CN114767879A - Docetaxel malignant tumor targeting microsphere and preparation method and application thereof - Google Patents
Docetaxel malignant tumor targeting microsphere and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses docetaxel malignant tumor targeted microspheres and a preparation method and application thereof, belonging to the technical field of functional materials, wherein the specific preparation method comprises the following steps: (1) preparing blank microspheres; (2) preparing folic acid modified microspheres; (3) docetaxel was loaded. Meanwhile, the invention also discloses docetaxel malignant tumor targeted microspheres prepared by the preparation method and application thereof in preparation of anti-breast cancer drugs. The blank microspheres prepared by the multiple emulsion method have the average particle size of 22.38 mu m, and the cumulative release amount of 72 hours can reach more than 80 percent when the blank microspheres are measured in human plasma. In addition, the preparation method provided by the invention is simple and convenient to popularize and use.
Description
Technical Field
The invention relates to the field of functional polymer materials, in particular to docetaxel malignant tumor targeting microspheres and a preparation method and application thereof.
Background
Cancer seriously harms human health, becomes one of killers of human beings and is the first cause of common death. The incidence of breast cancer in the world is on the rise from the end of the 20 th century and the 70 th century, the development is rapid, the survival quality is poor, the breast cancer is one of malignant tumors with poor treatment effects in all tumors, most of the malignant tumors belong to the late stage, the surgical resection rate is low, the breast cancer is not sensitive to whole-body chemotherapy and radiotherapy, and the whole-body chemotherapy has the defects of poor targeting, poor curative effect, great toxic and side effects and the like.
Docetaxel, also called taxotere, belongs to a taxoid antitumor drug, is suitable for treating locally advanced or metastatic breast cancer, is also suitable for treating locally advanced or metastatic non-small cell lung cancer and ovarian cancer, and even after chemotherapy mainly based on cisplatin fails. The mechanism of action of taxotere is to potentiate tubulin polymerization and inhibit microtubule depolymerization, resulting in the formation of stable nonfunctional microtubule bundles, thus disrupting the mitosis of tumor cells. The taxol is 3 times higher than taxol in intracellular concentration and has long intracellular retention time, which is the important reason why the taxol has greater antitumor activity than taxol in vitro test.
A target drug delivery system belongs to the third-generation drug dosage form, the traditional drug is embedded in a matrix or a carrier, the absorption, the viscosity increasing, the bracket adhesion or the membrane barrier and other effects of the matrix are utilized to improve the drug stability, reduce the peak valley phenomenon of the blood concentration, delay the drug release speed, improve the drug target location, slow the drug absorption, prolong the effect, reduce the toxicity, improve the drug effect and the safety degree, solve the defects of short half-life period, difficult long-term maintenance of the blood concentration, large systemic toxic and side effects, difficult tolerance of patients and the like of the traditional drug, especially the anti-tumor drug, is an important development trend of the current anti-tumor drug research, and can provide a direction for searching a new treatment method.
Therefore, how to provide a docetaxel malignant tumor targeting agent is a technical problem which needs to be solved urgently by those skilled in the art.
Disclosure of Invention
The invention aims to provide a docetaxel malignant tumor targeting preparation as well as a preparation method and application thereof, which aim to solve the problems in the prior art and observe cytotoxicity, targeting property and killing effect on tumor cells through cell experiments.
In order to achieve the purpose, the invention provides the following scheme:
a preparation method of docetaxel malignant tumor targeted microspheres comprises the following steps:
(1) preparing blank microspheres: uniformly mixing Tris buffer solution, polysorbate 20 and PLGA dichloromethane solution to obtain a first multiple emulsion, then pouring the first multiple emulsion into polyvinylpyrrolidone PBS buffer solution to obtain a second multiple emulsion, continuously stirring to remove organic solvent, and then sequentially carrying out centrifugal separation, water washing and freeze drying to obtain blank microspheres;
(2) preparing folic acid modified microspheres: sequentially adding a DMS0 solution of folic acid and a triethylamine catalyst into the blank microsphere dispersion liquid to react for 24 hours in a dark place, separating a product after the reaction is finished, washing the product for 3 times by using a trss buffer solution, and dialyzing the product in deionized water to obtain folic acid modified microspheres;
(3) Docetaxel loading: sequentially adding docetaxel and HCI solutions into folic acid modified microsphere aqueous dispersion, stirring and reacting for 12 hours, and separating a product to obtain the docetaxel malignant tumor targeted microsphere.
Has the beneficial effects that: the invention firstly synthesizes blank microspheres, folic acid is combined on a microsphere carrier in a covalent bond mode, and the blank microspheres are used as the carrier of docetaxel. Then microsphere-folic acid compound MFC containing folic acid is synthesized, and docetaxel is loaded into the hollow cavity structure of MFC to prepare blank microsphere-folic acid-docetaxel compound microsphere, so that the ideal nano drug carrier with targeting property is obtained.
Preferably, the volume ratio of PLGA to dichloromethane in the dichloromethane solution of PLGA in step (1) is 60: 40;
the addition amount ratio of the Tris buffer solution, the polysorbate 20 and the PLGA dichloromethane solution is 100 ml: 100 mg: 80 mL;
the mass fraction of polyvinylpyrrolidone in the PBS buffer solution of polyvinylpyrrolidone is 2%;
the ratio of the addition amount of the first multiple emulsion to the PBS buffer solution of polyvinylpyrrolidone is 20mL:30 mL.
Preferably, the stirring speed in the step (1) is 500r/min, and the stirring time is 2 min; the continuous stirring speed is 1000r/min, and the stirring time is 3 h.
Preferably, the concentration of the DMSO solution of folic acid in the step (2) is 0.031 g/ml;
the solvent of the blank microsphere dispersion liquid is water, and the concentration of the solvent is 0.28 mg/mL;
the volume ratio of the DMS0 solution of folic acid, the triethylamine catalyst and the blank microsphere dispersion liquid is 2: 0.1: 25.
preferably, the reaction time in step (2) is 24h under the condition of avoiding light.
Preferably, the concentration of the HCl solution in the step (3) is 1 mg/ml;
the concentration of the folic acid modified microsphere aqueous dispersion is 0.19 mg/mL.
Preferably, the adding amount ratio of the docetaxel to the folic acid modified microsphere aqueous dispersion is 1: 1;
the volume ratio of the HCl solution to the folic acid modified microspheres is 1: 1.
Preferably, the reaction temperature in the step (3) is 80 ℃, and the stirring speed is 200 r/min.
A docetaxel malignant tumor targeting microsphere prepared by the preparation method.
An application of docetaxel malignant tumor targeting microspheres in the preparation of anti-breast cancer drugs.
The invention discloses the following technical effects: the invention utilizes a multiple emulsion method to prepare blank microspheres, firstly, membrane materials of the microspheres are dissolved in a proper amount of organic solvent, a small amount of aqueous phase solution is added according to a proportion, the W/O emulsion with stable state is obtained by processing with methods such as ultrasound or oscillation, then a large amount of aqueous phase solution is added for the second emulsification treatment to obtain W/O/W emulsion, and the organic solvent is removed by reduced pressure evaporation to obtain microsphere suspension. The blank microspheres prepared by the multiple emulsion method have the average particle size of 22.38 mu m, and the cumulative release amount of 72h can reach over 80 percent when the blank microspheres are measured in human plasma. In addition, the preparation method provided by the invention is simple and convenient to popularize and use.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without inventive exercise.
FIG. 1 is an electron microscope image of docetaxel malignant tumor targeting microspheres obtained in example 1;
FIG. 2 is a graph showing the encapsulation efficiency and drug loading of docetaxel malignant tumor targeting microspheres obtained in example 1 as a function of pH;
FIG. 3 is a graph showing the release profile of docetaxel malignant tumor-targeting microspheres obtained in example 1;
FIG. 4 shows the gene identification of FR of SKBR-3 breast cancer cells;
FIG. 5 is an optical microscope photograph of intracellular distribution of docetaxel malignant tumor-targeting microspheres obtained in example 1;
FIG. 6 is a confocal scanning laser microscope showing the intracellular distribution of docetaxel malignant tumor targeting microspheres obtained in example 1;
FIG. 7 shows MTT cell growth curves after treatment of SKBR-3 breast cancer cells by different methods.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in further detail below.
Example 1
A method for preparing docetaxel malignant tumor targeting preparation specifically comprises the following steps:
(1) buffer solution preparation
Preparing a Tris buffer solution: weighing 12.11g of Tris alkali to be dissolved in 950-970 mL of deionized water, dropwise adding HCl with the concentration of 4mol/L while stirring, measuring the pH value of the solution to the required pH value by using a pH meter, and then adding water to complement to 1L to obtain 0.1mol/L Tris-HCl buffer solution;
preparing a PBS buffer solution: weighing 8.0g NaCl, 0.2g KCl and 1.44g Na2HPO4、0.24g KH2PO4Dissolving in 800mL of distilled water, adjusting the solution to 7.4 by using HCl, and finally adding distilled water to a constant volume of 1L to obtain 0.01mol/L PBS buffer solution;
(2) Preparation of blank microspheres
Taking 100mL of Tris buffer solution, adding 100mg of polysorbate 20, mixing with 80mL of methylene dichloride containing PLGA (the volume ratio of PLGA to methylene dichloride is 60:40V: V), stirring for 2min at 500/min to prepare a W/O/W type first multiple emulsion, pouring 20mL of the first multiple emulsion into 30mL of PBS (pH6.5) solution containing 2% polyvinylpyrrolidone, stirring for 2min at 500/min to prepare a W/O/W type second multiple emulsion, stirring for 3h at room temperature of 1000/min to remove an organic solvent to obtain microspheres, centrifuging, washing with water, and freeze-drying to obtain 2.98g of blank microspheres;
(3) preparation of folic acid modified microspheres
0.062gFA was dissolved in 2m1 DMS0 and stirred for 2 h. The solution is added into a blank microsphere aqueous dispersion with the concentration of 25m1 of 0.28mg/ml (folic acid is greatly excessive relative to the blank microspheres), and after 100uL of triethylamine catalyst is added, the whole reaction system is subjected to light-shielding reaction for 24 hours. After the reaction is finished, separating 2.98g of product, washing for 3 times by using Tris buffer solution with pH9.18, dialyzing in deionized water, and removing unreacted micromolecules to obtain folic acid modified microspheres;
(4) docetaxel Loading
5mg of docetaxel and HCI aqueous solution (1mg/ml) is added into 5mg of folic acid modified microsphere aqueous dispersion with the concentration of 0.19mg/ml (the volume ratio of hydrochloric acid to folic acid modified microsphere aqueous dispersion is 1: 1). The whole reaction system is stirred at a stirring speed of 200r/min at 80 ℃ for 12h, and then 2.66g of product is isolated.
Technical effects
1. Electron micrograph of composite
As shown in FIG. 1, the nanospheres with distinct cavity-like structures can be seen under an electron microscope, wherein the core is FMPM and the shell is IPPAFDCM, and the particle size is about 200 nm.
2. Encapsulation efficiency and drug loading
The encapsulation efficiency is the percentage of the drug carried by the particles in the solution to the total amount of the drug, and is a research index for the utilization rate of the drug. The encapsulation efficiency of the product in the invention is pH-dependent (as shown in FIG. 2), and when the pH value is increased, the encapsulation efficiency is also increased. The encapsulation efficiency is about 50% in an environment with a pH value of 5, and is nearly 100% when the pH value is 8. And at a pH value of about 7.4 suitable for human bodies, the encapsulation rate can reach 95%, and the drug loading (the drug loading refers to the percentage of the drug carried by the particles in the total amount of the particles) at the moment can also reach 50%.
3. Release profile:
the in vitro release rate of the drug microspheres at the pH value of 6 and 7.4 at 37 ℃ is respectively detected. pH values of 6 and 7.4 were chosen because this acid-base environment is approximately similar to the growth environment of human normal and tumor cells. As shown in fig. 3, the release rate of the drug varies with time and is pH dependent, and the release rate in the environment of pH6 is faster than pH7.4, 60% and 40% after lOh, respectively.
4. Identification of human breast cancer SKBR-3 cell FR gene
And detecting the FR gene expression of the SKBR-3 cells by an RT PCR method. As shown in FIG. 4, the upper band of the right lane, 281bp, is p-actin, and serves as a reference; the lower band is 100bp, and is an FR gene band, which is indicated as FR positive. The results showed that SKBR-3 cells highly express FR.
5. The complex is distributed in the cell:
as shown in fig. 5-6, under an optical microscope, the folic acid-free nanocomposites were distributed outside and on the cell membrane of SKBR-3 cells (fig. 5(a) and 5(c)), while the folic acid-containing nanocomposites were distributed mainly inside the cells (fig. 5(b) and 5 (d)); the same phenomenon was observed in the digested SKBR-3 cells (FIGS. 5(e) and 5 (f)).
Since docetaxel is autofluorescent, the distribution can be directly observed under a confocal laser scanning microscope. As shown in fig. 6, the drug-containing nanocomplex is phagocytosed into the cell by the cell in the form of particles, and the nanoparticles are clearly visible inside the cell (fig. 6 (a)); as a control, the docetaxel folate-free nanocomplex alone was not phagocytosed by the cells, and distributed only on the outside and cell membrane of the cells, and no nanoparticles were shown in the form of hollow inside the cells (fig. 6 (b)).
6. Cytotoxicity results:
after SKBR-3 human breast cancer cells are digested from a culture bottle, the cells are inoculated to a 96-well plate after counting, 3000 cells per well are inoculated into 5000 cells, high-sugar DMEM culture solution containing penicillin, streptomycin and 10% FBS is added for culture for 48 hours, and after the cells are successfully attached to the wall, seed microspheres + folic acid, seed microspheres + drugs, seed microspheres + folic acid + drugs and the cells are respectively added for co-culture, and then experiments are carried out.
As shown in fig. 7, on the MTT cell growth curve, it can be seen that the seed microsphere and the seed microsphere folic acid have no inhibitory effect on the growth of SKBR-3 breast cancer cells, while the seed microsphere + drug and the seed microsphere + drug + folic acid all have inhibitory effect on SKBR-3 breast cancer cells, and particularly after 36 hours, the inhibitory effect of the nanocomposite seed microsphere + drug + folic acid on cells is significantly greater than that of the seed microsphere + drug (p < o.o5, n ═ 3).
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.
Claims (10)
1. A preparation method of docetaxel malignant tumor targeted microspheres is characterized by comprising the following steps:
(1) preparing blank microspheres: uniformly mixing Tris buffer solution, polysorbate 20 and PLGA dichloromethane solution to obtain a first multiple emulsion, then pouring the first multiple emulsion into polyvinylpyrrolidone PBS buffer solution to obtain a second multiple emulsion, continuously stirring to remove organic solvent, and then sequentially carrying out centrifugal separation, water washing and freeze drying to obtain blank microspheres;
(2) preparing folic acid modified microspheres: sequentially adding a DMS0 solution of folic acid and a triethylamine catalyst into the blank microsphere dispersion liquid to react for 24 hours in a dark place, separating a product after the reaction is finished, washing the product for 3 times by using a trss buffer solution, and dialyzing the product in deionized water to obtain folic acid modified microspheres;
(3) loading docetaxel: adding docetaxel and HCI solution into folic acid modified microsphere aqueous dispersion in sequence, stirring and reacting for 12h, and separating the product to obtain the docetaxel malignant tumor targeted microsphere.
2. The method for preparing docetaxel malignant tumor targeting microspheres according to claim 1, wherein the volume ratio of PLGA to dichloromethane in the dichloromethane solution of PLGA in the step (1) is 60: 40;
The addition amount ratio of the Tris buffer solution, the polysorbate 20 and the PLGA dichloromethane solution is 100 ml: 100 mg: 80 mL;
the mass fraction of polyvinylpyrrolidone in the PBS buffer solution of polyvinylpyrrolidone is 2%;
the ratio of the addition amount of the first multiple emulsion to the PBS buffer solution of polyvinylpyrrolidone is 20mL:30 mL.
3. The method for preparing docetaxel malignant tumor targeted microspheres according to claim 1, wherein the stirring speed in the step (1) is 500r/min, and the stirring time is 2 min; the continuous stirring speed is 1000r/min, and the stirring time is 3 h.
4. The method of claim 1, wherein the concentration of the DMSO solution of folic acid in the step (2) is 0.031 g/ml;
the concentration of the blank microsphere dispersion liquid is 0.28 mg/mL;
the volume ratio of the DMS0 solution of folic acid, the triethylamine catalyst and the blank microsphere dispersion liquid is 2: 0.1: 25.
5. the method for preparing docetaxel malignant tumor targeted microspheres of claim 4, wherein the light-shielding reaction time in the step (2) is 24 h.
6. The method for preparing docetaxel malignant tumor targeted microspheres of claim 1, wherein the concentration of the HCl solution in the step (3) is 1 mg/ml;
The concentration of the folic acid modified microsphere aqueous dispersion is 0.19 mg/mL.
7. The method for preparing docetaxel malignant tumor targeted microspheres according to claim 6, wherein the adding amount ratio of the docetaxel to the folic acid modified microsphere aqueous dispersion is 1: 1;
the volume ratio of the HCl solution to the folic acid modified microspheres is 1: 1.
8. The method for preparing docetaxel malignant tumor targeting microspheres as claimed in claim 1, wherein the reaction temperature in the step (3) is 80 ℃ and the stirring speed is 200 r/min.
9. The docetaxel malignant tumor targeting microsphere prepared by the method for preparing the docetaxel malignant tumor targeting microsphere as claimed in any one of claims 1 to 8.
10. The use of the docetaxel malignant tumor targeted microsphere of claim 9 in the preparation of an anti-breast cancer medicament.
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| US20100166872A1 (en) * | 2005-10-21 | 2010-07-01 | Amarjit Singh | Novel improved compositions for cancer therapy |
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| US20100166872A1 (en) * | 2005-10-21 | 2010-07-01 | Amarjit Singh | Novel improved compositions for cancer therapy |
| CN101283976A (en) * | 2008-05-30 | 2008-10-15 | 济南基福医药科技有限公司 | Anticancer sustained-release gel injection containing taxone medicine |
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