CN113304313A - Preparation of injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF, and product and application thereof - Google Patents

Preparation of injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF, and product and application thereof Download PDF

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CN113304313A
CN113304313A CN202110705011.XA CN202110705011A CN113304313A CN 113304313 A CN113304313 A CN 113304313A CN 202110705011 A CN202110705011 A CN 202110705011A CN 113304313 A CN113304313 A CN 113304313A
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rare earth
drug
bone cement
calcium phosphate
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崔大祥
杨迪诚
徐艳
朱君
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Shanghai National Engineering Research Center for Nanotechnology Co Ltd
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Abstract

A preparation method of injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF nanoparticles comprises the steps of synthesizing Eu, Gd MOF nanoparticles by a step-by-step synthesis method; chemically synthesizing to prepare a tumor-targeted high-molecular polymer; preparing tumor-targeted rare earth MOF nanoparticles and loads of antitumor drugs by coordination synthesis and physical adsorption; finally, the mixture is mixed with bone cement powder to prepare the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nano particles. The nanometer rare earth MOF particles with fluorescence up-conversion luminescence property, magnetic property and drug loading capacity are prepared, and the provided bone cement modification formula has targeted developing capacity and targeted drug delivery capacity, can be used for targeted treatment of orthopedic tumors, and can be used for filling and repairing bone defects.

Description

Preparation of injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF, and product and application thereof
Technical Field
The invention relates to a method in the technical field of biomedical materials, in particular to a preparation method of injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF nanoparticles, and a product and application thereof.
Background
In clinical application, the drug-loaded bone cement has good performance in treating bone defects caused by cancer, and the bone cement coated with anticancer drugs is usually implanted into the bone defect part for carrying out chemotherapy of the cancer. In the processes of material imaging and subsequent drug targeting tracing of minimally invasive surgery, fluorescence tracking is an important approach, and selection of an appropriate biological fluorescence probe is particularly important. The biological fluorescent probe materials which are most widely applied at present mainly comprise organic dyes and semiconductor quantum dots. Among them, the organic dye has unstable luminescent property, and the semiconductor quantum dot has good luminescent property but large biological toxicity. The rare earth up-conversion fluorescent nano material has great potential in biomedical application due to unique optical and biological properties. Meanwhile, magnetic resonance imaging is also a common means for tumor radiodiagnosis, and a proper contrast agent has important significance for improving detection sensitivity and signal specificity. The nanometer rare earth MOF is a metal framework material based on rare earth nanoparticles, has up-conversion luminescence characteristics, magnetic properties and coordination metal drug-loaded framework, can combine tumor targeting, molecular imaging and drug-loaded treatment functions together due to unique characteristics and structure, and is beneficial to developing a nanometer drug-loaded system for diagnosis and treatment.
Disclosure of Invention
The invention aims to provide a preparation method of injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF nanoparticles.
Yet another object of the present invention is to: provides a wrapped IR780@ silica body product prepared by the method.
Yet another object of the present invention is to: provides an application of the product.
The purpose of the invention is realized by the following scheme: a preparation method of injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF is characterized in that rare earth MOF nano particles of Eu and Gd are synthesized by a step-by-step synthesis method; preparing a tumor-targeted high-molecular polymer; preparing tumor-targeted rare earth MOF nanoparticles and loads of antitumor drugs; the preparation method of the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nanoparticles comprises the following steps:
(1) preparing rare earth MOF nano particles of Eu and Gd:
reacting terephthalic acid H2IPA, europium salt and gadolinium salt are dissolved in a mixed solution of N, N-Dimethylformamide (DMF) and water, and the phthalic acid (H)2IPA), europium salt and gadolinium salt in a molar ratio of 1:1:1, adding a small amount of polyvinylpyrrolidone (PVP, K30) as a surfactant, stirring and heating the reactants at 100 ℃ in an oil bath for 10 min, filtering, and performing vacuum drying at room temperature to obtain MOF nano particles of Eu and Gd products;
(2) preparing a tumor-targeted high-molecular polymer:
n-isopropylacrylamide (NIPAM), trithiocarbonate (DATC), Azobisisobutyronitrile (AIBN) was added as 300: 3: 1 in nitrogen atmosphere, wherein DATC is used as a chain transfer agent, AIBN is used as an initiator, reactants are stirred and heated for 24 hours in an oil bath at the temperature of 65 ℃ to obtain PNIPAM-DATC, and then the PNIPAM-DATC and N-hydroxysuccinimide acrylate (NAOS) are mixed according to the mass ratio of 10: 3, carrying out reversible addition-fragmentation chain transfer polymerization (RAFT) reaction, taking AIBN as an initiator, carrying out the whole reaction in a nitrogen atmosphere, stirring and heating reactants in an oil bath for 12-48 h at the temperature of 65 ℃, and obtaining a polymer PNIPAM-DATC-PNAOS; dissolving PNIPAM-DATC-PNAOS and a tumor antagonist in dimethyl sulfoxide (DMSO), adding triethylamine, stirring and reacting for 24 hours at room temperature, dialyzing a product after the reaction is finished, and freeze-drying to obtain a high molecular polymer of the grafted targeted antitumor drug, wherein the high molecular polymer is marked as PNIPAM-DATC-antagonist;
(3) preparing drug-loaded tumor-targeted rare earth MOF nanoparticles:
dispersing PNIPAM-DATC-antagonist and the rare earth MOF nano particles obtained in the step (1) in water, adding a small molecular antitumor drug, adding dilute hydrochloric acid to adjust the pH to 4.5, stirring at room temperature under the protection of nitrogen for reaction for 24 hours, centrifuging the product after the reaction is finished, and performing vacuum drying on solid particles at room temperature to obtain drug-loaded tumor targeted rare earth MOF nano particles;
(4) preparing injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF nanoparticles:
the nanoparticles are mixed with injectable calcium phosphate bone cement solid-phase powder and are blended with bone cement curing liquid, and the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nanoparticles can be obtained.
Preferably, the tumor antagonist of step (2) is a tumor targeting antagonist having a carboxyl functional group, such as a GnRHR receptor antagonist (Cetrorelix).
The micromolecule anti-tumor medicine in the step (3) is a water-soluble tumor treatment medicine.
The mixing ratio of the nano particles and the bone cement in the step (4) is 0.01-5% by mass.
The invention provides a drug-loaded rare earth MOF (metal organic framework) modified injectable calcium phosphate bone cement which is prepared by any one of the methods.
The invention also provides application of the drug-loaded rare earth MOF modified injectable calcium phosphate bone cement in preparation of a targeted drug delivery system material based on the orthopedic tumor.
The synthesis route of the drug-loaded tumor-targeted rare earth MOF nanoparticles is as follows:
Figure DEST_PATH_IMAGE001
the nanometer rare earth MOF particles with fluorescence up-conversion luminescence property, magnetic property and drug loading capacity are prepared, and the provided bone cement modification formula has targeted developing capacity and targeted drug delivery capacity, can be used for targeted treatment of orthopedic tumors, and can be used for filling and repairing bone defects. The rare earth MOF nanoparticles are combined with tumor-targeted polymer molecules through coordination bonds of rare earth elements, and meanwhile, micromolecular antitumor drugs are loaded through physical adsorption, so that the versatility of the rare earth MOF nanoparticles is realized.
Detailed Description
The following examples are carried out on the premise of the technical scheme of the invention, and detailed embodiments and specific operation procedures are given, but the scope of the invention is not limited to the following examples.
Example 1
An injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF is prepared by synthesizing Eu, Gd MOF nano particles by a step-by-step synthesis method; preparing a tumor-targeted high-molecular polymer; preparing tumor-targeted rare earth MOF nanoparticles and loads of antitumor drugs; the preparation method of the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nanoparticles comprises the following steps:
(1) preparing rare earth MOF nanoparticles:
1 mmol of terephthalic acid H2IPA, 1 mmol of europium nitrate hexahydrate and 1 mmol of gadolinium nitrate hexahydrate are dissolved in 30 ml of mixed solution of N, N-dimethylformamide DMF and water, a small amount of polyvinylpyrrolidone (PVP, K30) is added as a surfactant, reactants are stirred and heated in an oil bath at the temperature of 100 ℃ for 10 min, and after filtration, vacuum drying is carried out at room temperature to obtain product MOF nano particles of Eu and Gd;
(2) the synthesis of the tumor-targeted high molecular polymer and the synthesis route of the drug-loaded tumor-targeted rare earth MOF nanoparticles are as follows:
n-isopropylacrylamide NIPAM, trithiocarbonate DATC and azobisisobutyronitrile AIBN were mixed in a 300: 3: 1, dissolving the mixture in 4 mL of anhydrous dioxane in a nitrogen atmosphere, wherein trithiocarbonate DATC is used as a chain transfer agent, azobisisobutyronitrile AIBN is used as an initiator, and the reactant is stirred and heated in an oil bath at 65 ℃ for 24 hours to obtain PNIPAM-DATC; and mixing the obtained product PNIPAM-DATC and N-hydroxysuccinimide acrylate NAOS in a mass ratio of 10: 3, performing RAFT reaction, taking azobisisobutyronitrile AIBN as an initiator, performing the whole reaction in a nitrogen atmosphere, stirring and heating reactants in an oil bath at 65 ℃ for 12-48 h to obtain a polymer PNIPAM-DATC-PNAOS; dissolving 0.5 g of PNIPAM-DATC-PNAOS and 5mg of antagonist (ceftorelix) of tumor targeting antagonist GnRHR receptor with carboxyl functional group in 5 mL of dimethyl sulfoxide DMSO, adding 1 mL of triethylamine, stirring at room temperature for reaction for 24h, dialyzing the product after the reaction is finished, and freeze-drying to obtain a high-molecular polymer grafted with the targeting antitumor drug, wherein the high-molecular polymer is marked as PNIPAM-DATC-ceftorelix;
(3) preparing drug-loaded tumor-targeted rare earth MOF nanoparticles:
dispersing 10mg of PNIPAM-DATC-Cetrorelix and the 10mg rare earth MOF nano particle small molecular anti-tumor drug doxorubicin hydrochloride into 4 mL of deionized water, adding dilute hydrochloric acid to adjust the pH value to 4.5, stirring at room temperature under the protection of nitrogen for reaction for 24h, centrifuging the product after the reaction is finished, and performing vacuum drying on solid particles at room temperature to obtain drug-loaded tumor targeted rare earth MOF nano particles, wherein the structural formula of the final product is as the final product in the step of the synthetic route;
(4) preparing injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF nanoparticles:
and mixing 10mg of the drug-loaded tumor-targeted rare earth MOF nano particles with 0.2g of injectable calcium phosphate bone cement solid-phase powder, and blending with a bone cement curing solution to obtain the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nano particles.
Example 2
An injectable calcium phosphate cement modified by rare earth MOF carrying drugs, the steps (1) to (3) are the same as the example 1, except that the step (4) is prepared by the following steps:
5mg of drug-loaded tumor-targeted rare earth MOF nanoparticles are mixed with 0.2g of injectable calcium phosphate bone cement powder and blended with bone cement curing liquid to obtain the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nanoparticles.
Example 3
An injectable calcium phosphate cement modified by rare earth MOF carrying drugs, the steps (1) to (3) are the same as the example 1, except that the step (4) is prepared by the following steps:
and (3) mixing 20mg of drug-loaded tumor targeted rare earth MOF nanoparticles with 0.2g of injectable calcium phosphate bone cement powder, and blending with a bone cement curing liquid to obtain the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nanoparticles.

Claims (8)

1. A preparation method of injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF is characterized in that rare earth MOF nano particles of Eu and Gd are synthesized by a step-by-step synthesis method; preparing a tumor-targeted high-molecular polymer; preparing tumor-targeted rare earth MOF nanoparticles and loads of antitumor drugs; the preparation method of the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nanoparticles comprises the following steps:
(1) preparing rare earth MOF nano particles of Eu and Gd:
reacting terephthalic acid H2IPA, europium salt and gadolinium salt are dissolved in a mixed solution of N, N-dimethylformamide DMF and water, and the phthalic acid (H)2IPA), europium salt and gadolinium salt in a molar ratio of 1:1:1, adding a small amount of polyvinylpyrrolidone (PVP, K30) as a surfactant, oil-bath stirring and heating the reactants at 100 ℃ for 10 min, filtering, and vacuum-drying at room temperature to obtain MOF nano particles of Eu and Gd products;
(2) preparing a tumor-targeted high-molecular polymer:
n-isopropylacrylamide NIPAM, trithiocarbonate DATC and azobisisobutyronitrile AIBN were mixed in a 300: 3: 1, dissolving in anhydrous dioxane in a nitrogen atmosphere, wherein trithiocarbonate DATC is used as a chain transfer agent, azobisisobutyronitrile AIBN is used as an initiator, and the reactant is stirred and heated in an oil bath at the temperature of 65 ℃ for 24 hours to obtain PNIPAM-DATC; and mixing PNIPAM-DATC and N-hydroxysuccinimide acrylate NAOS in a mass ratio of 10: 3, performing RAFT reaction, taking azobisisobutyronitrile AIBN as an initiator, performing the whole reaction in a nitrogen atmosphere, stirring and heating reactants in an oil bath at 65 ℃ for 12-48 h to obtain a polymer PNIPAM-DATC-PNAOS; dissolving PNIPAM-DATC-PNAOS and a tumor targeting antagonist with a carboxyl functional group in dimethyl sulfoxide (DMSO), adding triethylamine, stirring at room temperature for reaction for 24 hours, dialyzing a product after the reaction is finished, and freeze-drying to obtain a high-molecular polymer of the grafted targeting antitumor drug, wherein the high-molecular polymer is marked as PNIPAM-DATC-antagonist;
(3) preparing drug-loaded tumor-targeted rare earth MOF nanoparticles:
dispersing PNIPAM-DATC-antagonist and rare earth MOF nano-particles in water, adding a small molecular antitumor drug, adding diluted hydrochloric acid to adjust the pH to 4.5, stirring and reacting at room temperature for 24 hours under the protection of nitrogen, centrifuging a product after the reaction is finished, and performing vacuum drying on solid particles at room temperature to obtain drug-loaded tumor targeted rare earth MOF nano-particles;
(4) preparing injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF nanoparticles:
the drug-loaded tumor-targeted rare earth MOF nano particles are mixed with injectable calcium phosphate bone cement solid-phase powder, the mixing ratio of the drug-loaded tumor-targeted rare earth MOF nano particles to the bone cement is 0.01-5% by mass, and the mixture is blended with bone cement curing liquid to obtain the drug-loaded rare earth MOF nano particle modified injectable calcium phosphate bone cement.
2. The preparation method of the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF according to claim 1, wherein the tumor-targeted antagonist with carboxyl functional groups in the step (3) is at least GnRHR receptor antagonist Cetrorelix.
3. The preparation method of the injectable calcium phosphate cement carrying the drug rare earth MOF modification, according to claim 1, characterized in that the small-molecule antitumor drug in the step (4) is a water-soluble tumor treatment drug.
4. The preparation method of the injectable calcium phosphate bone cement with the drug-loaded rare earth MOF modification, according to any one of claims 1 to 3, is characterized by comprising the following steps:
(1) preparing rare earth MOF nanoparticles:
1 mmol of terephthalic acid H2IPA, 1 mmol of europium nitrate hexahydrate, and 1 mmol of gadolinium nitrate hexahydrate were dissolved in 30 ml of NAdding trace polyvinylpyrrolidone (PVP, K30) as a surfactant into a mixed solution of N-dimethylformamide DMF and water, carrying out oil bath stirring and heating on reactants at the temperature of 100 ℃ for 10 min, filtering, and carrying out vacuum drying at room temperature to obtain MOF nano particles of Eu and Gd products;
(2) synthesis of tumor-targeted high-molecular polymer:
n-isopropylacrylamide NIPAM, trithiocarbonate DATC and azobisisobutyronitrile AIBN were mixed in a 300: 3: 1, dissolving the mixture in 4 mL of anhydrous dioxane in a nitrogen atmosphere, wherein trithiocarbonate DATC is used as a chain transfer agent, azobisisobutyronitrile AIBN is used as an initiator, and the reactant is stirred and heated in an oil bath at 65 ℃ for 24 hours to obtain PNIPAM-DATC; and mixing the obtained product PNIPAM-DATC and N-hydroxysuccinimide acrylate NAOS in a mass ratio of 10: 3, performing RAFT reaction, taking azobisisobutyronitrile AIBN as an initiator, performing the whole reaction in a nitrogen atmosphere, stirring and heating reactants in an oil bath at 65 ℃ for 12-48 h to obtain a polymer PNIPAM-DATC-PNAOS; dissolving 0.5 g of PNIPAM-DATC-PNAOS and 5mg of antagonist (ceftorelix) of tumor targeting antagonist GnRHR receptor with carboxyl functional group in 5 mL of dimethyl sulfoxide DMSO, adding 1 mL of triethylamine, stirring at room temperature for reaction for 24h, dialyzing the product after the reaction is finished, and freeze-drying to obtain a high-molecular polymer grafted with the targeting antitumor drug, wherein the high-molecular polymer is marked as PNIPAM-DATC-ceftorelix;
(3) preparing drug-loaded tumor-targeted rare earth MOF nanoparticles:
dispersing 10mg of PNIPAM-DATC-Cetrorelix and the 10mg of rare earth MOF nano particle small molecular anti-tumor drug doxorubicin hydrochloride into 4 mL of deionized water, adding the deionized water, adding dilute hydrochloric acid to adjust the pH value to 4.5, stirring the mixture at room temperature under the protection of nitrogen to react for 24 hours, centrifuging the product after the reaction is finished, and performing vacuum drying on solid particles at room temperature to obtain drug-loaded tumor targeted rare earth MOF nano particles;
(4) preparing injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF nanoparticles:
and mixing 10mg of the drug-loaded tumor-targeted rare earth MOF nano particles with 0.2g of injectable calcium phosphate bone cement solid-phase powder, and blending with a bone cement curing solution to obtain the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nano particles.
5. The preparation method of the injectable calcium phosphate bone cement carrying the drug rare earth MOF modification according to claim 4, characterized in that the step (4) is prepared by the following steps:
5mg of drug-loaded tumor-targeted rare earth MOF nanoparticles are mixed with 0.2g of injectable calcium phosphate bone cement powder and blended with bone cement curing liquid to obtain the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nanoparticles.
6. The preparation method of the injectable calcium phosphate bone cement carrying the drug rare earth MOF modification according to claim 4, characterized in that the step (4) is prepared by the following steps:
and (3) mixing 20mg of drug-loaded tumor targeted rare earth MOF nanoparticles with 0.2g of injectable calcium phosphate bone cement powder, and blending with a bone cement curing liquid to obtain the injectable calcium phosphate bone cement modified by the drug-loaded rare earth MOF nanoparticles.
7. An injectable calcium phosphate cement modified by carrying rare earth MOF, which is characterized by being prepared according to the method of any one of claims 1 to 6.
8. Use of the drug-loaded rare earth MOF-modified injectable calcium phosphate cement according to claim 7 in the preparation of a material based on an orthopedic tumor-targeted drug delivery system.
CN202110705011.XA 2020-12-29 2021-06-24 Preparation of injectable calcium phosphate bone cement modified by drug-loaded rare earth MOF, and product and application thereof Pending CN113304313A (en)

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CN105505392A (en) * 2015-12-09 2016-04-20 中国科学院福建物质结构研究所 Rare-earth oxyfiuoride nanometer material, and preparation method and application thereof
CN107970489A (en) * 2017-11-29 2018-05-01 上海纳米技术及应用国家工程研究中心有限公司 Carry preparation method of injectable type bone cement of medicine organic phosphoric acid modified zirconia and products thereof and application
CN110665014A (en) * 2019-10-15 2020-01-10 上海纳米技术及应用国家工程研究中心有限公司 Preparation method of rare earth MOF nanoparticles with dual-mode imaging function

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Application publication date: 20210827