CN107158473B - Calcium phosphate bone cement embedded with drug-loaded silica plastid and preparation method and application thereof - Google Patents
Calcium phosphate bone cement embedded with drug-loaded silica plastid and preparation method and application thereof Download PDFInfo
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Abstract
A calcium phosphate bone cement embedded with a drug-loaded silica body, a preparation method and application thereof. The invention relates to a modified bone cement solid-phase powder obtained by mixing a self-curing component and a heating nano material, wherein an alpha-tricalcium phosphate material has a wrapping and carrying effect, and paclitaxel @ silicon plastid has an anticancer effect; the sodium phosphate is used as a main body, and the phosphorylated chitosan, the hydroxypropyl methylcellulose and the gelatin are used as modifiers to prepare the neutral bone cement curing liquid, so that the injectability of the formula is improved; the bone cement solid-phase powder is mixed with the curing liquid, so that the main components of hydroxyapatite and paclitaxel @ siliceous body of the cured product are increased, and the bone cement solid-phase powder has good degradation capability in organisms. The method is simple, the raw materials are simple, and the method is suitable for mass production. The developed new drug-loading formula improves the biocompatibility of the original bone cement, and the injectability of the silica calcium phosphate bone cement embedded with the drug-loading is improved by adding paclitaxel @ silica with a thermotherapy effect.
Description
Technical Field
The invention relates to a method in the technical field of biomedical materials, in particular to embedded drug-loaded silica body calcium phosphate bone cement and a preparation method and application thereof.
Technical Field
Bone tumors (bone tumors) are tumors that occur in the bone or its accessory tissues (blood vessels, nerves, bone marrow, etc.) and are common diseases. The exact cause is not known, as are other body tissues. Tumors are classified into benign tumors and malignant tumors. Benign tumors are easy to clean, generally do not transfer, do not relapse, and only have extrusion and blocking effects on organs and tissues; malignant tumors destroy the structure and function of tissues and organs, necrotize together to bleed and infect, seriously threatening human life. Bone tumors or neoplasia are primarily surgically scraped or resected. The tumor surgery is intended to be thorough in order to prevent recurrence or malignant change, and the surgery is performed after resection by filling a synthetic bone repair material for filling and treatment. Although the operation can rapidly remove the primary focus, if the removal is not clean, the cancer cells can still spread, however, the chemotherapy drugs such as paclitaxel, doxorubicin hydrochloride, daunorubicin, vincristine and the like have effective effects on curing patients or obviously prolonging the life of the patients, but have considerable toxic and side effects on normal cells of human bodies. The research on the preparation of anticancer drugs to reduce toxic and side effects is focused.
The silica body drug carrier material is a novel carrying material formed by a sol/gel method and a self-assembly process, the content of Si in the silica body is lower than 4%, and a silica network structure with a layer of atomic thickness is formed in a lipid layer, so that the stability is improved, and the problem of poor stability is solved. Like liposome, the liposome has a lipid bilayer membrane vesicle structure, has good biocompatibility, can be biodegraded, and can not remain in the organism. It can embed hydrophilic and lipophilic medicines, and even amphipathic medicines. The silica plastid can be used as a drug carrier to deliver various substances with different functions, such as small-molecule anti-cancer drugs, protein drugs, genes, magnetic particles and the like, so that the combination of multiple drugs or multiple treatment methods is realized, and the silica plastid becomes a powerful tool for diagnosing cancers and killing cancer cells. The release rate of the internal drug can be controlled by regulating the condensation degree of Si-O-Si on the surface of the silica body. Studies have demonstrated that as the degree of condensation of Si-O-Si increases, the rate of drug release decreases.
The invention combines the drug silicon body embedding technology and the injectable inorganic calcium phosphate bone cement material, can form an artificial bone after being injected in vivo, fixes the silicon body drug in the artificial bone after the alpha-tricalcium phosphate is hydrated, and slowly releases and degrades the drug along with the gradual degradation of the shell layer, thereby being safely metabolized out of the body.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a preparation method of embedded drug-loaded silica plastid calcium phosphate bone cement.
The purpose of the invention is realized by the following technical scheme:
the preparation method of the embedded drug-loaded silica plastid calcium phosphate bone cement is characterized by comprising the following steps:
(1) mixing the self-curing component with the heated nano material to obtain modified bone cement solid-phase powder, wherein the alpha-tricalcium phosphate material has a wrapping and carrying effect, and the paclitaxel @ silicon plastid has an anticancer effect;
(2) the sodium phosphate is used as a main body, and the phosphorylated chitosan, the hydroxypropyl methylcellulose and the gelatin are used as modifiers to prepare the neutral bone cement curing liquid, so that the injectability of the formula is improved;
(3) the bone cement solid-phase powder is mixed with the curing liquid, so that the main components of hydroxyapatite and paclitaxel @ siliceous body of the cured product are increased, and the bone cement solid-phase powder has good degradation capability in organisms.
The phosphoric acid solution in the step (2) contains 10-20% of sodium phosphate, 0.01-1% of phosphorylated chitosan, 0.01-1% of hydroxypropyl methyl cellulose and 0.01-1% of gelatin by mass; the preparation method is dissolving at room temperature or heating below 60 deg.C for assisting dissolving, and mechanical stirring or magnetic stirring can be used as auxiliary material.
The mass fraction of the paclitaxel @ siliceous body in the step (1) is 0.1-1%.
The particle size of the alpha-tricalcium phosphate is 15-100nm, and the particle size of the paclitaxel @ siliceous body is 100-200 nm; the mixing was done by thoroughly grinding the powder in a dry environment using an agate mortar.
The method comprises the following specific steps:
(1) preparation of a silica body raw material:
adding hexadecylamine and an ethanol solvent into a three-necked bottle, adding 1/2 mol of bromohexadecane after fully dissolving, adding a catalyst of anhydrous sodium carbonate, stopping reaction after refluxing for 120h, and repeatedly refining to obtain dicetylamine; adding dicetylamine and succinic anhydride into dry tetrahydrofuran, reacting for 24 hr, concentrating, dissolving with chloroform, washing with 10% citric acid and saturated sodium chloride, evaporating solvent to obtain crude product, and recrystallizing with acetonitrile to obtain fine powder; reacting the refined product with aminopropyl triethoxysilane under the catalysis of 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) to prepare a silica body crude raw material, and refining by column chromatography to obtain a silica body refined raw material;
(2) preparation of paclitaxel-loaded silica:
dissolving the components obtained in the step (1) with chloroform, removing the solvent by rotary evaporation, adding a water solution into a lipid membrane, performing ultrasonic dispersion, and performing rotary oscillation in a water bath at 60 ℃ to obtain a suspension; extruding the mixture through a carbonate membrane with the aperture of 50nm to obtain a silica body with uniform particle size; during drug loading, dissolving the components with chloroform, performing rotary evaporation to remove the solvent, adding paclitaxel and other drugs, adding a water solution into a lipid membrane, performing ultrasonic dispersion and rotary oscillation in a water bath at 60 ℃ to obtain a suspension, extruding the suspension through a carbonate membrane with the pore size of 50nm to obtain a drug-loaded targeting silica with uniform particle size, and performing freeze drying to obtain solid powder;
(3) preparation of the drug-carrying silica bone cement:
preparing 10% sodium dihydrogen phosphate solution by room temperature dissolution or ultrasonic-assisted dissolution, and optionally mechanical stirring or magnetic stirring;
adding phosphorylated chitosan into the solution according to the formula of the curing solution to prepare a phosphorylated chitosan solution with the mass fraction of 0.01-1%;
adding hydroxypropyl methyl cellulose and gelatin into the sodium phosphate-phosphorylated chitosan solution according to the formula of the curing solution to obtain the final curing solution modified by 0.01-1% of hydroxypropyl methyl cellulose and 0.01-1% of gelatin in mass fraction;
mixing the calcium sulfate bone cement with the paclitaxel-loaded silica body prepared in the step (2) according to the mass ratio of 1000:1, 500:1 and 200:1 or 100:1 by fully grinding the powder in a dry environment by using an agate mortar;
the bone cement powder and the curing liquid are blended according to the required solid-liquid ratio, and the embedded drug-loaded silica plastid calcium phosphate bone cement with proper curing time and better injectability can be obtained.
If the curing solution is not used for a long time, the curing solution is preserved in an environment of 4 ℃ and pre-dissolved before use. The pre-dissolving mode is heating at 37 ℃ or below to make the curing liquid become flowable liquid.
The drug-loaded silica-embedded calcium phosphate bone cement is characterized by being prepared according to any one of the methods.
An application of embedding medicine-carrying silica plastid calcium phosphate bone cement.
The invention has the advantages that:
1. the preparation method is simple, the used raw materials are simple, and the preparation method is suitable for mass production.
2. The developed new drug-loading formula improves the biocompatibility of the original bone cement, and the injectability of the silica calcium phosphate bone cement embedded with the drug-loading is improved by adding paclitaxel @ silica with a thermotherapy effect.
Drawings
1. FIG. 1 is an SEM photograph of the silica vector and paclitaxel @ silica as claimed in examples 1, 2, 3 and 4.
2. FIG. 2 is an SEM photograph of the cured bone cement containing the silica body prepared in example 1.
3. FIG. 3 is a mechanical curve of the bone cement blocks cured in examples 1, 2, 3 and 4.
4. FIG. 4 is a graph showing the comparison between the tumor cell inhibition effect of the heat-producing bone cement and the tumor cell inhibition effect of the ordinary bone cement of example 4.
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
Dispersing alpha-tricalcium phosphate in absolute ethyl alcohol to prepare 40g/L solution, mixing at 400rpm, carrying out liquid phase grinding for 4h, adding 1000:1 of paclitaxel @ silica, adding 0.5% of gelatin, continuing ball milling for 15min in a ball mill, and carrying out rotary evaporation on the obtained solution to obtain powder. Wherein alpha-tricalcium phosphate: paclitaxel @ siliceous body =1000:1
0.1g of phosphorylated chitosan, 0.15g of gelatin and 0.1g of hydroxypropylmethylcellulose were weighed and dissolved in 19.65g of sodium hydrogen phosphate solution to prepare a bone cement solidification solution containing 20% of sodium hydrogen phosphate, 1% of phosphorylated chitosan, 1.5% of gelatin and 1% of hydroxypropylmethylcellulose.
Mixing the bone cement powder and the solidifying liquid according to a solid-liquid ratio of 2-2.5g/mL, and measuring the initial setting time to be 11 min according to a standard ASTM C191.
Example 2
Dispersing alpha-tricalcium phosphate in absolute ethyl alcohol to prepare 40g/L solution, mixing at 400rpm, carrying out liquid phase grinding for 4h, adding 500:1 of paclitaxel @ silica, adding 0.5% of gelatin, continuing ball milling for 15min in a ball mill, and carrying out rotary evaporation on the obtained solution to obtain powder. Wherein alpha-tricalcium phosphate: paclitaxel @ siliceous body =500:1
0.1g of phosphorylated chitosan, 0.15g of gelatin and 0.1g of hydroxypropylmethylcellulose were weighed and dissolved in 19.65g of sodium hydrogen phosphate solution to prepare a bone cement solidification solution containing 20% of sodium hydrogen phosphate, 1% of phosphorylated chitosan, 1.5% of gelatin and 1% of hydroxypropylmethylcellulose.
Mixing the bone cement powder and the solidifying liquid according to a solid-liquid ratio of 2-2.5g/mL, and measuring the initial setting time of 15min according to standard ASTM C191.
Example 3
Dispersing alpha-tricalcium phosphate in absolute ethyl alcohol to prepare 40g/L solution, mixing at 400rpm, carrying out liquid phase grinding for 4h, adding 200:1 of paclitaxel @ silica, adding 0.5% of gelatin, continuing ball milling for 15min in a ball mill, and carrying out rotary evaporation on the obtained solution to obtain powder. Wherein alpha-tricalcium phosphate: paclitaxel @ siliceous body =200:1
0.1g of phosphorylated chitosan, 0.15g of gelatin and 0.1g of hydroxypropylmethylcellulose were weighed and dissolved in 19.65g of sodium hydrogen phosphate solution to prepare a bone cement solidification solution containing 20% of sodium hydrogen phosphate, 1% of phosphorylated chitosan, 1.5% of gelatin and 1% of hydroxypropylmethylcellulose.
Mixing the bone cement powder and the solidifying liquid according to a solid-liquid ratio of 2-2.5g/mL, and measuring the initial setting time of 16 min by referring to the standard ASTM C191.
Example 4
Dispersing alpha-tricalcium phosphate in absolute ethyl alcohol to prepare 40g/L solution, mixing at 400rpm, carrying out liquid phase grinding for 4h, adding 100:1 of paclitaxel @ silica particles into the solution, adding 0.5% of gelatin, continuing ball milling for 15min in a ball mill, and carrying out rotary evaporation on the obtained solution to obtain powder. Wherein alpha-tricalcium phosphate: paclitaxel @ siliceous mass particle =100:1
0.1g of phosphorylated chitosan, 0.15g of gelatin and 0.1g of hydroxypropylmethylcellulose were weighed and dissolved in 19.65g of sodium hydrogen phosphate solution to prepare a bone cement solidification solution containing 20% of sodium hydrogen phosphate, 1% of phosphorylated chitosan, 1.5% of gelatin and 1% of hydroxypropylmethylcellulose.
Mixing the bone cement powder and the solidifying liquid according to a solid-liquid ratio of 2-2.5g/mL, and measuring the initial setting time to be 18min according to a standard ASTM C191.
The prepared bone cement solidified material is shown in figure 2, after the bone cement is solidified, alpha-tricalcium phosphate is subjected to hydration reaction, particles grow into needle shapes in the hydration process, the needle structures are mutually interwoven, the mechanical strength is certain, and the shape and the performance of the bone cement are not influenced on the whole because the silica particles are solidified in the material.
The bone blocks obtained after curing the bone cements of examples 1-4 doped with paclitaxel @ silica are shown in fig. 3. In example 1, the content of silica is very low (one thousandth of the mass fraction). Until the content of the silica in the example 4 is increased to one percent of the mass fraction, the mechanical properties after curing are not reduced compared with those of the blank control group.
The cured bone cement scaffolds of example 4 were placed in culture dishes containing MG osteosarcoma cells, and the cell survival rate was compared for 24 hours, and the results are shown in FIG. 4. The blank group is the bone cement filled with silica, and the observation result shows that no obvious cytotoxicity exists, and the bone cement solidified group filled with paclitaxel @ silica in examples 1-4 shows that the cell survival rate is 92.7% in example 1, 84.4% in example 2, 72.3% in example 3 and 59.3% in example 4. The results indicate that paclitaxel-embedded bulk bone cement has good cancer cell killing efficacy.
Claims (5)
1. The preparation method of the embedded drug-loaded silica plastid calcium phosphate bone cement is characterized by comprising the following steps:
(1) mixing a self-curing component and a heating nano material, wherein the self-curing component is an alpha-tricalcium phosphate material, the heating nano material is paclitaxel @ silicon body, and modified bone cement solid-phase powder is obtained, wherein the alpha-tricalcium phosphate material has a wrapping and carrying effect, and the paclitaxel @ silicon body has an anticancer effect;
(2) the sodium phosphate is used as a main body, and the phosphorylated chitosan, the hydroxypropyl methylcellulose and the gelatin are used as modifiers to prepare the neutral bone cement curing liquid, so that the injectability of the formula is improved;
(3) the bone cement solid-phase powder is mixed with the curing liquid, so that the main component of hydroxyapatite of the cured product is increased, and the paclitaxel @ siliceous body has good degradation capability in organisms;
the mass fraction of sodium phosphate in the curing liquid in the step (2) is 10-20%, the mass fraction of phosphorylated chitosan is 0.01-1%, the mass fraction of hydroxypropyl methyl cellulose is 0.01-1%, and the mass fraction of gelatin is 0.01-1%; the preparation method is dissolving at room temperature or heating below 60 ℃ for assisting dissolving, and mechanical stirring or magnetic stirring can be assisted;
the mass fraction of the paclitaxel @ siliceous body in the step (1) is 0.1-1%;
the particle size of the alpha-tricalcium phosphate is 15-100nm, and the particle size of the paclitaxel @ siliceous body is 100-200 nm; the mixing was done by thoroughly grinding the powder in a dry environment using an agate mortar.
2. The preparation method of the embedded drug-loaded silica plastid calcium phosphate bone cement according to claim 1, which is characterized by comprising the following steps:
(1) preparation of a silica body raw material:
adding hexadecylamine and an ethanol solvent into a three-necked bottle, adding 1/2 mol of bromohexadecane after fully dissolving, adding a catalyst of anhydrous sodium carbonate, stopping reaction after refluxing for 120h, and repeatedly refining to obtain dicetylamine; adding dicetylamine and succinic anhydride into dry tetrahydrofuran, fully reacting for 24h, concentrating, dissolving with chloroform, sequentially washing with 10% citric acid and saturated sodium chloride solution, evaporating solvent to obtain crude product, and recrystallizing with acetonitrile for refining; reacting the refined product with aminopropyl triethoxysilane under the catalysis of 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) to prepare a silica body crude raw material, and refining by column chromatography to obtain a silica body refined raw material;
(2) preparation of paclitaxel-loaded silica:
dissolving the components obtained in the step (1) with chloroform, performing rotary evaporation to remove the solvent, adding paclitaxel, adding water solution into the lipid membrane, performing ultrasonic dispersion and rotary oscillation in a water bath at 60 ℃ to obtain a suspension, extruding the suspension through a carbonate membrane with the pore size of 50nm to obtain a targeting silica body with uniform drug-loaded particle size, and performing freeze drying to obtain solid powder;
(3) preparation of the drug-carrying silica bone cement:
preparing 10% sodium phosphate solution by room temperature dissolution or ultrasonic-assisted dissolution, and mechanical stirring or magnetic stirring;
adding phosphorylated chitosan into the solution according to the formula of the curing solution to prepare a phosphorylated chitosan solution with the mass fraction of 0.01-1%;
adding hydroxypropyl methyl cellulose and gelatin into the sodium phosphate-phosphorylated chitosan solution according to the formula of the curing solution to obtain the final curing solution modified by 0.01-1% of hydroxypropyl methyl cellulose and 0.01-1% of gelatin in mass fraction;
mixing the calcium phosphate bone cement and the paclitaxel-loaded silica gel prepared in the step (2) according to the mass ratio of 1000:1, 500:1 and 200:1 or 100:1 by fully grinding the powder in a dry environment by using an agate mortar;
the bone cement powder and the curing liquid are blended according to the required solid-liquid ratio, and the embedded drug-loaded silica plastid calcium phosphate bone cement with proper curing time and better injectability can be obtained.
3. The method for preparing the calcium phosphate cement with embedded drug-loaded silica body according to claim 2, wherein if the curing fluid is not used for a long time, the curing fluid is preserved in an environment of 4 ℃ and pre-dissolved before being used; the pre-dissolving mode is heating at 37 ℃ or below to make the curing liquid become flowable liquid.
4. An embedded drug-loaded silica-based calcium phosphate cement, prepared according to the method of any one of claims 1 to 3.
5. The use of the embedded drug-loaded silica body calcium phosphate bone cement according to claim 4.
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| BRPI0817237A2 (en) * | 2007-09-28 | 2015-06-16 | Zomanex Llc | Methods and formulations for converting intravenous and injectable drugs into oral dosage forms |
| CN101362066A (en) * | 2008-09-27 | 2009-02-11 | 同济大学 | Preparation method of liposome embedded quantum dots silicon dioxide microspheres and products thereof |
| CN101485904A (en) * | 2009-02-13 | 2009-07-22 | 天津大学 | Injectable calcium sulphate-based sustained-release implantation component containing medicine-carrying particle and application |
| CN102895216A (en) * | 2012-10-24 | 2013-01-30 | 中山大学 | Anti-cancer medicament silicon plastid microcapsule and preparation method thereof |
| CN103585132A (en) * | 2012-10-24 | 2014-02-19 | 中山大学 | Preparation method of paclitaxel silicon plastid microcapsule |
| CN104288833A (en) * | 2014-09-30 | 2015-01-21 | 深圳先进技术研究院 | Composite active bone cement containing sustained release drug-loading nanoparticles and preparation method of bone cement |
| CN106146544A (en) * | 2015-04-28 | 2016-11-23 | 东北林业大学 | A kind of preparation method of silica nodule precursor organosilan |
| CN105251058A (en) * | 2015-11-05 | 2016-01-20 | 上海纳米技术及应用国家工程研究中心有限公司 | Method for preparing drug-loaded injection type calcium sulfate bone cement for promoting bone growth |
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