CN112089690A - Artesunate hyaluronate, nano micelle preparation thereof, preparation method and application thereof - Google Patents
Artesunate hyaluronate, nano micelle preparation thereof, preparation method and application thereof Download PDFInfo
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- hyaluronidase
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- 239000000693 micelle Substances 0.000 title claims abstract description 65
- 229960004991 artesunate Drugs 0.000 title claims abstract description 50
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 title description 2
- 229940014041 hyaluronate Drugs 0.000 title description 2
- 239000002245 particle Substances 0.000 claims abstract description 14
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 12
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 12
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 12
- 238000004108 freeze drying Methods 0.000 claims abstract description 11
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- 239000003814 drug Substances 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 12
- 230000003213 activating effect Effects 0.000 claims description 12
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
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- 238000000034 method Methods 0.000 claims description 10
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- 239000000463 material Substances 0.000 claims description 6
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- 239000012190 activator Substances 0.000 claims description 2
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- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical class C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 4
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
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- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
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- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Chemical group CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
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- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical group O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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Abstract
The invention discloses a hyaluronidase Artesunate, a nano micelle preparation thereof, a preparation method and an application thereof, wherein the effective component of the hyaluronidase Artesunate is composed of the Artesunate and hyaluronic acid, the Artesunate is a main effective component, the hyaluronic acid is used as a carrier and a targeting molecule and is connected with the Artesunate through a chemical bond to form the hyaluronidase Artesunate, and then the hyaluronidase Artesunate is formed by self-assembling to form nano micelles and freeze-drying. The particle size of the hyaluronidase-free artesunate nano micelle is 100-200 nm, the freeze-dried artesunate nano micelle has good stability, and has better acidity response release characteristic after being injected into a human body, and a cytotoxicity test proves that the hyaluronidase-free artesunate nano micelle has stronger tumor cell toxicity effect compared with pure artesunate.
Description
Technical Field
The invention belongs to the technical field of antitumor drugs, and particularly relates to a nano micelle preparation, and a preparation method and application thereof.
Background
Artesunate (ASA for short), Mr 384.42, chemical name dihydroartemisinin-l, 2-alpha-succinic acid monoester, is one of the important derivatives of artemisinin, a new antimalarial drug with sesquiterpene lactones. ASA serving as an antimalarial drug with a brand-new structure has the characteristics of high efficiency, quick effect, low toxicity, difficult tolerance generation and the like; and the solubility is good, the preparation form is flexible, the administration is convenient, and the preparation is widely applied to clinic. Since the research in 1980, the researchers have conducted intensive research on the pharmacological actions of ASA, and as a result, it has been found that ASA has not only antimalarial action but also immunoregulatory, antitumor, hepatoprotective, anti-inflammatory, and smooth muscle relaxing effects. Because ASA has small toxic and side effects, good tolerance, convenient use and the like, the anti-tumor effect of ASA is widely regarded by people. Some researchers believe that the antitumor effect of artemisinin drugs is related to their antimalarial mechanism and the vigorous iron metabolism of tumor cells. The nucleic acid metabolism of cancer cells is vigorous, a large amount of iron is needed, most of tumor cells have high-density transferrin receptors on the surfaces, and normal cells have fewer transferrin receptors; the artemisinin drugs containing endoperoxide bridges promote the decomposition of peroxy groups of artemisinin to generate free radicals to exert destructive effect through divalent iron ions. Therefore, more free radicals can be formed in tumor cells than normal cells, and the effect of oxidative stress damage on DNA and mitochondria can be achieved, so that a certain specific killing effect is achieved.
Hyaluronic acid (abbreviated as HA), a natural glycosaminoglycan formed by repeated alternate connection of disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine, is widely distributed in mammal loose connective tissue and bone marrow extracellular matrix, and plays an important role in cell biology aspects such as cell migration, proliferation, differentiation, adhesion, gene expression and the like. More than half of the HA in the body is distributed in the skin, which not only HAs unique hydrodynamic properties, but also is excellent in biocompatibility. In recent years, HA HAs received much attention in the field of nanomedicine. The HA hydrophilic shell can avoid phagocytosis of mononuclear macrophages and prolong the blood circulation time of the medicine, and is a good carrier for various medicines, especially hydrophobic medicines. The differentiation-type protein CD44 receptor is the major HA-binding receptor. The CD44 receptor allows HA to interact with specific cell surfaces, and this interaction HAs been studied extensively. Can be used as a medium for specifically transporting the nano preparation to tumor cells.
Drugs are often encapsulated in a nano-drug delivery system clinically in order to reduce dose, reduce side effects and increase biocompatibility. However, no nano-drug preparation combining ASA and HA HAs been reported so far.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a hyaluronidase artesunate, a nano micelle preparation thereof, a preparation method and application thereof. It is desired to improve the biocompatibility of a drug and effectively prolong the blood circulation time of the drug in an organism.
One of the technical schemes adopted by the invention for solving the technical problems is as follows:
a hyaluronated Artesunate formed from hyaluronic acid and Artesunate linked by chemical bonds. Specifically, the hyaluronidase Artesunate (HA-ASA) is a high molecular compound formed by ester bond connection of hyaluronic acid and Artesunate, and the structural formula of the compound is shown as the following formula:
the second technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of artesunate with hyaluronic acid comprises the steps of reacting artesunate with activated carboxyl with hyaluronic acid in an organic solvent at 40-50 ℃ for 36-48 hours under the protection of nitrogen; dialyzing the reacted material, and freeze-drying to obtain the hyaluronic acid artesunate.
Further, the carboxyl activation method of artesunate comprises the following steps: dissolving ASA in an organic solvent, adding an activating agent, and performing carboxyl activation for 0.5-2 h under the protection of nitrogen.
In a preferred embodiment of the invention, the activator comprises at least one of EDC HCl or 4-Dimethylaminopyridine (DMAP).
The third technical scheme adopted by the invention for solving the technical problems is as follows:
a nano-micelle preparation of artesunate hyalurated, the nano-micelle preparation comprises nano-micelles formed by self-assembly of artesunate hyalurated (HA-ASA). In the nano micelle preparation, the artesunate is used as a main drug, and the hyaluronic acid is used as a carrier and a targeting molecule.
Wherein the particle size of the nano micelle of the hyaluronated artesunate is 100-200 nm.
In a preferred embodiment of the present invention, the nanomicelle formulation is a lyophilized formulation.
Further preferably, the nanomicelle preparation further comprises a lyoprotectant.
Still further preferably, the lyoprotectant includes at least one of sorbitol, mannitol, sucrose, or dextran.
The fourth technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of a nano micelle preparation of the hyaluronated artesunate comprises the following steps: dispersing the hyaluronidase Artesunate in an organic solvent, adding the solution into water, shaking for reaction for 2-6 h, then dialyzing to remove impurities and the organic solvent, filtering, and freeze-drying to obtain the nano micelle preparation of the hyaluronidase Artesunate. In a preferred embodiment of the present invention, the organic solvent includes at least one of dimethyl sulfoxide, N-dimethylformamide, formamide, or the like.
Further, the filtration was performed using a 0.22 μm microporous membrane.
Further, the dialysis time is 10-24 h.
Further, the hyaluronated artesunate is dissolved in an organic solvent, ultrasonically dispersed for 0.5-1 h at room temperature, and then added into water.
In a preferred embodiment of the invention, during the process of preparing the nano micelle of the artesunate hyalurated by freeze-drying, a freeze-drying protective agent is added; the freeze-drying protective agent comprises at least one of dextran, sucrose, mannitol or sorbitol and the like.
The fifth technical scheme adopted by the invention for solving the technical problems is as follows:
an application of a hyaluronidase-free artesunate nano micelle preparation in preparing antitumor drugs is provided.
Such uses include, for example, the use to treat cervical cancer.
The equipment, reagents, processes, parameters and the like related to the invention are conventional equipment, reagents, processes, parameters and the like except for special description, and no embodiment is needed.
In the dialysis of the present invention, a person skilled in the art can select a suitable dialysis membrane according to the difference between the molecular weight of the molecule to be retained and the molecular weight of the impurity, and the detailed description of the embodiment will not be provided.
All ranges recited herein include all point values within the range.
As used herein, "about" or "about" and the like refer to a range or value within plus or minus 20 percent of the stated range or value.
In the present invention,% is mass% and ratio is mass ratio unless otherwise specified.
In the invention, the room temperature, namely the normal environment temperature, can be 10-30 ℃.
The invention has the beneficial effects that: the HA-ASA nano micelle preparation HAs the particle size of 100-200 nm and good response release characteristic, and cytotoxicity tests prove that the HA-ASA nano micelle preparation HAs stronger tumor cytotoxicity effect compared with simple use of ASA, and HAs the characteristics of strong targeting property, long circulation and low toxicity.
Drawings
FIG. 1 is a chemical reaction diagram of a synthesis process of HA-ASA in an embodiment of the present invention, wherein A is HA structural formula, B is ASA structural formula, and C is HA-ASA structural formula.
FIG. 2 is a particle size distribution and transmission electron micrograph (a) of HA-ASA nano-micelle and a Zeta potential distribution chart (b) in example 1 of the present invention.
FIG. 3 is an IR spectrum of HA-ASA in example 1 of the present invention, wherein A is ASA pure drug, B is HA pure drug, C is a physical mixture of ASA and HA, and D is HA-ASA raw material in example 1 of the present invention.
FIG. 4 is a nuclear magnetic hydrogen spectrum of HA-ASA in example 2 of the present invention, wherein A is ASA pure drug, B is HA pure drug, and C is HA-ASA raw material.
FIG. 5 is a graph showing the drug release profiles of HA-ASA nano-micelle preparation and ASA pure drug in PBS solution with pH of 7.4 in example 2 of the present invention, wherein A is ASA pure drug and B is HA-ASA nano-micelle preparation.
Fig. 6 is a graph of ASA drug release curves of the HA-ASA nanomicelle formulation of example 3 under different pH environments, where a is an ASA drug release curve at pH5.0, B is an ASA drug release curve at pH6.5, and C is an ASA drug release curve at pH 7.4.
Fig. 7 is a comparison graph of cytotoxicity of HA-ASA nanomicelle preparation and ASA pure drug for cervical cancer cells in example 4 of the present invention, where a is HA, B is ASA, and C is HA-ASA nanomicelle preparation.
Fig. 8 is a graph showing the hydrated particle size of the HA-ASA nanomicelle formulation of the present invention in water and in PBS.
Detailed Description
The technical solution of the present invention will be further illustrated and described below with reference to the accompanying drawings by means of specific embodiments.
The names of the drugs used in the present invention are shown in Table 1:
TABLE 1
Example 1
(1) Dissolving ASA in dimethyl sulfoxide, adding an activating agent EDC & HCl according to the molar ratio of the ASA to the activating agent of 1:2, performing carboxyl activation for 0.5h at 45 ℃ under the protection of nitrogen, then adding a formamide solution of HA, wherein the molar ratio of the ASA to the HA is 1:2, and performing esterification for 48h at 45 ℃ under the protection of nitrogen;
(2) dialyzing the material obtained in the step (1) to obtain HA-ASA dialysate;
(3) vacuum freeze-drying the HA-ASA dialysate obtained in the step (2) to obtain a corresponding HA-ASA raw material;
(4) dissolving the HA-ASA raw material obtained in the step (3) in dimethyl sulfoxide to obtain an HA-ASA organic solution, and ultrasonically dispersing for 0.5h at room temperature;
(5) slowly adding the HA-ASA organic solution obtained in the step (4) into deionized water with the volume 9 times that of the organic solution, placing the mixture in a shaker at room temperature for reaction for 3 hours, and then dialyzing for 24 hours to obtain HA-ASA micelle solution;
(6) filtering the HA-ASA micelle solution by a 0.22 mu m microporous filter membrane to obtain an HA-ASA nano micelle solution with the particle size of 180 nm;
(7) adding 2 wt% of mannitol into the HA-ASA nano micelle solution, pre-freezing at the condensation temperature of-80 ℃ and carrying out vacuum freeze drying under the vacuum degree of 10Pa to obtain the HA-ASA nano micelle preparation.
Example 2
(1) Dissolving ASA in dimethyl sulfoxide, adding an activating agent EDC & HCl according to the molar ratio of the ASA to the activating agent of 1:2, performing carboxyl activation for 1h at 50 ℃ under the protection of nitrogen, then adding a formamide solution of HA, wherein the molar ratio of the ASA to the HA is 1:2, and performing esterification for 36h at 50 ℃ under the protection of nitrogen;
(2) dialyzing the material obtained in the step (1) to obtain HA-ASA dialysate;
(3) vacuum freeze-drying the HA-ASA dialysate obtained in the step (2) to obtain a corresponding HA-ASA raw material;
(4) dissolving the HA-ASA raw material obtained in the step (3) in dimethyl sulfoxide to obtain an HA-ASA organic solution; ultrasonically dispersing for 1h at room temperature;
(5) slowly adding the HA-ASA organic solution obtained in the step (4) into deionized water with the volume 9 times that of the organic solution, placing the mixture in a table at room temperature for reaction for 1 hour, and dialyzing the HA-ASA micelle dispersion liquid obtained after the reaction for 12 hours to obtain HA-ASA micelle solution;
(6) filtering the HA-ASA micelle solution by a 0.22 mu m microporous filter membrane to obtain an HA-ASA nano micelle solution with the particle size of 200 nm;
(7) and adding 5 wt% of dextran into the HA-ASA nano micelle, pre-freezing at the condensation temperature of-80 ℃ and carrying out vacuum freeze drying in the environment of 10Pa of vacuum degree to obtain the HA-ASA nano micelle preparation.
Example 3
(1) Dissolving ASA in dimethyl sulfoxide, adding an activating agent EDC & HCI according to the molar ratio of the ASA to the activating agent being 1:2, performing carboxyl activation for 2h at 45 ℃ under the protection of nitrogen, then adding a formamide solution of HA, wherein the molar ratio of the ASA to the HA is 1:2, and performing esterification for 36h at 45 ℃ under the protection of nitrogen;
(2) dialyzing the material obtained in the step (1) to obtain HA-ASA dialysate;
(3) vacuum freeze-drying the HA-ASA dialysate obtained in the step (2) to obtain a corresponding HA-ASA raw material;
(4) dissolving the HA-ASA raw material obtained in the step (3) in N, N-dimethylformamide to obtain an organic solution of HA-ASA; ultrasonic dispersion is carried out for 0.5h at room temperature;
(5) slowly adding the HA-ASA organic solution obtained in the step (4) into deionized water with the volume 9 times that of the organic solution, placing the mixture in a shaker at room temperature for reaction for 3 hours, and then dialyzing for 24 hours to obtain HA-ASA micelle solution;
(7) filtering the HA-ASA micelle solution by a 0.22 mu m microporous filter membrane to obtain an HA-ASA nano micelle solution with the particle size of 194 nm;
(8) adding 2 wt% of sucrose into the HA-ASA nano micelle solution, pre-freezing at the condensation temperature of-80 ℃ and carrying out vacuum freeze drying under the vacuum degree of 10Pa to obtain the HA-ASA nano micelle preparation.
Example 4
(1) Dissolving ASA in dimethyl sulfoxide, adding an activating agent EDC & HCl according to the molar ratio of the ASA to the activating agent of 1:2, performing carboxyl activation for 2h at 45 ℃ under the protection of nitrogen, then adding a formamide solution of HA, wherein the molar ratio of the ASA to the HA is 1:2, and performing esterification for 48h at 45 ℃ under the protection of nitrogen;
(2) dialyzing the material obtained in the step (1) to obtain HA-ASA dialysate;
(3) vacuum freeze-drying the HA-ASA dialysate obtained in the step (2) to obtain a corresponding HA-ASA raw material;
(4) dissolving the HA-ASA raw material obtained in the step (3) in dimethyl sulfoxide to obtain an HA-ASA organic solution; ultrasonic dispersion is carried out for 0.5h at room temperature;
(5) slowly adding the HA-ASA organic solution obtained in the step (4) into deionized water with the volume 9 times that of the organic solution, placing the mixture in a table at room temperature for reaction for 6 hours, and dialyzing the HA-ASA micelle dispersion liquid obtained after the reaction for 24 hours to obtain HA-ASA micelle solution;
(6) filtering the HA-ASA micelle solution by a 0.22 mu m microporous filter membrane to obtain an HA-ASA nano micelle solution with the particle size of 190 nm;
(7) and adding 5 wt% of sorbitol into the HA-ASA nano micelle solution, pre-freezing at the condensation temperature of-80 ℃ and carrying out vacuum freeze drying in the environment of 10Pa of vacuum degree to obtain the HA-ASA nano micelle preparation.
As shown in the particle size distribution and the transmission electron microscope image in FIG. 2(a), the HA-ASA nano-micelle prepared by the embodiment of the invention is spherical, the particle size is about 100-200 nm, and the Zeta potential distribution diagram in FIG. 2(b) shows that the potential of the HA-ASA nano-micelle is about-23 mV.
From the IR spectrum of HA-ASA in FIG. 3, it can be seen that HA-ASA produced 1753cm of new ASA different from ASA-1New characteristic peak of 1744cm-1. It can be seen from the HA-ASA nuclear magnetic hydrogen spectrum diagram in FIG. 4 that the HA-ASA characteristic peak shifts to low field under the influence of chemical bond.
As shown in the drug release curve of the HA-ASA nano-micelle preparation shown in FIG. 5, the drug release curves of ASA and ASA pure drugs (i.e. not prepared into nano-micelle form) in the pH7.4 environment show that the HA-ASA nano-micelle HAs an obvious sustained release effect.
As can be seen from the release condition of the main drug ASA in the HA-ASA nano-micelle preparation shown in fig. 6 under different pH environments, the HA-ASA nano-micelle HAs a sustained release effect under different pH conditions, and HAs a higher release rate in an acidic environment, suggesting that the HA-ASA nano-micelle preparation may have a potential targeting effect on a tumor site.
As can be seen from the comparison graph of the HA-ASA nano-micelle preparation and the ASA pure drug on the cytotoxicity of the cervical cancer cells in FIG. 7, the tumor cytotoxicity test result shows that the HA-ASA nano-micelle preparation HAs cytotoxicity about 1.4 times that of the ASA pure drug on the cervical cancer cells under the conditions that the ASA concentration is 75 mug/mL and the culture time is 24 h.
As can be seen from the hydrated particle size diagram of the HA-ASA nano-micelle preparation in water and in PBS in FIG. 8, the HA-ASA of the present invention can self-assemble to form nano-micelles in both water and PBS.
In conclusion, the HA-ASA nano micelle preparation HAs the advantages that the particle size of the nano micelle is 100-200 nm, the stability is good, and the slow release characteristic is good; cytotoxicity tests show that the HA-ASA nano micelle preparation HAs stronger tumor inhibition effect.
The above description is only a preferred embodiment of the present invention, and therefore should not be taken as limiting the scope of the invention, which is defined by the appended claims and their equivalents.
Claims (10)
1. A hyaluronated artesunate characterized by: the hyaluronidase-free artesunate is formed by connecting hyaluronic acid and artesunate through ester bonds, and the structural formula of the hyaluronidase-free artesunate is shown as the following formula:
2. a method for preparing the hyaluronated artesunate of claim 1, wherein the method comprises the steps of: reacting the artesunate after the carboxyl activation with hyaluronic acid in an organic solvent at 40-50 ℃ for 36-48 h under the protection of nitrogen; dialyzing the reacted material, and freeze-drying to obtain the hyaluronic acid artesunate.
3. The method of claim 2, wherein: the method for activating the carboxyl of the artesunate comprises the following steps: dissolving artesunate in an organic solvent, adding an activating agent, and activating carboxyl for 0.5-2 h under the protection of nitrogen.
4. The production method according to claim 3, characterized in that: the activator includes at least one of EDC HCl or 4-dimethylaminopyridine.
5. A nanomicelle formulation of hyaluronated artesunate of claim 1, wherein: the nano-micelle preparation comprises nano-micelles formed by self-assembly of the hyaluronated artesunate.
6. The nanomicelle formulation of hyaluronated artesunate according to claim 5, wherein: the particle size of the nano micelle is 100-200 nm.
7. The nanomicelle formulation of hyaluronated artesunate according to claim 5, wherein: the nano micelle preparation is a freeze-drying preparation and also comprises a freeze-drying protective agent; the freeze-drying protective agent comprises at least one of sorbitol, mannitol, sucrose or dextran.
8. A method for preparing the nanomicelle formulation of artesunate hyalurated according to any one of claims 5 to 7, characterized in that: dispersing the hyaluronidase Artesunate in an organic solvent, adding the solution into water, shaking for reaction for 2-6 h, then dialyzing, filtering and freeze-drying to obtain the nano micelle preparation of the hyaluronidase Artesunate.
9. The production method according to claim 2, 3 or 8, characterized in that: the organic solvent includes at least one of dimethyl sulfoxide, formamide or N, N-dimethylformamide.
10. Use of the nanomicelle formulation of artesunate hyalurated according to any one of claims 5 to 7 for the preparation of an antitumor medicament.
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