CN111072976A - Controllable synthesis method for preparing HA-PEI targeted drug carrier with high yield - Google Patents
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Abstract
The invention relates to a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, which is characterized in that the HA-PEI targeted drug carrier is prepared with NHS (N-hydroxysuccinimide, Chinese name: N-hydroxysuccinimide), EDC (1-ethyl-3- (3-dimethylamino propyl) carbodiimide, 1- (3-dimethylamino propyl) -3-ethyl carbodiimide, HA (Hyaluronic acid, Chinese name: polyethyleneimine) and PEI (Poly (ethylene), and polyethyleneimine) as raw materials by a microwave radiation method with high yield. The main synthesis method comprises the following steps: mixing HA with NHS and EDC, dropwise adding PEI into the mixed solution to obtain a precursor mixed solution, transferring the precursor mixed solution into a normal-pressure microwave reactor with a condensation reflux device, cooling the obtained solution to room temperature, pouring the solution into a dialysis bag, dialyzing for 12-24 hours, freeze-drying at-40-60 low temperature for 12-120 hours, and collecting a sample. The synthesis method has the advantages that: the raw materials are nontoxic and harmless, the cost is low, the synthesis efficiency is high, the appearance is controllable, the synthesized medicine meets the absorption requirement of a human body, and the medicine is expected to be put into the medical industry to obtain a good effect.
Description
[ technical field ]: the invention relates to a synthesis method of a targeted drug, in particular to a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield.
[ technical background ]: in the last two decades, nano-drugs have been playing a positive role in clinical practice of tumor and cancer therapy, and the purpose of the nano-drugs is to improve the curative effect and selectivity of traditional drug therapy, alleviate the pain of patients, and reduce the side effects (Sara Maiolino, Annapina Russo, Valentia Paglira, et al. biological degradable with polyethylene and hydrophilic for the targeted delivery of docetaxel to air cancer cells [ J ]. Journal of biological technology, 2015, 13 (1): 2-4). Through the use of targeted drugs, a protective shell can be provided for expensive active substances, and theoretically, degradation protection of the drugs can be provided, so that the interaction and side effects of the drugs and healthy cells are limited, and therefore, the targeted drugs become hot spots for research of people. The targeted medicine is a high-tech therapeutic medicine generated by the development of modern medicine, biomolecular science and biological cytology, and can prevent the growth of cancer cells through the action of specific molecular targets necessary for carcinogenesis and tumor growth. The common means for treating cancer is chemotherapy and radiotherapy, but the price is high, the side effect is great, and the last straw is often crushed. The targeted drugs are divided into antibody drugs and kinase inhibitors, the antibody drugs have extremely strong targeting property and long half-life, but the production cost is high, and the large-scale investment in the pharmaceutical industry is not easy; the kinase inhibitor has small relative molecular mass, can be orally taken, has short half life and low production cost.
The nano-drug and the intermediate are novel polymers and can be used for treating cancers. HA and PEI Polymers, PEls can produce Anti-cancer effects by electrostatic interaction with cell membranes (Huang Z, Yang Y, Jiang Y, et al, Anti-tumor biological responses of tumor-associated macrophages via toll-like receptors 4triggered by biological Polymers [ J ]. Biomaterials, 2013, 34 (3): 746. 755; Wang, Shengpeng; Zhang, Jinming; Wang, Yitao; et al, Hyaluronic acid-coated PEI-polymeric binders treated co-delivery of polynucleotide and miR-542-3p for triple hybrid fiber receptor, Nanodiological PEI and PEI-PEI, Saudi-biological technologies, Saudi-12, Saudi-biological technologies, Saudi-2016. 12, Saudi-biological technologies, Saudi-2016. multidigi-drug, Miyaura biological technologies, Miudi-molecular biological technologies, Miyaura-3 p, Miyaura molecular biological technologies, Miyaura, Polychairi-biological technologies, Miyaura, The shape is irregular, so that a quick, low-cost and slow targeting medicament with good effect is urgently needed to be found.
Aiming at the existing technical problems and urgent needs of anticancer drugs, the invention provides a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, the dosage of the targeted drug prepared by the method accords with the absorption rate of a human body, the targeted drug effect is strong, the cost is low, and the targeted drug is expected to be put into the pharmaceutical industry for batch production.
[ summary of the invention ]: the invention discloses a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, the method realizes controllable appearance of the targeted drug, can prolong the effective period of the drug, can slowly release the drug, HAs strong targeted drug, reduces the pain of patients, HAs low cost of the synthesized drug, is expected to be put into the pharmaceutical industry, and HAs good development prospect in the medical industry.
[ technical solution of the present invention ]: the invention relates to a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, which comprises the following specific synthesis steps:
a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield is characterized in that NHS, EDC, HA and PEI are used as raw materials, the HA-PEI targeted drug carrier is prepared by a microwave radiation method, and the reaction steps are as follows:
firstly, weighing 0.1000 g-2.0000 g of sodium salt, dissolving in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium salt solution;
secondly, respectively weighing 0.0100 g-1.8000 g of HA and 0.0010 g-1.0000 g of PEI into 2 beakers, respectively adding 5-20 ml of the prepared sodium salt solution, and ultrasonically vibrating for 5-120 min for later use after the ultrasonic treatment is finished;
thirdly, weighing 0.0100-0.2200 g of NHS and 0.0100-0.3550 g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 5-120 min for later use after the ultrasonic oscillation is finished;
fourthly, after mixing HA with NHS/EDC, adding PEI: firstly transferring 30 ml of NHS/EDC solution prepared in the third step into a 200ml round-bottom flask, then transferring 0.0100 g-1.8000 g of HA solution prepared in the second step into the round-bottom flask, and then quickly adding a solution containing 0.0010 g-1.0000 g of PEI to obtain a precursor solution;
fifthly, transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to be 100-1200W, heating the solution to 10-100 ℃, and continuously reacting for 1-120 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature;
and sixthly, pouring the solution after the reaction into a dialysis bag with the aperture of 5-20 microns, placing the dialysis bag into constant-temperature circulating high-purity water at the temperature of 25 ℃, dialyzing for 12-24 hours at normal temperature, gradually whitening the color in the dialysis process, pouring the product into a sterilized clean 200ml beaker, freeze-drying for 12-120 hours at the low temperature of-40 to-60 when the impurity content in the dialysis bag is equal to the high-purity water value, and collecting a sample for later use.
2. The sodium salt according to claim 1, wherein the sodium salt is one, two or more of sodium sulfite, sodium phosphite, sodium bromate, sodium bromide, sodium nitrate, sodium bicarbonate, sodium carbonate, sodium gluconate, sodium chlorate, sodium chloride, sodium sulfate, sodium thiosulfate, sodium phosphate, sodium pyrophosphate, sodium formate, sodium persulfate, sodium silicate, sodium perchlorate, sodium iodide, sodium acetate, sodium hypochlorite, sodium acrylate, sodium propionate and sodium benzoate.
[ advantages and effects of the invention ]: the invention relates to a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, the synthesis route is simple to operate, and raw materials are cheap and easy to obtain; the invention has the innovation points that the synthesized targeted drug has controllable appearance, is in a hollow spherical structure, delays the valid period of expensive active ingredients, can be slowly released for a long time, particularly has the release rate of the compound conforming to the rate absorbed by human bodies, has strong targeted drug, reduces the side effect of drug pairs, reduces the production cost, has high synthesis efficiency, improves the curative effect and lightens the economic burden of families of patients. The targeting drug synthesized by the invention can overcome the trouble that a patient takes medicines for a plurality of times a day; because the preparation process is simple and the curative effect is good, the material is expected to be put into the pharmaceutical industry and produced in batches, and multiple medical tests of mice and the like prove that the material has good effect.
Drawings
FIG. 1 shows the structural formula of HA as a raw material
FIG. 2 is a structural formula diagram of PEI as a raw material
FIG. 3 is a structural formula diagram of NHS as a raw material
FIG. 4 is a structural formula diagram of raw material EDC
FIG. 5 is the nuclear magnetic spectrum of HA as the raw material
FIG. 6 is a nuclear magnetic spectrum of PEI as a raw material
FIG. 7 is a nuclear magnetic spectrum diagram of HA-PEI as a synthetic target product, which shows obvious characteristic peaks
FIG. 8 is a scanning electron microscope photomicrograph of HA-PEI of the synthetic sample
FIG. 9 is a scanning electron microscope photomicrograph of HA-PEI as a synthesized sample
FIG. 10 shows an atmospheric microwave reactor with reflux condensation
[ embodiments ] of the present invention:
example 1: synthesis of targeted drug carrier by microwave radiation method with heating power of 100W and heating temperature of 20 DEG C
Weighing 0.1200g of sodium chloride, dissolving in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium chloride solution; respectively weighing 0.0250g of HA and 0.0150g of PEI in 2 beakers, respectively adding 15ml of the prepared sodium salt solution, and carrying out ultrasonic oscillation for 15min for later use after the ultrasonic oscillation is finished; weighing 0.1800g of NHS and 0.0550g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 50min for later use after the ultrasonic oscillation is finished; NHS/EDC mixed HA, PEI added dropwise: firstly, transferring a prepared 30 ml NHS/EDC solution into a 200ml round-bottom flask, then transferring a solution containing 0.0250g HA into the round-bottom flask, and dropwise adding a solution containing 0.0150g PEI to obtain a precursor solution; transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to be 100W, heating the solution to 20 ℃, and continuously reacting for 10 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature; pouring the reacted solution into a dialysis bag with the aperture of 5 microns, placing the dialysis bag into constant-temperature circulating high-purity water, dialyzing at normal temperature for 24 hours, pouring the product into a sterilized clean 200ml beaker, freezing and drying at the low temperature of 60 ℃ below zero for 100 hours when the color gradually turns white and the impurity content in the dialysis bag is equal to the number of the high-purity water in the dialysis bag, and collecting a sample for later use. The structural formulas of the raw materials HA, PEI, NHS and EDC are respectively shown in figures 1, 2, 3 and 4, the nuclear magnetic spectrograms of the raw materials HA and PEI are shown in figures 5 and 6, the nuclear magnetic spectrogram of the HA-PEI polymer synthesized by a microwave radiation method is shown in figure 7, the peak near the abscissa 2.75 can be obtained from figure 7 to show that the polymerization degree of HA and PEI is high, the controllable polymerization of a molecular chain is completed, the scanning electron microscope picture of the HA-PEI polymer is shown in figures 8 and 9, and the scanning electron microscope picture and the nuclear magnetic spectrogram can be obtained.
Example 2: synthesis of targeted drug carrier by microwave radiation method with heating power of 800W and heating temperature of 20 DEG C
Weighing 0.500g of sodium sulfate, dissolving the sodium sulfate in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium sulfate solution; respectively weighing 0.4000g of HA and 0.0500g of PEI in 2 beakers, respectively adding 5ml of the prepared sodium salt solution, ultrasonically vibrating for 15min, and standing by after the ultrasonic is finished; weighing 0.0100g of NHS and 0.0200g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 50min for later use after the ultrasonic oscillation is finished; NHS/EDC mixed HA, PEI added dropwise: firstly, transferring a prepared 30 ml of NHS/EDC solution into a 200ml round-bottom flask, then transferring a solution containing 0.4000g of HA into the round-bottom flask, and dropwise adding a solution containing 0.0500g of PEI to obtain a precursor solution; transferring the precursor solution to a microwave reactor (as shown in figure 10) with normal pressure and reflux condensation, adjusting the microwave radiation power to 800W, heating the solution at the temperature of 20 ℃, and continuously reacting for 3 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature; pouring the reacted solution into a dialysis bag with the aperture of 10 microns, placing the dialysis bag into constant-temperature circulating high-purity water, dialyzing at normal temperature for 24 hours, pouring the product into a sterilized clean 200ml beaker, freeze-drying the product at the low temperature of minus 40 ℃ for 80 hours in the dialysis process, and collecting a sample for later use, wherein the scanning electron microscope image and the nuclear magnetic spectrum of the HA-PEI polymer synthesized under the conditions are the same as those in example 1, and good beneficial effects are obtained in medical experiments.
Example 3: synthesis of targeted drug carrier by microwave radiation method with heating power of 400W and heating temperature of 40 DEG C
Weighing 0.500g of sodium acetate, dissolving in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium acetate solution; respectively weighing 0.2000g of HA and 0.0170g of PEI in 2 beakers, respectively adding 5ml of the prepared sodium salt solution, and ultrasonically oscillating for 5min for later use after the ultrasonic oscillation is finished; 0.0220g of NHS and 0.0350g of EDC are weighed, dissolved in 30 ml of deionized water, ultrasonically vibrated for 5min and reserved after the ultrasonic vibration is finished; NHS/EDC mixed HA, PEI added dropwise: firstly, transferring a prepared 30 ml NHS/EDC solution into a 200ml round-bottom flask, then transferring a solution containing 0.2000g HA into the round-bottom flask, and dropwise adding a solution containing 0.0170g PEI to obtain a precursor solution; transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to 400W, heating the solution to 40 ℃, and continuously reacting for 10 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature; pouring the reacted solution into a dialysis bag with the aperture of 10 microns, placing the dialysis bag into constant-temperature circulating high-purity water, dialyzing at normal temperature for 12 hours, pouring the product into a sterilized clean 200ml beaker, freeze-drying the product at the low temperature of minus 60 ℃ for 60 hours in the dialysis process, and collecting a sample for later use, wherein the scanning electron microscope image and the nuclear magnetic spectrum of the HA-PEI polymer synthesized under the conditions are the same as those in example 1, and good beneficial effects are obtained in medical experiments.
Example 4: synthesis of targeted drug carrier by microwave radiation method with heating power of 600W and heating temperature of 40 DEG C
0.6500g of sodium gluconate is weighed and dissolved in 20ml of deionized water, and the solution is heated to 30 ℃ to form sodium gluconate solution; respectively weighing 0.3500g of HA and 0.0400g of PEI in 2 beakers, respectively adding 5ml of the prepared sodium salt solution, and carrying out ultrasonic oscillation for 5min for later use after the ultrasonic oscillation is finished; weighing 0.0260g of NHS and 0.0500g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 25min for standby after the ultrasonic oscillation is finished; NHS/EDC mixed HA, PEI added dropwise: firstly, transferring a prepared 30 ml of NHS/EDC solution into a 200ml round-bottom flask, then transferring a solution containing 0.3500g of HA into the round-bottom flask, and dropwise adding a solution containing 0.0400g of PEI to obtain a precursor solution; transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to 600W, heating the solution to 40 ℃, and continuously reacting for 10 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature; pouring the reacted solution into a dialysis bag with the aperture of 10 microns, placing the dialysis bag into constant-temperature circulating high-purity water, dialyzing at normal temperature for 12 hours, pouring the product into a sterilized clean 200ml beaker, freeze-drying the product at the low temperature of minus 60 ℃ for 70 hours in the dialysis process, and collecting a sample for later use, wherein the scanning electron microscope image and the nuclear magnetic spectrum of the HA-PEI polymer synthesized under the conditions are the same as those in example 1, and good beneficial effects are obtained in medical experiments.
Comparative example:
reference (Sahiner N, Sagbas S, Sahine)r M，et al.Polyethyleneimine modifiedpoly(Hyaluronic acid)particles with controllable antimicrobial and anticancereffects[J]Carbohydrate polymers, 2017, 159: 29-38.) provides a synthetic method for preparing the HA-PEI targeted drug: dispersing HA particles weighing 1g in a suspension containing 10 wt% NaIO4Is stirred at 500 rpm for 12 hours, then precipitated with excess acetone, washed with acetone by centrifugation at least 2 times and subjected to NalO4The treated 0.5g HA particles were placed in 20mL aqueous solutions containing different concentrations of PEI (0.5, 1 and 2mL) for 12 hours. The precipitation was carried out with HA: PEI particles in a weight ratio of 1: 1, 1: 1 and 1: 2, and an excess of acetone was added. The HA-PEl particles were washed at least 2 times with an acetone-water mixture, centrifuged for 10 minutes at 10000rpm, dried with a heat gun, and stored in closed containers for drug loading and release studies.
The invention relates to a controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield, which is characterized in that NHS, EDC, HA and PEI are taken as raw materials, the HA-PEI targeted drug carrier is prepared by a microwave radiation method, and the reaction steps are as follows: weighing 0.1000 g-2.0000 g of sodium salt, dissolving in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium salt solution; respectively weighing 0.0100 g-1.8000 g of HA and 0.0010 g-1.0000 g of PEI into 2 beakers, respectively adding 5-20 ml of the prepared sodium salt solution, and carrying out ultrasonic oscillation for 5-120 min for later use after the ultrasonic oscillation is finished; weighing 0.0100-0.2200 g of NHS and 0.0100-0.3550 g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 5-120 min for later use after the ultrasonic oscillation is finished; after NHS/EDC mixed HA, PEI: firstly transferring 30 ml of NHS/EDC solution prepared in the third step into a 200ml round-bottom flask, then transferring 0.0100 g-1.8000 g of HA solution prepared in the second step into the round-bottom flask, and then quickly adding a solution containing 0.0010 g-1.0000 g of PEI to obtain a precursor solution; transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to be 100-1200W, heating the solution at the temperature of 10-100 ℃, and stopping the reaction for 1-120 minutes; after the microwave reaction is finished, cooling the obtained solution to room temperature; pouring the reacted solution into a dialysis bag with the aperture of 5-20 microns, placing the dialysis bag into constant-temperature circulating high-purity water at the temperature of 25 ℃, dialyzing for 12-24 hours at normal temperature, gradually whitening the color in the dialysis process, pouring the product into a sterilized clean 200ml beaker, freeze-drying for 12-120 hours at the low temperature of-40-60 ℃ and collecting a sample for later use, wherein the impurity content in the dialysis bag is equal to the number of the high-purity water. The HA-PEI targeted drug carrier synthesized by the invention HAs controllable appearance, can delay the effective period of the drug, can be slowly released, HAs strong targeted drug, is not easy to damage normal cells and reduce the harm of side effects to human bodies, HAs strong targeting property, is not easy to damage normal cells, and HAs good effect in medical experiments, and can be produced in batches.
Claims (2)
1. A controllable synthesis method for preparing an HA-PEI targeted drug carrier with high yield is characterized in that NHS, EDC, HA and PEI are used as raw materials, the HA-PEI targeted drug carrier is prepared by a microwave radiation method, and the reaction steps are as follows:
firstly, weighing 0.1000 g-2.0000 g of sodium salt, dissolving in 20ml of deionized water, and heating the solution to 30 ℃ to form a sodium salt solution;
secondly, weighing 0.0100 g-1.8000 g of HA and 0.0010 g-1.0000 g of PEI respectively in 2 beakers, adding 5-20 ml of the prepared sodium salt solution respectively, and carrying out ultrasonic oscillation for 5-120 min for later use after the ultrasonic oscillation is finished;
thirdly, weighing 0.0100-0.2200 g of NHS and 0.0100-0.3550 g of EDC, dissolving in 30 ml of deionized water, and ultrasonically oscillating for 5-120 min for later use after the ultrasonic oscillation is finished;
fourthly, after mixing HA with NHS/EDC, adding PEI: firstly transferring 30 ml of NHS/EDC solution prepared in the third step into a 200ml round-bottom flask, then transferring 0.0100 g-1.8000 g of HA solution prepared in the second step into the round-bottom flask, and then quickly adding a solution containing 0.0010 g-1.0000 g of PEI to obtain a precursor solution;
fifthly, transferring the precursor solution to a microwave reactor with normal pressure and reflux condensation, adjusting the microwave radiation power to be 100-1200W, heating the solution to 10-100 ℃, and continuously reacting for 1-120 minutes to stop; after the microwave reaction is finished, cooling the obtained solution to room temperature;
and sixthly, pouring the solution after the reaction into a dialysis bag with the aperture of 5-20 microns, placing the dialysis bag into constant-temperature circulating high-purity water at the temperature of 25 ℃, dialyzing for 12-24 hours at normal temperature, gradually whitening the color in the dialysis process, pouring the product into a sterilized clean 200ml beaker, freeze-drying for 12-120 hours at the low temperature of-40 to-60 when the impurity content in the dialysis bag is equal to the high-purity water value, and collecting a sample for later use.
2. The sodium salt of claim 1, wherein the sodium salt is one, two or more of sodium sulfite, sodium phosphite, sodium bromate, sodium bromide, sodium nitrate, sodium bicarbonate, sodium carbonate, sodium gluconate, sodium fluoride, sodium chloride, sodium sulfate, sodium thiosulfate, sodium phosphate, sodium pyrophosphate, sodium formate, sodium persulfate, sodium silicate, sodium monofluoride, sodium iodide, sodium acetate, sodium hypofluoride, sodium acrylate, sodium propionate and sodium benzoate.
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