AU2015377981B2

AU2015377981B2 - Reductively degradable polyzwitterionic nano-micelles and preparation method thereof

Info

Publication number: AU2015377981B2
Application number: AU2015377981A
Authority: AU
Inventors: Caihua NI; Gang Shi; Luyan WU; Liping Zhang
Original assignee: Jiangnan University
Current assignee: Jiangnan University
Priority date: 2015-03-31
Filing date: 2015-04-22
Publication date: 2017-04-20
Anticipated expiration: 2035-04-22
Also published as: WO2016155051A1; CN104788689A; CN104788689B; AU2015377981A1

Abstract

Abstract The invention relates to the field of biomedical materials, and more particularly to reductively degradable polyzwitterionic nano-micelles and preparation method 5 thereof Firstly, taurine, N, N-bis(acryloyl) cystamine and dodecylamine are copolymerized by michael addition reaction to get a poly (taurine-co- N, N bis(acryloyl) cystamine-co-dodecylamine) terpolymer, then the terpolymer forms nano-micelles in aqueous solution via self-assembly. The nano-micelles have sensitive pH and reduction response because the units such as amines, disulfide bonds and 10 zwitterions are contained in the chain segment of the termplymer. Furthermore, the zwitterions give the nano-micelles excellent resistance to non-specific protein adsorption. The nano-micelles of the invention are noncytotoxic and can be completely degraded in vivo, and thus has a good application prospect as anticancer drug carriers.

Description

- 1 - 2015377981 31 Mar 2017

Reductively Degradable Polyzwitterionic Nano-micelles and Preparation Method thereof

Field of the Invention 5 The present invention relates to the field of biomedical materials, and more particularly to a method for preparing reductively degradable polyzwitterionic nanomicelles.

Description of the Related Art

Any discussion of the prior art throughout the specification should in no way be 10 considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

Polymeric nano-micelles highlight a bright prospect in the field of treatment of malignant tumors as a chemotherapy drug carrier. Nano-micelles of injection form will penetrate some barriers of body tissues with blood circulation to reach the 15 position of tumors, so that the drugs are released in lesion locations, thereby greatly improving the bio availability and reducing the toxicity. Ideal nano-micelles must meet the following basic requirements as the drug carriers: suitable micelle particle size within 200 nanometers; being stable during the long-term body circulation without non-specific protein absorption; having a certain ratio of drug loading and the 20 property of targeted drug delivery as well as good biocompatibility and biodegradability.

In order to ensure the stability of the nano-micelles in an aqueous medium, people usually modify the out layer of micelles using hydrophilic materials, and currently the commonly used hydrophilic material is polyethylene glycol (PEG). However, the 25 recent studies have shown that PEG have a certain hydrophobicity besides the hydrophilicity, and will be oxidized in the presence of oxygen and transition metal ions (existing in most biochemistry related solution). The possible immune response is also observed in PEG-modified protein drugs. Furthermore, the shielding effect of PEG shell of nano-micelles is unfavorable to the intracellular uptake of nano-micelles. -2- 2015377981 31 Mar 2017

In recent years, some researchers have made a lot of studies on non-fouling materials, it is founded that polyzwitterions have a unique anti-fouling property. Common zwitterionic polyelectrolyte includes a poly(sulphobetaine 2-methyl methacrylate) (PSBMA), poly(carboxyl betaine 2-methyl methacrylate) (PCBMA), Poly(2-5 methacryloyloxy ethyl phosphorylcholine) (PMPC) or the like. As shown in fig. 1, it has been determined that these materials are effective non-fouling materials, and can maintain the stability of micelles in a composite media. Thus, polyzwitterionic materials may be excellent alternative products of PEG.

However, currently the polyzwitterions reported in literatures are usually polymerized 10 by vinyl monomers containing positive and negative charges, and they are nondegradable and hard to excrete in body, and thus can not meet the usage requirements of human body, this will become the bottleneck of practical application of such materials.

It is an object of the present invention to overcome or ameliorate at least one of the 15 disadvantages of the prior art, or to provide a useful alternative.

Summary of the Invention

According to a first aspect, the present invention provides a method for preparing reductively degradable polyzwitterionic nano-micelles, comprising steps of: (1) copolymerizing three monomers of N, N-bis(acryloyl) cystamine, aliphatic 20 amine and taurine to obtain a terpolymer, wherein the carbon chain length of the aliphatic amine is C8-C16; (2) purifying, drying and dissolving the terpolymer to get a terpolymer solution; (3) adding dropwise ultrapure water into the terpolymer solution under constant stirring ; and 25 (4) dialyzing the terpolymer solution obtained from the step (3) to get the nano micelles.

According to a second aspect, the present invention provides a reductively degradable polyzwitterionic nano-micelle comprising a terpolymer copolymerized by three monomers of N, N-bis(acryloyl) cystamine, aliphatic amine and taurine, wherein the 2015377981 31 Mar 2017 -2a- carbon chain length of the aliphatic amine is C8-C16.

According to a third aspect, the present invention provides use of the reductively degradable polyzwitterionic nano-micelle of the invention in preparing chemotherapeutic drug carriers. 5 Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

In order to solve the above technical problems, one object of the invention is to 10 provide reductively degradable polyzwitterionic nano-micelles and preparation method thereof. The nano-micelles have good biocompatibility and can be completely degraded in vivo without any residual.

In one aspect, the invention provides a reductively degradable polyzwitterionic nanomicelle containing a terpolymer synthesized by N, N-bis(acryloyl) cystamine, 15 aliphatic amine and taurine, wherein the carbon chain length of the aliphatic amine is C8-C16. If the carbon chain length is less than C8, the terpolymer has poor hydrophobicity and is hard to form micelles. If the carbon chain length is more than Cl6, the terpolymer has poor solubility and is also hard to form micelles. In order to prevent the molecular weight of the terpolymer from becoming smaller, the mole 20 number of N, N-bis(acryloyl) cystamine is equal to the sum of the mole number of aliphatic amine and the mole number of taurine, and the mole ratio of N, N-bis(acryloyl) cystamine, aliphatic amine and taurine is 1 : 0.2-0.9 : 0.8-0.1. The three monomers have respective functions in nano-micelles: (1) N, N-bis(acryloyl) cystamine has disulfide bonds, and is stable in non-reducing environment and subject 25 to breaking in reducing environment, this make the micelles have reduction response. (2) Aliphatic amine is nontoxic and soluble in solvents such as methanol and ethanol, -3- and it is commonly used in synthesis of surfactants, also, aliphatic amine has a certain hydrophobicity, this will lay the foundation for the self-assembly and drug loading of high polymers. (3) Taurine has many physiological functions and is a nutrient essential to human health, the molecule of taurine has both amino and sulfonic acid 5 groups, and thus has the zwitterionic nature, this will give an excellent resistance to non-specific protein absorption.

In the invention, dodecylamine with the carbon strain length of C12 is preferably selected as one of the monomers of terpolymer, to effectively balance hydrophobicity and solubility of the terpolymer. Dodecylamine is a straight strain aliphatic primary 10 amine, and thus has more balanced hydrophobicity and solubility.

In another aspect, the invention also provides a method for preparing reductively degradable polyzwitterionic nano-micelles, orderly comprises the following steps: (1) copolymerizing three monomers of N, N-bis(acryloyl) cystamine, aliphatic amine and taurine to obtain a terpolymer, wherein the carbon chain length of the 15 aliphatic amine is C8-C16. (2) purifying, drying and dissolving the terpolymer to get a terpolymer solution, wherein the solvent is selected the group consisting of tetrahydrofuran, N, N-dimethylformamide, dioxane, isopropanol or absolute ethanol, and they are good solvents used in organic synthesis reaction. Preferably, tetrahydrofuran is used, which 20 is a heterocyclic organic compound and is one of the strong polar ethers. Tetrahydrofuran is a colorless volatile liquid and usually used as a medium polar solvent in chemical reactions. (3) adding dropwise ultrapure water into the terpolymer solution under constant stirring . and 25 (4) dialyzing the terpolymer solution obtained from the step (3) to get the nano micelles.

In an embodiment, in the step (1), the reaction system of the copolymerization is a mixed solvent containing deionized water, methanol and ethanol. Specifically, the volume ratio of deionized water, methanol and ethanol is 7 : 2 : 1-1.5, and the ratio of -4- components of the mixed solvent can be adjusted in terms of the reaction conditions.

In an embodiment, in the step (1), the copolymerization is carried out under heating of 50°C' oil bath at least 3 days in the atmosphere of nitrogen.

In an embodiment, in the step (2), after purification and drying, the terpolymer is 5 dissolved in tetrahydrofuran to get the terpolymer solution.

In an embodiment, in the step (4), a dialysis bag with molecular weight cut-off 3500 is used to dialyze the terpolymer soluiton at least 48 hours to get the nano-micelles. The dialysis bag is used to remove the unreacted small molecules and oligomers, because the polymers with low molecular weight are not easy to form micelles. Various 10 dialysis bags can be used and the dialysis bags with molecular weight cut-off 3500 can achieve the above purpose.

Michael Addition is an addition reaction of nucleophilic reagents with α, β unsaturated carbonyl compounds. Double bonds are contained in the molecule of N, N-bis(acryloyl) cystamine, and primary amines are contained in the molecule of 15 taurine and dodecylamine, michael addition reaction occurs between the double bonds and the primary amines to form the copolymerization products. According to the principle of copolymerization, when the mole number of two type of groups of copolymerization is equal, polymers with high molecular weight can be obtained. Thus, the embodiments of the invention are designed so that the mole number of N, 20 N-bis(acryloyl) cystamine is equal to the sum of the mole number of aliphatic amine and the mole number of taurine, and the mole ratio of N, N-bis(acryloyl) cystamine, aliphatic amine and taurine is 1 : 0.2-0.9 : 0.8-0.1, this will effectively achieve the high molecular weight polymers. In the copolymer segment some units such as amines, disulfide bonds and zwitterions are contained. 25 In still another aspect, the invention also provides use of the reductively degradable polyzwitterionic nano-micelle in preparing chemotherapeutic drug carriers. Glutathione is a reductive tripeptide, and its concentration in tumour cells is 100-1000 times of that in body fluid. After the drug-loaded nano-micelles enter into the tumour cells, the double bonds of the polymers break under the reduction of glutathione so -5- that the polymers degrade to release the drugs. Furthermore, a weak acid environment is present within the tumour cells and the nano-micelles contain amino groups, thus, the nano-micelles have pH sensitivity and reduction sensitivity, and the structure of micelles will change under the stimulation of intracellular environment of tumour 5 cells to facilitate the drug release.

Due to the above technical solutions, the present invention has the following advantages as compared with the prior art: 1. Some units such as amines and disulfide bonds are present in the copolymer chain segment, thus, the copolymer has pH sensitivity and reduction sensitivity, and the 10 structure of micelles will change in the weak acidic and reductive environment within tumour cells to facilitate the drug release. 2. The polyzwitterions will give the nano-micelles excellentresistance to non-specific protein absorption, thus, the nano-micelles has special anti-fouling property. 3. The disulfide bonds are in the main chain of the polymers, and after the nano-15 micelles enter the tumour cells, the disulfide bonds will break under the stimulation of high concentration of glutathione within cells. The nano-micelles will degrade completely in vivo without any residual, and thus has a practical application value as anti cancer drug carriers. 4. The nano-micelles are non-cytotoxic and can meet the security standard of human 20 use. 5. Michael addition is used to synthesize the high polymers, and the method is simple and can be carried out in moderate conditions without any catalyst or other additives. Furthermore, the reaction is completed fully without any by-products and pure products will be obtained. 25 Brief Description of the Drawings

Fig. 1 shows the zwitterionic poly electrolyte of the prior art.

Fig.2 is a schematic view of the copolymerization of N, N-bis(acryloyl) cystamine, aliphatic amine and dodecylamine of the invention.

Fig.3 shows the transmission electron microscope images of the reductively -6- degradable polyzwitterionic nano-micelles of the invention.

Fig.4 shows the size distribution of the reductively degradable polyzwitterionic nanomicelles at pH 7.4 of the invention, wherein a, b, c, d, e respectively represents the reductively degradable polyzwitterionic nano-micelles obtained by N, N-bis(acryloyl) 5 cystamine, aliphatic amine and taurine with a mole ratio of 1 : 0.2 : 0.8, 1 : 0.5 : 0.5, 1 : 0.6 : 0.4, 1 : 0.8 : 0.2, 1 : 0.9 : 0.1.

Fig.5 shows the change of Zeta potential of the polyzwitterionic nano-micelles with pH value, wherein the mole ratio of N, N-bis(acryloyl) cystamine, aliphatic amine and dodecylamine is 1 : 0.2 : 0.8. 10 Fig.6 shows the particle size change of the polyzwitterionic nano-micelles in 10 mM glutathione solution with time of the invention, wherein PBS and GSH respectively represents phosphate buffer solution and glutathione solution.

Fig.7 shows the particle size change of the polyzwitterionic nano-micelles in different protein solutions according to the invention, wherein BSA represents bovine serum 15 albumin and FBS represents fetal bovine serum.

Fig. 8 shows the cytotoxicity results of the reductively degradable polyzwitterionic nano-micelles of the invention.

Description of the Preferred Embodiments

The invention will be further illustrated in more detail with reference to 20 accompanying drawings. It is noted that, the following embodiments only are intended for purposes of illustration and are not intended to limit the scope of the invention.

Embodiment 1 (1) synthesis of N, N-bis(acryloyl) cystamine 25 11.6 g of cystamine dihydrochloride was added into a 250 mL single-necked flask, and 50 mL distilled water was added to dissolve cystamine dihydrochloride under stirring. The flask was placed in 0°C ice water mixture. 8g of sodium hydroxide solid was weighted and dissolved into 20 mL distilled water, and the resulting solution of - 7 - sodium hydroxide was added into the single-necked flask by one time. 19 mL pre-refined acryloyl chloride was mixed with 3 mL dichloromethane to obtain a mixed solution, and the mixed solution was added dropwise into the single-necked flask within 40 minutes by a constant pressure funnel, and the reaction was carried out at 5 25 °C for 16h. The reaction product was filtered, washed with deionized water by 3 times , and recrystallized with ethyl acetate, and finally dried in a vacuum oven for 24h to get the final product N, N-bis(acryloyl) cystamine. (2) synthesis of poly (taurine-co- N, N-bis(acryloyl) cystamine-co-dodecylamine) terpolymer

10 3.5 mL distilled water, 1 mL methanol and 0.5 mL ethanol were mixed in a 50 mL three-necked flask, and N, N-bis(acryloyl) cystamine, taurine and dodecylamine were dissolved in the resulting mixed solution to obtain a reaction solution, then the reaction solution was heated up to 50°C by an oil bath pan in the atmosphere of nitrogen to react for 3 days. The product was dissolved in 10 mL ultrapure water and 15 moved into a dialysis bag with molecular weight cut-off 3500-7000D to dialyze for 4 days, then poly (taurine-co- N, N-bis(acryloyl) cystamine-co-dodecylamine) terpolymer was obtained after freeze-drying. The copolymerization process of N, N-bis(acryloyl) cystamine, taurine and dodecylamine is shown in fig.2. The ratios of N, N-bis(acryloyl) cystamine, taurine and dodecylamine in the mixed solution are listed 20 in the table 1 and only 5 terpolymer formulations are described herein, in practical applications, the ratio of the three monomers can be adjusted according to the size requirements of nano-micelles.

Table 1 (synthesis formulation of terpolymer)

Sample N, N-bis(acryloyl) cystamine (MW 260) Taurine (MW 125) Dodecylamine (MW 185) a 1 (mmol) 0.2 (mmol) 0.8 (mmol) 260(mg) 25 (mg) 148(mg) b 1 (mmol)260 (mg) 0.5 (mmol) 62.5 (mg) 0.5 (mmol) 92.5(mg) c 1 (mmol) 0.6 (mmol) 0.4 (mmol) -8- 260 (mg) 75 (mg) 74(mg) d 1 (mmol) 0.8 (mmol) 0.2 (mmol) 260 (mg) 100(mg) 37(mg) e 1 (mmol) 0.9 (mmol) 0.1 (mmol) 260 (mg) 112.5(mg) 18.5(mg) (3) preparation of reductively degradable polyzwitterionic nano-micelles 10 mg of poly (taurine-co- N, N-bis(acryloyl) cystamine-co-dodecylamine) terpolymer was dissolved in 1 mL tetrahydrofuran, and 10 mL ultrapure water was added dropwise into the resulting solution under constant stirring. After stirring for 5 3h, the solution was transferred into a dialysis bag with molecular weight cut-off 3500 and dialyzed for 48h to obtain the reductively degradable polyzwitterionic nanomicelles. The molecular weight cut-off of the dialysis bag can be adjusted as required and usually is at least 3500. As shown in fig.3, the scanning electron micrograph of the reductively degradable polyzwitterionic nano-micelles is illustrated, and fig.s 3a-10 3e respectively represents the terpolymers of formulations a-e of table 1. It can be seen that the reductively degradable polyzwitterionic nano-micelles basically are spherical and have uniform size distribution. When the ratio of taurine in components becomes larger, the micelles transform into columnar micelles.

The ratio of the three monomers can be adjusted according to the size requirements of 15 injection nano-micelles. As shown in fig.4, the particle size of the nano-micelles increases with the increase of the content of taurine. When the mole ratio of N, N-bis(acryloyl) cystamine, taurine and dodecylamine is 1 : 0.8 : 0.2, the particle size of nano-micelles is medium and typical, and the chemical property of different particle size of nano-micelles is consistent. Thus, unless otherwise specified herein, the nano-20 micelles mentioned in the subsequent embodiments of the invention are intended to mean the nano-micelles of such ratio.

Embodiment 2 pH sensitivity of the reductively degradable polyzwitterionic nano-micelles

The reductively degradable polyzwitterionic nano-micelles of the embodiment 1 were -9- respectively placed in buffer solutions of pH 5.0, 6.5, 7.4 and 10.0, and the Zeta potential change was observed by means of a zeta potential analyzer, the results are shown in fig. 5, wherein the ratio of N, N-bis(acryloyl) cystamine, taurine and dodecylamine was 1 : 0.8 : 0.2. In the fig.5, the solution is weak alkaline when 5 pH=7.4, and the amino groups of the micelles are hard to take in protons, so that the positive electricity is restrained and the negatively charged ions are primary, thus, the Zeta potential value is negative. The amino groups of the micelles take in protons to form ammonium positive ions in the acidic conditions of pH=5.0 and pH=6.5, and the protonation degree is increased with the increase of time, and thus the Zeta potential 10 becomes positive value.

Embodiment 3 reduction sensitivity of the reductively degradable polyzwitterionic nano-micelles The reductively degradable polyzwitterionic nano-micelles of the embodiment 1 are placed in 10 mM glutathione solution and the ratio of N, N-bis(acryloyl) cystamine, 15 taurine and dodecylamine is 1: 0.8 : 0.2. The particle size change of nano-micelles with time was tested by Laser Light Scattering Spectrometer, and the reduction response was observed. The results was illustrated in fig.6, in the PBS buffer solution without glutathione (GSH), the particle size of the nano-micelles was not changed 24h later. However, in the 10 mM glutathione solution, the particle size of the nano-20 micelles became smaller 12h later, this shows that some disulfide bonds are broken and the molecular weight decreases, so that the copolymer self-assembles again to form nano-micelles with small particle size. With the time increase of the nanomicelles in GSH solution, more disulfide bonds are broken and the copolymer become small molecules, so that the micelles tends to disintegrate and the particle size 25 increases.

Embodiment 4

Resistance to non-specific adsorption of bovine serum albumin of the reductively degradable polyzwitterionic nano-micelles -10-

The reductively degradable polyzwitterionic nano-micelles of the embodiment 1 (wherein the mole ratio of N, N-bis(acryloyl) cystamine, taurine and dodecylamine was 1 : 0.8 : 0.2) were placed in PBS buffer solution (pH=7.4) containing 45g/L bovine serum albumin and incubated for 24h, and the change of particle size was 5 monitored by Laser Light Scattering Spectrometer and the resistance to the nonspecific adsorption of bovine serum albumin was observed. The results are shown in fig. 7, the particle size of the nano-micelles contacting different proteins are contrasted with that of nano-micelles not contacting any protein, in this figure, BSA represents bovine serum albumin, FBS represents fetal bovine serum. It can be seen from the 10 fig.7 that, after contacting with bovine serum albumin and fetal bovine serum for a certain time, the particle size of the synthesized 5 nano-micelle samples remains the same and is the same as that of the nano-micelles in the buffer solution without proteins. The results show that no adsorption is present between the nano-micelles and the proteins, and this further confirms the resistance to non-specific adsorption of 15 bovine serum albumin of the nano-micelles.

Embodiment 5 biocompatibility of the reductively degradable polyzwitterionic nano-micelles 3T3 cells frozen at -80°Cwere rapid unfrozen in a 37°C water bath pan, and then transferred into a centrifuge tube containing 7 mL RPMI-1640 culture solution and 20 centrifuged at 800 rpm. RPMI-1640 culture solution containing 10% fetal bovine serum was used to blow cells to obtain a single-cell suspension, then the single-cell suspension was transferred into a 50 mL culture flask and cultured in an incubator containing 5% CO2 at 37°C.

Taking the sample of the reductively degradable polyzwitterionic nano-micelles as 25 research objects, the cytotoxicity of the nanoparticles formed by the nano-micelles was tested by MTT method. Mouse fibroblast cells were inoculated in 96-well plate at 1.2><105/mL with 100pL in each well. After incubation for 24h, the culture solution in each well was suctioned out. Then the above culture solution was added into negative control groups (each contains RPMI-1640 culture solution of pH7.4 or pH6.5, 10% - 11 - fetal bovine serum ), positive control groups (each contains 0.64% phenol medium) and sample groups (each contains RPMI-1640 culture solution of pH7.4 or pH6.5, 10% fetal bovine serum ) respectively, and continuously incubated in an incubator containing 5% CO2 at 37°C for 24h and 48h respectively, wherein 4 parallel wells are 5 designed for each group. The culture plate was taken out for observation of the cells under microscopy, and the status of cell growth was evaluated. Then 20pL MTT was added to continue the cell culture for 4h, the liquid in the wells of the culture plate was suctioned out and dimethyl sulfoxide was added into, then absorbance (A) at 570 nm was tested by a microplate reader to calculate the cell viability. As shown in fig. 8, 10 the cell viability of 3T3 and Hela cells in different concentration of nano-micelle solutions was 94%-100%, and in the same condition, the cell viability of two type of cells is close to each other. The cell viability decreases with the increase of concentration of nano-micelles and generally is greater than 80% this can meet the standard of biocompatibility. 15 The above preferred embodiments are described for illustration only, and are not intended to limit the scope of the invention. It should be understood, for a person skilled in the art, that various improvements or variations can be made therein without departing from the spirit and scope of the invention, and these improvements or variations should be covered within the protecting scope of the invention.

Claims

What is claimed is:

1. A method for preparing reductively degradable polyzwitterionic nano-micelles, comprising steps of: (1) copolymerizing three monomers of N, N-bis(acryloyl) cystamine, aliphatic amine and taurine to obtain a terpolymer, wherein the carbon chain length of the aliphatic amine is C8-C16; (2) purifying, drying and dissolving the terpolymer to get a terpolymer solution; (3) adding dropwise ultrapure water into the terpolymer solution under constant stirring ; and (4) dialyzing the terpolymer solution obtained from the step (3) to get the nanomicelles.
2. The method as claimed in claim 1, wherein in the step (1) the reaction system of the copolymerization is a mixed solvent containing deionized water, methanol and ethanol.
3. The method as claimed in claim 1 or claim 2, wherein the aliphatic amine is dodecylamine.
4. The method as claimed in any one of claims 1 to 3, wherein in the step (1) the copolymerization is performed under heating of 50“Coil bath at least 3 days in the atmosphere of nitrogen.
5. The method as claimed in any one of claims 1 to 4, wherein in the step (2), after purification and drying, the terpolymer is dissolved in tetrahydrofuran to get the terpolymer solution.
6. The method as claimed in any one of claims 1 to 5, wherein in the step (4) a dialysis bag with molecular weight cut-off 3500 is used for dialysis at least 48 hours to get the nano-micelles.
7. The method as claimed in any one of claims 1 to 6, wherein for the three monomers, the mole number of N, N-bis(acryloyl) cystamine is equal to the sum of the mole number of aliphatic amine and the mole number of taurine, and the mole ratio of N, N-bis(acryloyl) cystamine, aliphatic amine and taurine is 1 :0.2-0.9:0.8-0.1.
8. A reductively degradable polyzwitterionic nano-micelle comprising a terpolymer copolymerized by three monomers of N, N-bis(acryloyl) cystamine, aliphatic amine and taurine, wherein the carbon chain length of the aliphatic amine is C8-C16.
9. The reductively degradable polyzwitterionic nano-micelle as claimed in claim 8, wherein in the terpolymer, the mole number of N, N-bis(acryloyl) cystamine is equal to the sum of the mole number of aliphatic amine and the mole number of taurine, and the mole ratio of N, N-bis(acryloyl) cystamine, aliphatic amine and taurine is 1 :0.2-0.9:0.8-0.1.
10. Use of the reductively degradable polyzwitterionic nano-micelle as claimed in claim 8 or 9 in preparing chemotherapeutic drug carriers.