CN108926531B - Nano micelle with dual responsiveness of reduction and pH, and preparation method and application thereof - Google Patents
Nano micelle with dual responsiveness of reduction and pH, and preparation method and application thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
A nano micelle with dual responsiveness of reduction and pH has a hydrophilic shell and a hydrophobic core, wherein the hydrophilic shell is polyoxazoline, and the hydrophobic core is polyurethane which is formed by self-assembly of amphiphilic polyurethane. The hydrophobic chain segment of the amphiphilic polyurethane is polyurethane containing reduction-sensitive disulfide bonds, and the hydrophilic chain segment is polyoxazoline with pH responsiveness. The nano micelle with dual responsiveness of reduction and pH is applied as a drug carrier, and the degradation environment of the application of the nano micelle as the drug carrier is intracellular reduction environment and acidic environment. After entering tumor cells, the nano micelle with dual responsiveness of reduction and pH is quickly degraded under the dual actions of cell reducibility conditions and acid environment of endosomes/lysosomes, so that the drug is quickly released, the problems of slow drug release and easy drug resistance of a drug carrier are solved, and the curative effect is improved.
Description
Technical Field
The invention belongs to the fields of chemical synthesis and biomedicine, and particularly relates to a nano micelle with dual responsiveness of reduction and pH, and a preparation method and application thereof.
Background
The nano micelle can improve the stability of the hydrophobic anticancer drug in an aqueous solution through solubilization, can carry an imaging dye and the drug simultaneously, and realizes the real-time monitoring of the observation and treatment efficacy. The drug-loaded nano-micelle can reach a tumor part through a passive targeting effect, so that the toxic and side effects of the hydrophobic anticancer drug in normal tissues are reduced, and the effect of treating cancers by the drug is improved. These excellent properties of nanomicelles provide a more effective method of administration for cancer chemotherapy.
The drug carriers such as the aggregates formed by self-assembly of the amphiphilic polymer, such as nano particles, nano micelles and polymer vesicles, can prolong the circulation time of the drug carriers in vivo and increase the accumulation of the drug carriers at tumor sites, but the drug carriers cannot be effectively released, so that the drug effect is reduced. According to the intracellular environment of tumor cells, a nano-drug carrier with environmental responsiveness (such as pH, temperature, oxidation reduction and the like) is developed, so that the release rate of the drug can be effectively improved, the toxic and side effects of the drug in vivo are reduced, and the treatment effect of the anti-cancer drug is improved. The biocompatibility and biodegradability of the biomedical material are important factors to be considered in clinical application, and the polyurethane material has good biocompatibility and stable physicochemical property, and has wide application in biomedicine, such as heart valves, artificial blood vessels, artificial catheters and the like.
The micelle assembled by the amphiphilic polyurethane with the polyoxazoline as the hydrophilic segment has pH responsiveness due to the swelling property of the polyoxazoline in an acidic environment. This property allows polyurethane drug-loaded micelles to rapidly swell and release drugs in the acidic environment of the endosome/lysosome of the cells (pH 5.0-5.5). The existing single-response polymer drug-loaded micelle can only release about 70% of anticancer drugs (Yao, et al. RSC adv.2016,6: 9082-.
Disclosure of Invention
The invention aims to provide a nano micelle with reduction and pH dual responsiveness, and a preparation method and application thereof, so as to solve the problem that an amphiphilic copolymer forms a drug carrier through self-assembly, and the drug carrier cannot effectively release drugs, so that the drug effect is low.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a nano micelle with dual responsiveness of reduction and pH has a hydrophilic shell and a hydrophobic core, and is formed by self-assembly of amphiphilic polyurethane. The hydrophobic chain segment of the amphiphilic polyurethane is polyurethane containing reduction-sensitive disulfide bonds, and the hydrophilic chain segment is polyoxazoline with pH responsiveness.
Further, the amphiphilic polyurethane is polyoxazoline-polyurethane-polyoxazoline, the hydrophilic shell is polyoxazoline, the molecular weight of polyoxazoline is 1500-10000Da, the hydrophobic core is polyurethane, and the molecular weight of polyurethane is 2000-50000 Da.
In the preparation method of the amphiphilic polyurethane, polyester diol with hydroxyl at the end reacts with diisocyanate in an organic solvent to synthesize a polyurethane prepolymer in an inert atmosphere, and then the polyurethane prepolymer is capped with polyoxazoline at room temperature to obtain a final product.
Further, the polyester diol is polycaprolactone, polycarbonate or polylactic acid; the diisocyanate is cystamine diisocyanate CDI, L-lysine ethyl ester diisocyanate LDI or hexamethylene diisocyanate HDI.
Further, the preparation method also comprises the following steps: in an inert atmosphere, carrying out ring-opening polymerization on 2-ethyl-2-oxazoline by using methyl p-toluenesulfonate to obtain the polyoxazoline.
The preparation method of the nano micelle with reduction and pH dual responsiveness comprises the following steps: firstly dissolving the amphiphilic polyurethane in an organic solvent, dripping secondary water under the condition of stirring at room temperature, and forming the nano micelle with polyoxazoline as a hydrophilic shell and polyurethane as a hydrophobic core through self-assembly.
The nano micelle with double responsiveness of reduction and pH is used as a drug carrier.
Furthermore, the degradation environment of the nano-micelle when being used as a drug carrier is a reduction environment and/or an acidic environment in cells.
Further, the reducing environment is an environment in which a thiol-containing molecule is present.
Further, the thiol-group-containing molecule is glutathione.
Compared with the prior art, the invention has the beneficial effects that:
1. the main chain of the amphiphilic polyurethane contains a reduction-sensitive disulfide bond, the stable reduction-responsive nano micelle can be obtained by self-assembling the amphiphilic polyurethane, has smaller critical micelle concentration and is not easy to dissociate outside cells and in blood, the stability of the drug encapsulated by the nano micelle is ensured, and the problems of easy leakage of the drug in vivo, low carrying efficiency, short circulation time and the like are overcome;
2. the hydrophilic section of the amphiphilic polyurethane is polyoxazoline, has pH responsiveness, and can be quickly released in the acidic environment of endosome/lysosome in cells.
3. After entering tumor cells, the nano micelle with dual responsiveness of reduction and pH is quickly degraded under the dual actions of cell reducibility conditions and acid environment of endosomes/lysosomes, so that the drug is quickly released, the problems of slow drug release and easy drug resistance of a drug carrier are solved, and the curative effect is improved.
The specific implementation mode is as follows:
example 1: synthesis of polycaprolactone diol (Mn 1000Da)
Polycaprolactone diol (PCL) is prepared by using caprolactone (-CL) as starting material and dithioglycol (HES) in stannous octoate (Sn (Oct)2) Is obtained by ring-opening polymerization under the catalysis of (2).
The specific operation is as follows:
42.1mL of toluene, HES (0.102g,0.6590mmol), Sn (Oct.) were added to a closed reaction flask with a stirrer in a glove box under nitrogen atmosphere2(0.081g,0.1997mmol), -CL (7.22g,63.27mmol), then the reactor was sealed and removed from the glove box and placed in an oil bath at 100 ℃ for 24h of polymerization. After the reaction is finished, the reaction solution is concentrated and precipitated in glacial ethyl ether, filtered and dried in vacuum for 24 hours to obtain the product PCL-SS-PCL. Yield: 85.1 percent.
Example 2: synthesis of the Polymer PEtOz-OH (Mn. 5000Da)
Preparing end-capped hydrophilic polymer polyoxazoline PEtOz-OH, wherein polyoxazoline is a polymer, and the synthesis of the polyoxazoline is to perform ring-opening polymerization on 2-ethyl-2-oxazoline by methyl p-toluenesulfonate under the protection of nitrogen. The specific operation is as follows:
to dry acetonitrile were added methyl p-toluenesulfonate (0.34g,1.834mmol) and 2-ethyl-2-oxazoline (10g,100.9mmol), the mixture was heated to 100 ℃ and the reaction was stirred for 24 h. After the reaction, the reaction mixture was cooled to room temperature, 0.1mL of KOH (1N) was added thereto, and the mixture was stirred at room temperature for 4 hours, and then separated by precipitation with ethyl acetate. The polymer PEOZ-OH was purified by dialysis against deionized water (MWCO:3500g/mol) for two days, during which the dialysis medium was replaced and finally freeze-dried to give the product PEtOz-OH. Yield: 87.6 percent.
Example 3: synthesis of the Polymer PEtOz-PU (SS) -PEtOz
The preparation method of the amphiphilic polyurethane comprises the following steps: firstly, polycaprolactone diol and diisocyanate are reacted at 65 ℃ to synthesize a polyurethane prepolymer, and then the polyurethane prepolymer is terminated with terminal hydroxy polyoxazoline at room temperature to obtain a final product.
The specific operation is as follows:
under the protection of nitrogen, 1g, namely 1mmol of polycaprolactone diol is subjected to azeotropic boiling with toluene, water is taken, and then dissolved in 10mL of anhydrous DMF, then CDI (1.05mmol, 0.214g) is added, stirring is carried out at the temperature of 65 ℃ for reaction for 24h, polyoxazoline (0.1mmol, 0.5g) is taken and dissolved in 5mL of anhydrous DMF, and the polyoxazoline solution is dropped into the solution under the condition of ice-water bath and reacted for 48h at room temperature. After the reaction is finished, concentrating and settling the mixture in methanol/ethyl acetate, and drying the mixture in vacuum to obtain PEtOz-PU (SS) -PEtOz; the ratio of methanol to ethyl acetate is v/v and is 1: 10. Yield: 54.1 percent.
Example 4: preparation of polyoxazoline-polyurethane (SS) -polyoxazoline (PEtOz-PU (SS) -PEtOz) nano micelle
The polymer PEtOz-PU (SS) -PEtOz nanomicelle is prepared by a dialysis method. The specific process is as follows: 2mg of the polymer was dissolved in 1mL of dimethyl sulfoxide, and 1.5mL of deionized water was added dropwise thereto with stirring at 25 ℃. The resulting solution was stirred for 1 hour, filled into a dialysis bag (SPECTRA/POR, MWCO:3500), and dialyzed with deionized water for 24 hours.
Example 5: preparation of control group polyoxazoline-polyurethane-polyoxazoline (PEtOz-PU-PEtOz) nano micelle
The polymer PEtOz-PU-PEtOz nano micelle is prepared by a dialysis method. The specific process is as follows: 2mg of the polymer PEtOz-PU-PEtOz were dissolved in 1mL of dimethyl sulfoxide, and 1.5mL of deionized water was added dropwise thereto with stirring at 25 ℃. The resulting solution was stirred for 1 hour, filled into a dialysis bag (SPECTRA/POR, MWCO:3500) prepared in advance, and dialyzed with deionized water for 24 hours.
Amphiphilic polyurethane micelles were prepared according to examples 4 and 5, and the size and distribution of the formed nano-micelles were measured, with the results shown in table 1:
TABLE 1 amphiphilic polyurethane nanomicelle of different hydrophobic segments
Example 6: reductive degradation of dual-responsiveness polyoxazoline-polyurethane (SS) -polyoxazoline nano-micelle
In this example, DTT solution (10mM) was used to mimic the presence of intracellular GSH. Specifically, the weighed DTT was added to a glass sample cell of 2.0mL of PEtOz-PU (SS) -PEtOz polymer nanomicelle (0.001 mg/mL) under nitrogen atmosphere so that the final DTT concentration was 10 mM. Micelles without DTT were used as controls. The two glass sample cells were then sealed with rubber stoppers, shaken up, placed in a 37 ℃ constant temperature shaker (200rpm), and the change in micelle size was measured by DLS at 37 ℃ for the selected time. DLS results show that the micelle particle size increases from 110nm to 280nm after 4h and reaches 761nm after 8 h. The particle size of the micelle is basically unchanged after 24 hours, which shows that the polyurethane micelle has good reduction responsiveness, and under the reduction condition of 10mM DTT, the disulfide bond is broken, the micelle swells, and the particle size is continuously increased.
Example 7: coated model small molecule anticancer drug adriamycin
Encapsulation of anticancer drugs by PEtOz-PU-PEtOz and PEtOz-PU (SS) -PEtOz micelles is achieved by dialysis. Taking the example of PEtOz-PU (SS) -PEtOz, 2.4mg of the polymer is dissolved in 1mL of dimethyl sulfoxide, doxorubicin required by the designed drug-loading amount is added into the polymer, ultrasonic treatment is carried out for 0.5h, 1.5mL of secondary water is slowly dripped into the dimethyl sulfoxide solution under the condition of stirring at room temperature, and ultrasonic treatment is carried out for 1h after the dripping is finished. Then, the mixed solution was transferred to a dialysis bag (MWCO: 3500), dialyzed for 24 hours, and then taken out.
Determination of the encapsulation efficiency of DOX in polymer nanobelts: a certain amount of drug-loaded nano-micelle is taken, water is removed by a freeze-drying method, then 0.5mL of dimethyl sulfoxide is added to dissolve the micelle, then ultrasonic treatment is carried out for 1 hour, 20 mu L of the solution is taken and added into 3mL of dimethyl sulfoxide, and the encapsulation efficiency is calculated by combining a standard curve of adriamycin through a fluorescence test.
The encapsulation efficiency (mass of doxorubicin in the nano micelle/mass of doxorubicin charged) x 100%
Nano-micelles with different drug-loading rates of two polymers were prepared according to example 7, and the size, distribution, encapsulation efficiency, etc. of the obtained nano-micelles were tested, and the results are shown in table 2:
TABLE 2 drug-loaded micelles of two polymers with different drug-loading rates
Example 8: triggered release of doxorubicin-loaded drug-loaded micelles
In this example, sodium acetate buffer solution was used to simulate the intracellular endosome/lysosome acidic environment (pH 5.0-5.5). The DOX-loaded PEtOz-PU (SS) -PEtOz drug-loaded micelles were divided into two portions and loaded into respective dialysis bags, the former being immersed in 40mL of a sodium acetate buffer solution (20mM, pH 5.0) containing 10mM DTT, and the latter being immersed in 40mL of PB (20mM) and placed in a 37 ℃ constant temperature shaker (200 rpm). The dialysis liquid outside the dialysis bag is taken at a set volume at a certain time interval to measure the fluorescence intensity and is supplemented with a corresponding volume of fresh liquid. The experiment was continued for 24 hours.
The results show that: the double-responsiveness nanomicelle loaded with DOX can rapidly release DOX in a sodium acetate buffer solution at 37 ℃ in 10mM DTT, and the release amount of the PEtOz-PU (SS) -PEtOzz drug-loaded micelle is up to 95%. Under PB (20mM, pH 7.4) conditions in the absence of DTT, PEtOz-PU (SS) -PEtOz polymer loaded micelles released only 25% of DOX within 24 h. Experimental results show that the PEtOz-PU (SS) -PEtOz drug-loaded micelle containing disulfide bonds has responsiveness to the intracellular environment, can release drugs more quickly in the in vivo environment and improves the curative effect.
Claims (7)
1. A nano micelle with dual responsiveness of reduction and pH comprises a hydrophilic shell and a hydrophobic core, and is characterized in that the nano micelle with dual responsiveness is formed by self-assembly of amphiphilic polyurethane, the hydrophobic chain segment of the amphiphilic polyurethane is polyurethane containing disulfide bonds with reduction sensitivity, and the hydrophilic chain segment of the amphiphilic polyurethane is polyoxazoline with pH responsiveness; the amphiphilic polyurethane is polyoxazoline-polyurethane-polyoxazoline, the hydrophilic shell is polyoxazoline, the molecular weight of polyoxazoline is 1500-10000Da, the hydrophobic core is polyurethane, and the molecular weight of polyurethane is 2000-50000 Da;
the structural formula of the amphiphilic polyurethane is shown as the following formula:
2. the preparation method of amphiphilic polyurethane of claim 1, characterized in that under the protection of nitrogen, polycaprolactone diol is azeotroped with toluene to take water and then dissolved in anhydrous DMF, then CDI is added, and stirring reaction is carried out for 24h under the condition of 65 ℃ to obtain a mixed solution; dissolving polyoxazoline in anhydrous DMF, dripping into the mixed solution under the condition of ice-water bath, and reacting for 48h at room temperature; after the reaction is finished, concentrating and settling the mixture in methanol/glacial ethyl ether, and drying the mixture in vacuum to obtain the amphiphilic polyurethane.
3. The method for preparing nano-micelle with reduction and pH dual responsiveness of claim 1, wherein the amphiphilic polyurethane is firstly dissolved in an organic solvent, secondary water is dripped into the amphiphilic polyurethane under the condition of stirring at room temperature, and the nano-micelle with polyoxazoline as a hydrophilic shell and polyurethane as a hydrophobic core is formed through self-assembly.
4. Use of the reducing and pH responsive nanomicelle of claim 1 as a drug carrier.
5. The use of the reducing and pH responsive nanomicelle as claimed in claim 4, wherein the degradation environment of the nanomicelle as a drug carrier is intracellular reducing environment and/or acidic environment.
6. The use of the reducing and pH responsive nanomicelle as claimed in claim 5, wherein the reducing environment is an environment where thiol-containing molecules are present.
7. The use of the reduced and pH responsive nanomicelle as claimed in claim 6, wherein the thiol-group containing molecule is glutathione.
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| CN111228218B (en) * | 2020-02-21 | 2021-11-02 | 江苏师范大学 | Temozolomide nano prodrug micelle and preparation method and application thereof |
| CN111450265B (en) * | 2020-06-04 | 2022-09-23 | 东南大学 | Targeting pH-sensitive polymer vesicle loaded with gold-drug compound and preparation method thereof |
| CN112315910B (en) * | 2020-11-10 | 2023-03-24 | 南开大学 | Nano-carrier with dual responses of pH and hypoxic and preparation method and application thereof |
| CN113136017B (en) * | 2021-04-02 | 2022-08-09 | 中国科学院合肥物质科学研究院 | Polyurethane with pH response and self-healing performance and preparation method thereof |
| CN114181360A (en) * | 2021-12-08 | 2022-03-15 | 南京工业大学 | Ultrasonic wave stimulus response polyurethane and preparation method thereof |
| CN115010913B (en) * | 2022-06-17 | 2023-05-26 | 广东工业大学 | PH/reduction dual-response polymer micelle and preparation method and application thereof |
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