Dithiolane-modified beta-cyclodextrin, preparation method thereof and application of dithiolane-modified beta-cyclodextrin as drug carrier

Abstract

The invention relates to dithiolane modified beta-cyclodextrin, a preparation method thereof and application of the dithiolane modified beta-cyclodextrin as a drug carrier. The method comprises the following steps: carrying out acylation reaction on beta-cyclodextrin and lipoic acid, and modifying different numbers of dithiolane on the beta-cyclodextrin by changing a feeding ratio; the beta-cyclodextrin has a plurality of hydroxyl groups, and the activity of the hydroxyl groups at the C6 position is relatively high. The hydrophobic cavity of the dithiolane-modified beta-cyclodextrin can be loaded with a hydrophobic small-molecule drug, and the hydrophobic small-molecule drug can be loaded into the dithiolane-modified beta-cyclodextrin under the condition of heating reflux to form a nano-drug. The disulfide bond on the surface of the nano-drug and sulfydryl on protein or lipid on the outer side of a cell membrane are subjected to dynamic covalent thiol exchange, so that the nano-drug enters cells through a thiol-mediated cellular uptake way, endosomes and lysosomes can be avoided, the drug is quickly and directly delivered to the cytoplasm, degradation of the drug in the lysosomes is reduced, and the drug delivery efficiency is improved. The utilization rate of small-molecule drugs is improved, side effects are reduced, and better curative effects are achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical engineering, and specifically relates to a dithiolane-modified beta-cyclodextrin, a preparation method thereof, and an application thereof as a drug carrier. Background Art

[0002] The interior of cyclodextrin (CDs) molecules is a hydrophobic cavity with a three-dimensional morphology, and the exterior is hydrophilic. It can form water-soluble inclusion complexes with a variety of hydrophobic drugs, thereby optimizing the solubility, dissolution rate and stability of hydrophobic drugs. In addition, inclusion complexes based on cyclodextrins can reduce drug elimination, achieve prolonged blood circulation and sustained drug release. In recent years, a series of modified cyclodextrins have been reported that selectively graft different substituents on the primary or secondary surface of cyclodextrins through ether, ester or amide bonds, improve the drug properties of natural cyclodextrins, and study their application as drug carriers, providing a new perspective for cancer treatment. For example, there are 21 -OH groups outside the β-CD cavity, but due to the formation of stable intramolecular hydrogen bonds between -OH, its interaction with water molecules is weakened. Therefore, by chemically modifying cyclodextrins to destroy intramolecular hydrogen bonds, it is possible to increase the solubility of cyclodextrins in aqueous solutions. Currently common modified cyclodextrins include methylated cyclodextrin, hydroxyethyl cyclodextrin, hydroxypropyl cyclodextrin, sulfonyl ether β-cyclodextrin, ethyl cyclodextrin, acetyl cyclodextrin, sulfate cyclodextrin, phosphate cyclodextrin and carboxymethyl cyclodextrin.

[0003] Effective intracellular delivery is crucial for the successful application of many therapeutic agents, and it is directly related to whether the drug can achieve the desired therapeutic goal. However, traditional drug delivery systems often enter cells through endocytosis, resulting in drugs being trapped in endosomes / lysosomes and unable to be effectively released into the cytoplasm, thus affecting the therapeutic effect. In recent years, delivery carriers based on the thiol exchange pathway have attracted widespread attention because they do not rely on the endocytosis pathway, can avoid endosomes and lysosomes, and can quickly and directly deliver drugs to the cytoplasm. The mechanism of the thiol exchange pathway is as follows: first, the disulfide-rich polymer carrier undergoes dynamic covalent thiol exchange with the thiol groups on the outer proteins or lipids of the cell membrane to connect to the cell membrane; secondly, transient micelle pores are formed under the action of counterions, allowing the polymer to quickly pass through the cell membrane into the cytoplasm; finally, the polymer is depolymerized under the reduction of glutathione (GSH), and the drug coupled to the polymer is released into the cytoplasm. In addition, repeated thiol exchange or thiol-mediated transcytosis between cells can efficiently penetrate tissue barriers and achieve deep drug delivery.

[0004] Based on the excellent delivery performance of the thiol exchange pathway carrier, we believe that modifying the dithiolane group to cyclodextrin can significantly improve its delivery performance. However, there are no reports on the use of dithiolane-modified cyclodextrin for drug delivery, especially cyclodextrin modified with multiple dithiolanes. After searching, there is an article reporting the use of lipoic acid-NHS to modify β-cyclodextrin to obtain a single dithiolane-modified cyclodextrin, but the article did not study its application in drug loading and drug delivery (Detection of Carbendazim by Surface-Enhanced Raman Scattering UsingCyclodextrin Inclusion Complexes on Gold Nanorods, Anal. Chem. 2009, 81, 2895–2903).

[0005] Cyclodextrin delivery of hydrophobic drugs often enters cells through endocytosis, resulting in the drug being trapped in endosomes / lysosomes and unable to be effectively released into the cytoplasm. Endowing cyclodextrin with thiol exchange properties may solve this problem. Therefore, the present invention provides a method of modifying cyclodextrin with dithiolane to improve the shortcomings of cyclodextrin in drug delivery. After searching, there is no related report on the use of dithiolane-modified cyclodextrin for drug delivery. Summary of the invention

[0006] The purpose of the present invention is to provide a dithiolane-modified cyclodextrin and a preparation method thereof and application thereof as a drug carrier.

[0007] To achieve the above object, the present invention adopts the following technical solutions: A method for preparing dithiolane-modified β-cyclodextrin comprises: subjecting β-cyclodextrin to an acylation reaction with lipoic acid to obtain dithiolane-modified β-cyclodextrin, and modifying β-cyclodextrin with different numbers of dithiolanes by changing the feed ratio.

[0008] Furthermore, the preparation method of the above-mentioned dithiolane-modified β-cyclodextrin comprises the following steps: S1: dissolving mono-(6-amino-6-deoxy)-β-cyclodextrin in ultrapure water at 30-45° C., adjusting the pH to 7.6-8.0, to obtain a mono-(6-amino-6-deoxy)-β-cyclodextrin solution; S2: dissolving DL-α-lipoic acid-NHS in 1,4-dioxane to obtain a DL-α-lipoic acid-NHS solution; S3: slowly dropwise adding the DL-α-lipoic acid-NHS solution of step S2 to the mono-(6-amino-6-deoxy)-β-cyclodextrin solution of step S1, stirring at 30-45° C. for 24-28 h, and then precipitating in a mixture of acetonitrile and water in a volume ratio of 5:1, and finally collecting and washing the precipitate, and freeze-drying to obtain dithiolane-modified β-cyclodextrin, wherein each β-cyclodextrin molecule is modified with one dithiolane; Wherein, the molar ratio of the mono-(6-amino-6-deoxy)-β-cyclodextrin in step S1 to the DL-α-lipoic acid-NHS in step S2 is 1.2-1.8:1.

[0009] Furthermore, the preparation method of the above-mentioned dithiolane-modified β-cyclodextrin comprises the following steps: S1: dissolving β-cyclodextrin in DMSO to obtain a β-cyclodextrin solution; S2: dissolving lipoic acid and 1,1'-carbonyldiimidazole in DMSO, stirring at room temperature for 2 h, then adding triethanolamine, stirring at room temperature for 3 h to obtain an activated lipoic acid solution; S3: slowly dropwise adding the activated lipoic acid solution of step S2 to the β-cyclodextrin solution of step S1, stirring at room temperature overnight, and then dialyzing in ultrapure water for 24 hours using a dialysis bag with a molecular weight cutoff of 1000 kDa, and freeze-drying the dialysate to obtain dithiolane-modified β-cyclodextrin, wherein each β-cyclodextrin molecule is modified with 2 to 3 dithiolanes; Wherein, the molar ratio of the β-cyclodextrin in step S1 to the lipoic acid in step S2 is 1:1.8-2.4.

[0010] Furthermore, the preparation method of the above-mentioned dithiolane-modified β-cyclodextrin comprises the following steps: S1: dissolving β-cyclodextrin in DMSO to obtain a β-cyclodextrin solution; S2: dissolving lipoic acid and 1,1'-carbonyldiimidazole in DMSO, stirring at room temperature for 2 h, then adding triethanolamine, stirring at room temperature for 3 h to obtain an activated lipoic acid solution; S3: slowly dropwise adding the activated lipoic acid solution of step S2 to the β-cyclodextrin solution of step S1, stirring at room temperature overnight, and then dialyzing in ultrapure water for 24 hours using a dialysis bag with a molecular weight cutoff of 1000 kDa, and freeze-drying the dialysate to obtain dithiolane-modified β-cyclodextrin, wherein each β-cyclodextrin molecule is modified with 3 to 4 dithiolanes; Wherein, the molar ratio of the β-cyclodextrin in step S1 to the lipoic acid in step S2 is 1:6-7.

[0011] Furthermore, the preparation method of the above-mentioned dithiolane-modified β-cyclodextrin comprises the following steps: S1: dissolving β-cyclodextrin in DMSO to obtain a β-cyclodextrin solution; S2: dissolving lipoic acid and 1,1'-carbonyldiimidazole in DMSO, stirring at room temperature for 2 h, then adding triethanolamine, stirring at room temperature for 3 h to obtain an activated lipoic acid solution; S3: slowly dropwise adding the activated lipoic acid solution of step S2 to the β-cyclodextrin solution of step S1, stirring at room temperature overnight, and then dialyzing in ultrapure water for 24 hours using a dialysis bag with a molecular weight cutoff of 1000 kDa, and freeze-drying the dialysate to obtain dithiolane-modified β-cyclodextrin, wherein each β-cyclodextrin molecule is modified with 5 to 6 dithiolanes; Wherein, the molar ratio of the β-cyclodextrin in step S1 to the lipoic acid in step S2 is 1:11-13.

[0012] A dithiolane-modified beta-cyclodextrin is prepared by the above-mentioned preparation method.

[0013] The above-mentioned dithiolane-modified β-cyclodextrin is used as a drug carrier.

[0014] A nano drug comprises a drug carrier and a raw material drug loaded by the drug carrier. The drug carrier is the above-mentioned dithiolane-modified β-cyclodextrin, and the raw material drug is a small molecule hydrophobic drug. The small molecule hydrophobic drugs include sorafenib, propranolol, doxorubicin, amphotericin B, gefitinib, methotrexate, and paclitaxel.

[0015] The preparation method of the above-mentioned nano drug is as follows: dissolving dithiolane-modified β-cyclodextrin and a small molecule hydrophobic drug in a DMSO-water mixture with a volume ratio of 8:2, heating and refluxing at 70-80°C for 24 hours, and then dialyzing in ultrapure water for 24 hours using a dialysis bag with a molecular weight cutoff of 1000 kDa to obtain the nano drug; Wherein, the molar ratio of the dithiolane-modified β-cyclodextrin to the small molecule hydrophobic drug is 1:1-1.5.

[0016] The significant advantages of the present invention are: The present invention provides a preparation method of dithiolane-modified β-cyclodextrin, wherein β-cyclodextrin and lipoic acid are subjected to an acylation reaction to obtain dithiolane-modified β-cyclodextrin, and different numbers (1, 2-3, 3-4, 5-6) of dithiolane can be modified on the β-cyclodextrin molecule by changing the feed ratio. There are multiple hydroxyl groups on β-cyclodextrin, and the hydroxyl group at the C6 position has higher activity, because the hydroxyl group at the C6 position is located outside the β-cyclodextrin molecule, and the steric hindrance is small, thereby showing higher reaction activity. The hydrophobic cavity of dithiolane-modified β-cyclodextrin can load hydrophobic small molecule drugs, and the hydrophobic small molecule drugs can be loaded into the dithiolane-modified β-cyclodextrin under heating reflux conditions to form nanomedicines. The disulfide bonds on the surface of nanodrugs undergo dynamic covalent thiol exchange with the thiol groups on the proteins or lipids on the outside of the cell membrane, allowing them to enter the cells through the thiol-mediated cellular uptake pathway, avoiding endosomes and lysosomes, and delivering drugs to the cytoplasm quickly and directly, reducing drug degradation in lysosomes, improving the utilization rate of small molecule drugs, and reducing side effects, thereby achieving better therapeutic effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 : Mass spectrum of LA-β-CD.

[0018] Figure 2 : Mass spectrum of 1.0LA-β-CD.

[0019] Figure 3 : Mass spectrum of 3.3LA-β-CD.

[0020] Figure 4 : Mass spectrum of 6.0LA-β-CD.

[0021] Figure 5 : A, particle sizes of LA-β-CD-SOR, 1.0LA-β-CD-SOR, 3.3LA-β-CD-SOR, and 6.0LA-β-CD-SOR in water; B, particle size changes of 3.3LA-β-CD incubated in serum.

[0022] Figure 6 :3.3Electron microscopy image and mapping results of LA-β-CD-SOR.

[0023] Figure 7 :3.3CCK8 results of LA-β-CD-SOR.

[0024] Figure 8 :3.3 Results of cellular uptake and uptake mechanism of LA-β-CD-SOR. DETAILED DESCRIPTION

[0025] In order to make the contents of the present invention easier to understand, the technical solution of the present invention is further described below in conjunction with specific implementation methods, but the present invention is not limited thereto.

[0026] The main reagents used in the present invention are shown in the following table: Example 1: Preparation of dithiolane-modified β-cyclodextrin (1) S1: Dissolve 1.7025 g (1.5 mmol) of mono-(6-amino-6-deoxy)-β-cyclodextrin in 20 ml of ultrapure water at 40°C, and adjust the pH to 7.6 with 1 M hydrochloric acid solution to obtain a mono-(6-amino-6-deoxy)-β-cyclodextrin solution; S2: Dissolve 0.3033 g (1 mmol) of DL-α-lipoic acid-NHS in 15 ml of 1,4-dioxane to obtain a DL-α-lipoic acid-NHS solution; S3: The DL-α-lipoic acid-NHS solution of S2 was slowly added dropwise to the mono-(6-amino-6-deoxy)-β-cyclodextrin solution of S1, stirred at 40°C for 24 hours, and then precipitated in a 5:1 acetonitrile-water mixture (100 ml) at room temperature for 30 minutes. Finally, the precipitate was collected and washed three times with a 5:1 acetonitrile-water mixture, and freeze-dried at -44°C and a vacuum degree of 90 Pa for 24 hours to obtain dithiolane-modified β-cyclodextrin, recorded as LA-β-CD. (2) S1: Dissolve 0.57 g (0.5 mmol) of β-CD in 8 ml of DMSO to obtain a β-CD solution; S2: 0.206 g (1.0 mmol) of lipoic acid and 0.33 g (2.0 mmol) of CDI were dissolved in 6 ml of DMSO, stirred at room temperature for 2 h, and then 0.09 ml of TEA was added, and stirred at room temperature for 3 h to obtain an activated lipoic acid solution; S3: The activated lipoic acid solution of S2 was slowly added dropwise to the β-CD solution of S1, stirred at room temperature overnight, and then dialyzed in ultrapure water for 24 hours using a 1000 kDa dialysis bag. The dialysate was freeze-dried at -44°C and a vacuum degree of 90 Pa for 24 hours to obtain dithiolane-modified β-cyclodextrin, recorded as 1.0LA-β-CD. (3) S1: Dissolve 0.57 g (0.5 mmol) of β-CD in 8 ml of DMSO to obtain a β-CD solution; S2: 0.68 g (3.3 mmol) of lipoic acid and 0.81 g (5.0 mmol) of CDI were dissolved in 10 ml of DMSO, stirred at room temperature for 2 h, and then 0.3 ml of TEA was added, and stirred at room temperature for 3 h to obtain an activated lipoic acid solution; S3: The activated lipoic acid solution of S2 was slowly added dropwise to the β-CD solution of S1, stirred at room temperature overnight, and then dialyzed in ultrapure water for 24 hours using a 1000 kDa dialysis bag. The dialysate was freeze-dried at -44°C and 90 Pa vacuum for 24 hours to obtain dithiolane-modified β-cyclodextrin, recorded as 3.3LA-β-CD. (4) S1: Dissolve 0.57 g (0.5 mmol) of β-CD in 8 ml of DMSO to obtain a β-CD solution; S2: 1.24 g (6.0 mmol) of lipoic acid and 1.14 g (7.0 mmol) of CDI were dissolved in 15 ml of DMSO, stirred at room temperature for 2 h, and then 0.55 ml of TEA was added, and stirred at room temperature for 3 h to obtain an activated lipoic acid solution; S3: The activated lipoic acid solution of S2 was slowly added dropwise to the β-CD solution of S1, stirred at room temperature overnight, and then dialyzed in ultrapure water for 24 h using a 1000 kDa dialysis bag. The dialysate was freeze-dried at -44 °C and a vacuum degree of 90 Pa for 24 h to obtain dithiolane-modified β-cyclodextrin, recorded as 6.0LA-β-CD.

[0030] The prepared dithiolane-modified β-cyclodextrin was detected by matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI TOF), and the mass spectra of LA-β-CD, 1.0LA-β-CD, 3.3LA-β-CD and 6.0LA-β-CD were obtained, corresponding to Figure 1 , Figure 2 , Figure 3 and Figure 4 .like Figure 1 As shown, the molecular weight of LA-β-CD is 1322.41, (M+H) + is 1322.41, (M+Na) + The molecular formula is 1344.40, and the elemental analysis confirms that it is C 50 H 83 NO 35 S 2 , proving that one dithiolane ring is modified on one β-cyclodextrin molecule. Figure 2 As shown, the main molecular weights of 1.0LA-β-CD are 1511.6, 1699.9, (M1+Na) + is 1533.6, (M2+Na) +The molecular formula is 1721.9, and the elemental analysis shows that it is C 58 H 94 O 37 S 4 , C 66 H 106 NO 38 S 6 , proving that 2 to 3 dithiolanes are modified on one β-cyclodextrin molecule. Figure 3 As shown, the main molecular weights of 3.3LA-β-CD are 1699.9 and 1888.2 (M1+Na) + is 1721.9, (M2+Na) + The molecular formula is 1910.2, and the elemental analysis shows that it is C 66 H 106 NO 38 S 6 , C 74 H 118 O 39 S 8 , proving that 3 to 4 dithiolanes are modified on one β-cyclodextrin molecule. Figure 4 As shown, the main molecular weights of 6.0LA-β-CD are 2076.5 and 2264.8, (M1+K) + is 2114.5, (M2+K) + The molecular formula is 2302.8, and the molecular formula is determined to be C by elemental analysis. 82 H 130 NO 40 S 10 , C 90 H 142 O 41 S 12 , proving that 5 to 6 dithiolanes were modified on one β-cyclodextrin molecule. The above results prove that the dithiolane-modified β-cyclodextrin was successfully prepared.

[0031] Example 2: In vitro characterization of dithiolane-modified β-cyclodextrin-sorafenib nanodrug The dithiolane-modified β-cyclodextrin prepared in Example 1 is loaded with sorafenib, and the specific steps are as follows: Dithiolane-modified β-cyclodextrin (selected from any one of LA-β-CD, 1.0LA-β-CD, 3.3LA-β-CD, and 6.0LA-β-CD) and sorafenib are added in a molar ratio of 1:1, dissolved in 10 ml of a DMSO-water mixture with a volume ratio of 8:2, heated to reflux at 75°C for 24 hours, and then dialyzed in ultrapure water with a 1000 kDa dialysis bag for 24 hours to obtain a nanodrug formed by dithiolane-modified β-cyclodextrin and sorafenib. The nanodrug formed by LA-β-CD and sorafenib was recorded as β-CD-SOR, the nanodrug formed by 1.0LA-β-CD and sorafenib was recorded as 1.0LA-β-CD-SOR, the nanodrug formed by 3.3LA-β-CD and sorafenib was recorded as 3.3LA-β-CD-SOR, and the nanodrug formed by 6.0LA-β-CD and sorafenib was recorded as 6.0LA-β-CD-SOR.

[0032] Through dynamic light scattering (DLS) and transmission electron microscopy (TEM) characterization, the group with appropriate particle size and good nanoparticle morphology was selected; then the stability of different groups of nanodrugs in serum-containing culture medium was examined, and the optimal group was selected for the next step of research.

[0033] The particle sizes of β-CD-SOR, 1.0LA-β-CD-SOR, 3.3LA-β-CD-SOR, and 6.0LA-β-CD-SOR in water are as follows: Figure 5 As shown in A, from Figure 5 As can be seen in Figure B, the particle size of 3.3LA-β-CD-SOR in water and serum does not change significantly, and the polydispersity index (PDI) is around 0.2, indicating that it has good stability. Figure 6 As shown, it is shown that the synthesized dithiolane-modified cyclodextrin can successfully load sorafenib.

[0034] Example 3: Biocompatibility study of nanomedicine formed by dithiolane-modified β-cyclodextrin and sorafenib The cytotoxicity of the nanomedicine was studied using 3.3LA-β-CD-SOR in Example 2, and the specific steps were as follows: 5 × 10 cells were seeded per well of a 96-well cell culture plate. 3 Hepa1-6 cells and cultured at 37°C with 5% CO 2Then, different concentrations of 3.3LA-β-CD-SOR (according to the concentration of sorafenib of 0, 0.25, 0.5, 1, 5, 10 μM) were added to the culture wells and incubated for another 24 h under the same conditions; after the incubation, 10 μL of CCK-8 reagent was added to each well, and the culture plate was returned to the incubator for further incubation for 1 h; finally, the absorbance of each well was measured at a wavelength of 450 nm using a microplate reader.

[0035] 3.3 Effect of LA-β-CD-SOR on the proliferation of Hepa1-6 cells Figure 7 As shown in the figure, compared with pure sorafenib, the viability of Hepa1-6 cells in the 3.3LA-β-CD-SOR group remained at a higher level, indicating that the metabolic activity of the cells was not inhibited and the integrity of the cell membrane was maintained. This result not only confirms the low toxicity characteristics of 3.3LA-β-CD-SOR, but also reflects their good biocompatibility at the cellular level.

[0036] Example 4: Cellular uptake mechanism of dithiolane-modified β-cyclodextrin-sorafenib nanodrug The 3.3LA-β-CD-SOR in Example 2 was labeled with Acy5, and then its uptake mechanism was studied. The specific steps are as follows: 1.1 mg (0.007 mmol) 1-adamantine and 1 µl (0.007 mmol) TEA were added to 2 ml DMSO containing 4.4 mg (0.0056 mmol) Sulfo-Cy5-NHS, stirred at room temperature for 24 h, and then freeze-dried for 24 h at -44 °C and vacuum of 90 Pa to obtain ACy5. 3.3LA-β-CD-SOR, ACy5 and sorafenib were added at a molar ratio of 1:0.5:0.5, dissolved in 10 ml of a DMSO-water mixture with a volume ratio of 8:2, heated to reflux at 75 °C for 24 h, and then dialyzed in ultrapure water with a 1000 kDa dialysis bag for 24 h to obtain Acy5-labeled 3.3LA-β-CD-SOR.

[0037] In a 48-well cell culture plate, 5 × 10 4 Hepa1-6 cells and cultured at 37°C with 5% CO 2Incubator for 24 h. Then, the cells were pretreated for 30 min with the thiol inhibitor DTNB (4.8 mM), the endocytosis inhibitor chlorpromazine (10 μg / mL), the endocytosis inhibitor wortmannin (50 nM) and the endocytosis inhibitor methyl-β-cyclodextrin (M-β-CD, 50 μM), respectively. Then, Acy5-labeled 3.3LA-β-CD-SOR was added in the presence of the inhibitors and cultured for another 3 h. After digestion with 0.5 mM EDTA at 37 °C, the cells were detached from the surface of the culture plate with a pipette and then collected by centrifugation at 1000 rpm for 3 min. Wash twice with PBS to remove EDTA, and finally resuspend the cells in PBS. Cell fluorescence was analyzed on a BeckmanCoulter CytoFlex flow cytometer, and 10 were counted for each event. 4 cells.

[0038] 3.3 The uptake mechanism of LA-β-CD-SOR Figure 8 As shown in the figure, endocytosis inhibitors (wortmannin, chlorpromazine and methyl-β-cyclodextrin) had no obvious inhibition on the cellular uptake of 3.3LA-β-CD-SOR, while the thiol inhibitor DTNB could significantly reduce its cellular uptake efficiency, further indicating that 3.3LA-β-CD-SOR mainly enters cells through the thiol exchange pathway.

[0039] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention should fall within the scope of the present invention.

Claims

1. A method for preparing dithiolane-modified β-cyclodextrin, characterized in that: The beta-cyclodextrin is subjected to an acylation reaction with lipoic acid to obtain dithiolane-modified beta-cyclodextrin, and different numbers of dithiolane are modified on the beta-cyclodextrin by changing the feed ratio.

2. The preparation method according to claim 1, characterized in that: The following steps are involved: S1: dissolving mono-(6-amino-6-deoxy)-β-cyclodextrin in ultrapure water at 30-45° C., adjusting the pH to 7.6-8.0, to obtain a mono-(6-amino-6-deoxy)-β-cyclodextrin solution; S2: dissolving DL-α-lipoic acid-NHS in 1,4-dioxane to obtain a DL-α-lipoic acid-NHS solution; S3: slowly dropwise adding the DL-α-lipoic acid-NHS solution of step S2 to the mono-(6-amino-6-deoxy)-β-cyclodextrin solution of step S1, stirring at 30-45° C. for 24-28 h, and then precipitating in a mixture of acetonitrile and water in a volume ratio of 5:1, and finally collecting and washing the precipitate, and freeze-drying to obtain dithiolane-modified β-cyclodextrin, wherein each β-cyclodextrin molecule is modified with one dithiolane; Wherein, the molar ratio of the mono-(6-amino-6-deoxy)-β-cyclodextrin in step S1 to the DL-α-lipoic acid-NHS in step S2 is 1.2-1.8:

1.

3. The preparation method according to claim 1, characterized in that: The following steps are involved: S1: dissolving β-cyclodextrin in DMSO to obtain a β-cyclodextrin solution; S2: dissolving lipoic acid and 1,1'-carbonyldiimidazole in DMSO, stirring at room temperature for 2 h, then adding triethanolamine, stirring at room temperature for 3 h to obtain an activated lipoic acid solution; S3: slowly dropwise adding the activated lipoic acid solution of step S2 to the β-cyclodextrin solution of step S1, stirring at room temperature overnight, and then dialyzing in ultrapure water for 24 hours using a dialysis bag with a molecular weight cutoff of 1000 kDa, and freeze-drying the dialysate to obtain dithiolane-modified β-cyclodextrin, wherein each β-cyclodextrin molecule is modified with 2 to 3 dithiolanes; Wherein, the molar ratio of the β-cyclodextrin in step S1 to the lipoic acid in step S2 is 1:1.8-2.

4.

4. The preparation method according to claim 1, characterized in that: The following steps are involved: S1: dissolving β-cyclodextrin in DMSO to obtain a β-cyclodextrin solution; S2: dissolving lipoic acid and 1,1'-carbonyldiimidazole in DMSO, stirring at room temperature for 2 h, then adding triethanolamine, stirring at room temperature for 3 h to obtain an activated lipoic acid solution; S3: slowly dropwise adding the activated lipoic acid solution of step S2 to the β-cyclodextrin solution of step S1, stirring at room temperature overnight, and then dialyzing in ultrapure water for 24 hours using a dialysis bag with a molecular weight cutoff of 1000 kDa, and freeze-drying the dialysate to obtain dithiolane-modified β-cyclodextrin, wherein each β-cyclodextrin molecule is modified with 3 to 4 dithiolanes; Wherein, the molar ratio of the β-cyclodextrin in step S1 to the lipoic acid in step S2 is 1:6-7.

5. The preparation method according to claim 1, characterized in that: The following steps are involved: S1: dissolving β-cyclodextrin in DMSO to obtain a β-cyclodextrin solution; S2: dissolving lipoic acid and 1,1'-carbonyldiimidazole in DMSO, stirring at room temperature for 2 h, then adding triethanolamine, stirring at room temperature for 3 h to obtain an activated lipoic acid solution; S3: slowly dropwise adding the activated lipoic acid solution of step S2 to the β-cyclodextrin solution of step S1, stirring at room temperature overnight, and then dialyzing in ultrapure water for 24 hours using a dialysis bag with a molecular weight cutoff of 1000 kDa, and freeze-drying the dialysate to obtain dithiolane-modified β-cyclodextrin, wherein each β-cyclodextrin molecule is modified with 5 to 6 dithiolanes; Wherein, the molar ratio of the β-cyclodextrin in step S1 to the lipoic acid in step S2 is 1:11-13.

6. A dithiolane-modified β-cyclodextrin, characterized in that: The method is prepared according to any one of claims 1 to 5.

7. Use of the dithiolane-modified β-cyclodextrin according to claim 6 as a drug carrier.

8. A nano drug, characterized in that: The invention comprises two parts: a drug carrier and a raw material drug loaded by the drug carrier. The drug carrier is the dithiolane-modified β-cyclodextrin as claimed in claim 6. The raw material drug is a small molecule hydrophobic drug. The small molecule hydrophobic drugs include sorafenib, propranolol, doxorubicin, amphotericin B, gefitinib, methotrexate and paclitaxel.

9. The method for preparing the nano drug according to claim 8, characterized in that: The dithiolane-modified β-cyclodextrin and the small molecule hydrophobic drug were dissolved in a DMSO-water mixture with a volume ratio of 8:2, heated to reflux at 70-80°C for 24 hours, and then dialyzed in ultrapure water with a dialysis bag with a molecular weight cutoff of 1000 kDa for 24 hours to obtain the nanodrug; Wherein, the molar ratio of the dithiolane-modified β-cyclodextrin to the small molecule hydrophobic drug is 1:1-1.5.

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