CN115844855A - Self-amplifying nano-drug carrier and preparation method thereof - Google Patents
Self-amplifying nano-drug carrier and preparation method thereof Download PDFInfo
- Publication number
- CN115844855A CN115844855A CN202211390821.1A CN202211390821A CN115844855A CN 115844855 A CN115844855 A CN 115844855A CN 202211390821 A CN202211390821 A CN 202211390821A CN 115844855 A CN115844855 A CN 115844855A
- Authority
- CN
- China
- Prior art keywords
- nano
- drug
- self
- amplifying
- glucan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a self-amplifying nano-drug carrier and a preparation method thereof, wherein the nano-drug carrier is constructed by an amphiphilic copolymer, one end of a molecular chain of the amphiphilic copolymer is hydrophilic polyethylene glycol, and the other end of the molecular chain of the amphiphilic copolymer is hydrophobic glucan; the nano-drug carrier has an acid-triggered response characteristic, and can release the coated drug in a self-amplification manner under a tumor microenvironment after being coated with the drug; the preparation method comprises the steps of reacting carboxyl functionalized glucan and amino functionalized polyethylene glycol to prepare glucan-polyethylene glycol copolymer, then carrying out hydrophobic modification on the glucan to prepare amphiphilic copolymer, and coating the amphiphilic copolymer with a drug to construct a nano drug carrier. The nano-drug carrier prepared by the invention can be rapidly disintegrated in a weak acid microenvironment of a tumor part and release the loaded drug, so that the concentration of the free drug in the tumor cells is improved, and the treatment effect of the tumor is greatly improved.
Description
Technical Field
The invention relates to a drug carrier and a preparation method thereof, in particular to a self-amplifying nano drug carrier and a preparation method thereof.
Background
Chemotherapy is currently widely used as a common means of treating cancer, due to the less trauma it causes to cancer patients. However, since chemotherapy is a systemic treatment, the use of chemotherapy allows the drug to be transmitted to most organs and tissues of the body through the blood circulation. These chemotherapeutic agents are generally highly cytotoxic. They can kill both tumor cells and cells in normal tissues. They cause irreversible damage and serious side effects to the patient. The nano-drug carrier provides a new way for solving the problem of side effects caused by chemotherapy. The nano-drug carrier is considered as a potential drug delivery system, and can provide a drug with a targeting function for the treatment of anti-tumor drugs.
The therapeutic activity of the drug can be activated only by releasing the drug from the carrier, and the concentration of the effective drug cannot be increased only by enriching the nano carrier. When the drug release rate is low, the drug concentration in the tumor cells is low, and the tumor cells can resist the low-concentration drugs through drug efflux, self-repair function and the like. Therefore, it is required that the nano-carrier rapidly releases the coated drug after entering the tumor cells to kill the tumor cells, which is difficult in the actual research and development process.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a self-amplifying nano-drug carrier which can be rapidly disintegrated and release a loaded drug in a weak acid microenvironment of a tumor part, and is beneficial to improving the concentration of free drugs in tumor cells, thereby greatly improving the treatment effect of tumors; the invention also aims to provide a preparation method of the self-amplifying nano-drug carrier.
The technical scheme is as follows: the self-amplification nano-drug carrier is constructed by an amphiphilic copolymer with acid-triggered response characteristics, one end of a molecular chain of the amphiphilic copolymer is hydrophilic polyethylene glycol, and the other end of the molecular chain of the amphiphilic copolymer is hydrophobic glucan; the nano-drug carrier has an acid-triggered response characteristic, and can automatically release the coated drug in a tumor microenvironment in an amplification manner after being coated with the drug.
Further, the preparation method of the amphiphilic copolymer with the acid-triggered response characteristic comprises the following steps:
(1) Dissolving carboxyl functionalized glucan and amino functionalized polyethylene glycol in N, N-dimethylformamide, adding a catalyst for reaction, dialyzing, and freeze-drying to obtain a glucan-polyethylene glycol copolymer;
(2) Dripping acrolein into benzene solution of trimethyl bromosilane, stirring, and heating to room temperature for reaction to obtain a compound 1; then, adding p-toluenesulfonic acid monohydrate, adding the glucan-polyethylene glycol copolymer and alcohol for heating reaction, diluting, washing, drying, concentrating and purifying to obtain a compound 2; and dissolving the compound 2 in acetone, adding sodium iodide, dialyzing, and freeze-drying to obtain the amphiphilic copolymer with the acid-triggered response characteristic.
Further, the reaction time in the step (1) is 12-26h; the stirring time in the step (2) is 10-60 minutes, the mixture is heated to room temperature to react for 30-180 minutes, the reaction temperature of the glucan-polyethylene glycol copolymer and the alcohol is 50-100 ℃, the reaction time is 8-24 hours, and the treatment time at room temperature after the sodium iodide is added is 12-36 hours; the diluting solvent is benzene, and the washing solvent is 5% sodium bicarbonate and water.
Further, the catalyst in the step (1) is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide; the mole ratio of the glucan to the polyethylene glycol is 1: (0.8-1.2), and the molecular weight is 2-20 KDa.
Further, the molar ratio of the acrolein to the benzene solution of trimethyl bromosilane in the step (2) is 1: (0.5 to 2.0); the alcohol is ethanol, propanol, isopropanol, butanol, pentanol or hexanol; the molar ratio of the compound 1 to the toluenesulfonic acid monohydrate is 1: (0.01 to 0.1); the molar ratio of the compound 1, the glucan-polyethylene glycol copolymer and the alcohol is 1: (0.05-0.2): (0.8-1.2); the molar ratio of the compound 2 to the sodium iodide is 1: (50-200).
The preparation method of the nano-drug after the self-amplifying nano-drug carrier coats the drug comprises the following steps: the amphiphilic copolymer with the acid-triggered response characteristic and the chemotherapeutic drug are dissolved in dichloromethane, and after full dissolution, deionized water is dripped in, after ultrasonic emulsification, organic solvent is removed, and after centrifugal cleaning, freeze-drying is carried out, thus obtaining nano-drug powder.
Further, the ratio of the amphiphilic copolymer, the drug and the organic solvent is 10g: (0.2-1.5) g: (0.5-2) mL; the volume ratio of the organic solvent to the deionized water is 1: (5-20); the chemotherapy medicine is paclitaxel, adriamycin or camptothecin.
The reaction principle of the invention is referred to the following process:
the first step is as follows:
the second step is that:
the amphiphilic copolymer (hydrophobic glucan-polyethylene glycol copolymer) for forming the nano-drug carrier has unique advantages. The hydrolysis mechanism of the hydrophobic dextran-polyethylene glycol copolymer under the tumor weak acid condition is as follows: the hydrophobic dextran-polyethylene glycol copolymer can be triggered to hydrolyze in weak acid environment to generate dextran-polyethylene glycol compound, acrolein and I - And H + The resulting product will further accelerate the hydrolysis of the hydrophobic dextran-polyethylene glycol copolymer. Therefore, the hydrolysis of the hydrophobic glucan-polyethylene glycol copolymer in a weak acid environment has a self-amplifying characteristic, and once triggered, the hydrolysis is rapid.
Has the advantages that: compared with the prior art, the invention has the following remarkable advantages: the nano-carrier can be triggered under a tumor weak acid microenvironment, the hydrophobic end is hydrolyzed to form hydrophilic glucan, and meanwhile, a hydrolysate contains a large amount of H + The preparation method can reduce the local pH value and accelerate the degradation of the nano-carrier, thereby improving the controlled release rate of the drug and greatly improving the treatment effect of the tumor.
Drawings
FIG. 1 is a transmission electron microscope photograph of the nano-drug prepared in example 1;
FIG. 2 is a TEM image of the nano-drug treated by the diluted HCl solution with pH 6.8 prepared in example 4;
FIG. 3 is a graph of pH of the nano-drug solution as a function of time.
Detailed Description
The technical scheme of the invention is further explained by combining the attached drawings.
Example 1
The self-amplifying nano-drug carrier is constructed by an amphiphilic copolymer, one end of a molecular chain of the amphiphilic copolymer is hydrophilic polyethylene glycol, and the other end of the molecular chain of the amphiphilic copolymer is hydrophobic glucan; the nano-drug carrier has an acid-triggered response characteristic, and can release the coated drug in a self-amplification manner in a tumor microenvironment after being coated with the drug. The preparation method comprises the following steps:
s1, dissolving 1g of carboxyl functionalized glucan (with the molecular weight of 2 KDa) and 1g of amino functionalized polyethylene glycol (with the molecular weight of 2 KDa) in N, N-dimethylformamide, adding 0.1g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.06g N-hydroxysuccinimide as catalysts, reacting for 24h, dialyzing, and reacting after freeze-drying to prepare the copolymer.
S2.1.6mL of trimethylbromosilane is added into 10mL of benzene, then 0.8mL of acrolein is slowly dropped into the mixture, the obtained mixture is stirred for 30 minutes, and the mixture is heated to room temperature for 60 minutes to obtain a compound 1; to the above mixture solution was added 50mg of toluenesulfonic acid monohydrate, and then 1.8g of dextran-polyethylene glycol copolymer and 0.96mL of n-butanol. Heating at 75 ℃ for 18 h, diluting with benzene, washing with 5% sodium bicarbonate and aqueous solution, drying over magnesium sulfate, concentrating, and purifying by column chromatography gives compound 2 as a powder. Then, 0.5mg of Compound 2 was dissolved in 20mL of acetone, and 1.5g of sodium iodide was added thereto and the mixture was treated at room temperature for 20 hours. Dialyzing and freeze-drying to obtain the amphiphilic polymer 3 (hydrophobic dextran-polyethylene glycol copolymer).
S3, dissolving 50mg of polymer 3,5mg of paclitaxel in 2mL of dichloromethane, fully dissolving, dropwise adding into 40mL of deionized water, ultrasonically emulsifying, removing dichloromethane in a system through rotary evaporation, centrifugally cleaning, and freeze-drying to obtain nano-drug powder consisting of self-amplified nano-carriers.
Example 2
The self-amplification nano-drug carrier is constructed by an amphiphilic copolymer, one end of a molecular chain of the amphiphilic copolymer is hydrophilic polyethylene glycol, and the other end of the molecular chain of the amphiphilic copolymer is hydrophobic glucan; the nano-drug carrier has an acid-triggered response characteristic, and can release the coated drug in a self-amplification manner in a tumor microenvironment after being coated with the drug. The preparation method comprises the following steps:
s1, dissolving 2g of carboxyl functionalized glucan (with the molecular weight of 4 KDa) and 2g of amino functionalized polyethylene glycol (with the molecular weight of 4 KDa) in N, N-dimethylformamide, adding 0.1g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.06g N-hydroxysuccinimide as catalysts, reacting for 24 hours, dialyzing, and reacting after freeze-drying to prepare the copolymer.
S2.1.6mL of trimethylbromosilane is added into 10mL of benzene, then 0.9mL of acrolein is slowly dripped in, the obtained mixture is stirred for 30 minutes and is heated to room temperature for 60 minutes, and a compound 1 is obtained; to the above mixture solution was added 50mg of toluenesulfonic acid monohydrate, followed by 3.8g of dextran-polyethylene glycol copolymer and 1.25mL of hexanol. Heating at 75 ℃ for 18 h, diluting with benzene, washing with 5% sodium bicarbonate and aqueous solution, drying over magnesium sulfate, concentrating, and purifying by column chromatography gives compound 2 as a powder. Then, 1.0mg of Compound 2 was dissolved in 20mL of acetone, and 2.3g of sodium iodide was added thereto and the mixture was treated at room temperature for 20 hours. Dialyzing and freeze-drying to obtain the amphiphilic polymer 3 (hydrophobic glucan-polyethylene glycol copolymer).
S3, dissolving 50mg of polymer 3,5mg of adriamycin in 2mL of dichloromethane, dropwise adding into 40mL of deionized water after full dissolution, removing dichloromethane in a system through rotary evaporation after ultrasonic emulsification, centrifugally cleaning, and freeze-drying to obtain nano-drug powder consisting of self-amplified nano-carriers.
Example 3
The self-amplifying nano-drug carrier is constructed by an amphiphilic copolymer, one end of a molecular chain of the amphiphilic copolymer is hydrophilic polyethylene glycol, and the other end of the molecular chain of the amphiphilic copolymer is hydrophobic glucan; the nano-drug carrier has an acid-triggered response characteristic, and can release the coated drug in a self-amplification manner in a tumor microenvironment after being coated with the drug. The preparation method comprises the following steps:
s1, dissolving 1g of carboxyl functionalized glucan (molecular weight is 2 KDa) and 1g of amino functionalized polyethylene glycol (molecular weight is 4 KDa) in N, N-dimethylformamide, adding 0.1g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.06g N-hydroxysuccinimide as catalysts, reacting for 24 hours, dialyzing, and reacting after freeze-drying to prepare the copolymer.
S2.1.6mL of trimethylbromosilane is added into 10mL of benzene, then 0.8mL of acrolein is slowly dripped in, the obtained mixture is stirred for 30 minutes and is heated to room temperature for 60 minutes, and a compound 1 is obtained; to the above mixture solution, 50mg of toluenesulfonic acid monohydrate was added, followed by 2.7g of dextran-polyethylene glycol copolymer and 0.96mL of n-butanol. Heating at 75 ℃ for 18 h, diluting with benzene, washing with 5% sodium bicarbonate and aqueous solution, drying over magnesium sulfate, concentrating, and purifying by column chromatography gives compound 2 as a powder. Then, 0.8mg of Compound 2 was dissolved in 20mL of acetone, and 2.0g of sodium iodide was added thereto and the mixture was treated at room temperature for 20 hours. Dialyzing and freeze-drying to obtain the amphiphilic polymer 3 (hydrophobic glucan-polyethylene glycol copolymer).
S3, dissolving 50mg of polymer 3,5mg of paclitaxel in 1.5mL of dichloromethane, dropwise adding into 40mL of deionized water after full dissolution, removing dichloromethane in a system by rotary evaporation after ultrasonic emulsification, centrifugally cleaning, and freeze-drying to obtain nano-drug powder consisting of self-amplified nano-carriers.
Example 4
After dissolving the nano-drug prepared in example 1 in water, it was observed by a transmission electron microscope. The results are shown in FIG. 1. From the TEM images, it can be seen that the nano-drug is spherical with a particle size of about 100nm. FIG. 2 is a TEM image of the above-mentioned nano-drug dissolved in a dilute hydrochloric acid solution having a pH of 6.8 after 10 minutes, showing that the nano-drug was completely disintegrated. Therefore, the prepared nano-medicament has very good acid response characteristic.
Example 5
Measuring the change in pH over time indicates acid amplified degradation. 10mL of an aqueous solution having a pH of 6.8 was prepared using diluted hydrochloric acid, 20mg of the nano-drug prepared in example 1 was added, and the change in pH of the solution was observed in real time using a pH meter, and the record was as shown in FIG. 3. The pH value of the solution can be found to be rapidly reduced, which indicates that H can be generated in the process of decomposing the nano-drug + 。
Claims (10)
1. A self-amplifying nano-drug carrier is characterized in that: the nano-drug carrier is constructed by an amphiphilic copolymer with acid-triggered response characteristics, wherein one end of a molecular chain of the amphiphilic copolymer is hydrophilic polyethylene glycol, and the other end of the molecular chain of the amphiphilic copolymer is hydrophobic glucan; the nano-drug carrier has an acid-triggered response characteristic, and can release the coated drug in a self-amplification manner in a tumor microenvironment after being coated with the drug.
2. The self-amplifying nano-drug carrier according to claim 1, wherein: the preparation method of the amphiphilic copolymer with the acid-triggered response characteristic comprises the following steps:
(1) Dissolving carboxyl functionalized glucan and amino functionalized polyethylene glycol in N, N-dimethylformamide, adding a catalyst for reaction, dialyzing, and freeze-drying to obtain a glucan-polyethylene glycol copolymer;
(2) Dripping acrolein into benzene solution of trimethyl bromosilane, stirring, and heating to room temperature for reaction to obtain a compound 1; then, adding p-toluenesulfonic acid monohydrate, adding the glucan-polyethylene glycol copolymer and alcohol for heating reaction, diluting, washing, drying, concentrating and purifying to obtain a compound 2; and dissolving the compound 2 in acetone, adding sodium iodide, dialyzing, and freeze-drying to obtain the amphiphilic copolymer with the acid-triggered response characteristic.
3. The self-amplifying nano-drug carrier of claim 2, wherein: in the step (1), the catalyst is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide.
4. The method for preparing a self-amplifying nano-drug carrier according to claim 2, wherein: the mole ratio of the glucan to the polyethylene glycol in the step (1) is 1:0.8 to 1.2, and the molecular weight of the polymer is 2 to 20KDa.
5. The self-amplifying nano-drug carrier according to claim 2, wherein: the molar ratio of the acrolein to the benzene solution of the trimethyl bromosilane in the step (2) is 1:0.5 to 2.0.
6. The self-amplifying nano-drug carrier of claim 2, characterized in that: the alcohol in the step (2) is ethanol, propanol, isopropanol, butanol, pentanol or hexanol.
7. The self-amplifying nano-drug according to claim 2, wherein: the molar ratio of the compound 1 to the toluenesulfonic acid monohydrate in the step (2) is 1:0.01 to 0.1; the molar ratio of the compound 1, the glucan-polyethylene glycol copolymer and the alcohol is 1:0.05 to 0.2:0.8 to 1.2.
8. The self-amplifying nanocarrier of claim 2, wherein: the molar ratio of the compound 2 to the sodium iodide in the step (2) is 1:50 to 200.
9. The nano-drug coated by the self-amplifying nano-drug carrier according to claim 1, wherein the preparation method comprises: dissolving the amphiphilic copolymer with the acid-triggered response characteristic and the chemotherapeutic drugs in dichloromethane, fully dissolving, then dropping deionized water, ultrasonically emulsifying, removing the organic solvent, centrifugally cleaning, and freeze-drying to obtain nano-drug powder.
10. The method for preparing a nano-drug according to claim 9, characterized in that: the ratio of the amphiphilic copolymer to the drug to the organic solvent is 10g:0.2 to 1.5g:0.5 to 2mL; the volume ratio of the organic solvent to the deionized water is 1:5 to 20; the chemotherapy drug is paclitaxel, adriamycin or camptothecin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211390821.1A CN115844855A (en) | 2022-11-07 | 2022-11-07 | Self-amplifying nano-drug carrier and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211390821.1A CN115844855A (en) | 2022-11-07 | 2022-11-07 | Self-amplifying nano-drug carrier and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115844855A true CN115844855A (en) | 2023-03-28 |
Family
ID=85662738
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211390821.1A Pending CN115844855A (en) | 2022-11-07 | 2022-11-07 | Self-amplifying nano-drug carrier and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115844855A (en) |
-
2022
- 2022-11-07 CN CN202211390821.1A patent/CN115844855A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210338585A1 (en) | Aptamer bioconjugate drug delivery device | |
| US10245244B2 (en) | Pharmaceutical formulations for the treatment of pulmonary arterial hypertension | |
| AU2008240545B2 (en) | Nanoparticles comprising a cyclodextrin and a biologically active molecule and uses thereof | |
| AU2015208699B2 (en) | Nanoencapsulation of hydrophilic active compounds | |
| JP5685243B2 (en) | Pharmaceutical carrier, its preparation method and use | |
| EP1835888B1 (en) | Cholanic acid-chitosan complex forming self-aggregates and preparation method thereof | |
| US8282944B2 (en) | Metal complexes incorporated within biodegradable nanoparticles and their use | |
| JP4262090B2 (en) | Anticancer agent-chitosan complex forming self-aggregate and method for producing the same | |
| CN112826939A (en) | Abdominal perfusion nano-medicine and preparation method and application thereof | |
| CN101888845B (en) | Metal complexes incorporated within biodegradable nanoparticles and their use | |
| CN114081953B (en) | Prodrug dendrimer nano-carrier and preparation method and application thereof | |
| Si et al. | CD-MOFs: From preparation to drug delivery and therapeutic application | |
| Marabada et al. | Cyclodextrin based nanoparticles for smart drug delivery in colorectal cancer | |
| CN115844822B (en) | Oral drug-loaded micelle composition and preparation method thereof | |
| KR20200122255A (en) | pH sensitive drug delivery system using Poly acrylic acid-graft- Polyhedral oligomeric silsesquioxane | |
| CN115844855A (en) | Self-amplifying nano-drug carrier and preparation method thereof | |
| CN114748637B (en) | Phenylboronic acid modified nanocrystalline drug stabilization system and preparation method and application thereof | |
| CN113616620B (en) | An Luoti nix albumin nano-particles, preparation method and application thereof and preparation containing same | |
| Patel et al. | Characterization of calcium alginate beads of 5-fluorouracil for colon delivery | |
| CN109276720B (en) | Metal-organic complex nano material and preparation method and application thereof | |
| CN114796155B (en) | Natural active substance-zein nano-particles and preparation method and application thereof | |
| CN107982543B (en) | Protein-isothiocyanate bond and application thereof | |
| CN101181273A (en) | Method for preparing chitosan-polyasparagic acid-5efudix nano particle | |
| CN116212051B (en) | Hydroxycamptothecin malignant tumor targeting microsphere and preparation method and application thereof | |
| CN115814107A (en) | Bone-targeting nanoparticle for treating osteoporosis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |