CN110548173A - preparation method of chemoembolization microsphere with microwave sensitization effect - Google Patents
preparation method of chemoembolization microsphere with microwave sensitization effect Download PDFInfo
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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Abstract
the invention relates to a preparation method of chemoembolization microspheres with microwave sensitization effect, which comprises the steps of dispersing 8-12g of polyethanol microspheres in pure water, adding a hydroxyl activator to activate alcoholic hydroxyl groups of the polyethanol microspheres, wherein the mass ratio of tosyl chloride, 4-Dimethylaminopyridine (DMAP), triethylamine Et3N and the hydroxyl activator is 1:1.0-1.5:0.2-0.5:1.5, stirring at room temperature overnight, washing the polyethanol microspheres for a plurality of times by using the pure water, reacting the microspheres and the microwave sensitization compound at 60 ℃ for 10 hours, and finally dispersing the microspheres in the pure water again to absorb water and swell to obtain the chemoembolization microspheres with the microwave sensitization effect. The chemoembolization porous microsphere with the microwave sensitization effect provided by the invention is simple in preparation method and easy to operate in steps, and the prepared product has good microwave sensitization and temperature rise and tumor vascular embolization functions, is regular and spherical, and has high porosity, narrow particle size distribution and controllable particle size.
Description
Technical Field
The invention relates to a preparation method of chemoembolization microspheres with microwave sensitization efficacy, belonging to the technical field of drug synthesis.
Background
Liver cancer is currently the second cancer of worldwide incidence. Patients with early stage liver cancer usually have no adverse reactions because liver cancer tissues lack sufficient nerves. By the time symptoms of the disease are present, the patient is generally at an intermediate or advanced stage. And the disease of liver cancer progresses rapidly, so the death rate of liver cancer is very high. Liver cancer has become one of the most serious conditions that endanger human health. The number of new liver cell liver cancer cases per year is more than 85 ten thousand worldwide, and more than 55 percent of the cases are in China. Primary liver cancer is the fourth most common malignant tumor in China and the third leading cause of tumor death. About 47 ten thousand new HCC cases are newly added in China every year. In the death ranking of main malignant tumors in 2018 in China, the death ranking of liver cancer causes male is the second, and the death ranking of liver cancer causes female is the third. Because the liver cancer is difficult to diagnose and discover in time, the primary liver cancer which can be really treated by operation is less than 10 percent, and the metastatic liver cancer is more less than 5 percent. Aiming at the liver cancer patients discovered in the early stage, tumor cells with the diameter of less than 3 cm can be killed by a minimally invasive operation, such as microwave ablation and radio frequency ablation. While in the middle and late stage liver cancer patients with tumors larger than 3 cm, a palliative treatment mode, namely, arterial embolization chemotherapy (TACE) is needed.
Microwave ablation has become increasingly accepted in recent years as an emerging curative treatment for cancer. The microwave thermotherapy converts electromagnetic wave energy into heat energy, and kills tumor cells by heat ablation. Under the guidance of imaging equipment, the implanted microwave antenna is inserted into the tumor body by microwave ablation, ions in tissue cells around the microwave antenna are released to vibrate and mutually impact and rub, and the local temperature of over 60 ℃ can be generated in a short time, so that the purpose of treating the tumor is achieved. The cancer cells are thermolabile, and can be inactivated at a temperature of more than 42 ℃, and the tumor tissue can undergo irreversible coagulation necrosis at a high temperature of more than 60 ℃. Because the method has the advantages of simplicity, convenience, no wound or minimal wound, high accuracy, good safety, relatively low price and the like, the thermal ablation technology is generally concerned in clinic, optimizes the liver cancer treatment mode to a certain extent, and has good medical application potential. However, damage to normal tissue is also sometimes inevitable during treatment. In order to realize efficient and targeted treatment of tumors, researchers are urgently needed to research a microwave sensitizing material which can be applied to clinic. The material needs to satisfy the following conditions: the microwave hyperthermia treatment method has the advantages of good biocompatibility, good microwave sensitization effect, specific enrichment at tumor positions and reduction of side effects of microwave hyperthermia on normal tissues.
Transcatheter chemoembolization (TACE) is a palliative treatment for middle and late stage liver cancer, and embolization microspheres are essential materials. The embolizing material has developed rapidly since the first use in interventional therapy in the last 70 th century, and products currently on the market include gelatin sponges, polyvinyl alcohol particles, embolizing microspheres, and the like. Wherein, the gelatin sponge and the polyvinyl alcohol particles have irregular appearance and poor elastic deformation, so that the embolism effect is not ideal; the embolism microsphere has a perfect spherical shape, a smooth surface and good elastic deformation recovery capability, so that a better treatment effect is achieved, and the embolism microsphere gradually occupies the main stream position of the interventional embolism material.
A Chinese patent CN201611146116.1, published by the research of physicochemical technology of Chinese academy of sciences, discloses the application of chemoembolization porous microspheres with microwave sensitization function in the preparation of drugs or preparations for treating tumors, wherein the adsorbates of the microspheres are inorganic salts and chemotherapeutics, the skeleton of the microspheres is polylactic glycolic acid, the diameter of the microspheres is 20700 mu m, and the specific surface is more than 10m 2/g.
Disclosure of Invention
The invention aims to solve the problems and provides a preparation method of chemoembolization microspheres with microwave sensitization effect, which is simple.
the invention adopts the following technical scheme: a preparation method of chemoembolization microspheres with microwave sensitization efficacy is characterized in that: the method comprises the following steps:
(1) Dispersing 8-12g of the polyethanol microsphere in pure water, adding a hydroxyl activating agent to activate alcoholic hydroxyl of the polyethanol microsphere, wherein the mass ratio of tosyl chloride, 4-dimethylaminopyridine DMAP, triethylamine Et3N and the hydroxyl activating agent is 1:1.0-1.5:0.2-0.5:1.5, stirring overnight at room temperature, washing the polyethanol microsphere for a plurality of times by adopting the pure water, wherein the 4-dimethylaminopyridine DMAP and Et3N are used as alkaline catalysts and can absorb HCl generated by the reaction, thereby realizing the balance of the activation reaction;
(2) Dehydrating the microspheres with acetone, wherein the addition amount of the acetone is 40-60 times of the volume of the microspheres, dispersing the microspheres in tetrahydrofuran, and adding 0.5-1.0g of a microwave sensitization compound;
(3) Reacting the microspheres and the microwave sensitization compound in water bath at 60-65 ℃ for 10 hours, and washing the microspheres for several times by adopting tetrahydrofuran;
(4) Dispersing the microspheres in pure water again, swelling for 2-3h, washing with pure water for several times, and dispersing in physiological saline.
Further, the particle size of the polyethylene microspheres in the step (1) is 100-500 microns.
Further, the microwave sensitization compound is a compound with phenolic hydroxyl.
Further, the microwave sensitization compound comprises:
further, the hydroxyl activating agent is tosyl chloride.
further, the microwave sensitization compound in the step (3) is subjected to carboxyl protection treatment before reaction.
the chemoembolization porous microsphere with the microwave sensitization effect provided by the invention is simple in preparation method and easy to operate in steps, and the prepared product has good microwave sensitization and temperature rise and tumor vascular embolization functions, is regular and spherical, and has high porosity, narrow particle size distribution and controllable particle size.
Drawings
FIG. 1 is a TEM image of the chemoembolization porous microsphere with microwave sensitization effect prepared in example 2 of the present invention.
Detailed Description
the invention will now be further described with reference to specific examples.
The microwave sensitization compound in the embodiment of the invention adopts the following substances, and the chemical formula is as follows:
The synthetic route is as follows: protecting 3-phenolic hydroxyl of estrone by adopting a node group, reducing 17-carbonyl by KBH4 to obtain estradiol-3-benzyl ether 1, generating benzyl lactate by using carboxyl of lactic acid through potassium salt and benzyl chloride, generating succinic acid- (2-benzyl lactate) monoester 2 by using hydroxyl and succinic anhydride in organic base (such as pyridine), condensing 1 and 2 in DCC/DMAP/CH2Cl2 to obtain benzyl-protected sensitizer succinic acid-3-benzyl-17 beta-estradiol-2- (benzyl lactate) ester 3, and then reducing, hydrogenating and debenzylating by 3 to obtain microwave sensitizing compound I.
The first embodiment is as follows:
Dispersing 8g of 300-micron polyvinyl alcohol microspheres with the particle size of 100-inch sodium chloride in pure water, adding a hydroxyl activating agent to activate alcoholic hydroxyl groups of the polyvinyl alcohol microspheres, wherein the mass ratio of tosyl chloride, 4-dimethylaminopyridine DMAP, triethylamine Et3N to the hydroxyl activating agent is 1:1.2:0.3:1.5, stirring overnight at room temperature, washing for 5 times with the pure water, dehydrating the microspheres with acetone with the volume of 40 times of the microspheres, dispersing the microspheres in tetrahydrofuran, adding 0.5g of a microwave sensitization compound, reacting for 10 hours in a water bath at 60 ℃, washing the microspheres for 5 times with the tetrahydrofuran, dispersing the microspheres in the pure water again to absorb water for 2 hours, washing for 5 times with the pure water, and dispersing the microspheres in physiological saline.
Example two:
10g of 500-micron-sized ethanol microspheres with the particle size of 300-5 are dispersed in pure water, hydroxyl activating agent is added to activate the alcoholic hydroxyl groups of the ethanol microspheres, wherein the mass ratio of the tosyl chloride, the 4-dimethylaminopyridine DMAP, the triethylamine Et3N and the hydroxyl activating agent is 1:1.2:0.3:1.5, and the mixture is stirred at room temperature overnight. Washed 5 times with pure water. And then, dehydrating the microspheres by using acetone with the volume 50 times that of the microspheres, dispersing the microspheres in tetrahydrofuran, adding 1.0g of a microwave sensitization compound, reacting for 10 hours in a water bath at 60 ℃, and then washing the microspheres for 5 times by using the tetrahydrofuran. And then the microspheres are dispersed in pure water again to absorb water and swell for 3 hours. Washing with pure water for 5 times, and dispersing in physiological saline. As can be seen from the TEM image in FIG 1, the obtained chemoembolization porous microspheres with microwave sensitization efficacy are regular spheres, and have high porosity, narrow particle size distribution and 73-145 micrometers particle size range.
Example three:
dispersing 12g of 300-micron polyvinyl alcohol microspheres with the particle size of 100-inch sodium chloride in pure water, adding a hydroxyl activating agent to activate alcoholic hydroxyl groups of the polyvinyl alcohol microspheres, wherein the mass ratio of tosyl chloride, 4-dimethylaminopyridine DMAP, triethylamine Et3N to the hydroxyl activating agent is 1:1.2:0.3:1.5, stirring overnight at room temperature, washing for 5 times with the pure water, dehydrating the microspheres with acetone, dispersing the microspheres in tetrahydrofuran by using a microsphere volume of 60 times, adding 0.5g of a microwave sensitization compound I, reacting for 12 hours in a water bath at 65 ℃, washing the microspheres for 5 times with the tetrahydrofuran, dispersing the microspheres in the pure water again to absorb water and swell for 3 hours, washing for 5 times with the pure water, and dispersing the microspheres in physiological saline.
Claims (6)
1. A preparation method of chemoembolization microspheres with microwave sensitization efficacy is characterized in that: comprises the following steps
(1) dispersing 8-12g of the polyethanol microspheres in pure water, adding a hydroxyl activating agent to activate alcoholic hydroxyl groups of the polyethanol microspheres, wherein the mass ratio of tosyl chloride, 4-Dimethylaminopyridine (DMAP), triethylamine (Et 3N) and the hydroxyl activating agent is 1:1.0-1.5:0.2-0.5:1.5, stirring at room temperature overnight, and washing the polyethanol microspheres for a plurality of times by adopting the pure water;
(2) Dehydrating the microspheres with acetone, wherein the addition amount of the acetone is 40-60 times of the volume of the microspheres, dispersing the microspheres in tetrahydrofuran, and adding 0.5-1.0g of a microwave sensitization compound;
(3) Reacting the microspheres and the microwave sensitization compound in water bath at 60-65 ℃ for 10-12h, and washing the microspheres with tetrahydrofuran for several times;
(4) Dispersing the microspheres in pure water again, swelling for 2-3h, washing with pure water for several times, and dispersing in physiological saline.
2. The method for preparing the chemoembolization microsphere with microwave sensitization efficacy according to claim 1, wherein: the particle size of the polyvinyl alcohol microspheres in the step (1) is 100-500 microns.
3. the method for preparing the chemoembolization microsphere with microwave sensitization efficacy according to claim 1, wherein: the microwave sensitization compound is a compound with phenolic hydroxyl.
4. the method for preparing the chemoembolization microsphere with microwave sensitization efficacy according to claim 3, wherein: the microwave sensitization compound comprises:
5. The method for preparing the chemoembolization microsphere with microwave sensitization efficacy according to claim 1, wherein: the hydroxyl activating agent is tosyl chloride.
6. The method for preparing the chemoembolization microsphere with microwave sensitization efficacy according to claim 1, wherein: and (4) performing carboxyl protection treatment on the microwave sensitization compound in the step (3) before reaction.
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