CN109134869B - Hydrogen peroxide response type targeted fluorescent drug-loaded nano material and preparation method thereof - Google Patents
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Abstract
The invention relates to a hydrogen peroxide response type targeted fluorescent drug-loaded nano material and a preparation method thereof, belonging to the technical field of nano materials, and the structural formula is as follows:
the preparation method comprises the steps of PHEMA synthesis, FPEG synthesis, PHEMA-Sim/Prv/Com/Lo-FPEG-ISO-1 synthesis and the like. The nano particles prepared by the invention have high drug utilization degree, a fluorescence calibration function and a function of targeting atherosclerotic plaques.
Description
Technical Field
The invention belongs to the technical field of nano materials, and particularly relates to a nano drug-loaded material with hydrogen peroxide response and targeted fluorescence capability and a preparation method thereof.
Background
The polyhydroxyethyl methacrylate is easy to modify due to a unique polyhydroxy structure, and has certain application in the medical field. However, it is not common to use poly (hydroxyethyl methacrylate) as a vehicle for diagnosis and treatment by carrying drugs, fluorescent polymers and target molecules.
Atherosclerosis is a common cardiovascular and cerebrovascular disease, and is a chronic inflammatory disease, wherein the atherosclerosis is hidden in the early stage and has unobvious symptoms, and can finally cause high-risk diseases such as myocardial infarction and apoplexy. In the aspect of treatment, the atherosclerosis disease can be cured only by means of stents, operations and the like at the later stage. In the early stage, oral statins are common, but the treatment mode has the problems of low medicament utilization rate, slow effect, serious side effect and the like. In addition, atherosclerosis lacks the pH-sensitive capacity of traditional diseases and more specific drug release control switches must be sought in nanomedicine. Among them, active oxygen clusters such as hydrogen peroxide are active in the early stage of atherosclerosis and can be used as a specific switch.
The traditional single functional drug system can not meet the requirements of the existing molecular therapy of the atherosclerosis. The better diagnosis and treatment effect can be achieved only by comprehensively applying multiple comprehensive functions such as target positioning, fluorescence detection, drug release control and the like. In the field of atherosclerotic diseases, the application of a nano drug-loaded system integrating diagnosis and treatment is relatively lacked, and supplement and improvement are urgently needed.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: overcomes the defects and problems in the background technology, and provides a drug-loaded nano material which responds to hydrogen peroxide and has the targeted fluorescence characteristic and a preparation method thereof.
The technical problem of the invention is realized by the following scheme:
a hydrogen peroxide response type targeted fluorescent drug-loaded nano material has the following structural formula:
wherein m: n is 4: 1;
selected from the following structures:
a preparation method of a hydrogen peroxide response type targeted fluorescent drug-loaded nano material comprises the following steps:
(1) dissolving a statin in anhydrous dichloromethane, dissolving 5-10 times of molar equivalent of oxalyl chloride in the anhydrous dichloromethane, dripping the statin solution into the oxalyl chloride solution under the condition of ice salt bath, continuing to react for 2-3 hours after dripping is finished, then removing the solvent and excessive oxalyl chloride by rotary evaporation, and drying in vacuum to obtain yellow powder;
(2) dissolving the yellow powder prepared in the step (1) in dichloromethane, dropping the obtained solution into dichloromethane solution of polyhydroxyethyl methacrylate, continuing to react for 1-5 h after the dropping is finished, and then performing rotary evaporation, drying and the like to obtain yellow pasty solid, wherein the mass ratio of the yellow powder to the polyhydroxyethyl methacrylate is 1: 3.
(3) Dissolving fluorescent polyethylene glycol, the yellow pasty solid prepared in the step (2), a tautomerase activity inhibitor (ISO-1) and 4-Dimethylaminopyridine (DMAP) in dichloromethane according to a molar ratio of 1: 0.1-0.2 to obtain a mixed solution, then dripping a dichloromethane solution of dicyclohexylcarbodiimide into the mixed solution, wherein the dosage of dicyclohexylcarbodiimide is 1.2-1.5 times of that of the fluorescent polyethylene glycol by mol, continuously reacting for 24 hours at room temperature after dripping is finished, and then filtering, dialyzing and drying to obtain a brown solid, namely the hydrogen peroxide response type targeted fluorescent drug-loaded nano material.
The statin drug can be pravastatin, simvastatin, mevastatin or lovastatin.
The fluorescent polyethylene glycol can be prepared according to the following method:
adding anhydrous citric acid, polyethylene glycol monomethyl ether and cysteine into a dry round-bottom flask according to the molar ratio of 1: 1-1.2: 0.2-0.5, repeatedly flushing and pumping argon into the flask to ensure that oxygen is completely removed, heating to melt the mixture at 120-150 ℃, reacting for 1-3 h, cooling to 100-120 ℃, continuing to react for 1-2 h, dissolving the product in deionized water after the reaction is finished, and filtering, dialyzing, rotary evaporating and drying to obtain a yellow waxy solid, namely the fluorescent polyethylene glycol.
The simvastatin prodrug, the fluorescent polyethylene glycol and the target molecule ISO-1 targeting macrophages to inhibit migration factors are modified on PHEMA respectively to synthesize the amphiphilic polymer PHEMA-Sim-FPEG-ISO-1 which can target macrophages, sensitively control drug release of hydrogen peroxide and emit fluorescence, and form the nano micelle. As the hydrogen peroxide level and the macrophage number of the arteriosclerosis focus are obviously increased, the PHEMA-Sim-FPEG-ISO-1 prepared by the invention can actively aggregate to the arteriosclerosis focus and release medicine when reaching the focus, thereby greatly improving the utilization rate of the medicine.
In conclusion, the invention has the following beneficial effects:
1. the nano particles prepared by the invention can effectively improve the utilization rate of the medicine through a new medicine release mode.
2. The invention carries out special modification on the traditional polyethylene glycol, and has the fluorescence function while keeping biocompatibility. The administration monitoring is convenient.
3. According to the invention, by introducing macrophage target molecules, the prepared nanoparticles have the function of targeting atherosclerotic plaques.
Description of the drawings:
FIG. 1 is a nuclear magnetic map of fluorescent polyethylene glycol prepared in example 2.
Fig. 2 is a nuclear magnetic map of hydrogen peroxide-responsive targeted fluorescent drug-loaded nanoparticles prepared in example 4.
Fig. 3 is a transmission scanning electron microscope of the hydrogen peroxide-responsive targeted fluorescent drug-loaded nanoparticles prepared in example 4.
FIG. 4 is a photograph of fluorescent substance of fluorescent polyethylene glycol prepared in example 2 under UV lamp irradiation.
Fig. 5 is a fluorescent substance photo of the hydrogen peroxide-responsive targeted fluorescent drug-loaded nanoparticles prepared in example 4 under the irradiation of an ultraviolet lamp.
Detailed Description
The synthesis route of the hydrogen peroxide response type targeted fluorescent drug-loaded nano material is as follows:
example 1: synthesis of Polyhydroxyethylmethacrylate (PHEMA)
Polyhydroxyethylmethacrylate (PHEMA) was synthesized by the ATRP method. 2-bipyridine (0.06g), CuCl (0.28g), 4mL of N, N' -dimethylformamide, 4mL of hydroxyethyl methacrylate, and 0.15mL of 2-bromo-2-methacrylate were sequentially added to a multi-bake, evacuated, and argon-filled branched vial. And vacuumizing and filling argon again to ensure that the reaction system is in an oxygen-free state. Placing the bottle in 70 deg.C oil bath pot for reaction for 6 hr, dissolving the mixture in methanol, and adding Al2O3Removing impurities with neutral column, rotary steaming the filtrate, concentrating, precipitating with diethyl ether, centrifuging, oven drying, and processing to obtain PHEMA as white powder.
Example 2: synthesis of fluorescent polyethylene glycol (FPEG)
Anhydrous citric acid (0.96g), polyethylene glycol monomethyl ether 2000(2g) and cysteine (0.6g) were added to a pre-dried 50mL round bottom flask and argon was repeatedly flushed into the flask 3 times to ensure complete oxygen scavenging. The mixture was then melted and allowed to react for 2h at 140 ℃ and the temperature was reduced to 120 ℃ and allowed to continue for 1 h. And after the reaction is finished, dissolving the product in deionized water, dialyzing for one week by using a dialysis bag with the molecular weight cutoff of 2000, and performing rotary evaporation and drying to obtain yellow waxy solid FPEG. From the nuclear magnetic diagram of fig. 1, it can be seen that each H position and peak area of the target product have good attribution. The fluorescent polyethylene glycol prepared in this example exhibited yellow fluorescence under UV irradiation, as shown in FIG. 4 (the figure is black and white, without color information, but the sample exhibited yellow fluorescence in the original color photograph).
Example 3: synthesis of Hydrogen peroxide-responsive simvastatin Polymer (PHEMA-Sim)
First, simvastatin (1.72g) was dissolved in 20mL of anhydrous dichloromethane, and oxalyl chloride (5.02g) was dissolved in 5mL of anhydrous dichloromethane. Under the condition of ice salt bath, dropping simvastatin solution into oxalyl chloride solution at the speed of 1 drop per second, continuing to react for 2 hours after the dropping is finished, gradually changing the reaction solution from colorless to yellow, and finishing the reaction. The solvent and excess oxalyl chloride were then removed by rotary evaporation and dried under vacuum to give acylchloride simvastatin as a yellow powder, 1.84g, which was redissolved in 20mL of dry dichloromethane. Then, PHEMA (0.9g) prepared in example 1 is dissolved in 50mL of anhydrous dichloromethane, the dichloromethane solution dissolved with acyl chloride simvastatin is dripped into the PHEMA solution at the speed of 1 drop per second under the protection of argon, after the dripping is finished, the reaction is continued for 2 hours, and after the reaction is finished, the solvent is removed to obtain a crude product. Finally dialyzing the obtained sample by a dialysis bag with the molecular weight cutoff of 5000 for 3 days to remove unreacted simvastatin and PHEMA, and performing rotary steaming and drying to obtain yellow pasty solid PHEMA-Sim.
Example 4: synthesis of hydrogen peroxide-responsive targeted fluorescent drug-loaded nanoparticles (PHEMA-Sim-FPEG-ISO-1)
PHEAM-Sim (0.92g) prepared in example 3, FPEG (0.56g) prepared in example 2, ISO-1(0.044g) and DMAP (0.012g) were dissolved in 30mL of dichloromethane, and DCC (0.08g) was dissolved in 4mL of dichloromethane and added dropwise to the former mixed solution at a rate of 1 drop per second. After the dropwise addition, the reaction was continued at room temperature for 24 hours. After the reaction is finished, filtering, dialyzing and drying to obtain a target product PHEMA-Sim-FPEG-ISO-1. The nuclear magnetic diagram is shown in FIG. 2, and it can be seen from FIG. 2 that each H position and peak area of the target product have good attribution. As shown in FIG. 3, the transmission scanning electron microscope is capable of forming spherical structures with a particle size of about 90nm from FIG. 3. The prepared sample exhibited blue fluorescence under UV illumination as shown in FIG. 5 (the figure is black and white, with no color information, but the sample exhibited blue fluorescence in the original color photograph).
Example 5: synthesis of hydrogen peroxide-responsive statin polymer (PHEMA-Prv/Com/Lo)
Similar results to example 3 were obtained by replacing simvastatin in example 3 with equimolar pravastatin, mevastatin or lovastatin.
Example 6:
the PHEAM-Sim in example 4 was replaced with PHEMA-Prv/Com/Lo to obtain nanoparticles similar to those in example 4.
Claims (4)
1. A hydrogen peroxide response type targeted fluorescent drug-loaded nano material has the following structural formula:
wherein m: n is 4: 1;
selected from the following structures:
2. the preparation method of the hydrogen peroxide-responsive targeted fluorescent drug-loaded nanomaterial of claim 1, comprising the following steps:
(1) dissolving a statin in anhydrous dichloromethane, dissolving 5-10 times of molar equivalent of oxalyl chloride in the anhydrous dichloromethane, dripping the statin solution into the oxalyl chloride solution under the condition of ice salt bath, continuing to react for 2-3 hours after dripping is finished, then removing the solvent and excessive oxalyl chloride by rotary evaporation, and drying in vacuum to obtain yellow powder;
(2) dissolving the yellow powder prepared in the step (1) in dichloromethane, dropping the obtained solution into dichloromethane solution of polyhydroxyethyl methacrylate, continuing to react for 1-5 hours after the dropping is finished, and then performing rotary evaporation, drying and the like to obtain yellow pasty solid, wherein the mass ratio of the yellow powder to the polyhydroxyethyl methacrylate is 1: 3;
(3) dissolving fluorescent polyethylene glycol, the yellow pasty solid prepared in the step (2), a tautomerase activity inhibitor and 4-dimethylaminopyridine into dichloromethane according to a molar ratio of 1: 0.1-0.2 to obtain a mixed solution, then dripping the dichloromethane solution of dicyclohexylcarbodiimide into the mixed solution, wherein the dosage of dicyclohexylcarbodiimide is 1.2-1.5 times of that of the fluorescent polyethylene glycol by mol, continuously reacting for 24 hours at room temperature after dripping is finished, and then filtering, dialyzing and drying to obtain a brown solid, namely the hydrogen peroxide response type targeted fluorescent drug-loaded nano material.
3. The preparation method of the hydrogen peroxide-responsive targeted fluorescent drug-loaded nanomaterial according to claim 2, wherein the statin drug is pravastatin, simvastatin, mevastatin or lovastatin.
4. The preparation method of the hydrogen peroxide-responsive targeted fluorescent drug-loaded nanomaterial according to claim 2 or 3, characterized in that the fluorescent polyethylene glycol is prepared according to the following method:
adding anhydrous citric acid, polyethylene glycol monomethyl ether and cysteine into a dry round-bottom flask according to the molar ratio of 1: 1-1.2: 0.2-0.5, repeatedly flushing and pumping argon into the flask to ensure that oxygen is completely removed, heating to melt the mixture at 120-150 ℃, reacting for 1-3 h, cooling to 100-120 ℃, continuing to react for 1-2 h, dissolving the product in deionized water after the reaction is finished, and filtering, dialyzing, rotary evaporating and drying to obtain a yellow waxy solid, namely the fluorescent polyethylene glycol.
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| CN110132502B (en) * | 2019-05-22 | 2021-05-25 | 北京航天试验技术研究所 | Active material capable of indicating existence of hydrogen through color change |
| CN110302396B (en) * | 2019-07-22 | 2021-07-09 | 吉林大学 | Multifunctional liposome based on hydrogen peroxide response and preparation method and application thereof |
| CN111471185B (en) * | 2020-05-12 | 2021-09-14 | 陕西师范大学 | Triple-stimulus-responsive block polymer micelle and preparation method and application thereof |
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