KR102156733B1 - Self-assembled polymeric micelles of phosphonium glycol chitosan derivatives specifically targeting mitochondria, preparation method and uses thereof - Google Patents

Abstract

The present invention relates to a self-assembled polymer micelle of a mitochondrial-targeted phosphonium glycol chitosan derivative, a preparation method thereof, and a use thereof, wherein the phosphonium glycol chitosan derivatives (GC-TPP and GME-TPP) have little cytotoxicity, It is excellent in migration into the cell, and after it is moved into the cell, it specifically moves to the mitochondria, as well as hydrophobic drugs such as anticancer agents can be easily mounted inside the micelles of the present invention, which has an excellent effect as a drug delivery system. There is.

Description

Self-assembled polymeric micelles of phosphonium glycol chitosan derivatives specifically targeting mitochondria, preparation method and uses thereof {Self-assembled polymeric micelles of phosphonium glycol chitosan derivatives specifically targeting mitochondria, preparation method and uses thereof}

The present invention relates to a self-assembled polymer micelle of a mitochondrial-targeted phosphonium glycol chitosan derivative, a method for preparing the same, and a use thereof.

Biopharmaceuticals are becoming more and more important in the pharmaceutical industry, and among them, research based on drug delivery systems is being actively conducted worldwide. In order to maximize the therapeutic effect while minimizing side effects, the drug delivery system (DDS) aims to effectively maintain blood levels for a long time and selectively deliver drugs to target sites. In previous chemotherapy treatments, as the number of administration of the drug carrier increases, multi-drug resistance (MDR) of anticancer drugs occurs, and continuous drug administration does not have a significant effect. As one of the methods to overcome this, it can be maintained in the blood for a long time. A method of manufacturing a delivery system having a nano-sized size and maintaining the concentration of a drug through the delivery system has been disclosed, and another method is a method of binding the drug to a polymer for selective delivery to a disease site, that is, a target site.

On the other hand, chitosan [β-(1-4)-2-amino-2-deoxy-D-glucan] is a kind of natural polysaccharide produced by deacetylation of chitin. Chitosan is not toxic, has low immunogenicity, antibacterial effect, anticancer effect and biodegradability.

In addition, glycol chitosan is a kind of chitosan derivative, a cationic polymer having a primary amine group on the surface, has the characteristics of chitosan at all pHs, and has an advantage of good solubility compared to chitosan. In addition, various derivatives can be made through the 2-amine-2-deoxy moiety of glycol chitosan, and it is very easy to bind to functional ligands.

In addition, TPP (Triphenylphosphonium) is Staphylococcus epidermidis and Escherichia coli ), as well as anti-cancer activity, is well known as a mitochondrial target structure. TPP's unique chemical structure, which has a lipophilic group and a positively charged phosphonium group by a phenyl group, has low activation energy entering the mitochondrial membrane, which is a nonpolar lipid environment, from an aqueous solution outside the mitochondria, so it can easily pass through. In recent studies, TPP has been used to bind water-soluble polymers or to bind amphiphilic copolymers to target mitochondria.

On the other hand, as a technology related to the present invention, a glycol chitosan-diqualinium self-assembling polymer micelle, a preparation method and a use thereof are disclosed in Korean Patent No. 1720458, but the mitochondrial target type phosphonium glycol of the present invention There is no disclosure regarding self-assembled polymer micelles of chitosan derivatives, methods for preparing the same, and uses thereof.

The present invention was derived from the above requirements, and the present invention relates to a self-assembled polymer micelle of a mitochondrial target type phosphonium glycol chitosan derivative, a preparation method thereof, and a use thereof, and the phosphonium glycol chitosan derivative of the present invention (GC-TPP and GME-TPP) have almost no cytotoxicity, excellent migration into cells, and after being moved into cells, they specifically migrate to mitochondria, as well as hydrophobic drugs such as anticancer agents. By confirming that it can be easily mounted inside the micelle, the present invention was completed.

In order to achieve the above object, the present invention provides a polymer consisting of glycol chitosan or a derivative thereof; and triphenylphosphonium.

In addition, the present invention provides a micelle formed by self-assembly of a GC-TPP or GME-TPP polymer consisting of the glycol chitosan or a derivative thereof; and triphenylphosphonium.

In addition, the present invention provides a drug delivery system comprising micelles formed by self-assembly of the GC-TPP or GME-TPP polymer.

In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the drug delivery system.

The present invention relates to a self-assembled polymer micelle of a mitochondrial-targeted phosphonium glycol chitosan derivative, a method for preparing the same, and a use thereof, and the drug delivery system of the present invention has no cytotoxicity, and is specifically mitochondrial after migration into the longitudinal direction. Since it has a characteristic of moving to, it can be usefully used for mitochondrial target drug delivery.

1 is a block diagram showing the self-assembled GC-TPP and GME-TPP micelles and mitochondrial targeting steps thereof.
Figure 2 shows the synthesis of GC-TPP, GC-MA and GME-TPP polymers.
3 is a ¹ H NMR spectrum for GC, GC-MA, GC-MA-EDA and GME-TPP.
4 is an FT-IR spectrum for GC, GC-TPP, GME-TPP and TPP.
5 shows the shapes of GC-TPP and GME-TPP measured by FE-SEM (Field Emission Scanning Electron Microscope) and the size of particles measured by dynamic light scattering (DLS), (A,C) is GC- TPP, (B,D) is GME-TPP (scale bars= 500 nm).
Figure 6 is a result of confirming the cell binding of the polymer using a flow cytometer, AlexaFluor 488-labeled 0.1 ㎍ / ㎖ of GC, GME, GC-TPP and GME-TPP treated for 24 hours HeLa cells treated with nothing cells It is a histogram showing the change in green fluorescence intensity compared to (Control). (A) Control, (B) GC, (C) GME, (C) GC-TPP, (E) GME-TPP (F) GC, GME, GC-TPP and GME-TPP are overlapped graphs.
7 is a confocal laser microscope image of HeLa cell lines. Nucleus polymers were stained with Bisbenzimide (Hochest 33342, blue) and Alexafluor 488 (green), and mitochondria were stained with Mitotracker Red FM. Yellow fluorescence is a result of superimposing fluorescence images of polymer (green) and Mitotracker (red).
8 is a result of confirming the cell viability (%) of HEK 293 (A), HeLa (B), NIH3T3 (C) and HepG2 (D) cells.
9 is a result of confirming the cytotoxicity of GC, GC-TPP and GME-TPP in HEK 293 (A), HeLa (B), NIH3T3 (C) and HepG2 (D) cells.
10 is a confocal image confirming that GC-TPP and GME-TPP target mitochondria in HeLa cells.

The present invention relates to a polymer consisting of glycol chitosan or a derivative thereof; and triphenylphosphonium (FIG. 1).

The polymer is characterized in that it is a mitochondrial target type, and is a GC-TPP polymer prepared by reacting glycol chitosan (GC) and triphenylphosphonium (TPP) chloride in a reaction first solvent according to the following Scheme (1);

In the reaction second solvent, methyl acrylate (MA) was added to the amine group of glycol chitosan (GC) to synthesize glycol chitosan-methylacrylate (GC-MA), and ethylenediamine (EDA) was added to the synthesized GC-MA. ) To synthesize GC-MA-EDA (GME), and reacting the synthesized GME with triphenylphosphonium (TPP) chloride. It is a GME-TPP polymer.

[Scheme 1]

In Reaction Scheme 1, n is independently an integer ranging from 1 to 10,000.

The reaction first solvent or reaction second solvent is independently at least one selected from water, C ₁ ~ C ₄ lower alcohol, acetone, DMF (dimethylformamide), DMSO (dimethyl sulfoxide), acetonitrile, and THF (Tetrahydrofuran). Preferably, it is a mixture of water and a lower alcohol of C ₁ ~ C ₄ more preferably, most preferably methanol, but is not limited thereto.

The reaction temperature in Scheme 1 is preferably 20 to 60°C, more preferably 30 to 45°C, and the preferred reaction time is 1 to 5 days, more preferably 2 to 4 days, but limited thereto no.

In addition, the present invention relates to a micelle formed by self-assembly of a GC-TPP or GME-TPP polymer consisting of the glycol chitosan or a derivative thereof; and triphenylphosphonium. The glycol chitosan-triphenylphosphonium (GC-TPP) micelle may contain a hydrophobic drug therein, and the hydrophobic drug is preferably an anticancer agent, more preferably doxorubicin, but is not limited thereto.

In addition, the present invention relates to a drug delivery system comprising micelles formed by self-assembly of the GC-TPP or GME-TPP polymer.

In addition, the present invention relates to a pharmaceutical composition for preventing or treating cancer comprising the drug delivery system. The cancer is preferably cervical cancer, liver cancer, stomach cancer, breast cancer, lung cancer, brain cancer, glioma, prostate cancer, uterine cancer, or skin cancer, but is not limited thereto.

The pharmaceutical composition of the present invention may further include a carrier, excipient, or diluent in addition to the drug delivery system, and the pharmaceutical composition of the present invention may be administered orally or parenterally. When administered parenterally, the pharmaceutical composition may be administered externally to the skin or intraperitoneally, or , It is preferable to select intravenous, intramuscular, subcutaneous, intrauterine dura mater or cerebrovascular injection.

The pharmaceutical composition of the present invention may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, syrups, etc.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized agents, and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin, glycero gelatin, and the like may be used.

The composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, the'pharmaceutically effective amount' means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type of disease, severity, and drug activity of the patient. , Sensitivity to drugs, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.

The dosage of the composition of the present invention can be used in various ranges according to the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and severity of disease.

Hereinafter, the present invention will be described in more detail using examples. These examples are only for describing the present invention in more detail, and it is apparent to those of ordinary skill in the art that the scope of the present invention is not limited thereto.

1. Material purchase

Glycol chitosan (60% or more, degree of deacetylation = 91.6%), methyl acrylate (99%), methanol (anhydrous, 99.8%), ethylenediamine (99% or more), (methoxycarbonylmethyl) triphenylphos Phonium bromide (98%) and Nile Red were purchased from Sigma-Aldrich.

Using gel permeation chromatography (GPC) through TSKgel G5000pWxl-CP and TSKgel G3000PWx1-CP columns, the glycol chitosan molecular weight (Mn=198kDa, Mw=490kDa) and dispersion index (Mw/Mn)=2.47 were confirmed. EZ-cytox reagent (EZ-cytox enhanced cell viability assay kit) and EZ-LDH reagent (Cell Cytoxicity Assay Kit) were purchased from Daeil Lab Service (Seoul, Korea). Fetal bovine serum (FBS), Dulbecco's modified Eagle medium (DMEM) and 100× antibiotic-antibacterial agents were purchased from Githersburg, MD, USA. Alexafluor488 5-SDP ester (Sulfodichlorophenol Ester) and MitoTracker ^® Red CMXRos were purchased from Invitrogen (Seoul, Korea).

2. Cell culture

Human liver cancer cell line HepG ₂ , human embryonic kidney-derived cell line HEK 293, cervical cancer cell line HeLa and mouse normal fibroblasts NIH-3T3 were mixed with 10% FBS, 90% DMEM (Dulbecco's modified eagle medium) and 1% antibiotics with humidity 5% CO _{Is 2} , Incubated under conditions of 37°C.

Example 1.Glycol Chitosan ( GC )-T Of Liphenylphosphonium (TPP) synthesis

GC-TPP was synthesized through a chemical reaction called Michael addition reaction (FIG. 2). First, (methoxycarbonylmethyl) triphenylphosphonium bromide was transferred to a 250 ml round bottom flask and mixed with 90 ml methanol for 10 minutes at room temperature. Then, glycol chitosan dissolved in distilled water (10 ml) was placed in a 250 ml round bottom flask. A 250 ml round bottom flask was filled with nitrogen gas and incubated at 37° C. for 3 days while shaking at 140 rpm. After 3 days, methanol was evaporated, and the product was dialyzed against distilled water for 3 days using a membrane having a molecular weight of 1000 Da. On the first day, dialysis was performed in 100% methanol, on the second day, a mixture of methanol and distilled water was dialyzed, and on the last day, dialysis was performed with 100% distilled water. The final product was lyophilized under vacuum.

To obtain GC-MA, methyl acrylate and 90 ml of methanol were added to a 250 ml round bottom flask and stirred. Then, glycol chitosan dissolved in distilled water (10 ml) was put into a 250 ml round bottom flask. A 250 ml round-bottom flask was filled with nitrogen gas and incubated at 37° C. for 3 days while shaking at 140 rpm. After 3 days, ethylenediamine was put into a 250 ml round bottom flask and reacted. After filling the inside of the flask with nitrogen gas, it was reacted in a shaking incubator at 37° C. at 140 rpm for 3 days. After 3 days, methylacrylate and methanol from the product were evaporated. GC-MA-EDA was obtained by dialysis in distilled water for 1 day using a dialysis membrane having a molecular weight of 1000 Da and freeze drying.

GC-MA-EDA was dissolved in the above solution (methanol:distilled water=9:1, v/v), added to a 250 ml round bottom flask and stirred. Then, triphenylphosphonium bromide (methoxycarbonylmethyl) dissolved in methanol was added to the flask. The flask was filled with nitrogen gas and incubated for 3 days at 37° C. with shaking at 140 rpm. After 3 days, methanol was evaporated, and the product was dialyzed against distilled water for 3 days using a membrane having a molecular weight of 1000 Da. Dialysis was performed with 100% methanol on the first day, methanol and distilled water on the second day, and 100% distilled water on the last day. The final product was lyophilized under vacuum.

GC, GC-TPP, GC-MA, GC-MA-EDA and GME-TPP are ¹ H nuclear magnetic resonance spectroscopy (AVANCE, 600, FT-NMR, Germany Bruker) and Fourier transform infrared spectroscopy (FT-IR, Bio-Rad Laboratories Inc., Cambridge, USA) (Figures 3 and 4).

GC (Glycol chitosan): ¹ H-NMR (600MHz, D ₂ O, ppm) δ2.0-2.1 (NHCOCH ₃ , acetyl group), 2.6-2.8 (H2 of deacetylated monomer), 3.4-3.9 (H2~H8, multiplet, D-glucosamine unit and hydroxyl ethyl substituents), 4.3-4.5(H1)

GC-TPP (Glycol chitosan-Triphenylphosphonium): ¹ H-NMR (600MHz, D ₂ O, ppm) δ2.0-2.1 (NHCOCH ₃ , acetyl group), 2.8-3.0 (H2 of deacetylated monomer), 3.2-3.4 ( H9 of methylene in TPP), 3.6-4.0 (H2~H8, multiplet, D-glucosamine unit and hydroxyl ethyl substituents), 7.5-7.7 (H10 of phenyl rings in TPP)

GC-MA (Glycol chitosan-Methyl acrylate): ¹ H-NMR (600MHz, D ₂ O, ppm) δ2.0-2.1 (NHCOCH ₃ , acetyl group), 2.4-2.6 (H2, OCCH ₂ , H10 of deacetylated monomer) ), 2.8-3.0 (H ₂ CCH ₂ N, H9), 3.4-3.9 (H2~H8, multiplet, D-glucosamine unit and hydroxyl ethyl substituents), 4.3-4.5(H1)

GC-MA-EDA (Glycol chitosan-Methyl acrylate-Ethylenediamine): ¹ H-NMR (600 MHz, D ₂ O, ppm) δ2.0-2.1 (NHCOCH ₃ , acetyl group), 2.3-2.5 (H2 in deacetylated monomer) , OCCH, H10), 2.9-3.1(H ₂ CCH ₂ N, H9), 3.2-3.4(CONHCH ₂ , H11), 3.4-3.9(H2~H8, multiplet, D-glucosamine unit and hydroxyl ethyl substituents), 4.4 -4.5 (H1)

GME-TPP (Glycol chitosan-Methyl acrylate-Ethylenediamine-Triphenylphosphonium): ¹ H-NMR (600MHz, D ₂ O, ppm) δ2.0-2.1 (NHCOCH ₃ , acetyl group), 2.5-2.7 (H2 in deacetylated monomer, OCCH, H10), 2.8-3.1 (HCCHN, H9), 3.2-3.4 (H9 of methylene in TPP, CONHCH ₂ , H11), 3.4-3.9 (H2-H8, multiplet, D-glucosamine units and hydroxyl ethyl substituents) , 7.5-8.0 (H13 of phenyl rings in TTP)

Example 2. GC - TPP Wow GME - TPP of TPP Content analysis

To measure the TPP content of GC-TPP and GME-TPP, an ultraviolet/visible spectrophotometer (Optizen POP, Mecasys, Korea) was used. First, TPP was dissolved in methanol and distilled water at a volume ratio of 1:1 to prepare each concentration. The absorbance at a wavelength of 267.6 nm was measured, and a standard curve was created. Thereafter, GC-TPP and GME-TPP were dissolved in methanol and distilled water at a volume ratio of 1:1, and the absorbance was measured and compared with a standard curve.

As a result, as disclosed in Table 1, the degree of substitution of GC-TPP was 11% in 1H-NMR and 26% in UV-Vis spectroscopy. For GME-TPP, it was 36% in 1H-NMR and 45% in UV-Vis spectroscopy.

Degree of substitution of TPP in glycol chitosan (GC) percentage of grafting ratio(%) polymers 1H NMR UV-spectroscopy GC-TPP 11 26 GME-TPP 36 45

Example 3. Measurement of size and zeta potential

(1) FE- SEM (Field Emission Scanning Electron Microscopy) and dynamic light scattering (DLS) analysis

FE-SEM images were observed with a field emission scanning electron microscope (FE-SEM, ZEISS Merlin Compact, Carl Zeiss Inc., Germany) at 30 kV. GC-TPP and GME-TPP were dissolved in distilled water and sonicated at 30 to 40°C for 15 to 20 minutes. 10 µl of a sample was placed on the surface of a 300 mesh copper grid and dried for 16 hours in a naturally dried state, and then confirmed.

The average diameter was measured by a dynamic light scattering (DLS) method at 25° C. using an ELS-Z instrument (Photal, Otusuka Electronics, Otsuka, Japan). The sample was dissolved in distilled water and confirmed by sonicating at 30-40° C. for 15-20 minutes.

(2) surface zeta potential analysis

The surface zeta potential was measured at 25°C using a Zetasizer Nano-Zs (Malvern Instruments Ltd., Worcestershire, UK). The sample was prepared in the same manner as the DLS sample.

The results are as shown in Table 2 below, the size of GC-TPP measured by FE-SEM is 210 nm, the size of GME-TPP is 430 nm, the particle size of GC-TPP dissolved in water and measured by DLS is It was found that the particle size of GME-TPP was 590±10nm and 760±20nm (FIG. 5), the zeta potential of GC-TPP was 18.3±1mV, and the zeta potential of GC-TPP was 25.9±4mV.

Average diameter and zeta potential values of GC-TPP and GME-TPP Diameter size (nm) FE-SEM DLS Zeta potential (mV) GC-TPP 210 590±10 18.3±1 GME-TPP 430 760±20 25.9±4

Example 4. In vitro Confirmation of absorption and distribution in cells

HeLa cells were used to investigate the intracellular uptake and distribution of GC-TPP and GME-TPP.

The cells were plated on an 8-well plate (u-slide 8 well, ibidi, Germany) at a density of 5.0×10 ³ cells/well, and cultured at 37° C. containing 5% CO ₂ . Glycol chitosan (GC), GC-TPP and GME-TPP were labeled with AlexaFluor488 5-SDP ester (Sulfodichlorophenol Ester). After 24 hours, a fluorescently labeled sample (final concentration = 5 μg/ml) was treated on the cells and cultured in an incubator. Mitochondria were treated with a mitotracker for 5 minutes at room temperature. Nuclear staining of cells was treated with Hochest33342 (Bisbenzimidetrihydrochloride) for 5 minutes. After washing the cells with DPBS, they were analyzed using a confocal laser microscope (Zeiss, Oberkochen, Germany).

Intracellular uptake of GC, GME, GC-TPP and GME-TPP was analyzed in HeLa cells using fluorescence with flow cytometry (FACS Canto II, BD Biosciences). For flow cytometry, about 2.0×10 ⁵ cells were cultured in a 6-well plate for 24 hours. The next day, the cells were treated with samples labeled with AlexaFluor488 on GC, GME, GC-TPP and GME-TPP for 24 hours at 0.1 μg/μl per well. Cells were collected by centrifugation at 1500 rpm for 3 minutes and resuspended in 500 μl of DPBS. The fluorescence intensity of 1.0×10 ⁴ cells for each cell sample was performed using BD Cell Quest Pro Software.

As a result, as disclosed in FIGS. 6 and 7, GC and GME without TPP connection appeared slightly increased compared to Control, but the amount was very small. This indicates that GC and GME itself are difficult to enter cells. On the other hand, it was confirmed that GC-TPP and GME-TPP linked to TPP contained a larger amount of nanoparticles than GC and GME. In addition, it was confirmed that more GME-TPP was introduced than GC-TPP.

Example 5. In Vitro cell Survival rate (%) analysis

For cytotoxicity assessment, human liver cancer cell line HepG ₂ , human embryonic kidney-derived cell line HEK 293, cervical cancer cell line HeLa, and mouse normal fibroblast NIH-3T3 were inoculated at a density of 1.0×10 ⁴ cells/well in a 96-well tissue culture plate. And cultured in DMEM containing 10% FBS at 37°C.

The next day, the cells were treated with various concentrations (100, 50, 25, 12.5 µg/ml) of each sample for 24 hours, and 10µl of EZ-Cytox and EZ-LDH reagents were added to each well. After 2 hours, EZ-Cytox and EZ-LDH were measured at 450 nm and 590 nm using a 96-well microplate reader (VersaMax, molecular Devices, Sunnyvale, CA, USA).

Cell viability(%) = [(Absorbance of control-Absorbance of sample)/Absorbance of control]×100

As a result, as disclosed in FIG. 8, even with the treatment of GC, GC-TPP and GME-TPP according to the present invention, the cell viability was almost similar to that of no treatment, and as disclosed in FIG. 9 There was also little cytotoxicity.

Example 6. Confocal Through the microscope GC - TPP And GME - TPP Mitochondrial target evaluation of ( CLSM )

GC-TPP and GME-TPP containing Nile Red were prepared using a dialysis method to determine whether GC-TPP and GME-TPP target to mitochondria. The sample solution was dialyzed against 4 L of distilled water using a molecular weight cut-off 1,000 Da dialysis membrane for 1 day at room temperature. The mitochondrial target was observed with a confocal laser scanning microscope.

HeLa cells were inoculated into an 8-well plate at a concentration of 1.0×10 ⁴ cells per well and cultured for 24 hours. The next day, the cells were treated with GC-TPP and GME-TPP containing Nile Red at a concentration of 0.1 µg/µl. After incubation, cells were stained with Hoechst 33342 and Mitotracker Red for 5 minutes. Then, the cells were washed with DPBS and analyzed using a Zeiss LSM 5 Live confocal laser microscope.

As a result, as disclosed in FIG. 10, it was confirmed that the GC-TPP and GME-TPP of the present invention target mitochondria.

Claims (11)

It is a GC-TPP polymer prepared by reacting glycol chitosan (GC) and triphenylphosphonium (TPP) chloride in the reaction first solvent according to the following scheme (1);
In the reaction second solvent, methyl acrylate (MA) was added to the amine group of glycol chitosan (GC) to synthesize glycol chitosan-methylacrylate (GC-MA), and ethylenediamine (EDA) was added to the synthesized GC-MA. ) To synthesize GC-MA-EDA (GME), and reacting the synthesized GME with triphenylphosphonium (TPP) chloride, and is a GME-TPP polymer, characterized in that:
[Scheme 1]

In Reaction Scheme 1, n is independently an integer ranging from 1 to 10,000. The polymer according to claim 1, wherein the polymer is a mitochondrial target type. delete The method of claim 1, wherein the reaction first solvent or reaction second solvent is independently water, C ₁ ~ C ₄ lower alcohol, acetone, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, and tetrahydrofuran (THF). Polymer, characterized in that at least one selected from. A micelle formed by self-assembly of the GC-TPP or GME-TPP polymer of any one of claims 1, 2 and 4. The micelle according to claim 5, wherein the micelles formed by self-assembly of the GC-TPP or GME-TPP polymer have a hydrophobic drug therein. The micelle according to claim 6, wherein the hydrophobic drug is an anticancer agent. A drug delivery system comprising micelles formed by self-assembly of the GC-TPP or GME-TPP polymer of claim 5. The drug delivery system of claim 8, wherein the drug delivery system is a drug delivery system having doxorubicin mounted therein. A pharmaceutical composition for preventing or treating cancer comprising the drug delivery system of claim 9. The pharmaceutical composition for preventing or treating cancer according to claim 10, wherein the cancer is cervical cancer, liver cancer, gastric cancer, breast cancer, lung cancer, brain cancer, glioma, prostate cancer, uterine cancer or skin cancer.

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