Novel gold nanoparticle-based targeting preparation as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicine, and provides a novel gold nanoparticle-based targeting preparation as well as a preparation method and application thereof. The targeting preparation provided by the invention contains a gold nanoparticle core, a connecting molecule, a targeting ligand and a therapeutic agent, the connecting molecule and the targeting ligand sequentially modify gold nanoparticles, the therapeutic agent is loaded at the drug loading capacity of 1-50wt%, and the mass ratio of the targeting ligand to the gold nanoparticles is (1: 5)-(1: 100). The targeting preparation provided by the invention can efficiently cross the blood brain barrier, obviously reduce Abeta deposition in the brain, is high in enrichment degree of a targeting region in the brain, can down-regulate miR-146a-5p to inhibit neuroinflammation, and can be used for treating neurodegenerative diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, and particularly relates to a novel gold nanoparticle-based targeted preparation and a preparation method and application thereof. BACKGROUND

[0002] Alzheimer's disease (AD) is the most common neurodegenerative disease and has become a major global public health challenge. According to the global burden of disease research data, the number of AD patients worldwide in 2019 exceeded 50 million, and it is showing a continuous growth trend with the aging of the population. The core pathological features of AD are the abnormal deposition of β-amyloid (Aβ) in the brain to form senile plaques and the over-phosphorylation of tau protein to form neurofibrillary tangles, accompanied by neuroinflammation, neuron death and progressive decline in cognitive function, which not only seriously affects the quality of life of patients, but also brings a heavy burden to families and the medical system.

[0003] However, the current AD treatment faces two major bottlenecks: one is the low BBB penetration efficiency. The BBB, as a physiological barrier to protect the central nervous system (CNS), can prevent most exogenous substances from entering the brain. Traditional small molecule drugs (such as curcumin and WGX50) have potential anti-inflammatory and anti-Aβ aggregation effects, but due to poor water solubility and insufficient BBB penetration rate (usually <1%), it is difficult to achieve effective therapeutic concentration in the brain, resulting in limited clinical efficacy. The second is the lack of drug delivery targeting. After administration of existing non-targeted preparations, the drug is widely distributed in the body, not only wasting drug dosage, but also easily accumulating in non-target organs (such as liver and kidney) to cause toxic side effects, and cannot precisely act on the core area of AD pathological damage (such as hippocampus and cortex), further weakening the treatment effect.

[0004] In the field of drug carrier research, traditional nanocarriers (such as liposomes and polymer nanoparticles) have attempted to solve the above problems, but still have obvious limitations: some carriers have poor biocompatibility and are easily cleared by the immune system in the body; some carriers have insufficient stability and are prone to drug leakage in blood circulation; and most carriers lack active targeting mechanisms and still rely on passive targeting (such as EPR effect), making it difficult to efficiently cross the BBB and accumulate in the brain lesion site. In addition, due to the multi-target regulation requirements for AD pathological mechanisms, a single drug or ordinary carrier cannot simultaneously achieve the synergistic effect of "penetrating BBB - targeted accumulation - regulating pathological pathways", and cannot improve AD pathological damage from the molecular and cellular levels.

[0005] Gold nanoparticles (AuNPs) have shown promise in drug delivery due to their unique physicochemical properties (such as good biocompatibility, tunable particle size and surface chemistry, and strong surface plasmon resonance). However, existing AuNP-based formulations still have room for improvement: they lack specific targeting ligands (such as insulin, which can penetrate the brain via the blood-brain barrier via insulin receptors), resulting in insufficient targeting; the drug loading method is unstable, leading to drug detachment; and there is a lack of precise regulatory design targeting key pathological aspects of Alzheimer's disease (AD) (such as Aβ deposition and neuroinflammation), failing to fully realize the synergistic therapeutic effect of AuNPs carriers and drugs. Therefore, developing novel AuNP-based targeted formulations with efficient blood-brain barrier penetration, targeted enrichment properties, and the ability to synergistically regulate the pathological mechanisms of AD has become a key direction for overcoming the current challenges in AD treatment. Summary of the Invention

[0006] The first aspect of the present invention provides a gold nanoparticle-based targeted formulation comprising a gold nanoparticle core, a linker molecule for surface modification, a targeting ligand capable of mediating crossing of the blood-brain barrier, and a therapeutic agent for treating central nervous system diseases, wherein the linker molecule and the targeting ligand are sequentially modified on the surface of the gold nanoparticle, and the therapeutic agent is loaded onto the modified gold nanoparticle to form a nanocomposite, wherein the mass ratio of the targeting ligand to the gold nanoparticle is 1:5 to 1:100.

[0007] Specifically, the linker molecule is a biocompatible molecule containing thiol or amino groups.

[0008] Specifically, the target ligands described include insulin, insulin analogs, or insulin receptor-binding molecules.

[0009] Specifically, the gold nanoparticles have a particle size of 10-500 nm.

[0010] More specifically, the gold nanoparticles have a particle size of 30-200 nm.

[0011] Specifically, the zeta potential of the gold nanoparticles is -5 mV to -50 mV.

[0012] Specifically, the therapeutic agent is loaded via covalent bonding or physical adsorption, with a drug loading of 1-50 wt%.

[0013] More specifically, the therapeutic agent includes WGX50 and its derivatives, curcumin and its derivatives, or pharmaceutically acceptable salts of the foregoing.

[0014] A second aspect of the present invention provides a method for preparing any of the above-described targeted formulations, comprising the following steps: S1. Preparation of gold nanoparticles by chemical reduction method; S2. Surface modification is achieved by reacting the linker molecules with gold nanoparticles at pH 6.0-8.0 for 2-24 hours. S3. Connect the target ligand to the modified gold nanoparticles via chemical coupling or electrostatic self-assembly. S4. Load the therapeutic agent onto the gold nanoparticles obtained in step S3 to obtain the final nanocomposite.

[0015] Specifically, in S1, the chemical reduction method is preferably the citrate reduction method, and the reaction temperature is 80-100°C.

[0016] Specifically, in S4, the reaction of the load is carried out in a buffer solution at pH 8.0-10.0 for 12-48 hours.

[0017] A third aspect of the invention provides the use of any of the above-described targeted formulations in the preparation of medicaments for treating neurodegenerative diseases, including but not limited to Alzheimer's disease, vascular dementia, or mixed dementia.

[0018] Specifically, the drug exerts its therapeutic effect by regulating miR-146a-5p expression levels and / or reducing β-amyloid protein deposition in the brain.

[0019] A fourth aspect of the present invention provides a pharmaceutical composition comprising any of the above-described targeted formulations.

[0020] Specifically, the dosage forms of the pharmaceutical composition include, but are not limited to: liquid solutions only, lyophilized powders, pre-filled syringes only, pre-filled syringes, lyophilized powders, tablets, capsules, granules, sprays, oral dispersible tablets / films, sublingual tablets / lozenges, implants, microneedle patches, gels, creams / ointments, suppositories, liposomes / nanoparticles, exosome carriers, inhaled dry powder (DPI), in situ gels, compound preparations, or child-friendly formulations (flavored granules, oral drops).

[0021] Specifically, the pharmaceutical composition further includes pharmaceutical excipients.

[0022] More specifically, the pharmaceutical excipients include any one or more of the following: binders, fillers, disintegrants, lubricants, preservatives, antioxidants, flavoring agents, fragrances, solubilizers, emulsifiers, solubilizers, or osmotic pressure regulators.

[0023] Specifically, the pharmaceutical composition is administered to the subject via oral, intravenous, or nasal administration.

[0024] A fifth aspect of the present invention provides a method for treating a neurodegenerative disease, the method comprising administering to a subject a therapeutically effective amount of any of the above-described targeted agents.

[0025] Compared with the prior art, the present invention has the following beneficial effects: 1. The targeted formulations (GX-T, CT) provided by this invention have controllable particle size and excellent dispersibility, which are suitable for in vivo delivery requirements and can efficiently cross the blood-brain barrier.

[0026] 2. The targeted formulation provided by this invention can significantly reduce Aβ plaque deposition in the brains of AD model rats (e.g., 87.3% reduction in the GX-T group), and its pathological improvement effect is superior to that of non-targeted formulations and free drugs.

[0027] 3. The targeted formulation provided by this invention can accumulate in specific areas of the brain (such as the hippocampus), and the fluorescence intensity is 2.8-3.5 times that of the non-targeted group, which greatly improves the drug delivery efficiency.

[0028] 4. Targeted agents can downregulate miR-146a-5p expression, inhibit neuroinflammation, and improve the pathological mechanism of AD at the molecular level. Attached Figure Description

[0029] Figure 1 UV-Vis absorption spectrum of bare gold nanoparticles (AuNPs).

[0030] Figure 2 Dynamic light scattering particle size distribution of bare gold nanoparticles (AuNPs).

[0031] Figure 3 A is the X-ray diffraction pattern of the bare gold nanoparticles (AuNPs) of this invention, B is the X-ray diffraction pattern of cysteine-modified gold nanoparticles (Cys-AuNPs), and C is the X-ray diffraction pattern of the curcumin non-targeted formulation (C-NT).

[0032] Figure 4 Scanning electron microscope image of bare gold nanoparticles (AuNPs).

[0033] Figure 5 UV-Vis absorption spectrum of cysteine-modified gold nanoparticles (Cys-AuNPs).

[0034] Figure 6 Fourier transform infrared spectrum of cysteine-modified gold nanoparticles (Cys-AuNPs).

[0035] Figure 7 Scanning electron microscope image of cysteine-modified gold nanoparticles (Cys-AuNPs).

[0036] Figure 8: UV-Vis absorption spectrum of WGX50 targeted formulation (GX-T).

[0037] Figure 9 Fourier transform infrared spectrum of WGX50 targeted formulation (GX-T).

[0038] Figure 10 X-ray diffraction pattern of WGX50 targeted formulation (GX-T).

[0039] Figure 11 Scanning electron microscopy results of the WGX50 targeted formulation (GX-T).

[0040] Figure 12 UV-Vis absorption spectrum of curcumin-targeted formulation (CT).

[0041] Figure 13 Fourier transform infrared spectrum of curcumin-targeted formulation (CT).

[0042] Figure 14 Scanning electron microscope image of curcumin-targeted formulation (CT).

[0043] Figure 15 UV-Vis absorption spectrum of WGX50 non-targeted formulation (GX-NT).

[0044] Figure 16 Fourier transform infrared spectrum of WGX50 non-targeted formulation (GX-NT).

[0045] Figure 17 Scanning electron microscopy results of the non-targeted formulation of WGX50 (GX-NT).

[0046] Figure 18 Immunohistochemical staining of Aβ plaques in brain tissue of rats in the GX-T group.

[0047] Figure 19 Comparison of fluorescence imaging of targeted and non-targeted agents in rat brain. Detailed Implementation

[0048] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0049] Example 1 Preparation of gold nanoparticles (AuNPs) Preparation method: 12.5 mL of a 25 mM chloroauric acid (HAuCl4) solution was placed in a round-bottom flask and heated to 100 °C in an oil bath with continuous stirring. When the solution began to boil vigorously, 12.5 mL of a preheated 1% (w / v) sodium citrate solution was quickly added, and the reaction was continued with stirring for 15 minutes. During the reaction, the solution color gradually changed from pale yellow to deep red, and finally to a stable brick red, indicating that gold nanoparticles had formed. After the reaction was completed, the solution was cooled to room temperature to obtain a bare AuNPs dispersion.

[0050] UV-Vis spectral testing: A BIOBASE BK-UV1900PC UV-Vis spectrophotometer was used. 1 mL of AuNPs dispersion was placed in a quartz cuvette, with deionized water as a blank control. The entire wavelength range of 300-700 nm was scanned at a medium speed with a spectral bandwidth of 2 nm.

[0051] DLS particle size analysis: The AuNPs dispersion was diluted with ultrapure water to a concentration of approximately 0.1 mg / mL and placed in a Malvern Zetasizer Nano ZS90 particle size analyzer. The mixture was equilibrated at 25°C for 120 seconds. A scattering angle of 173° and a laser wavelength of 633 nm were used. Three consecutive measurements were taken and the average value was recorded.

[0052] X-ray diffraction (XRD): The AuNPs dispersion was concentrated by centrifugation and then drop-coated onto a glass slide, which was then allowed to air dry to form a thin film. A Rigaku Ultima IV X-ray diffractometer was used with a Cu Kα radiation source (λ=1.5406 Å), operating voltage 40 kV, current 40 mA, scanning range 2θ=10-80°, and scanning speed 2° / min.

[0053] Scanning electron microscopy (SEM) observation: 10 μL of AuNPs dispersion was dropped onto a silicon wafer, allowed to dry naturally, and then sputtered with gold. The morphology was observed using a ZEISS Gemini SEM 300 field emission scanning electron microscope at an accelerating voltage of 5-10 kV and a working distance of 8-10 mm, magnified at 30,000-200,000 times.

[0054] Energy dispersive X-ray spectroscopy (EDX): Elemental analysis was performed simultaneously with SEM observation using an Oxford X-MaxN spectrometer. The acquisition time was 60 seconds and the detector working distance was 9.1 mm.

[0055] Experimental results: Bare AuNPs exhibit a characteristic SPR absorption peak at 500.5 nm. Figure 1 DLS showed that the particle size distribution was polydisperse, with the main peaks located at approximately 10 nm and 100 nm. Figure 2The XRD pattern shows sharp diffraction peaks at 2θ = 38.02°, 44.54°, 64.98°, and 77.8°. Figure 3 SEM showed that AuNPs were irregularly spherical with a particle size of approximately 30-40 nm. Figure 4 The EDX assay showed that the gold content was 13.46% by weight (Table 1).

[0056] Table 1 Example 2 Preparation of cysteine-modified gold nanoparticles (Cys-AuNPs) Preparation method: Take 10 mL of the AuNPs dispersion prepared in Example 1, add 2.5 mL of 0.05 M cysteine ​​solution (adjust pH to 7.4 with NaOH), and react in a constant temperature shaker at 100 rpm in the dark for 2 hours at 37°C, then let stand for 24 hours.

[0057] FTIR testing: After centrifuging 5 mL of Cys-AuNPs dispersion, the precipitate was collected, mixed with KBr, and compressed into a pellet. A Nicoletti S50 Fourier transform infrared spectrometer was used, with a scanning range of 4000-500 cm⁻¹. -1 4 cm resolution -1 The number of scans was 32.

[0058] The UV-Vis, DLS, SEM, and EDX testing methods are the same as in Example 1.

[0059] Experimental results: UV-Vis showed that the SPR peak redshifted to 529 nm. Figure 5 FTIR at 3000 cm⁻¹ -1 A broad peak appears at 1500-2000cm. --1 and 1000 cm -1 The following regions show characteristic peaks of cysteine ​​( Figure 6 SEM showed that Cys-AuNPs exhibited an irregular cubic morphology with a particle size of 35-40 nm. Figure 7 EDX showed that the gold content increased to 52.13%, and sulfur was detected (Table 2).

[0060] Table 2 Example 3 Preparation of WGX50 Targeted Formulation (GX-T) Preparation method: Take 8 mL of the Cys-AuNPs dispersion prepared in Example 2, and add dropwise 2 mL of insulin solution with a concentration of 2 mg / mL (dissolved in 0.01N HCl, pH adjusted to 5.5±0.1). Stir at room temperature for 12 hours. Separately, dissolve WGX50 in tetrahydrofuran to prepare a 5% (w / v) solution, add carbodiimide (CDI) to a concentration of 50 mg / mL, and activate the reaction for 2 hours before removing excess CDI. Mix the activated WGX50 with the AuNPs-insulin complex in 0.1 M carbonate buffer (pH 9.5) and react at 4°C for 18 hours. Finally, add 0.1 M ethanolamine for blocking for 2 hours, centrifuge and wash three times to obtain the GX-T targeted formulation.

[0061] UV-Vis testing: The method is the same as in Example 1, but the scanning range is extended to 300-800 nm.

[0062] FTIR test: The method is the same as in Example 2, using Attenuated Total Reflection (ATR) mode to directly test the liquid sample.

[0063] XRD test: The method is the same as in Example 1, but the sample is a naturally dried nanocomposite film.

[0064] SEM test: The sample was observed after being fixed with glutaraldehyde and freeze-dried.

[0065] Experimental results: UV-Vis exhibits a double peak at 375 nm and 493 nm. Figure 8 FTIR shows WGX50-T at 3384.79 cm. -1 and 2928.96 cm -1 There is a characteristic peak ( Figure 9 XRD showed a decrease in the intensity of the characteristic peaks of WGX50-T. Figure 10 SEM showed that GX-T consisted of well-dispersed nanoparticles with a particle size of approximately 100-200 nm. Figure 11 ).

[0066] Example 4 Preparation of curcumin-targeted formulation (CT) Preparation method: Following the same method as in Example 3, WGX50 was replaced with curcumin. A 5% curcumin THF suspension was activated with CDI and then reacted with an AuNPs-insulin complex to obtain a CT-targeted formulation.

[0067] The UV-Vis, FTIR, and SEM testing methods are the same as in Example 3.

[0068] UV-Vis showed that CT exhibited characteristic absorption in the 300-350 nm range, with a peak value of 0.241778 ( ). Figure 12FTIR shows the shift of the characteristic peak of Curcumin-T (). Figure 13 SEM showed that the CT surface was rough, with a particle size of 100-450 nm. Figure 14 ).

[0069] Comparative Example 1: Preparation of WGX50 non-targeted formulation (GX-NT) Preparation method: The insulin coupling step in Example 3 was omitted. The activated WGX50 was directly reacted with Cys-AuNPs in pH 9.5 carbonate buffer for 18 hours, and the remaining steps were the same.

[0070] Characterization method: Same as in Example 3.

[0071] Experimental results: UV-Vis data shows that WGX50-NT has an absorption peak at 429 nm. Figure 15 FTIR at 3325.57 cm⁻¹ -1 and 2908.80cm -1 There is a characteristic peak ( Figure 16 SEM showed that WGX50-NT exhibited a relatively uniform distribution. Figure 17 ).

[0072] Comparative Example 2: Preparation of Curcumin Non-Targeted Formulation (C-NT) The insulin coupling step in Example 4 is omitted; the remaining operations are the same as in Example 4. Take 8 mL of the Cys-AuNPs dispersion prepared in Example 2 and add it directly to a curcumin THF solution activated by CDI (activation method as in Example 4). React in 0.1 M carbonate buffer (pH 9.5) at 4°C for 18 hours. Add 0.1 M ethanolamine for blocking for 2 hours, centrifuge and wash three times to obtain the C-NT non-targeted formulation.

[0073] Characterization methods: X-ray diffraction was performed using the same method as in Example 1, and the results are shown below. Figure 7 .

[0074] Example 6: Treatment and Efficacy Evaluation of Alzheimer's Disease Rat Model Animal model establishment: SPF-grade SD rats were injected intraperitoneally with 0.5 mL of AlCl3 solution (100 mg / kg) once daily for 15 consecutive days, except for the healthy control group.

[0075] The dosage of the targeted agent is 20 mg / kg body weight, and the specific regimen is as follows: Administration method: oral gavage; Dosage frequency: once daily; Dosage period: 30 consecutive days; Dosage calculation: Calculated based on the equivalent dose of the active pharmaceutical ingredient (WGX50 or curcumin), not the total weight of the nano-formulation.

[0076] This dosage is suitable for all test groups: WGX50 group (WXG50 active pharmaceutical ingredient); Curcumin group (curcumin); GX-T group (WGX50 targeted formulation); GX-NT group (WGX50 non-targeted formulation); CT group (curcumin-targeted preparation); C-NT group (curcumin non-targeting preparation); The control group consisted of normal rats that received no treatment.

[0077] Detection method: Immunohistochemical staining: Brain tissue was fixed, embedded in paraffin, and cut into 5 μm thick sections. Endogenous peroxidase was blocked with 3% H2O2, and the tissue was incubated overnight at 4°C with Aβ primary antibody (1:200), followed by incubation with secondary antibody at room temperature for 1 hour. DAB staining was then performed, and hematoxylin was used for counterstaining.

[0078] miRNA extraction: Take 200 μL of serum and add 700 μL of lysis buffer, and follow the instructions of the miRNeasy Serum / Plasma Kit. Detect RNA concentration and purity (A260 / A280 ratio) using Nanodrop.

[0079] qPCR detection: SYBR Green method was used, and the reaction system was 20 μL (cDNA 2 μL, primers 0.4 μL each, 2×Master Mix 10 μL, water 7.2 μL).

[0080] Forward primer (SEQ ID NO.1): 5ʹ-TGCGCTGAGAACTGAATTCCAT-3ʹ; Reverse primer (SEQ ID NO.2): 5ʹ-CCAGTGCAGGGTCCGAGGTATT-3ʹ.

[0081] Reaction conditions: 95℃ pre-denaturation for 30 seconds, 95℃ denaturation for 5 seconds, 60℃ annealing extension for 30 seconds, for a total of 40 cycles. U6 was used as an internal control, and 2... - The relative expression level was calculated using the ΔΔCt method.

[0082] Tissue fluorescence imaging: Frozen sections of brain tissue were fixed with 4% paraformaldehyde for 10 minutes, washed with PBS, and observed under a ZEISS LSM 880 confocal microscope. The excitation wavelengths were 488 nm (green fluorescence) and 405 nm (blue DAPI), and the emission wavelengths were collected in the ranges of 500-550 nm and 420-480 nm.

[0083] Experimental results: Immunohistochemistry showed that Aβ plaques decreased by 87.3% in the GX-T group ( Figure 18 Fluorescence microscopy showed that the fluorescence intensity of the targeted formulation was 2.8-3.5 times that of the non-targeted group. Figure 19 qPCR showed that the miR-146a-5p ΔCt value in the GX-T group was -2.63 (Table 3).

[0084] Table 3 Comparing the ΔCt values ​​of the curcumin-treated groups (sample 1: 2.825633, sample 2: 3.858) with those of the non-targeted curcumin preparation (C-NT) and the targeted curcumin preparation (CT), it was found that the ΔCt value of the targeted curcumin preparation group (sample 6: 0.5421) was lower, indicating that it could downregulate the expression of miRNA-146a-5p. This suggests that targeted delivery of curcumin may more effectively regulate the level of miRNA-146a-5p, thereby achieving better efficacy in the treatment of Alzheimer's disease (AD).

[0085] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A gold nanoparticle-based targeted formulation, characterized in that, The gold nanoparticle-based targeted formulation comprises a gold nanoparticle core, a linker molecule for surface modification, a targeting ligand capable of mediating crossing the blood-brain barrier, and a therapeutic agent for treating central nervous system diseases. The linker molecule and the targeting ligand are sequentially modified on the surface of the gold nanoparticle, and the therapeutic agent is loaded onto the modified gold nanoparticle to form a nanocomposite. The mass ratio of the targeting ligand to the gold nanoparticle is 1:5 to 1:

100.

2. The targeted formulation according to claim 1, characterized in that, The linker molecule is a biocompatible molecule containing thiol or amino groups.

3. The targeted formulation according to claim 1, characterized in that, The targeted ligands include insulin, insulin analogs, or insulin receptor-binding molecules.

4. The targeted formulation according to claim 1, characterized in that, The gold nanoparticles have a particle size of 10-500 nm.

5. The targeted formulation according to any one of claims 1, characterized in that, The therapeutic agent is loaded via covalent bonding or physical adsorption, with a drug loading of 1-50 wt%.

6. The targeted formulation according to claim 5, characterized in that, The therapeutic agents include WGX50 and its derivatives, curcumin and its derivatives, or pharmaceutically acceptable salts of the foregoing.

7. A method for preparing the targeted formulation according to any one of claims 1-6, characterized in that, The method includes the following steps: S1. Preparation of gold nanoparticles by chemical reduction method; S2. Surface modification is achieved by reacting the linker molecules with gold nanoparticles at pH 6.0-8.0 for 2-24 hours. S3. Connect the target ligand to the modified gold nanoparticles via chemical coupling or electrostatic self-assembly. S4. Load the therapeutic agent onto the gold nanoparticles obtained in step S3 to obtain the final nanocomposite.

8. The use of the targeted formulation according to any one of claims 1-6 in the preparation of a medicament for treating neurodegenerative diseases, characterized in that, The neurodegenerative diseases mentioned include Alzheimer's disease, vascular dementia, or mixed dementia.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the targeted formulation according to any one of claims 1-6.

10. The pharmaceutical composition according to any one of claims 9, characterized in that, The pharmaceutical composition is administered to the subject via oral, intravenous, or nasal routes.

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