CN104004196B - A kind of preparation method and applications of degradable over-branched polyamidoamine - Google Patents

Abstract

The invention discloses a preparation method and application of degradable hyperbranched polyamidoamine. The present invention uses bifunctional monomers containing disulfide bonds or ketal bonds and trifunctional monomers containing amino groups 1·(2·aminoethyl)piperazine (AEPZ) or diethylenetriamine (DETA) as main raw materials, Degradable hyperbranched polyamidoamines were prepared by one-pot Michael addition polymerization, and polyethylene glycol (PEG) and folic acid (FA) were coupled on this basis to obtain folic acid-targeted, PEGylated degradable hyperbranched polyamidoamines. polyamidoamine. The raw materials of the present invention are easy to obtain, the preparation method is simple, and the prepared polymer drug carrier not only has the advantages of hyperbranched polyamidoamine, that is, a three-dimensional branched structure, a large number of cavities in the molecule, low viscosity, a large number of functional groups and simple preparation. methods, etc., and is biodegradable. In addition, the grafting of the PEG segment at the end improves the water solubility and stability of the carrier material, and the coupling of FA endows the carrier with active targeting of tumor cells.

Description

A kind of preparation method and application of degradable hyperbranched polyamidoamine

technical field

The invention belongs to the technical field of polymer materials, and in particular relates to a preparation method and application of degradable hyperbranched polyamidoamine for drug controlled release.

Background technique

Hyperbranched polyamidoamine not only has similar structure and characteristics to dendritic polyamidoamine, but also is easy to prepare without careful separation and purification, and the required polymer can be synthesized from monomers in one-step method, so it has been favored by many researchers. of favor. Hyperbranched polyamidoamine has a cavity inside, which can wrap drug molecules, such as genes, anti-tumor drugs, etc.; a large number of terminal groups on the molecular surface can not only improve the performance of the material itself through various modifications, but also connect genes and antibodies. Active substances, which provide great convenience for the design of sustained-release and targeted formulations.

Modification of the end groups of hyperbranched polyamidoamine cationic polymers can change its chemical properties and even affect its physical properties, such as charge, hydrophilicity, solubility, etc. Polyethylene glycol (PEG) is the most widely used particle surface modification material. The hydrophilic PEG chain can form a steric hindrance to increase the stability of the particle and prevent it from aggregating. The uptake of the endothelial system prolongs the circulation time of the carrier in the body and improves the bioavailability of the drug.

The ideal drug carrier material should be non-toxic and biocompatible. It can not only protect the activity of the drug, but also degrade into small molecules in the body and be easily metabolized by the human body. This requires the carrier material to be biodegradable. However, most of the hyperbranched polymer gene and drug carriers reported so far are non-degradable, which not only has certain biological toxicity, but also cannot fully release the genes and drugs. The introduction of functional monomers during the preparation of hyperbranched polymers can achieve the degradability of polymer materials. The researchers found that the concentration of reduced glutathione (GSH) in human cells is 2-10mM, much higher than the concentration of extracellular GSH (2-10μM); for tumor cells, the concentration of GSH in the cells is higher than that of normal cells. The concentration of GSH in tumor cells is 4 times higher, which leads to a large difference in the reduction potential of tumor cells inside and outside. In addition, the pH of different tissue environments in the human body is also different. For example, the pH of normal human blood is 7.4, the pH of the extracellular environment of normal tissues is 7.2-7.4, and the pH of the extracellular environment of tumor tissues is 6.2-6.8. Tumor cells The pH values of endosomes and lysosomes are 5.5-6.5 and 4.5-5.0, respectively. Therefore, by introducing functional monomers containing disulfide bonds or ketal bonds, the prepared polymers can be reduced-responsive or pH-responsive, and can be used as drug and gene carriers to achieve controlled release of drugs and genes. Function: No drug or gene is released in the blood circulation, and when it reaches the acidic or reducing environment of the tumor, it degrades and releases the drug and gene quickly, which improves the therapeutic effect of the drug and the transfection efficiency of the gene.

Ideal drug carrier materials should not only be biocompatible, but also have active targeting. Existing studies have demonstrated that a membrane glycoprotein (FR) linked to glycosylated phosphatidylinositol on the surface of tumor cells can specifically bind to folic acid (FA). FR is overexpressed in most human tumor cells, but rarely expressed in normal tissues and organs. Therefore, modifying folic acid on the surface of the hyperbranched polymer can endow the carrier material with active tumor targeting, and greatly improve the bioavailability of drugs and genes.

Contents of the invention

Purpose of the invention: In order to solve the technical problems existing in the prior art, the present invention proposes a preparation method and application of degradable hyperbranched polyamidoamine, in order to provide a degradable, environmentally responsive and high bioavailability polymers as drug carriers.

Technical content: In order to achieve the above-mentioned technical purpose, the present invention proposes a preparation method of degradable hyperbranched polyamidoamine, which includes the following steps: 2.0-6.0 mmol of bifunctional monomers containing disulfide bonds or ketal bonds and 2.0 ～6.0mmol trifunctional monomers containing amino groups are mixed in methanol or N,N-dimethylformamide (DMF), preferably in methanol, considering that methanol is cheap, relatively less toxic, and has less environmental pollution , and then carry out Michael addition polymerization at 40-60°C under magnetic stirring, and add 2.0-6.0 mmol of trifunctional monomers containing amino groups after 4-8 days to react for 1-3 days to obtain a crude product, so that the polymer terminal In this way, on the one hand, the surface of the polymer contains a large number of amino groups, which is conducive to polymer modification, such as the modification of substances with carboxyl groups (folate), and on the other hand, the amino group is positively charged, which is conducive to the combination with Gene combination can improve gene transfection efficiency. Purify the crude product, and then dry it in vacuum at room temperature to obtain the final product degradable hyperbranched polyamidoamine. The specific purification method includes pouring the obtained crude product into a large amount of diethyl ether under vigorous stirring, separating the precipitate by centrifugation, then dissolving the precipitate in methanol, and precipitating in 5% concentrated hydrochloric acid in acetone solution , separated and dried.

Wherein, the bifunctional monomer is N,N'-bis(acryloyl)cystamine, 2,2-dimethylacryloyloxy-1-ethoxypropane or 2,2-dimethylacrylamide Any one of base-1-ethoxypropane; the trifunctional monomer is 1-(2-aminoethyl)piperazine or diethylenetriamine.

In order to increase the biocompatibility of hyperbranched polyamidoamine polymer, the present invention also proposes a preparation method of degradable PEGylated hyperbranched polyamidoamine, comprising the following steps: adding 2.0 to 6.0 mmol of disulfide bond-containing or Difunctional monomers with ketal bonds and 2.0~6.0mmol trifunctional monomers containing amino groups are mixed in methanol or N,N-dimethylformamide, and then Michael addition polymerization is carried out at 40~60°C under magnetic stirring After 4 to 8 days, add 2.0 to 6.0 mmol polyethylene glycol methacrylate to react for 1 to 3 days, purify the obtained product, and then dry it in vacuum at room temperature to obtain the final product degradable PEGylated hyperbranched polyamide amine. Wherein, the above-mentioned purification method is the same as the preparation method in the preparation method of degradable hyperbranched polyamidoamine.

Wherein, the bifunctional monomer is N,N'-bis(acryloyl)cystamine, 2,2-dimethylacryloyloxy-1-ethoxypropane or 2,2-dimethylacrylamide Any one of base-1-ethoxypropane; the trifunctional monomer is 1-(2-aminoethyl)piperazine or diethylenetriamine.

The weight average molecular weight of the polyethylene glycol methacrylate is any one or more of 350, 750, 1000, 2000 or 5000.

In order to provide a hyperbranched polyamidoamine with good targeting, the present invention also proposes a preparation method of folic acid functionalized degradable hyperbranched polyamidoamine, comprising the following steps:

(1) Mix 2.0-6.0 mmol of bifunctional monomers containing disulfide bonds or ketal bonds with 2.0-6.0 mmol of trifunctional monomers containing amino groups in an organic solvent, and perform Michael addition at 40-60 °C under magnetic stirring. After 4 to 8 days, add 2.0 to 6.0 mmol polyethylene glycol methacrylate to react for 1 to 3 days, purify the obtained product, and then dry it in vacuum at room temperature to obtain a degradable PEGylated hyperbranched polyamide Amine; wherein, the above-mentioned purification method is the same as the preparation method in the preparation method of degradable hyperbranched polyamidoamine.

(2) Add 10-60 μmol folic acid, 10-60 μmol 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 10-60 μmol N-hydroxysuccinimide and 10-20 μL Dissolve triethylamine in 5-30mL DMSO, and stir overnight at room temperature with magnetic force to form FA active ester; In DMSO solution, react at room temperature in the dark for 1 to 2 days, dialyze and purify the crude product in distilled water, and freeze-dry to obtain the final product folic acid functionalized degradable hyperbranched polyamidoamine.

Wherein, the bifunctional monomer is N,N'-bis(acryloyl)cystamine, 2,2-dimethylacryloyloxy-1-ethoxypropane or 2,2-dimethylacrylamide Any one of base-1-ethoxypropane; the trifunctional monomer is 1-(2-aminoethyl)piperazine or diethylenetriamine; the polyethylene glycol methacrylate The weight average molecular weight is any one or more of 350, 750, 1000, 2000 or 5000.

The present invention further proposes the application of the above-mentioned degradable hyperbranched polyamidoamine, degradable PEGylated hyperbranched polyamidoamine and folic acid functionalized degradable hyperbranched polyamidoamine as a carrier for drug controlled release

Beneficial effects: the present invention prepares degradable environment-responsive hyperbranched polyamidoamine by introducing functional monomers and adopting one-pot Michael addition polymerization reaction. The preparation method is simple and the purification is easy. The polymerization method uses methanol as a solvent and adopts a one-pot Michael addition polymerization reaction, and the preparation is simple and the pollution is small. On this basis, functionalized degradable environment-responsive hyperbranched polyamidoamines were obtained by modifying PEG and FA with terminal amino groups. The prepared polymer material not only has environmental responsiveness and biodegradability, but also has good stability and biocompatibility. The introduction of functional monomers containing disulfide bonds or ketal bonds not only endows the polymer carrier material with environmental responsiveness and degradability, that is, it can be degraded in the reducing environment of cells and acidic environment, and can realize the controlled release of drugs. Improved drug utilization. Using polyethylene glycol (PEG) to modify the structure of its terminal functional groups can improve the water solubility and stability of the drug delivery system and reduce its interaction with plasma proteins and non-targeted cells; The folic acid ligand carries out targeted modification on it, thereby endowing the carrier with the ability to actively target tumor cells, in order to improve the therapeutic effect of the drug. Using this material as a drug carrier can maintain stability in the blood circulation, and when it reaches the tumor cell environment, it can quickly and fully release the drug due to degradation, realizing the timed and fixed-point release of the drug. The product obtained by the method of the invention has great application prospects in the field of drug controlled release.

Description of drawings

Fig. 1 is a synthetic circuit diagram of degradable hyperbranched polyamidoamine;

Fig. 2 is the Raman spectrum of degradable hyperbranched polyamidoamine;

Fig. 3 is the potential value of degradable hyperbranched polyamidoamine under different pH conditions;

Fig. 4 is the situation of carrier binding DNA under different mass ratios of carrier material and DNA, wherein, 1 is DNA plasmid; The mass ratio of carrier material and DNA in 2～5 is respectively 10:1, 15:1, 20:1 and 25:1.

Fig. 5 is a schematic diagram showing that the prepared degradable hyperbranched polyamidoamine can be broken correspondingly in reducing or acidic environment.

detailed description

Example 1

3.0 mmol of disulfide bond-containing bifunctional monomer N,N′-bis(acryloyl)cystamine (BAC) and 3.0 mmol of trifunctional monomer 1-(2-aminoethyl)piperazine (AEPZ) were dissolved in methanol Mix in medium temperature, carry out Michael addition polymerization at 50°C under magnetic stirring, add 3 mmol of AEPZ after 5 days and react for 1 day to convert all the double bonds at the end of the polymer into amino groups, and the obtained products are successively precipitated by ether and acetone. The product was purified, and the precipitated product was vacuum-dried at room temperature to obtain a white powder degradable hyperbranched polyamidoamine. The obtained product was subjected to Raman, potential test and nuclear magnetic test, and the results are shown in Fig. 2 and Fig. 3 . Among them, as shown in Figure 2, 507cm ^-1 is the absorption peak of the disulfide bond, indicating that the disulfide bond can be successfully introduced into the polymer hyperbranched polyamidoamine through the one-pot Michael addition polymerization reaction. It can be seen from Figure 3 that the potential of the prepared degradable hyperbranched polyamidoamine is positive in the pH range of 3 to 9, and the potential value increases with the increase of acidity, indicating that the degradable hyperbranched polyamidoamine can be degraded. The amidoamine surface has a large number of amino groups.

The NMR result of the prepared hyperbranched polyamidoamine is:

¹ H NMR (400MHz, D ₂ O, δ): 2.30-2.42 (-CH ₂ CONH-), 2.58-2.79 (>NCH ₂ ), 3.22-3.32 (-NHCH ₂ ). ¹³ C NMR (400 MHz, D ₂ O, δ): 29.50-30.08(-CH ₂ CONH-), 36.27-37.02(-NHCH ₂ CH ₂ SS-), 37.86-38.76(-NHCH ₂ ), 49.06-49.81(>NCH ₂ ).IR(KBr , cm ^-1 ): 3,600-3, 140 (-NH ₂ , -NH), 2970-2815 (CH ₂ , CH ₃ ), 1,654, 1,550 (C=O).

Example 2

3.0 mmol of disulfide bond-containing bifunctional monomer N,N′-bis(acryloyl)cystamine (BAC) and 1.50 mmol of trifunctional monomer 1-(2-aminoethyl)piperazine (AEPZ) were dissolved in methanol Mix in medium temperature, carry out Michael addition polymerization at 50°C under magnetic stirring, add 3 mmol of AEPZ after 5 days and react for 2 days to convert all the double bonds at the end of the polymer into amino groups, and the obtained products are successively precipitated by ether and acetone. The product was purified, and the precipitated product was vacuum-dried at room temperature to obtain a white powdery reductively degradable hyperbranched polyamidoamine.

Example 3

Mix 2.0 mmol of disulfide bond-containing bifunctional monomer N,N′-bis(acryloyl)cystamine (BAC) and 3.0 mmol of trifunctional monomer diethylenetriamine (DETA) in methanol, 50°C, magnetic Carry out Michael addition polymerization under stirring, add 1 mmol of DETA after 5 days and react for 3 days to convert all the double bonds at the end of the polymer into amino groups. The obtained product is purified by ether precipitation, acetone precipitation and other methods successively. Vacuum drying at room temperature gave white powdery reductively degradable hyperbranched polyamidoamine.

Example 4

4.0 mmol of bifunctional monomer 2,2-dimethylacryloyloxy-1-ethoxypropane containing ketal bonds and 4.0 mmol of trifunctional monomer 1-(2-aminoethyl)piperazine (AEPZ ) were mixed in methanol, and Michael addition polymerization was carried out at 50°C under magnetic stirring. After 5 days, 3 mmol of AEPZ was added to react for 1 day to convert all double bonds at the end of the polymer into amino groups. The obtained product was precipitated with ether, acetone The product is purified by methods such as precipitation, and the precipitated product is vacuum-dried at room temperature to obtain a white powdery acid-degradable hyperbranched polyamidoamine.

Example 5

Mix 5.0 mmol of ketal bond-containing bifunctional monomer 2,2-dimethylacrylamido-1-ethoxypropane with 4.0 mmol of trifunctional monomer 1-(2-aminoethyl)piperazine (AEPZ) Mix in methanol, and carry out Michael addition polymerization at 50°C under magnetic stirring. After 5 days, add 4 mmol of AEPZ to react for 1 day to convert all double bonds at the end of the polymer into amino groups. The obtained product is precipitated with ether and acetone successively. etc. to purify the product, and vacuum-dry the precipitated product at room temperature to obtain a white powdery acid-degradable hyperbranched polyamidoamine.

Example 6

6.0 mmol of disulfide bond-containing bifunctional monomer N,N′-bis(acryloyl)cystamine (BAC) and 5.0 mmol of trifunctional monomer 1-(2-aminoethyl)piperazine (AEPZ) were dissolved in methanol Mix in medium temperature, carry out Michael addition polymerization at 50°C under magnetic stirring, add 4 mmol of PEGMA after 5 days and react for 2 days to graft PEG at the end of the polymer, and the obtained product is purified by ether precipitation, acetone precipitation and other methods successively , the precipitated product was vacuum-dried at room temperature to obtain a white powder degradable PEGylated hyperbranched polyamidoamine.

The NMR results of the degradable PEGylated hyperbranched polyamidoamine prepared are as follows:

¹ H NMR (400MHz, D ₂ O, δ): 3.58-3.72 (OCh ₂ CH ₂ OOCCH(CH ₃ )NH-), 3.74-3.87 (OCH ₂ CH ₂ OOCCH(CH ₃ )NH-), 3.70-3.55 (-CH ₂ CH ₂ O), 3.19-3.28(-OCH ₃ ), 3.17-3.27(-NHCH ₂ ), 2.68-2.84(>NCH ₂ ), 2.32-2.41(-CH ₂ CONH-).IR(KBr , cm ^-1 ): 3,600-3,300 (-NH ₂ , -NH), 2990-2800 (CH ₂ , CH ₃ ), 1,646, 1,530 (C=O), 1,110 (COC).

Example 7

3.0 mmol of disulfide bond-containing bifunctional monomer N,N′-bis(acryloyl)cystamine (BAC) and 3.0 mmol of trifunctional monomer 1-(2-aminoethyl)piperazine (AEPZ) were dissolved in methanol Mix in medium temperature, carry out Michael addition polymerization at 50°C under magnetic stirring, add 1 mmol of PEGMA after 5 days and react for 2 days to graft PEG at the end of the polymer, and the obtained product is purified by ether precipitation, acetone precipitation and other methods successively , the precipitated product was vacuum-dried at room temperature to obtain a white powder degradable PEGylated hyperbranched polyamidoamine.

Example 8

5.0 mmol of disulfide bond-containing bifunctional monomer N,N′-bis(acryloyl)cystamine (BAC) and 4.0 mmol of trifunctional monomer 1-(2-aminoethyl)piperazine (AEPZ) were dissolved in methanol Mix in medium temperature, carry out Michael addition polymerization at 50°C under magnetic stirring, add 2 mmol of PEGMA after 6 days and react for 2 days to graft PEG at the end of the polymer, and the obtained product is purified by ether precipitation, acetone precipitation and other methods successively , the precipitated product was vacuum-dried at room temperature to obtain a white powder degradable PEGylated hyperbranched polyamidoamine.

Example 9

In DMSO, mix 20 μmol folic acid (FA) with 40 μmol 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), 40 μmol N-hydroxysuccinimide (NHS ) and 10 μL triethylamine were dissolved in 5 mL DMSO, and magnetically stirred at room temperature overnight to form FA active ester. Then the above reaction solution was slowly added to 15 μmol of the PEGylated hyperbranched polyamidoamine DMSO solution prepared in Example 6, and reacted at room temperature in the dark for 1 day. The crude product was purified by dialysis in distilled water and then lyophilized to form folic acid functionalized degradable Hyperbranched polyamidoamine carrier material.

The NMR results of the prepared folic acid functionalized degradable hyperbranched polyamidoamine are as follows:

¹ H NMR (400MHz, D ₂ O, δ): 8.55-8.74 (=N-CH=C<), 7.62-7.73, (-NH-C ₆ H ₄ -CONH-, two hydrogens near the amino group), 6.54-6.75 (-NH-C ₆ H ₄ -CONH-, two hydrogens near the carbonyl group), 4.41-4.52 (-CH ₂ -NH-C ₆ H ₄ ), 4.28-4.42 (-CH ₂ COOH), 3.59 -3.71(OCH ₂ CH ₂ OOCCH(CH ₃ )NH-), 3.75-3.85(OCH ₂ CH ₂ OOCCH(CH ₃ )NH-), 3.42-3.71(-CH ₂ CH ₂ O), 3.25-3.34(- OCH ₃ ), 3.12-3.27 (-NHCH ₂ -), 2.68-2.94 (>NCH ₂ -), 2.05-2.32 (-CH ₂ CH ₂ CON<), 1.93-2.08 (-CH ₂ CH ₂ CON<).

Example 10

In DMSO, 30 μmol folic acid (FA) was mixed with 50 μmol 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl), 50 μmol N-hydroxysuccinimide (NHS ) and 20 μL triethylamine were dissolved in 10 mL DMSO, and magnetically stirred at room temperature overnight to form FA active ester. Then slowly add the above reaction solution to 10 μmol of the PEGylated hyperbranched polyamidoamine DMSO solution prepared in Example 6, and react in the dark at room temperature for 1 day. The crude product is purified by dialysis in distilled water and freeze-dried to form folic acid functionalized degradable Hyperbranched polyamidoamine carrier material.

Example 11

The folic acid (FA) coupling degradable PEGylated hyperbranched polyamidoamine carrier material prepared in Example 9 was dissolved in TE buffer solution (pH7.5), and according to the ratio of 10:1 to 25:1, the material and The mass ratio of DNA was slowly added to an equal volume of DNA solution. The reaction mixed solution was gently vortexed with a vortex, and reacted at room temperature for 0.5h to 2h. Then electrophoresis was carried out, and the results are shown in Figure 4. From left to right in the figure are the experiments where the amount ratio of carrier material to DNA is 10:1, 15:1, 20:1 and 25:1. It can be seen from the figure that when the amount of material and DNA is 10:1, the The movement of DNA in the agarose gel can be completely blocked, indicating that the carrier material has a good ability to concentrate DNA.

Fig. 5 is a schematic diagram showing that the prepared degradable hyperbranched polyamidoamine can be broken correspondingly in reducing or acidic environment. Since the functional bifunctional monomer contains a disulfide bond or a ketal bond, it can be broken accordingly in a reducing or acidic environment. In the present invention, functional bifunctional monomers (containing disulfide bonds or ketal bonds) and trifunctional monomers containing amino groups 1-(2-aminoethyl)piperazine (AEPZ) or diethylenetriamine ( DETA) obtained degradable hyperbranched polyamidoamines with a large number of amino groups on the surface through one-pot Michael addition polymerization, and PEGylated folic acid-targeted degradable polyamidoamines could be obtained by modifying PEG and folic acid. Since the hyperbranched polymer has a large number of cavities inside and a large number of positively charged amino groups on the surface, it can be used to encapsulate drugs or genes, so it can be used as a drug carrier material. This polymer carrier material not only has good biocompatibility and active targeting, but also breaks and degrades a large number of internal disulfide bonds or ketal bonds in a reducing or acidic environment, so it can effectively control drug activity. It is an ideal drug carrier.

Claims (9)

1. A preparation method for degradable hyperbranched polyamidoamine, characterized in that it comprises the steps of: 2.0 to 6.0 mmol containing a disulfide bond or a ketal bond-containing difunctional monomer and 2.0 to 6.0 mmol containing an amino group trifunctional monomer Mix the functional group monomers in methanol or N, N-dimethylformamide, carry out Michael addition polymerization at 40-60°C under magnetic stirring, and add 2.0-6.0 mmol of bifunctional monomers again after 4-8 days to react 1 After ~3 days, the obtained product was purified and vacuum-dried at room temperature to obtain a final product degradable hyperbranched polyamidoamine. 2. the preparation method of degradable hyperbranched polyamidoamine according to claim 1, is characterized in that, described bifunctional monomer is N, N '-two (acryloyl) cystamine, 2,2-dimethyl Acryloyloxy-1-ethoxypropane or 2,2-dimethylacrylamido-1-ethoxypropane; the trifunctional monomer is 1-(2-amine ethyl)piperazine or diethylenetriamine. 3. A method for preparing a degradable PEGylated hyperbranched polyamidoamine, characterized in that it comprises the steps of: mixing 2.0 to 6.0 mmol of a bifunctional monomer containing a disulfide bond or a ketal bond with 2.0 to 6.0 mmol containing Amino trifunctional monomers are mixed in methanol or N,N-dimethylformamide, Michael addition polymerization is carried out at 40-60°C under magnetic stirring, and 2.0-6.0mmol polyethylene methacrylate is added after 4-8 days The diol ester is reacted for 1-3 days, the obtained product is purified, and then vacuum-dried at room temperature to obtain a degradable PEGylated hyperbranched polyamidoamine as the final product. 4. the preparation method of the degradable PEGylated hyperbranched polyamidoamine according to claim 3 is characterized in that, the bifunctional monomer is N, N'-bis(acryloyl)cystamine, 2,2 - any one of dimethylacryloyloxy-1-ethoxypropane or 2,2-dimethylacrylamide-1-ethoxypropane; the trifunctional monomer is 1-( 2-aminoethyl)piperazine or diethylenetriamine. 5. the preparation method of the degradable PEGylated hyperbranched polyamidoamine according to claim 3, is characterized in that, the weight-average molecular weight of described polyethylene glycol methacrylate is 350,750,1000,2000 or Any one or more of 5000. 6. A preparation method of folic acid functionalized degradable hyperbranched polyamidoamine, characterized in that, comprising the steps: (1) Mix 2.0 to 6.0 mmol of bifunctional monomers containing disulfide bonds or ketal bonds with 2.0 to 6.0 mmol of trifunctional monomers in methanol or N, N-dimethylformamide, 40 to 60 ° C, Carry out Michael addition polymerization under magnetic stirring, add 2.0-6.0mmol polyethylene glycol methacrylate to react for 1-3 days after 4-8 days, purify the obtained product, and then dry it in vacuum at room temperature to obtain degradable PEG Hyperbranched polyamidoamine; (2) Add 10-60 μmol folic acid, 10-60 μmol 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 10-60 μmol N-hydroxysuccinimide and 10-60 μmol Dissolve 20 μL triethylamine in 5-30 mL DMSO, stir overnight at room temperature with magnetic force to form FA active ester; then slowly add the above reaction solution to 10-60 μmol of degradable PEGylated hyperbranched polyamidoamine prepared in step (1) in DMSO solution at room temperature for 1 to 2 days in the dark, and the crude product was purified by dialysis in distilled water and then freeze-dried to obtain the final product folic acid functionalized degradable hyperbranched polyamidoamine. 7. the preparation method of folic acid functionalized degradable hyperbranched polyamidoamine according to claim 6, is characterized in that, described bifunctional monomer is N, N '-bis (acryloyl) cystamine, 2,2 - any one of dimethylacryloyloxy-1-ethoxypropane or 2,2-dimethylacrylamide-1-ethoxypropane; the trifunctional monomer is 1-( 2-aminoethyl)piperazine or diethylenetriamine. 8. the preparation method of folic acid functionalization degradable hyperbranched polyamidoamine according to claim 6, is characterized in that, the weight average molecular weight of described polyethylene glycol methacrylate is 350,750,1000,2000 or Any one or more of 5000. 9. The application of the final product prepared by the preparation method according to claim 1 or 3 or 6 as a carrier for drug controlled release.