Andrographolide molecular imprinting recessive drug carrier and preparation method thereof

Abstract

The invention discloses an andrographolide molecular imprinting recessive drug carrier and a preparation method thereof, and relates to the field of nanoscale drug carriers. The andrographolide molecular imprinting recessive drug carrier is prepared from the following raw materials in parts by weight: 2.5 to 4.3 parts of 2-ethyl-2-oxazoline; 1.529 to 2.584 parts of iodine; 2.28 to 4.573 parts of acetic anhydride; 0.332 to 0.968 part of a coarse carrier; the coarse carrier is an andrographolide molecularly imprinted material. The invention relates to a method for preparing an andrographolide molecular imprinting recessive drug carrier. The method comprises the following steps: preparing a coarse carrier; and preparing the drug carrier. According to the invention, iodine substitution, active group acetylation and poly (2-ethyl-2-oxazoline) substitution reaction are carried out on a crude carrier, and the drug carrier (ADR / PEOX-MMIP) with immune escape performance and pH / oxidation reduction / light response is prepared.

Description

Technical Field

[0001] The invention relates to the field of nano-scale drug carriers, in particular to an andrographolide molecular imprinting recessive drug carrier and a preparation method thereof. Background Art

[0002] Andrographolide (ADR) is a diterpene lactone compound extracted from the plant Andrographolide of the Acanthaceae family. Modern pharmacological studies have shown that andrographolide has anti-inflammatory, antibacterial, antiviral, antitumor, immunomodulatory, liver-protecting and choleretic effects. However, andrographolide itself has many shortcomings such as poor stability, low water solubility and low bioavailability, which greatly limits its clinical application.

[0003] Molecular imprinted polymer (MIP) is a polymer that has affinity with specific template molecules. Currently, MIP has been applied to the field of nanoscale drug carriers, especially in drug delivery systems (DDS), showing the potential for controlled release and large drug loading. However, MIP drug carriers with nanoscale size are often misidentified as pathogens or other harmful entities by the immune system in the body, and then cleared by the immune cells in the body, which makes the circulation time of MIP drug carriers carrying drugs in the blood shorter, and some drugs are cleared before they can be released, reducing the therapeutic effect.

[0004] In summary, it is of great significance to develop an andrographolide MIP drug carrier with immune escape properties based on molecular imprinting technology. Summary of the invention

[0005] The purpose of the present invention is to overcome the shortcomings of the prior art and to provide an andrographolide molecular imprinting stealth drug carrier and a preparation method thereof, which solves the problems of poor stability, low water solubility and low bioavailability in the current clinical application of andrographolide, and also solves the problem that the MIP drug carrier is easily cleared by the immune system in the body, resulting in reduced therapeutic effect.

[0006] The technical scheme of the present invention is: andrographolide molecular imprinting stealth drug carrier, the raw materials and weight proportions of the raw materials are as follows: 2.5-4.3 parts of 2-ethyl-2-oxazoline; 1.529-2.584 parts of iodine; 2.28-4.573 parts of acetic anhydride; 0.332-0.968 parts of crude carrier; the crude carrier is andrographolide molecular imprinting material.

[0007] A further technical solution of the present invention is: the raw materials and the weight proportions of the raw materials are as follows: 3.427 parts of 2-ethyl-2-oxazoline; 2.03 parts of iodine; 3.375 parts of acetic anhydride; and 0.578 parts of a crude carrier.

[0008] A further technical solution of the present invention is: the raw materials and the weight proportions of the raw materials are as follows: 3.427 parts of 2-ethyl-2-oxazoline; 1.529 parts of iodine; 2.28 parts of acetic anhydride; and 0.332 parts of a crude carrier.

[0009] A further technical solution of the present invention is: the raw materials and the weight proportions of the raw materials are as follows: 3.427 parts of 2-ethyl-2-oxazoline; 2.584 parts of iodine; 4.573 parts of acetic anhydride; and 0.968 parts of a crude carrier.

[0010] The technical solution of the present invention is: a method for preparing andrographolide molecular imprinting stealth drug carrier, the steps are as follows:

[0011] S01, prepare crude carrier:

[0012] a, Preparation of Fe3O4 microspheres coated with a thin SiO2 layer;

[0013] b, Preparation of hollow magnetic mesoporous SiO2 microspheres with multilayer SiO2;

[0014] c, grafting acryloyl β-cyclodextrin onto the product prepared in step b;

[0015] d, c are prepared in steps and the obtained product is reacted with andrographolide to form an inclusion compound;

[0016] e, d The andrographolide in the obtained product is bonded to the functional monomer via a non-covalent bond;

[0017] f, eluting andrographolide in the product prepared in step e to obtain a crude carrier ADR-MMIP;

[0018] S02, preparing drug carrier:

[0019] a, Preparation of ADR / I-MMIP based on the substitution reaction of iodine with the crude support;

[0020] b, acetylation of the active groups in ADR / I-MMIP;

[0021] c, The drug carrier ADR / PEOX-MMIP was prepared based on the substitution reaction of poly(2-ethyl-2-oxazoline) and ADR / I-MMIP with acetylated active groups.

[0022] A further technical solution of the present invention is: step S01 further includes pre-step I and pre-step II, the pre-step I is arranged before sub-step a, and the pre-step II is arranged before sub-step c; there is no order of precedence between the pre-step I and the pre-step II;

[0023] Preparing Fe3O4 microspheres: dissolving Fecl3·6H2O, C6H5O7Na3·H2O and urea in ultrapure water, stirring thoroughly, adding polyacrylamide and stirring continuously until completely dissolved to obtain solution No. Ⅰ; transferring solution No. Ⅰ to a polytetrafluoroethylene-lined autoclave, heating at 200°C for 12h, then cooling naturally to room temperature, collecting the obtained product with a magnet, washing repeatedly, and finally vacuum drying to obtain Fe3O4 microspheres;

[0024] Preparatory step II: Preparation of acryloyl β-cyclodextrin: dissolve β-cyclodextrin in KOH solution to obtain solution No. II; place solution No. II in an ice bath at 0-5°C, add acryloyl chloride dropwise to obtain solution No. III with floccules; react solution No. III at 40°C for 6h to generate a white precipitate; separate the precipitate and place it in ethanol, store it in a refrigerator at 0-12°C for 12h, and finally vacuum dry to obtain acryloyl β-cyclodextrin, recorded as AA-β-CD.

[0025] A further technical solution of the present invention is: each sub-step of step S01 is detailed as follows:

[0026] a. Preparation of Fe3O4 microspheres coated with a thin layer of SiO2: 0.204 parts of Fe3O4 microspheres were ultrasonically dispersed in solution No. 1 to obtain a Fe3O4 suspension; solution No. 1 consisted of 80.026 parts of ethanol, 20.627 parts of ultrapure water and 2.452 parts of 28% ammonia water; tetraethyl orthosilicate was added dropwise to the Fe3O4 suspension under stirring, and stirring was continued for 1 hour after the addition was completed, and then the obtained product was separated by a magnet, and then repeatedly washed, and finally vacuum dried to obtain Fe3O4&SiO2;

[0027] b. Preparation of hollow magnetic mesoporous SiO2 microspheres with multilayer SiO2: 0.204 parts of Fe3O4&SiO2 vacuum-dried powder were ultrasonically dispersed in 120.364 parts of ethanol, and then 2.452 parts of 28% ammonia water were added to obtain solution No. 2; 0.623 parts of pore-forming agent were ultrasonically dispersed and dissolved in 160 parts of pure water to obtain solution No. 3; solution No. 2 and solution No. 3 were stirred and mixed to obtain mixed solution No. 1, and ethyl orthosilicate was added dropwise to the mixed solution No. 1 while maintaining the stirring state. After the addition was completed, stirring was continued for 6 hours, and then the obtained product was separated by a magnet and repeatedly washed; then the obtained product was placed in anhydrous ethanol solution containing NH4NO3 with a mass concentration of 0.6%, and condensed and refluxed at 70°C for 24 hours to remove the pore-forming agent, and then the obtained product was separated by a magnet, and then repeatedly washed, and finally vacuum dried to obtain Fe3O4&SiO2&mSiO2;

[0028] c. Grafting acryloyl β-cyclodextrin onto the product prepared in step b: dissolving 0.328 parts of AA-β-CD in 10.01 parts of an organic solvent, adding sodium hydride, stirring under a nitrogen atmosphere, and filtering out the unreacted sodium hydride to obtain solution No. 4; placing solution No. 4 at 90°C, stirring and adding 0.124 parts of 3-glycidyloxypropyltrimethoxysilane, stirring for 5 hours after the addition, adding 0.423 parts of Fe3O4&SiO2&mSiO2, condensing and refluxing at 120°C for 20 hours, separating the product with a magnet, washing it thoroughly, and finally drying it in vacuum to obtain Fe3O4&SiO2&mSiO2-AA-β-CD;

[0029] d, c are prepared in steps to react the obtained product with andrographolide to form an inclusion compound: 0.223 parts of Fe3O4&SiO2&mSiO2-AA-β-CD are ultrasonically dispersed in 30.267 parts of ultrapure water, and then 35.112 parts of andrographolide are added, and the ultrasonic dispersion is continued for 6 hours, and then the product is stored in a refrigerator at 0-12°C for 12 hours, and then the obtained product is separated by a magnet, and then repeatedly washed, and finally vacuum dried to obtain Fe3O4&SiO2&mSiO2-AA-β-CD / ADR;

[0030] e, d are steps to prepare the andrographolide in the obtained product and bind it with the functional monomer through non-covalent bonds: 0.08 parts of Fe3O4&SiO2&mSiO2-AA-β-CD / ADR are ultrasonically dispersed in 17.235 parts of methanol, and then 0.029 parts of functional monomer are added, the functional monomer is 4-amino-4'-methylacrylamide azobenzene, and the reaction is carried out at room temperature for 12 hours to fully prepolymerize andrographolide and the functional monomer; then 0.446 parts of glycol dimethacrylate, 0.13 parts of N,N'-bis(acryloyl)cystamine, 0.062 parts of azobisisobutyronitrile, 0.0012 parts of copper bromide and 0.002 parts of pentamethyldiethylenetriamine are added, and the reaction is carried out at 70°C in a nitrogen atmosphere for 24 hours, and then the obtained product is separated with a magnet, and then fully washed and finally vacuum dried.

[0031] ADR-MMIP without eluted andrographolide was obtained;

[0032] f. Eluting the andrographolide in the obtained product in step e to obtain a crude carrier ADR-MMIP: The ADR-MMIP from which andrographolide has not been eluted is washed with methanol for multiple times, and then placed in a Soxhlet extractor. Then, andrographolide is repeatedly eluted with an eluent prepared with 70% by volume methanol and 30% by volume acetic acid until andrographolide is no longer detected in the eluent, and then the eluent is repeatedly washed with methanol.

[0033] Finally, vacuum drying was performed to obtain a crude carrier, which was named ADR-MMIP.

[0034] A further technical solution of the present invention is: each sub-step of step S02 is detailed as follows:

[0035] a. ADR / I-MMIP is prepared based on the substitution reaction of iodine and a crude carrier; 4.732-6.874 parts of dimethylformamide, 0.510-1.852 parts of triphenylphosphine and 1.529-2.584 parts of iodine are added to a flask, 0.332-0.968 parts of the crude carrier are added when heated to 70°C, and the mixture is reacted for 20 hours under a nitrogen atmosphere, and then 1.5-4.6 parts of a 3 mol / L sodium methoxide solution are added to obtain a mixed solution No. 2, and the mixed solution No. 2 is placed in an ice bath at 0-5°C for 20 minutes, and the obtained product is separated by a magnet, and then repeatedly washed, and finally vacuum dried to obtain ADR / I-MMIP;

[0036] b. Acetylate the active groups in ADR / I-MMIP: add 0.279-0.849 parts of vacuum-dried ADR / I-MMIP, 2.28-4.573 parts of acetic anhydride, 0.003-0.005 parts of 4-dimethylaminopyridine and 3.590-4.734 parts of pyridine into a flask, and react under condensation reflux at room temperature for 48 hours under a nitrogen atmosphere to obtain solution No. 5; pour solution No. 5 into 125.75-180.632 parts of ice water at 0-5°C, then separate the obtained product with a magnet, wash it repeatedly, and finally vacuum dry it to obtain ADR / I-MMIP with acetylated active groups;

[0037] c. Preparation of drug carrier ADR / PEOX-MMIP based on substitution reaction of poly(2-ethyl-2-oxazoline) and active group acetylated ADR / I-MMIP: 0.052-0.194 parts of active group acetylated ADR / I-MMIP, 2.5-4.2 parts of 2-ethyl-2-oxazoline and 14.209-16.305 parts of acetonitrile were added into a flask, and the mixture was condensed and refluxed at 80°C for 72 hours under nitrogen atmosphere. The product was then separated by a magnet, washed repeatedly, and finally dried in vacuum to obtain andrographolide molecularly imprinted stealth drug carrier: ADR / PEOX-MMIP; during the reaction, 2-ethyl-2-oxazoline was subjected to cationic ring-opening polymerization to obtain a hydrophilic long-chain polymer: poly(2-ethyl-2-oxazoline).

[0038] A further technical solution of the present invention is that the material portions involved in steps S01 and S02 are all portions by weight.

[0039] A further technical solution of the present invention is: the pore-forming agent in step b of step S01 is hexadecyltrimethylammonium bromide, and the organic solvent mentioned twice in step c of step S01 is N,N-dimethylformamide.

[0040] In step S02, the material portions involved are all parts by weight.

[0041] Compared with the prior art, the present invention has the following advantages:

[0042] 1. It selects the functional monomer "4-amino-4'-methylacrylamide azobenzene" with light / pH dual response characteristics and the cross-linking agent "N,N'-bis(acryloyl)cystamine" with redox response characteristics, and uses molecular imprinting technology and reverse atom transfer radical polymerization to prepare a crude carrier with pH / redox / light response; poly(2-ethyl-2-oxazoline) is introduced into the crude carrier to prepare the latent andrographolide imprinted poly(2-ethyl-2-oxazoline) drug carrier ADR / PEOX-MMIP.

[0043] 2. Compared with traditional andrographolide drug preparations, the latent andrographolide-imprinted poly (2-ethyl-2-oxazoline) drug carrier ADR / PEOX-MMIP has the characteristics of good stability, large drug loading capacity, precise release and low toxicity.

[0044] 3. The hidden material poly(2-ethyl-2-oxazoline) introduced into the drug carrier (ADR / PEOX-MMIP) enables the drug carrier to inhibit macrophage uptake, thereby increasing the circulation time of andrographolide in the blood and improving the therapeutic effect.

[0045] The present invention is further described below in conjunction with the figures and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 This is a flow chart for the preparation of crude vector ADR-MMIP;

[0047] Figure 2 for Figure 1 Structural diagram of two inclusion compounds (step e of step S01);

[0048] Figure 3 for Figure 1 Structural diagram of two prepolymerization products (step S01 e sub-step);

[0049] Figure 4 for Figure 1 Structural diagram of two grafted products (step c of step S01);

[0050] Figure 5 The flow chart for the preparation of andrographolide molecularly imprinted stealth drug carrier ADR / PEOX-MMIP;

[0051] Figure 6 for Figure 5 Structural diagram of ADR-MMIP without eluted andrographolide (step e of step S01);

[0052] Figure 7 for Figure 5 Structural diagram of ADR-MMIP (step f of step S01);

[0053] Figure 8 for Figure 5 Structural diagram of ADR / I-MMIP (step a of step S02);

[0054] Fig. 9 for Figure 5 Structural diagram of ADR / I-MMIP (step b of step S02) with acetylation of active groups;

[0055] Fig.10 for Figure 5 The structure of ADR / PEOX-MMIP (final product) in;

[0056] Fig.11 Comparison of infrared spectra of ADR-MMIP, ADR / I-MMIP, and ADR / PEOX-MMIP;

[0057] Fig.12 Transmission electron micrograph of ADR / PEOX-MMIP. DETAILED DESCRIPTION

[0058] Embodiment 1:

[0059] The andrographolide molecular imprinting stealth drug carrier has the following raw materials and weight proportions of each raw material: 3.427 parts of 2-ethyl-2-oxazoline, 2.03 parts of iodine, 3.375 parts of acetic anhydride, and 0.578 parts of a crude carrier. The crude carrier is an andrographolide molecular imprinting material.

[0060] Embodiment 2:

[0061] The andrographolide molecular imprinting stealth drug carrier has the following raw materials and weight proportions of each raw material: 3.427 parts of 2-ethyl-2-oxazoline, 1.529 parts of iodine, 2.28 parts of acetic anhydride, and 0.332 parts of a crude carrier. The crude carrier is an andrographolide molecular imprinting material.

[0062] Embodiment 3:

[0063] The andrographolide molecular imprinting stealth drug carrier has the following raw materials and weight proportions of each raw material: 3.427 parts of 2-ethyl-2-oxazoline, 2.584 parts of iodine, 4.573 parts of acetic anhydride, and 0.968 parts of a crude carrier. The crude carrier is an andrographolide molecular imprinting material.

[0064] Embodiment 4:

[0065] The andrographolide molecular imprinting stealth drug carrier has the following raw materials and weight proportions of each raw material: 2.5 parts of 2-ethyl-2-oxazoline, 2.03 parts of iodine, 2.28 parts of acetic anhydride, and 0.332 parts of a crude carrier. The crude carrier is an andrographolide molecular imprinting material.

[0066] Embodiment 5:

[0067] The andrographolide molecular imprinting stealth drug carrier has the following raw materials and weight proportions of each raw material: 4.3 parts of 2-ethyl-2-oxazoline, 2.03 parts of iodine, 4.573 parts of acetic anhydride, and 0.968 parts of a crude carrier. The crude carrier is an andrographolide molecular imprinting material.

[0068] Embodiment 6:

[0069] The andrographolide molecular imprinting stealth drug carrier has the following raw materials and weight proportions of each raw material: 2.5 parts of 2-ethyl-2-oxazoline, 1.529 parts of iodine, 3.375 parts of acetic anhydride, and 0.332 parts of a crude carrier, which is an andrographolide molecular imprinting material.

[0070] Embodiment 7:

[0071] The andrographolide molecular imprinting stealth drug carrier has the following raw materials and weight proportions of each raw material: 4.3 parts of 2-ethyl-2-oxazoline, 2.584 parts of iodine, 3.375 parts of acetic anhydride, and 0.968 parts of a crude carrier. The crude carrier is an andrographolide molecular imprinting material.

[0072] Embodiment 8:

[0073] The andrographolide molecular imprinting stealth drug carrier has the following raw materials and weight proportions of each raw material: 2.5 parts of 2-ethyl-2-oxazoline, 1.529 parts of iodine, 2.28 parts of acetic anhydride, and 0.578 parts of a crude carrier, which is an andrographolide molecular imprinting material.

[0074] Embodiment 9:

[0075] The andrographolide molecular imprinting stealth drug carrier has the following raw materials and weight proportions of each raw material: 2.5 parts of 2-ethyl-2-oxazoline, 1.529 parts of iodine, 4.573 parts of acetic anhydride, and 0.578 parts of a crude carrier, which is an andrographolide molecular imprinting material.

[0076] The preparation method of Example 1 is as follows:

[0077] S01, prepare crude carrier:

[0078] a. Preparation of Fe3O4 microspheres coated with a thin layer of SiO2: 0.204 parts of Fe3O4 microspheres were ultrasonically dispersed in solution No. 1 to obtain a Fe3O4 suspension; solution No. 1 consisted of 80.026 parts of ethanol, 20.627 parts of ultrapure water and 2.452 parts of ammonia water with a mass concentration of 28%; tetraethyl orthosilicate was added dropwise to the Fe3O4 suspension under stirring, and stirring was continued for 1 hour after the addition was completed, and then the obtained product was separated by a magnet, and then repeatedly washed with anhydrous ethanol and ultrapure water, and finally vacuum dried to obtain Fe3O4&SiO2;

[0079] b. Preparation of hollow magnetic mesoporous SiO2 microspheres with multilayer SiO2: 0.204 parts of Fe3O4&SiO2 vacuum-dried powder were ultrasonically dispersed in 120.364 parts of ethanol, and then 2.452 parts of 28% ammonia water were added to obtain solution No. 2; 0.623 parts of pore-forming agent were ultrasonically dispersed and dissolved in 160 parts of pure water to obtain solution No. 3; solution No. 2 and solution No. 3 were stirred and mixed to obtain mixed solution No. 1, and ethyl orthosilicate was added dropwise to the mixed solution No. 1 while maintaining the stirring state. After the addition was completed, stirring was continued for 6 hours, and then the obtained product was separated with a magnet and repeatedly washed; then the obtained product was placed in anhydrous ethanol solution containing NH4NO3 with a mass concentration of 0.6%, and condensed and refluxed at 70°C for 24 hours to remove the pore-forming agent, and then the obtained product was separated with a magnet, and then repeatedly washed with ultrapure water and ethanol, and finally vacuum dried to obtain Fe3O4&SiO2&mSiO2;

[0080] c. Grafting acryloyl β-cyclodextrin onto the product prepared in step b: dissolving 0.328 parts of AA-β-CD in 10.01 parts of an organic solvent, adding sodium hydride, stirring under a nitrogen atmosphere, and filtering out the unreacted sodium hydride to obtain solution No. 4; placing solution No. 4 at 90°C, stirring and adding 0.124 parts of 3-glycidyloxypropyltrimethoxysilane, stirring for 5 hours after the addition, adding 0.423 parts of Fe3O4&SiO2&mSiO2, condensing and refluxing at 120°C for 20 hours, separating the product with a magnet, and then washing with an organic solvent, ultrapure water, methanol and acetone in turn, and finally drying under vacuum to obtain Fe3O4&SiO2&mSiO2-AA-β-CD;

[0081] d, c are prepared in steps to react the obtained product with andrographolide to form an inclusion compound: 0.223 parts of Fe3O4&SiO2&mSiO2-AA-β-CD are ultrasonically dispersed in 30.267 parts of ultrapure water, and then 35.112 parts of andrographolide are added, and the ultrasonic dispersion is continued for 6 hours, and then the product is stored in a refrigerator at 0-12°C for 12 hours, and then the obtained product is separated by a magnet, and then repeatedly washed with ultrapure water, and finally vacuum dried to obtain Fe3O4&SiO2&mSiO2-AA-β-CD / ADR;

[0082] e, d are steps to prepare the andrographolide in the obtained product and bind it to the functional monomer through non-covalent bonds: 0.08 parts of Fe3O4&SiO2&mSiO2-AA-β-CD / ADR are ultrasonically dispersed in 17.235 parts of methanol, and then 0.029 parts of functional monomer are added, the functional monomer is 4-amino-4'-methylacrylamide azobenzene, and the reaction is carried out at room temperature for 12 hours to fully prepolymerize andrographolide and the functional monomer; then 0.446 parts of glycol dimethacrylate, 0.13 parts of N,N'-bis(acryloyl)cystamine, 0.062 parts of azobisisobutyronitrile, 0.0012 parts of copper bromide and 0.002 parts of pentamethyldiethylenetriamine are added, and the reaction is carried out at 70°C in a nitrogen atmosphere for 24 hours, and then the obtained product is separated by a magnet, and then fully washed and finally vacuum dried to obtain ADR-MMIP without eluting andrographolide;

[0083] f. Eluting andrographolide from the product prepared in step e to obtain a crude carrier ADR-MMIP: The ADR-MMIP from which andrographolide has not been eluted is rinsed with methanol for multiple times, and then placed in a Soxhlet extractor. The andrographolide is then repeatedly eluted with an eluent composed of 70% by volume methanol and 30% by volume acetic acid until andrographolide is no longer detected in the eluent. The product is then repeatedly washed with methanol to remove the eluent, and finally dried in vacuum to obtain a crude carrier, which is recorded as ADR-MMIP.

[0084] S02, preparing drug carrier:

[0085] a. ADR / I-MMIP is prepared based on the substitution reaction of iodine and a crude carrier; 4.732-6.874 parts of dimethylformamide, 0.510-1.852 parts of triphenylphosphine and 1.529-2.584 parts of iodine are added to a round-bottom flask, 0.332-0.968 parts of the crude carrier are added when heated to 70°C, and the mixture is reacted for 20 hours under a nitrogen atmosphere, and then 1.5-4.6 parts of a 3 mol / L sodium methoxide solution are added to obtain a mixed solution No. 2, and the mixed solution No. 2 is placed in an ice bath at 0-5°C for 20 minutes, and the obtained product is separated by a magnet, and then repeatedly washed with methanol, and finally dried under vacuum at room temperature to obtain ADR / I-MMIP;

[0086] b. Acetylate the active groups in ADR / I-MMIP: add 0.279-0.849 parts of vacuum-dried ADR / I-MMIP, 2.28-4.573 parts of acetic anhydride, 0.003-0.005 parts of 4-dimethylaminopyridine and 3.590-4.734 parts of pyridine to a round-bottom flask, and react under condensation reflux at room temperature for 48 hours under a nitrogen atmosphere to obtain solution No. 5; pour solution No. 5 into 125.75-180.632 parts of ice water at 0-5°C, then separate the obtained product with a magnet, and then repeatedly wash it with methanol, and finally dry it under vacuum at room temperature to obtain ADR / I-MMIP with acetylated active groups;

[0087] c. Preparation of ADR / PEOX-MMIP based on the substitution reaction of poly(2-ethyl-2-oxazoline) and active group acetylated ADR / I-MMIP: 0.052-0.194 parts of active group acetylated ADR / I-MMIP, 2.5-4.2 parts of 2-ethyl-2-oxazoline and 14.209-16.305 parts of acetonitrile were added into a flask, and the mixture was condensed and refluxed at 80°C for 72 hours under a nitrogen atmosphere. The product was then separated by a magnet, washed repeatedly, and finally dried in vacuum to obtain andrographolide molecularly imprinted stealth drug carrier: ADR / PEOX-MMIP; during the reaction, 2-ethyl-2-oxazoline was subjected to cationic ring-opening polymerization to obtain a hydrophilic long-chain polymer: poly(2-ethyl-2-oxazoline).

[0088] Preferably, the pore-forming agent in step b of S01 is hexadecyltrimethylammonium bromide, and the organic solvent mentioned twice in step c of S01 is N,N-dimethylformamide.

[0089] Preferably, step S01 further includes pre-processing I and pre-processing II, wherein pre-processing I is arranged before sub-step a, and pre-processing II is arranged before sub-step c; there is no order of precedence between pre-processing I and pre-processing II. In pre-processing I and pre-processing II, the parts involved are all parts by weight.

[0090] Preparing Fe3O4 microspheres: dissolving Fecl3·6H2O, C6H5O7Na3·H2O and urea in ultrapure water, stirring thoroughly, adding polyacrylamide and stirring continuously until completely dissolved to obtain solution No. Ⅰ; transferring solution No. Ⅰ to a polytetrafluoroethylene-lined autoclave, heating at 200°C for 12h, then cooling naturally to room temperature, collecting the obtained product with a magnet, and then repeatedly washing with anhydrous ethanol and ultrapure water, and finally vacuum drying to obtain Fe3O4 microspheres;

[0091] Preparatory step II: Preparation of acryloyl β-cyclodextrin: dissolving β-cyclodextrin in KOH solution to obtain solution No. II; placing solution No. II in an ice bath at 0-5°C, adding acryloyl chloride dropwise to obtain solution No. III with flocs; reacting solution No. III at 40°C for 6 hours to generate a white precipitate; separating the precipitate and placing it in ethanol, which is then placed in a refrigerator at 0-12°C for 12 hours and finally dried in vacuo to obtain acryloyl β-cyclodextrin, recorded as AA-β-CD.

[0092] Explanation of special terms: Poly(2-ethyl-2-oxazoline) is the name of the drug, which is clearly recorded in the Material Safety Data Sheet of Poly(2-ethyl-2-oxazoline) issued by Alfa Aesar (China) Chemical Co., Ltd.

[0093] The preparation method of Example 1 is briefly described in conjunction with the accompanying drawings:

[0094] See also Figures 1 to 4 , Fe3O4 reacts with TEOS (tetraethyl orthosilicate) to generate Fe3O4&SiO2 (S01 step a sub-step product), then Fe3O4&SiO2 reacts with CTAB (hexadecyltrimethylammonium bromide) and TEOS (tetraethyl orthosilicate), removes CTAB, and generates Fe3O4&SiO2&mSiO2 (S01 step b sub-step product). AA-β-CD (acryloyl β-cyclodextrin) is grafted onto Fe3O4&SiO2&mSiO2 to generate Fe3O4&SiO2&mSiO2-AA-β-CD (S01 step c sub-step product). Andrographolide (ADR) is embedded in Fe3O4&SiO2&mSiO2-AA-β-CD to form an inclusion complex, and two structures of Fe3O4&SiO2&mSiO2-AA-β-CD / ADR (S01 step d sub-step product) are obtained. The two structures of Fe3O4&SiO2&mSiO2-AA-β-CD / ADR are pre-polymerized with a functional monomer (4-amino-4'-methylacrylamidoazobenzene) to generate two structures of pre-polymer products. The two structures of pre-polymer products are combined with a cross-linking agent, an initiator and a catalyst, and RATRP (reverse atom transfer radical polymerization method) is used to generate ADR-MMIP without eluting andrographolide (S01 step e sub-step product). The ADR-MMIP without eluting andrographolide is eluted (removing) andrographolide (ADR) to obtain a crude carrier ADR-MMIP (S01 step f sub-step product).

[0095] See also Figures 5 to 10, from left to right in the upper left corner of the figure are ADR-MMIP without eluted andrographolide and ADR-MMIP, respectively. ADR-MMIP undergoes substitution reaction with iodine to generate ADR / I-MMIP (S02 step a sub-step product). ADR / I-MMIP reacts with 4-dimethylaminopyridine (DMAP Pyridine) and acetic anhydride ((CH3CO)2O) to generate active group acetylated ADR / I-MMIP (S02 step b sub-step product). ADR / I-MMIP undergoes substitution reaction with poly (2-ethyl-2-oxazoline) to generate the final product: andrographolide molecular imprinting stealth drug carrier ADR / PEOX-MMIP.

[0096] See also Fig.11 In the figure, ac are the infrared spectra of ADR-MMIP (step f product of S01), ADR / I-MMIP (step a product of S02) and ADR / PEOX-MMIP (final product), respectively. Compared with a, the 3386 cm-1 wavelength generated by the OH stretching vibration of β-cyclodextrin in b is -1 The peak at 522cm becomes very weak and almost disappears. -1 and 463cm -1 The peak at 2919cm-1 is also significantly stronger, which is caused by the stretching vibration of CI, indicating that -OH is replaced by iodine. -1 The peak at 522cm -1 The band intensity at 1646cm -1 and 1059cm -1 Two new absorption peaks appeared at , which were caused by the stretching vibration of C=O and CN in PEOX. All the above information showed that PEOX had been successfully transplanted onto the imprinting layer.

[0097] See also Fig.12 , transmission electron micrographs are usually used to reflect the morphology and structure of microscopic particles. It can be seen that ADR / PEOX-MMIP has a relatively regular spherical structure with a diameter of about 200nm. The black part of the sphere is the Fe3O4 core, and there is a light-colored part inside the Fe3O4 core, indicating that the Fe3O4 core has a hollow structure. In addition, the outer surface of the Fe3O4 core has a lighter-colored fuzzy structure, which contains a mesoporous SiO2 layer and PEOX hidden materials, indicating that ADR / PEOX-MMIP was successfully prepared.

[0098] The key technologies in the preparation of ADR / PEOX-MMIP are as follows:

[0099] 1. The functional monomer "4-amino-4'-methacrylamide azobenzene" with light / PH dual response characteristics and the cross-linking agent "N,N'-bis(acryloyl)cystamine" with redox response characteristics were selected, and molecular imprinting technology and reverse atom transfer radical polymerization were used to prepare a crude carrier with pH / redox / light response;

[0100] 2. The β-cyclodextrin in the crude carrier contains a large number of hydroxyl groups. Under the catalysis of triphenylphosphine, iodine reacts with the hydroxyl groups to generate ADR / I-MMIP;

[0101] 3. Acetylate the amine groups and unreacted hydroxyl groups in ADR / I-MMIP using acetic anhydride, 4-dimethylaminopyridine (catalyst) and pyridine (catalyst) to generate ADR / I-MMIP with acetylated active groups;

[0102] 4. Poly(2-ethyl-2-oxazoline) was selected to replace the iodine in the active group acetylated ADR / I-MMIP to generate andrographolide molecular imprinting stealth drug carrier.

[0103] Combined with comparative experiments, the technical effect of ADR / PEOX-MMIP is explained:

[0104] The following experiments also involve ADR / PEOX-MNIP (a drug carrier prepared without molecular imprinting technology), drug-loaded ADR / PEOX-MMIP, and drug-loaded ADR-MMIP. Among them, ADR / PEOX-MNIP is prepared based on the preparation method in Example 1, except for the step of adding andrographolide (step d of S01). Among them, drug-loaded ADR / PEOX-MMIP is ADR / PEOX-MMIP prepared based on the preparation method in Example 1, which is soaked in an ADR solution to fully adsorb ADR, and then separated by a magnet, fully washed and vacuum dried. Among them, drug-loaded ADR-MMIP is ADR-MMIP prepared based on the preparation method in Example 1, which is soaked in an ADR solution to fully adsorb ADR, and then separated by a magnet, fully washed and vacuum dried.

[0105] Experiment 1: Dynamic adsorption experiment of ADR / PEOX-MMIP on template molecules. By comparing the adsorption performance of ADR / PEOX-MMIP and ADR / PEOX-MNIP at the same concentration but different adsorption times, it is proved that the drug carrier prepared by molecular imprinting technology has relatively better adsorption performance.

[0106] Experimental procedure: 33 mg of ADR / PEOX-MMIP in Example 1 was taken and divided into 11 portions, each of 3 mg. The 11 portions of ADR / PEOX-MMIP were dispersed in 11 portions of 0.08 mg·mL-1 33 mg of ADR / PEOX-MNIP (drug carrier prepared without molecular imprinting technology) was taken and divided into 11 portions, each with 3 mg. The 11 portions of ADR / PEOX-MNIP (drug carrier prepared without molecular imprinting technology) were dispersed in 11 portions of 0.08 mg mL -1 5mL of andrographolide methanol solution was used as the control group. All samples in the experimental group and the control group were subjected to oscillation operation. The 11 samples in the experimental group were subjected to solid-liquid separation with an external magnetic field at 1, 3, 5, 7, 10, 15, 20, 30, 40, 50, and 60min, respectively. The 11 samples in the control group were subjected to solid-liquid separation with an external magnetic field at 1, 3, 5, 7, 10, 15, 20, 30, 40, 50, and 60min, respectively, to obtain 22 supernatants. UV detection was performed on the 22 supernatants and their respective adsorption capacities were calculated. The experimental group and the control group were tested in parallel 3 times, and the final result was the average value of the 3 experiments. The experimental data are shown in Table 1.

[0107] Table 1: Experimental data of dynamic adsorption of template molecules

[0108]

[0109]

[0110] Results analysis: As shown in Table 1, the adsorption capacity of ADR / PEOX-MNIP for template molecules (andrographolide) in both the experimental and control groups increased with time, and both reached adsorption equilibrium in 3 minutes. Under the same conditions, the adsorption capacity of the experimental group was significantly greater than that of the control group.

[0111] Experiment 2: Static adsorption experiment of ADR / PEOX-MMIP on template molecules. By comparing the adsorption performance of ADR / PEOX-MMIP and ADR / PEOX-MNIP at different concentrations and the same adsorption time, it is proved that the drug carrier prepared by molecular imprinting technology has relatively better adsorption performance.

[0112] Take 36mg of ADR / PEOX-MMIP in Example 1, divide it into 12 parts, each 3mg, and 12 parts of ADR / PEOX-MMIP are dispersed in 12 parts of andrographolide methanol solutions (5mL) with gradient distribution of concentration as the experimental group. Take 36mg of ADR / PEOX-MNIP (drug carrier prepared by molecular imprinting technology not used), divide it into 12 parts, each 3mg, and 12 parts of ADR / PEOX-MNIP (drug carrier prepared by molecular imprinting technology not used) are dispersed in 12 parts of andrographolide methanol solutions (5mL) with gradient distribution of concentration as the control group. A total of 24 samples of the experimental group and the control group are shaken at room temperature for 3min and then solid-liquid separation is carried out with an external magnetic field to obtain 24 parts of supernatants. UV detection is carried out on 24 parts of supernatants respectively and the adsorption capacity of each is calculated. The experimental group and the control group are all parallel experiments 3 times, and the final result is the average value of 3 experiments, and the experimental data are shown in Table 2.

[0113] Table 2: Experimental data of static adsorption of template molecules by two materials

[0114]

[0115]

[0116] Results analysis: As shown in Table 2, the adsorption capacity of ADR / PEOX-MMIP in the experimental group and ADR / PEOX-MNIP in the control group for the template molecule (andrographolide) increased with the increase of andrographolide concentration. -1 When the adsorption capacity of ADR / PEOX-MMIP and ADR / PEOX-MNIP both tended to be stable (i.e., reached the maximum adsorption capacity). And under the same conditions, the adsorption capacity of the experimental group was significantly greater than that of the control group.

[0117] Experiment 3: ADR / PEOX-MMIP selective adsorption experiment on template molecules. By comparing the adsorption amount of ADR / PEOX-MMIP on andrographolide and dehydroandrographolide of the same concentration, it is proved that ADR / PEOX-MMIP has a strong selective adsorption ability for ADR.

[0118] Experimental procedure: Take 3 mg of ADR / PEOX-MMIP from Example 1 and add it to a solute concentration of 0.08 mg·mL -1 3 mg of ADR / PEOX-MNIP was added to the adsorbent solution with a solute concentration of 0.08 mg mL -1of the solution to be adsorbed, as a control group. The solvent of the adsorption solution is anhydrous methanol, and the solute of the adsorption solution is a mixture of andrographolide and dehydroandrographolide (the mass fractions of the two are equal). After 2 samples of the control group and the experimental group were oscillated at room temperature for 3 minutes, solid-liquid separation was performed in an external magnetic field to obtain 2 supernatants. The concentrations of andrographolide and dehydroandrographolide in the 2 supernatants were detected by UV, and the adsorption amounts of andrographolide and dehydroandrographolide in the experimental group and the control group were calculated respectively. The experimental group and the control group were tested in parallel 3 times, and the final result was the average value of the 3 experiments. The experimental data are shown in Table 3.

[0119] Table 3: Experimental data of selective adsorption of template molecules

[0120]

[0121]

[0122] Results analysis: From Table 3, we can see that the distribution coefficient of andrographolide in the experimental group (156.73 mL·g -1 ) is much larger than the distribution coefficient of dehydroandrographolide (69.55 mL·g -1 ), and the relative selectivity coefficient of ADR / PEOX-MMIP in the experimental group for andrographolide (2.25) was much greater than that of ADR / PEOX-MNIP in the control group (1.57). The selective adsorption of andrographolide by ADR / PEOX-MMIP was 1.44 times that of ADR / PEOX-MNIP, which fully demonstrated that ADR / PEOX-MMIP had a strong selective recognition ability for andrographolide.

[0123] Experiment 4: Experiment on the release performance of template molecules by ADR / PEOX-MMIP. By comparing the cumulative release rate of ADR from drug-loaded ADR / PEOX-MMIP under different pH environments, it is proved that the release of template molecules from ADR / PEOX-MMIP has pH responsiveness. By comparing the cumulative release rate of ADR from drug-loaded ADR / PEOX-MMIP with or without the addition of glutathione (GSH), it is proved that the release of template molecules from ADR / PEOX-MMIP has redox responsive characteristics. By comparing the cumulative release rate of ADR from drug-loaded ADR / PEOX-MMIP with or without light, it is proved that the release of template molecules from ADR / PEOX-MMIP has light responsive characteristics.

[0124] Experimental process: 80 mg of drug-loaded ADR / PEOX-MMIP was divided into 8 portions, each with 10 mg. The 8 portions of ADR / PEOX-MMIP were dispersed in 8 buffers (20 mL) with different conditions (condition variables: different pH, presence or absence of reduced reagent, and presence or absence of external light). The 8 samples were oscillated at room temperature and 3 mL of supernatant (the supernatant did not contain drug-loaded ADR / PEOX-MMIP) was taken out from the 8 samples at a predetermined time interval. In order to maintain the total volume of the solution at 20 mL, an equal volume of the original solution should be added immediately after each supernatant was taken out. The concentration of andrographolide in the supernatant taken out each time was measured by UV, so as to calculate the cumulative release rate of andrographolide at different times. The above experimental process was repeated 3 times in parallel, and the final result was the average value of the 3 experiments. The experimental data are shown in Table 4.

[0125] Table 4: Experimental data on release performance of andrographolide

[0126]

[0127]

[0128] Experimental results: As shown in Table 4, the cumulative release of andrographolide from ADR / PEOX-MMIP under different conditions gradually increased with time until the release equilibrium was reached.

[0129] By comparing the three vertical columns of data with only pH variables, it can be seen that the cumulative release rate of ADR from drug-loaded ADR / PEOX-MMIP increases with the increase of solution pH value, reaching a maximum value of 29.99% at a pH value of 8.2, proving that ADR / PEOX-MMIP has pH-responsive characteristics under different pH conditions.

[0130] Comparing the six vertical columns of data with and without the addition of the reducing agent GSH, it can be seen that when GSH is present, the cumulative release rate of ADR from the drug-loaded ADR / PEOX-MMIP is significantly increased. For example, at 210h, the maximum cumulative release rate increased from 10.94%, 16.71% and 28.78% to 16.44%, 20.64% and 44.38%, respectively, which fully demonstrates that ADR / PEOX-MMIP is sensitive to the reducing environment.

[0131] Comparing the data of the four vertical columns with and without visible light (410nm UVS), it can be seen that under the condition of visible light VIS (410nm UVS) irradiation, the cumulative release rate of ADR from drug-loaded ADR / PEOX-MMIP increased significantly. For example, at pH 8.2 and 10mM GSH, the irradiation of visible light VIS can increase the cumulative release rate from 44.38% to 73.10% at 210h.

[0132] In summary, the release of andrographolide from ADR / PEOX-MMIP has multiple responses to pH / redox / light.

[0133] Experiment 5: Inhibition of macrophage phagocytosis experiment, by observing the phagocytosis of mouse macrophages to different concentrations of drug-loaded ADR / PEOX-MMIP and different concentrations of drug-loaded ADR / PEOX-MMIP, it was proved that ADR / PEOX-MMIP has immune escape characteristics.

[0134] Experimental process:

[0135] Macrophage culture: One strain (one tube) of RAW264.7 mouse macrophages was cultured in DMEM medium containing 10% fetal bovine serum and 1% antibiotic-antimycotic solution. The concentration of the cell suspension was adjusted using DMEM medium to a final concentration of 8×10 4 CFU·mL -1 Then, 100 μL of the cell suspension was inoculated into two groups of 96-well plates (the amount of cell suspension in each well of the two groups of well plates was the same). The two groups of well plates were named well plate A and well plate B, and the inoculation area on each well plate was divided into four sub-areas, named A-1, A-2, A-3, A-4, B-1, B-2, B-3 and B-4, respectively. Well plates A and B were cultured in an incubator at 37°C and 5% CO2 for 24 h.

[0136] Preparation of drug-loaded solution: The loading capacity of ADR (andrographolide) in ADR-MMIP and ADR / PEOX-MMIP is 41.43 mg·mL -1 and 11.46 mg·mL- are 1, in order to achieve the purpose of containing equal amounts of ADR (andrographolide), the concentrations of drug-loaded ADR-MMIP are configured to be 0, 4.83, 12.07, and 24.14 μg·mL -1 Four groups of DMEM culture medium solutions were prepared with drug-loaded ADR / PEOX-MMIP concentrations of 0, 17.45, 43.63, and 67.26 μg mL -1 The concentration of drug-loaded ADR-MMIP was 4.83 μg mL -1 The concentration of ADR / PEOX-MMIP in DMEM medium was 17.45 μg mL -1 The ADR concentration in the DMEM medium solution was 0.2 μg mL -1 ; Among them, the concentration of drug-loaded ADR-MMIP was 12.07 μg·mL -1 The concentration of ADR / PEOX-MMIP in DMEM medium was 43.63 μg·mL -1The DMEM medium solution contained ADR at a concentration of 0.5 μg mL -1 ; Among them, the concentration of drug-loaded ADR-MMIP was 24.14 μg·mL -1 The concentration of ADR / PEOX-MMIP in DMEM medium was 67.26 μg mL -1 The DMEM medium solution contained ADR at a concentration of 1 μg mL -1 .

[0137] Take 25 μL of each of the solution with a drug-loaded ADR-MMIP concentration of 0, the solution with a drug-loaded ADR-MMIP concentration of 4.83, the solution with a drug-loaded ADR-MMIP concentration of 12.07, the solution with a drug-loaded ADR-MMIP concentration of 24.14, the solution with a drug-loaded ADR / PEOX-MMIP concentration of 0, the solution with a drug-loaded ADR / PEOX-MMIP concentration of 17.45, the solution with a drug-loaded ADR / PEOX-MMIP concentration of 43.63, and the solution with a drug-loaded ADR / PEOX-MMIP concentration of 67.26, and add them to all wells in the A-1 area, all wells in the A-2 area, all wells in the A-3 area, all wells in the A-4 area, all wells in the B-1 area, all wells in the B-2 area, all wells in the B-3 area, and all wells in the B-4 area. The 4 groups of solutions added to plate A are used as the control group, and the 4 groups of solutions added to plate B are used as the experimental group. After the above addition operation was completed, the two well plates were cultured in an incubator at 37° C. and 5% CO 2 for 24 h to allow the macrophages to fully phagocytize the drug-loaded ADR-MMIP or drug-loaded ADR / PEOX-MMIP.

[0138] The supernatant in each well was removed by suction (to remove dead cells) to ensure that the cells in each well of the two wells were all living cells. The solutions in each well of the two wells were then washed with PBS (phosphate buffer) (the internal solutions of the wells in the four sub-areas of each well were washed separately to wash away the drug-loaded ADR-MMIP or drug-loaded ADR / PEOX-MMIP in the external solution of the living cells), and then an appropriate amount of cell lysis solution was added to each well of the two wells and repeatedly shaken, and finally the absorbance of the solution in each well of the two wells was measured by UV (224nm), so as to calculate the ADR concentration in the 4 solutions of the experimental group and the 4 solutions of the control group. The experiment was repeated 3 times, and the final result was the average value. The experimental data are shown in Table 5.

[0139]

[0140] Experimental results: As shown in Table 5, at different ADR initial concentrations (0.2, 0.5, 1 μg mL -1), the absorbance values ​​of andrographolide in the experimental group were lower than those in the control group. SPSS statistical analysis showed that the relevant differences between the two at any concentration were statistically significant (P<0.05). This shows that the phagocytosis of ADR / PEOX-MMIP by RAW264.7 mouse macrophages is significantly less than that of ADR-MMIP. Therefore, ADR / PEOX-MMIP can inhibit the uptake of macrophages, that is, ADR / PEOX-MMIP has immune escape characteristics.

Claims

1. Andrographolide molecular imprinting stealth drug carrier, characterized by: The raw materials and the weight proportion of each raw material are as follows: 2.5-4.3 parts of 2-ethyl-2-oxazoline; 1.529-2.584 parts of iodine; 2.28-4.573 parts of acetic anhydride; 0.332-0.968 parts of crude carrier; the crude carrier is andrographolide molecular imprinting material.

2. The andrographolide molecularly imprinted stealth drug carrier according to claim 1, characterized in that: The raw materials and the weight proportion of each raw material are as follows: 3.427 parts of 2-ethyl-2-oxazoline; 2.03 parts of iodine; 3.375 parts of acetic anhydride; and 0.578 parts of a crude carrier.

3. The andrographolide molecularly imprinted stealth drug carrier according to claim 2, characterized in that: The raw materials and the weight proportion of each raw material are as follows: 3.427 parts of 2-ethyl-2-oxazoline; 1.529 parts of iodine; 2.28 parts of acetic anhydride; and 0.332 parts of a crude carrier.

4. The andrographolide molecularly imprinted stealth drug carrier according to claim 2, characterized in that: The raw materials and the weight proportion of each raw material are as follows: 3.427 parts of 2-ethyl-2-oxazoline; 2.584 parts of iodine; 4.573 parts of acetic anhydride; and 0.968 parts of a crude carrier.

5. A method for preparing the andrographolide molecularly imprinted stealth drug carrier according to any one of claims 1 to 4, characterized in that the steps as follows: S01, prepare crude carrier: a, Preparation of Fe3O4 microspheres coated with a thin SiO2 layer; b, Preparation of hollow magnetic mesoporous SiO2 microspheres with multilayer SiO2; c, grafting acryloyl β-cyclodextrin onto the product prepared in step b; d, c are prepared in steps and the obtained product is reacted with andrographolide to form an inclusion compound; e, d The andrographolide in the obtained product is bonded to the functional monomer via a non-covalent bond; f, eluting andrographolide in the product prepared in step e to obtain a crude carrier; S02, preparing drug carrier: a, Preparation of ADR / I-MMIP based on the substitution reaction of iodine with the crude support; b, acetylation of the active groups in ADR / I-MMIP; c, The drug carrier ADR / PEOX-MMIP was prepared based on the substitution reaction of poly(2-ethyl-2-oxazoline) and the active group acetylated ADR / I-MMIP.

6. The method for preparing the andrographolide molecularly imprinted stealth drug carrier according to claim 5, characterized in that: Step S01 also includes pre-step I and pre-step II, wherein step I is provided before sub-step a, and step II is provided before sub-step c; there is no order of precedence between steps I and II; Preparing Fe3O4 microspheres: dissolving Fecl3·6H2O, C6H5O7Na3·H2O and urea in ultrapure water, stirring thoroughly, adding polyacrylamide and stirring continuously until completely dissolved to obtain solution No. Ⅰ; transferring solution No. Ⅰ to a polytetrafluoroethylene-lined autoclave, heating at 200°C for 12h, then cooling naturally to room temperature, collecting the obtained product with a magnet, washing repeatedly, and finally vacuum drying to obtain Fe3O4 microspheres; Preparing step II: preparing acryloyl β-cyclodextrin: dissolving β-cyclodextrin in KOH solution to obtain solution II; Solution II was placed in an ice bath at 0-5°C, and acryloyl chloride was added dropwise to obtain solution III with flocs; solution III was reacted at 40°C for 6 hours to generate a white precipitate; the precipitate was separated and placed in ethanol, and then placed in a refrigerator at 0-12°C for 12 hours, and finally vacuum dried to obtain acryloyl β-cyclodextrin, recorded as AA-β-CD.

7. The method for preparing the andrographolide molecularly imprinted stealth drug carrier according to claim 6, characterized in that: The various sub-steps of step S01 are detailed as follows: a. Preparation of Fe3O4 microspheres coated with a thin layer of SiO2: 0.204 parts of Fe3O4 microspheres were ultrasonically dispersed in solution No. 1 to obtain a Fe3O4 suspension; solution No. 1 consisted of 80.026 parts of ethanol, 20.627 parts of ultrapure water and 2.452 parts of 28% ammonia water; tetraethyl orthosilicate was added dropwise to the Fe3O4 suspension under stirring, and stirring was continued for 1 hour after the addition was completed, and then the obtained product was separated by a magnet, and then repeatedly washed, and finally vacuum dried to obtain Fe3O4&SiO2; b. Preparation of hollow magnetic mesoporous SiO2 microspheres with multilayer SiO2: 0.204 parts of Fe3O4&SiO2 vacuum-dried powder were ultrasonically dispersed in 120.364 parts of ethanol, and then 2.452 parts of 28% ammonia water were added to obtain solution No. 2; 0.623 parts of pore-forming agent were ultrasonically dispersed and dissolved in 160 parts of pure water to obtain solution No. 3; solution No. 2 and solution No. 3 were stirred and mixed to obtain mixed solution No. 1, and ethyl orthosilicate was added dropwise to the mixed solution No. 1 while maintaining the stirring state. After the addition was completed, stirring was continued for 6 hours, and then the obtained product was separated by a magnet and repeatedly washed; then the obtained product was placed in anhydrous ethanol solution containing NH4NO3 with a mass concentration of 0.6%, and condensed and refluxed at 70°C for 24 hours to remove the pore-forming agent, and then the obtained product was separated by a magnet, and then repeatedly washed, and finally vacuum dried to obtain Fe3O4&SiO2&mSiO2; c. Grafting acryloyl β-cyclodextrin onto the product prepared in step b: dissolving 0.328 parts of AA-β-CD in 10.01 parts of an organic solvent, adding sodium hydride, stirring under a nitrogen atmosphere, and filtering out the unreacted sodium hydride to obtain solution No. 4; placing solution No. 4 at 90°C, stirring and adding 0.124 parts of 3-glycidyloxypropyltrimethoxysilane, stirring for 5 hours after the addition, adding 0.423 parts of Fe3O4&SiO2&mSiO2, condensing and refluxing at 120°C for 20 hours, separating the product with a magnet, washing it thoroughly, and finally drying it in vacuum to obtain Fe3O4&SiO2&mSiO2-AA-β-CD; d, c are prepared in steps to react the obtained product with andrographolide to form an inclusion compound: 0.223 parts of Fe3O4&SiO2&mSiO2-AA-β-CD are ultrasonically dispersed in 30.267 parts of ultrapure water, and then 35.112 parts of andrographolide are added, and the ultrasonic dispersion is continued for 6 hours, and then the product is stored in a refrigerator at 0-12°C for 12 hours, and then the obtained product is separated by a magnet, and then repeatedly washed, and finally vacuum dried to obtain Fe3O4&SiO2&mSiO2-AA-β-CD / ADR; e, d are prepared in steps, and the andrographolide and the functional monomer in the obtained product are bonded to each other through non-covalent bonds: 0.08 parts of Fe3O4&SiO2&mSiO2-AA-β-CD / ADR are ultrasonically dispersed in 17.235 parts of methanol, and then 0.029 parts of functional monomer are added, the functional monomer is 4-amino-4'-methylacrylamide azobenzene, and the reaction is carried out at room temperature for 12 hours to fully prepolymerize andrographolide and the functional monomer; then 0.446 parts of glycol dimethacrylate, 0.13 parts of N,N'-bis(acryloyl)cystamine, 0.062 parts of azobisisobutyronitrile, 0.0012 parts of copper bromide and 0.002 parts of pentamethyldiethylenetriamine are added, and the reaction is carried out at 70°C in a nitrogen atmosphere for 24 hours, and then the obtained product is separated by a magnet, and then fully washed, and finally vacuum dried to obtain ADR-MMIP without eluting andrographolide; f. Eluting andrographolide from the product prepared in step e to obtain a crude carrier: The ADR-MMIP from which andrographolide has not been eluted is rinsed with methanol for multiple times, and then placed in a Soxhlet extractor. The andrographolide is then repeatedly eluted with an eluent composed of 70% by volume methanol and 30% by volume acetic acid until andrographolide is no longer detected in the eluent. The eluent is then repeatedly washed with methanol to remove the eluent, and finally vacuum dried to obtain a crude carrier, which is recorded as ADR-MMIP.

8. The method for preparing the andrographolide molecularly imprinted stealth drug carrier according to claim 7, characterized in that: The various sub-steps of step S02 are detailed as follows: The various sub-steps of step S02 are detailed as follows: a. ADR / I-MMIP is prepared based on the substitution reaction of iodine and a crude carrier; 4.732-6.874 parts of dimethylformamide, 0.510-1.852 parts of triphenylphosphine and 1.529-2.584 parts of iodine are added to a flask, 0.332-0.968 parts of the crude carrier are added when heated to 70°C, and the mixture is reacted for 20 hours under a nitrogen atmosphere, and then 1.5-4.6 parts of a 3 mol / L sodium methoxide solution are added to obtain a mixed solution No. 2, and the mixed solution No. 2 is placed in an ice bath at 0-5°C for 20 minutes, and the obtained product is separated by a magnet, and then repeatedly washed, and finally vacuum dried to obtain ADR / I-MMIP; b. Acetylate the active groups in ADR / I-MMIP: add 0.279-0.849 parts of vacuum-dried ADR / I-MMIP, 2.28-4.573 parts of acetic anhydride, 0.003-0.005 parts of 4-dimethylaminopyridine and 3.590-4.734 parts of pyridine into a flask, and react under condensation reflux at room temperature for 48 hours under a nitrogen atmosphere to obtain solution No. 5; pour solution No. 5 into 125.75-180.632 parts of ice water at 0-5°C, then separate the obtained product with a magnet, wash it repeatedly, and finally vacuum dry it to obtain ADR / I-MMIP with acetylated active groups; c. Preparation of ADR / PEOX-MMIP based on the substitution reaction of poly(2-ethyl-2-oxazoline) and active group acetylated ADR / I-MMIP: 0.052-0.194 parts of active group acetylated ADR / I-MMIP, 2.5-4.2 parts of 2-ethyl-2-oxazoline and 14.209-16.305 parts of acetonitrile were added into a flask, and the mixture was condensed and refluxed at 80°C for 72 hours under a nitrogen atmosphere to generate andrographolide molecularly imprinted stealth drug carrier: ADR / PEOX-MMIP; during the reaction, 2-ethyl-2-oxazoline was subjected to cationic ring-opening polymerization to obtain a hydrophilic long-chain polymer: poly(2-ethyl-2-oxazoline).

9. The method for preparing the andrographolide molecularly imprinted stealth drug carrier according to claim 8, characterized in that: The material parts involved in steps S01 and S02 are all parts by weight.

10. The method for preparing the andrographolide molecularly imprinted stealth drug carrier according to claim 9, characterized in that: The pore-forming agent in step b of S01 is hexadecyltrimethylammonium bromide, and the organic solvent mentioned twice in step c of S01 is both N,N-dimethylformamide.

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