomaterial, and likewise the expression does not denote Gd2O3、bTiO2The molar relationship between PEG and PEG is 1:1: 1.
The term "Gd2O3-bTiO2PEG-GE11 "denotes a targeting molecule with Gd2O3-bTiO2-PEG surface-COOH dehydration condensation to form a contrast/photothermal therapy complex, likewise not representing Gd2O3、bTiO2The molar relationship between PEG and GE11 is 1:1:1: 1.
The term "bTiO2"is reduced black titanium dioxide.
The beneficial effects that this application can produce include:
1) the composite nano material provided by the application is formed by magnetic resonance imaging nano particles (such as Gd)2O3) And bTiO2And (4) forming. Gd (Gd)2O3The nano particles are non-ionic gadolinium-based contrast agents, and exist in a crystalline state, so that the nano particles have better biocompatibility, better magnetic sensitivity than gadolinium ions and more excellent imaging performance; bTiO2Under the irradiation of near infrared light, the material is used for photo-thermal treatment, can kill tumor cells without damaging normal tissues, and has the characteristics of safety, no toxicity and excellent biocompatibility due to safety and effectiveness.
2) When the composite nano material is used for photothermal therapy, near-infrared two-region laser can be adopted for irradiation, and the region laser has deeper tissue penetration depth and allows greater laser power density. Therefore, a better therapeutic effect can be achieved.
3) The composite nano material provided by the application is a diagnosis and treatment integrated nano composite, is expected to realize early diagnosis, accurate positioning and in-situ treatment of tumors, and real-time tracking and prognosis monitoring in the treatment process, and can be better applied to tumor treatment.
4) When the composite nano material provided by the application is used for MRI (magnetic resonance imaging), compared with clinical Magnevit, the composite nano material has stronger MRI signals at low concentration.
5) The composite nano material is modified by a modifying macromolecule (such as COOH-PEG-COOH), and can stably exist in water or physiological saline solution.
6) The nano composite material can be used for MRI imaging materials of T1, disease detection, tumor diagnosis and treatment and the like.
7) The nano composite material is connected with targeting molecules, can be directionally gathered to a tumor part, and avoids adverse reactions caused by dispersion to other parts of a body.
8) The nano composite material is prepared by adopting a one-pot method, and the method has the advantages of simple process, easiness in operation, low cost and easiness in large-scale production.
Drawings
FIG. 1 is Gd in example 12O3-bTiO2Schematic structural diagram of the PEG-GE11 material.
FIG. 2 is a TEM image of a series of materials from example 1, where a is bTiO2B is Gd2O3-bTiO2C is Gd2O3-bTiO2-PEG。
FIG. 3 is Gd in example 12O3-bTiO2Element distribution map of (c).
FIG. 4 is Gd in example 12O3-bTiO2The result of the particle size distribution of (1).
FIG. 5 is Gd in example 12O3-bTiO2The T1MRI imaging of the material and the T1 imaging result at the same concentration as the Maruginea. (TR ═ 18.20, TE ═ 300).
FIG. 6 is Gd in example 12O3-bTiO2The photo-thermal temperature rise diagram.
FIG. 7 is Gd in example 12O3-bTiO2XPS chart of (a).
FIG. 8 is Gd in example 12O3-bTiO2T1 weighted magnetic resonance imaging angiogram of PEG.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
One of the purposes of the invention is to provide a gadolinium-titanium composite nanomaterial integrating diagnosis and treatment, which has the advantages of good biocompatibility, excellent water solubility, excellent MRI imaging performance and remarkable photo-thermal heating performance, thus having the functions of integrating tumor diagnosis and treatment and simultaneously having the capability of reducing toxic and side effects.
The invention also aims to provide a preparation method of the material with the excellent performance, which is environment-friendly, safe, simple in process, low in cost and high in yield.
The material is of a particle structure at least wrapped with magnetic resonance imaging nanoparticles and titanium dioxide nanoparticles; the imaging nanoparticles are imaging nanoparticles with ultra-small particle size, and the imaging nanoparticles are one or more selected from nanoparticles with magnetic resonance imaging function; the titanium dioxide nano particles are one or more of nano rods, nano spheres and various shapes.
A method for preparing a diagnosis and treatment integrated gadolinium-titanium composite nano material (namely, a contrast/photothermal treatment compound), which comprises the following steps:
a) preparation of bTiO2Nanoparticles;
b) preparation of Gd2O3-bTiO2A composite nanomaterial;
c) preparation of Gd2O3-bTiO2-a PEG composite nanomaterial;
d) preparation of Gd2O3-bTiO2-PEG-GE11 composite nanomaterial, i.e. contrast/photothermal therapy complex.
In the present application, step a) prepares bTiO2When the nano-particles are prepared, P25 is used as a raw material, NaBH4As a strong reducing agent.
P25 with NaBH in step a)4Quality ofThe ratio is 4:1 to 1:1, preferably 2:1 to 1:1, and more preferably 1: 1.
The grinding time of the grinding in the step a) is 10-40 min, preferably 20-40 min, and more preferably 40 min.
The protective gas in the step a) is nitrogen or argon.
The calcining time in the step a) is 1-4 h, preferably 2-4 h, and more preferably 3 h.
In the step a), the heating rate is 5-20 ℃/min, the optimized heating rate is 1-15 ℃/min, and the optimized heating rate is 10 ℃/min.
The post-treatment operation of cleaning can be carried out after the material in the step a) is kept stand overnight.
The washing of the material in step a) is 2 water 2 alcohol.
Specifically, in the present application, the washing pattern of "2 water 2 alcohol" is: the water is deionized water, the alcohol is ethanol, and the washing is alternate washing, namely, one time of water and one time of alcohol, and the other time of water and one time of alcohol. The rest is similar and will not be described in detail.
The drying temperature of the material in the step a) is 50-70 ℃, preferably 60-70 ℃, more preferably 70 ℃, and the material is subsequently sealed and stored in a refrigerator at 4 ℃.
In the present application, step b) prepares Gd2O3-bTiO2When the nano material is compounded, the prepared bTiO2Based on Gd (NO)3)3·6H2O or GdCl3·6H2O is used as Gd source, and DEG (diethylene glycol) is used as solvent.
bTiO in step b)2The molar ratio of Gd precursor to Gd precursor is 5:1 to 1:5, preferably 2.5:1 to 1:2.5, more preferably 2.5: 1.
The PH of the solution in the step b) is required to be 8-10, and a reagent for adjusting the PH of the solution is any one of NaOH, KOH and ammonia water.
The temperature and time corresponding to the gradient temperature rise in the reaction process in the step b) last for 10-30min, preferably 10-20 min, and more preferably 10min at 100 ℃; at 140 ℃, lasting for 0.5-2 h, preferably 0.5-1 h, and more preferably 1 h; 175 ℃ for 2-6 h, preferably 3-5 h, and more preferably 4 h.
In the step b), the stirring speed is 400-1000 rpm, preferably 400-800 rpm, and more preferably 600 rpm.
In the step b), the material is washed by 2 times of water and 2 alcohols (4 times) to 4 times of water and 4 alcohols (8 times), preferably 3 times of water and 3 alcohols (6 times) to 4 times of water and 4 alcohols (8 times), more preferably 4 times of water and 4 alcohols (8 times), and finally the material is dispersed in deionized water and stored in a refrigerator at 4 ℃.
In the present application, when the surface of the composite nanomaterial is modified in step c), COOH-PEG-COOH is used as a modifying polymer, and the corresponding molecular weight is 1000 to 4000, preferably 1000 to 3000, and more preferably 2000.
Gd in step c)2O3-bTiO2The mass ratio to COOH-PEG-COOH is 1:10, preferably 1:8, more preferably 1: 5.
The reaction temperature in step c) was room temperature.
In the step c), the stirring time is 8-20 hours, preferably 10-15 hours, and more preferably 12 hours.
In the step c), the rotating speed is 400-1000 rpm, the optimized rotating speed is 400-800 rpm, and the more optimized rotating speed is 600 rpm.
And c), cleaning the material in the step c) to 3 times of water (namely centrifugally washing the material for 3 times by using deionized water), and finally dispersing the material in the deionized water and storing the material in a refrigerator at 4 ℃.
In this application, step d) EDC/NHS as the activator and GE11 as the targeting molecule.
Gd in step d)2O3-bTiO2-PEG 0.01 mmol; EDC 0.02 mmol; NHS is 0.01-0.03 mmol, and the optimized value is 0.02 mmol; GE11 was 4 mg.
After the activator is added in the step d), stirring is required to be carried out for 10-40 min, preferably 20-30 min, and more preferably 20 min.
GE11 in step d) was added dropwise to a concentration of 50 mg/mL.
In the step d), the reaction temperature is 4 ℃, the reaction time is 12-24 hours, and the optimized reaction time is 16 hours.
In the step d), the stirring speed is 400-1000 rpm, preferably 400-800 rpm, and more preferably 600 rpm.
And d), cleaning the material in the step d) to 2 water 2 alcohol, and finally dispersing the material in deionized water and storing the deionized water in a refrigerator at 4 ℃.
Yet another aspect of the present invention relates to the use of the diagnosis and treatment integrated composite nanomaterial, wherein the use is at least one of the preparation of an MRI contrast material, the preparation of a disease diagnosis material, the preparation of a photothermal therapeutic agent, and the preparation of a diagnosis and treatment integrated nano preparation.
Yet another aspect of the invention relates to an article of manufacture that is a medical-grade integrated gadolinium-titanium composite nanomaterial.
General test methods Water dispersibility test (test hydrodynamic diameter DLS)
Testing an instrument: the Malvern Nano-ZS type dynamic light scattering particle size analyzer has the following test conditions: scatter angle 173 °;
particle size distribution test
Testing an instrument: the Malvern Nano-ZS type dynamic light scattering particle size analyzer has the following test conditions: scatter angle 173 °;
TEM test
Testing an instrument: JEOL-2100 model Transmission Electron microscope; and (3) testing conditions are as follows: 200Kv, 101. mu.A; and the nano material to be tested is dispersed in water for testing;
MRI relaxation rate measurement
Testing an instrument: a MesoMR23-060H-I nmr analysis and imaging system; test conditions were T1: TR is 300ms, TE is 18.20 ms;
t1 weighted imaging of MRI
Testing an instrument: a MesoMR23-060H-I nmr analysis and imaging system; test conditions were T1: TR 300ms, TE 18.20 ms.
In the present application, COOH-PEG-COOH was purchased from Highai Yao Biotech Co.
P25 was purchased from ACROS reagent inc.
Example 1
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, adding into deionized water overnight, and removing unreactedNaBH of4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g of solid NaOH, dissolving the solid NaOH in 90.6ml of DEG, transferring the solution into a 250ml three-neck flask after the solid NaOH is completely dissolved, and then weighing 0.8mmol of gadolinium nitrate hexahydrate, and adding the gadolinium nitrate hexahydrate into the alkaline solution; weighing bTiO simultaneously22mmol, dissolving in 20ml DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction conditions are 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), cooling to room temperature after complete reaction, washing the material with 4 water and 4 alcohol for 8 times, dispersing into deionized water again, and storing in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(0.25mmol as bTiO)2The rest of the examples are analogous to example 1, i.e. 20mg of bTiO2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2PEG 0.01mmol (0.01mmol is bTiO)2Similar to example 1) in 10mL of ice water, 0.02mmol of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), 0.02mmol of NHS (N-hydroxysuccinimide) and 0.02mmol of-COOH on the surface of the material were added and stirred for 20min to activate-COOH on the surface of the material, 4mg of GE11(80uL, 50mg/mL) were added dropwise and the reaction was carried out overnight at 4 ℃ (600 rpm as described above; time 16h), the prepared Gd2O3-bTiO2-PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example2、Gd2O3-bTiO2、Gd2O3-bTiO2Detection of the PEG material by TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc.
FIG. 1 is the material Gd2O3-bTiO2Schematic diagram of PEG-GE11, the structure of the material and the individual components can be clearly shown.
In FIG. 2, a, b and c are bTiO respectively2、Gd2O3-bTiO2、Gd2O3-bTiO2TEM results corresponding to PEG, it is possible to see bTiO2、Gd2O3-bTiO2The particle size (the particle size of a single nanoparticle is between 20 and 40 nm) and the dispersibility of the two are not obviously different, but the dispersibility of the material modified by the modified polymer is obviously improved.
FIG. 3 is Gd2O3-bTiO2The distribution of Gd element in bTiO can be clearly seen2Surface, the successful synthesis of the material is demonstrated. And a material binding stability experiment (Gd is performed)2O3-bTiO2Mixing the material and a complete culture solution (the composition is DMEM: FBS is 9:1 in volume ratio), treating the mixture in a constant-temperature shaking incubator (37 ℃ and 150rpm) for 72 hours, carrying out ICP characterization on the supernatant and the precipitate of the material, determining the concentrations of Ti and Gd, comparing the concentrations with the results without treatment, obtaining the experimental result of stable combination, and indicating that the two are combined stably.
FIG. 4 is Gd2O3-bTiO2The particle size distribution, the particle size of the material is mainly concentrated at about 250nm, and the larger particle size is caused by aggregation of the material due to larger concentration in sample preparation.
FIG. 5 is Gd2O3-bTiO2The T1 weighted magnetic resonance imaging and the T1 imaging result of the standard substance under low concentration in the figure represent the gray value of the T1 magnetic resonance imaging, which can indicate the imaging performance of the material, and the larger the value, the better the T1 imaging effect. The results show that the synthesized material has good T1 weighted magnetic resonance imaging effect, and compared with the current clinical Marugineal display, the material of the application has better imaging effect at low concentration.
FIG. 6 is Gd2O3-bTiO2The corresponding experimental parameters of the photothermal heating effect are that the power density is 1.0w/cm2 and the illumination time is 5 min. The result shows that the material has good photo-thermal heating effect under the irradiation of near infrared light, the temperature can rise by about 27 ℃ under the concentration of 200ug/ml (the middle line), and the initial temperature is higher when combined with a human body, so that the temperature can easily reach more than 50 ℃, and the purpose of killing and killing tumors is achieved.
FIG. 7 is Gd2O3-bTiO2The results of XPS (Ex.) show that Gd is present as Gd2O3The successful synthesis of the material is further demonstrated, consistent with literature reports.
FIG. 8 is Gd2O3-bTiO2T1 weighted magnetic resonance imaging angiography of PEG, and the result proves that contrast difference between blood vessels and surrounding tissues is obvious after the composite material is injected intravenously for a period of time, further indicates that the material has excellent magnetic resonance imaging performance.
Example 2
(1) Weighing 3.0g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) 0.906g of solid NaOH is weighed and dissolved in 90.6ml of DEG (diethylene glycol), after complete dissolution, the mixture is transferred into a 250ml three-neck flask, then 0.8mmol of gadolinium nitrate hexahydrate is weighed and added into the alkaline solution, and bTiO is weighed simultaneously2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is that the rpm is 600rpm, the temperature is maintained at 100 ℃ for 10min, the temperature is maintained at 140 ℃ for 1h, the temperature is maintained at 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to the chamberThe material was rinsed 4 times with 4 water and 4 alcohol, redispersed in deionized water, and stored in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2-PEG (polyethylene glycol), the material obtained was washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2-PEG 0.01mmol dispersed in 10mL of ice water, 0.02mmol EDC (N-hydroxysuccinimide), 0.02mmol NHS (N-hydroxysuccinimide) added and stirred for 20min to activate-COOH on the surface of the material, 4mg GE11(80uL, 50mg/mL) added dropwise and reacted overnight at 4 ℃ (600 rpm described above; time 16h) to prepare Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 22、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 3
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 20 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) 0.906g of solid NaOH was weighed and dissolved in 90.6ml of DEG, and after complete dissolution, the solution was transferred to a 250ml three-necked flask,then 0.8mmol gadolinium nitrate hexahydrate is weighed and added into the alkaline solution, and bTiO is weighed simultaneously2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 32、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 4
(1) Weighing 1.5g of P25 solid and NaBH41.5g of the solid was put in a mortar, ground for 30 minutes and transferred to a porcelain boat, and reacted in a tube furnace (reaction conditions: reaction at 350 ℃ for 2 hours, heating rate 10 ℃ C.)Min, protective gas is nitrogen) to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2-PEG, the resulting material was washed 3 times centrifugally with deionized water, redispersed in deionized water, and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 42、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 5
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 1.5 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2-PEG 0.01mmol dispersed in 10mL ice water, adding 0.02mmol EDC and 0.02mmol NHS and stirring for 20min to activate-COOH on the material surface, adding 4mg GE11(80uL, 50mg/mL) dropwise, and reacting at 4 deg.C overnightGd prepared according to the formula (rotating speed of 600rpm, time of 16h)2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 52、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 6
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 1.0h, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 62、Gd2O3-bTiO2、Gd2O3-bTiO2-The results of TEM, particle size distribution, XRD, XPS, T1 weighted imaging of MRI, etc. of PEG material are basically the same as those of example 1.
Example 7
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, and protective gas of argon) to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Take 0.25mmol Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2-Dispersing PEG 0.01mmol in 10mL ice water, adding EDC 0.02mmol and NHS 0.02mmol, stirring for 20min to activate-COOH on the material surface, adding GE11 4mg (80uL, 50mg/mL) dropwise, reacting overnight at 4 deg.C (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 72、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 8
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 5 ℃/min, and protective gas of argon) to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolved in 20ml DEG, dispersed by cell crusher, and added dropwise to the above mixed solutionFinally, DEG is used for fixing the volume to 160ml, the mixture is placed on a magnetic stirrer for reaction (the reaction condition is that the rotating speed is 600rpm, the temperature is maintained at 100 ℃ for 10min, the temperature is maintained at 140 ℃ for 1h, the temperature is maintained at 175 ℃ for 4h), and Gd is obtained after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2-PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water, and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 82、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 9
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 20 ℃/min, and protective gas of argon) to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4Subsequent 2-water 2-alcohol centrifugal washingWashing for 4 times, drying at 70 deg.C, and storing in 4 deg.C refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2-PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water, and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 92、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 10
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then centrifugally washed 4 times with 2 water and 2 alcohol, dried at 60 ℃ and stored in a refrigerator at 4 ℃.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, and carrying out stirring reaction at the rotating speed of 600rpm for 12h at room temperature to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 102、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 11
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, then weighing 2.0mmol gadolinium nitrate hexahydrate to add to the alkaline solution, and weighing bTiO at the same time22.0mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C for 10min, 140 deg.C for 1h, 175 deg.C for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2-PEG, the resulting material was washed 3 times centrifugally with deionized water, redispersed in deionized water, and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2-PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water, and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 112、Gd2O3-bTiO2、Gd2O3-bTiO2-The results of TEM, particle size distribution, XRD, XPS, T1 weighted imaging of MRI, etc. of PEG material are basically the same as those of example 1.
Example 12
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, then weighing 2.0mmol gadolinium nitrate hexahydrate to add to the alkaline solution, and weighing bTiO at the same time21.0mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C for 10min, 140 deg.C for 1h, 175 deg.C for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding deionized water into a 100ml beaker to a constant volume of 30ml, carrying out ultrasonic treatment for 30min to completely disperse, and simultaneously weighing COOH-Dissolving 100mg of PEG-COOH (W ═ 2000) in 20ml of deionized water, stirring, ultrasonically mixing uniformly, dripping into the above solution, stirring at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01 mmol-PEG in 10mL ice water, adding 0.02mmol EDC and 0.02mmol NHS, stirring for 20min to activate-COOH on the material surface, adding 4mg GE11(80uL and 50mg/mL) dropwise, reacting overnight at 4 deg.C (stirring for 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 122、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 13
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, then weighing 1.0mmol gadolinium nitrate hexahydrate to add to the alkaline solution, and weighing bTiO at the same time22.0mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C for 10min, 140 deg.C for 1h, 175 deg.C for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 132、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 14
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) 0.906g of solid NaOH was weighed out and dissolved in 90.6ml of DEG, and after complete dissolution, the mixture was transferred to a 250ml three-neck flask, and then six solid NaOH was weighed outAdding 1.0mmol gadolinium nitrate hydrate into the alkaline solution, and weighing bTiO22.0mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 400rpm, 100 deg.C for 10min, 140 deg.C for 1h, 175 deg.C for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2-PEG, the resulting material was washed 3 times centrifugally with deionized water, redispersed in deionized water, and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2-Dispersing PEG 0.01mmol in 10mL ice water, adding EDC 0.02mmol and NHS 0.02mmol, stirring for 20min to activate-COOH on the material surface, adding GE11 4mg (80uL, 50mg/mL) dropwise, reacting overnight at 4 deg.C (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 142、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 15
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction condition: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protectionGas is nitrogen) to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, then weighing 1.0mmol gadolinium nitrate hexahydrate to add to the alkaline solution, and weighing bTiO at the same time22.0mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 800rpm, 100 deg.C for 10min, 140 deg.C for 1h, 175 deg.C for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 152、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 16
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium chloride hexahydrate to add into the alkaline solution, and weighing bTiO at the same time2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2-PEG 0.01mmol dispersed in 10mL ice water, 0.02mmol EDC and 0.02mmol NHS added and stirred for 20min to activate-COOH on the surface of the material, 4mg GE11(80uL, 50mg/mL) added dropwise and reacted overnight at 4 ℃ (speed 6 uL)00 rpm; time 16h), Gd prepared2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 162、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 17
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 1.27g of solid KOH, dissolving in 90.6ml of DEG, transferring to a 250ml three-neck flask after complete dissolution, weighing 0.8mmol of gadolinium nitrate hexahydrate, adding to the alkaline solution, and weighing bTiO2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2-PEG to obtainThe resulting material was washed 3 times centrifugally with deionized water, redispersed in deionized water, and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 172、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 18
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 20min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 182、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 19
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolved in 20ml DEG, dispersed by cell crusher, and added dropwise to the above mixed solutionThen, DEG is used to fix the volume to 160ml, the mixture is put on a magnetic stirrer to react (the reaction condition is that the rpm is 600rpm, the temperature is maintained at 100 ℃ for 10min, the temperature is maintained at 140 ℃ for 1.5h, the temperature is maintained at 175 ℃ for 4h), and Gd is obtained after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 192、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 20
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4Subsequent 2 water 2 alcohol centrifugal washing4 times, drying at 70 deg.C, and storing in 4 deg.C refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C maintaining for 10min, 140 deg.C maintaining for 1.0h, 175 deg.C maintaining for 3h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2-PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water, and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 202、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 21
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C maintaining for 10min, 140 deg.C maintaining for 1.0h, 175 deg.C maintaining for 4h), and obtaining Gd after reaction2O3-bTiO2Cool to room temperature, wash the material 2 water 2 alcohol 4 times, redisperse in deionized water, and store in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 212、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 22
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C maintaining for 10min, 140 deg.C maintaining for 1.0h, 175 deg.C maintaining for 4h), and obtaining Gd after reaction2O3-bTiO2Cooling to room temperature, 3 times washing the material with 3 water and 3 alcohol, dispersing again in deionized water, and storing in a refrigerator at 4 deg.C.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 222、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 23
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C maintaining for 10min, 140 deg.C maintaining for 1.0h, 175 deg.C maintaining for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding into 100ml beaker, adding deionized water to constant volume to 30ml, performing ultrasonic treatment for 30min to completely disperse, and weighing CODissolving OH-PEG-COOH (W is 3000)100mg in deionized water 20ml, stirring, ultrasonically mixing, dripping into the above solution, stirring at 600rpm at room temperature for 12 hr to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 232、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 24
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolving in 20ml DEG, dispersing by cell crusher, dripping into the above mixed solution, metering to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C maintaining for 10min, 140 deg.C maintaining for 1.0h, 175 deg.C maintaining for 4h), reacting completely,obtaining Gd2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding deionized water into a 100ml beaker, fixing the volume to 30ml with deionized water, performing ultrasonic treatment for 30min to completely disperse, simultaneously weighing 160mg of COOH-PEG-COOH (W2000) to dissolve in 20ml of deionized water, stirring, performing ultrasonic mixing, dropwise adding into the solution, and stirring at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2-PEG, the resulting material was washed 3 times centrifugally with deionized water, redispersed in deionized water, and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2-Dispersing PEG 0.01mmol in 10mL ice water, adding EDC 0.02mmol and NHS 0.02mmol, stirring for 20min to activate-COOH on the material surface, adding GE11 4mg (80uL, 50mg/mL) dropwise, reacting overnight at 4 deg.C (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 242、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 25
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) 0.906g of solid NaOH was weighed out and dissolved in 90.6ml of DEG, and after complete dissolution, the solution was transferred to 250ml of threeIn a flask, 0.8mmol gadolinium nitrate hexahydrate is weighed and added into the alkaline solution, and bTiO is weighed simultaneously22mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C maintaining for 10min, 140 deg.C maintaining for 1.0h, 175 deg.C maintaining for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding deionized water into a 100ml beaker, fixing the volume to 30ml with deionized water, performing ultrasonic treatment for 30min to completely disperse, simultaneously weighing 200mg of COOH-PEG-COOH (W2000) and dissolving in 20ml of deionized water, stirring, performing ultrasonic mixing, dropwise adding into the solution, and stirring at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 252、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 26
1) Weighing 1.5g of P25 solid and NaBH41.5g of the solid was put in a mortar, ground for 30 minutes, transferred to a porcelain boat, and reacted in a tube furnace (reaction conditions: reaction at 350 ℃ C. for 3 hours, liter)The temperature rate is 10 ℃/min, the protective gas is nitrogen) to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C maintaining for 10min, 140 deg.C maintaining for 1.0h, 175 deg.C maintaining for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm for 8h at room temperature to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 262、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 27
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C maintaining for 10min, 140 deg.C maintaining for 1.0h, 175 deg.C maintaining for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm for 15h at room temperature to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2-PEG 0.01mmol dispersed in 10mL ice water, 0.02mmol EDC and 0.02mmol NHS added and stirred for 20min to activate-COOH on the surface of the material, and 4mg GE11(80uL, 50mg/mL) added dropwise) Overnight at 4 ℃ (600 rpm; time 16h), Gd prepared2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 272、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 28
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C maintaining for 10min, 140 deg.C maintaining for 1.0h, 175 deg.C maintaining for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.01mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 282、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 29
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolving in 20ml DEG, dispersing by cell crusher, adding dropwise into the above mixed solution, diluting to 160ml with DEG, placing on magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C maintaining for 10min, 140 deg.C maintaining for 1.0h, 175 deg.C maintaining for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 30min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed 600 rpm; time 16h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 292、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 30
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time22mmol, dissolved in 20ml DEG, dispersed by a cell crusher,dropwise adding into the above mixed solution, diluting to 160ml with DEG, placing on a magnetic stirrer for reaction (reaction conditions: rotation speed 600rpm,100 deg.C for 10min, 140 deg.C for 1.0h, 175 deg.C for 4h), and obtaining Gd after reaction2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2Dispersing 0.01mmol of-PEG in 10mL of ice water, adding 0.02mmol of EDC and 0.02mmol of NHS, stirring for 20min, activating-COOH on the surface of the material, adding 4mg of GE11(80uL and 50mg/mL) dropwise, reacting at 4 ℃ overnight (rotation speed of 600rpm, time of 20h), and preparing Gd2O3-bTiO2PEG-GE11 was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 302、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 31
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) 0.906g of solid NaOH is weighed and dissolved in 90.6ml of DEG, after the solid NaOH is completely dissolved, the mixture is transferred into a 250ml three-neck flask, then 0.8mmol of manganese dichloride is weighed and added into the alkaline solution, and bTiO is weighed simultaneously22mmol, dissolving in 20ml DEG, dispersing by cell crusher, dripping into the above mixed solution, metering to 160ml with DEG, placing on magnetic stirrer for reaction (reaction condition: 600 rpm; 37 ℃; reaction 2h), and obtaining MnO2-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol MnO2-bTiO2(i.e., 20mg bTiO)2) Adding deionized water into a 100ml beaker, fixing the volume to 30ml with deionized water, performing ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH (W2000) to dissolve in 20ml of deionized water, stirring, performing ultrasonic mixing, dropwise adding into the solution, stirring at the rotating speed of 600rpm at room temperature to react for 12h to obtain MnO2-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing MnO2-bTiO2-PEG 0.01mmol dispersed in 10mL of ice water, 0.02mmol EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), 0.02mmol NHS (N-hydroxysuccinimide) added and stirred for 20min to activate-COOH on the surface of the material, 4mg HA (80uL, 50mg/mL) added dropwise and reacted overnight at 4 ℃ (600 rpm; time 16h) to prepare MnO2The bTiO2-PEG-HA was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 312、MnO2-bTiO2、MnO2-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 32
(1) Weighing P25 solid 1.5g、NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) 1.7mmol sodium citrate dihydrate and 0.08mmol FeCl were weighed3·6H2Dissolving O in 100ml DEG, transferring to a 250ml three-neck flask after completely dissolving, and weighing bTiO22mmol, dissolving in 20ml DEG, dispersing by a cell crusher, dripping into the mixed solution, then keeping the volume to 160ml by DEG, adjusting the pH to 5.8 by NaOH, then adding 2.0mmol of urea, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃, and 24 hours for reaction), and obtaining Fe after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) 0.25mmol of Fe is taken2O3-bTiO2(i.e., 20mg bTiO)2) Adding deionized water into a 100ml beaker, fixing the volume to 30ml with deionized water, performing ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH (W2000) to dissolve in 20ml of deionized water, stirring, performing ultrasonic mixing, dropwise adding into the solution, and stirring at the rotating speed of 600rpm at room temperature for 12h to obtain Fe2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Fe2O3-bTiO2-PEG 0.01mmol dispersed in 10mL of ice water, 0.02mmol EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), 0.02mmol NHS (N-hydroxysuccinimide) added and stirred for 20min to activate-COOH on the surface of the material, 4mg HA (80uL, 50mg/mL) added dropwise and reacted overnight at 4 ℃ (600 rpm; time 16h) to prepare Fe2O3-bTiO2-PEG-HA was washed 4 times by 2 water 2 alcohol centrifugation and redispersed in deionized waterAnd stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 322、Fe2O3-bTiO2、Fe2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 33
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) Adding 100mg of COOH-PEG-COOH (W2000) into 20ml of deionized water in a 100ml beaker, carrying out ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH, dissolving into 20ml of deionized water, stirring, carrying out ultrasonic mixing, dropwise adding into the solution, carrying out stirring reaction at the rotating speed of 600rpm at room temperature for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) BalanceTaking Gd2O3-bTiO2-PEG 0.01mmol dispersed in 10mL of ice water, 0.02mmol EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), 0.02mmol NHS (N-hydroxysuccinimide) added and stirred for 20min to activate-COOH on the surface of the material, 4mg HA (80uL, 50mg/mL) added dropwise and reacted overnight at 4 ℃ (600 rpm; time 16h), and the prepared Gd2O3-bTiO2-PEG-HA was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 332、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Example 34
(1) Weighing 1.5g of P25 solid and NaBH4Grinding 1.5g of solid in a mortar for 30 minutes, transferring the ground solid to a porcelain boat, and reacting in a tube furnace (reaction conditions: reaction at 350 ℃ for 3 hours, heating rate of 10 ℃/min, protective gas of nitrogen), to obtain bTiO2。bTiO2Naturally cooling, putting into deionized water overnight, and removing unreacted NaBH4And then washed 4 times with 2 water 2 alcohol centrifugation, dried at 70 ℃ and stored in a 4 ℃ refrigerator.
(2) Weighing 0.906g solid NaOH to dissolve in 90.6ml DEG, transferring to a 250ml three-neck flask after completely dissolving, weighing 0.8mmol gadolinium nitrate hexahydrate to add into the alkaline solution, and weighing bTiO at the same time2Dissolving 2mmol of Gd in 20ml of DEG, dispersing by a cell crusher, dripping into the mixed solution, finally fixing the volume to 160ml by DEG, placing on a magnetic stirrer for reaction (the reaction condition is 600rpm,100 ℃ for 10min, 140 ℃ for 1h, 175 ℃ for 4h), and obtaining Gd after the reaction is completed2O3-bTiO2Cooled to room temperature, 4 water 4 alcohol washes the material 8 times, redisperses in deionized water, and stores in a refrigerator at 4 ℃.
(3) Taking 0.25mmol of Gd2O3-bTiO2(i.e., 20mg bTiO)2) In a 100ml beaker, deionizedFixing the volume of water to 30ml, performing ultrasonic treatment for 30min to completely disperse, simultaneously weighing 100mg of COOH-PEG-COOH (W2000) to dissolve in 20ml of deionized water, stirring, performing ultrasonic mixing, dropwise adding into the solution, and stirring at the rotating speed of 600rpm at room temperature to react for 12h to obtain Gd2O3-bTiO2PEG, the material obtained is washed 3 times by centrifugation with deionized water, redispersed in deionized water and stored in a refrigerator at 4 ℃.
(4) Weighing Gd2O3-bTiO2-PEG 0.01mmol dispersed in 10mL of ice water, 0.02mmol EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), 0.02mmol NHS (N-hydroxysuccinimide) added and stirred for 20min to activate-COOH on the surface of the material, 4mg FA (80uL, 50mg/mL) added dropwise and reacted overnight at 4 ℃ (600 rpm; time 16h), prepared Gd2O3-bTiO2-PEG-HA was washed 4 times by 2 water 2 alcohol centrifugation, redispersed in deionized water and stored in a refrigerator at 4 ℃.
Results
bTiO obtained in example 342、Gd2O3-bTiO2、Gd2O3-bTiO2TEM, particle size distribution, XRD, XPS, T1-weighted imaging by MRI, etc. of the PEG material are essentially the same as in example 1.
Comparative example 1 preparation of bTiO by Mg thermal reduction2
(1) Weighing 20mmol of P25 powder and 10mmol of Mg powder, mixing in a mortar, transferring to a porcelain boat, and sealing with tinfoil paper.
(2) The sealed porcelain boat is put into a tube furnace to react (the reaction condition is Ar gas protection and calcination is carried out for 4h at 650 ℃)
(3) After cooling, the reaction mixture was washed with an excess of dilute hydrochloric acid to remove unreacted Mg.
(4) And (3) centrifugally washing the Mg-removed material for 3 times by using deionized water, drying at 70 ℃, and finally sealing and storing in a refrigerator at 4 ℃.
Results
bTiO obtained in comparative example 12Partial Mg element is doped in the material, and the effect generated by the element after entering a human body is unknown, so that toxic and side effects can be caused; and the calcination temperature is 650 ℃, the temperature is too highAnd (4) determining potential safety hazards.
Comparative example 2H2Preparation of bTiO by reduction method2
(1) 1.5g of P25 powder was weighed, transferred to a porcelain boat, and sealed with tinfoil paper.
(2) The sealed porcelain boat is put into a tube furnace, and mixed gas (H25 percent and Ar95 percent) is introduced into the tube furnace at the gas flow rate of 50ml/min for reaction (the reaction conditions are that the temperature rise rate is 5 ℃/min, and the calcination is carried out for 3 hours at the temperature of 600 ℃).
(3) After cooling, the material was washed 4 times with 2 water and 2 alcohol, dried at 70 ℃ and finally stored in a 4 ℃ freezer under sealed conditions.
Results
The bTiO2 obtained in the comparative example 2 has insufficient oxygen defect concentration and limited photo-thermal heating performance, and is difficult to meet the requirements of photo-thermal treatment, and meanwhile, the dangerous gas of hydrogen is involved in the experiment, so that the experiment danger is increased.
Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.
Claims (9)
1. A composite nanomaterial, the composite nanomaterial comprising magnetic resonance imaging nanoparticles and reduced titanium dioxide nanoparticles;
the particle size of the magnetic resonance imaging nano particles is smaller than that of the reduced titanium dioxide nano particles;
the magnetic resonance imaging nano particles are attached to the surfaces of the reduced titanium dioxide nano particles;
wherein the reduced titanium dioxide nanoparticles are titanium dioxide nanoparticles subjected to reduction treatment.
2. The composite nanomaterial of claim 1, wherein the magnetic resonance imaging nanoparticle is an imaging metal oxide nanoparticle;
the imaging metal oxide contains magnetic resonance imaging metal elements;
the magnetic resonance imaging metal element is selected from any one of gadolinium, manganese and iron.
3. The composite nanomaterial according to claim 1, wherein the particle size of the reduced titania nanoparticles is 20-50 nm;
the particle size of the magnetic resonance imaging nanoparticles is 1-2 nm.
4. The composite nanomaterial according to claim 1, wherein in the composite nanomaterial, the mass content of Ti element is 50-90%, and the mass content of magnetic resonance imaging metal element is 10-50%;
preferably, the reduced titania nanoparticles have any one of a rod-like shape, a spherical shape, an approximately spherical shape, and an irregular shape;
preferably, the particle size of the composite nano material is 50-300 nm.
5. The composite nanomaterial of claim 1, wherein the composite nanomaterial is a gadolinium-titanium composite nanomaterial;
the gadolinium-titanium composite nanomaterial comprises Gd2O3Nanoparticles and reduced titania nanoparticles;
the Gd2O3The nanoparticles are attached to the surface of the reduced titania nanoparticles.
6. The method for preparing a composite nanomaterial according to any of claims 1 to 5, characterized in that it comprises at least:
a) obtaining reduced titanium dioxide nanoparticles;
b) reacting a mixture containing a magnetic resonance imaging nanoparticle source and reduced titanium dioxide nanoparticles under an alkaline condition to obtain the composite nanomaterial;
preferably, in step b), the magnetic resonance imaging nanoparticle source comprises any one of gadolinium source, manganese source, iron source;
the gadolinium source is gadolinium salt;
the manganese source is manganese salt;
the iron source is iron salt;
preferably, the gadolinium salt is selected from Gd (NO)3)3·6H2O、GdCl3·6H2O、Gd(SO4)3·6H2Any one of O;
the manganese salt is selected from MnCl2、Mn(NO3)2、Mn(SO4)2Any one of (a);
the iron salt is selected from Fe (NO)3)3·6H2O、FeCl3·6H2O、Fe(SO4)3·6H2Any one of O;
preferably, in the step b), the molar ratio of the reduced titanium dioxide nanoparticles to the magnetic resonance imaging nanoparticle source is 5: 1-1: 5;
wherein the moles of the reduced titania nanoparticles are based on the moles of titania;
the number of moles of the magnetic resonance imaging nanoparticle source is calculated by the number of moles of the magnetic resonance imaging nanoparticle source;
preferably, in step b), the alkaline conditions are conditions containing alkaline substances;
the alkaline substance is selected from NaOH, KOH and NH3·H2Any one of O;
preferably, in step b), the reaction comprises a stage I, a stage II and a stage III which are carried out continuously and sequentially;
the stage I comprises the following steps: heating to 95-105 ℃, and preserving heat for 10-30 min;
the stage II comprises the following steps: heating to 130-150 ℃, and keeping the temperature for 0.5-2 h;
the stage III comprises: heating to 170-180 ℃, and preserving heat for 2-6 h;
preferably, the step b) includes:
b-1) obtaining a solution I containing an alkaline substance and a gadolinium source;
b-2) obtaining a dispersion containing reduced titanium dioxide nanoparticles;
b-3) dropwise adding the dispersion liquid into the solution I, fixing the volume, heating to 90-100 ℃, and keeping the temperature for 5-15 min; then, continuously heating to 130-150 ℃, and preserving heat for 0.5-2 h; then, continuously heating to 170-180 ℃, and preserving heat for 3-5 hours to obtain the composite nano material;
preferably, in the step b-1), the content of the alkaline substance in the solution I is 8-12 mg/ml;
the content of the gadolinium source in the solution I is 0.008-0.03 mmol/ml;
preferably, in the step b-2), the content of the reduced titania nanoparticles in the dispersion is 0.05 to 0.1 mmol/ml.
7. A complex contrast/photothermal therapy agent, which is prepared from the composite nanomaterial according to any one of claims 1 to 5 and the composite nanomaterial obtained by the preparation method according to claim 6.
8. The method for preparing the complex contrast/photothermal therapy agent according to claim 7, wherein the preparation method comprises the steps of:
i) treating the composite nano material by a modified macromolecule to obtain a modified composite nano material;
II) reacting the solution containing the modified composite nano material and the targeting molecule in the presence of an activating agent to obtain the contrast/photothermal therapy compound agent;
preferably, in step i), the modifying polymer is selected from any one of COOH-PEG-COOH, HOOC-PDMS-COOH, and polyacrylic acid;
preferably, in step i), the mass ratio of the composite nanomaterial to the modifying polymer is 1: 5-10;
wherein the mass of the composite nanomaterial is based on the mass of the reduced titanium dioxide nanoparticles;
preferably, in step ii), the targeting molecule is selected from any one of GE11, folic acid, hyaluronic acid;
preferably, in the step II), the activator is selected from any one of an activator I, an activator II and an activator III;
wherein the activating agent I is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide;
the activating agent II is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole;
the activating agent III is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxy-7-azobenzotriazole;
preferably, in step ii), the ratio of the modified composite nanomaterial to the targeting molecule is 0.01: 3-5 mmol/mg;
preferably, in the step II), the content of the modified composite nano material in the solution is 0.0005-0.002 mmol/ml;
the content of the targeting molecule in the solution is 0.2-0.6 mg/ml;
wherein the moles of the modified composite nanomaterial are based on the moles of reduced titanium dioxide;
preferably, in the step II), the content of the activating agent in the solution is 0.002-0.006 mmol/ml.
9. The contrast/photothermal therapy composite agent according to claim 7 or the contrast/photothermal therapy composite agent obtained by the production method according to claim 8 is used in the fields of MRI contrast materials, disease diagnosis materials, photothermal therapy materials, and diagnostic and therapeutic integrated nanomaterials.
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