CN108191995A - It is a kind of to restore sensitive amphiphilic polysaccharide derivative and its preparation method and application - Google Patents

Abstract

The invention belongs to field of pharmaceutical preparations, are related to a kind of amphiphilic polysaccharide derivative for restoring sensitivity and its preparation method and application.Its structure is as shown in following chemical formula：

Description

A reduction-sensitive amphiphilic polysaccharide derivative and its preparation method and use

technical field

The invention belongs to the field of pharmaceutical preparations, and relates to a reduction-sensitive amphiphilic polysaccharide derivative, a preparation method and application thereof.

Background technique

Malignant tumor is a major disease that threatens human health, and it is the main cause of mortality, which is increasing year by year. Drug chemotherapy is one of the main treatment methods for tumors at present, but common anti-tumor drugs have strong hydrophobicity, low bioavailability, poor selectivity, prone to multidrug resistance, and high toxicity. Bad situation for failure. At present, the solubility of drugs is often increased by adding surfactants or making nano-formulations. However, due to the high CMC of some low-molecular surfactants, they are easy to leak a large amount after being injected into the blood, and a large amount of surfactants will have toxic side effects, while nanotechnology only achieves primary passive targeting through the EPR effect in the body, or the release position If it cannot be effectively controlled, it is easy to cause the curative effect of the drug to be limited. Therefore, the anti-tumor system that achieves efficient targeting and smooth release at the target site has attracted much attention. In addition, the reduction of multidrug resistance is often achieved by means of combination drugs. However, multi-drug co-carrier systems usually result in uncoordinated release, low drug loading of main anti-tumor drugs, and ineffective targeting. Therefore, the establishment of a drug-loading system that is safe, efficiently targeted to tumor cells, released at a reasonable location, and synergistically multifunctional is one of the goals pursued by the current design of anti-tumor drug delivery systems.

Vitamin E succinate is a highly effective and low-toxic tumor cell growth inhibitor. It is non-toxic to normal tissues and cells, but it can be used in combination with various drugs such as paclitaxel and doxorubicin to synergistically inhibit tumor cells. The role of cell growth, and can increase the accumulation of antineoplastic drugs in tumor cells. Polyethylene glycol 1000 vitamin E succinate is based on vitamin E succinate, which is esterified with a hydrophilic group PEG1000 to make it water-soluble. It can be used to pack insoluble drugs, and because of its safety and Good emulsification and solubilization performance and loaded in the United States Pharmacopoeia. Therefore, using vitamin E succinate as a base to prepare derivatives as an antitumor drug carrier has its unique advantages.

Polysaccharides have a wide range of sources and are important components of all living organisms. They play an important role in maintaining the normal metabolism of living organisms and regulating cell growth. They have good biodegradability and biocompatibility. And some polysaccharides have a broad-spectrum targeting ability, and their structures are easy to carry out structural modification due to a large number of active groups. Natural polysaccharides have many advantages as pharmaceutical polymer materials, so polysaccharides are widely used as carrier derivatives. Pay attention to. Heparin, a class of highly sulfated linear natural polysaccharides, has attracted attention due to its biodegradability, good biocompatibility, targeting of differentiated tumor epithelial cells, and anti-tumor adjuvant therapy.

In order to satisfy the stability of the microparticle system in the blood and achieve the EPR effect, after the general nano-preparation reaches the tumor site, its efficacy is often affected due to the slow release of the drug, and it is also easy to cause drug resistance. Therefore, the responsive triggered rapid release drug delivery system targeting the microenvironment of the tumor site can meet the needs of curative effect without affecting the stability of the drug delivery system in the blood circulation before reaching the target site. The content of reduced glutathione in tumor cells is 4-10 times that of normal tissues and 1000 times that of the blood circulation system, so the reduction-sensitive nano-drug delivery system designed for the difference between tumor cells and other physiological environments can be This reduction-sensitive characteristic can quickly depolymerize the derivative carrier when it reaches the tumor cells, so that it can release vitamin E and co-load chemotherapy drugs more quickly, enhance the accumulation of drugs in the tumor site, and help improve efficacy, reduce side effects and reduce The occurrence of drug resistance.

Contents of the invention

The purpose of the present invention is to provide a reduction-sensitive amphiphilic polysaccharide derivative that is biodegradable and can be used to carry antitumor drugs.

Another object of the present invention is to provide a preparation method of the above-mentioned derivatives.

Another object of the present invention is to provide the use of the above-mentioned derivatives in the preparation of drug carriers or anti-tumor drugs.

To achieve the above object, the present invention firstly provides a reduction-sensitive amphiphilic polysaccharide derivative, whose structure is shown in the following chemical formula:

The disulfide bonds contained in this structure can be specifically degraded in the reducing environment of tumor cells, wherein: GLY is a polysaccharide, and the polysaccharide is unfractionated heparin or low molecular weight heparin; n is an integer from 1 to 16, and m is 1 An integer of ~16, the sum of n+m is 2 ~ 18, D is vitamin E succinate, R is the number of hydrophobic groups substituted on the polysaccharide molecule, and the number of substitutions is an integer of 2 ~ 600.

The method for preparing the reduction-sensitive amphiphilic polysaccharide derivative is characterized in that it comprises the following steps:

(1) Dissolving the polysaccharide in a reaction solvent, using a linking arm containing a disulfide bond and both ends of which are amino groups, and performing a condensation reaction under the action of an activator to obtain a polysaccharide intermediate containing a disulfide bond;

(2) dissolving vitamin E succinate in a reaction solvent, under the action of an activator, undergoes a condensation reaction with the polysaccharide intermediate obtained in step (1) to obtain a reduction-sensitive amphiphilic polysaccharide-vitamin E succinic acid ester derivatives.

more specific:

The connecting arm is cystamine.

The reaction solvent is water, methanol, N, N-dimethylformamide, tetrahydrofuran, pyridine, ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, acetone, dimethyl sulfoxide, formamide , N-methylpyrrolidone or any two mixed solvents.

The activator is EDC and NHS, or EDC and HOBt, or EDC and DMAP.

The present invention also provides the use of the reduction-sensitive amphiphilic polysaccharide derivative or the reduction-sensitive amphiphilic polysaccharide derivative prepared by the method in the preparation of drug carriers or anti-tumor drugs.

more specific:

The anti-tumor drug is an anti-tumor drug composition, which is made of drug-loaded nanomicelles made of pharmaceutically active or pharmacologically active molecules and amphiphilic polysaccharide-vitamin E succinate derivatives; the described pharmaceutically active or pharmacologically active molecules include Paclitaxel, docetaxel, doxorubicin, camptothecin, hydroxycamptothecin, retinoic acid, 9-cis retinoic acid, methotrexate, aminopterin, oleanolic acid, ursolic acid, rattan Yellow acids, glycyrrhizic acids, vinblastine, vincristine, mitoxantrone.

The preparation of the drug-loaded nano-micelle includes the following steps: ultrasonically dissolving the amphiphilic polysaccharide-vitamin E succinate derivative and water in a ratio of 3 to 50:1000 by weight, and dissolving the pharmaceutically active substance dissolved in the solvent. Or pharmacologically active molecules are mixed, after ultrasonic or high-pressure homogeneous treatment, organic solvents and free drugs are removed by dialysis, ultrafiltration or column separation, and freeze-dried to obtain nano drug-loaded micelles with a particle size of 10-1000nm.

The solvent is water, formamide, absolute ethanol, N,N-dimethylformamide or dimethylsulfoxide.

The reduction-sensitive amphiphilic polysaccharide derivatives can be used for intravascular injection, intramuscular injection, oral administration or external application. Among them, injections, lyophilized powder injections are preferred for injection, tablets, capsules, pills, syrups, granules, and oral solutions are preferred for oral administration, and patches, liniments, lotions, and gels are preferred for external administration. , lotion, ointment.

The present invention uses the natural polysaccharide heparin as the skeleton, and connects the hydrophobic tumor cell growth inhibitor vitamin E succinate with the carboxyl group on the skeleton through a disulfide bond linking arm to make it an amphiphilic derivative with reduction sensitivity. It can self-assemble into polymer micelles, and entrap drugs into nanosystems. The self-assembly system has the following characteristics: ① It can self-assemble in aqueous solution to form nanomicelles, form a core-shell structure, and achieve good entrapment of insoluble chemotherapeutic drugs. ② Stable in the blood circulation, after being passively targeted to the tumor site through the EPR effect, it further enters the tumor cells through passive diffusion or endocytosis, and is quickly released in the tumor cells by the microenvironment with high reducing concentration The drug and vitamin E succinate realize the synergistic anti-cancer of the two. The drug-carrying system can thus be beneficial to improve the efficacy of the drug.

Concrete implementation principle of the present invention is as follows:

The hydrophobic tumor growth inhibitor vitamin E succinate was introduced into the carboxyl group of the polysaccharide through a specifically degradable linker containing a disulfide bond, making it amphiphilic and sensitive to reducing environments, and self-assembled in aqueous media into nanomicelles. Hydrophobic vitamin E succinate is associated into the core, and the hydrophilic chain of polysaccharide molecules forms a hydrophilic shell, which has the functions of improving anti-tumor activity, stabilizing micelles, and effectively avoiding the capture of the mononuclear-phagocyte system. At the same time, the amphiphilic polysaccharide-vitamin E succinate derivative is an excellent drug carrier, especially for insoluble antitumor drugs. After the amphiphilic polysaccharide-derivative micelle reaches the lesion site, its disulfide bond linking arm can be specifically degraded by the high-concentration reducing substance glutathione in the lesion cells, and the combination of vitamin E succinate and hydrophilic group The rapid separation leads to the rapid release of the drug, acting on the lesion site, which can significantly improve the free drug concentration and curative effect at the lesion site. The derivative can also be used as a drug carrier, and has a controllable particle size of 10-1000nm, smooth surface, good uniformity, good redispersibility, high drug loading capacity and encapsulation efficiency. The derivatives can be used for intravascular or intramuscular injection, orally or externally.

The synthesis route of the reduction-sensitive amphiphilic polysaccharide derivative of the present invention and the preparation method of the pharmaceutical or physiologically active composition are described in detail as follows:

1. Synthesis of reduction-sensitive amphiphilic polysaccharide derivatives

1. Synthesis of polysaccharide intermediates

Reaction of polysaccharides with linker arms terminated by amino groups

Dissolve heparin in the reaction solvent, add a connecting arm containing a disulfide bond and amino groups at both ends, and use 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and hydroxysuccinimide Amine (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) are reacted as activators, and the excess is used after 12h to 48h of reaction The acetone precipitates the polysaccharide, and the precipitate is separated and purified by suction filtration to obtain a heparin polysaccharide intermediate.

The synthetic route is shown in the following formula:

2. Synthesis of heparin-vitamin E succinate derivatives

Dissolving the heparin polysaccharide intermediate in the reaction solvent, adding vitamin E succinate, reacting for 12h to 48h, using excess acetone to precipitate the polysaccharide derivative, suction filtering and separating and purifying the precipitate to obtain the derivative.

The synthetic route is shown in the following formula:

2. Preparation method of amphiphilic polysaccharide-vitamin E succinate derivative nanomicelle

Dissolve the prepared amphiphilic polysaccharide derivative in water according to the ratio of 2-30 mg of amphiphilic polysaccharide derivative dissolved in 1 mL of water, and prepare heparin with a particle size of 10-1000 nm through ultrasonic or high-pressure homogenization - Vitamin E succinate derivative micelles.

3. Using the amphiphilic polysaccharide-vitamin E succinate micelles as a carrier to prepare a pharmaceutical composition carrying insoluble antitumor drugs.

Amphiphilic polysaccharide derivatives and water are ultrasonically dissolved with a probe in a ratio of 3 to 50:1000 by weight, and after physical mixing with 0.5 to 3ml of a solvent-dissolved therapeutically effective amount of insoluble or slightly water-soluble organic drugs, ultrasonically Or use dialysis or ultrafiltration or column separation to remove organic solvents and free drugs after high-pressure homogeneous treatment, and freeze-dry to obtain nano drug-loaded micelles with a particle size of 10 to 1000 nm. The solvent is water, formamide, Absolute ethanol, N,N-dimethylformamide or dimethyl sulfoxide.

4. The polysaccharide-vitamin E succinate derivative micelle is used as a carrier to prepare a pharmaceutical composition, which can be used as a payload for anti-tumor drugs.

Drugs that can use this amphiphilic polysaccharide derivative as a carrier include: paclitaxel, docetaxel, doxorubicin, camptothecin, hydroxycamptothecin, tretinoin, 9-cis retinoic acid, methotrexate , aminopterin, oleanolic acid, ursolic acid, gambogic acids, glycyrrhizic acids, vinblastine, vincristine, mitoxantrone, etc., but not limited to these listed drugs.

The present invention has the following advantages:

1. The present invention introduces vitamin E succinate on the polysaccharide heparin with a disulfide bond linking arm, so the disulfide bond has high stability in the internal environment of the body circulation and extracellular environment, but it is easy to be reduced by the high concentration of the lesion cells. Substances (such as glutathione, etc.) are degraded, which avoids the disadvantages of drugs not being released and being cleared when they fail to exert their efficacy, and can significantly improve bioavailability and curative effect.

2. The amphiphilic polysaccharide-vitamin E succinate derivative provided by the present invention has the advantage of triggering drug release at the site of a biological lesion.

3. The amphiphilic polysaccharide-vitamin E succinate derivative provided by the present invention can spontaneously form nanomicelles in water, and has good physical encapsulation load for insoluble antitumor drugs. For example: Physical loading of Paclitaxel up to 38.2% (w/w).

4. The amphiphilic polysaccharide-vitamin E succinate derivative provided by the present invention can be used for intravenous injection, intramuscular injection, oral or external application. The derivative has high safety, and the particle size can be controlled within 10-1000nm.

5. The amphiphilic polysaccharides provided by the present invention can self-assemble in aqueous media to form nanomicelles, avoiding the use of chemical crosslinking agents, a large amount of organic solvents and heating conditions, and the preparation process is simple; its hydrophobic core can physically wrap more Other insoluble anti-tumor drugs, thereby significantly solubilizing chemotherapy drugs; in addition, vitamin E succinate and physically encapsulated chemotherapy drugs are simultaneously released to achieve synergistic anti-cancer functions. As an anti-tumor drug delivery carrier, the drug-loading system has multiple functions of biodegradability, intracellular release, and synergistic anti-cancer.

Detailed ways

Embodiment 1: Preparation of heparin-vitamin E succinate

In concrete implementation, the present invention can be realized by the following steps:

0.1 heparin, 1 mmol cystamine, 0.2 mmol EDC and 0.2 mmol NHS were dissolved in formamide, reacted for 24 hours, precipitated with excess acetone, and filtered with suction. Add water to redissolve the precipitate, and dialyze with distilled water for 48 hours (MWCO=3500), and freeze-dry the disulfide bond-containing product. Dialyze with distilled water for 48 hours (MWCO=3500), freeze-dry to obtain the heparin intermediate.

0.1 mmol of heparin intermediate, 0.1 mmol of vitamin E succinate, 0.1 mmol of EDC and 0.1 mmol of NHS were dissolved in N,N-dimethylformamide, reacted for 24 hours, precipitated with excess acetone, and filtered with suction. Add water to redissolve the precipitate, dialyze with distilled water for 48 hours (MWCO=3500), and freeze-dry to obtain the heparin-vitamin E succinate derivative carrier.

Embodiment 2: Preparation of heparin-vitamin E succinate

In concrete implementation, the present invention can be realized by the following steps:

0.1 heparin, 1 mmol cystamine, 0.2 mmol 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and 0.2 mmol hydroxysuccinimide (NHS) were dissolved in formamide and reacted for 12 h Afterwards, precipitate with excess acetone and filter with suction. Add water to redissolve the precipitate, and dialyze with distilled water for 48 hours (MWCO=3500), and freeze-dry the disulfide bond-containing product. Dialyze with distilled water for 48 hours (MWCO=3500), freeze-dry to obtain the heparin intermediate.

0.1 mmol of heparin intermediate, 0.3 mmol of vitamin E succinate, 0.1 mmol of EDC and 0.1 mmol of NHS were dissolved in N,N-dimethylformamide, reacted for 12 hours, precipitated with excess acetone, and filtered with suction. Add water to redissolve the precipitate, dialyze with distilled water for 48 hours (MWCO=3500), and freeze-dry to obtain the heparin-vitamin E succinate derivative carrier.

Example 3: Preparation and characterization of heparin-vitamin E succinate polymer micelles.

1. Preparation of amphiphilic heparin-vitamin E succinate nanomicelles: Dissolve 20 mg of heparin-vitamin E succinate derivatives in 3 mL of water and stir at room temperature for 1 hour, then homogenize by ultrasonication or high pressure in an ice bath, 0.45 μm Membrane filtration, that is, too.

2. Determination of the coupling amount of vitamin E succinate in amphiphilic heparin-vitamin E succinate: After the derivative was dissolved in a suitable solvent, UV and ¹ H-NMR were used. The results are shown in Table 1.

3. Particle size: The particle size of the sample was measured using a laser particle size analyzer NicompTM 380ZLS Zeta Potential/ParticleSizer (Santa Barbara, California, USA). The results are shown in Table 1.

Table 1 Characterization of heparin-vitamin E succinate polymer micelles

Example 4: Preparation and characterization of paclitaxel-encapsulated amphipathic heparin-vitamin E succinate nanomicelle composition

1. Preparation process:

(1) Ice bath ultrasonic method

Amphiphilic heparin-vitamin E succinate 18mg, dissolved in 3mL water and stirred at room temperature for 0.5h. Paclitaxel 10mg was dissolved in an appropriate amount of ethanol in advance. Then it was added dropwise to the derivative solution, and after ultrasonication with an ice-bath probe for 30 min, it was dialyzed in distilled water with a dialysis bag (MWCO=3500) for 12 h at room temperature, centrifuged (3000 rpm) for 15 min, filtered through a 0.45 μm filter membrane, and freeze-dried.

(2) High pressure homogenization method

Amphiphilic heparin vitamin E succinate 18mg, dissolved in 3mL water and stirred at room temperature for 0.5h. Paclitaxel 10mg was dissolved in an appropriate amount of ethanol in advance. Then it was added dropwise to the derivative solution, and after ultrasonication with an ice-bath probe for 30 min, it was dialyzed in distilled water with a dialysis bag (MWCO=3500) for 12 h at room temperature, centrifuged (3000 rpm) for 15 min, filtered through a 0.45 μm filter membrane, and freeze-dried.

2. Characterization

(1) Calculate the content of physically entrapped paclitaxel by HPLC method. Column: Platisil ODS (250×4.6mm, 5μm); guard column (Dalian Elite C18); mobile phase: methanol: water = 75:25 (V/V); detection wavelength: 227nm; flow rate: 1.0mL/min; column temperature : 30°C; injection volume: 20 μL. The results are shown in Table 2:

(2) The particle size of the sample was measured with a laser particle size analyzer NicompTM 380ZLS Zeta Potential/Particle Sizer (Santa Barbara, California, USA). The results are shown in Table 2.

Table 2 Drug loading and particle size of heparin-vitamin E succinate polymer micelles

Example 5: Preparation and characterization of heparin-vitamin E succinate self-assembled nanomicelle composition physically entrapped doxorubicin

1. Preparation process

Amphiphilic heparin-vitamin E succinate 18 mg, dissolved in 3 mL of water and stirred at room temperature for 1 h. Dissolve 10 mg of doxorubicin hydrochloride in N,N-dimethylformamide (DMF), add 200 μl of TEA, and add it dropwise to the derivative solution. After ultrasonication with an ice-bath probe for 30 min, use a dialysis bag (MWCO=3500) in Distilled water was dialyzed at room temperature for 12 hours, centrifuged (3000 rpm) for 15 minutes, filtered with a 0.45 μm membrane filter, and freeze-dried.

2. Determination of the content of physically loaded doxorubicin in amphiphilic heparin-vitamin E succinate nanomicelles

The content of doxorubicin was determined by fluorescence spectroscopy (excitation wavelength/emission wavelength were 488nm/570nm). Calculation of drug loading for physically entrapped drugs. The results are shown in Table 3.

Table 3 Drug loading and particle size of heparin-vitamin E succinate polymer micelles

Example 6: The in vitro release performance of the self-assembled nanomicelle composition of paclitaxel heparin-vitamin E succinate derivatives in a reducing environment

in vitro release test

1. Prepare release media containing different concentrations of reduced glutathione (0, 20 mM, pH 7.4). Accurately weigh an appropriate amount of amphiphilic heparin-vitamin E succinate drug-loaded micelles freeze-dried product, redissolve with 5% glucose solution and dilute to a PTX concentration of 0.5mg/mL, take 1mL of the PTX-loaded micelles solution and dialyze In a bag (MWCO=14000), tie both ends tightly, put it into a beaker containing 150mL release medium, place the beaker in a constant temperature oscillator (37°C, 100rpm), pour out the release medium according to the set time, and immediately Add fresh release medium to the outside of the dialysis bag in time, and the removed release medium is passed through a 0.45 μm microporous filter membrane before being put on the machine.

2. Calculate the content of physically entrapped paclitaxel by HPLC method. Column: PlatisilODS (250×4.6mm, 5μm); guard column (Dalian Elite C18); mobile phase: methanol: ammonium acetate (35mM, pH5.0) = 73:27 (V/V); detection wavelength: 227nm; flow rate: 1.0mL/min; column temperature: 30°C; injection volume: 20μL. The results are shown in Table 4.

24h cumulative release (%) under different glutathione (GSH) concentration environments in table 4

When the concentration of GSH in the release medium was low (no addition, 10 μM GSH), the release amount of the micelles was lower than 15% in 4 hours, and there was no burst release phenomenon, which indicated that PTX was encapsulated in the hydrophobic core of the micelles. Drug micelles release less drug. However, in the high-concentration GSH (20mM GSH, simulating the highly reducing environment in tumor cells) medium, the release amount of the drug-loaded micelles increased significantly, and the release amount was 88% in 24 hours. The effect of the change of GSH concentration on the release of the drug-loaded beam indicates that the drug-loaded system is sensitive to reduction.

Example 7

^After the tumor volume of tumor-bearing nude mice grew to 100mm, they were randomly divided into three groups, with 5 nude mice in each group, and were given paclitaxel-loaded micellar preparation/Taxol commercial preparation/normal saline at 10 mg/kg, for the first time The drug administration was counted as the 0th day, and the drug was given once every two days, and the drug was injected into the tail vein on the 0, 3, 6, 9, 12, and 15 days respectively. The mice were dissected, and the tumor tissue was removed to measure the tumor weight and calculate the tumor inhibition rate. IR (%)=[(Wc-Wt)/Wc]×100% (5-2), wherein, IR represents the tumor inhibition rate, Wc represents the average tumor weight of the control group, and Wt represents the average tumor weight of the administration group. The experimental results are shown in Table 5.

The tumor inhibition rate of table 5 polysaccharide-vitamin E succinate polymer micelle

The results show that the reduction-sensitive heparin-vitamin E succinate polymer micelle has significantly improved curative effect than the commercially available one.

Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that the specific embodiments we have described are only illustrative, rather than used to limit the scope of the present invention. Equivalent modifications and changes made by skilled personnel in accordance with the spirit of the present invention shall fall within the protection scope of the claims of the present invention.

Claims (9)

1. a kind of restore sensitive amphiphilic polysaccharide derivative, it is characterised in that：Its structure is as shown in following chemical formula：

The disulfide bond included in the structure can in tumour cell selective degradation under reproducibility environment, wherein：GLY is polysaccharide, The polysaccharide is unfraction heparin or low molecular weight heparin；N is 1~16 integer, and m is 1~16 integer, n+m summations for 2~ 18, D be Vitamin E succinate, and R is the number of hydrophobic grouping substitution on polysaccharide molecule, substituted number be 2~600 it is whole Number.

2. a kind of preparation method of the sensitive amphiphilic polysaccharide derivative of reduction as claimed in claim 1, it is characterised in that： Include the following steps：

(1) polysaccharide is dissolved in reaction dissolvent, using the linking arm for containing disulfide bond and both ends being all amino, is acted in activator Lower carry out condensation reaction, obtains the polysaccharide intermediate containing disulfide bond；

(2) Vitamin E succinate is dissolved in reaction dissolvent, under activator effect, among the polysaccharide that is obtained with step (1) Condensation reaction occurs for body to get with the sensitive amphiphilic polysaccharide-Vitamin E succinate derivative of reduction.

3. the preparation method of the sensitive amphiphilic polysaccharide derivative of reduction according to claim 2, it is characterised in that：It is described Linking arm is cystamine.

4. the preparation method of the sensitive amphiphilic polysaccharide derivative of reduction according to claim 2, it is characterised in that：It is described Reaction dissolvent for water, methanol, n,N-Dimethylformamide, tetrahydrofuran, pyridine, ethyl acetate, dichloromethane, chloroform, One kind or arbitrary two kinds of mixed solvent in carbon tetrachloride, acetone, dimethyl sulfoxide (DMSO), formamide, N-Methyl pyrrolidone.

5. the preparation method of the sensitive amphiphilic polysaccharide derivative of reduction according to claim 2, it is characterised in that：It is described Activator is EDC and NHS or EDC and HOBt or EDC and DMAP.

6. as described in claim 1 restore sensitive amphiphilic polysaccharide derivative or as described in claim 2-5 any one The purposes of the amphiphilic polysaccharide derivative of reduction sensitivity prepared by method in preparing pharmaceutical carrier or preparing antitumor drug.

7. purposes according to claim 6, it is characterised in that：The antitumor drug is antineoplastic pharmaceutical compositions, by Medicament-carried nano micelle is made with amphiphilic polysaccharide derivative in pharmaceutical active or pharmacological activity molecule；The pharmaceutical active or pharmacology Bioactive molecule include taxol, Docetaxel, adriamycin, camptothecine, hydroxycamptothecin, tretinoin, 9-cis-retinoic acid, Methotrexate (MTX), aminopterin, oleanolic acid, ursolic acid, gambogic acid, Radix Glycyrrhizae acids, vincaleukoblastinum, vincristine, mitoxantrone.

8. purposes according to claim 7, it is characterised in that：It is described that medicament-carried nano micelle is made, include the following steps：Two Parent's property polysaccharide derivates, by weight the Proportioning probe ultrasonic dissolution for being 3~50: 1000, are lived with water with the pharmacy dissolved through solvent Property or pharmacological activity molecular mixing, removed after ultrasound or high-pressure homogeneous processing with dialysis or ultrafiltration or post separation method organic The nano drug-carrying micella for being made that grain size is 10~1000nm is lyophilized in solvent and free drug.

9. purposes according to claim 8, it is characterised in that：The solvent is water, formamide, absolute ethyl alcohol, N, N- bis- Methylformamide or dimethyl sulfoxide.