Glycine-copper coordination polymer as well as preparation method and application thereof

Abstract

The preparation method comprises the following steps: dissolving hyaluronic acid in water, then adding a sodium hydroxide solution and a copper chloride solution, uniformly stirring, and then adding a sodium oxamate solution to react, thereby generating the oxamate-copper coordination polymer. Compared with the prior art, the oxamic acid-copper coordination polymer prepared by the invention can consume glutathione which is highly expressed in a tumor microenvironment and dissociate and release copper ions and oxamic acid under triggering, so that copper ion mediated copper death is remarkably sensitized, and a remarkable anti-tumor effect and safety are shown.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of nanomaterials, and particularly to a oxamic acid-copper coordination polymer, a preparation method and application thereof. BACKGROUND

[0002] Lung cancer is one of the highest incidence and mortality rates of malignant tumors worldwide, seriously threatening human health. Its incidence and mortality rates are the highest among all cancers. Although surgical treatment, chemotherapy, radiotherapy and targeted therapy are widely used in clinical practice, the effect of these methods is poor for patients with advanced lung cancer and metastasis, and there are significant side effects, such as nausea, vomiting, hair loss, bone marrow suppression, skin reactions and pneumonia.

[0003] In addition, treatment options and effects depend largely on the type of lung cancer, stage, overall health of the patient and the presence of specific genetic mutations. Cell death is an important phenomenon in life activities, and its research has always been a hot spot in the field of life sciences. There are various ways of cell death, including apoptosis, pyroptosis, necrosis, ferroptosis and cuproptosis.

[0004] In recent years, cuproptosis, as a new type of programmed cell death, has attracted much attention due to its unique mechanism. Cuproptosis occurs through the direct combination of copper ions with lipoylated components in the tricarboxylic acid cycle (TCA), leading to the aggregation of lipoylated proteins and the loss of iron-sulfur cluster proteins, which in turn triggers protein toxic stress and ultimately leads to cell death. This unique mechanism of death provides a new approach to tumor treatment, especially considering the significant differences in energy metabolism between tumor cells and normal cells. The mechanism of cuproptosis has not been fully elucidated, and there are limitations such as lack of selectivity, potential toxicity to normal cells and limited biocompatibility. In addition, the application of cuproptosis in tumor treatment still faces challenges, and there is little research on its sensitization therapy. SUMMARY

[0005] The purpose of the present application is to develop a highly efficient cuproptosis sensitization material to further improve the effectiveness of cuproptosis in tumor treatment, thereby providing a oxamic acid-copper coordination polymer, a preparation method and application thereof.

[0006] The purpose of the present application can be achieved by the following technical solutions:

[0007] In the tumor microenvironment (TME), glutathione (GSH) is a key antioxidant and detoxifying agent that maintains redox balance, which is crucial for the rapid proliferation of tumor cells and escape from immune surveillance.

[0008] The oxalate-copper coordination polymer provided by the application is a copper ion-mediated copper death for GSH overexpression in TME, that is, it is responsive to GSH overexpression in TME, can dissociate and release oxalate and copper ions, and significantly sensitizes copper ion-mediated copper death.

[0009] One of the technical solutions of the application is to provide an oxalate-copper coordination polymer (named Cu-Ox), which is a nanoscale crystal obtained by simultaneously forming a coordination bond between N and O atoms on the oxalate ligand and copper ions.

[0010] The crystal structure is cooperatively constrained by the rigidity of the oxalate ligand and the metal coordination geometry of the copper ions.

[0011] The second technical solution of the application is to provide a preparation method of the oxalate-copper coordination polymer according to the above-mentioned one of the technical solutions, comprising the following steps:

[0012] Dissolve hyaluronic acid (HA) in water, then add sodium hydroxide solution and copper chloride solution and stir uniformly, and then add sodium oxalate solution for reaction, thereby generating oxalate-copper coordination polymer.

[0013] In some specific embodiments, the ratio of hyaluronic acid, water, sodium hydroxide solution, copper chloride solution, and sodium oxalate solution is 1 mg: 10 mL: 0.2 mL: 1 mL: 1 mL, wherein the concentration of sodium hydroxide solution, copper chloride solution, and sodium oxalate solution is 0.1 M.

[0014] In some specific embodiments, the reaction temperature is 80°C, and the reaction time is 3h.

[0015] The third technical solution of the application is to provide an application of the oxalate-copper coordination polymer according to the above-mentioned one of the technical solutions in the preparation of a copper death sensitization preparation.

[0016] The fourth technical solution of the application is to provide an application of the oxalate-copper coordination polymer according to the above-mentioned one of the technical solutions in the preparation of an antitumor drug and / or kit.

[0017] In some specific embodiments, the drug and / or kit is a drug and / or kit for improving the sensitivity of tumor cells to copper death.

[0018] In some specific embodiments, the drug and / or kit is a drug and / or kit for targeted consumption of glutathione.

[0019] In some specific embodiments, the drug and / or kit further comprises a dispersion component.

[0020] In some embodiments, the dispersion component is selected from any one of water, a phosphate solution.

[0021] Oxamic acid plays an important role in organisms, as it is a precursor for the synthesis of glutathione (GSH), an important antioxidant that helps maintain cell health. In addition, oxamic acid is also involved in protein synthesis and the maintenance of nitrogen balance. Copper ions have multiple important physiological functions in the human body, and appropriate intake of copper ions is essential for maintaining human health.

[0022] The present application takes oxamic acid and copper ions as the research object, successfully prepares an oxamic acid-copper coordination polymer (Cu-Ox), and applies it as a sensitized copper death sensitization preparation for GSH overexpression in the tumor microenvironment, and applies it to the research of the strategy of sensitized copper death.

[0023] The principle that the Cu-Ox provided by the present application can improve the sensitivity of tumor cells to ferroptosis is as follows:

[0024] When Cu-Ox enters the tumor, it can consume the overexpressed endogenous GSH in the tumor microenvironment, and release copper ions and oxamic acid. With the depletion of GSH, copper ions can more effectively bind to lipidated mitochondrial enzymes, causing abnormal aggregation of lipidated DLAT (a key component of pyruvate dehydrogenase complex), and further disrupting the tricarboxylic acid cycle metabolism, triggering cellular protein toxicity stress, and ultimately leading to Cu-Ox-mediated copper death. At the same time, the released oxamic acid further weakens the energy metabolism by inhibiting LDHA (lactate dehydrogenase A), thereby enhancing the effect of copper death and improving the sensitivity of tumor cells to copper death. LDHA is an enzyme highly expressed in tumor cells, and inhibiting the expression of LDHA can further weaken the energy metabolism of tumor cells, thereby significantly improving the sensitivity of tumor cells to copper death.

[0025] Compared with the prior art, the present application has the following beneficial effects:

[0026] (1) Precise targeting and specific response: The present application uses oxamic acid-copper coordination polymer (Cu-Ox) as a copper death sensitization preparation, which can be triggered by the high expression of glutathione (GSH) in the tumor microenvironment to release copper ions and oxamic acid. This feature realizes precise targeting of the tumor microenvironment, significantly reducing the potential impact on normal tissues, thereby realizing specific response to the tumor microenvironment. This precise targeting mechanism not only improves the safety of treatment, but also provides a more precise intervention means for tumor treatment.

[0027] (2) significantly enhance the copper death effect: the present application uses oxammonium-copper coordination polymer (Cu-Ox) as a copper death sensitization preparation. The released oxamic acid can effectively inhibit the glycolysis process of tumor cells, and then significantly enhance the copper death mediated by copper ions. Compared with traditional copper death nanomaterials, Cu-Ox exhibits more significant copper death sensitization effect, significantly enhances the treatment effect of copper death, and improves the anti-tumor activity. This innovative mechanism provides a more efficient and specific solution for copper death treatment strategy, and is expected to become an important breakthrough in the field of tumor treatment. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 Characterization of oxammonium-copper coordination polymer (Cu-Ox) prepared in Example 1.

[0029] Figure 2 Oxammonium-copper coordination polymer prepared in Example 1 for glutathione consumption ability.

[0030] Figure 3 Oxammonium-copper coordination polymer (Cu-Ox) prepared in Example 1 showed obvious drug burst mode in PBS buffer solution at pH 6.0. a figure is the cumulative release curve of copper ions under different conditions. b figure is the cumulative release curve of oxamic acid under different conditions.

[0031] Figure 4 Oxammonium-copper coordination polymer (Cu-Ox) prepared in Example 1 for in vitro killing of different tumor cells.

[0032] Figure 5 Oxammonium-copper coordination polymer (Cu-Ox) prepared in Example 1 for in vitro copper death inhibitor experiment.

[0033] Figure 6 Oxammonium-copper coordination polymer (Cu-Ox) prepared in Example 1 for cell death mechanism research.

[0034] Figure 7 Oxammonium-copper coordination polymer (Cu-Ox) prepared in Example 1 for evaluating the anti-tumor effect in A549 mouse model. DETAILED DESCRIPTION

[0035] The present application will be described in detail below in conjunction with the drawings and specific examples. The present embodiment is implemented on the premise of the technical solution of the present application, and gives detailed implementation and specific operation process, but the protection scope of the present application is not limited to the following examples.

[0036] In the following examples and comparative examples, the raw materials or processing techniques, unless otherwise specified, are all conventional commercially available raw material products or conventional processing techniques in the art.

[0037] Example 1

[0038] The present example provides an oxalate-copper coordination polymer (Cu-Ox) and a preparation method thereof, comprising the following steps:

[0039] First, 1 mg of hyaluronic acid (HA) was dissolved in 10 mL of water, 0.2 mL of 0.1 M NaOH aqueous solution was added, 1 mL of 0.1 M CuCl2 aqueous solution was added and stirred for 10 minutes, 1 mL of 0.1 M sodium oxalate aqueous solution was added and stirred for 5 minutes, and then reacted at 80°C for 3 hours. After centrifugation and washing three times, the oxalate-copper coordination polymer Cu-Ox was collected.

[0040] As shown in Figs. Figure 1 (a) and (b) are SEM and TEM of Cu-Ox, respectively. As can be seen from the figures, the prepared oxalate-copper coordination polymer (Cu-Ox) is in the form of particles, with a particle size length of about 150 nm and a width of about 100 nm.

[0041] Figure 1 (c) is the normalized XANES spectrum of Cu K edge of Cu foil, Cu2O, CuPc, CuO and oxalate-copper coordination polymer (Cu-Ox), showing that the absorption edge position of Cu element is between CuPc (copper phthalocyanine) and CuO (copper oxide). The results show that Cu 2+ is successfully intercalated into the oxalate-copper coordination polymer, and the valence state is similar to CuPc and CuO, but in a unique chemical environment.

[0042] Figure 1 (d) is the Fourier transform spectrum of Cu K edge of Cu foil, Cu2O, CuPc, CuO and oxalate-copper coordination polymer (Cu-Ox). As shown in Fig. Figure 1 d, the FT-EXAFS curve is observed at about and respectively, which are characteristic peaks belonging to Cu-O and Cu-N scattering paths, confirming that Cu 2+ forms coordination bonds with oxygen atoms and nitrogen atoms. Further through R-Fit and K-Fit fitting analysis with CuO, CuPc standard samples, the coordination structure of Cu 2+ in Cu-Ox is verified.

[0043] Figure 1Fig. 1h is a wavelet transform (WT) pattern of Cu foil, CuPc, CuO and Cu-Ox, the Cu K-edge EXAFS oscillations were analyzed by wavelet transform (WT), by identifying the characteristic frequencies and intensities of the oscillations, the contributions of Cu-O and Cu-N bonds in Cu-Ox were revealed. The WT analysis results further confirmed the Cu 2+ coordination relationship with oxygen atoms and nitrogen atoms.

[0044] The above analysis shows that in the oxammonium-copper coordination polymer (Cu-Ox), Cu 2+ forms coordination bonds with N atoms and O atoms at the same time, and the total coordination number is 5, so it is proved that the target oxammonium-copper coordination polymer (Cu-Ox) is successfully prepared.

[0045] The prepared Cu-Ox was characterized as follows:

[0046] (1) In vitro study of the response of Cu-Ox to GSH: A solution of oxammonium-copper coordination polymer (Cu-Ox) with a concentration of 100 pg / mL was prepared using a phosphate buffer with a pH of 6.0, and the volume of the reaction system was 2 mL. Subsequently, 5 mM reduced glutathione (GSH) was added or not added to each reaction system, and samples were taken at different time points. The concentration of copper ions in the solution was determined by inductively coupled plasma optical emission spectrometry (ICP-OES), and the concentration of oxamic acid was analyzed by high performance liquid chromatography (HPLC).

[0047] As Figure 3 shown in Fig. 1h, Cu-Ox exhibited a significant drug burst mode in PBS buffer solution with a pH of 6.0. Fig. (a) is the cumulative release curve of copper ions under different conditions, and Fig. (b) is the cumulative release curve of oxamic acid under different conditions. In the presence of an acidic environment and GSH, the cumulative release rates of copper ions and oxamic acid were 73.4% and 85.4%, respectively, which proved that Cu-Ox exhibited good drug release characteristics in the presence of an acidic environment and GSH.

[0048] (2) In vitro evaluation of the consumption ability of Cu-Ox to glutathione (GSH): The detection was carried out by using 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) method. The principle is based on the reaction of GSH with DTNB to generate yellow product 5-thio-2-nitrobenzoic acid (TNB), which has a characteristic absorption peak at 412 nm.

[0049] The experimental method is as follows: after different concentrations (100 and 150 pg / mL) of Cu-Ox were incubated with 5 mM GSH, DTNB reagent was added, and the absorbance change at 412 nm was determined by ultraviolet-visible spectroscopy.

[0050] As shown in Figure 2 , with the increase of Cu-Ox concentration (100 pg / mL, 150 pg / mL), the absorption peak intensity at 412 nm decreased significantly, indicating that Cu-Ox can effectively consume GSH. This burst phenomenon may be related to the structural change of Cu-Ox in acidic environment, which may promote the dissociation of the internal structure of Cu-Ox, thereby accelerating the release of the drug.

[0051] (3) In vitro study of Cu-Ox on the killing power of different tumor cells:

[0052] To evaluate the in vitro cytotoxicity of Cu-Ox, A549 tumor cells insensitive to copper death and ABC1 tumor cells sensitive to copper death were selected for the experiment. Cells were seeded in 96-well plates at a density of 1 x 10 4 cells per well and cultured at 37°C, 5% CO2 for 12 hours to allow them to adhere fully. Then, 100 pg / mL of Cu-Ox, corresponding concentration of Cu 2+ (as a control), corresponding concentration of oxalate (as a control), corresponding concentration of CuCl2 combined with oxalate (as a control) were added to the cells, and in the Cu-Ox treatment group, GSH with a final concentration of 5 mM was added or not added, GSH was used to simulate the in vivo reducing environment; 5 replicates were set for each concentration. After incubation at 37°C, 5% CO2 for 12 hours and 24 hours, the culture medium was aspirated, 100 pL of basal medium and 10 pL of CCK-8 solution were added to each well, and incubation was continued for 30 minutes to allow CCK-8 to react with viable cells to determine the absorbance (OD 450 ) of each well to quantitatively evaluate cell viability.

[0053] As shown in Figure 4 , the control group (Control), CuCl2 group, oxalate group and Cu-Ox alone group (without GSH) did not show significant cytotoxicity in A549 and ABC1 cells. However, when Cu-Ox was used to treat cells in the presence of GSH, the mortality rates of A549 and ABC1 cells increased to 45% and 62.4%, respectively. The cell death rate induced by the combination of CuCl2 and oxalate was almost the same as that of the Cu-Ox + GSH group. This result confirms that the mixture composed of Cu 2+ and oxalate has the same biological activity as Cu 2+ and oxalate released after GSH response of the pre-synthesized Cu-Ox material.

[0054] As shown in Figure 4 a(A549, copper death insensitive cells) and Figure 4As shown in b (ABC1, copper-sensitive cells), Cu-Ox only significantly induced tumor cell death in the presence of GSH. Although the two cell types showed different sensitivities to copper death, Cu-Ox exhibited similar killing efficiencies in both A549 and ABC1 cells (mortality rates of 45% vs. 62.4%, respectively), indicating that Cu-Ox successfully sensitized copper-insensitive tumor cells by consuming GSH overexpressed in the tumor microenvironment.

[0055] (4) In vitro study of the cytotoxic effect of Cu-Ox on inhibiting copper cell death:

[0056] A549 cells were distributed at a rate of 1 × 10⁶ cells per well. 4 Cells were seeded at a density of 1000 cells per well in 96-well plates. All cells were incubated with 5 mM glutathione (GSH) for 24 hours before subsequent experimental procedures were performed.

[0057] For the analysis of copper death inhibitors, they were divided into the UK 5099+Cu-Ox group and the Cu-Ox group.

[0058] UK 5099+Cu-Ox group: pretreated with 100 nM copper death inhibitor UK 5099 (mitochondrial pyruvate carrier inhibitor) for 12 hours, followed by incubation with Cu-Ox material at concentration gradients for 24 hours. Cell viability was finally quantitatively detected by CCK-8 assay.

[0059] Cu-Ox group: Cells were incubated with Cu-Ox materials at different concentration gradients for 24 hours, and cell viability was finally quantitatively detected by the CCK-8 assay.

[0060] For copper ion chelation analysis, it was divided into the BCS+Cu-Ox group and the BCS group.

[0061] BCS+Cu-Ox group: A549 cells were pretreated with different concentrations of copper ion chelating agent—cuprous disulfonic acid (BCS)—for 12 hours, and then 100 μg / mL Cu-Ox was added. Cell viability was detected after 24 hours.

[0062] BCS group: A549 cells were treated with different concentrations of BCS, and cell viability was detected after 24 hours.

[0063] like Figure 5 As shown in (a), A549 cells pretreated with the copper death inhibitor UK 5099 in combination with Cu-Ox had a significantly higher survival rate than cells pretreated with Cu-Ox alone, with a survival rate of over 80%.

[0064] like Figure 5(b) As shown, the rescue rate of cells in the Cu-Ox treatment group combined with the copper chelator BCS was as high as 82.5% compared with the Cu-Ox group. The above all indicate that the cell death induced by Cu-Ox is closely related to copper death, and Cu-Ox can release copper ions and oxammonium in response to overexpressed GSH, induce copper death, and thus significantly enhance the killing effect on tumor cells.

[0065] (5) In vitro exploration of the reaction mechanism of Cu-Ox sensitized copper death by Western blotting

[0066] A549 cells (5 x 10 5 cells per well) were seeded in 6-well plates and set up in 5 groups: (1) Control; (2) ES-Cu (Elesclomol (STA-4783) is an effective copper ion carrier that can promote copper death, 100 μg / mL); (3) CuCl2(100 μg / mL); (4) oxammonium (100 μg / mL); (5) Cu-Ox (100 μg / mL) + GSH (5 mM). After adding the materials in each group, incubation was continued for 16 h, and after digestion, the cells were collected and lysed in lysis buffer. Subsequently, the cells were collected for standard Western blotting process (BCA protein assay) to detect the protein content. Then, the proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a polyvinylidene fluoride (PVDF) membrane. After blocking with 5% skim milk for 90 min, the primary antibody (including DLAT, FDX1, LIAS, and LDHA) was incubated overnight on a shaker (4°C), and then the secondary antibody was incubated for 1 h at room temperature. Finally, the membrane was visualized by an ECL plus detection system.

[0067] As shown in Figure 6 a and b, the expression of DLAT (dihydrolipoyl S-acetyltransferase) in A549 cells after different treatments and quantitative analysis, lanes 1-5 are Control, ES-Cu, CuCl2, oxammonium, Cu-Ox + GSH, respectively. In combination with the expression of oligomers and DLAT, it can be seen that ES-Cu and Cu-Ox + GSH treatments both cause obvious oligomerization of lipidated DLAT, indicating that the combination of copper ions with lipidated DLAT triggers oligomerization and protein toxicity stress, causing metabolic disorders in cells.

[0068] As shown in Figure 6Fig. c-f show the expression of LDHA (lactate dehydrogenase A), FDX1 (iron-sulfur protein) and LIAS (lipoamide synthetase) in A549 cells after different treatments and quantitative analysis. Lanes 1-5 are Control, ES-Cu, CuCl2, oxalate, Cu-Ox+GSH, respectively. It can be seen that the expression of FDX1, LIAS and LDHA in A549 cells treated by Cu-Ox+GSH is significantly down-regulated.

[0069] LIAS is an iron-sulfur cluster protein involved in the biosynthesis of thioctic acid and is a key enzyme for the lipoic modification of intracellular proteins. After Cu-Ox+GSH treatment, the accumulation of copper ions interferes with the function of mitochondrial iron-sulfur cluster proteins, leading to a decrease in LIAS expression.

[0070] FDX1 plays a key regulatory role in the lipoic modification of proteins in cells by binding to LIAS. The interaction between FDX1 and LIAS ensures the normal progress of protein lipoic modification, and lipoic-modified proteins play an important role in regulating the entry of key carbon into the tricarboxylic acid cycle (TCA cycle). As a reductase, FDX1 is an upstream regulator of protein lipoic modification and is involved in the regulation of the lipoic modification of proteins such as DLAT. During the process of copper death, FDX1 reduces Cu 2+ to more toxic Cu + , which inhibits the synthesis of iron-sulfur cluster proteins and ultimately induces cell death. After Cu-Ox+GSH treatment, there is an overload of copper ions, and FDX1 interacts with the overloaded Cu 2+ , promoting the occurrence of copper death, so the expression of FDX1 decreases.

[0071] LDHA is a key enzyme in the glycolytic pathway, responsible for converting pyruvate to lactate, and plays a core role in the Warburg effect of tumor cells. Oxalate released by Cu-Ox+GSH inhibits the activity of LDHA, reduces lactate production, affects the energy metabolism of tumor cells, further promotes the aggregation of lipoic proteins, and enhances the effect of copper death.

[0072] The above results demonstrate that Cu-Ox, by releasing copper ions and oxalate, not only induces the oligomerization of lipoic proteins and the down-regulation of LIAS and FDX1, but also interferes with the energy metabolism of tumor cells by inhibiting the activity of LDHA, thereby achieving the sensitization effect of copper death.

[0073] (6) A549 mouse models were used as models to evaluate the anti-tumor effect of Cu-Ox in A549 mouse models by tail vein injection of Cu-Ox.

[0074] A549 cells in the logarithmic growth phase were trypsinized, resuspended with pre-cooled PBS and adjusted to a density of 1x107 cells / mL. 100 μL of the cell suspension (containing 1 x 10 6 cells) was injected subcutaneously into the armpit of each 5-week-old Balb / C nude mouse. When the tumor volume of the mice reached about 100 mm 3 When the tumor volume of the mice reached about 100 mm 2 The tumor volume (V) was calculated according to V = (width

[0075] As shown in Figure 7 a, it is a flowchart of the experiment.

[0076] As shown in Figure 7 b, c, e, it is the tumor photo, volume and weight of the A549 mouse model after 14 days of Cu-Ox treatment. I-IV represent Control, CuCl2, oxalate and Cu-Ox, respectively. It can be seen that the tumor volume and weight after Cu-Ox treatment are significantly reduced, indicating that it has good anti-tumor efficiency.

[0077] As shown in Figure 7 d, it is the body weight of the A549 mouse model after 14 days of Cu-Ox treatment. It can be seen that the body weight of the mice in each group does not change significantly, indicating that Cu-Ox has good biological safety.

[0078] As shown in Figure 7 f, it is the survival rate of the A549 mouse model after 37 days of Cu-Ox treatment. It can be seen that Cu-Ox treatment shows 100% survival rate.

[0079] These results show that Cu-Ox not only shows good biocompatibility and low toxicity in vitro, but also shows significant anti-tumor effect and safety in in vivo experiments.

[0080] The foregoing description of the embodiments has been presented for the purpose of illustration and description. It is not intended to be exhaustive or to limit the application to the precise form disclosed. Modifications and variations are possible in light of the above teachings or can be acquired from practice of the application. As well, the description is presented in the context of the preferred embodiments as a number of alternatives. It is not intended to limit the application to the precise form described.

Claims

1. An oxaline-copper coordination polymer, characterized in that, It is a nanoscale crystal obtained by forming coordination bonds between N and O atoms on oxaline ligands and copper ions.

2. A method for preparing the oxaline-copper coordination polymer as described in claim 1, characterized in that, Includes the following steps: Hyaluronic acid is dissolved in water, followed by the addition of sodium hydroxide solution and copper chloride solution and stirring until homogeneous. Then, sodium oxalate solution is added to react and generate oxaline-copper coordination polymer.

3. The preparation method according to claim 2, characterized in that, The ratio of hyaluronic acid, water, sodium hydroxide solution, copper chloride solution, and sodium oxalate solution is 1 mg: 10 mL: 0.2 mL: 1 mL: 1 mL, wherein the concentrations of sodium hydroxide solution, copper chloride solution, and sodium oxalate solution are all 0.1 M.

4. The preparation method according to claim 2, characterized in that, The reaction temperature was 80℃ and the reaction time was 3 hours.

5. The use of the oxaline-copper coordination polymer as described in claim 1 in the preparation of copper death sensitizers.

6. The use of the oxaline-copper coordination polymer as described in claim 1 in the preparation of antitumor drugs and / or kits.

7. The application according to claim 6, characterized in that, The drug and / or kit are drugs and / or kits for increasing the sensitivity of tumor cells to copper death.

8. The application according to claim 6, characterized in that, The drug and / or kit are drugs and / or kits that target and deplete glutathione.

9. The application according to claim 6, characterized in that, The drug and / or kit also include a dispersion component.

10. The application according to claim 9, characterized in that, The dispersion components are selected from either water or phosphate solution.

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