A nano-sensitizer loaded with hafnium-bonded heme and preparation and application thereof

Abstract

The application discloses a kind of nano sensitizing agent loaded with hafnium bonded heme and its preparation and application, belong to tumor treatment technical field.By adding hafnium salt solution to DSPE-PEG-NH2 solution, mix evenly, then add heme solution, incubate, obtain the nano sensitizing agent of the application.The nano sensitizing agent of the application not only can enhance the deposition of rays in tumor target area, but also can produce hydrogen and oxygen under the mediation of ultrasound, combine it with X-ray irradiation, ultrasound combined treatment tumor, can promote tumor cell apoptosis, improve the microenvironment of tumor hypoxia, reduce the radiotherapy resistance of tumor caused by hypoxia, effectively improve tumor immunosuppression environment, play the effect of efficient elimination of tumor.

Description

Technical Field

[0001] This invention belongs to the field of tumor treatment technology, specifically relating to a nano-sensitizer loaded with hafnium-bonded heme and its preparation and application. Background Technology

[0002] Hypoxia and the highly immunosuppressive nature of the tumor microenvironment (TME) are important drivers of tumor radioresistance.

[0003] During radiotherapy, radiation induces double-strand breaks in tumor cell DNA, leading to cell death. However, rapid vasodilation within the tumor causes severe hypoxia, which, combined with dense connective tissue and high levels of interstitial pressure, can make the tumor resistant to radiotherapy. Hypoxia can also trigger the activation of hypoxia-inducible factor (HIF) signaling, leading to uncontrolled tumor proliferation that enhances invasiveness and metastatic progression while protecting immune-mediated clearance. High concentrations of glutathione (GSH) and other reducing agents within the tumor can repair radiation damage, further limiting its therapeutic efficacy.

[0004] The tumor microenvironment (TME), composed of the stroma, non-malignant cells, blood vessels, and tumor-derived factors, accumulates at the tumor site. As the tumor progresses, the TME undergoes a series of complex changes, including hypoxia, increased acidity levels, and altered redox homeostasis, which often lead to impaired anti-tumor immunity.

[0005] Gas therapy is a cancer treatment approach that requires the accumulation of specific gaseous signaling molecules to achieve robust therapeutic effects. Several gases play important endogenous roles in a range of physiological processes, including nitric oxide, sulfur dioxide, carbon monoxide, and hydrogen sulfide. Hydrogen can modulate metabolic activity in tumor cells, reduce ATP levels, and promote apoptosis, without having any corresponding effect on ATP levels in normal cells. Due to its ultra-low molecular weight, hydrogen can penetrate deep into target tissues through biological membranes and the dense tumor microenvironment. Therefore, developing nanoplatforms capable of releasing hydrogen in response to external energy fields within the target tumor offers great promise as a method for cancer therapy. Oxygen is also important in therapeutic strategies, including radiotherapy, chemotherapy, photodynamic therapy, and sonicotropic therapy, because it can modulate the characterization of the tumor microenvironment. Under higher concentrations of oxygen, HIF-1α undergoes ubiquitination and protease-mediated degradation within cells. Therefore, combining therapies that increase the levels of these gases with other anticancer treatment strategies offers great promise for the future management of affected patients. Summary of the Invention

[0006] The purpose of this invention is to overcome hypoxia and immunosuppression in the tumor microenvironment, improve the sensitivity of tumors to radiotherapy, and enhance the therapeutic effect, by providing a nano-sensitizer, its preparation method, and its application.

[0007] Ultrasonic catalysis refers to the ability of certain nanomaterials to mediate the splitting of water by ultrasonic energy to produce hydrogen and oxygen, both of which can be used in anti-tumor therapy. The nano-sensitizer of this invention is suitable for ultrasound-mediated hydrogen / oxygen gas therapy and can activate anti-tumor immunity.

[0008] The objective of this invention is achieved through the following technical solution:

[0009] A nanosensitizer comprising nanoparticles loaded with hafnium-bonded heme, wherein the nanoparticles are preferably liposomes, and the liposomes are preferably polyethylene glycol-modified liposomes.

[0010] The preparation method of the nano-sensitizer includes the following steps: adding a hafnium salt solution to a DSPE-PEG-NH2 solution, stirring and mixing, then adding a heme solution, and incubating with stirring to obtain nanoparticles loaded with hafnium-bonded heme.

[0011] In the preparation method of the nano-sensitizer, the hafnium salt includes hafnium chloride, hafnium sulfate, hafnium ethanol, etc.; the heme is preferably heme chloride; the hafnium salt solution, DSPE-PEG-NH2 solution, and heme solution are preferably methanol solution or ethanol solution; the stirring and mixing time is preferably 1-10 minutes, and the incubation time under stirring is preferably 2-5 hours. The mass ratio of hafnium salt, DSPE-PEG-NH2, and heme is preferably 10-40:50-100:8-15.

[0012] The preparation method of the nano-sensitizer also includes the steps of centrifugation and washing the precipitate.

[0013] Further, the preparation method of the nano-sensitizer includes the following steps: adding 10-40 mg / mL of hafnium salt solution dropwise to 10-20 mg / mL of DSPE-PEG-NH2 methanol solution, stirring for 1-10 minutes, then adding 8-15 mg / mL of heme methanol solution, and incubating with stirring for 2-5 hours; centrifuging and washing the precipitate with ethanol to obtain nanoparticles loaded with hafnium-bonded heme. The volume ratio of hafnium salt solution, DSPE-PEG-NH2 methanol solution, and heme methanol solution is 1:5:1.

[0014] The nano-sensitizer of this invention comprises nanoparticles loaded with hafnium-bonded heme. Hafnium, a high atomic number element, exhibits exceptionally high photoelectric absorption coefficient and secondary ionization under X-ray irradiation, enabling it to deliver a greater radiation dose to surrounding cells, thereby enhancing X-ray deposition within tumors and increasing tumor cell killing. This nano-sensitizer also responds to ultrasound, converting hydrogen ions into hydrogen molecules and rapidly generating large amounts of hydrogen gas. Furthermore, it can decompose excessively high levels of H2O2 within the tumor microenvironment, promoting oxygen generation to overcome tumor hypoxia, thus improving the efficacy of radiotherapy and subsequently inducing anti-tumor immunity. The hydrogen and oxygen generated by the ultrasound-mediated water splitting of this invention can induce pro-inflammatory macrophage polarization and enhance T-cell infiltration into the target tumor.

[0015] The application of the aforementioned nano-sensitizer in the preparation of tumor therapeutic drugs. This nano-sensitizer can be used in combination with X-ray irradiation and / or ultrasound to treat tumors.

[0016] A tumor treatment drug comprising the aforementioned nanosensitizer, and may also comprise a pharmaceutically acceptable carrier or excipient.

[0017] Compared with the prior art, the present invention has the following advantages and effects: Compared with other nanosensitizers, the nanosensitizer loaded with hafnium-bonded heme can not only enhance the deposition of radiation in the tumor target area, but also generate hydrogen and oxygen under ultrasound-mediated conditions. Hydrogen can reduce the ATP level in tumor cells and promote tumor cell apoptosis, while oxygen can improve the hypoxic microenvironment in the tumor and reduce the radiotherapy resistance of the tumor caused by hypoxia. This strategy can effectively improve the tumor immunosuppressive environment and achieve the effect of efficiently eliminating tumors. Attached Figure Description

[0018] Figure 1 This is a characterization diagram of HAHf NPs, a nano-sensitizer loaded with hafnium-bonded heme. A: Transmission electron microscopy image showing the morphology of HAHf NPs. B, C: Full X-ray photoelectron spectroscopy and hafnium fine spectrum, confirming the presence of the main elements in the material and determining the binding energy of hafnium. D: (αhν) 2 Curves versus hv. E: Mott-Schottky curve. F: Schematic diagram of HAHf-catalyzed water molecule splitting under US irradiation. G, H: Curves of H2 and O2 generation and release over time.

[0019] Figure 2 The cell survival rate is 4T1 cells after co-incubation with different concentrations of HAHf NPs.

[0020] Figure 3This study describes the therapeutic effect of HAHf NPs, a nano-sensitizer loaded with hafnium-bonded heme, on 4T1 breast tumor cells in vitro. A: HIF-1α fluorescence staining images of 4T1 cells after different treatments under hypoxic conditions, showing that HAHf NPs alleviate hypoxia in breast tumor cells under ultrasound-mediated treatment. B: Cell viability was detected by CCK-8 assay, confirming the effect of HAHf NPs in enhancing radiotherapy and killing breast tumor cells under ultrasound-mediated treatment. C: DNA double-strand breaks were detected in cells of different treatment groups using γ-H2AX staining. D: Cell colony formation assays of different treatment groups showed the inhibitory effect of HAHf NPs on the proliferation of breast tumor cells under ultrasound-mediated treatment. *P<0.05, **P<0.01, ***P<0.005; Student t-test.

[0021] Figure 4 The HAHf NPs, nano-sensitizers loaded with hafnium-bonded heme, promote ultrasound-mediated H2 and O2 generation in vivo. A, B: Representative PA diagrams of intratumoral oxygen saturation and corresponding quantitative results. C: Changes in intratumoral H2 concentration with US irradiation duration (n=3). D, E: Fluorescent staining detection of intratumoral hypoxia (D) and quantitative results (E). *P<0.05, **P<0.01, ***P<0.005; Student t-test.

[0022] Figure 5 The figures show the tumor growth curves (A) and body weight change curves (B) of tumor-bearing mice in different treatment groups.

[0023] Figure 6 The values ​​represent the intratumoral ATP content in tumor-bearing mice under different treatment groups.

[0024] Figure 7 This describes the changes in intratumoral immune activity in 4T1 tumor-bearing mice treated with HAHf NPs. A, B: Flow cytometry analysis (A) and quantification of M1 and M2 marker protein (CD86 and CD206, respectively) expression (B). C: Western blotting assessment of protein levels of M1 markers (TNF-α, iNOS) and M2 markers (arginase 1, IL-10) in the tumor. D: IFN-γ secretion. E, F: Immunohistochemical staining (E) and intratumoral CD86 expression. + Quantitative analysis of T cells (F). *P<0.05, **P<0.01, ***P<0.005; Student t-test.

[0025] Figure 8This study investigated the therapeutic effects of HAHf NPs, nano-sensitizers loaded with hafnium-bonded heme, on tumors in vivo. AC: Changes in tumor volume (A, B) and weight (C) in each treatment group. D, E: Changes in mouse survival rate (D) and body weight (E) over time. F: TUNEL and H&E staining images of representative tumor tissue sections from mice in each treatment group; 1-6 represent control, US, RT, HAHf+US, HAHf+RT, and HAHf+US+RT, respectively. *P<0.05, **P<0.01, ***P<0.005; Student t-test. Detailed Implementation

[0026] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto.

[0027] The present invention provides a method for preparing a nano-sensitizer loaded with hafnium-bonded heme, which specifically includes the following steps: 1 mL of hafnium chloride methanol solution (10-30 mg / mL), hafnium sulfate methanol solution (10-40 mg / mL), or hafnium ethanol solution (10-30 mg / mL) is added dropwise to 5 mL of DSPE-PEG-NH2 methanol solution (13.2 mg / mL). After stirring continuously for 5 minutes, 1 mL of methanol solution containing 8-15 mg of heme chloride is added dropwise, and the mixture is incubated at room temperature with stirring for 3 hours. The mixture is then centrifuged, and the precipitate is washed several times with ethanol to obtain the nano-sensitizer loaded with hafnium-bonded heme.

[0028] Example 1: Preparation and characterization of hafnium-bonded heme nanosensitizers (HAHf NPs)

[0029] 1 mL of hafnium chloride methanol solution (20 mg / mL) was added dropwise to 5 mL of DSPE-PEG-NH2 methanol solution (13.2 mg / mL). After stirring continuously for 5 minutes, 1 mL of methanol solution containing 10 mg of heme chloride was added dropwise, and the mixture was incubated at room temperature with stirring for 3 hours. The mixture was then centrifuged at 3000 rpm, and the precipitate was washed several times with ethanol to obtain hafnium-bonded heme nano-sensitizers (HAHf NPs).

[0030] Transmission electron microscopy images show that HAHf NPs are spherical in shape with an average particle size of 400 nm. Figure 1 A). XPS spectral analysis confirmed the presence of C1s, O1s, and Hf4f peaks in HAHf NPs. Figure 1 B), while XPS fine spectral scanning showed that the peaks with binding energies of 17.38 eV and 18.97 eV were attributed to Hf4f7 / 2 and Hf4f5 / 2, respectively. Figure 1 C). (αhν) 2 With hv curve ( Figure 1D) Mott-Schottky curve ( Figure 1 E) shows that the band gap of HAHf NPs is 2.7 eV and the valence gap is -0.9 eV. These results suggest that HAHf promotes H + -H2 (reduction potential: 0V) and OH - -O2 (oxidation potential: +1.23V) provides theoretical support. Figure 1 F). Further analysis was performed using gas chromatography to detect 100 μg / mL HAHf NPs at a frequency of 1 MHz and an energy density of 3 W / cm². 2 The performance of catalytic water splitting to H2 production under ultrasonic (US) treatment was investigated. The results showed that the H2 production level increased in a time-dependent manner, reaching an output of 1.3 μL after 25 min. Figure 1 G) indicates that US treatment induces the catalytic cracking of water by HAHf to produce H2. The concentrations of 100 μg / mL HAHf NPs were also measured at a frequency of 1 MHz and an energy density of 3 W / cm³. 2 The ability and efficiency of O2 release in deoxygenated and normoxic PBS under ultrasonic (US) treatment were studied. The results showed that O2 was rapidly released in deoxygenated PBS, increasing to a concentration of 4.5 mg / L within 25 min. Figure 1 These results indicate that HAHfNPs can alleviate hypoxia in the tumor microenvironment (TME).

[0031] Example 2: Cytotoxicity of Hafnium-Bound Heme Nanosensitizers (HAHf NPs)

[0032] To assess the biocompatibility of HAHf NPs, their cytotoxicity was analyzed using the CCK-8 assay. After co-incubating 4T1 cells with HAHf NPs at concentrations up to 100 μg / mL for 24 hours, the 4T1 cells still maintained a viability of over 90%. Figure 2 ).

[0033] Example 3: Hafnium-bonded heme nanosensitizers (HAHf NPs) for in vitro treatment of 4T1 breast tumor cells.

[0034] To detect the ability of HAHf NPs to eliminate hypoxia and kill tumor cells.

[0035] First, the ability of HAHf-mediated ultrasound-mediated oxygen production under hypoxic conditions was tested. 4T1 cells were treated with different methods (control group, HAHf group, and HAHf+US group). Taking the HAHf+US group as an example, 4T1 cells were cultured with 50 μg / mL HAHf NPs for 4 hours, followed by ultrasound treatment with a US intensity of 1 W / cm². 2 After 5 min, the cells were incubated under hypoxic conditions (1% O2) for 24 h, followed by HIF-1a staining. Confocal images ( Figure 3 A) indicates that, compared with the control, treatment with HAHf NPs alone can improve hypoxia; the HIF-1α fluorescence signal in the HAHf+US group almost completely disappeared, which is consistent with the significant improvement in hypoxia of tumor cells catalyzed by HAHf to release O2 from water molecule splitting and catalyzed by H2O2 to produce O2 after US irradiation, thus enhancing oxygen utilization.

[0036] 4T1 cells were divided into 6 groups (1: control group; 2: US group; 3: RT group; 4: HAHf+RT group; 5: HAHf+US group; 6: HAHf+US+RT group). Cell viability was detected using the CCK-8 assay. Taking the HAHf+US+RT group as an example, 4T1 cells were cultured with 50 μg / mL HAHf NPs for 4 hours, followed by sonication at a US intensity of 1 W / cm². 2 After 5 minutes, a 6 Gy respiration (RT) was administered. The control group, RT group (6 Gy), or US group (1 W / cm²) were included. 2 Cell death was relatively low in the HAHf+RT and HAHf+US groups (within 5 minutes); the survival rate of tumor cells in both groups was approximately 60%, a decrease attributed to the presence of higher-order Hf and the effect of US-induced H2 production; the survival rate of tumor cells in the HAHf+US+RT group was 30.8%. Figure 3 B). Since Hf increases the radiosensitivity of tumor cells, DNA damage in tumor cells treated with the same CCK8 regimen was further assessed by γ-H2AX staining. Figure 3 C), consistent with the above results. Cell colony formation experiments were then performed. Taking the HAHf+US group at an RT dose of 6 Gy as an example, 4T1 cells were co-cultured with 50 μg / mL HAHf NPs for 4 hours, followed by sonication at a US intensity of 1 W / cm². 2 After 5 minutes, a 6 Gy reaction (RT) was performed. Cell colony formation assays also showed that cell proliferation was significantly inhibited in the HAHf+US+RT group, with significantly fewer colonies compared to the RT group. Figure 3 D). These results indicate that HAHf+US+RT treatment can effectively eliminate breast tumor cells in vitro.

[0037] Example 4: Ultrasound-mediated promotion of H2 and O2 generation in vivo using nano-sensitizers loaded with hafnium-bonded heme (HAHf NPs).

[0038] Photoacoustic (PA) imaging was used to monitor changes in oxyhemoglobin-related PA signals over time. A subcutaneous tumor model was constructed in the right hindquarters of BALB / c mice using 4T1 cells, and tumors were allowed to grow to 400 mm². 3Following this, HAHf NPs were injected (iv, 10 mg / kg, 100 μL). Twelve hours later, the target tumor sites in the recipient mice were measured by US at 3 W / cm². 2 The tumor was irradiated with high power for 10 minutes. The change in intratumoral oxygen saturation (sO2) over time was measured; it peaked 12 hours after US irradiation and then decreased slightly. Figure 4 A). Twelve hours after HAHf NP injection, a significant amount of SO2 was observed at the target tumor site due to the catalytic activity of heme chloride. Quantitative analysis of these PA images supports the above results. Figure 4 (B) This demonstrates that US enhances the penetration of the target tumor, and HAHf catalyzes water splitting to generate O2. Gas chromatography (GC) quantitatively measured the H2 content induced by US irradiation within the target tumor, showing that H2 levels within the tumor increased in a time-dependent manner following US irradiation. Figure 4 C).

[0039] Further evaluation was conducted to assess the treatment's ability to alleviate intratumoral hypoxia. A BALB / c mouse subcutaneous tumor model was constructed using 4T1 cells, and tumors were allowed to reach approximately 400 mm². 3 Six hours after injection of HAHf NPs (iv, 10 mg / kg, 100 μL), mice bearing 4T1 tumors received a single US irradiation (3 W / cm²). 2 Tumors were irradiated for 10 minutes each time, followed by a second US irradiation 6 hours later. Tumors were harvested on the third day for HIF-1a fluorescent staining. Results are shown below. Figure 4 In sections D and E, compared to the control group, no significant changes in tumor hypoxia were detected in the US group, while the HAHf group showed some degree of mild hypoxia relief; the HAHf+US group showed almost complete relief of intratumoral hypoxia, consistent with a significant decrease in HIF-1α expression. This significant relief of intratumoral hypoxia is beneficial for improving the treatment efficacy of other regimens.

[0040] Example 5: Hafnium-bonded heme nanosensitizers (HAHf NPs) promote pro-inflammatory M1 reprogramming of M2-like tumor-associated macrophages.

[0041] First, put 10 5 A subcutaneous tumor model was constructed by subcutaneously injecting 4T1 cells in the logarithmic growth phase into the right posterior buttock of female BALB / c mice. The tumor volume of the tumor-bearing mice was approximately ~200 mm². 3 At that time, they were randomly assigned to 4 treatment groups (n = 5 animals / group): (1) control; (2) US; (3) HAHf; (4) HAHf+US. Taking the fourth group as an example, HAHf NPs (10 mg / kg, 100 μL) were injected via the tail vein, and the US intensity was 3 W / cm. 2The treatment lasted 10 minutes, and ultrasound was performed 24 hours after injection. The day of treatment was designated as day 0. Tumor growth curves and body weight change curves for each treatment group were analyzed. Figure 5 In the control group, tumor volume increased rapidly, and neither US nor HAHf could inhibit this trend. HAHf+US treatment effectively inhibited tumor growth. On the last day of observation, the intratumoral ATP content of tumor-bearing mice under the same treatment was found to be significantly lower in the HAHf+US group than in other groups. Figure 6 ).

[0042] Next, the ability of HAHf+US treatment to promote in vivo repolarization of tumor-associated macrophages (TAMs) in subcutaneous 4T1 tumor-bearing mice was evaluated. After tumor volume and mouse body weight were observed, tumors, spleens, or blood samples were collected for flow cytometry analysis on day 18. The results showed a significantly high frequency of M2TAMs in the tumors of the control group, US group, or HAHf group, consistent with the fact that US or HAHf alone could not promote macrophage repolarization. Figure 7 (A, B). Conversely, in the HAHf+US group, M2 CD206+ signaling levels decreased, and the frequency of CD86+M1-like TAMs increased accordingly, consistent with M2-M1 repolarization. These data suggest that HAHf-mediated H2 production after US irradiation contributes to the altered macrophage polarization in these breast tumors. Western blotting further confirmed that, compared with HAHf or US alone, HAHf+US treatment significantly increased TNF-α and iNOS (M1) levels and significantly decreased IL-10 and arginase 1 (M2) levels. Figure 7 C). Furthermore, HAHf+US treatment is associated with higher levels of the M1-related pro-inflammatory cytokine IFN-γ (C). Figure 7 D). Immunohistochemical staining revealed that HAHf+US treatment enhanced CD8+ in 4T1 tumors. + T cell infiltration ( Figure 7 E, F) confirmed that HAHf+US treatment improved the composition of the tumor immune microenvironment.

[0043] The above results indicate that HAHf treatment can induce M2-M1 macrophage repolarization and intratumoral CD8 activation. + T cell activation leads to enhanced immune activation. The ability of HAHf NPs to promote the reprogramming of tumor-associated macrophages from a pro-tumorigenic M2 phenotype to a pro-inflammatory M1 phenotype offers great promise for effective anti-tumor immunotherapy strategies.

[0044] Example 6: Hafnium-bonded heme nanosensitizers (HAHf NPs) for in vivo tumor treatment.

[0045] 10 5A subcutaneous tumor model was constructed by subcutaneously injecting 4T1 cells in the logarithmic growth phase into the right posterior buttock of female BALB / c mice. The tumor volume of the tumor-bearing mice was approximately ~200 mm². 3 At that time, they were randomly assigned to 6 treatment groups (n = 5 animals / group): (1) control; (2) US; (3) RT; (4) HAHf+US; (5) HAHf+RT; (6) HAHf+US+RT. Taking the sixth group as an example, HAHf NPs (10 mg / kg, 100 μL) were injected via the tail vein. The day of injection was day 0 of the observation. The US intensity was 3 W / cm. 2 The procedure was performed for 10 minutes, followed by US (surgical radiotherapy) 24 hours after HAHf injection, and then radiotherapy at a dose of 6 Gy. Results showed that US alone had no adverse effect on tumor growth, while radiotherapy alone had a slight inhibitory effect in the early stages, but subsequent rapid tumor growth was due to tumor radioresistance. Figure 8 (A and B). However, effective tumor growth inhibition was observed in the HAHf+US and HAHf+RT groups, consistent with HAHf's ability to increase tumor sensitivity to RT, and also demonstrating that US-induced H2 generation effectively promoted gas therapy for these tumors. More significant and durable tumor growth inhibition was observed in the HAHf+US+RT group, primarily due to US-catalyzed O2 and H2 generation and the synergistic sensitization of the tumor to radiotherapy. These results were confirmed by final tumor weight measurements observed on day 18 in these treatment groups. Figure 8 C), and mouse body weight measurements showed no evidence of drug-related adverse reactions in any group, consistent with excellent biosafety profiles. Figure 8 E). Survival analysis showed that most mice in both the control and US groups died within 40 days due to tumor growth and lack of treatment response. Figure 8 D), while the number of mice dying in the RT group, HAHf+US group, and HAHf+RT group was reduced, and all mice in the HAHf+US+RT group were still alive and healthy after 40 days. These results demonstrate the excellent anti-tumor performance of this combination therapy, and are further supported by H&E and TUNEL staining results of tumor sections from these treated mice. Figure 8 In the HAHf+US+RT group, tumor cells exhibited loose cell arrangement, nuclear dissolution and fragmentation, and significant inhibition of cell proliferation.

[0046] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A nano-sensitizer, characterized in that: The nano-sensitizer is a nanoparticle loaded with hafnium-bonded heme; The preparation method of the nano-sensitizer includes the following steps: adding a hafnium salt solution to a DSPE-PEG-NH2 solution, mixing well, then adding a heme solution, incubating, and obtaining nanoparticles loaded with hafnium-bonded heme.

2. The nano-sensitizer according to claim 1, characterized in that: The nanoparticles are liposomes.

3. The nano-sensitizer according to claim 2, characterized in that: The liposomes mentioned are polyethylene glycol-modified liposomes.

4. The nano-sensitizer according to claim 1, characterized in that: The hafnium salts mentioned include hafnium chloride, hafnium sulfate, and hafnium ethanol.

5. The nano-sensitizer according to claim 1, characterized in that: The hafnium salt solution, DSPE-PEG-NH2 solution, or heme solution is a methanol solution or an ethanol solution.

6. The nano-sensitizer according to claim 1, characterized in that: The mass ratio of hafnium salt, DSPE-PEG-NH2, and heme is 10-40 : 50-100 : 8-15.

7. The use of the nanosensitizer according to any one of claims 1-6 in the preparation of tumor therapeutic drugs.

8. The application according to claim 7, characterized in that: The aforementioned nano-sensitizer is used in combination with X-ray irradiation and / or ultrasound to treat tumors.

9. A tumor treatment drug, characterized in that: It includes the nanosensitizer according to any one of claims 1-6.

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