CN105251013A - Degradable water-soluble antitumor polymer prodrug with redox responsiveness and preparation method thereof - Google Patents
Degradable water-soluble antitumor polymer prodrug with redox responsiveness and preparation method thereof Download PDFInfo
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- 229920000642 polymer Polymers 0.000 title claims abstract description 67
- 229940002612 prodrug Drugs 0.000 title claims abstract description 40
- 239000000651 prodrug Substances 0.000 title claims abstract description 40
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 37
- 230000004043 responsiveness Effects 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 26
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000008064 anhydrides Chemical group 0.000 claims abstract description 4
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 claims abstract description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 claims abstract description 3
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 3
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 claims abstract 2
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
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- 238000000034 method Methods 0.000 claims description 9
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- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical group O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 5
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical group C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 5
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
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- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 2
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- 238000011068 loading method Methods 0.000 abstract description 5
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- MSAHTMIQULFMRG-UHFFFAOYSA-N 1,2-diphenyl-2-propan-2-yloxyethanone Chemical compound C=1C=CC=CC=1C(OC(C)C)C(=O)C1=CC=CC=C1 MSAHTMIQULFMRG-UHFFFAOYSA-N 0.000 description 1
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- DZZAHLOABNWIFA-UHFFFAOYSA-N 2-butoxy-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(OCCCC)C(=O)C1=CC=CC=C1 DZZAHLOABNWIFA-UHFFFAOYSA-N 0.000 description 1
- BQZJOQXSCSZQPS-UHFFFAOYSA-N 2-methoxy-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(OC)C(=O)C1=CC=CC=C1 BQZJOQXSCSZQPS-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a degradable water-soluble antitumor polymer prodrug with redox responsiveness and a preparation method thereof. The antitumor polymer prodrug has a special comb type structure, polylactide is adopted as the main chain, and a side chain is bonded to a large number of oligomeric polyethylene glycol branched chain and antitumor drug molecules. The preparation method includes: subjecting functionalized polylactide with a norbornene containing side group to 1, 3-dipolar cycloaddition reaction with azide group terminated oligomeric polyethylene glycol monomethyl ether and thiol-ene click chemical reaction with mercaptoethanol in order, thus obtaining the comb type water-soluble polymer containing an oligomeric polyethylene glycol branched chain and hydroxyl side group, using the comb type water-soluble polymer to initiate dithiodipropionic anhydride ring opening, and further bonding the antitumor drug molecules, thus obtaining the antitumor polymer prodrug. The water-soluble antitumor polymer prodrug has moderate and controllable drug loading capacity, is easily degradable, and has redox responsiveness. At the same time, the preparation method is economical, efficient and nontoxic.
Description
Technical Field
The invention relates to a degradable water-soluble anti-tumor prodrug with redox responsiveness and a preparation method thereof, belonging to the field of biomedical polymers.
Background
In the past decade, the macromolecule nano-carrier is considered to be the most common and simple nano-drug delivery carrier due to its small size, good biocompatibility and degradability, long-term retention in blood circulation system, controllable drug loading, easy chemical modification and surface modification, etc. In general, the high molecular type nano-carriers can be classified into three categories according to the mechanism of drug loading, including polymeric prodrugs by chemical bonding, polymeric micelles by hydrophobic interaction, and polymeric vesicles by physical encapsulation. Compared with the antitumor small molecule drugs, the polymer nano-carrier has the following advantages: the solubility of the insoluble drug is improved, and the drug is protected from being degraded in advance when the drug does not reach an action part; improving the kinetics and tissue distribution of the drug's action in vivo; the toxic and side effects of the small molecular antitumor drug on normal tissues are reduced; the pharmacological property of the drug can be improved without changing the drug molecules; help the drug cross some biological barriers, such as epithelial and endothelial cells; realize the intracellular delivery of the drug; small molecule drugs with different physicochemical properties and different action mechanisms can be transmitted together; can integrate imaging and treatment, and realize real-time tracking and curative effect evaluation of drug delivery.
The macromolecule bonding drug generally refers to a nano drug formed by covalent bond interaction between a carrier material and a drug, and is also called a macromolecule prodrug. Compared with polymer micelles and vesicles which physically wrap the drugs, the polymer prodrug can effectively reduce the burst release of the drugs and improve the solubility of the hydrophobic drugs; in blood circulation, the carrier material can effectively protect drug molecules and avoid drug aggregation, degradation and passivation; the blood circulation time of the medicine is prolonged, and the medicine is promoted to be enriched in tumor tissues through active or passive targeting; after entering tumor cells, the drug molecules can release the original drug through different mechanisms. Generally, the carrier material and the drug are connected through degradable chemical bonds such as ester bonds, peptide bonds, pH responsive chemical bonds and the like, so that the drug controlled release is realized in cells through lysosomal enzymes, reductive conditions, endosomal low pH and other conditions.
Disclosure of Invention
Aiming at the problems of poor degradability, low drug-loading rate, lack of stimulation responsiveness and the like of the anti-tumor polymer prodrug in the prior art, the invention aims to provide the anti-tumor prodrug which is completely biodegradable, has moderate and controllable drug-loading rate, redox response and contains a modifiable group.
It is another object of the present invention to provide an economical, efficient and non-toxic method for preparing high purity antineoplastic prodrugs.
In order to achieve the above technical objects, the present invention provides a degradable water-soluble anti-tumor polymer prodrug with redox responsiveness, having a structure of formula 1 or formula 2:
wherein,
b is an antitumor drug molecular group with hydroxyl;
d is an antitumor drug molecular group with amino;
x is 20-100, y is 1-10, z is 8-17, and x, y and z are integers.
The antitumor drug molecular group with hydroxyl is one or more of a paclitaxel group, a docetaxel group, an adriamycin group or a camptothecin group.
The molecular group of the antitumor drug with amino is adriamycin group.
The invention also provides a preparation method of the degradable water-soluble anti-tumor polymer prodrug with redox responsiveness, which comprises the following steps: the polymer with the structure shown in the formula 3 sequentially performs 1, 3-dipolar cycloaddition reaction with oligomeric polyethylene glycol monomethyl ether with azido group at the end group and performs mercapto-alkene click chemical reaction with mercaptoethanol to obtain a polymer with the structure shown in the formula 4; initiating ring opening of dithiodipropionic anhydride by using the polymer with the structure shown in the formula 4 to obtain a polymer with the structure shown in the formula 5; the obtained polymer with the structure of the formula 5 and the molecules of the antitumor drugs are subjected to esterification reaction or condensation reaction to obtain the antitumor drug;
wherein x is 20-100, y is 1-10, z is 8-17, and x, y and z are integers.
In a preferred scheme, the anti-tumor drug molecules are one or more of paclitaxel, docetaxel, adriamycin and camptothecin. The paclitaxel group, the docetaxel group and the camptothecin group are anti-tumor drug molecules containing hydroxyl; and the adriamycin is an anti-tumor drug molecule containing hydroxyl and hydroxyl simultaneously.
In a preferable scheme, the polymer with the structure shown in the formula 5 and antitumor drug molecules with hydroxyl take dicyclohexylcarbodiimide as a condensing agent, N, N-dimethyl-p-aminopyridine takes a catalyst to perform esterification reaction at the temperature of 0-30 ℃ to obtain the degradable water-soluble antitumor polymer prodrug with redox responsiveness.
In a more preferable scheme, the molar amount of the N, N-dimethyl-p-aminopyridine is 0.5-2 times of the content of carboxyl in the polymer with the structure shown in the formula 5.
In a preferred scheme, in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, the structural polymer shown in the formula 5 and the antitumor drug molecule with amino carry out condensation reaction to obtain the degradable water-soluble antitumor polymer prodrug with redox responsiveness.
In a more preferable embodiment, the molar amount of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 1 to 2 times of the carboxyl group content in the polymer having the structure of formula 5.
In a more preferable scheme, the molar amount of the N-hydroxysuccinimide is 0.5-2 times of the carboxyl content in the polymer with the structure shown in the formula 5.
In a preferred scheme, the degradable water-soluble anti-tumor polymer prodrug with redox responsiveness is purified by dialysis and ether sedimentation separation.
In the technical scheme of the invention, the sulfydryl-alkene click chemical reaction is carried out in the presence of a photosensitizer under the irradiation of ultraviolet light of 250-400 nm.
The photosensitizer is one or more of 1-hydroxycyclohexyl phenyl ketone, benzophenone, 2-methylbenzophenone, 4-phenylbenzophenone, 3, 4-dimethyl benzophenone, 4' -bis (diethylamino) benzophenone, benzoin methyl ether, benzoin dimethyl ether, benzoin ethyl ether, benzoin isopropyl ether, benzoin n-butyl ether or benzoin isobutyl ether.
The reaction time of the sulfydryl-alkene click chemistry is 3-12 h.
The invention discloses a method for preparing a polymer (norbornene functionalized polylactides) with a structure shown in formula 3: carrying out substitution reaction on lactide and N-bromosuccinimide (NBS) in carbon tetrachloride or benzene solution at 60-90 ℃ under the catalytic action of dibenzoyl peroxide (BPO) to obtain bromolactide; carrying out elimination reaction on the obtained bromolactide in a dichloromethane solvent under the action of triethylamine at 0-5 ℃ to obtain double-bond lactide; carrying out Diels-Alder reaction on the obtained double-bond lactide and freshly distilled cyclopentadiene in a carbon tetrachloride or benzene solution at the temperature of 60-90 ℃ to obtain lactide containing norbornene side groups; TBD or DBU is used as a catalyst, dichloromethane is used as a solvent, ring opening polymerization is carried out at-20-40 ℃, and then the norbornene functionalized polylactides are obtained.
The synthesis route of the redox-responsive degradable water-soluble antitumor polymer prodrug of the invention is as follows:
with an antineoplastic drug molecule, Paclitaxel ═For example, the following steps are carried out:
compared with the prior art, the technical scheme of the invention has the following beneficial effects:
simultaneously introducing a large number of oligomeric polyethylene glycol branched chains and anti-tumor drug molecules bonded by disulfide bonds on a polylactide main chain for the first time.
The oligomeric polyethylene glycol is introduced into the main chain of the polylactide, and the whole polymer has a special comb-shaped structure due to the introduction of a large number of oligomeric polyethylene glycol branched chains, has better water solubility and biocompatibility, has good dispersibility in a human body, and is easy to discharge from the kidney of the human body, so that the problem that the polyethylene glycol with high molecular weight is difficult to discharge is solved.
The adopted polylactide has good biodegradability and biocompatibility and has no residue in a human body.
Especially, the anti-cancer drug molecules are linked with the polymer by disulfide bonds, so that the anti-cancer drug has redox responsiveness and can achieve the purpose of controlled release.
The invention reacts with oligomeric polyethylene glycol monomethyl ether (mOEG) through click reaction, has no side reaction, high yield and simple post-treatment.
The preferred process of purifying the drug molecules can obtain the antitumor prodrug with high purity through dialysis and sedimentation.
The preparation method of the antitumor prodrug has the advantages of low cost, high yield, safety, no toxicity and wide application.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of a methanol-initiated polylactide containing norbornene functionalization of the pendant group.
FIG. 2 is a nuclear magnetic hydrogen spectrum of a comb copolymer containing norbornene functionalized polylactide and oligomeric polyethylene glycol monomethyl ether as side groups.
FIG. 3 is a nuclear magnetic hydrogen spectrum of a comb-type water-soluble polymer containing hydroxyl side groups.
FIG. 4 is a nuclear magnetic hydrogen spectrum of a comb-type water-soluble polymer containing pendant carboxyl groups and having redox properties.
FIG. 5 is a nuclear magnetic hydrogen spectrum of an antitumor prodrug having a paclitaxel drug molecule bonded to its side chain.
FIG. 6 is an IR spectrum of an antitumor prodrug of a norbornene-functionalized polylactide having a side group, B a graft copolymer of a norbornene-functionalized polylactide having a side group and oligo (poly (ethylene glycol) monomethyl ether), C a comb-type water-soluble polymer having a hydroxyl side group, D a comb-type water-soluble polymer having a carboxyl side group and having redox properties, and E a side chain linked to an oxytetracycline drug molecule.
FIG. 7 is a gel chromatogram of a comb-type water-soluble polymer containing pendant carboxyl groups and having redox properties, wherein A is a norbornene-functionalized polylactide having pendant groups, B is a graft copolymer of a norbornene-functionalized polylactide having pendant groups and oligomeric polyethylene glycol monomethyl ether, C is a comb-type water-soluble polymer containing pendant hydroxyl groups, and D is a gel chromatogram of a comb-type water-soluble polymer containing pendant carboxyl groups and having redox properties.
Detailed Description
The following examples are intended to further illustrate the present disclosure, but not to limit the scope of the invention as claimed.
Example 1
1. Graft copolymer with side group containing norbornene functionalized polylactide and oligomeric polyethylene glycol monomethyl ether
Under the protection of nitrogen, 0.100g (double bond: 0.00048mol) of a norbornene-functionalized polylactide (nuclear magnetic hydrogen spectrum shown in FIG. 1, IR spectrum shown in FIG. 6A, gel chromatogram shown in FIG. 7A) was completely dissolved in 5mL of ethyl acetate, and then 0.147g (0.0024mol) of oligo (poly (ethylene glycol) monomethyl ether having an azide group as a terminal group was added and reacted at 80 ℃ for 72 hours. And (5) carrying out reaction in an oil bath kettle. After the reaction was complete, ethyl acetate was spun off, the dichloromethane was dissolved, precipitated three times with anhydrous ether, drained and dried in vacuo overnight. Is a graft copolymer of poly lactide with side group containing norbornene functionalization and oligomeric polyethylene glycol monomethyl ether, and is marked as polymer P1. The structural representation is shown in a nuclear magnetic hydrogen spectrum (figure 2), an infrared image (figure 6B) and a molecular weight distribution (figure 7B), which indicate that the polymer is successfully synthesized.
2. Preparation of comb-type water-soluble polymer containing hydroxyl side group
Under the protection of nitrogen, 0.478g (double bond: 0.17mmol) of polymer P1 is dissolved in 1.5mL of Tetrahydrofuran (THF), 13mg (double bond: 0.17mmol) of mercaptoethanol is added, a proper amount of initiator benzoin ethyl ether is added into the system, the system is placed under an ultraviolet lamp with the wavelength of 365nm for irradiation for 1h, after the reaction is finished, the mixture is dialyzed for 48h with secondary water, and the product is frozen and dried, and the polymer P2 is obtained. The structural representation is shown in a nuclear magnetic hydrogen spectrum (figure 3), an infrared image (figure 6C) and a molecular weight distribution (figure 7C), which indicate that the polymer is successfully synthesized.
3. Preparation of comb-type water-soluble polymer containing carboxyl side group and having redox property
0.222g (double bond: 0.042mmol) of the polymer P2 was dissolved in 1.5mL of pyridine under nitrogen protection, 0.08g (0.42mmol) of dithiodipropionic anhydride was added in a molar ratio of 10/1 to P2, and an appropriate amount of 4-Dimethylaminopyridine (DMAP) was added to the system and reacted at 70 ℃ for 48 hours. And (3) carrying out reaction in an oil bath pot, dialyzing for 48h by using secondary water after the reaction is finished, and cooling to dry, wherein the mark is the polymer P3. The structural representation is shown in a nuclear magnetic hydrogen spectrum (figure 4), an infrared image (figure 6D) and a molecular weight distribution (figure 7D), which indicate that the polymer is successfully synthesized.
4. Preparation of water-soluble anti-tumor prodrug of paclitaxel drug molecule linked on side chain
Dissolving 0.073g (0.013mmol) of polymer P3 in 5mL of tetrahydrofuran, adding 0.011g (0.012mmol) of paclitaxel, adding a solution of DCC in DMF into a 25mL reaction bottle within 10min, adding a catalytic amount of DMAP, and stirring at normal temperature for 48 h; after the reaction is finished, filtering to remove insoluble substances; after the reaction is finished, the ether is settled to obtain the water-soluble anti-tumor prodrug. The structural representation is shown in a nuclear magnetic hydrogen spectrum (figure 5), which indicates that the polymer has been successfully synthesized
5. Preparation of water-soluble antitumor prodrug with side chain linked with adriamycin drug molecule
Adding polymer P3, EDC & HCl and NHS into a dry reaction bottle in sequence under the protection of nitrogen, vacuumizing for three times, adding 50mL of dichloromethane, stirring at room temperature for reaction for 24h, adding 250mL of dichloromethane for dilution, washing with saturated saline for three times, adding anhydrous MgSO4Drying, spinning drying, settling with ether to obtain viscous solid, and vacuum drying overnight. The resulting product was added to a dry reaction flask under nitrogen, 69.6mg (0.12mmol) of doxorubicin hydrochloride was further added, after three times of degassing, anhydrous DMF was added, 12.1mg (0.12mmol) of TEA was added dropwise, and the reaction was carried out at 30 ℃ for 72 hours. After the reaction, the diethyl ether settled to obtain red solid. The structure is characterized in the infrared (FIG. 6E), which shows that the polymer has been successfully synthesized.
Claims (10)
1. A degradable water-soluble antitumor polymer prodrug with redox responsiveness, which is characterized by having a structure shown in formula 1 or formula 2:
wherein,
b is an antitumor drug molecular group with hydroxyl;
d is an antitumor drug molecular group with amino;
x is 20-100, y is 1-10, z is 8-17, and x, y and z are integers.
2. The degradable water-soluble antitumor polymer prodrug with redox responsiveness of claim 1, wherein the antitumor drug molecule group with hydroxyl group is one or more of a paclitaxel group, a docetaxel group, an adriamycin group or a camptothecin group.
3. The degradable water-soluble antitumor polymer prodrug with redox responsiveness of claim 1, wherein the antitumor drug molecule group with amino group is adriamycin group.
4. A preparation method of the degradable water-soluble antitumor polymer prodrug with redox responsiveness according to any one of claims 1 to 3, wherein the polymer with the structure shown in formula 3 sequentially undergoes 1, 3-dipolar cycloaddition reaction with oligomeric polyethylene glycol monomethyl ether with an azido group as an end group and thiol-ene click chemical reaction with mercaptoethanol to obtain the polymer with the structure shown in formula 4; initiating ring opening of dithiodipropionic anhydride by using the polymer with the structure shown in the formula 4 to obtain a polymer with the structure shown in the formula 5; the obtained polymer with the structure shown in the formula 5 and the molecules of the antitumor drug are subjected to esterification reaction or condensation reaction to obtain the antitumor polymer prodrug;
wherein,
x is 20-100, y is 1-10, z is 8-17, and x, y and z are integers.
5. The method for preparing the degradable water-soluble antitumor polymer prodrug with redox responsiveness according to claim 4, wherein the antitumor drug molecules are one or more of paclitaxel, docetaxel, doxorubicin and camptothecin.
6. The method for preparing the degradable water-soluble antitumor polymer prodrug with the redox responsiveness as claimed in claim 4, wherein the polymer with the structure shown in formula 5 and the antitumor drug molecule with the hydroxyl group are subjected to esterification reaction at 0-30 ℃ by using dicyclohexylcarbodiimide as a condensing agent and N, N-dimethyl-p-aminopyridine as a catalyst to obtain the degradable water-soluble antitumor polymer prodrug with the redox responsiveness.
7. The method for preparing the degradable water-soluble antitumor polymer prodrug with redox responsiveness of claim 6, wherein the molar amount of dicyclohexylcarbodiimide is 1-2 times of the carboxyl content in the polymer with the structure shown in formula 5; the molar amount of the N, N-dimethyl-p-aminopyridine is 0.5-2 times of the content of carboxyl in the polymer with the structure shown in the formula 5.
8. The method for preparing the degradable water-soluble anti-tumor polymer prodrug with redox responsiveness of claim 4, wherein the degradable water-soluble anti-tumor polymer prodrug with redox responsiveness is separated and purified by dialysis and ether sedimentation.
9. The method for preparing the degradable water-soluble antitumor polymer prodrug with redox responsiveness according to claim 4, wherein the polymer with the structure shown in formula 5 and the antitumor drug molecule with amino group are subjected to condensation reaction in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide to obtain the degradable water-soluble antitumor polymer prodrug with redox responsiveness.
10. The method for preparing the degradable water-soluble antitumor polymer prodrug with redox responsiveness of claim 9, wherein the molar amount of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is 1-2 times of the carboxyl content in the polymer with the structure shown in the formula 5; the molar amount of the N-hydroxysuccinimide is 0.5-2 times of the carboxyl content in the polymer with the structure shown in the formula 5.
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