Idebenone-based bioactive nanomicelles, their preparation methods, and applications

Abstract

This invention discloses a bioactive nanomicelle based on idebenone. By designing idebenone molecules with hydrophobic ends and functionalized hydrophilic polyethylene glycol, it exhibits excellent responsiveness, antioxidant properties, and cellular safety, making it suitable as a carrier for delivering drugs, genes, or other bioactive molecules for therapeutic and diagnostic applications. This invention also discloses a method for preparing this idebenone-based bioactive nanomicelle. The method for synthesizing the amphiphilic polymer of IDBP is simple, with mild reaction conditions, easy synthesis, convenient post-processing, high yield, and easy industrial production. The prepared amphiphilic polymer exhibits spontaneous assembly behavior in aqueous solution, forming a stable nanomicelle structure. This demonstrates the great potential of idebenone-based bioactive nanomicelles in drug delivery, potentially improving drug stability, bioavailability, and targeting.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a bioactive nanomicelle based on idebenone, its preparation method, and its application. Background Technology

[0002] Oxidative stress is an early event accompanying mitochondrial dysfunction. High-energy electron transfer is an essential step in the production of adenosine triphosphate (ATP); however, it is also a source of reactive oxygen species (ROS). The accumulation of ROS can damage several biomolecules, including lipids, proteins, and nucleic acids, leading to cytotoxicity. Idebenone (IDB), an analogue of coenzyme Q, was first developed by Takeda Pharmaceutical Company in Japan. Due to its high lipid solubility, it can easily cross biological membranes and the blood-brain barrier; simultaneously, its antioxidant capacity is 100 times that of coenzyme Q, exhibiting excellent antioxidant and free radical scavenging functions. Idebenone can donate electrons to reduce the effects of free radicals and support the mitochondrial respiratory chain to promote ATP production. Therefore, it is commonly used to treat diseases caused by brain dysfunction, including cerebral infarction, cerebral hemorrhage, and sequelae of atherosclerosis, such as cognitive impairment, emotional disorders, language disorders, and dementia.

[0003] However, idebenone's lipophilicity and stability issues limit its application in treating acute and chronic inflammatory diseases. Nanotechnology can effectively improve drug stability and lipid-water partition coefficient, making drugs more easily recognized and phagocytosed by mononuclear macrophages and reticuloendothelial tissue. Modification and functionalization of nanoparticle surfaces improve the interaction between nanoparticles and biological systems, while also enabling rapid in vivo clearance of nanoparticles, thus promoting the application of nanomedicines in biomedicine. Although liposomes are widely used as drug delivery carriers due to their good biocompatibility and low toxicity, they also suffer from drug leakage and poor stability, limiting their development. Summary of the Invention

[0004] This invention aims to at least partially solve one of the technical problems in related technologies. Therefore, the main objective of this invention is to provide a bioactive nanomicelle based on idebenone; furthermore, this invention aims to provide a method for preparing and applying this bioactive nanomicelle based on idebenone.

[0005] The objective of this invention is achieved through the following technical solution:

[0006] A bioactive nanomicelle based on idebenone, the chemical structure of which is shown in general formula I:

[0007]

[0008] Where X is O, S or NH; R is an active end group with functionalization and targeting.

[0009] In some specific embodiments, the R group is selected from -OCH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2COOH,

[0010] One of them.

[0011] A method for preparing idebenone-based bioactive nanomicelles, as described above, specifically comprises the following steps:

[0012] 1) Under an inert atmosphere, idebenone, an acid-binding agent, and an active end-group polyethylene glycol derivative are mixed in an organic solvent to obtain a mixed solution;

[0013] 2) Under ice bath conditions, oxalyl chloride solution was added dropwise to the aforementioned mixed solution and allowed to react completely to obtain an amphiphilic polymer of idebenone;

[0014] 3) The amphiphilic polymer was treated and purified, and the purified product was placed in an aqueous solution for ultrasonic treatment followed by standing to obtain a solution of bioactive nanomicelles based on idebenone; the reaction equations involved are as follows:

[0015]

[0016] In step 3), the amphiphilic polymer is processed and purified. This involves purifying the initial product of the amphiphilic polymer of idebenone obtained in step 2) using a silica gel column. Alternatively, the mixed solution after the reaction in step 2) can be evaporated under reduced pressure to remove the organic solvent, and then purified by column chromatography to obtain the amphiphilic polymer of idebenone.

[0017] In some specific embodiments, the active end-group polyethylene glycol derivative has an average molecular weight of 500 Da, 1000 Da, 2000 Da, 5000 Da, or 10000 Da.

[0018] In some specific embodiments, the acid-binding agent is selected from one or more of sodium metal, potassium metal, sodium hydride, calcium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate, potassium carbonate, triethylamine, and N,N-diisopropylethylamine;

[0019] The organic solvent is selected from one or more of dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, tetrahydrofuran, or 1,4-dioxane.

[0020] In some specific embodiments, the concentration range of idebenone in the organic solvent in step 2) is 0.01 mmol / mL to 1.0 mmol / mL.

[0021] In some specific embodiments, the molar ratio of idebenone to the active end-group polyethylene glycol derivative in step 2) is 1:(1-1.3).

[0022] The application of the aforementioned idebenone-based bioactive nanomicelles or idebenone-based bioactive nanomicelles prepared according to the aforementioned preparation method in pharmaceuticals, functional foods, foods for special medical purposes or other biological products.

[0023] In some specific embodiments, the use of idebenone-based bioactive nanomicelles in the preparation of medicaments for the prevention and / or treatment of synucleinosis.

[0024] Furthermore, the synucleinosis is one or more of Parkinson's disease (PD), Parkinson's dementia (PDD), Lewy body dementia (DLB), Lewy body variant of Alzheimer's disease (LBVAD), multiple system atrophy (MSA), simple autonomic failure (PAF), or neurodegeneration with brain iron accumulation type 1 (NBIA-I).

[0025] Compared with the prior art, the present invention has at least the following advantages:

[0026] 1) The idebenone-based bioactive nanomicelles provided by this invention are designed with idebenone molecules with hydrophobic ends and functionalized hydrophilic polyethylene glycol, wherein the hydrophilic and hydrophobic ends are linked by responsive oxalate bonds or other responsive linking units, such as carbonate bonds, disulfide bonds, ether bonds, or Click reactions. These idebenone-based bioactive nanomicelles have a particle size of approximately 55.02±2.54 nm, a Zeta potential of -13.90±0.78 mV, uniform particle size distribution without adhesion or breakage, and repulsive forces between the nanomicelle aggregates, resulting in a stable dispersed state. Furthermore, these idebenone-based bioactive nanomicelles can react with hydrogen peroxide, and the UV spectral signal of their mixed solution changes over time, indicating that they are responsive. Moreover, these idebenone-based bioactive nanomicelles exhibit excellent antioxidant properties and cellular safety, and can be used as carriers to deliver drugs, genes, or other bioactive molecules for therapeutic and diagnostic applications.

[0027] 2) The method for preparing idebenone-based bioactive nanomicelles provided by this invention has a simple synthesis method for the amphiphilic polymer, mild reaction conditions, convenient post-processing, high yield, and is easy to industrialize. Moreover, the prepared amphiphilic polymer exhibits spontaneous assembly behavior in aqueous solution, forming a stable nanomicelle structure. This makes idebenone-based nanomicelles have great potential in the field of drug delivery, and can improve the stability, bioavailability, and targeting of drugs.

[0028] 3) This application successfully designed and synthesized a series of amphiphilic polymers based on the ROS-scavenging properties of idebenone. These amphiphilic polymers link their hydrophobic and hydrophilic ends via hydrogen peroxide-responsive oxalate bonds. Nanomice solutions were prepared using ultrasonic processing technology, effectively improving drug delivery and targeting performance. These amphiphilic polymers possess a series of unique properties, including controllable particle size, good biocompatibility, long cycle time, high stability, and high drug loading. Simultaneously, this application constructed a drug carrier system of ROS-scavenging nanoparticles. Through detailed studies of the ROS-scavenging ability of these self-assembled nanomicelles and their regulatory role in the inflammatory microenvironment, and a comprehensive evaluation of the cellular oxidative repair functions of these nanomedicines, this application provides crucial information for a deeper understanding of the efficacy and mechanism of action of nanomicelles in treating central nervous system degenerative diseases related to oxidative stress. Based on the excellent antioxidant and cellular safety of idebenone bioactive nanomicelles, they can be further used as effective carriers for drugs, genes, or other bioactive molecules for therapeutic and diagnostic applications. This research provides strong support for the development of novel treatment options and drug delivery systems, and is expected to play an important role in improving patients' quality of life and treating related diseases. Attached Figure Description

[0029] To more clearly illustrate the specific embodiments of the present invention, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below.

[0030] Figure 1 This is the 1H NMR spectrum of the amphiphilic polymer in deuterated chloroform (see the original text). 1 H NMR spectrum;

[0031] Figure 2 This is the 1H NMR spectrum of the amphiphilic polymer in deuterated water (as described in this application). 1 H NMR spectrum;

[0032] Figure 3 This is the infrared spectrum of the amphiphilic polymer of this application;

[0033] Figure 4 This application presents the UV spectra of idebenone bioactive nanomicelles at different time points after the addition of hydrogen peroxide.

[0034] Figure 5 This application contains a particle size distribution diagram and TEM image of idebenone bioactive nanomicelles.

[0035] Figure 6 This is a DPPH radical scavenging diagram of idebenone bioactive nanomicelles in this application;

[0036] Figure 7 This application is for a safety evaluation of idebenone bioactive nanomicelles in cells;

[0037] Figure 8 This application evaluates the activity of different concentrations of IDBP in PC12 cells after stimulation with rotenone.

[0038] Figure 9 This is a confocal image of PC12 cells stimulated with rotenone and measured using the DCFH-DA probe to determine reactive oxygen species levels.

[0039] Figure 10 This is a confocal image of α-synuclein level expression in PC12 cells stimulated by rotenone, as described in this application. Detailed Implementation

[0040] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. The following embodiments are merely descriptive and not limiting, and should not be construed as limiting the scope of protection of the present invention.

[0041] When a quantity, concentration, or other value or parameter is described as a range, preferred range, or preferred upper and lower limits, it should be understood that it is equivalent to specifically disclosing any range by combining any pair of upper or preferred values ​​with any lower or preferred values, regardless of whether the range is specifically disclosed. Unless otherwise stated, the numerical range values ​​listed herein include the endpoints of the range and all integers and fractions within that range.

[0042] Unless otherwise stated, all percentages, parts, ratios, etc. in this document are by weight.

[0043] The materials, methods, and embodiments described herein are exemplary and should not be construed as limiting unless otherwise stated.

[0044] Unless otherwise specified, all materials, methods, apparatuses, and detection devices described in this article are commercially available. Experimental methods not specified in the embodiments are generally performed under conventional conditions or as recommended by the manufacturer.

[0045] Example 1: Preparation of amphiphilic polymers of general formula I:

[0046] The specific preparation steps of the amphiphilic polymer of IDBP provided by this invention are as follows: Under nitrogen protection, idebenone (1 mmol), methoxy polyethylene glycol-hydroxy (molecular weight 1000) (1.05 mmol) and diisopropylisopropylamine (2 mmol) are mixed in anhydrous dichloromethane (10 mL), and oxalyl chloride (1 mmol) is added dropwise under ice bath conditions, and the reaction is carried out for 2 hours. The reaction progress is monitored using a thin-layer chromatography plate. After the reactants have reacted completely, the reaction is stopped to obtain the crude product of the IDBP compound. The crude product is concentrated, purified by silica gel column chromatography, and eluted with methanol / dichloromethane (volume ratio 1 / 15) to obtain the amphiphilic polymer of IDBP (general formula I) with a yield of 72%. This embodiment describes the preparation of the obtained amphiphilic polymer of IDBP (IDBP). 1000 Hydrogen nuclear magnetic resonance (HNMR) and infrared spectroscopy were performed, and the results showed that the hydrogen NNMR... 1 H NMR data such as Figure 1 As shown, the infrared spectral data are as follows Figure 3 As shown; from Figure 1 It can be seen that IDBP 1000 In deuterated chloroform hydrogen nuclear magnetic resonance 1 The characteristic peaks of idebenone and some characteristic peaks of methoxy polyethylene glycol in H NMR indicate that the hydrophobic end of idebenone and the hydrophilic end of methoxy polyethylene glycol are linked by oxalate bonds.

[0047] To further verify the structure of the amphiphilic polymer, the methoxy polyethylene glycol-hydroxyl group with a molecular weight of 1000 was replaced with methoxy polyethylene glycol-hydroxyl groups with molecular weights of 500 and 2000, while the rest of the preparation method was the same as that for the methoxy polyethylene glycol-hydroxyl group with a molecular weight of 1000. IDBPs with hydrophilic methoxy polyethylene glycol (molecular weights of 500 and 2000) were synthesized using the above method. 500 and IDBP 2000 p-idebenone (IDB) and IDBP 1000 IDBP 500 and IDBP 2000 Characterized by infrared spectra, such as Figure 2 It can be seen that 1750-1800cm -1 Range IDBP 1000 IDBP 500 and IDBP 2000 The formation of oxalate bonds; in summary, the combination of amphiphilic polymers... 1 1H NMR and infrared spectral data indicate that the amphiphilic polymer of IDBP represented by general formula I was successfully prepared.

[0048] Example 2: Preparation of bioactive nanomicelles based on idebenone:

[0049] Based on Example 1, the amphiphilic polymer (10 mg) was placed in deionized water (10 mL), sonicated for 3 min, and then allowed to stand at room temperature for 10 min to prepare an idebenone bioactive nanomicelle solution (1 mg / mL).

[0050] The amphiphilic polymer was dissolved in deuterium water and chlorochloroform (10 mg / mL), respectively, and samples were sent for hydrogen nuclear magnetic resonance (NMR) detection. 1 HNMR data such as Figure 1 and Figure 2 As shown in the figure, it can be seen that the amphiphilic polymers in deuterated water show a slight difference in signal intensity between the hydrophobic end idebenone and the hydrophilic end methoxy polyethylene glycol in deuterated chloroform. In deuterated water, the amphiphilic polymers form nanomicelle aggregates through hydrophilic-hydrophobic self-assembly. The hydrophilic end methoxy polyethylene glycol has a stronger signal and is located in the outer layer of the micelles, while the hydrophobic end idebenone has a weaker signal and is located in the inner layer of the micelles.

[0051] Example 3: Performance testing of the prepared idebenone-based bioactive nanomicelles

[0052] 1) Physical property testing

[0053] The amphiphilic polymer (IDBP) was prepared using the preparation method of Example 1. 1000 Simultaneously, following the method in Example 2, a nanomicelle solution was prepared to obtain an idebenone bioactive nanomicelle solution (1 mg / mL). The particle size distribution and zeta potential of the 1 mg / mL idebenone bioactive nanomicelle solution were measured (see Example 2). Figure 4 (AB). Simultaneously, a solution of idebenone bioactive nanomicelles (1 mg / mL) was dropped onto a prepared dust-free wax plate. A carbon-copper mesh was inserted into the droplet using tweezers. After standing for 15 minutes, the mesh was removed and placed on filter paper. The morphology of the nanoparticles was observed using a high-resolution transmission electron microscope (see [link to image]). Figure 4 C); As can be seen from the figure, the amphiphilic polymer forms nanomicelle aggregates in the aqueous phase. The aggregates are uniformly dispersed and without adhesion or breakage. The particle size is approximately 55.02±2.54 nm, and the Zeta potential is -13.90±0.78 mV. The measured potential indicates that the particles are in a stable dispersed state due to the repulsive force between the nanomicelle aggregates.

[0054] 2) Responsiveness

[0055] The amphiphilic polymer (IDBP) was prepared using the preparation method of Example 1. 500Following the method in Example 2, a nanomicelle solution was prepared to obtain idebenone bioactive nanomicelle solution (1 mg / mL). The prepared idebenone bioactive nanomicelle solution was then incubated in hydrogen peroxide solution. The mass concentration of the nanomicelle solution in the incubation system was 1 mg / mL, and the concentration of the hydrogen peroxide solution was 100 mM. Samples were taken at different time points (0.25, 1, 2, 3, 4, 5, 6, 7 h) to measure the UV spectrum of the solution. The UV spectra at different time points were plotted (see...). Figure 5 The graph shows that the ultraviolet spectral signal changes over time, indicating a responsiveness; this suggests that the oxalate ester bonds react under the action of hydrogen peroxide.

[0056] 3) Antioxidant activity

[0057] 400 μL of amphiphilic polymer (IDBP) containing different concentrations was used. 500 IDBP 1000 and IDBP 2000 Methanol solutions (0 mg / mL, 0.5625 mg / mL, 1.125 mg / mL, 2.25 mg / mL, 4.5 mg / mL, 9 mg / mL, and 18 mg / mL) were mixed with 400 μL of fresh DPPH methanol solution (100 μg / mL). The mixture was then rapidly added to 96-well plates and incubated at 37°C in the dark with a shaker. The absorbance at 520 nm (labeled A) was measured using a microplate reader (Epoch, BioTek, USA) at different time points (0, 5, 10, 30, 60, 480 to 720 min). t DPPH radical scavenging activity is expressed as a percentage of DPPH inhibition, expressed as: (A0-A t ) / A0×100%, where A0 is the initial absorbance, A t The absorbance values ​​are shown at different time points. The antioxidant activity of the amphiphilic polymers is shown in [reference needed]. Figure 6 As shown in the figure, the DPPH method is a widely used method for determining antioxidant activity. It can be seen from the figure that the scavenging of DPPH free radicals is positively correlated with the concentration of the amphiphilic polymer and with the incubation time. The DPPH free radical scavenging experiment shows that all three amphiphilic polymers prepared have antioxidant activity.

[0058] 4) Cell safety

[0059] The amphiphilic polymer (IDBP) was prepared using the preparation method of Example 1. 1000 Then, following the method in Example 2, a nanomicelle solution was prepared to obtain an idebenone bioactive nanomicelle solution for cell safety evaluation. Specific measures were as follows: different cell types (HUVECs, L02, PC12, and RAW264.7) were cultured at 1 × 10⁻⁶ cells per well.4 Cells were seeded at a density of [insert density here] into 96-well plates and cultured overnight. Afterward, they were treated for 12 hours with different doses (specifically 0 μg / mL, 1 μg / mL, 5 μg / mL, 10 μg / mL, 25 μg / mL, 50 μg / mL, 100 μg / mL, and 200 μg / mL) of idebenone bioactive nanomicelles. Cell viability was then determined using the Cell Counting Kit-8 (CCK-8) method. Figure 7 As shown, the safety of HUVECs, L02, PC12 and RAW264.7 cells in idebenone bioactive nanomicelles was determined, indicating that idebenone bioactive nanomicelles have good cell safety in the dosage range of 1-100 μg / mL. However, when the concentration of idebenone bioactive nanomicelles is greater than 100 μg / mL, it shows certain cell damage in HUVECs, L02 and PC12 cells.

[0060] Example 4: Protective effect of idebenone-based bioactive nanomicelles against rotenone-induced cytotoxicity

[0061] 1) Evaluation of the therapeutic effect of idebenone-based bioactive nanomicelles on rotenone-induced cytotoxicity

[0062] The amphiphilic polymer (IDBP) was prepared using the preparation method of Example 1. 1000 Then, following the method in Example 2, a nanomicelle solution was prepared to obtain an idebenone bioactive nanomicelle solution for evaluating rotenone-induced cytotoxicity therapy. Specific measures are as follows: PC12 cells were cultured at 1 × 10⁻⁶ cells per well. 4 Cells were seeded at a density of [insert density here] into 96-well plates and cultured overnight. Afterward, they were pretreated for 2-6 hours with different doses of idebenone bioactive nanomicelle medium solution (5, 10, 25 μg / mL), followed by stimulation with 2 μM rotenone for 24 hours. Cell viability was then determined using the CCK-8 assay. Figure 8 As shown in the figure, compared with the control group, stimulation of PC12 cells with 2 μM rotenone for 24 hours induced significant cytotoxicity. Pretreatment of cells with different doses of idebenone bioactive nanomicelles produced certain cytoprotective effects. The figure also shows that 10 μg / mL of idebenone bioactive nanomicelles had a good effect on rotenone-induced cytotoxicity.

[0063] 2) Evaluation of the antioxidant effect of idebenone-based bioactive nanomicelles on rotenone-induced PC12 cells

[0064] PC12 cells were used at a rate of 5 × 10⁶ cells per well. 4Cells were seeded at a density of [insert density here] in 12-well plates (containing circular glass slides) and cultured in 1 mL of complete culture medium. After overnight culture, the cell culture medium was replaced with one containing 10 μg / mL of IDPB amphiphilic polymer (IDPB). 1000 Fresh complete culture medium was used. After incubation for 6 hours, the culture medium was removed, and the cells were washed three times with PBS. Then, the cells were treated with 2 μM rotenone for 24 hours. The culture medium solution was discarded, and the cells were washed three times with PBS. 10 μM DCFH-DA in PBS was added, and the cells were incubated at 37.5°C in the dark for 40 minutes. The culture medium was discarded, and the cells were washed 3-5 times with PBS to remove the probe. The cells were then fixed with 4% paraformaldehyde. Observation was performed using a confocal laser scanning microscope (CLSM) (Olympus FV3000, Japan). Images were quantitatively analyzed using ImageJ software. Experimental results are shown below. Figure 9 As shown, rotenone stimulation of cells induces oxidative stress damage. In the model group, rotenone stimulation resulted in the production of large amounts of reactive oxygen species (ROS) (green fluorescence). The ROS levels in rotenone-pretreated cells were significantly lower than those in the model group, showing a statistically significant difference. Furthermore, the oxidation levels in normal cells treated with idebenone nanomicelles were not significantly different from those in the control group, indicating that 10 μg / mL idebenone nanomicelles have a significant antioxidant effect on rotenone-induced PC12 cells without cytotoxicity during rotenone-induced cellular oxidation.

[0065] 3) Evaluation of the effect of idebenone bioactive nanomicelles on rotenone-induced synuclein expression in PC12 cells;

[0066] PC12 cells were used at a rate of 5 × 10⁶ cells per well. 4 Cells were seeded at a density of 12-well plates (containing circular glass slides) and cultured in 1 mL of growth medium. After overnight culture, the cell culture medium was replaced with fresh medium containing 10 μg / mL idebenone bioactive nanomicelles. After 6 h of culture, cells were washed three times with PBS. Cells were then treated with 2 μM rotenone for 24 h, followed by fixation with 4% paraformaldehyde. After three washes with PBS, cells were blocked with 3% BSA in 1×TBST at room temperature for 0.5 h, and then incubated overnight at 4°C with α-synuclein polyclonal antibody (1:250; Proteintech, 10842-1-AP). After three washes with PBS, cells were incubated with Cy3-labeled IgG (H+L) (1:400; Boster Biotechnology, BA1032) at room temperature for 1 h, and finally incubated with DAPI for 5 min. The samples were then washed three times with PBS. Confocal laser scanning microscopy (CLSM) was used for observation using an Olympus FV3000 confocal microscope (Japan), and fluorescence intensity was measured using ImageJ software. Experimental results are as follows: Figure 10As shown, rotenone-stimulated cells showed significantly higher α-synuclein expression compared to normal cells. Idebenone-pretreated rotenone-stimulated cells showed significantly lower α-synuclein expression compared to the model group. Idebenone-pretreated normal cells showed no significant difference in α-synuclein expression compared to the normal group. This indicates that 10 μg / mL idebenone-pretreated idebenone-induced α-synuclein expression in PC12 cells has a certain inhibitory effect on rotenone-induced α-synuclein expression.

[0067] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be covered within the scope of the claims and specification of the present invention.

Claims

1. An idebenone bioactive nanomicelle-based composition, characterized in that, The nanomicelles are self-assembled in aqueous solution from compounds with chemical structures as shown in general formula I. I； Where X is O, S, or NH; R is -OCH3; The idebenone-based bioactive nanomicelles are prepared by the following method, specifically including the following steps: 1) Under an inert atmosphere, idebenone, an acid-binding agent, and an active end-group polyethylene glycol derivative are mixed in an organic solvent to obtain a mixed solution; 2) Under ice bath conditions, oxalyl chloride solution was added dropwise to the aforementioned mixed solution and allowed to react completely to obtain an amphiphilic polymer of idebenone; 3) The amphiphilic polymer of idebenone was purified, and the purified product was placed in an aqueous solution for ultrasonic treatment and then allowed to stand to obtain a bioactive nanomicelle solution based on idebenone. wherein said active end group polyethylene glycol derivative has an average molecular weight of 500 Da, 1000 Da, 2000 Da, 5000 Da, or 10000 Da, wherein said active end group polyethylene glycol derivative has the formula HXCH2CH2(OCH2CH2) n R.

2. The idebenone-based bioactive nanomicelles according to claim 1, characterized in that, The acid-binding agent is selected from one or more of sodium metal, potassium metal, sodium hydride, calcium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate, potassium carbonate, triethylamine, and N,N-diisopropylethylamine.

3. The idebenone-based bioactive nanomicelles according to claim 1, characterized in that, The organic solvent mentioned in step 1) is selected from one or more of dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, tetrahydrofuran, or 1,4-dioxane.

4. The idebenone-based bioactive nanomicelles according to claim 1, characterized in that, The concentration range of idebenone in organic solvents in step 1) is 0.01-1.0 mmol / mL.

5. The idebenone-based bioactive nanomicelles according to claim 1, characterized in that, The molar ratio of idebenone to the active end-group polyethylene glycol derivative in step 1) is 1:(1-1.3).

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