CN112121175B - Dextran nano-drug precursor based on disulfiram, preparation method and application thereof - Google Patents
Dextran nano-drug precursor based on disulfiram, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a dextran nano-drug precursor based on disulfiram, a preparation method and application thereof. The present invention provides a polymeric drug delivery system with a redox response. The nano-prodrug can be reduced into sulfhydryl by reduced glutathione in cancer cells, has a response mechanism, and causes the structure of the carrier to be changed so as to lead the drug to be quickly released. The nano-drug precursor has 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 chemical modification based on sulfhydrylation glucan, which is used for preparing disulfide bond connected glucan-diethyl dithiocarbamate and is applied to an intelligent drug delivery system.
Background
In the field of cancer chemotherapy, nano-drug prodrugs have been widely studied. Nano-drug precursors are generally classified into carrier nano-drug precursors and biological nano-drug precursors. The carrier nano-drug precursor is mainly formed by connecting an active compound with a carrier through a covalent bond, and the active compound falls off and plays a pharmacological action after a certain reaction in vivo. Dextran is a natural polysaccharide that is widely used in the preparation of nano-drug precursors due to its excellent biocompatibility.
Disulfiram (DSF), a member of the dithiocarbamate family, is an FDA approved alcoholism drug that can react with redox-sensitive sulfhydryl groups (sulfhydryl groups) to form diethyldithiocarbamate (DDTC) in combination with copper ions (Cu) 2+ ) Forming toxic complexes. Numerous documents report that the levels of copper ions in serum and in tumors are high among many malignant tumors, including solid tumors and hematological cancers. DDTC is prepared by combining with metal Cu 2+ The ability to form complexes to inhibit proteasome activity in cancer cells, thereby inhibiting tumor growth. Although disulfiram has excellent anticancer efficacy, it has poor stability, low solubility, fast metabolism and easy clearance in blood circulation. These factors limit the clinical use of disulfiram. How to design a drug delivery system based on disulfiram by utilizing a nano carrier is a feasible method for improving the bioavailability of the drug and enhancing the anti-tumor effect, and is a technical problem to be solved urgently.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to overcome the defects in the prior art and provide a disulfiram-based glucan nano-drug precursor, a preparation method and application thereof. The dextran is taken as a framework, the side chain of the dextran is subjected to sulfhydryl modification, and disulfide bond connected dextran-DDTC coupling body is prepared through exchange reaction. The disulfiram-based dextran nano-drug precursors self-assemble to form nanoparticles. In addition, in the absence of Cu + The nano-drug precursor shows lower toxicity. In the presence of Cu + Under the condition of (1), the nano-drug precursor shows higher anticancer effect, and can realize the effective drug delivery purpose for treating cancers.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
a preparation method of a dextran nanometer prodrug based on disulfiram comprises the following steps:
(1) Reacting glucan with phenyl nitrochloroformate to obtain side chain hydroxylation glucan;
(2) Reacting the side chain hydroxylated glucan obtained in the step (1) with mercaptoethylamine to obtain mercaptodextran;
(3) Reacting the mercaptodextran obtained in step (2) with 2,2' -dithiodipyridine to obtain a polymer containing disulfide bonds;
(4) Reacting the disulfide bond-containing polymer obtained in the step (3) with diethyl dithiocarbamate to obtain a prodrug which takes glucan as a framework and carries diethyl dithiocarbamate.
As a preferable technical scheme of the invention, in the step (1), the dosage of glucan is 0.5-5 g, and then the dosage of phenyl nitrochloroformate is 0.2-1.5 mg;
as a preferable technical scheme of the invention, in the step (2), the amount of the side chain hydroxylation glucan is 0.5-5 g, and the amount of the mercaptoethylamine is 0.05-2 g;
as a preferred embodiment of the present invention, in the step (3), the amount of mercaptodextran is 20 to 500mg, and the amount of dithiodipyridine is 0.05 to 5g.
In a preferred embodiment of the present invention, in the step (4), the amount of the disulfide bond-containing polymer is 20 to 500mg, and the amount of the diethyldithiocarbamate is 0.005 to 0.2g.
In a preferred embodiment of the present invention, in the step (1), a reaction is performed to react phenyl nitrochloroformate with at least one hydroxyl group in dextran.
As a preferred technical scheme of the present invention, in the step (1), the step of the method for obtaining the side chain hydroxylated glucan is as follows: and (3) reacting the mixture containing the phenyl nitrochloroformate, the glucan and the pyridine at the temperature of between 50 ℃ below zero and 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 hydroxylation glucan. It is further preferable to react a mixture containing phenyl nitrochloroformate, dextran, liCl, and pyridine.
As a preferred technical solution of the present invention, in the step (2), the steps of the method for obtaining mercaptodextran are as follows: the method 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 to separate out a precipitate, mixing the precipitate, deionized water, dithiothreitol and hydrochloric acid, stirring for 1-6 hours, and purifying and drying to obtain the mercaptoglucan.
As a preferred embodiment of the present invention, in the step (3), the method for obtaining a disulfide bond-containing polymer comprises the steps of: mixing mercaptodextran, dimethyl sulfoxide and 2,2' -dithiodipyridine, reacting for not more than 3 days under the protection of inert gas, and purifying and drying to obtain the polymer containing disulfide bonds. It is further preferable to mix the mercaptodextran, dimethyl sulfoxide, 2' -dithiodipyridine and 2-mercaptopyridine for reaction;
as a preferred embodiment of the present invention, in the step (4), the step of the method for obtaining the diethyldithiocarbamate-loaded prodrug comprises the steps of: mixing a polymer containing disulfide bonds, dimethyl sulfoxide and diethyl dithiocarbamate, reacting for not more than 3 days under the protection of inert gas, and purifying and drying to obtain a prodrug taking glucan as a framework and loading the diethyl dithiocarbamate.
The dextran nanometer drug precursor based on the disulfiram is prepared by the preparation method of the dextran nanometer drug precursor based on the disulfiram.
The application of the dextran nanometer prodrug based on disulfiram in the invention takes the dextran nanometer prodrug based on disulfiram as a cancer drug carrier for the assembly preparation of nanometer drug particles with intelligent response type for treating tumors.
The invention relates to application of a dextran nanometer prodrug based on disulfiram, which is used for transporting and releasing cancer drugs into blood according to the dosage that the concentration of the disulfiram in the blood is not higher than 2 mu M.
Compared with the prior art, the invention has the following obvious prominent substantive features and obvious advantages:
1. the dextran is used as a framework, so that the nano-drug precursor has good hydrophilicity and good biocompatibility, and the polymer can have longer in vivo circulation time in vivo;
2. the disulfide bond is introduced into the polymer, so that the polymer has the characteristic of redox response, and the polymer can be used as a cancer drug carrier to effectively release the drug;
3. the method is simple and feasible, has low cost and is suitable for popularization and application.
Drawings
FIG. 1 shows the synthetic routes for mercaptodextran of the various embodiments of the present invention.
FIG. 2 is a nuclear magnetic resonance spectrum of dextran hydroxylation dextran and side chain sulfhydrylation dextran of the first embodiment of the present invention.
Figure 3 is a synthetic route for DDTC-loaded nanopharmaceutical precursors of various embodiments of the invention.
FIG. 4 shows a disulfide-bond-containing polymer and a DDTC-supporting prodrug according to an embodiment of the present invention 1 H-NMR spectrum.
Fig. 5 is a graph showing cytotoxicity of a disulfiram-based dextran nano-pro-drug of the first embodiment of the present invention in the presence or absence of copper ions.
Detailed Description
The foregoing aspects are further described in conjunction with specific embodiments, and the following detailed description of preferred embodiments of the present invention is provided:
embodiment one:
in this example, referring to fig. 1 and 3, a method for preparing a dextran nano-drug precursor based on disulfiram comprises the following steps:
(1) Side chain hydroxylation dextran preparation:
weighing 1g of glucan and 200mg of LiCl in a 100mL three-neck flask, placing in a vacuum drying oven, setting the temperature to 75 ℃, and drying for 72h under vacuum; after drying was completed, 10mL of anhydrous N, N-Dimethylformamide (DMF) was added to the reaction mass and the oil bath temperature was set at 90 ℃ and stirred until the liquid was clear; removing the oil bath after the liquid is clarified, standing and cooling, placing in an ice bath, slowly and continuously introducing nitrogen for protection, then adding 0.59mL of pyridine to make the pyridine dosage be twice the molar quantity of the phenyl p-nitrochloroformate, then adding 0.75mg of phenyl p-nitrochloroformate in batches, and reacting for 24 hours under the ice bath condition (0 ℃); the amount of phenyl p-nitrochloroformate was calculated as 20% substitution of the sugar ring-OH;
after the reaction is finished, dropwise adding the solution into 200mL of absolute ethyl alcohol, stirring at the temperature of 4 ℃ to precipitate and separate out a reaction product, collecting a solid through a suction filtration device, fully washing the solid with absolute ethyl ether, and finally placing the obtained solid in a vacuum drying oven to be dried under the vacuum condition that the temperature is set at 75 ℃ to obtain white solid powder side chain hydroxylated glucan, namely side chain hydroxylated glucan, as shown in figure 1;
(2) Preparation of mercaptodextran:
putting 1g of glucan with hydroxylated side chains into a 100mL three-neck flask, adding 10mL of DMF under the condition of introducing nitrogen, stirring until the solution is clear and transparent, weighing 0.19g of mercaptoethylamine, adding into the reaction, and continuously introducing nitrogen to react for 24 hours; the dosage of the mercaptoethylamine is 2 times of the molar quantity of the substituent of the phenyl p-nitro chloroformate; after the reaction is completed, dropwise adding the reaction solution into 150mL of absolute ethyl alcohol, stirring at the temperature of 4 ℃ to enable the reactant to be fully precipitated and separated out, and centrifuging the mixture 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 dissolution, 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 2h; adding the dissolved solution into an ultrafiltration device for ultrafiltration purification, and finally, freeze-drying the purified sample in a freeze dryer to obtain white flocculent solid, namely the side chain thiolated polymer, as shown in figure 1;
(3) Preparation of disulfide bond-containing polymers:
200mg of the side chain sulfhydrylated polymer is weighed and placed in a 25mL three-neck flask, 5mL of DMSO is added to be dissolved under the condition of introducing nitrogen, then 0.11g of dithiodipyridine and 0.011g of 2-mercaptopyridine are sequentially weighed and added into the reaction, the dosage of the dithiodipyridine is 2 times of the molar weight of-SH, the dosage of the 2-mercaptopyridine is 0.1 time of the molar weight of the dithiodipyridine, after the reaction is carried out for 48 hours under the condition of introducing nitrogen, the solution after the reaction is completely placed in an ultrafiltration device for ultrafiltration purification, and finally the purified sample is placed in a freeze dryer for freeze drying, so that white flocculent solid polymer containing disulfide bonds is obtained, namely the polymer containing disulfide bonds, and the polymer is shown in figure 3;
(4) Preparation of a prodrug with dextran as a backbone and a diethyldithiocarbamate supported:
200mg of polymer containing disulfide bonds and a 10mL reaction bottle are weighed, added with 2mL of LDMSO and stirred for dissolution; weighing 0.042g of DDTC in a 1mL EP tube, enabling the dosage of the DDTC to be 1.5 times of the molar quantity of-Py, adding 0.5mLDMSO, oscillating and dissolving by a vortex oscillator, and then dropwise adding into a reaction bottle for reacting for 24 hours; and after the reaction is finished, placing the solution into an ultrafiltration device for ultrafiltration purification, and finally, placing the purified sample into a freeze dryer for freeze drying to obtain the dextran nano-drug precursor based on disulfiram, see figure 3.
Experimental test analysis:
the intermediate material prepared in this example and the target disulfiram-based dextran nano-drug precursor were used as test samples for experimental verification.
1. Intermediate and target disulfiram-based dextran nano-drug prodrug characterization:
FIG. 2 is a nuclear magnetic resonance spectrum of dextran hydroxylated dextran and side chain mercaptodextran of the present example. FIG. 4 shows the disulfide-bond-containing polymer and DDTC-supporting prodrug of the present example 1 H-NMR spectrum. As can be seen from FIGS. 2 and 4, the characteristic peaks at chemical shifts 7-9ppm in FIG. 2 (A) are proton peaks on the benzene ring of the PNC, indicating that the PNC was successfully grafted to dextran. FIG. 2 (B) Nuclear magnetic Hydrogen Spectrometry of Dex-SH, compared to Dex-PNC after further reaction with mercaptoethylamineThe proton peak on the benzene ring of PNC at 7-9ppm completely disappeared, while the hydrogen peak of mercaptoethylamine appeared at 2-3ppm, indicating complete substitution of PNC with mercaptoethylamine. And calculating according to the H peak area of the benzene ring of the PNC group and the H peak area of the 1-position of the glucan sugar ring to obtain the substitution degree of the PNC as DS 15. FIG. 4 (A) shows proton peaks of pyridine ring at 7-9ppm for nuclear magnetic hydrogen spectrum of disulfide bond containing polymer, indicating that dithiodipyridine was successfully reacted onto dextran side chains; after further reaction with the drug molecule, it is seen from FIG. 4 (B) that the characteristic peak at 7-9ppm in the nuclear magnetic resonance spectrum disappeared, and the characteristic peak of the methyl hydrogen of the drug molecule appears at 1ppm, indicating that the pyridine ring is completely exchanged with the drug molecule. Indicating successful preparation of DDTC-loaded prodrugs.
2. Cytotoxicity map test assay:
the dextran nano-drug precursor based on disulfiram of the embodiment is used as a cancer drug carrier, and is used for an assembly preparation experiment of nano-drug particles with intelligent response for treating tumors, when the nano-drug particles with different disulfiram concentrations are used for simulating 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 chart of the dextran nano-drug based on disulfiram of the embodiment under the condition of copper ions or no copper.
The dextran-based nano precursor based on disulfiram of the redox response of the embodiment aims at taking dextran as a framework, carrying out sulfhydryl modification on side chain hydroxyl groups, obtaining disulfide-bond-connected DDTC through exchange reaction, and preparing the disulfide-bond-connected dextran-DDTC conjugate body. The results show that the dextran nano-drug precursors based on disulfiram self-assemble to form nano-particles for application in smart drug delivery systems. At a dose of 4. Mu.M disulfiram, the composition contains Cu + Under the conditions of (2) cell activity of less than 30% and in the absence of Cu + Under conditions of (2) cell activity higher than 90%; at a dose of 4. Mu.M disulfiram, the composition contains Cu + Under the conditions of (1) the cell activity is higher than 60%, and in the absence of Cu + Under the conditions of above 90% cell activity, which is shown to be less toxic. Therefore, in the absence of Cu + Under the condition of (1) nano-prodrugThe body showed lower toxicity. In the presence of Cu + The nano-prodrug exhibits a higher anticancer effect.
In this example, dextran was used as a backbone, and p-nitro phenyl chloroformate (PNC) was used to react with hydroxyl groups on the dextran saccharide units
Embodiment 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-drug precursor based on disulfiram comprises the following steps:
(1) Side chain hydroxylation dextran preparation:
weighing 5g of glucan and 200mg of LiCl in a 100mL three-neck flask, placing in a vacuum drying oven, setting the temperature to be 75 ℃, and drying for 72h under vacuum; after drying was completed, 10mL of anhydrous N, N-Dimethylformamide (DMF) was added to the reaction mass and the oil bath temperature was set at 90 ℃ and stirred until the liquid was clear; removing the oil bath after the liquid is clarified, standing and cooling, placing in an ice bath, slowly and continuously introducing nitrogen for protection, then adding 1.18mL of pyridine to make the pyridine dosage be twice the molar quantity of the phenyl p-nitrochloroformate, then adding 1.5mg of phenyl p-nitrochloroformate in batches, and reacting for 72h under the ice bath condition (0 ℃);
after the reaction is finished, dropwise adding the solution into 200mL of absolute ethyl alcohol, stirring at the temperature of 4 ℃ to precipitate and separate out a reaction product, collecting a solid through a suction filtration device, fully washing the solid with absolute ethyl ether, and finally placing the obtained solid in a vacuum drying oven to be dried under the vacuum condition that the temperature is set at 75 ℃ to obtain white solid powder side chain hydroxylated glucan, namely side chain hydroxylated glucan, as shown in figure 1;
(2) Preparation of mercaptodextran:
placing 5g of glucan with hydroxylated side chains into a 100mL three-neck flask, adding 10mL of DMF under the condition of introducing nitrogen, stirring until the solution is clear and transparent, weighing 2g of mercaptoethylamine, adding into the reaction, and continuously introducing nitrogen to react for 72h; the dosage of the mercaptoethylamine is 2 times of the molar quantity of the substituent of the phenyl p-nitro chloroformate; after the reaction is completed, dropwise adding the reaction solution into 150mL of absolute ethyl alcohol, stirring at the temperature of 4 ℃ to enable the reactant to be fully precipitated and separated out, and then removing supernatant by using a 50mL centrifuge tube; adding 20mL of deionized water into a 100mL round-bottom flask, adding 1g of dithiothreitol, stirring for dissolution, 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 6h; adding the dissolved solution into an ultrafiltration device for ultrafiltration purification, and finally, freeze-drying the purified sample in a freeze dryer to obtain white flocculent solid, namely the side chain sulfhydrylation polymer, as shown in figure 1;
(3) Preparation of disulfide bond-containing polymers:
weighing 500mg of the side chain sulfhydrylated polymer, placing the side chain sulfhydrylated polymer into a 25mL three-neck flask, adding 5mL of DMSO to dissolve under the condition of introducing nitrogen, sequentially weighing 5g of dithiodipyridine and 0.011g of 2-mercaptopyridine, adding the dithiodipyridine into the reaction to enable the dosage of the dithiodipyridine to be 2 times of the molar quantity of-SH and enable the dosage of the 2-mercaptopyridine to be 0.1 time of the molar quantity of the dithiodipyridine, placing the solution after the reaction is completely reacted into an ultrafiltration device for ultrafiltration purification after the reaction is carried out for 72 hours under the condition of introducing nitrogen, and finally, placing the purified sample into a freeze dryer for freeze drying to obtain white flocculent solid polymer containing disulfide bonds, namely the polymer containing disulfide bonds, and referring to figure 3;
(4) Preparation of a prodrug with dextran as a backbone and a diethyldithiocarbamate supported:
weighing 500mg of polymer containing disulfide bonds and a 10mL reaction bottle, adding 2mL of LDMSO, 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 the molar quantity of-Py, adding 0.5mLDMSO, oscillating and dissolving by using a vortex oscillator, and then dropwise adding into a reaction bottle to react for 72h; and after the reaction is finished, placing the solution into an ultrafiltration device for ultrafiltration purification, and finally, placing the purified sample into a freeze dryer for freeze drying to obtain the dextran nano-drug precursor based on disulfiram, see figure 3.
Experimental test analysis:
the intermediate material prepared in this example and the target disulfiram-based dextran nano-drug precursor were used as test samples for experimental verification.
In the preparation method of the disulfiram-based glucan nanometer precursor with redox response characteristics, glucan is selected as a framework, and the drug is connected with a polymer framework through disulfide bonds. The present invention provides a polymeric drug delivery system with a redox response. The nano-prodrug can be reduced into sulfhydryl by reduced glutathione in cancer cells, has a response mechanism, and causes the structure of the carrier to be changed so as to lead the drug to be quickly released. The nano-drug precursor has good biological safety and better effect of killing cancer cells, and provides an intelligent drug delivery system for treating tumors.
The embodiments of the present invention have been described above with reference to the accompanying drawings, but the present invention is not limited to the embodiments described above, and various changes, modifications, substitutions, combinations or simplifications can be made according to the purposes of the present invention, which are the spirit and principles of the technical solution of the present invention, and the present invention is not departing from the technical principles and the inventive concept of the present invention, as long as the present invention is satisfied by the equivalent substitution.
Claims (6)
1. A preparation method of a dextran nanometer prodrug based on disulfiram uses dextran as a framework, carries out sulfhydryl modification on a side chain of the dextran, and prepares a disulfide bond connected dextran-DDTC coupling body through exchange reaction; the method is characterized by comprising the following steps of:
(1) Reacting glucan with phenyl nitrochloroformate to obtain side chain hydroxylation glucan; the method for obtaining the side chain hydroxylation glucan comprises the following steps:
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, precipitating a precipitate, and drying to obtain side chain hydroxylation glucan;
(2) Reacting the side chain hydroxylated glucan obtained in the step (1) with mercaptoethylamine to obtain mercaptoglucan; the method for obtaining the sulfhydryl glucan comprises the following steps:
the method comprises the steps of (1) 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 to separate out a precipitate, mixing the precipitate, deionized water, dithiothreitol and hydrochloric acid, stirring for 1-6h, and purifying and drying to obtain mercaptoglucan;
(3) Reacting the mercaptodextran obtained in step (2) with 2,2' -dithiodipyridine to obtain a polymer containing disulfide bonds; the method for obtaining the polymer containing disulfide bonds comprises the following steps:
mixing mercaptodextran, dimethyl sulfoxide and 2,2' -dithiodipyridine, reacting for not more than 3 days under the protection of inert gas, and purifying and drying to obtain a polymer containing disulfide bonds;
(4) Reacting the disulfide bond-containing polymer obtained in the step (3) with diethyl dithiocarbamate to obtain a prodrug which takes glucan as a framework and carries diethyl dithiocarbamate;
the method for obtaining the diethyl dithiocarbamate-loaded prodrug comprises the following steps:
mixing a polymer containing disulfide bonds, dimethyl sulfoxide and diethyl dithiocarbamate, and under the protection of inert gas, carrying out purification and drying for a reaction time of not more than 3 days to obtain a prodrug taking glucan as a framework and carrying diethyl dithiocarbamate; the diethyl dithiocarbamate is DDTC;
the resulting disulfiram-based dextran nano-drug precursor self-assembles to form nanoparticles.
2. The method for preparing a disulfiram-based glucan nano-drug precursor according to claim 1, wherein in the step (1), the dosage of glucan is 0.5-5 g, and the dosage of phenyl nitrochloroformate is 0.2-1.5 mg;
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 the step (3), the amount of the mercaptodextran is 20-500 mg, and the amount of the dithiodipyridine is 0.05-5 g;
in the step (4), the amount of the disulfide bond-containing polymer is 20 to 500mg, and the amount of the diethyldithiocarbamate is 0.005 to 0.2g.
3. In step (1), a reaction is performed to react phenyl nitrochloroformate with at least one hydroxyl group in dextran.
4. A disulfiram-based dextran nano-drug prodrug characterized by: a preparation method of a dextran nanometer prodrug based on disulfiram according to any one of claims 1-3.
5. Use of a disulfiram-based dextran nano-drug precursor according to claim 4, characterized in that: the dextran nanometer drug precursor based on disulfiram is used as a cancer drug carrier for the assembly preparation of nanometer drug particles with intelligent response type for treating tumors.
6. Use of a disulfiram-based dextran nano-drug precursor according to claim 5, characterized in that: the cancer drug is delivered and released into the blood at a dose where the concentration of disulfiram in the blood is no greater than 2 μm.
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