Application of composite nanoporous platinum-based coordination polymer in the preparation of drugs or external preparations for promoting diabetic wound healing

Abstract

The present invention relates to the use of a composite nanoporous platinum-based coordination polymer in the preparation of a medicine or external preparation for promoting diabetic wound healing. The specific composite nanoporous platinum-based coordination polymer can not only simulate the antioxidant enzyme POD to catalyze the consumption of hydrogen peroxide to improve hypoxia, but also simulate the glutathione reductase to catalyze the generation of GSH to regulate the endogenous GSH level, thereby effectively removing ROS, promoting macrophage polarization and anti-inflammation, restoring cell proliferation ability and enhancing cell migration ability, so as to comprehensively promote the rapid healing of diabetic wounds.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and more specifically, to the use of a composite nanoporous platinum-based coordination polymer in the preparation of a medicine or an external preparation for promoting diabetic wound healing. Background Art

[0002] Diabetic wounds, as a serious chronic wound, are one of the main complications of diabetic patients, exposing them to a high risk of amputation. Among the nearly 463 million diabetic patients worldwide, chronic diabetic wounds are very common, causing a global health problem. The restoration of skin integrity and balance after injury is a complex dynamic process, including hemostasis, inflammation, and proliferation stages. However, there are glycosylated residues in the wounds of diabetic patients. Hyperglycemia symptoms not only weaken the polarization ability of M1 pro-inflammatory macrophages in the affected area to M2 anti-inflammatory macrophages, but also lead to excessive enrichment of M1 macrophages, increase the level of advanced glycation end products (AGEs), and induce overexpression of ROS, leading to excessive activation of inflammatory cells and matrix metalloproteinases (MMPs). The above factors cause the cells in the wound to be in a microenvironment of long-term inflammation and oxidative stress, destroying the balance in the cells, causing the wound to continue to produce excessive inflammatory factors and difficult to heal. Therefore, controlling local inflammation in diabetic wounds is one of the keys to treating diabetic wound healing.

[0003] At present, the common anti-inflammatory drugs in clinical practice, such as non-steroidal anti-inflammatory drugs, glucocorticoids, free radical scavengers, antioxidants, and pro-inflammatory monoclonal antibodies, have shortcomings such as increased anticoagulation, strong hormone side effects, and large injection doses, so their use is limited; secondly, these anti-inflammatory drugs rarely have the effect of directly downregulating ROS and regulating immune homeostasis. Therefore, it is very necessary to construct an anti-inflammatory strategy that can simultaneously achieve ROS scavenging and cell homeostasis regulation for the effective treatment of diabetic wounds.

[0004] Endogenous antioxidant reduced glutathione (GSH) is a natural reducing agent in the body, which is mainly produced by glutathione reductase under the action of coenzyme NADPH. It not only participates in the regulation of intracellular redox balance, but also affects the immune system to play an important biological function in maintaining the intracellular balance.

[0005] Nanozymes are a class of substances that can efficiently simulate the natural cascade catalytic system in the body under complex physiological environments. They have the advantages of low cost, high catalytic efficiency, and strong modifiability. They can well overcome the shortcomings of poor stability and strong environmental dependence of natural enzymes. Nanozymes with iron, copper, gold, platinum, cerium, carbon dots, etc. as catalytic centers have been proven to simulate natural antioxidant enzymes (SOD, POD, CAT, GPx, etc.) or antioxidant catalytic cascade systems in the body. They have good stability and ROS scavenging ability (such as a patented cascade enzyme nanosystem that promotes diabetic wound healing and its preparation method and application), and are one of the most commonly used and effective means of scavenging ROS for anti-inflammatory purposes. However, it is difficult to completely solve the fundamental problem of imbalance in the immune homeostasis of inflammatory cells by only improving the characteristic indicators of the inflammatory microenvironment, and it is difficult to simultaneously achieve both ROS scavenging and cell homeostasis regulation, thus making it difficult to effectively treat diabetic wounds.

[0006] Therefore, it is of great significance to develop nanozymes that can both scavenge ROS and effectively generate GSH, so as to achieve an anti-inflammatory strategy that combines ROS scavenging with cell homeostasis regulation for the effective treatment of diabetic wounds. Summary of the invention

[0007] The purpose of the present invention is to overcome the problem that the above-mentioned existing drugs are difficult to play a role in removing ROS while effectively maintaining the effective existence of GSH under high oxidative stress levels, and to provide a specific composite nanoporous platinum-based coordination polymer, which is used to prepare a drug or external preparation for promoting diabetic wound healing. The specific composite nanoporous platinum-based coordination polymer can not only simulate the antioxidant enzyme POD to catalyze the consumption of hydrogen peroxide to improve hypoxia, but also simulate glutathione reductase to generate GSH to regulate the endogenous GSH level, thereby effectively removing ROS, promoting macrophage polarization and anti-inflammation, restoring cell proliferation ability and enhancing cell migration ability, so as to comprehensively promote the rapid healing of diabetic wounds.

[0008] The above-mentioned object of the present invention is achieved by the following technical solutions:

[0009] Application of a composite nanoporous platinum-based coordination polymer in the preparation of a drug or external preparation for promoting diabetic wound healing, wherein the composite nanoporous platinum-based coordination polymer has a core-shell structure, wherein the core is an inorganic platinum nanoparticle containing zero valence, and the shell is a nanoporous platinum coordination polymer composed of platinum ions and two conjugated organic ligands with acid-sensitive groups;

[0010] The conjugated organic ligand with an acid-sensitive group is a triazine imine derivative and terephthalic acid, wherein the molecular structure of the triazine imine derivative is shown in the following formula (I):

[0011]

[0012] The specific composite nanoporous platinum-based coordination polymer of the present invention is derived from the previous research of the inventor of the present invention (see patent CN112870355B). In the previous research, it was found that the specific composite nanoporous platinum-based coordination polymer has good biocompatibility, low toxicity and other characteristics, can specifically respond to the acidic microenvironment of the tumor at a low radiation dose, and can deliver inorganic platinum nanoparticles (Pt NPs) deep into the tumor in a graded delivery manner. The inorganic platinum nanoparticles are effectively enriched in the body, improve radiotherapy sensitivity, and improve the tumor hypoxic environment, so as to achieve the purpose of killing tumor cells, improving radiotherapy effects, and treating cancer at a low radiation dose.

[0013] The inventor of the present invention unexpectedly discovered that the specific composite nanoporous platinum-based coordination polymer also has the effect of promoting diabetic wound healing. Specifically, on the one hand, the outer layer polymer material of the specific composite nanoporous platinum-based coordination polymer can well protect the catalytic activity of the surface of platinum nanoparticles, so that it can exert its original catalytic performance and simulate the activity of POD antioxidant enzyme; on the other hand, the nano-confinement ability of the outer layer material produces diffusion restriction on platinum nanoparticles, changes the distance between platinum nanoparticles, and enables it to have a plasma resonance effect under the action of ultrasound, and by promoting electronic polarization, realizes the transfer of H on NADPH to the substrate GSSG to generate GSH. The combined effect of the two aspects enables the specific composite nanoporous platinum-based coordination polymer to not only simulate the antioxidant enzyme POD to catalyze the consumption of hydrogen peroxide to improve hypoxia, but also simulate the glutathione reductase to catalyze the generation of GSH to regulate the endogenous GSH level, thereby effectively removing ROS, promoting macrophage polarization and anti-inflammation, restoring cell proliferation ability and enhancing cell migration ability, so as to comprehensively promote the rapid healing of diabetic wounds.

[0014] Preferably, the composite nanoporous platinum-based coordination polymer is used in the preparation of a drug or external preparation for restoring cell proliferation ability to promote diabetic wound healing.

[0015] Preferably, the composite nanoporous platinum-based coordination polymer is used in the preparation of a drug or external preparation for enhancing cell migration ability to promote diabetic wound healing.

[0016] Preferably, the composite nanoporous platinum-based coordination polymer is used in the preparation of a drug or external preparation for scavenging ROS to promote diabetic wound healing.

[0017] Preferably, the composite nanoporous platinum-based coordination polymer is used in the preparation of a drug or external preparation for promoting polarization of macrophages into M2 macrophages to promote diabetic wound healing.

[0018] Preferably, the composite nanoporous platinum-based coordination polymer is used in the preparation of a medicine or external preparation for consuming hydrogen peroxide to improve hypoxia and promote diabetic wound healing.

[0019] Preferably, the medicine or external preparation further comprises a pharmaceutically acceptable excipient.

[0020] More preferably, the pharmaceutically acceptable excipient is a carrier, a preservative, a hydrogel, an excipient, a diluent, a wetting agent, a thickener or an emollient.

[0021] More preferably, the medicine or external preparation is a cream, a gel, an ointment, a wound dressing, a spray, a powder, a lotion, a suspension or an injection.

[0022] Preferably, the medicine or external preparation is an ultrasound therapeutic agent for promoting diabetic wound healing.

[0023] It should be understood that the ultrasound therapeutic agent refers to an agent or external preparation used to treat diabetic wounds with the assistance of ultrasound.

[0024] As an ultrasound therapeutic agent, the drug or external preparation can be used with the assistance of ultrasound to achieve a better effect in promoting diabetic wound healing.

[0025] Preferably, the average particle size of the composite nanoporous platinum-based coordination polymer is 180-250 nm.

[0026] Preferably, the method for preparing the composite nanoporous platinum-based coordination polymer comprises the following steps:

[0027] The triazine imine derivative and terephthalic acid are dissolved in an organic solvent, the platinum salt is dissolved in water, and then the two solutions are mixed evenly, reacted at 85-100° C. for 10-16 hours, centrifuged to obtain a solid, washed, and dried to obtain a platinum-based coordination polymer.

[0028] More preferably, the molar ratio of the triazine imine derivative to terephthalic acid is 1-2:1.5-2.5.

[0029] More preferably, the platinum salt is K2PtCl4.

[0030] More preferably, the mass volume ratio of the triazine imine derivative to the organic solvent is 1 mg:0.7-1 mL.

[0031] More preferably, the mass volume ratio of the platinum salt to water is 2 mg:1-1.5 mL.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The specific composite nanoporous platinum-based coordination polymer of the present invention can not only simulate the antioxidant enzyme POD to catalyze the consumption of hydrogen peroxide to improve hypoxia, but also simulate the glutathione reductase to catalyze the production of GSH to regulate the endogenous GSH level, thereby effectively removing ROS, promoting macrophage polarization and anti-inflammation, restoring cell proliferation ability and enhancing cell migration ability, so as to comprehensively promote the rapid healing of diabetic wounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is a graph showing changes in the characteristic ultraviolet absorption value of TMB caused by the composite nanoporous platinum-based coordination polymer of Example 1 catalyzing hydrogen peroxide at different concentrations to cause the TMB indicator to develop color.

[0035] Figure 2 This is the Michaelis-Menten equation fitting diagram of the composite nanoporous platinum-based coordination polymer of Example 1.

[0036] Figure 3 is the enzyme kinetic parameter K of the composite nanoporous platinum-based coordination polymer of Example 1 m 、V max Result graph.

[0037] Figure 4 This is a diagram of GSH generated under ultrasound mediation of the composite nanoporous platinum-based coordination polymer of Example 1.

[0038] Figure 5 This is a high-resolution mass spectrum of the composite nanoporous platinum-based coordination polymer of Example 1, in which GSH is generated under ultrasound and combines with the color developer DTNB to produce GS-TNB.

[0039] Figure 6 High resolution mass spectrum of the positive control group (pure GSH+DTNB) prepared for the production of GS-TNB from the composite nanoporous platinum-based coordination polymer of Example 1.

[0040] Figure 7 This is a graph showing the effect of the composite nanoporous platinum-based coordination polymer of Example 1 on the proliferation of fibroblasts L929 intravenous endothelial cells HUVECs under ultrasound-mediated conditions.

[0041] Figure 8 This is a diagram of the composite nanoporous platinum-based coordination polymer of Example 1 and its removal of intracellular ROS under ultrasound-mediated conditions.

[0042] Fig. 9 This is a diagram showing the effect of the composite nanoporous platinum-based coordination polymer of Example 1 on promoting the migration of keratinocytes HaCaT.

[0043] Fig.10This is a graph showing the results of fluorescent immunostaining of the composite nanoporous platinum-based coordination polymer of Example 1 mixed in GelMA and its effect on polarization of macrophages in diabetic wounds under ultrasound.

[0044] Fig.11 This is a statistical diagram of the proportion of M2 and M1 phenotype macrophages in diabetic wounds induced by the composite nanoporous platinum-based coordination polymer mixed in GelMA of Example 1 and ultrasound.

[0045] Fig.12 This is a diagram of the composite nanoporous platinum-based coordination polymer of Example 1 mixed in GelMA and its healing effect in treating diabetic wounds under ultrasound.

[0046] Fig.13 This is a statistical graph of the wound healing area caused by the composite nanoporous platinum-based coordination polymer mixed in GelMA and its treatment of diabetes under ultrasound. DETAILED DESCRIPTION

[0047] In order to more clearly and completely describe the technical solution of the present invention, the present invention is further described in detail by specific examples below. It should be understood that the specific examples described herein are only used to explain the present invention and are not used to limit the present invention. Various changes can be made within the scope of the present invention. Unless otherwise specified, the reagents and materials used in the present invention are commercially available.

[0048] Example 1 Preparation of composite nanoporous platinum-based coordination polymer

[0049] The composite nanoporous platinum-based coordination polymer of this embodiment is derived from the previous patent CN112870355B of the inventor of the present invention. Its specific preparation method, physical and chemical properties and characterization information can be found in Example 1 and performance test part 1 (1) to (5) of patent CN112870355B.

[0050] In the present invention, the composite nanoporous platinum-based coordination polymers are referred to as PNAs (referred to as nPPCPs in patent CN112870355B) and are used for the activity evaluation or testing of Examples 2-3.

[0051] Example 2 Evaluation of the Enzymatic Kinetics of Composite Nanoporous Platinum-based Coordination Polymer POD and GR

[0052] (1) Determination of POD enzyme activity

[0053] POD enzyme activity of PNAs was determined using H2O2 as POD substrate. TMB (0.2 mg mL -1), H2O2 (4 mM) and PNAs (25, 50, 75, 100, 125, 150, 200 μM Pt) were mixed in HAc-NAc buffer solution (pH = 5.5) at room temperature, and the change in ultraviolet absorption of the indicator TMB at the characteristic absorption point of 652 nm was measured. Secondly, in the case of H2O2 as substrate, PNAs (25 μM Pt) and TMB (0.2 mg mL -1 ) and different concentrations of H2O2 (2, 4, 8, 10, 20, 40, 80 mM) were added to HAc-NAc buffer solution (pH = 5.5). The absorbance change of the reaction mixture at 652 nm was measured in time scan mode to evaluate POD-like activity (n = 3 per group). Figure 1 and Figure 2 According to the formula v = k / (e L), the initial translation rate at the corresponding substrate concentration was calculated, where e is equal to the molar absorption coefficient of the indicator oxidized TMB (39000 M -1 cm -1 ) and L is equal to 1cm. Finally, the enzyme kinetic parameter K of PNAs simulating POD enzyme was obtained by Michaelise-Menten equation m 3.53mM, V max 2.58×10 -8 MS -1 ,See Figure 3 The above results confirmed that PNAs have the ability to act as nanozymes to mimic the antioxidant enzyme POD and catalyze hydrogen peroxide at room temperature.

[0054] (2) Determination of GR enzyme activity

[0055] GSSG was used as GR substrate and NADPH as GR coenzyme to determine the GR enzyme activity of PNAs. 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) interacts with the sulfhydryl group of glutathione to produce a colored product GS-TNB, which provides a reliable method for the determination of glutathione in solution. GSSG (500μM) and PNAs (100μg mL -1 ) was reacted in the GSH / GSSG assay kit buffer solution (Beyotime S0053) at room temperature for 5 min. Then, DTNB (3 mg mL -1 ) and NADPH (0.5 mg mL -1 The ultrasound group was treated with 1 MHz, 0.5 W cm -2frequency-mediated for 5 minutes. The absorbance change of the indicator GS-TNB generated in the reaction mixture at 412 nm was measured in time scan mode to evaluate the GR-like activity (n=3 per group). In addition, high-resolution mass spectrometry was used to detect the DTNB and GSH-derived product GS-TNB at the characteristic molecular ion peak of m / z 503.06 to determine the presence of GSH. The positive control group obtained GS-TNB by adding GSH (0.1 μmol) to the DTNB (0.05 μmol) solution. The high-resolution mass spectrometry conditions were: ion source: HESI (negative ion mode); spray voltage: 3.0 kv; drying gas: N2; drying gas temperature: 350°C. By using UV spectrophotometry to observe the temporal trend of the characteristic absorption of GS-TNB at 412 nm, we observed that exposure to ultrasound (1 MHz, 0.5 W cm -2 ) of 100 mg mL -1 The changes in the absorption of PNAs were significantly greater than those in the control group, ultrasound alone group, and PNAs group ( Figure 4 ). Using high-resolution mass spectrometry analysis, it was found that the characteristic signal peak of GS-TNB m / z 503.05435 (negative ion mode) and the corresponding isotope signal ( Figure 5 ). Similarly, the characteristic peak of GS-TNB was also observed at m / z 503.05508 (negative ion mode) in the positive control group (pure GSH + DTNB), which matched the theoretical value of 504.06 ( Figure 6 ). The above results all prove that PNAs can produce GS-DTNB under ultrasound, indicating that PNAs as nanozymes have the ability to simulate GR enzyme activity at room temperature.

[0056] Example 3 Enhances oxidative stress cell proliferation and migration, removes ROS and macrophage polarization to effectively promote diabetic wound healing

[0057] (1) Cell proliferation

[0058] The ability of PNAs to scavenge reactive oxygen species was evaluated by using H2O2 as a representative of reactive oxygen species. The ability of PNAs to scavenge H2O2 was determined by mixing with 1 mM H2O2. The PNAs+ultrasound (US) group was irradiated with 1 MHz, 0.5 W cm -2The cells were exposed to the frequency of 5 min. L929, HaCaTs, and HUVECs were purchased from ATCC. Human skin fibroblasts (HSFs) were cultured in DMEM; Gibco (10% fetal bovine serum). Meanwhile, human umbilical vein endothelial cells (HUVECs) and HaCaT cells were maintained in RPMI 1640 medium ((Gibco, 10% FBS). A H2O2-stimulated oxidative stress cell model was established to determine the ROS clearance rate and cell proliferation rate, thereby determining the antioxidant properties of PNAs. We further examined the effects of different concentrations of PNAs and PNAs + ultrasound on the proliferation of L929 and HUVECs. See Figure 7 , 5 μg·mL -1 or 10 μg mL -1 The proliferation rates of L929 and HUVECs induced by PNAs were significantly higher than those in the H2O2 group, and there was no significant difference between the two concentration groups. It is worth noting that the cell proliferation rate induced by PNAs+ultrasound was higher, with 10 μg mL -1 The proliferation rate of the PNAs+ultrasound group exceeded 5 μg·mL -1 PNAs+ultrasound group. This indicates that under the action of ultrasound, the higher the concentration of PNAs, the stronger the ability to produce GSH and clear H2O2.

[0059] (2) ROS removal

[0060] The ability of the samples to scavenge ROS was evaluated using the 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe. Stronger green fluorescence represents higher levels of ROS in the cells. H2O2 and samples were introduced into a 6-well plate containing cultured cells. After a 12-hour incubation period, the DCFH-DA probe was added and further incubated for 20 minutes. Subsequently, images of the different experimental groups were captured using a fluorescence microscope. Figure 8 It can be clearly seen that the addition of PNAs (10 μg mL -1 ) group was significantly lower than that in the H2O2 group of the high oxidative stress model, and the fluorescence in the PNAs+ultrasound group was almost invisible, indicating that the level of ROS in the cells of this group was extremely low.

[0061] (3) Cell migration

[0062] To evaluate cytotoxicity and mobility, we used L929, HUVECs, and HaCaTs. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) analysis was performed to evaluate the cytotoxicity of PNAs. Cells were assigned to various treatment conditions and placed on the cultured cells. In the ultrasound treatment group, samples were exposed to 1 MHz, 0.5 W cm -2The cells were ultrasonicated for 5 minutes. On the second day, MTT solution was added to each well, incubated for 2 hours, and then the absorbance at 490 nm was measured. A scratch test was performed using a 100 μL pipette to evaluate cell migration under different treatments. Cell migration was then photographed and recorded over the next 24 hours. ROS significantly inhibited HaCaT cell migration, while PNAs (10 μg mL -1 ) significantly increased cell migration, and the effect of PNAs+ultrasound on cell migration was more obvious, significantly exceeding that of the H2O2 group and the control group ( Fig. 9 ). These results suggest that the ROS scavenging effects observed in a series of in vitro tests can be attributed to the antioxidant enzyme function of PNAs and their ability to generate GSH under ultrasound.

[0063] (4) Macrophage polarization

[0064] To evaluate the regulation of PNAs on the immune homeostasis of wound cells, we performed CD206 / CD86 immunofluorescence staining on wound tissues to assess the polarization of macrophages. Fig.10 The results clearly show that the proportion of CD86 (red) pro-inflammatory M1 macrophages in the inflammatory model caused by the H2O2 group was significantly increased, while the proportion of CD206 (green) anti-inflammatory M2 macrophages in the GelMA+PNAs group and the GelMA+PNAs+ultrasound group was significantly higher than that in the control and H2O2 groups. Quantitative analysis of the M2 / M1 ratios of the four groups showed that ( Fig.11 ), the M2 / M1 values ​​in the GelMA+PNAs group and the GelMA+PNAs+ultrasound group were significantly higher than those in the other groups, indicating that PNAs and their ultrasound can effectively regulate the immune homeostasis of cells in the wound and promote the polarization of macrophages to anti-inflammatory M2 macrophages.

[0065] (5) Diabetes-induced wound healing

[0066] To evaluate the therapeutic effect of PNAs on the healing of chronic wounds caused by diabetes, we established a mouse model of infected diabetic wounds. In the experiment, mice weighing 25 to 30 g were injected intramuscularly with streptozotocin (40 mg kg -1 ). After 3 weeks, blood glucose levels exceeded 16.1mmol L in two consecutive readings. -1 The mice were then anesthetized and their dorsal hair was completely removed. Subsequently, a full-thickness wound with a diameter of 10 mm was created using a skin biopsy punch and then inoculated with 10 μL of Staphylococcus aureus suspension (1×10 7 CFU mL -1 ) to establish an infected wound model. One day after infection, the bacterial colony count increased from 10 5 Increase to 106 CFU, indicating that the infection model has been successfully established. GelMA, GelMA+PNAs (10 μg mL -1 ) and GelMA+PNAs (10 μg mL -1 )+ultrasound (1MHz, 0.5W cm -2 , 5 minutes) to treat a single wound. Ultrasound treatment was only given once on the first day after gel treatment. Subsequently, wound photography was performed on the 3rd, 5th, 7th and 9th days to observe the degree of wound healing.

[0067] from Fig.12 and Fig.13 The recorded results show that on day 3, the wound area in the GelMA+PNAs+ultrasound group was significantly smaller than that in the other groups. On day 5, the wound area in the GelMA+PNAs+ultrasound group was further reduced. On day 7, the wound closure area was 60% in the GelMA+PNAs group and 80% in the GelMA+PNAs+ultrasound group, while the wound closure areas in the control group and the GelMA group remained at 40% and 50%, respectively. On day 9, 95% of the infected wounds had closed in the GelMA+PNAs+ultrasound treatment, while obvious wound areas were still observed in the control group and the GelMA group, and the wound closure in the GelMA+PNAs group was 70%. These results indicate that both PNAs and PNAs+ultrasound can accelerate the healing rate of diabetic infected wounds, and the effect of PNAs in promoting wound healing is particularly obvious in the presence of ultrasound.

[0068] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. Use of a composite nanoporous platinum-based coordination polymer in the preparation of an external preparation for promoting GSH production under ultrasound to promote diabetic wound healing, characterized in that: The composite nanoporous platinum-based coordination polymer has a core-shell structure, wherein the core is an inorganic platinum nanoparticle containing zero valence, and the shell is a nanoporous platinum coordination polymer composed of platinum ions and two conjugated organic ligands with acid-sensitive groups; The conjugated organic ligand with an acid-sensitive group is a triazine imine derivative and terephthalic acid, wherein the molecular structure of the triazine imine derivative is shown in the following formula (I): ； The external preparation is a gel; The external preparation is an ultrasonic therapeutic agent.

2. The application according to claim 1, characterized in that: The composite nanoporous platinum-based coordination polymer is used in preparing an external preparation for restoring cell proliferation ability and promoting diabetic wound healing.

3. The application according to claim 1, characterized in that: The composite nanoporous platinum-based coordination polymer is used in preparing an external preparation for enhancing cell migration ability and promoting diabetic wound healing.

4. The use according to claim 1, characterized in that: The composite nanoporous platinum-based coordination polymer is used in preparing an external preparation for removing ROS and promoting diabetic wound healing.

5. The use according to claim 1, characterized in that: The composite nanoporous platinum-based coordination polymer is used in preparing an external preparation for promoting macrophage polarization into M2 macrophages to promote diabetic wound healing.

6. The use according to claim 1, characterized in that: The external preparation further comprises pharmaceutically acceptable excipients.

7. The use according to claim 6, characterized in that: The pharmaceutically acceptable excipients are carriers, preservatives, excipients, diluents, wetting agents or thickening agents.

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