CN114767714B - Nanometer preparation of alkynyl-modified sorafenib derivative and silver wrapped by pore material, preparation method and application thereof - Google Patents
Nanometer preparation of alkynyl-modified sorafenib derivative and silver wrapped by pore material, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a nano preparation of an alkynyl modified sorafenib derivative and silver coated by a pore material, a preparation method and application thereof, wherein the size of the nano preparation is 80-120nm; the pore material is ZIF-8; the nano preparation comprises ZIF-8 pore materials, alkynyl modified sorafenib derivatives and nano silver; in the nano preparation, the mass percentage of the alkynyl modified sorafenib derivative is 7.3-7.7%. The nano preparation prepared by the invention has good acid response targeting release function; the nano preparation prepared by the invention comprises the alkynyl modified sorafenib derivative and silver ions, and has good synergistic anti-tumor effect.
Description
Technical Field
The invention relates to a composite nano preparation, in particular to a nano preparation of an alkynyl modified sorafenib derivative and silver coated by a pore material, a preparation method and application thereof, and belongs to the technical field of nano preparations.
Background
Liver cancer is one of the most common malignant tumors in clinic. Surgical excision of tumor tissue is the most effective means of treating early liver cancer. However, most liver cancer patients are in middle and late stages when they are diagnosed, and no surgical treatment means can be adopted. Therefore, the chemical drug treatment mode is the first choice for most liver cancer patients. Although the traditional chemotherapy can kill tumor cells to a certain extent, significant side effects of the medicines bring great pain to patients, and the chemotherapy medicines can kill normal liver cells at the same time, so that the life cycle of the patients cannot be prolonged obviously in most cases. Therefore, the exploration of effective medicaments for treating liver cancer with small side effects is a difficult problem to be solved in the current pharmaceutical chemistry field.
In clinical treatment of liver cancer, sorafenib is a targeted drug approved by many countries for advanced liver cancer. However, earlier studies indicate that sorafenib only has a better tumor inhibition effect on about 1/3 of liver cancer patients, and does not significantly increase the survival time of the patients. Therefore, how to reduce the side effects of sorafenib and achieve targeted sustained release of drug molecules in vivo is an urgent problem to be solved.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a nano preparation of a sorafenib derivative modified by alkynyl and silver coated by a pore material, a preparation method and application thereof, and the nano preparation realizes targeted slow release in vivo, has high release rate of medicinal components and strong killing capacity on target cells.
In order to solve the technical problems, the invention adopts the following technical scheme:
a nano preparation of an alkynyl modified sorafenib derivative and silver, wherein the nano preparation is coated with a pore material, and the size of the nano preparation is 80-120nm;
the pore material is ZIF-8;
the nano preparation comprises ZIF-8 pore materials, alkynyl modified sorafenib derivatives and nano silver;
in the nano preparation, the mass percentage of the alkynyl modified sorafenib derivative is 7.3-7.7%.
The structural formula of the alkynyl modified sorafenib derivative is as follows:
the preparation method comprises the steps of preparing ZIF-8 coated alkynyl modified sorafenib derivatives and adsorbing silver ions.
In the ZIF-8 wrapped alkynyl modified sorafenib derivative, the mass percentage of the alkynyl modified sorafenib derivative is 12.4-12.8%.
The preparation method of the ZIF-8-coated alkynyl modified sorafenib derivative comprises the following steps: uniformly stirring zinc nitrate, 2-methylimidazole and deionized water according to a molar ratio of 1:24-26:695-705 at room temperature to obtain white emulsion; adding an alkynyl modified sorafenib derivative into the prepared emulsion, and stirring uniformly to obtain a suspension; carrying out hydrothermal reaction on the prepared suspension for 1.4-1.6 hours at 128-132 ℃, cooling, centrifuging, washing with ethanol solution, and drying to obtain white solid, namely the ZIF-8 coated alkynyl modified sorafenib derivative.
The mole ratio of the alkynyl modified sorafenib derivative to the sum of the mole numbers of zinc nitrate, 2-methylimidazole and deionized water is 1:5.4-5.6.
The preparation method comprises the steps of adsorbing silver ions, dispersing ZIF-8 coated alkynyl modified sorafenib derivatives in methanol solution of silver nitrate, controlling stirring speed to be 380-420 revolutions per minute, stirring for 5.8-6.2 hours, centrifuging, washing with ethanol solution, and drying to obtain white powder, namely the nano preparation of the porous material coated alkynyl modified sorafenib derivatives and silver.
The molar concentration of the silver nitrate in the methanol solution of the silver nitrate is 0.024-0.026mol/L; the mass volume ratio of the ZIF-8 coated alkynyl modified sorafenib derivative to the silver nitrate methanol solution is 5 mg/0.8-1.2 mL.
The application of the nano preparation in preparing medicaments for treating liver cancer.
The invention successfully prepares the Sorafenib silver nano preparation wrapped by the ZIF-8 pore material, and researches the targeted antitumor activity of the preparation: firstly, carrying out alkynyl modification on sorafenib antitumor drug, wrapping the modified sorafenib derivative in ZIF-8 pore canal material to form host-guest composite material ASOR@ZIF-8, further immersing the ASOR@ZIF-8 composite material in 0.125 mol/L silver salt solution, and introducing silver ions into ZIF-8 pore canal through strong interaction of silver ions and alkynyl to prepare ASOR-Ag containing silver clusters inside x ZIF-8 composite nano preparation.
ZIF-8 is a porous inorganic-organic hybrid material with tetrahedral structural units through self-assembly reaction of zinc ions and dimethyl imidazole organic ligands, and has low toxicity, pore structure, higher surface area and good thermal stability. In addition, the ZIF-8 material with certain nano size can be decomposed under the specific pH condition, so that the controllable release function can be realized.
Compared with the prior art, the invention has the following beneficial effects:
(1) The nano preparation ASOR-Ag prepared by the invention x ZIF-8 has good acid response targeting release function, which indicates that the material can be well released at the tumor site. The alkyne-modified sorafenib derivative in phosphate buffer solution at ph5.5 can be well released from the composite material with increasing reaction time, and the release rate can reach about 83% after 36 hours.
(2) The nano preparation ASOR-Ag prepared by the invention x The @ ZIF-8 contains the alkynyl modified sorafenib derivative and silver ions, and has good synergistic anti-tumor effect; ASOR-Ag x HepG2 cell viability of group @ ZIF-8, 24 h, 48 h, 72 h was 75%, 56%, 34%, respectively.
Drawings
FIG. 1 is a structural formula of an alkynyl-modified sorafenib derivative prepared according to the invention;
FIG. 2 is an infrared spectrum of an alkynyl-modified sorafenib derivative and a sorafenib drug molecule prepared by the invention;
FIG. 3 is a nuclear magnetic hydrogen spectrum of an alkynyl-modified sorafenib derivative prepared according to the invention;
FIG. 4 is a transmission electron microscope image of the ZIF-8 coated alkynyl modified sorafenib derivative ASOR@ZIF-8 of the invention;
FIG. 5 ASOR-Ag prepared according to the present invention x A transmission electron microscope image of @ ZIF-8;
FIG. 6 ASOR-Ag prepared according to the present invention x In vitro release profile of @ ZIF-8 at different pH conditions;
FIG. 7 is a schematic diagram of ZIF-8, ASOR, ASOR@ZIF-8 and ASOR-Ag x Survival line plot of the @ ZIF-8 group HepG2 cells.
Detailed Description
Example 1
Synthesis of alkynyl modified sorafenib derivatives:
(1) Preparation of carboxylic acid intermediates
Sorafenib (3 g) and NaOH (3.87 g) are dissolved in 20 mL anhydrous ethanol solution, N 2 The protection is carried out,reflux reaction 8 h at 80 ℃. After the reaction is finished, the organic solvent is removed by low pressure spin, diluted hydrochloric acid (2 mol/L) is added to neutralize excessive alkali, the pH is regulated to be about 5, the color of the reaction solution is changed from blue to light pink, gray solid is separated out after the reaction is continued for 5 hours, the solution is filtered by a Buchner funnel, and is washed by a small amount of distilled water, and then the solution is dried in a vacuum drying box at 40 o Drying overnight at C afforded 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenoxy) picolinic acid (abbreviated as carboxylic acid intermediate) as a gray solid powder.
(2) Preparation of acid chloride intermediates
At N 2 Under protection, dissolve in CH at 0deg.C 2 Cl 2 Oxalyl chloride (381 μl) in (3 mL) was added dropwise to CH of the above carboxylic acid intermediate (1.35 g) 2 Cl 2 (20) mL) the solution was stirred and the colour gradually turned yellow, then a drop of DMF (0.025 mL) was added. The reaction mixture was stirred at 10 ℃ for 4 hours at a stirring rate of 120 rpm and concentrated under reduced pressure to give 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenoxy) pyridine carbonyl chloride (abbreviated as acid chloride intermediate) as a yellow solid.
(3) To prepare the alkynyl modified sorafenib derivative
Then, the acid chloride intermediate was mixed with triethylamine (3 mL) at 0℃for 10 minutes, followed by dropwise addition of CH of 4-methyl-N- (prop-2-yn-1-yl) benzene-1-sulfonamide (940 mg) 2 Cl 2 (5 mL) solution, stirring for 20 minutes. The temperature of the reaction mixture was then raised to 25 ℃ and stirring was continued for 10 h, with a stirring rate of 120 revolutions per minute. Then HCl aqueous solution (20 mL,1.2 mol/L) was added to neutralize the alkali in the system, the organic phase was collected, and the aqueous layer was treated with CH 2 Cl 2 Extraction was twice (30 mL each time). All organic extracts were collected, washed with saturated NaCl solution, dried (Na 2 SO 4 ) Dewatering and evaporating the solvent under reduced pressure to give a white solid as the final product, compound 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenoxy) -N- (prop-2-yn-1-yl) -N-p-toluenesulfonylpyridinium amide (alkynyl modified sorafenib derivative, molecular weight=642 g/mol), structural formula of which is shown in fig. 1.
The infrared spectrum of the alkynyl modified sorafenib derivative and the sorafenib drug molecule prepared by the invention is shown in figure 2.
Analysis shows that the infrared spectrum of the sorafenib derivative retains infrared characteristic absorption peaks of most of functional groups in the main structure of the sorafenib drug molecule, and the infrared characteristic absorption peaks are also found in 3129 and 2121 cm -1 The characteristic peak of telescopic vibration of alkyne hydrogen and alkyne respectively appears, and furthermore, at 1361 and 1361 cm -1 And 1221 cm -1 Asymmetric and symmetric stretching vibration characteristic peaks of s=o in the sulfonyl group also appear. In addition, sorafenib drug molecules are located at 3303 cm -1 And 3342 cm -1 The disappearance of the two stretching peaks also demonstrates that the N-H bond is replaced by a p-toluenesulfonyl (Ts) protecting group, as in 3301 cm -1 The single peak appearing at this point is then the characteristic absorption peak of C-NH-C. The above results demonstrate successful synthesis of alkynyl-modified sorafenib derivatives.
The nuclear magnetic hydrogen spectrum of the alkynyl modified sorafenib derivative prepared by the invention is shown in figure 3. The peaks at 2.412 ppm in FIG. 3 are assigned to methyl protons, 2.190 and 2.194 ppm to alkynyl protons, 5.082 and 5.086 ppm to methylene protons, 7.386 ppm and 7.372 ppm to the two imino protons, respectively, and the other peaks to aromatic protons. Nuclear magnetic hydrogen spectrum analysis shows that the alkynyl modified sorafenib derivative is successfully prepared.
Example 2 preparation method of ZIF-8 coated alkynyl-modified Sorafenib derivative (ASOR@ZIF-8)
The preparation method of the ASOR@ZIF-8 comprises the following steps:
uniformly stirring zinc nitrate, 2-methylimidazole and deionized water according to a molar ratio of 1:25:700 at room temperature to obtain white emulsion; adding the alkynyl modified sorafenib derivative prepared in the embodiment 1 into the prepared emulsion, and continuously stirring until the mixture is uniform to obtain a suspension; transferring the prepared suspension into a hydrothermal synthesis reaction kettle, carrying out hydrothermal reaction at 130 ℃ for 1.5. 1.5 h, cooling, centrifuging, washing with ethanol solution, and drying to obtain white solid, namely ASOR@ZIF-8, wherein the mass percentage of ASOR is 12.6% as shown by element analysis.
The mole ratio of the alkynyl modified sorafenib derivative to the sum of the mole numbers of zinc nitrate, 2-methylimidazole and deionized water is 1:5.5;
analysis of a transmission electron microscope image (figure 4) of the ASOR@ZIF-8 shows that the ASOR@ZIF-8 still maintains the icosahedron structure of the single ZIF-8, but the edges and corners of the polyhedron structure are slightly blurred, and the size is slightly larger than that of the ZIF-8 (75-110 nm), and is about 80-120 nm.
Example 3 ZIF-8 coated alkynyl-modified Sorafenib derivatives and silver nanoformulations (ASOR-Ag for short x Preparation method of @ ZIF-8)
The ASOR-Ag x The preparation method of @ ZIF-8 comprises the following steps: 50mg of ASOR@ZIF-8 nanomaterial prepared in example 2 above is dispersed in 10mL of 0.025 mol/L silver nitrate methanol solution, stirred for reaction 6h (stirring speed 400 rpm), centrifugally separated (10000 rpm), washed with ethanol solution and dried to obtain white powder, namely ASOR-Ag x The elemental analysis shows that the mass percentage of ASOR is 7.5 percent.
ASOR-Ag x Analysis of the transmission electron micrograph of @ ZIF-8 (FIG. 5) showed ASOR-Ag x Although the general configuration of ZIF-8 is maintained, the edges and corners of the polyhedral structure are completely blurred, the size is equivalent to ASOR@ZIF-8 (80-120 nm), and the existence of Ag nano particles can be obviously observed in the ZIF-8 framework.
Example 4 in vitro drug Release experiment
The in vitro drug release experiment method comprises the following steps: 16.1 mg ASOR,127.8 mg ASOR@ZIF-8 and 214.7 mg ASOR-Ag are respectively weighed x ZIF-8 powder was dispersed in a DMSO solution of 5 mL and sonicated for 5 minutes to give 0.005mol/L (calculated as ASOR) of DMSO dispersion, respectively. 0.1. 0.1 mL of the DMSO dispersion is added into 10mL of 0.01 mol/L phosphate buffer with pH of 5.5 or pH of 7.4 for drug slow release experimental study.
FIG. 6 shows the in vitro release profile of alkynyl modified sorafenib derivatives in phosphate buffers pH5.5 and pH7.4, wherein pH5.5 and pH7.4 represent the slightly acidic tumor microenvironment and normal tissue physiological environment, respectively. The results show that the alkynyl modified sorafenib derivative in phosphate buffer solution ph5.5 can be well released from the composite material with increasing reaction time, and the release rate can reach about 83% after 36 hours; the release rate of the alkynyl modified sorafenib derivative in the pH7.4 solution is relatively low, the sorafenib derivative tends to be flat in about 36 hours, and only about 38% of the alkynyl modified sorafenib is finally released from the composite material, so that the nano medicament prepared by the invention has a good acid response targeted release function, and the material can be well released at a tumor site.
EXAMPLE 5 liver tumor cell growth inhibition experiment
The experimental method for inhibiting the growth of liver cancer cells comprises the following steps: hepG2 cells were cultured in 96-well plates (2X 10) 3 Cells/well) were exponentially grown, 5×10 as determined by Cell Counting Kit method -5 mol/L ASOR-Ag x Killing effect of ZIF-8 nano preparation DMSO dispersion and control sample (ZIF-8, ASOR or ASOR@ZIF-8) on human hepatoma cell HepG 2.
The preparation method of the blank carrier ZIF-8 comprises the following steps: on the basis of example 2, the blank vector ZIF-8 is obtained without adding the alkynyl modified sorafenib derivative.
As can be seen from the analysis of FIG. 7, ASOR-Ag x The inhibition capacity of the @ ZIF-8 group on HepG2 cells is obviously better than that of other control groups, and the cell survival rates of 24 h, 48 h and 72 h are 75%, 56% and 34% respectively, so that the inhibition effect on the growth of liver tumor cells is good. The cell survival rates of 24 h, 48 h and 72 h of the single ZIF-8 vector are 97%, 96% and 95% respectively, and almost no inhibition effect is caused on HepG2, so that ZIF-8 is a low-toxicity porous vector; the ASOR has no obvious inhibition effect on HepG2 cells at lower experimental concentration, and the cell survival rates of 24 h, 48 h and 72 h are 91%, 89% and 85% respectively; the introduction of the pore material ZIF-8 enhances the inhibition effect of ASOR@ZIF-8 to a certain extent, and the cell survival rates of 24 h, 48 h and 72 h are 87%, 85% and 73% respectively, but relative to ASOR-Ag x Inhibition by @ ZIF-8 nanoformulationsThe effect is not obvious.
Claims (8)
1. A nano preparation of an alkynyl modified sorafenib derivative and silver coated by a pore material, which is characterized in that: the size of the nano preparation is 80-120nm;
the pore material is ZIF-8;
the nano preparation comprises ZIF-8 pore materials, alkynyl modified sorafenib derivatives and nano silver;
in the nano preparation, the mass percentage of the alkynyl modified sorafenib derivative is 7.3-7.7%;
the structural formula of the alkynyl modified sorafenib derivative is as follows:
2. the method for preparing the nano-preparation of claim 1, which is characterized in that: the preparation method comprises the steps of preparing ZIF-8 coated alkynyl modified sorafenib derivatives and adsorbing silver ions.
3. The preparation method according to claim 2, characterized in that: in the ZIF-8 wrapped alkynyl modified sorafenib derivative, the mass percentage of the alkynyl modified sorafenib derivative is 12.4-12.8%.
4. The preparation method according to claim 2, characterized in that: the preparation method of the ZIF-8-coated alkynyl modified sorafenib derivative comprises the following steps: uniformly stirring zinc nitrate, 2-methylimidazole and deionized water according to a molar ratio of 1:24-26:695-705 at room temperature to obtain white emulsion; adding an alkynyl modified sorafenib derivative into the prepared emulsion, and stirring uniformly to obtain a suspension; carrying out hydrothermal reaction on the prepared suspension for 1.4-1.6 hours at 128-132 ℃, cooling, centrifuging, washing with ethanol solution, and drying to obtain white solid, namely the ZIF-8 coated alkynyl modified sorafenib derivative.
5. The method of manufacturing according to claim 4, wherein: the mole ratio of the alkynyl modified sorafenib derivative to the sum of the mole numbers of zinc nitrate, 2-methylimidazole and deionized water is 1:5.4-5.6.
6. The preparation method according to claim 2, characterized in that: the preparation method comprises the steps of adsorbing silver ions, dispersing ZIF-8 coated alkynyl modified sorafenib derivatives in methanol solution of silver nitrate, controlling stirring speed to be 380-420 revolutions per minute, stirring for 5.8-6.2 hours, centrifuging, washing with ethanol solution, and drying to obtain white powder, namely the nano preparation of the porous material coated alkynyl modified sorafenib derivatives and silver.
7. The method of manufacturing according to claim 6, wherein: the molar concentration of the silver nitrate in the methanol solution of the silver nitrate is 0.024-0.026mol/L; the mass volume ratio of the ZIF-8 coated alkynyl modified sorafenib derivative to the silver nitrate methanol solution is 5 mg/0.8-1.2 mL.
8. The use of the nano-preparation of claim 1 in the preparation of a medicament for treating liver cancer.
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