CN115260511A

CN115260511A - Synthesis method and application of novel nano-targeting ligand based on stable matrix microenvironment strategy

Info

Publication number: CN115260511A
Application number: CN202210858285.7A
Authority: CN
Inventors: 宫腾; 李艳丽; 许川山; 黄剑文; 李凤潭
Original assignee: Guangzhou Medical University
Current assignee: Guangzhou Medical University
Priority date: 2022-07-20
Filing date: 2022-07-20
Publication date: 2022-11-01

Abstract

The invention discloses a synthesis method and application of a novel nano-targeting ligand polymer based on a stable matrix microenvironment strategy, wherein the synthesis method comprises the steps of dissolving 2, 5-dihydroxy terephthalic acid in 100mL of mixed solution of absolute ethyl alcohol and ultrapure water, and continuously stirring for 10min; then, dissolving ferric trichloride hexahydrate in 5mL of ultrapure water, and dispersing for 5min by using ultrasonic; adding ferric trichloride hexahydrate solution into 2, 5-dihydroxyterephthalic acid solution dropwise under the condition of continuous stirring, and reacting for 4 hours at 80 ℃; and after the reaction is finished, centrifuging and collecting a product, and washing the product for three times by using absolute ethyl alcohol to obtain the tumor-targeted nano-polymers HONPs. The invention breaks through the bottleneck problem of low catalytic efficiency of chemokinetic therapy (CDT), provides a treatment strategy for stabilizing the microenvironment of the tumor stroma, and provides a reference method and a research idea for efficient CDT anti-metastasis treatment.

Description

Synthesis method and application of novel nano-targeting ligand based on stable matrix microenvironment strategy

Technical Field

The invention relates to the technical field of anti-tumor metastasis treatment, in particular to a synthetic method and application of a novel nano targeting ligand based on a stable matrix microenvironment strategy.

Background

Tumor metastasis is the leading cause of eventual death in cancer patients. The primary conditions for tumor metastasis are degradation of extracellular matrix and destruction of basement membrane, while Matrix Metalloproteinase (MMP) and heparanase, which are key hydrolases for degradation of extracellular matrix (ECM) and remodeling of matrix microenvironment, have important promotion effects on tumor invasion and metastasis. To date, there are nearly 20 MMP enzymes discovered, and each can degrade almost all of the structural protein components in the ECM. Thus, inhibition of one or several types of MMP enzymes is not effective in preventing degradation of the ECM due to compensatory effects of other MMP enzymes, and studies have also shown that most MMP enzyme inhibitors are less resistant to metastasis. Fortunately, compared with MMP enzyme, only one heparanase is discovered at present, and both ECM and basement membrane destruction need the enzyme to participate, so that the enzyme has a close relationship with tumor angiogenesis and tumor metastasis, and becomes an important index for evaluating clinical prognosis of tumor patients. Research shows that the synthesis and secretion of heparanase in residual tumor cells after tumor treatment are obviously improved, the expression of the heparanase at tumor parts is induced to be obviously up-regulated, and the process of tumor metastasis is accelerated. Therefore, there is an urgent need to develop new formulations and new therapies targeting heparanase in order to efficiently kill primary tumors while combating metastasis induced following therapeutic stimulation.

In recent years, as an emerging tumor treatment approach, chemokinetic therapy (CDT) has been developed, which can treat endogenous hydrogen peroxide (H) by Fenton (Fenton) reaction of ferrous ions₂O₂) It is converted into hydroxyl radical (OH) with strong oxidizing property to induce tumor cell apoptosis. CDT does not require additional energy input compared to photodynamic therapy (PDT), and thereforeThe limitation of insufficient light penetration depth in the tissue is avoided. However, the catalytic activity of CDT is strongly dependent on the free Fe in the tumor region²⁺Ion content. In the presence of Fe²⁺In an ion-mediated Fenton reaction system, fe³⁺Conversion of ions to Fe²⁺The reaction rate of the ions (0.002-0.01M-1 s-1) is very slow, which severely limits the efficiency of the Fenton reaction. Many strategies have been proposed to accelerate Fe³⁺/Fe²⁺Conversion to enhance Fenton reaction efficiency. For example, introduction of photoexcited semiconductor materials to transport electrons to accelerate Fe³⁺But this strategy is severely limited by the poor penetration of ultraviolet light.

Therefore, the anti-metastasis nano preparation which can efficiently generate OH without excitation of an external field is reasonably designed, and the metastasis of the tumor is inhibited on the basis of killing the tumor to the maximum extent, so that the anti-metastasis nano preparation has important scientific research significance and clinical value.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a synthesis method and application of a novel nano-targeting ligand based on a stable matrix microenvironment strategy, and through the novel nano-targeting ligand HONPs, on one hand, surface unsaturated Fe is used for blood circulation³⁺The transferrin adsorbed by the ions and the nano-polymer can actively target to a tumor part, so that the tumor enrichment degree is obviously improved; on the other hand, in the acidic environment of tumor cells, organic ligands HO-NBC and metal ions Fe are released³⁺Fe can be accelerated by liberating HO-NBC with good electron transfer properties³⁺－Fe²⁺And the electron transfer circulation is adopted, so that the iron-based Fenton reaction efficiency is obviously improved, and the CDT efficiency is greatly improved. On the other hand, HO-NBC can obviously inhibit the activity of heparanase, prevent ECM collapse and degradation, limit the release of transfer-promoting cytokines VEGF and the like, and stabilize the microenvironment of tumor stroma, thereby effectively inhibiting tumor angiogenesis and tumor metastasis.

In order to achieve the purpose, the invention adopts the following technical scheme:

the synthesis method of the novel nano-targeting polymer based on the stable matrix microenvironment strategy comprises the steps of dissolving 2, 5-dihydroxy terephthalic acid in 100mL of mixed solution of absolute ethyl alcohol and ultrapure water, and continuously stirring for 10min; then, dissolving ferric trichloride hexahydrate in 5mL of ultrapure water, and dispersing for 5min by using ultrasonic; dropwise adding ferric trichloride hexahydrate solution into 2, 5-dihydroxy terephthalic acid solution under the condition of continuous stirring, and reacting for 4 hours at 80 ℃; and after the reaction is finished, centrifuging and collecting a product, and washing the product for three times by using absolute ethyl alcohol to obtain the tumor-targeted nano-polymers HONPs.

The ratio of the absolute ethyl alcohol to the ultrapure water is 2:3.

note that the centrifugation conditions were 12000rpm/min,10min.

As the application of the invention, the application of the synthetic method of the novel nano targeting ligand based on the stable matrix microenvironment strategy can be used for the enhanced CDT tumor killing and the effective treatment of tumor metastasis resistance.

It is noted that the HONPs nanopolymer surface coordinates unsaturated Fe in the blood circulation³⁺The ions can adsorb unsaturated transferrin in serum, so that the unsaturated transferrin can be specifically targeted to transferrin over-expressed on the surface of tumor cells, and the enrichment degree of the nano polymer on tumor parts is further improved.

It is noted that in the acidic environment of tumor cells, the HONPs nanopolymers release the organic ligand 2, 5-dihydroxyterephthalic acid (HO-NBC) and the metal ion Fe³⁺(ii) a Wherein the released HO-NBC has good electron transfer performance and can accelerate Fe³⁺－Fe²⁺Circulating and obviously improving the CDT curative effect.

The released HO-NBC can inhibit the activity of heparanase, further prevent ECM collapse degradation, limit the release of a transfer-promoting cytokine VEGF, stabilize a tumor matrix microenvironment and effectively inhibit tumor angiogenesis and tumor metastasis.

The invention has the beneficial effects that:

the invention relates to a HONPs nano coordination polymer with an active targeting function, and provides a method for synthesizing the HONPs nano coordination polymerRegulatory strategies to stabilize the matrix microenvironment are developed and used in enhanced CDT anti-metastatic therapy. In the blood circulation, HONPs surface are not saturated with Fe³⁺The ions can adsorb unsaturated transferrin in serum, so that the ions can be specifically targeted to transferrin receptors overexpressed on the surface of tumor cells, and the tumor enrichment efficiency of the ions is obviously improved; after entering tumor cells, the acid is degraded to release organic ligand HO-NBC and metal ion Fe³⁺. Wherein the released HO-NBC has good electron transfer performance and can accelerate Fe³ ⁺－Fe²⁺The electron transfer between the two greatly improves the chemical kinetics curative effect. More importantly, the free HO-NBC can obviously inhibit the activity of heparanase, prevent the collapse and degradation of extracellular matrix and stabilize the microenvironment of tumor stroma, thereby obviously inhibiting the generation of tumor angiogenesis and tumor metastasis. In-vitro solution, cell and animal experiment results show that the prepared nano-polymer has good biocompatibility, preliminarily realizes high-efficiency CDT killing of breast cancer cells, and simultaneously obviously limits the transfer behavior of the breast cancer cells. The invention breaks through the bottleneck problem of low CDT catalytic efficiency, provides a treatment strategy for stabilizing the microenvironment of the tumor matrix, and provides a reference method and a research thought for efficient CDT anti-metastasis treatment.

Drawings

FIG. 1 is a transmission electron microscope image of HONPs in an embodiment of the present invention;

FIG. 2 shows NH in an embodiment of the present invention₂Transmission electron microscopy images of NPs;

FIG. 3 is a scanning electron microscope image of HONPs in an embodiment of the present invention;

FIG. 4 is a graph of particle size distribution of HONPs in an embodiment of the present invention;

FIG. 5 is a potential diagram of HONPs in an embodiment of the present invention;

FIG. 6 is a diagram illustrating distribution of elements of HONPs in an embodiment of the present invention;

FIG. 7 is a graph of the spectra and corresponding elemental ratios of HONPs according to an embodiment of the present invention;

FIG. 8 is a Fourier transform infrared spectrum of HO-NBC and HONPs in an example of the present invention;

FIG. 9 is a XPS survey spectrum of HO-NBC in an example of the invention;

FIG. 10 is a XPS survey spectrum of HONPs according to an embodiment of the present invention;

FIG. 11 is a diagram showing O1 s XPS spectra of HO-NBC in an example of the present invention;

FIG. 12 is a schematic representation of O1 s XPS spectra of HONPs in an example of the present invention;

FIG. 13 is a schematic representation of Fe 2p XPS spectra of HONPs in an example of the present invention;

FIG. 14 shows HONPs and NH in an embodiment of the present invention₂XRD patterns of NPs;

FIG. 15 shows the nitrogen adsorption stripping of HONPs in an example of the present invention;

FIG. 16 is a schematic diagram of the aperture distribution of HONPs in an embodiment of the present invention;

FIG. 17 is a chart of the UV-VIS absorption spectra of methylene blue solutions after various treatments in accordance with example embodiments of the present invention;

FIG. 18 is a graph of the UV-VIS absorption spectrum of MB after HONPs treatment at different pH conditions in accordance with the present invention;

FIG. 19 is a graph of the UV-VIS absorption spectrum of MB treated by HONPs of different concentrations in accordance with the present invention;

FIG. 20 and FIG. 21 are H in the example of the present invention₂O₂Concentration-dependent and time-dependent HONPs processing MB UV-visible absorption spectra;

FIG. 22 is a cyclic voltammogram of HONPs and NH2NPs in an example of the present invention;

FIG. 23 is a confocal laser scanning microscope used to observe the endocytosis of free FITC or HONPs nanopolymers in 4T1 cells according to the embodiment of the present invention;

FIG. 24 is a staining analysis of live and dead cells of 4T1 cells after different treatments in the examples of the present invention, the live and dead cells were stained with calcein-AM (green) and PI (red), respectively;

FIG. 25 is a fluorescent image of HPF-stained 4T1 cells at pH7.4 or pH 6.5 after various treatments in accordance with the present invention;

FIG. 26 shows flow cytometry detection of PBS and NH in an embodiment of the invention₂At NPs and HONPsApoptosis of 4T1 cells.

Detailed Description

The present invention will be further described below, and it should be noted that the following examples are provided to illustrate the detailed embodiments and specific procedures based on the technical solution, but the scope of the present invention is not limited to the examples.

The invention relates to a synthesis method of a novel nano-targeting polymer based on a stable matrix microenvironment strategy, which comprises the steps of dissolving 2, 5-dihydroxy terephthalic acid in 100mL of mixed solution of absolute ethyl alcohol and ultrapure water, and continuously stirring for 10min; then, dissolving ferric trichloride hexahydrate in 5mL of ultrapure water, and dispersing for 5min by using ultrasonic; dropwise adding ferric trichloride hexahydrate solution into 2, 5-dihydroxy terephthalic acid solution under the condition of continuous stirring, and reacting for 4 hours at 80 ℃; and after the reaction is finished, centrifuging and collecting a product, and washing the product for three times by using absolute ethyl alcohol to obtain the tumor-targeted nano-polymers HONPs.

Further, the ratio of the absolute ethyl alcohol to the ultrapure water is 2:3.

further, the centrifugation condition of the invention is 12000rpm/min,10min.

Further, in the blood circulation, the HONPs nano-polymers coordinate unsaturated Fe on the surface³⁺The ions can adsorb unsaturated transferrin in serum, so that the unsaturated transferrin can be specifically targeted to transferrin over-expressed on the surface of tumor cells, and the enrichment degree of the nano polymer on tumor parts is further improved.

Further, in the acidic environment of tumor cells, the HONPs nano-polymers release organic ligand 2, 5-dihydroxyterephthalic acid (HO-NBC) and metal ion Fe³⁺(ii) a Wherein the released HO-NBC has good electron transfer performance and can accelerate Fe³⁺－Fe²⁺Circulation ofAnd the CDT curative effect is obviously improved.

Furthermore, the released HO-NBC can inhibit the activity of heparanase, thereby preventing ECM collapse degradation, limiting the release of a transfer-promoting cytokine VEGF and stabilizing tumors.

Example 1

1. Preparation and characterization of HONPs nano-sized coordination polymer

HONPs and NH₂NPs (control material) were prepared by a simple one-pot method. Images of a Transmission Electron Microscope (TEM) (fig. 1) and a Scanning Electron Microscope (SEM) (fig. 2) both show that the synthesized HONPs nanocomplexes are spherical structures, uniform in particle size and good in dispersibility, and have an average particle size of about 120nm. Meanwhile, the TEM image (fig. 3) shows the synthesized control material NH₂The NPs nanoparticles have an oblong structure with an average particle size of about 124nm. Furthermore, the DLS test (FIG. 4) showed that HONPs and NH₂The hydration kinetic diameters of the NPs were 135.0. + -. 3.7nm and 142.7. + -. 1.1nm, respectively, which is consistent with the results of TEM images. While Zeta potential test (FIG. 5) shows NH₂NPs are positively charged, and the potential is 9.15 +/-0.46 mV; HONPs are negatively charged, the potential is-12.30 +/-0.59 mV, and the particle surface of the negative charges is helpful for avoiding nonspecific clearance of a reticuloendothelial system and prolonging the circulation time in vivo.

Subsequently, the HONPs were analyzed for elemental composition and proportions using elemental mapping tests and X-ray energy spectroscopy (EDS). As expected, the HONPs material contains C, O, fe elements (fig. 6), and the ratio of each element is 46.84:29.90:23.26 (FIG. 7), it was confirmed that the prepared nanoparticles of the complex contained the respective charge components and the molar ratio of the elements substantially matched the charge molar ratio. Furthermore, fourier transform-infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and X-ray diffraction (XRD) spectra were used to confirm the composition state of HONPs. FT-IR spectrum (FIG. 8), and-OH stretching vibration peak (3080 cm) of free HO-NBC^－1) And C = O peak of stretching vibration (1650 cm)^－1) In contrast, the-OH expansion of HONPsVibration peak (3420 cm)^－1) And C = O peak of stretching vibration (1520 cm)^－1) A significant shift occurred, indicating Fe³⁺Possibly coordinated to free hydroxyl groups and hydroxyl groups on carboxylic acid groups. Then, XPS full spectrum (fig. 9, 10) further confirmed that the synthesized material contained C, O and Fe elements, which is consistent with the results of electron microscopy spectroscopy. The O1 s high resolution XPS spectra (FIG. 11, FIG. 12) show that the binding energy peaks of the O element in HONPs nano-aggregates are located at 531.88eV and 533.58eV, which are shifted to the low binding energy direction by 0.9eV and 0.2eV, respectively, compared with the O1 s XPS spectra of free HO-NBC, which indicates that HO-NBC does not exist in a free form in HONPs nano-material, but electronic interaction occurs, i.e. HO-NBC participates in coordination during the formation of nano-particles. The Fe 2p high resolution XPS spectrum (FIG. 13) shows that all iron atoms in HONPs are in a trivalent state, which provides a good precondition for HONPs to adsorb unsaturated transferrin in serum. In addition, in the XRD pattern (fig. 14), the swelling peak of the horps nano-polymer indicates that the horps are a typical amorphous material, i.e. the arrangement and combination of the components in the horps are irregular; and the synthesized reference material NH₂The crystal structure of the NPs was perfectly matched to the simulated data, confirming the control material NH₂NPs have been successfully prepared. Next, the specific surface area and pore size distribution of HONPs were further evaluated using the Brunner-Emmet-Teller (BET) specific surface area test. The correlation results show that the BET surface area of HONPs is 156.4323m²(iv)/g (FIG. 15); the pore diameter is mostly mesoporous, and the average pore diameter is 13.2365nm (figure 16). Taken together, these results indicate that HONPs nanopolymers have been successfully prepared.

2. CDT effect evaluation of nano-sized polymer aqueous solution

Researches show that the polyphenol or polyhydroxy medicine can be used as an electron shuttle, has good electron transfer performance and can accelerate Fe³⁺－Fe²⁺The conversion efficiency of (3) contributes to an increase in the efficiency of the Fenton reaction and an increase in the yield of the strongly oxidizing OH. Therefore, we used the classical Methylene Blue (MB) degradation experiment to evaluate the OH production of HONPs in vitro solution, where MB specifically captures OH, and it is at 664The absorbance at nm is inversely related to the OH yield. As shown in fig. 17, H alone₂O₂In the presence of the compound, generation of OH was hardly observed, and H was once present₂O₂After being mixed with Fe-based nano materials, the material shows stable OH generation; and with reference material NH₂Compared with NPs, HONPs show higher OH generation amount, which indicates that HONPs have higher catalytic efficiency. This also laterally demonstrates HO-NBC mediated Fe in HONPs nanocomposites³⁺To Fe²⁺The transformation can obviously enhance the generation of OH in the Fenton reaction and improve the Fenton reaction efficiency. Furthermore, we further investigated the pH dependence, concentration dependence and H dependence of OH produced by HONPs using MB degradation experiments₂O₂Concentration dependence and time dependence. As expected, the amount of OH catalyzed by HONPs decreased with the pH of the solution system (FIG. 18), the concentration of OH itself increased (FIG. 19), and H₂O₂The concentration increases (fig. 20) and the time increases (fig. 21), which is consistent with the conventional fenton reaction mechanism. To understand the mechanism behind the significant improvement of fenton efficiency by HONPs, we investigated the potential redox activity of HONPs using cyclic voltammetry. As shown in FIG. 22, with NH₂Compared with NPs, HONPs have higher oxidation-reduction potential, which shows that HONPs have more excellent electron transfer performance and are beneficial to accelerating Fe³⁺－Fe²⁺And (6) circulating. In conclusion, HONPs can catalyze H efficiently₂O₂Generates strong oxidizing OH and has self-reinforcing property.

3. Evaluation of CDT Effect at cellular level

Research shows that the surface of the Fe-based nano material is unsaturated Fe³⁺The ions can adsorb unsaturated transferrin in serum, so that the ions are specifically targeted to transferrin receptors over-expressed on the surface of tumor cells, and the cell internalization efficiency of the material is remarkably improved. Therefore, CLSM was used to indirectly explore the active targeting behavior of the HONPs nanopolymers by observing cellular uptake of the HONPs nanopolymers. As shown in fig. 23, 4T1 tumor cells successfully phagocytosed FITC-labeled HONPs (FITC-HONPs) nanopolymers; and phase with FITC treatment groupIn comparison, the intracellular green fluorescence of the FITC-HONPs treatment group is obviously enhanced, which means that the endocytosis amount of FITC-HONPs is far higher than that of free FITC, and the active targeting capability of HONPs nano-polymers is laterally confirmed.

H was first performed before systematic assessment of HONPs-mediated chemokinetic efficacy₂O₂Ligands HO-NBC, NH₂Evaluation of the cellular compatibility of NPs and HONPs. 4T1 cell pairs < 200. Mu.M H₂O₂Good compatibility, and good proliferation compatibility even at low concentrations. In addition, HO-NBC, NH in the concentration range of 0-200. Mu.g/mL₂The cell survival rate after NPs and HONPs treatment is more than 90%, which indicates that HO-NBC and NH₂NPs and HONPs have good biocompatibility for 4T1 cells. Subsequently, by adding a certain amount of H₂O₂And adjusting the pH to mimic the environment within the tumor cells to evaluate the CDT killing effect of the HONPs nanopolymers. NH at pH7.4₂The inhibitory effect of NPs nanoparticles on 4T1 cells is not significant; HONPs nanoparticles at 200. Mu.M H₂O₂The concentration showed moderate cell killing, but had some difference compared with the control material NH2NPs treated group. Notably, this difference is significantly amplified at pH 6.5, indicating that HONPs have superior CDT killing ability. Meanwhile, similar results are obtained after live/dead cell staining analysis is carried out on 4T1 cells in each treatment group by using Calcein-AM and PI. The green fluorescence of Calcein-AM represents live cells, while the red fluorescence of PI represents dead cells. As shown in fig. 24, the weakest green fluorescence and strongest red was found in 4T1 cells treated with HONPs + pH 6.5. Taken together, these results indicate that HONPs nanocomplexes have a high tumor suppression capacity.

In view of the aforementioned excellent OH production ability of HONPs in vitro solution, we further used HPF dye as specific OH fluorescent probe to evaluate the OH production in 4T1 cells after different treatments. As shown in fig. 25, compared to the other groups, the cells treated with HONPs and slightly acidic pH 6.5 showed the strongest green fluorescence, indicating the highest OH production, which further demonstrates the enhanced CDT efficacy of HONPs at the cellular level. Considering that the generation of OH by CDT may induce apoptosis, we tested the level of apoptosis of cells after different treatments using flow cytometry. Annexin V-FITC/PI staining results (figure 26) show that the apoptosis rate of HONPs nanoparticles induced under the slightly acidic condition of pH 6.5 can reach 53.85 percent, which is far higher than that of other treatment groups, and the result shows that HONPs can remarkably induce tumor cell apoptosis. From the above experimental results, it can be concluded that HONPs can produce high levels of OH in tumor cells and further induce apoptosis of tumor cells.

Various changes and modifications can be made by those skilled in the art based on the above technical solutions and concepts, and all such changes and modifications should be included in the protection scope of the present invention.

Claims

1. The synthesis method of the novel nano-targeting polymer based on the stable matrix microenvironment strategy is characterized by comprising the steps of dissolving 2, 5-dihydroxy terephthalic acid in 100mL of mixed solution of absolute ethyl alcohol and ultrapure water, and continuously stirring for 10min; then, dissolving ferric trichloride hexahydrate in 5mL of ultrapure water, and dispersing for 5min by using ultrasonic; dropwise adding ferric trichloride hexahydrate solution into 2, 5-dihydroxy terephthalic acid solution under the condition of continuous stirring, and reacting for 4 hours at 80 ℃; and after the reaction is finished, centrifuging and collecting a product, and washing the product for three times by using absolute ethyl alcohol to obtain the nano targeting ligand polymer HONPs nano ligand polymer.

2. The method for synthesizing the novel nano targeting polymer based on the microenvironment strategy of the stable matrix according to claim 1, wherein the ratio of the absolute ethyl alcohol to the ultrapure water is 2:3.

3. the method for synthesizing novel nano-targeting polymers based on the microenvironment strategy of the stable matrix according to claim 1, wherein the centrifugation conditions are 12000rpm/min,10min.

4. Use of the method of synthesis of novel nano-targeting ligands based on a stable matrix microenvironment strategy according to claim 1 for enhanced CDT tumor killing and effective anti-tumor metastasis therapy.

5. The application of the method for synthesizing the novel nano-targeting polymer based on the stable matrix microenvironment strategy is characterized in that the HONPs nano-polymer surface coordinates unsaturated Fe in the blood circulation³⁺The ions can adsorb unsaturated transferrin in serum, so that the ions are specifically targeted to transferrin over-expressed on the surface of tumor cells, and the enrichment degree of the nano polymer on tumor parts is improved.

6. The use of the method of claim 4 for the synthesis of novel nano-targeted polymers based on stable matrix microenvironment strategies, wherein the HONPs nano-polymers dissociate to release the organic ligands 2, 5-dihydroxyterephthalic acid (HO-NBC) and the metal ion Fe in the acidic environment of tumor cells³⁺(ii) a Wherein the released HO-NBC has good electron transfer performance and can accelerate Fe³⁺－Fe²⁺Circulating and obviously improving the CDT curative effect.

7. The application of the novel nano-targeting ligand polymer based on the stable matrix microenvironment strategy of claim 6, wherein the released HO-NBC can inhibit the activity of heparanase, thereby preventing ECM collapse degradation and limiting the release of the transfer-promoting cytokine VEGF, stabilizing the tumor matrix microenvironment, and effectively inhibiting tumor angiogenesis and tumor metastasis.