CN113679845A - Preparation method and application of polycarbonate drug-loaded nano-chemotherapy sensitizer based on nitric oxide - Google Patents
Preparation method and application of polycarbonate drug-loaded nano-chemotherapy sensitizer based on nitric oxide Download PDFInfo
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- CN113679845A CN113679845A CN202111000068.6A CN202111000068A CN113679845A CN 113679845 A CN113679845 A CN 113679845A CN 202111000068 A CN202111000068 A CN 202111000068A CN 113679845 A CN113679845 A CN 113679845A
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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Abstract
The invention discloses a preparation method and application of a polycarbonate drug-loaded nano-chemotherapy sensitizer based on nitric oxide. The sensitizer is formed by self-assembling polycarbonate block copolymer containing nitric oxide donor and micromolecular chemotherapeutic drugs. The sustained-release preparation has the advantages of good water solubility, small toxic and side effects, good stability in normal physiological environment and the like, and effectively solves the problems of poor water solubility, large toxic and side effects and the like of insoluble chemotherapeutic drugs such as adriamycin, mitoxantrone and the like in clinical use. Also has the characteristics of strong drug-loading capacity, obvious tumor targeting property, and capability of regulating and controlling a tumor microenvironment, so as to achieve an ideal chemotherapy sensitization effect and reduce the recurrence of tumors.
Description
Technical Field
The invention relates to biomedical polymer materials, pharmaceutical preparations and a preparation method thereof, in particular to preparation and application of a polycarbonate drug-loaded nano-chemotherapy sensitizer based on nitric oxide.
Background
Chemotherapy is one of the most extensive methods for treating cancer in clinic, and the main principle is to kill tumor cells and inhibit tumor proliferation by using the cytotoxic effect of chemotherapeutic drugs. However, tumor cells reduce the toxicity of chemotherapeutic drugs to themselves through various mechanisms, such as high levels of glutathione in tumor cells, over-expressed ATP-binding transporters of tumor cells, including P-glycoprotein, breast cancer drug-resistant protein and multidrug resistance-associated protein, and the like, after the chemotherapeutic drugs enter the tumor cells, can be detoxified by intracellular glutathione, can improve the antitumor activity of chemotherapeutic drugs by changing the tumor microenvironment, one of the key difficulties is the presence of large amounts of reduced Glutathione (GSH) in tumor cells, which, as a major electron donor in the cell, can bind to many electrophilic drugs, thereby promoting the detoxification and discharge of the antitumor drug, ensuring that the chemotherapeutic drug entering the cells is difficult to reach the corresponding target point to play the role, therefore, decreasing glutathione concentrations in tumor cells may increase the killing effect of chemotherapeutic drugs on tumor cells.
Nitric oxide is an endogenous signal molecule of the human body and is involved in the regulation of various physiological processes. However, the nitric oxide generated in vivo is limited, and is often difficult to meet the requirement of the body for coping with pathological changes, while exogenous nitric oxide is a very important supply measure, but most of the nitric oxide donor small molecule drugs have high water solubility, and large burst release of the drugs occurs at the initial release stage, so that the long-acting slow release is not facilitated, and particularly, the excessive concentration of nitric oxide as a vasodilator can cause the complete collapse of the human circulation. In the aspect of tumor treatment, low-concentration nitric oxide can induce angiogenesis to promote tumor growth, high-concentration nitric oxide can inhibit proliferation and metastasis of tumor cells, nitric oxide can react with endogenous free radicals to generate active substances such as active oxygen and active nitrogen, and the active substances can be used as a powerful oxidant and a nitrating agent to denature proteins, damage cell membranes, damage DNA and the like through oxidation and nitration reactions.
At present, most of chemotherapy drug matrixes are of multi-aromatic ring structures, and have the problems of poor water solubility, rapid blood clearance, poor drug targeting, large toxic and side effects on healthy tissues and the like, so that the application of the small-molecule chemotherapy drugs is limited. For example, the anthracenedione-type drug mitoxantrone is easily eliminated by intracellular high-concentration glutathione after entering tumor cells, and the chemotherapy effect is reduced, so in order to effectively improve the anti-tumor efficiency of chemotherapy and furthest enhance tumor elimination, a preparation which can simultaneously consume GSH in tumors and release nitric oxide to enhance oxidative stress and jointly enhance the treatment effect on the tumors through the synergistic effect of chemotherapeutic drugs is developed, and the chemotherapy sensitization system which can achieve good treatment effect through multiple sensitization modes is very attractive. However, to date, there are few reports on whether nanomaterials can be used cooperatively by an external sensitization mode and an internal sensitization mode to achieve the effect of improving chemotherapy simultaneously, and thus, the research on the aspects is of great significance.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a preparation method of a polycarbonate drug-loaded nano-chemotherapy sensitizer based on nitric oxide.
The invention also aims to provide application of the nitric oxide-based polycarbonate drug-loaded nano-chemosensitizer.
The technical scheme is as follows: the preparation method of the nitric oxide-based polycarbonate drug-loaded nano-chemotherapy sensitizer comprises the following steps: firstly, polyethylene glycol and a nitrate cyclic carbonate monomer are subjected to ring-opening polymerization to obtain a segmented copolymer, and then self-assembly is carried out to obtain the drug-loaded nanoparticles. The nitric oxide can be used as a sensitizer of a chemotherapeutic drug, namely, the tumor microenvironment is improved by reducing the content of intracellular glutathione and relatively activating oxidative stress, and the nitric oxide is matched with the chemotherapeutic drug to improve the killing capability of the drug to the tumor and improve the treatment effect of the chemotherapy.
The structural general formula of the polycarbonate block copolymer containing the nitric oxide donor is shown as follows:
further, the molecular weight of the polyethylene glycol is selected from 1000-. The molecular weight and size ratio of the polyethylene glycol to the polycarbonate is 1: 0.5-1.
Further, the preparation method of the nitric oxide-based polycarbonate drug-loaded nano-chemotherapy sensitizer comprises the following steps:
(1) synthesis of mPEG-PNTC: under the protection of inert gas, dissolving a cyclic carbonate monomer NTC in an organic solvent, then adding an initiator, and preparing a polycarbonate copolymer mPEG-PNTC through ring-opening polymerization;
(2) preparing medicine-carrying nano particles: firstly, the copolymer and the chemotherapeutic drug are dissolved in DMF solvent, and dialyzed in deionized water or PB buffer solution dialysis medium to obtain the polycarbonate drug-loaded nano particles.
Further, nitric oxide donor nitrate groups in the polymer micelle react with glutathione in cancer cell cells, consuming glutathione and releasing nitric oxide.
Further, the release process of nitric oxide breaks the redox balance in the tumor cells, reduces the content of glutathione, and activates oxidative stress in the tumor cells.
Further, the nitric oxide donor-based chemosensitizer nanoparticles can responsively release nitric oxide gas molecules under the stimulation of a tumor microenvironment, so as to change the tumor cell microenvironment. Nitric oxide released by the polycarbonate drug-loaded nanoparticles acts with endogenous active oxygen and is converted into active oxygen and active nitrogen substances with more oxidability, so that the oxidative stress state of tumor cells is activated, partial glutathione is consumed, and the tumor microenvironment is improved. And the derivative is used as a sensitizer of a chemotherapeutic drug, and the related sensitizing effect is to eliminate glutathione and nitric oxide in tumor cells to generate active oxygen active nitrogen substances with more oxidability, amplify the oxidative stress of the tumor cells and the like.
Further, the small molecule chemotherapeutic drug comprises: anthracyclines/anthracenediones and platinum drugs.
Further, anthracyclines/anthracenediones include doxorubicin, mitoxantrone, epirubicin; platinum drugs include cisplatin, carboplatin, or a mixture of both.
Further, the functional polycarbonate block copolymer is useful as a nitric oxide donor and as a drug carrier.
The preparation method of the polycarbonate drug-loaded nanoparticle containing the nitric oxide donor comprises the following steps:
(1) synthesis of mPEG-PNTC
Under the protection of inert gas, dissolving a cyclic carbonate monomer NTC in an organic solvent, then adding an initiator, and preparing the functional polycarbonate copolymer mPEG-PNTC through ring-opening polymerization reaction.
(2) Preparation of drug-loaded nanoparticles
The preparation method adopts a solvent dialysis displacement method, and preferably comprises the following specific steps: firstly, dissolving a polymer and a chemotherapeutic drug in a DMF solvent, then dripping the solution into deionized water under an ultrasonic condition, then filling the solution into a dialysis bag, dialyzing the solution in a deionized water or PB buffer solution dialysis medium, and periodically replacing the dialysis medium during dialysis, thereby finally obtaining the polycarbonate drug-loaded nanoparticles.
Further, the chemotherapeutic drugs include, but are not limited to: anthracyclines/anthracenediones, such as doxorubicin, mitoxantrone, epirubicin, and the like; platinum drugs, such as one or more of cisplatin, carboplatin, and the like.
The invention relates to an application of a polycarbonate drug-loaded nano-chemotherapy sensitizer based on nitric oxide in preparing a drug for treating tumor.
The functional polycarbonate drug-loaded nanoparticles have strong drug-loading capacity, organically integrate unique auxiliary antitumor activity of nitric oxide and good biological compatibility of polyethylene glycol, can overcome the problems of the absorption of insoluble drugs and short half-life of nitric oxide in vivo, can realize the purpose of cooperatively treating tumors by nitric oxide and chemotherapeutic drugs, realizes the comprehensive treatment of cancers, and is a great innovation in the drugs for treating cancers.
The functional polycarbonate drug-loaded nanoparticles have obvious tumor targeting property. Can realize passive targeting through EPR effect of detaining, utilize the reduction responsiveness of carbonate bond to realize the responsive drug release in the tumor cell, this design effectively improves the accumulation of chemotherapy medicine in tumor position, reduces chemotherapy medicine toxic and side effect.
The functional polycarbonate drug-loaded nanoparticles have the characteristic of regulating and controlling the tumor microenvironment. The nitrate group of the novel nitric oxide donor type compound can consume GSH in tumor cells, reduce the detoxification of the GSH to chemotherapeutic drugs, and enable more chemotherapeutic drugs to enter cell nuclei to play a role; meanwhile, the released nitric oxide enhances the oxidative stress of tumor cells, thereby generating damage to DNA double chains, proteins, lipids and the like of the cells, and achieving the effect of enhancing the chemotherapy treatment in the process of combining with chemotherapy medicaments.
Has the advantages that: compared with the prior art, the invention has the following advantages:
the functional polycarbonate drug-loaded nanoparticles have the advantages of good water solubility, small toxic and side effects, good stability in normal physiological environment and the like, and effectively solve the problems of poor water solubility, large toxic and side effects and the like of insoluble chemotherapeutic drugs such as adriamycin, mitoxantrone and the like in clinical use. Also has the characteristics of strong drug-loading capability, obvious tumor targeting property and capability of regulating and controlling a tumor microenvironment.
Drawings
FIG. 1 is a nuclear magnetic spectrum of the polymer PEG-PNTC of example 1;
FIG. 2 is a graph of the particle size of the drug-loaded micelle in example 2;
FIG. 3 shows the result of nitric oxide release of the polymer micelle of example 5 under GSH (10mM, pH 7.4);
FIG. 4 shows the release of mitoxantrone from the drug-loaded micelles of example 6 under GSH (10mM, pH 7.4);
FIG. 5 is a graph showing the results of intracellular glutathione content in example 9;
FIG. 6 is a graph showing the results of the cell viability assay in example 10.
Detailed Description
Example 1 Synthesis of Polymer mPEG-PNTC
Specifically, 0.1g of NTC monomer and 0.3g of mPEG are weighed in a glove box and put in a closed reactor, dichloromethane is added for dissolution, then 3 drops of bis (bis-trimethylsilyl) amine zinc catalyst are added, then the reactor is sealed, the mixture is transferred out of the glove box, oil bath is carried out for reaction at 30-50 ℃ for 48 hours, then glacial acetic acid is used for stopping the reaction, the mixture is precipitated in glacial ethyl ether, and finally the product is obtained through filtration and vacuum drying. The nuclear magnetic results show that the molecular weight is 5000-. The nuclear magnetic characterization is shown in figure 1.
Example 2 preparation of mitoxantrone-loaded nitric oxide donor-type chemotherapeutic sensitizers
0.1mL of the polymer mPEG-PNTC in DMF (10mg/mL) and 10. mu.L of mitoxantrone in DMF (20mg/mL) were mixed well, then the mixed solution was slowly added dropwise to phosphate buffer under sonication for 10min, followed by dialysis to remove the organic solvent and uncoated mitoxantrone. The mitoxantrone-encapsulated micelles were measured by a microplate reader. The Drug Loading (DLC) and encapsulation efficiency (DLE) were calculated by the following formulas:
drug loading (%) × 100% (mass of drug loaded/total mass of polymer and drug)
Encapsulation efficiency (%) - (loaded drug mass/total drug input) × 100%
When the theoretical drug loading of the mPEG-PNTC polymeric micelles to the mitoxantrone is 5%, 10%, 15% and 20%, the actual encapsulation rate is shown in Table 1.
TABLE 1 characterization of mitoxantrone-encapsulating polymeric micelles
The size of the sample was measured by a dynamic light scattering analyzer and the experimental results are shown in figure 2.
Example 3 preparation of Adriamycin-loaded micelles by dialysis
0.1mL of the polymer mPEG-PNTC in DMF (10mg/mL) and 10. mu.L of doxorubicin in DMF (20mg/mL) were mixed well, then the mixed solution was slowly added dropwise to phosphate buffer under sonication for 10min, followed by dialysis to remove the organic solvent and the uncoated doxorubicin. Doxorubicin-encapsulated micelles were measured by a microplate reader. The Drug Loading (DLC) and encapsulation efficiency (DLE) were calculated by the following formulas:
drug loading (%) × 100% (mass of drug loaded/total mass of polymer and drug)
Encapsulation efficiency (%) - (loaded drug mass/total drug input) × 100%
The size of the sample was measured by a dynamic light scattering analyzer.
Example 4 preparation of cisplatin-loaded micelles by dialysis
0.1mL of the polymer mPEG-PNTC in DMF (10mg/mL) and 10. mu.L of cisplatin in DMF (20mg/mL) were mixed well, then the mixed solution was slowly added dropwise to phosphate buffer under sonication for 10min, followed by dialysis to remove the organic solvent and uncoated cisplatin. Cisplatin-encapsulating micelles were measured by ICP. The size of the sample was measured by a dynamic light scattering analyzer.
Example 5 polymeric micelle in vitro NO Release assay
The amount of NO released was measured using Griss reagent. The in vitro release experiment of NO was performed at 37 ℃, taking two different media: (1) phosphate buffer, pH 7.4; (2) the phosphate buffer contained 10mM GSH. The prepared micelles (each NO: 100 μ M) were transferred to dialysis bags, placed in the corresponding buffer, then placed in a 37 ℃ constant temperature shaker, and at the indicated time point, the release medium was taken from the release system and supplemented with the same volume of medium, and the release medium taken out was mixed with Griss reagent and measured with a microplate reader under UV-540 nm. The release experiment was repeated three times. The experimental results are shown in figure 3.
Example 6 in vitro mitoxantrone Release assay with drug-loaded Polymer micelles
The in vitro release experiment of mitoxantrone was carried out at 37 ℃ in two different media: (1) phosphate buffer, pH 7.4; (2) the phosphate buffer contained 10mM GSH. And transferring the prepared drug-loaded micelle into a dialysis bag, placing the dialysis bag into a corresponding buffer solution, then placing the buffer solution into a constant-temperature shaking table at 37 ℃, taking a release medium from a release system at a specified time point, supplementing the medium with the same volume, freeze-drying and concentrating the release medium, and measuring the content of the mitoxantrone by using an enzyme labeling instrument. The experimental results are shown in figure 4.
Example 7 drug-loaded polymeric micelles in vitro doxorubicin release assay
The doxorubicin in vitro release assay was performed at 37 ℃ in two different media: (1) phosphate buffer, pH 7.4; (2) the phosphate buffer contained 10mM GSH. And transferring the prepared drug-loaded micelle into a dialysis bag, placing the dialysis bag into a corresponding buffer solution, then placing the dialysis bag into a constant-temperature shaking table at 37 ℃, taking a release medium from a release system at a specified time point, supplementing the medium with the same volume, freeze-drying and concentrating the release medium, and measuring the content of the adriamycin by using an enzyme labeling instrument.
Example 8 in vitro cisplatin Release test with drug-loaded Polymer micelles
The in vitro cisplatin release experiment was performed at 37 ℃ taking two different media: (1) phosphate buffer, pH 7.4; (2) the phosphate buffer contained 10mM GSH. And transferring the prepared drug-loaded micelle into a dialysis bag, placing the dialysis bag into a corresponding buffer solution, then placing the dialysis bag into a constant-temperature shaking table at 37 ℃, taking a release medium from a release system at a specified time point, supplementing the medium with the same volume, then freeze-drying and concentrating, and measuring the content of cisplatin by using ICP (inductively coupled plasma).
Example 9 measurement of intracellular glutathione content
Grouping experiments: blank control group, mitoxantrone group, mPEG-PNTC (1mg/mL) group, mPEG-PNTC @ mitoxantrone (1mg/mL, 1. mu.g/mL) group, and mPEG-PTMC @ mitoxantrone (1mg/mL, 1. mu.g/mL) group.
Inoculating the PC-3 cells into a 6-well plate, wherein the inoculation density is 1 plate and 105 plates, culturing for 24 hours, changing a fresh culture medium, adding medicaments into each group, acting for 48 hours, collecting the cells, precipitating the proteins by using a protein precipitation reagent, and detecting the GSH content of the cells of each group by using DTNB. The experimental results are shown in figure 5.
Example 10 determination of cell viability
Cell culture and grouping:
cell culture: human prostate cancer cells (PC-3) were cultured in F12K medium containing 10% fetal calf serum (containing 10% fetal calf serum, 100IU/mL penicillin and 100IU/mL streptomycin) at 37 ℃ under 5% CO2 conditions, and the medium was changed every 1-2 days depending on the cell growth.
Grouping experiments: the detection was carried out 48 hours after the intervention in the mPEG-PNTC (1mg/mL), mitoxantrone (1 group, m mL) and mPEG-PNTC @ mitoxantrone (1mg/mL, 1Lg/mL) groups. First, 100, detection is performed. The F12K suspension of the first cell is paved in a 96-well culture plate and is cultured for 12 hours under the conditions of 37 ℃ and 5% carbon dioxide, so that the coverage rate of the monolayer cell reaches 70% -80%. Then 10 μ L of different sets of drug solutions were added to each well. After 48h of co-incubation, 10. mu.L of 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyltetrazolium bromide (MTT) in PBS (5mg/mL) was added to each well and placed in an incubator for further 4h to allow the MTT to react with living cells. The MTT-containing medium was then removed, 150 μ L DMSO was added to each well to dissolve living cells and MTT-generated purple formazan crystals, and the absorbance at 490nm was measured for each absorption well using a plate reader, with experimental data performed in parallel in three sets. Cell viability was calculated for each experimental group as follows.
Cell viability (%) - (OD490 sample/OD 490 control). times.100%
The experimental results are shown in figure 6.
As can be seen from the results in FIG. 6, the use of mPEG-PNTC alone did not have much effect on the cell viability of PC-3. Meanwhile, compared with the single mitoxantrone, the combination of NO and mitoxantrone has a larger influence on the cell viability of PC-3.
From the above experimental results, it can be seen that nitric oxide can cooperate with mitoxantrone to increase mitoxantrone cytotoxicity.
Claims (10)
1. A preparation method of a polycarbonate drug-loaded nano-chemotherapy sensitizer based on nitric oxide is characterized by comprising the following steps: the nitric oxide self-assembly type molecular weight-change material is formed by self-assembling a polycarbonate block copolymer containing a nitric oxide donor and a small molecular weight chemotherapeutic drug.
2. The preparation method of the nitric oxide-based polycarbonate drug-loaded nano-chemosensitizer according to claim 1, wherein the preparation method comprises the following steps: firstly, polyethylene glycol and a nitrate cyclic carbonate monomer are subjected to ring-opening polymerization to obtain a segmented copolymer, and then self-assembly is carried out to obtain the drug-loaded nanoparticles.
3. The preparation method of the nitric oxide-based polycarbonate drug-loaded nano-chemosensitizer according to claim 2, wherein the preparation method comprises the following steps: the molecular weight of the polyethylene glycol is selected from 1000-; the molecular weight and size ratio of the polyethylene glycol to the polycarbonate is 1: 0.5-1.
4. The preparation method of the nitric oxide-based polycarbonate drug-loaded nano-chemosensitizer according to claim 1, wherein the preparation method comprises the following steps:
(1) synthesis of mPEG-PNTC: under the protection of inert gas, dissolving a cyclic carbonate monomer NTC in an organic solvent, then adding an initiator, and preparing a polycarbonate copolymer mPEG-PNTC through ring-opening polymerization;
(2) preparing medicine-carrying nano particles: firstly, the copolymer and the chemotherapeutic drug are dissolved in DMF solvent, and dialyzed in deionized water or PB buffer solution dialysis medium to obtain the polycarbonate drug-loaded nano particles.
5. The preparation method of the nitric oxide-based polycarbonate drug-loaded nano-chemosensitizer according to claim 1, wherein the preparation method comprises the following steps: nitric oxide donor nitrate groups in the polymer micelle react with glutathione in cancer cell cells to release nitric oxide.
6. The preparation method of the nitric oxide-based polycarbonate drug-loaded nano-chemosensitizer according to claim 1, wherein the preparation method comprises the following steps: the release process of the nitric oxide breaks the redox balance in the tumor cells, reduces the content of glutathione, relieves the detoxification effect of the tumor cells on the medicine, and activates the oxidative stress in the tumor cells.
7. The preparation method of the nitric oxide-based polycarbonate drug-loaded nano-chemosensitizer according to claim 1, wherein the preparation method comprises the following steps: the chemotherapy sensitizer nano-particles based on the nitric oxide donor can responsively release nitric oxide gas molecules under the stimulation of a tumor microenvironment to change the tumor cell microenvironment.
8. The preparation method of the nitric oxide-based polycarbonate drug-loaded nano-chemosensitizer according to claim 1, wherein the preparation method comprises the following steps: the small molecule chemotherapeutic drug comprises: anthracyclines/anthracenediones and platinum drugs.
9. The preparation method of the nitric oxide-based polycarbonate drug-loaded nano-chemosensitizer according to claim 8, wherein the preparation method comprises the following steps: anthracyclines/anthracenediones include doxorubicin, mitoxantrone, epirubicin; platinum drugs include cisplatin, carboplatin, or a mixture of both.
10. Use of the nitric oxide based polycarbonate drug loaded nano-chemosensitiser prepared according to any one of claims 1 to 9 for the preparation of a medicament for the treatment of tumours.
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