CN115919766A - Composite nano micelle and preparation method and application thereof - Google Patents
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Abstract
The application provides a composite nano micelle and a preparation method and application thereof, and relates to the technical field of biological medicines. The preparation method comprises the following steps: dissolving self-assembled amphiphilic peptide in water, adding a sound sensitive substance and an anti-tumor small molecule, uniformly mixing, and performing ultrasonic cleaning to obtain amphiphilic peptide nano micelle; and transferring the amphiphilic peptide nano micelle into a dialysis bag, and dialyzing in ultrapure water to finally obtain the composite nano micelle. The carrier of the composite nano micelle is a functional peptide with an amphiphilic group and an endothelial cell transmembrane peptide fragment, and can greatly enhance the specificity of aggregated tumor cells by combining RGD with integrin alphavbeta 3 overexpressed on the surface of glioma. The functional peptide entraps the phonosensitive agent Bengal red and the anti-glioma natural small molecule sulforaphane, so that the functional peptide is accurately targeted to the glioma part, passes through a blood brain barrier, implements RB-mediated sonodynamic therapy and cooperative tumor killing of SFN enriched to the glioma part, and realizes sensitization glioma treatment.
Description
Technical Field
The application relates to the technical field of biological medicines, in particular to a composite nano micelle and a preparation method and application thereof.
Background
Glioma (Gliomas) is the most common primary tumor of the central nervous system, accounts for about 40-50% of the tumors of the central nervous system, has an annual incidence rate of about 3-8 cases/10 ten thousand of people, and has the characteristics of difficult cure, high recurrence rate, high lethality rate and the like. Reported by the world health organization, there are about 50 million new cases of brain glioma each year worldwide, with about 2 million cases of death. Due to their high invasiveness and recurrence rates, patients have an average survival time of about 1-1.5 years, with a proportion of survival exceeding 5 years being less than 5%. At present, the treatment means of brain glioma still mainly comprises surgical excision, radiotherapy and chemotherapy. Because brain glioma has the characteristics of self-renewal and rapid proliferation of tumor stem cells, normal brain tissue can be invaded, and conventional surgical excision combined with chemoradiotherapy can stimulate the high-speed proliferation of tumor cells in the dormant period to cause tumor recurrence. In addition, due to the Blood-brain barrier (BBB), most chemotherapy drugs cannot effectively enter brain tissues, thereby limiting the chemoradiotherapy effect of brain gliomas. Therefore, how to improve the treatment effect of the brain glioma and reduce the recurrence rate is still a great problem to be solved for clinically treating the brain glioma. The blood brain barrier is composed of brain capillary walls and glial cells, is a natural blood brain barrier between blood plasma and brain cells, and only allows fat-soluble substances with molecular weight less than 400Da to pass through. The presence of the blood-brain barrier isolates about 98% of small molecules and 100% of drug molecules with potential therapeutic utility outside the brain parenchyma, which is the primary bottleneck in the treatment of central nervous system diseases. In order to deliver therapeutic drug molecules into the brain, many studies have explored a variety of approaches to increase the permeability of the blood brain barrier, including ligand receptor binding, formulation modification, injection of hypertonic drugs via arteries, direct intracerebral injection or infusion, and nasal administration, which, despite their efficacy, are somewhat traumatic and still have low delivery efficiency. In recent years, researchers have attempted to open the blood brain barrier through various physical, chemical and biological approaches to facilitate drug delivery, for example, laser interstitial thermotherapy as a non-invasive treatment for brain glioma can open the blood brain barrier for 40 days. However, there are certain risks associated with this treatment, such as heterogeneity of brain tissue and local cerebral perfusion affecting thermal conduction, laser damage to functional areas surrounding the tumor, etc. Compared with laser, ultrasound is more widely applied to the treatment of brain tumors due to the penetrability and safety of brain dense tissues. Repeated ultrasound scanning, as found by Leinenga et al, can transiently open the blood brain barrier and clear beta-amyloid, and restore memory and cognitive function in mouse models of Alzheimer's disease. This discovery provides a non-invasive, safe method for ultrasound to open the blood brain barrier for drug delivery. Therefore, researchers have been working on developing a new method for the ultrasound-assisted treatment of brain gliomas. One such technique is sonodynamic therapy (SDT), a strategy for co-therapy of diseases with ultrasound in combination with sonosensitizers.
Sonodynamic therapy is a method of treating tumors that combines ultrasound with a sonosensitive substance. On one hand, focused ultrasound can destroy cells by utilizing the mechanical action of sound energy, and on the other hand, the strong penetrating power of ultrasound to biological tissues can be utilized to activate the sound sensitive agent of deep tumor tissues at fixed points to generate substances such as active oxygen and the like to mediate the apoptosis of tumor cells. Various sonosensitive substances such as 5-ALA, photolon, photofrin, rose bengal and the like have obvious tumor killing effect under the action of ultrasound. However, the traditional sound-sensitive agents have some problems: (1) Most of the sound-sensitive agents are hydrophobic micromolecules, and have low water solubility; (2) Can not target tumor cells specifically, and has low bioavailability.
Disclosure of Invention
The purpose of the present application is to provide a composite nano micelle, which has the advantages of small particle size, high biocompatibility and high compatibility.
Another object of the present application is to provide a method for preparing a composite nano-micelle, which is simple and convenient.
Still another objective of the present application is to provide an application of the composite nano-micelle in the preparation of a drug for treating brain glioma.
The technical problem to be solved by the application is solved by adopting the following technical scheme.
In one aspect, an embodiment of the present application provides a method for preparing a composite nano micelle, including the following steps:
dissolving self-assembled amphiphilic peptide in water, adding a sound sensitive substance and an anti-tumor small molecule, uniformly mixing, and performing ultrasonic cleaning to obtain amphiphilic peptide nano micelle;
and transferring the amphiphilic peptide nano micelle into a dialysis bag, and dialyzing in ultrapure water to finally obtain the composite nano micelle.
On the other hand, the embodiment of the present application provides a composite nano-micelle prepared by the above preparation method.
On the other hand, the embodiment of the application also provides an application of the composite nano-micelle in preparing a medicament for treating brain glioma.
The invention has two functions of specifically killing tumor cells:
(1) The specificity of the chemical mechanism is as follows: the self-assembly peptide micelle is specifically combined with an alpha v beta 3 receptor on the surface of a tumor cell through RGD to enter the cell, and then SFN coupled with the RGD induces the tumor cell to generate excessive active oxygen, so that autophagic cell death is triggered.
(2) Specificity of physical mechanism: in the acoustic dynamic therapy, focused ultrasonic waves activate the sound sensitive agent RB to induce the generation of active oxygen in cells, so that apoptosis induced by the active oxygen is limited to tumor cells from a spatial position as much as possible. In conclusion, the designed polypeptide self-assembly micelle can achieve accurate targeted drug delivery to tumor tissues and induce tumor cell apoptosis through the specific organic combination of physiological, chemical and physical mechanisms.
Compared with the prior art, the embodiment of the application has at least the following advantages or beneficial effects:
1. the invention designs a nano micelle with high biocompatibility and compatibility, which is used for encapsulating natural brain glioma-resistant drug molecules, namely natural sulforaphane SFN and a sonosensitizer bengal RB, efficiently passes through a blood brain barrier by means of ultrasonic means, and utilizes the targeting glioma characteristic of RGD (integrin alpha overexpressed on the RGD and the surface of brain glioma) v β 3 Combined), exerts the synergic tumor killing effect of RB mediated sonodynamic therapy and SFN enriched to the part of the brain glioma and realizes the treatment of the brain glioma with enhanced sensitivity. In the invention, chemical modification and physical technology are combined, so that the sulforaphane exerts the biological effect in tumor cells, and the accurate treatment of the brain glioma is realized.
2. The blood brain barrier is a key bottleneck problem for preventing the high-efficiency delivery of the drug into the brain, and the delivery of the drug-loaded nanomaterial is considered as a breakthrough point for the diagnosis and treatment of nervous system diseases. The size of the nano material is a key factor influencing the entrance of the nano material into the brain, and the nano micelle has the particle size as small as 40nm, so that the blood brain barrier crossing efficiency of the nano micelle can be greatly improved.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are required to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present application and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained from the drawings without inventive effort.
FIG. 1 is a diagram showing the morphology of composite nanomicelles in the experimental examples of the present application;
FIG. 2 is an ultraviolet analysis spectrum and an HPLC spectrum of the composite nano-micelle of the experimental example of the present application;
FIG. 3 is a graph showing a comparison of the cell viability assay of U87MG in the experimental example of the present application;
FIG. 4 is a graph showing the detection of apoptosis in the experimental examples of the present application;
FIG. 5 is a diagram of the evaluation of the sonodynamic therapy of mice bearing in situ brain glioma based on functional nanomicelles in the experimental examples of the present application;
FIG. 6 shows the structural formula of self-assembled amphiphilic peptide in the present application.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions of the embodiments of the present application will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are not indicated by manufacturers and are commercially available.
It should be noted that, in the present application, the embodiments and features of the embodiments may be combined with each other without conflict. The present application will be described in detail below with reference to specific examples.
A preparation method of composite nano-micelle comprises the following steps:
dissolving self-assembled amphiphilic peptide in water, adding a sound sensitive substance and an anti-tumor small molecule, uniformly mixing, and performing ultrasonic cleaning to obtain amphiphilic peptide nano micelle;
and transferring the amphiphilic peptide nano micelle into a dialysis bag, and dialyzing in ultrapure water to finally obtain the composite nano micelle.
The invention utilizes the nanometer technology to prepare the sound sensitive agent into a nanometer compound, realizes the fixed-point release of the medicine by ultrasonic triggering, and realizes the multifunctional integrated treatment mode of tumor treatment and the like. The self-assembly peptide can overcome the disadvantages that the free state is unstable and is easy to be rapidly cleared by enzyme, and has the following advantages: (1) prolonging the circulation time of the sound-sensitive agent in the body; (2) Improving the distribution of the medicine in vivo, and increasing the effective concentration of the sonosensitizer in the tumor part; (3) The surface of the nano-composite can be modified with ligand molecules targeting tumors, so that the active transportation of the acoustic sensitivity agent is realized.
In some embodiments of the present application, the hydrophobic end group of the self-assembling amphiphilic peptide is C 18 The hydrophilic end group is targeted integration alpha v beta 3 ligand RGDS, the connecting bridge chain is R8, the structural formula is shown in figure 6, and the structural formula is as follows: (C18) GRRRRRRRRGDS, the self-assembling amphiphilic peptide is a kind of fragment with both amphiphilicity and endothelial cell membrane penetrationRGD is used as a hydrophilic group, C18 is used as a hydrophobic group, the peptides are connected through a penetrating peptide R8 and are self-assembled into a nano material, and the peptides are combined with alpha v beta 3 receptors on the surfaces of various malignant tumor cells through RGD, so that the specificity of the gathered tumor cells can be greatly enhanced. Therefore, the self-assembly nano material is applied to the cross-barrier delivery of the ultrasonic-triggered fixed-point release medicine or the sound-sensitive agent to the brain tumor tissue, and has important research and application values for the complete eradication of the brain glioma.
In some embodiments of the present application, the sonosensitive substance is bengal and the small anti-tumor molecule is a small molecule sulforaphane. The sound-sensitive substance has better active oxygen generation capacity, and is particularly activated only in a tumor microenvironment. In addition, sulforaphane (SFN), a natural product, is derived from cruciferous plants (broccoli, etc.), and has been widely reported to have strong inhibitory or killing effects on various tumor cells, such as ovarian cancer, oral cancer, prostate cancer, brain glioma, etc. Functional group-N = C = S in SFN is believed to have antioxidant and anticancer activity. Therefore, the SFN is transported to the tumor part in a targeted way through the self-assembly nano material, and has very important application value for enhancing the treatment of the brain glioma.
In some embodiments of the present application, the mass ratio of the self-assembled amphiphilic peptide, the sonosensitive substance and the anti-tumor small molecule is 2: (1-2): (1-2).
In some embodiments of the present application, the ultrasonic cleaning is performed at a temperature of 22-26 deg.C for 20-40min at a power of 25-30KHZ.
In some embodiments of the present application, the cut-off molecular weight of the dialysis bag is 800-1200 daltons, the ultrapure water is replaced every 4-6h, and the dialysis time is 36-60h.
A composite nano micelle is prepared by adopting the preparation method.
An application of a composite nano micelle in preparing a medicament for treating brain glioma.
The features and properties of the present application are described in further detail below with reference to examples.
Example 1
A composite nano micelle is prepared by adopting the following method:
with C 18 As a hydrophobic end group, the hydrophilic end group selects targeted integration alpha v beta 3 ligand RGDS, the connecting bridge chain selects a membrane penetrating peptide R8, and self-assembly amphiphilic peptide is synthesized; the structural formula of the amphiphilic peptide adopted in the embodiment is designed by the inventor and synthesized by Shanghai Qiangyao Biotech limited.
Dissolving self-assembled amphiphilic peptide in water, and then adding a sonosensitive substance bengal (RB) and natural anti-tumor small-molecule Sulforaphane (SFN) according to the mass ratio of 2:1:1, the misce bene is placed in the ultrasonic cleaner in the light-resistant, sets up the instrument parameter and does: carrying out ultrasonic cleaning at the temperature of 25 ℃ for 30min and the power of 28KHZ to obtain the amphiphilic peptide nano micelle;
and transferring the amphiphilic peptide nano micelle into a dialysis bag with the molecular weight cutoff of 1000 daltons, putting the dialysis bag into a beaker filled with ultrapure water for dialysis, replacing the ultrapure water every 4 hours, and dialyzing for 48 hours to obtain the RB and SFN-entrapped composite nano micelle.
Example 2
A composite nano micelle is prepared by adopting the following method:
with C 18 As a hydrophobic end group, the hydrophilic end group is selected from targeted integration alpha v beta 3 ligand RGDS, and the connecting bridge chain is selected from membrane-penetrating peptide R8 to obtain self-assembly amphiphilic peptide;
dissolving self-assembled amphiphilic peptide in water, and then adding a sound sensitive substance bengal (RB) and natural anti-tumor small-molecule Sulforaphane (SFN) in a mass ratio of 2:1:2, the misce bene is placed in the ultrasonic cleaner in the light-resistant, sets up the instrument parameter and does: carrying out ultrasonic cleaning at the temperature of 26 ℃ for 25min at the power of 25KHZ to obtain the amphiphilic peptide nano micelle;
and transferring the amphiphilic peptide nano micelle into a dialysis bag with the molecular weight cutoff of 1100 daltons, putting the dialysis bag into a beaker filled with ultrapure water for dialysis, replacing the ultrapure water every 4 hours, and dialyzing for 45 hours to obtain the RB and SFN-entrapped composite nano micelle.
Example 3
A composite nano micelle is prepared by adopting the following method:
with C 18 As a hydrophobic end group, the hydrophilic end group selects targeted integration alpha v beta 3 ligand RGDS, and the connecting bridge chain selects a membrane penetrating peptide R8 to obtain self-assembly amphiphilic peptide;
dissolving self-assembled amphiphilic peptide in water, and then adding a sound sensitive substance bengal (RB) and natural anti-tumor small-molecule Sulforaphane (SFN) in a mass ratio of 2:2:1, the misce bene is placed in the ultrasonic cleaner in the light-resistant, sets up the instrument parameter and is: the temperature is 22 ℃, the time is 30min, the power is 30KHZ, and the amphiphilic peptide nano micelle is obtained after ultrasonic cleaning;
and transferring the amphiphilic peptide nano micelle into a dialysis bag with the molecular weight cutoff of 900 daltons, putting the dialysis bag into a beaker filled with ultrapure water for dialysis, replacing the ultrapure water every 4 hours, and dialyzing for 50 hours to obtain the RB and SFN-entrapped composite nano micelle.
Example 4
A composite nano micelle is prepared by adopting the following method:
with C 18 As a hydrophobic end group, the hydrophilic end group selects targeted integration alpha v beta 3 ligand RGDS, and the connecting bridge chain selects a membrane penetrating peptide R8 to obtain self-assembly amphiphilic peptide;
dissolving self-assembled amphiphilic peptide in water, and then adding a sonosensitive substance bengal (RB) and natural anti-tumor small-molecule Sulforaphane (SFN) according to the mass ratio of 2:2:1, the misce bene is placed in the ultrasonic cleaner in the light-resistant, sets up the instrument parameter and is: carrying out ultrasonic cleaning at the temperature of 25 ℃ for 30min at the power of 25KHZ to obtain the amphiphilic peptide nano micelle;
and transferring the amphiphilic peptide nano micelle into a dialysis bag with the molecular weight cutoff of 1000 daltons, putting the dialysis bag into a beaker filled with ultrapure water for dialysis, replacing the ultrapure water once every 6 hours, and dialyzing for 60 hours to obtain the RB and SFN-entrapped composite nano micelle.
Examples of the experiments
The finished product prepared in example 1 was used for each composite nanomicelle in the experimental examples.
1. Characterization of composite nanomicelles
(1) Characterization of particle size and potential
And (3) taking 20 mu L of composite nano micelle, adding 1mL of deionized water for dilution, and measuring the particle size and the zeta potential of the nano micelle by using a Malvern particle sizer Zetasizer NanoZS. All micelles had a positive surface charge, as shown by A, B in fig. 1, with nanomicelles having a particle size of 50nm.
(2) Characterization of electron microscope
Taking 50 mu L of nano-micelle, and carrying out morphology characterization by a transmission electron microscope, wherein the obtained nano-micelle has the particle size of about 50nm, smooth surface and spherical structure as shown in figure 1C.
(3) Packet loading rate of RB and SFN
The RB entrapment rate can be calculated by drawing a standard curve with an ultraviolet spectrophotometer (fig. 2A). The highest absorption peak of RB at the wavelength of 564nm is measured, first, a standard is prepared by using RB (2-10 mu g/mL) water solutions with different concentrations, a standard curve is drawn by the absorbance measured at 564nm, the concentration of RB can be calculated by the standard curve and the dilution ratio of a sample, and the entrapment rate (EE) is calculated according to the following formula:
EE (%) = mass of drug in micelle/mass of drug put × 100%
Calculating the RB entrapment rate to be 17%;
the loading rate of SFN was obtained by HPLC analysis (fig. 2B), with the mobile phase acetonitrile: water =30 (v/v), flow rate 0.01mL/min, ultraviolet detection wavelength 215nm, column C18 reverse phase column, column temperature 40 ℃. The peak area was measured, and the inclusion ratio of SFN was 15% by area ratio.
2. Cytotoxicity test of nano-micelle under ultrasonic action
In order to verify that the anti-tumor activity of the composite nano-micelle can be remarkably enhanced under the ultrasonic action, the in-vitro culture of the human-derived brain glioma cells U87MG is adopted, stimulation is given to the RB alone and the nano-material (SFN @ RB @ SPM) which simultaneously entraps the RB and the SFN, and ultrasonic irradiation treatment is respectively carried out on the stimulation. Wherein the frequency of the ultrasound is 1.0MHz, the power is 1.0W/cm2, and the duration is 30s. Cytotoxicity of brain glioma by different treatment groups can be quantitatively detected by MTT. As shown in FIG. 3, the self-assembled polypeptide nano-micelle can reduce the survival rate of cells when the concentration of the entrapped RB is 3.5 mug/mL, and the toxicity effect of the nano-micelle on U87MG is remarkably enhanced by ultrasound.
3. Apoptosis test of nano-micelle under ultrasonic action
Based on the anti-tumor effect of the ultrasound combined nano-micelle SFN @ RB @ SPM on U87MG cells observed in cytotoxicity experiments, we further evaluated the apoptosis inducing effect. As shown in fig. 4, there was no significant difference between the control group and the RB-alone treated group before and after the sonication (8.43%, 11.3%,14.5%, 13.9%), the apoptosis rate of the nanomicelle sfn @ RB @ spm-induced cells was 28.1%, which was slightly higher than that of the control group and the RB-alone treated group, and the apoptosis rate of the nanomicelle sonication group was as high as 81.7%, indicating that the sonication could greatly enhance the apoptosis-inducing effect of the nanomicelle on U87MG, which is also consistent with the cytotoxicity experimental results described above.
4. Inhibition effect of self-assembled polypeptide nano micelle on mouse brain tumor
(1) Establishment of in-situ glioma animal model
A mouse model of the Hold in situ brain glioma is established through a brain stereotaxic instrument, the U87-Luc cell suspension is inoculated to the brain of the mouse, and the tumor formation condition of the nude mouse is investigated by using a living body imaging instrument of the mouse after two weeks. The tumor area of the brain will exhibit fluorescein-excited fluorescence after successful glioma inoculation.
(2) Functional nano micelle-based sonodynamic treatment evaluation of Holo in situ brain glioma mice
The successfully modeled components are taken as a control group and an experimental group at random, the experimental group injects the nano-micelle into a tumor-bearing mouse by vein, and the result of in vivo imaging of the small animal shows that the nano-micelle successfully penetrates through a blood brain barrier to enter the brain and maintains higher fluorescence intensity within 2-6 h. Therefore, in the later period of pharmacodynamic test, ultrasonic treatment is carried out 2h after administration, as shown in fig. 5, a represents the fluorescence intensity value of the head, B represents the fluorescence intensity change chart of the head of a nude mouse, C represents the imaging of the brain tumor area of the nude mouse after the pharmacodynamic test is finished, and D represents the weight change trend of the nude mouse.
Experiments show that under the action of ultrasound, the nano micelle treatment group successfully inhibits the tumor area of brain glioma and maintains the normal body weight of mice.
In summary, the composite nano micelle, the preparation method and the application thereof provided by the embodiment of the application have the following advantages:
1. the invention designs a nano micelle with high biocompatibility and compatibility, an entrapped natural anti-glioma drug molecule, namely natural sulforaphen SFN and a sonosensitizer Bengal RB, efficiently passes through a blood brain barrier by means of ultrasonic means, and utilizes the targeting glioma characteristic of RGD (integrin alpha overexpressed by RGD and the surface of glioma) v β 3 Combined), exerts the synergic tumor killing effect of RB mediated sonodynamic therapy and SFN enriched to the part of the brain glioma and realizes the treatment of the brain glioma with enhanced sensitivity. In the invention, chemical modification and physical technology are combined, so that the sulforaphane exerts the biological effect in tumor cells, and the accurate treatment of the brain glioma is realized.
2. The blood brain barrier is a key bottleneck problem for preventing the high-efficiency delivery of the drug into the brain, and the delivery of the drug-loaded nanomaterial is considered as a breakthrough point for the diagnosis and treatment of nervous system diseases. The size of the nano material is a key factor influencing the entrance of the nano material into the brain, and the nano micelle has the particle size as small as 40nm, so that the blood brain barrier crossing efficiency of the nano micelle can be greatly improved.
The embodiments described above are some, but not all embodiments of the present application. The detailed description of the embodiments of the present application is not intended to limit the scope of the claimed application, but is merely representative of selected embodiments of the application. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
Claims (8)
1. The preparation method of the composite nano micelle is characterized by comprising the following steps of:
dissolving self-assembled amphiphilic peptide in water, adding a sound sensitive substance and an anti-tumor small molecule, uniformly mixing, and performing ultrasonic cleaning to obtain amphiphilic peptide nano micelle;
and transferring the amphiphilic peptide nano micelle into a dialysis bag, and dialyzing in ultrapure water to finally obtain the composite nano micelle.
2. The method for preparing the composite nano-micelle of claim 1, wherein the hydrophobic end group of the self-assembled amphiphilic peptide is C 18 The hydrophilic end group is targeted integration alpha v beta 3 ligand RGDS, and the connecting bridge chain is R8.
3. The preparation method of the composite nano-micelle of claim 1, wherein the sonosensitive substance is bengal, and the anti-tumor small molecule is a small molecule sulforaphane.
4. The preparation method of the composite nano-micelle of claim 3, wherein the mass ratio of the self-assembled amphiphilic peptide to the sound sensitive substance to the anti-tumor small molecule is 2: (1-2): (1-2).
5. The preparation method of the composite nano-micelle of claim 1, wherein the ultrasonic cleaning temperature is 22-26 ℃, the time is 20-40min, and the power is 25-30KHZ.
6. The method for preparing composite nanomicelle according to claim 1, wherein the cut-off molecular weight of the dialysis bag is 800 to 1200 daltons, the ultrapure water is replaced every 4 to 6 hours, and the dialysis time is 36 to 60 hours.
7. A composite nano-micelle prepared by the preparation method of any one of the above claims 1 to 6.
8. Use of the composite nanomicelle according to claim 7 for the preparation of a medicament for the treatment of brain glioma.
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