CN112121175A - Dithiolan-based dextran nano prodrug, and preparation method and application thereof - Google Patents
Dithiolan-based dextran nano prodrug, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a dextran nano prodrug based on disulfiram, a preparation method and application thereof. The present invention provides a polymeric drug delivery system having a redox response. The nano-prodrug can reduce disulfide bonds into sulfydryl by reduced glutathione in cancer cells, has a response mechanism, and causes the structure of a carrier to be changed so as to quickly release the drug. The nano-prodrug shows good biological safety and better effect of killing cancer cells, and provides an intelligent drug delivery system for treating tumors.
Description
Technical Field
The invention relates to the technical field of polymers, in particular to a preparation method of a glucan-based nano prodrug with redox responsiveness, and more particularly relates to a disulfide-linked glucan-diethyl dithiocarbamate prepared based on chemical modification of thiolated glucan, and the disulfide-linked glucan-diethyl dithiocarbamate is applied to an intelligent drug delivery system.
Background
In the field of cancer chemotherapy, nano-prodrugs have been extensively studied. The nano-drug precursors are generally classified into carrier nano-drug precursors and biological nano-drug precursors. The carrier nano-drug precursor is mainly characterized in that an active compound is connected with a carrier through a covalent bond, and after a certain reaction in vivo, the active compound falls off and performs pharmacological activity. Dextran is a natural polysaccharide that is widely used for the preparation of nano-prodrugs due to its excellent biocompatibility.
Dithiolan (DSF) is a member of the dithiocarbamate family, is an FDA-approved alcohol poisoning drug that can react with redox-sensitive sulfhydryl (mercapto) groups to form diethyldithiocarbamate (DDTC) and bind copper ions (Cu)2+) A toxic complex is formed. A large number of documents report that the levels of copper ions are high in both serum and tumor in a variety of malignancies, including solid tumors and hematological cancers. DDTC through with Cu metal2+The ability to form complexes to inhibit proteasome activity in cancer cells, thereby inhibiting tumor growth. Although disulfiram has excellent anticancer effect, it has poor stability, low solubility, rapid metabolism and easy clearance in blood circulation. These factors limit the clinical use of disulfiram. How to design a disulfiram-based drug delivery system by using a nano carrier is a feasible method for improving the bioavailability of a drug and enhancing the anti-tumor effect, and the method becomes a technical problem to be solved urgently.
Disclosure of Invention
In order to solve the problems of the prior art, the invention aims to overcome the defects of the prior art and provide the disulfiram-based dextranThe invention relates to a rice prodrug, a preparation method and application thereof, and the glucose nano prodrug based on disulfiram with redox response can be used for treating cancers. The dextran is used as a framework, the side chain of the dextran is subjected to sulfydryl modification, and a disulfide-linked dextran-DDTC coupling body is prepared through exchange reaction. The dithiolan-based dextran nanopharmaceutical precursors self-assemble to form nanoparticles. In addition, the alloy does not contain Cu+The nanopharmaceutical precursor exhibits lower toxicity under the conditions of (1). In the presence of Cu+Under the condition, the nano prodrug shows higher anticancer effect and can realize the effective administration aim of treating cancer.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
a preparation method of a dextran nano prodrug based on disulfiram comprises the following steps:
(1) reacting glucan with nitro phenyl chloroformate to obtain side chain hydroxylated glucan;
(2) reacting the side chain hydroxylated glucan obtained in the step (1) with mercaptoethylamine to obtain mercaptolated glucan;
(3) reacting the thiolated dextran obtained in the step (2) with 2, 2' -dithiodipyridine to obtain a polymer containing disulfide bonds;
(4) and (3) reacting the disulfide bond-containing polymer obtained in the step (3) with diethyl dithiocarbamate to obtain a dextran-based prodrug carrying diethyl dithiocarbamate.
As a preferable technical scheme of the invention, in the step (1), the dosage of the glucan is 0.5-5 g, and the dosage of the nitrochloroformic acid phenyl ester is 0.2-1.5 mg;
as a preferable technical scheme of the invention, in the step (2), the amount of the side chain hydroxylated glucan is 0.5-5 g, and the amount of the mercaptoethylamine is 0.05-2 g;
in a preferred embodiment of the present invention, in the step (3), when the amount of the thiolated dextran is 20 to 500mg, the amount of the dithiodipyridine is 0.05 to 5 g.
In a preferred embodiment of the present invention, in the step (4), the amount of the polymer having disulfide bonds is 20 to 500mg, and the amount of the diethyldithiocarbamate is 0.005 to 0.2 g.
In a preferred embodiment of the present invention, in the step (1), the reaction is carried out to react phenyl nitrochloroformate with at least one hydroxyl group in dextran.
As a preferred embodiment of the present invention, in the step (1), the method for obtaining side chain-hydroxylated glucan comprises the steps of: and (2) reacting a mixture containing phenyl nitrochloroformate, glucan and pyridine at the temperature of-50 ℃ for not more than 3 days, adding the product into absolute ethyl alcohol, separating out a precipitate, and drying to obtain the side chain hydroxylated glucan. Further preferably, a mixture containing phenyl nitrochloroformate, dextran, LiCl and pyridine is reacted.
In a preferred embodiment of the present invention, in the step (2), the method for obtaining a thiolated dextran comprises the steps of: reacting a mixture of side chain hydroxylated glucan, mercaptoethylamine and dimethylformamide under the protection of inert gas for not more than 3 days, adding a product into absolute ethyl alcohol, separating out a precipitate, mixing the precipitate, deionized water, dithiothreitol and hydrochloric acid for 1-6h, and purifying and drying to obtain the mercaptolated glucan.
In a preferred embodiment of the present invention, in the step (3), the method for obtaining the disulfide bond-containing polymer comprises the steps of: mixing thiolated dextran, dimethyl sulfoxide and 2, 2' -dipyridyl disulfide, reacting for not more than 3 days under the protection of inert gas, and purifying and drying to obtain the polymer containing disulfide bonds. Further preferably, the thiolated dextran, dimethyl sulfoxide, 2' -dithiodipyridine and 2-mercaptopyridine are subjected to a mixed reaction;
in a preferred embodiment of the present invention, in step (4), the method for obtaining the diethyldithiocarbamate-loaded prodrug comprises the following steps: mixing a polymer containing disulfide bonds, dimethyl sulfoxide and diethyl dithiocarbamate, reacting for no more than 3 days under the protection of inert gas, and purifying and drying to obtain the prodrug which takes glucan as a framework and loads the diethyl dithiocarbamate.
The invention relates to a dextran nano prodrug based on disulfiram, which is prepared by using the preparation method of the dextran nano prodrug based on disulfiram.
The invention relates to application of a dextran nano prodrug based on disulfiram, which is used as a cancer drug carrier for assembling and preparing intelligent response type nano drug particles for treating tumors.
The application of the dextran nano prodrug based on dithiolan of the invention is to transport and release cancer drugs into blood according to the dosage of the dithiolan concentration in the blood which is not higher than 2 mu M.
Compared with the prior art, the invention has the following obvious and prominent substantive characteristics and remarkable advantages:
1. the invention uses glucan as a framework, so that the nano-drug precursor has good hydrophilicity and biocompatibility, and can ensure that the polymer can have longer in vivo circulation time;
2. the introduction of the disulfide bond into the polymer can ensure that the polymer has the characteristic of redox response, and can effectively release the drug when the polymer is used as a cancer drug carrier;
3. the method is simple and easy to implement, low in cost and suitable for popularization and application.
Drawings
FIG. 1 is a scheme showing the synthesis of thiolated dextran according to various embodiments of the present invention.
FIG. 2 is a nuclear magnetic hydrogen spectrum of dextran hydroxylated dextran and side chain thiolated dextran of the first embodiment of the present invention.
Fig. 3 is a synthesis route of DDTC loaded nano-prodrugs according to various embodiments of the present invention.
FIG. 4 shows a disulfide bond-containing polymer and DDTC-carrying prodrug according to example one of the present invention1H-NMR spectrum.
Fig. 5 is a graph of cytotoxicity of the dextran nano prodrug based on disulfiram in the presence or absence of copper ions according to the first embodiment of the present invention.
Detailed Description
The above-described scheme is further illustrated below with reference to specific embodiments, which are detailed below:
the first embodiment is as follows:
in this example, referring to fig. 1 and 3, a method for preparing a dextran nano prodrug based on dithiolan comprises the following steps:
(1) preparation of side chain hydroxylated dextran:
weighing 1g of glucan and 200mg of LiCl into a 100mL three-neck flask, placing the flask in a vacuum drying oven, setting the temperature to be 75 ℃, and drying for 72 hours under the vacuum condition; after the drying is finished, 10mL of anhydrous N, N-dimethyl formamide (DMF) is added into the reaction product, and the mixture is stirred until the liquid is clear under the condition that the oil bath temperature is 90 ℃; after the liquid is clarified, removing the oil bath, standing and cooling, placing in an ice bath, slowly and continuously introducing nitrogen for protection, then adding 0.59mL of pyridine to enable the using amount of the pyridine to be twice of the molar amount of the p-nitro phenyl chloroformate, then adding 0.75mg of p-nitro phenyl chloroformate in batches, and reacting for 24 hours under the ice bath condition (0 ℃); the dosage of the p-nitrophenyl chloroformate is calculated by the sugar ring-OH substitution degree of 20 percent;
after the reaction is finished, dropwise adding the solution into 200mL of absolute ethyl alcohol, stirring at 4 ℃, precipitating a reaction product, collecting a solid through a suction filtration device, fully washing with absolute ethyl ether, and finally placing the obtained solid in a vacuum drying oven, setting the temperature to be 75 ℃, and drying under vacuum conditions to obtain white solid powder side chain hydroxylated glucan, namely side chain hydroxylated glucan, which is shown in figure 1;
(2) preparation of thiolated dextran:
putting 1g of side chain hydroxylated glucan into a 100mL three-neck flask, adding 10mL of DMF under the condition of introducing nitrogen, stirring until the solution is clear and transparent, then weighing 0.19g of mercaptoethylamine, adding into the reaction, and continuously introducing nitrogen for reacting for 24 hours; the using amount of mercaptoethylamine is 2 times of the molar amount of the p-nitrophenyl chloroformate substituent; after the reaction is completed, dropwise adding the reaction solution into 150mL of absolute ethyl alcohol, stirring at 4 ℃ to fully precipitate the reactant, and centrifuging by using a 50mL centrifuge tube to remove the supernatant; adding 20mL of deionized water into a 100mL round-bottom flask, adding 1g of dithiothreitol, stirring for dissolving, adding 40 mu L of HCl solution with the concentration of 4M, adding the solid obtained after centrifugation into the round-bottom flask, and stirring for 2 hours; adding the dissolved solution into an ultrafiltration device for ultrafiltration and purification, and finally placing the purified sample into a freeze dryer for freeze drying to obtain white flocculent solid, namely the side chain sulfhydrylation polymer, and referring to figure 1;
(3) preparation of disulfide bond containing polymers:
weighing 200mg of the side chain thiolated polymer, placing the side chain thiolated polymer in a 25mL three-neck flask, adding 5mL of DMSO, dissolving the side chain thiolated polymer in nitrogen, sequentially weighing 0.11g of dipyridyl disulfide and 0.011g of 2-mercaptopyridine, adding the dithiodipyridyl disulfide and the 2-mercaptopyridine into the reaction, enabling the usage amount of the dipyridyl disulfide to be 2 times of the molar amount of-SH and the usage amount of the 2-mercaptopyridine to be 0.1 time of that of the dipyridyl disulfide, reacting for 48 hours in nitrogen, placing the completely reacted solution in an ultrafiltration device for ultrafiltration and purification, and finally placing the purified sample in a freeze dryer for freeze drying to obtain a white flocculent solid disulfide bond-containing polymer, namely the disulfide bond-containing polymer, and referring to fig. 3;
(4) preparation of dextran-based drug precursor loaded with diethyldithiocarbamate:
weighing 200mg of disulfide bond-containing polymer and a 10mL reaction flask, adding 2mLDMSO, stirring and dissolving; weighing 0.042g of DDTC in a 1mL EP tube, enabling the dosage of the DDTC to be 1.5 times of-Py molar weight, adding 0.5mLDMSO, shaking and dissolving by using a vortex oscillator, and then dropwise adding the mixture into a reaction bottle to react for 24 hours; and (3) after the reaction is finished, putting the solution into an ultrafiltration device for ultrafiltration purification, and finally putting the purified sample into a freeze dryer for freeze drying to obtain the dextran nano prodrug based on the disulfiram, which is shown in figure 3.
Experimental test analysis:
experimental tests were performed using the intermediate material prepared in this example and the target disulfiram-based dextran nanopharmaceutical precursor as test samples.
Characterization of first, intermediate and target disulfiram-based dextran nanopharmaceutical precursor:
FIG. 2 is a nuclear magnetic hydrogen spectrum of dextran hydroxylated dextran and side chain thiolated dextran of the present example. FIG. 4 shows the disulfide bond-containing polymer and DDTC-carrying prodrug of this example1H-NMR spectrum. As can be seen from FIGS. 2 and 4, the characteristic peak at chemical shift 7-9ppm in FIG. 2(A) is the proton peak on the benzene ring of PNC, indicating that PNC was successfully grafted to dextran. After further reaction with mercaptoethylamine, the proton peak on the phenyl ring of PNC at 7-9ppm in the nuclear magnetic hydrogen spectrum of Dex-SH of FIG. 2(B) completely disappeared, while the hydrogen peak of mercaptoethylamine appeared at 2-3ppm, indicating that PNC was completely substituted with mercaptoethylamine, compared with Dex-PNC. And calculating to obtain the PNC substitution degree DS 15 according to the area of the H peak of the benzene ring of the PNC group and the area of the H peak of the dextran sugar ring at the 1 position. FIG. 4(A) nuclear magnetic hydrogen spectrum of disulfide bond-containing polymer shows proton peaks of pyridine ring at 7-9ppm, indicating that dithiodipyridine successfully reacts to dextran side chain; after further reaction with the drug molecule, it can be seen from fig. 4(B) that the characteristic peak at 7-9ppm in the nuclear magnetic hydrogen spectrum disappears, and the characteristic peak of methyl hydrogen of the drug molecule appears at 1ppm, indicating that the pyridine ring is completely exchanged with the drug molecule. Indicating the successful preparation of DDTC loaded prodrugs.
Secondly, testing and analyzing a cytotoxicity map:
the dextran nano prodrug based on disulfiram in the embodiment is used as a cancer drug carrier, and is used for the assembly preparation experiment of nano drug particles with intelligent response type for treating tumors, when nano drug particles with different concentrations of disulfiram are measured to simulate the transportation and release of cancer drugs into blood, the corresponding cell activity is measured, as shown in fig. 5, and fig. 5 is a cytotoxicity diagram of the dextran nano prodrug based on disulfiram in the embodiment under the condition of copper ions or without copper.
This example redox-responsive dithiolan-based dextran-based nanoprecursor is intended to be used with dextranAnd (3) taking the glycan as a framework, modifying thiol-based words of hydroxyl groups of the side chain, and obtaining the DDTC connected by disulfide bonds through an exchange reaction to prepare the dextran-DDTC coupled body connected by disulfide bonds. The results show that the dextran prodrug based on disulfiram self-assembles to form nanoparticles for application in smart drug delivery systems. At a dithiolan concentration of 4 μ M in the presence of Cu+Under the condition of (1), the cell activity is lower than 30 percent, and the cell activity is not high in the condition of containing Cu+Under the conditions of (3), the cell activity is higher than 90%; at a dithiolan concentration of 4 μ M in the presence of Cu+Under the condition of (1), the cell activity is higher than 60 percent, and the cell activity is not high in Cu+The cell activity is higher than 90%, and the cell is low in toxicity. Therefore, it does not contain Cu+The nanopharmaceutical precursor exhibits lower toxicity under the conditions of (1). In the presence of Cu+Under the condition of (3), the nano prodrug shows higher anticancer effect.
This example uses dextran as backbone and utilizes p-nitrophenylchloroformate (PNC) to react with the hydroxyl groups on the dextran sugar units
Example two:
this embodiment is substantially the same as the first embodiment, and is characterized in that:
in this example, referring to fig. 1 and 3, a method for preparing a dextran nano prodrug based on dithiolan comprises the following steps:
(1) preparation of side chain hydroxylated dextran:
weighing 5g of glucan and 200mg of LiCl into a 100mL three-neck flask, placing the flask in a vacuum drying oven, setting the temperature to be 75 ℃, and drying for 72 hours under the vacuum condition; after the drying is finished, 10mL of anhydrous N, N-dimethyl formamide (DMF) is added into the reaction product, and the mixture is stirred until the liquid is clear under the condition that the oil bath temperature is 90 ℃; after the liquid is clarified, removing the oil bath, standing and cooling, placing in an ice bath, slowly and continuously introducing nitrogen for protection, then adding 1.18mL of pyridine to enable the using amount of the pyridine to be twice of the molar amount of the p-nitro phenyl chloroformate, then adding 1.5mg of p-nitro phenyl chloroformate in batches, and reacting for 72 hours under the ice bath condition (0 ℃);
after the reaction is finished, dropwise adding the solution into 200mL of absolute ethyl alcohol, stirring at 4 ℃, precipitating a reaction product, collecting a solid through a suction filtration device, fully washing with absolute ethyl ether, and finally placing the obtained solid in a vacuum drying oven, setting the temperature to be 75 ℃, and drying under vacuum conditions to obtain white solid powder side chain hydroxylated glucan, namely side chain hydroxylated glucan, which is shown in figure 1;
(2) preparation of thiolated dextran:
placing 5g of side chain hydroxylated glucan into a 100mL three-neck flask, adding 10mL of DMF under the condition of introducing nitrogen, stirring until the solution is clear and transparent, then weighing 2g of mercaptoethylamine, adding into the reaction, and continuously introducing nitrogen for reaction for 72 hours; the using amount of mercaptoethylamine is 2 times of the molar amount of the p-nitro phenyl chloroformate substituent; after the reaction is completed, dropwise adding the reaction solution into 150mL of absolute ethyl alcohol, stirring at 4 ℃ to fully precipitate and separate out the reactant, and centrifuging by using a 50mL centrifuge tube to remove supernatant; adding 20mL of deionized water into a 100mL round-bottom flask, adding 1g of dithiothreitol, stirring for dissolving, adding 40 mu L of HCl solution with the concentration of 4M, adding the solid obtained after centrifugation into the round-bottom flask, and stirring for 6 hours; adding the dissolved solution into an ultrafiltration device for ultrafiltration and purification, and finally placing the purified sample into a freeze dryer for freeze drying to obtain white flocculent solid, namely the side chain sulfhydrylation polymer, and referring to figure 1;
(3) preparation of disulfide bond containing polymers:
weighing 500mg of the side chain thiolated polymer, placing the side chain thiolated polymer in a 25mL three-neck flask, adding 5mL of DMSO, dissolving the side chain thiolated polymer in nitrogen, sequentially weighing 5g of dipyridyl disulfide and 0.011g of 2-mercaptopyridine, adding the dithiodipyridyl disulfide and the 2-mercaptopyridine into the reaction, enabling the usage amount of the dithiodipyridyl disulfide to be 2 times of the molar amount of-SH and the usage amount of the 2-mercaptopyridine to be 0.1 time of the dithiodipyridyl disulfide, reacting for 72 hours in nitrogen, placing the completely reacted solution in an ultrafiltration device for ultrafiltration and purification, and finally placing the purified sample in a freeze dryer for freeze drying to obtain a white flocculent solid disulfide bond-containing polymer, namely the disulfide bond-containing polymer, and referring to FIG. 3;
(4) preparation of dextran-based drug precursor loaded with diethyldithiocarbamate:
weighing 500mg of disulfide bond-containing polymer and a 10mL reaction flask, adding 2mLDMSO, stirring and dissolving; weighing 0.2g of DDTC in a 1mL EP tube, enabling the dosage of the DDTC to be 1.5 times of-Py molar weight, adding 0.5mLDMSO, shaking and dissolving by using a vortex oscillator, and then dropwise adding the mixture into a reaction bottle to react for 72 hours; and (3) after the reaction is finished, putting the solution into an ultrafiltration device for ultrafiltration purification, and finally putting the purified sample into a freeze dryer for freeze drying to obtain the dextran nano prodrug based on the disulfiram, which is shown in figure 3.
Experimental test analysis:
experimental tests were performed using the intermediate material prepared in this example and the target disulfiram-based dextran nanopharmaceutical precursor as test samples.
In the preparation method of the dextran nano precursor based on disulfiram with redox response characteristics, dextran is selected as a framework, and the drug is connected with the polymer framework through a disulfide bond. The present invention provides a polymeric drug delivery system having a redox response. The nano-prodrug can reduce disulfide bonds into sulfydryl by reduced glutathione in cancer cells, has a response mechanism, and causes the structure of a carrier to be changed so as to quickly release the drug. The nano-prodrug shows good biological safety and good effect of killing cancer cells, and provides an intelligent drug delivery system for treating tumors.
The embodiments of the present invention have been described with reference to the accompanying drawings, but the present invention is not limited to the embodiments, and various changes and modifications can be made according to the purpose of the invention, and any changes, modifications, substitutions, combinations or simplifications made according to the spirit and principle of the technical solution of the present invention shall be equivalent substitutions, as long as the purpose of the present invention is met, and the present invention shall fall within the protection scope of the present invention without departing from the technical principle and inventive concept of the present invention.
Claims (10)
1. A preparation method of a dextran nano prodrug based on disulfiram is characterized by comprising the following steps:
(1) reacting glucan with nitro phenyl chloroformate to obtain side chain hydroxylated glucan;
(2) reacting the side chain hydroxylated glucan obtained in the step (1) with mercaptoethylamine to obtain mercaptoylated glucan;
(3) reacting the thiolated dextran obtained in the step (2) with 2, 2' -dithiodipyridine to obtain a polymer containing a disulfide bond;
(4) and (3) reacting the disulfide bond-containing polymer obtained in the step (3) with diethyl dithiocarbamate to obtain a dextran-based prodrug carrying diethyl dithiocarbamate.
2. The method for preparing the disulfiram-based dextran nanopharmaceutical precursor of claim 1, wherein in step (1), the amount of dextran is 0.5-5 g, the amount of phenyl nitrochloroformate is 0.2-1.5 mg;
or in the step (2), the amount of the side chain hydroxylated glucan is 0.5-5 g, and the amount of the mercaptoethylamine is 0.05-2 g;
or in the step (3), the amount of the thiolated dextran is 20 to 500mg, and the amount of the dithiodipyridine is 0.05 to 5 g.
Or, in the step (4), if the amount of the polymer having disulfide bonds is 20 to 500mg, the amount of the diethyldithiocarbamate is 0.005 to 0.2 g.
3. The method of preparing a disulfiram-based dextran nanopharmaceutical precursor of claim 1 wherein in step (1) the reaction is performed to react phenyl nitrochloroformate with at least one hydroxyl group in the dextran.
4. The method for preparing the disulfiram-based dextran nanopharmaceutical precursor of claim 1, wherein in step (1), the side chain hydroxylated dextran is obtained by the steps of:
reacting a mixture containing phenyl nitrochloroformate, glucan and pyridine at the temperature of-50 ℃ for not more than 3 days, adding the product into absolute ethyl alcohol, separating out a precipitate, and drying to obtain the side chain hydroxylated glucan.
5. The method for preparing the disulfiram-based dextran nanopharmaceutical precursor of claim 1, wherein in step (2), the thiolated dextran is obtained by the steps of:
reacting a mixture of side chain hydroxylated glucan, mercaptoethylamine and dimethylformamide under the protection of inert gas for not more than 3 days, adding a product into absolute ethyl alcohol, separating out a precipitate, mixing the precipitate, deionized water, dithiothreitol and hydrochloric acid for 1-6h, and purifying and drying to obtain the mercaptolated glucan.
6. The method for preparing the disulfiram-based dextran nanopharmaceutical precursor of claim 1, wherein in step (3), the disulfide bond containing polymer is obtained by the steps of:
mixing thiolated dextran, dimethyl sulfoxide and 2, 2' -dipyridyl disulfide, reacting for not more than 3 days under the protection of inert gas, and purifying and drying to obtain the polymer containing disulfide bonds.
7. The method for preparing a dithiolan-based dextran nanopharmaceutical precursor as claimed in claim 1, wherein in step (4), the method for obtaining said diethyldithiocarbamate-loaded prodrug comprises the steps of:
mixing a polymer containing disulfide bonds, dimethyl sulfoxide and diethyl dithiocarbamate, reacting for no more than 3 days under the protection of inert gas, and purifying and drying to obtain the prodrug which takes glucan as a framework and loads the diethyl dithiocarbamate.
8. A disulfiram-based dextran nanopharmaceutical precursor characterized by: prepared by the method for preparing the dextran nano-prodrug based on disulfiram of any one of claims 1 to 7.
9. Use of the disulfiram-based dextran nanopharmaceutical of claim 8 wherein: the dextran nano prodrug based on the disulfiram is used as a cancer drug carrier for the assembly preparation of nano drug particles with intelligent response type for treating tumors.
10. Use of the disulfiram-based dextran nanopharmaceutical of claim 9 wherein: the cancer drug is transported and released into the blood at a dose at which the concentration of disulfiram in the blood is not higher than 2. mu.M.
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