An ultrasmall nanometer radiotherapy sensitizer, a preparation method and application thereof

Abstract

The application belongs to the technical field of biological medicine, and discloses a super-small nanometer radiotherapy sensitizer as well as a preparation method and application thereof. The super-small nanometer radiotherapy sensitizer comprises a super-small hafnium oxide matrix doped with functional metal ions, preferably, the surface of the super-small hafnium oxide matrix doped with functional metal ions has a surface modification layer. The preparation method comprises the following steps: dissolving hafnium source in anhydrous ethanol, adding sufficient trifluoroacetic acid, and constant-temperature stirring, then vacuum rotary evaporation drying to obtain hafnium trifluoroacetate powder; adding the hafnium trifluoroacetate, an organic solution containing metal ions that can be doped into the super-small hafnium oxide matrix and oleylamine into a container and stirring, programmed heating and constant-temperature reaction for a period of time under vacuum or inert gas alternating protection, adding excess ethanol into the container to precipitate after cooling to room temperature, washing and drying the precipitate; then removing the organic matter on the surface of the obtained dry powder to obtain super-small metal ion doped hafnium oxide, i.e. the super-small nanometer radiotherapy sensitizer.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to an ultra-small nanoscale sensitizer for adjuvant therapy in cancer radiotherapy, its preparation method, and its application. Background Technology

[0002] Radiotherapy is one of the core methods for the clinical treatment of malignant tumors, playing an irreplaceable role in the treatment of various solid tumors. However, radiation resistance (such as acquired resistance commonly found in common malignant tumors like triple-negative breast cancer and advanced non-small cell lung cancer) and radiation damage to normal tissues remain key clinical bottlenecks restricting the improvement of radiotherapy efficacy. Specifically, this manifests in two ways: First, radiation-resistant tumor cells can evade radiation damage by activating DNA damage repair pathways (such as the ATM / ATR pathway) and strengthening antioxidant stress systems (such as upregulating glutathione synthase expression), leading to increased tumor recurrence rates and a higher risk of distant metastasis. Second, traditional radiotherapy techniques lack sufficient tissue targeting; radiation energy can easily affect healthy tissues surrounding the tumor, such as bone marrow hematopoietic stem cells and gastrointestinal mucosal epithelial cells, causing serious complications such as bone marrow suppression and gastrointestinal ulcers, reducing patients' quality of life and treatment tolerance.

[0003] Hafnium oxide, typically represented by NBTXR3 ( Radiation sensitizers primarily exert their antitumor effects through physical sensitization mediated by their high atomic number (Z=72). Although clinical studies have demonstrated that these agents can delay tumor progression to some extent, they still have significant limitations in clinical application: First, their mechanism of action is singular, relying solely on physical sensitization through radiation energy deposition. They lack functional designs that can induce non-apoptotic tumor cell death, and cannot specifically regulate key pathways of acquired radioresistance in tumor cells to reverse acquired radioresistance, resulting in limited efficacy against radioresistant tumors. Second, their therapeutic spectrum is narrow, with limited inhibitory effects on primary tumor lesions and a lack of ability to inhibit distant metastases, making it difficult to meet the clinical needs for comprehensive tumor treatment. Third, the formulations lack stability; conventionally sized hafnium oxide nanoparticles struggle to penetrate deep into tumor tissue, while ultra-small particles are prone to aggregation, failing to balance targeting and bioavailability.

[0004] The introduction of functional metal ions provides a direction for solving this problem. It can induce copper death in tumor cells by binding to lipid-acylated mitochondrial proteins, thereby disrupting mitochondrial respiratory chain function and energy metabolism homeostasis. It can induce ferroptosis in tumor cells through the Fenton reaction, promote the accumulation of large amounts of intracellular lipid peroxides and overcome the antioxidant defense system; As a key regulator of pyroptosis-related signaling pathways, it can induce inflammatory pyroptosis in tumor cells by activating the Caspase-8 / Gasdermin C pathway, triggering cell membrane perforation and the release of damage-related molecules; Ce ions ( It can regulate the redox homeostasis of the tumor microenvironment through valence state cycling, and catalyze the generation of reactive oxygen species (ROS) in the acidic microenvironment to enhance oxidative damage while clearing excess ROS from normal tissues to reduce radiotherapy toxicity. Not only can it enhance oxidative damage through a Fenton-like reaction, but it can also act as a cGAS-STING pathway activator, promoting type I interferon secretion to initiate an anti-tumor immune response. This mechanism has been shown to delay tumor progression in materials such as polyoxometalates, but it has not yet been combined with ultrasmall hafnium oxide for radiosensitization in cancer therapy and reversal of tumor radioresistance. However, the application of functional metal ions faces the dual challenges of "toxicity-targeting," and some functional metal ions that can mediate tumor-specific death (such as free...) It has high biotoxicity and is prone to accumulation in solid organs such as the liver and kidneys when administered directly intravenously, causing serious toxic side effects. At the same time, it lacks the ability to target tumor tissues and is difficult to effectively accumulate at the lesion site, resulting in a narrow therapeutic window. Therefore, it is necessary to construct a carrier system to achieve stable loading and controllable delivery of functional metal ions, which can reduce the systemic toxicity of free metal ions and accurately release them at the tumor site to exert a biological killing effect.

[0005] Ultra-small (1-20 nm) nanomaterials possess excellent deep penetration into tumor tissue, high endocytosis efficiency, and enhanced permeation-retention (EPR) effect specific to the tumor microenvironment. These nanomaterials can significantly increase the concentration of sensitizers in tumor lesions, providing a key structural basis for targeted optimization of radiotherapy sensitization. However, existing ultra-small nano-sensitizers generally suffer from engineering application defects: their surface energy is significantly higher than that of conventionally sized nanomaterials, making them prone to aggregation and sedimentation in clinically relevant solutions such as physiological buffers and serum, resulting in extremely poor colloidal stability. This not only fails to meet the stringent clinical requirements for formulation homogeneity and stability but also leads to abnormally large particle sizes due to aggregation, directly negating the tumor tissue penetration advantage brought by ultra-small size, severely limiting their practical potential for translation from laboratory research to clinical application. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides an ultra-small nano-radiosensitizer, its preparation method, and its application. This fills the technological gap of underdeveloped ultra-small hafnium oxide functional materials and clarifies the application of hafnium oxide-based materials in the treatment of radioresistant tumors. The ultra-small hafnium oxide matrix serves as a carrier framework, utilizing the high X-ray absorption capacity of hafnium (Z=72) to enhance local radiotherapy dose deposition and improve physical sensitization. The doped metal ions include one or more of Cu, Fe, Co, Mn, and Ce, effectively inducing non-apoptotic cell death or activation of other cellular pathways such as cGAS-STING. By regulating related signaling pathways, it reverses acquired tumor radiation resistance, thereby achieving tumor treatment.

[0007] The technical solution of this invention is as follows: An ultra-small nano-radiotherapy sensitizer is characterized by comprising an ultra-small hafnium oxide matrix doped with functional metal ions.

[0008] Preferably, the surface of the ultrasmall hafnium oxide matrix doped with functional metal ions has a surface modification layer.

[0009] Preferably, the surface of the ultra-small hafnium oxide matrix doped with functional metal ions is modified with a surface modifier to form the surface modification layer.

[0010] Preferably, the surface modifier includes, but is not limited to: anionic surfactants, nonionic surfactants, amphoteric surfactants, and natural hydrophilic polymers; the methods for modifying the surface of the ultrasmall hafnium oxide matrix using the surface modifier include, but are not limited to: non-covalent modification, covalent bonding modification, and composite modification; the functional metal ion is one or more of Cu ions, Fe ions, Co ions, Mn ions, Ce ions, Ga ions, Mo ions, Pt ions, Au ions, and Ag ions.

[0011] Preferably, the particle size of the ultra-small hafnium oxide matrix doped with functional metal ions is 3~20nm; the crystal form of the ultra-small hafnium oxide matrix doped with functional metal ions is monoclinic phase, or a mixture of monoclinic and tetragonal phases, or a latticeless structure; wherein, the mass proportion of monoclinic phase in the mixture is not less than 50%.

[0012] Preferably, the total doping amount of the functional metal ions is 5-30% of the molar amount of Hf metal in the hafnium oxide matrix.

[0013] Preferably, the dosage form of the ultra-small nano-radiotherapy sensitizer is a powder, suspension, emulsion, or liposome.

[0014] A method for preparing an ultra-small nano-radiotherapy sensitizer, comprising the following steps: Preparation of hafnium trifluoroacetate: Hafnium source was dissolved in anhydrous ethanol, then sufficient trifluoroacetic acid was added and stirred at a constant temperature. Hafnium trifluoroacetate powder was then obtained by vacuum rotary evaporation. Preparation of ultra-small metal ion-doped hafnium oxide: The prepared trifluoroacetic acid hafnium, an organic solution containing metal ions that can be doped into the ultra-small hafnium oxide matrix, and oleylamine were added to a container and stirred. Under vacuum or alternating inert gas protection, the temperature was increased by a programmed process and kept constant for a period of time. After cooling to room temperature, excess ethanol was added to the container to precipitate the product. The precipitate was washed and dried. Then, the organic matter on the surface of the dried powder was removed to obtain ultra-small metal ion-doped hafnium oxide, which can be used as an ultra-small nano-radiotherapy sensitizer.

[0015] Preferably, the surface of the ultrasmall metal ion-doped hafnium oxide is modified with a surface modifier to obtain ultrasmall metal ion-doped hafnium oxide with a surface modification layer, which can be used as an ultrasmall nano-radiotherapy sensitizer.

[0016] An application of the aforementioned ultra-small nano-radiosensitizer in the preparation of adjuvant drugs for tumor radiotherapy.

[0017] Compared with existing technologies, the radiosensitizer provided by this invention comprises ultra-small metal ion-doped hafnium oxide. Hafnium oxide-based materials exhibit good biocompatibility and no significant toxic side effects. Ultra-small metal ion-doped hafnium oxide can enhance the radiation dose to local tumors and, in response to radiation, release the dopant ions, achieving intracellular accumulation of specific metal ions and triggering specific cell death. This material achieves, for the first time, the synergistic integration of ultra-small hafnium oxide with Cu / Fe / Co / Ce / Mn ions, overcoming the functional limitations of traditional hafnium oxide-based sensitizers. In some specific implementation examples, copper death-inducing function is introduced through Cu ions, constructing a triple synergistic mechanism of "physical sensitization (hafnium oxide) - copper death (Cu) - immune activation," specifically reversing radioresistance pathways and inhibiting metastasis, filling the gap in the field of ultra-small hafnium oxide-based materials for the treatment of radiation-resistant tumors. Attached Figure Description

[0018] Figure 1 This is a particle size characterization diagram of ultrasmall copper ion-doped hafnium oxide US-HfO2:Cu dispersed in cyclohexane provided in Example 1 of the present invention; In this figure, a is a transmission electron microscope (TEM) image of US-HfO2:Cu dispersed in cyclohexane, and b is the result of dynamic light scattering (DLS) particle size distribution test of US-HfO2:Cu in cyclohexane.

[0019] Figure 2 The structural characterization diagram of the SHMP-modified ultrasmall copper ion-doped hafnium oxide US-HfO2:Cu@SHMP provided in Example 1 of the present invention; In the figure, a is the TEM elemental distribution map of US-HfO2:Cu@SHMP, b is the TEM schematic diagram of US-HfO2:Cu@SHMP, c is the high-resolution TEM image, d is the XRD characterization map of US-HfO2:Cu and US-HfO2:Cu@SHMP, where the crystal structure of US-HfO2:Cu and US-HfO2:Cu@SHMP is monoclinic, e is the overall XPS map of US-HfO2:Cu@SHMP, and f is the 2p fine spectrum of Cu.

[0020] Figure 3 The characterization diagram of the dispersion of SHMP-modified ultrasmall copper ion-doped hafnium oxide US-HfO2:Cu@SHMP provided in Example 2 of the present invention; Wherein, a is the Zeta potential diagram of US-HfO2:Cu@SHMP, and b is the comparison diagram of the dispersibility of US-HfO2:Cu@SHMP in different solvents and 70mg / mL -1 Schematic diagram of an aqueous dispersion suspension.

[0021] Figure 4 Cell safety evaluation of the ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP provided in Example 3 of this invention; These include BEAS-2B human normal lung epithelial cells, Hacat human immortalized keratinocytes, HUVEC human umbilical vein endothelial cells, IEC-6 rat small intestinal crypt epithelial cells, HC11 mouse mammary epithelial cells, and 4T1R acquired radiation resistant mouse breast cancer cells.

[0022] Figure 5 The graphs and statistics of the radiosensitization effects of the ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP provided in Example 4 of this invention on radiotherapy of 4T1R acquired radiation-resistant mouse breast cancer cells under different radiation modes are shown. In this figure, a is a representative schematic diagram of the inhibition of 4T1R cell proliferation by US-HfO2:Cu@SHMP combined with EBRT or BT, and b is a statistical graph of figure a.

[0023] Figure 6 This invention provides a comparative experiment on the inhibition of 4T1R cell proliferation by ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP or ultra-small hafnium oxide nanosensitizer US-HfO2@SHMP combined with brachytherapy (BT). In this figure, a is a representative schematic diagram of the inhibition of 4T1R cell proliferation by US-HfO2:Cu@SHMP or ultra-small hafnium oxide nanosensitizer US-HfO2@SHMP combined with BT, and b is a statistical graph of figure a.

[0024] Figure 7 This is a diagram illustrating the mechanism by which the ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP, combined with brachytherapy, inhibits the proliferation of 4T1R cells, as provided in Example 6 of this invention. In the figure, a is the WB experiment result of copper death-related protein, b is a representative schematic diagram of FDX1 immunofluorescence experiment result, c is a statistical graph of b, d is a biological transmission electron microscopy schematic diagram of different treatment groups, e is a representative schematic diagram of DLAT immunofluorescence experiment result of different treatment groups, and f is a statistical graph of g.

[0025] Figure 8 This is a schematic diagram and treatment result diagram of primary tumor treatment in mice with breast cancer using the comparative ultra-small hafnium oxide nanosensitizer US-HfO2@SHMP or the ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP combined with brachytherapy (BT). (Example 7 of this invention) In the figure, a is a schematic diagram of brachytherapy in tumor-bearing mice, b is a target area planning diagram of primary tumor treatment in tumor-bearing mice, c is a schematic diagram of tumor volume changes in each group of mice during the monitoring period, and d is a pathological H&E and Ki67 analysis diagram of primary tumors in each group of mice 3 days after treatment.

[0026] Figure 9 This is an evaluation diagram showing the effect of the activation of the telepathic effect on the progression of distant tumors after the ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP combined with brachytherapy (BT) was used to treat the primary tumors of 4T1R breast cancer mice. In this diagram, a represents the change in distal tumor volume of each mouse in each treatment group during the monitoring period; b represents the statistical chart of distal tumor changes in each group of mice during the monitoring period; and c represents the statistical chart of distal tumor volume in each group of mice at the end of the monitoring period.

[0027] Figure 10 The image shows the therapeutic effect of the ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP combined with brachytherapy (BT) on lung tumor metastasis in 4T1R breast cancer mice, as provided in Example 9 of this invention. In the figure, a is a schematic diagram of lung tumor metastasis in mice in each group at the treatment endpoint, b is a statistical diagram of lung tumor metastasis foci, c is a representative figure of CD8+ immunohistochemical staining results of lung tissue in each group, and d is the statistical results of CD8+ index in each group.

[0028] Figure 11 This is a safety evaluation chart of organs 7 and 14 days after intratumoral injection of the ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP provided in Example 10 of the present invention.

[0029] Figure 12The structure characterization diagram of ultrasmall cerium ion-doped hafnium oxide US-HfO2:Ce provided in Example 11 of this invention; In the figure, a is the XRD characterization result of US-HfO2:Ce, whose crystal structure is monoclinic; b is the XPS full spectrum of US-HfO2:Ce; and c is the fine spectrum of Ce 3d.

[0030] Figure 13 The structure characterization diagram of the ultra-small iron ion-doped hafnium oxide US-HfO2:Fe provided in Example 12 of this invention; In the figure, a is the XRD characterization result of US-HfO2:Fe, whose crystal structure is monoclinic; b is the XPS full spectrum of US-HfO2:Fe; and c is the fine spectrum of Fe 2p.

[0031] Figure 14 The structure characterization diagram of ultra-small manganese ion-doped hafnium oxide US-HfO2:Mn provided in Example 13 of this invention; In the figure, a is the XRD characterization result of US-HfO2:Mn, whose crystal structure is monoclinic; b is the XPS full spectrum of US-HfO2:Mn; and c is the fine spectrum of Mn 2p.

[0032] Figure 15 This is a representative schematic diagram of cell activation and p-STING expression induced by ultra-small manganese ion-doped hafnium oxide US-HfO2:Mn combined with external irradiation radiotherapy (RT) provided in Example 14 of the present invention.

[0033] Figure 16 The image shows the XRD characterization of ultra-small cobalt ion-doped hafnium oxide US-HfO2:Co provided in Example 15 of this invention. Its crystal structure is a monoclinic phase.

[0034] Figure 17 This is a representative transmission electron microscope image of cells after cell death induced by ultra-small cobalt ion-doped hafnium oxide US-HfO2:Co combined with external irradiation radiotherapy (RT) as provided in Example 16 of the present invention.

[0035] Figure 18 This is a flowchart illustrating the preparation method of the ultra-small nano-radiotherapy sensitizer of the present invention. Detailed Implementation

[0036] The present invention will now be described in further detail with reference to the accompanying drawings. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0037] In the first aspect, this invention designs an ultra-small hafnium oxide-based nano-sensitizer. The preparation scheme specifically includes a binary composite system design of "ultra-small metal ion-doped hafnium oxide support - surface modification layer", as detailed below: The preparation methods of ultra-small metal ion-doped hafnium oxide materials (referring to ultra-small hafnium oxide matrix doped with functional metal ions, i.e., ultra-small hafnium oxide matrix doped with functional metal ions, which is the main material of ultra-small nano-radiotherapy sensitizers) include, but are not limited to: solution methods (hydrothermal / solvothermal methods, sol-gel methods, co-precipitation methods, microwave-assisted synthesis methods), gas phase methods (chemical vapor deposition CVD, physical vapor deposition PVD, spray pyrolysis methods), solid phase methods (high-energy ball milling methods, solid phase thermal decomposition methods), template methods (hard template methods using mesoporous silica, carbon nanospheres, etc. as templates or soft template methods using micelles formed by surfactants as templates), microemulsion methods, and other novel preparation technologies (laser ablation methods, electrochemical deposition methods, biomineralization methods).

[0038] The nanomaterials prepared by the above method can take into account the structural integrity of the ultra-small hafnium oxide matrix, the tunability of particle size, the uniformity of metal ion doping, and the surface modifiability, and can meet the core performance requirements of ultra-small nanoparticles.

[0039] The particle size of the ultra-small metal ion-doped hafnium oxide material is 3~20nm, preferably 5~10nm.

[0040] The nanoparticles of the above size can meet the size requirements for enhanced permeation retention (EPR) effect, enabling passive targeted enrichment in tumor tissues. They have the ability to penetrate deep into tumor tissues, break through the tumor stroma barrier, and diffuse into the tumor core area and metastatic microfoci. In addition, the advantage of the ultra-small size, which significantly increases the specific surface area as the particle size decreases, is conducive to increasing the contact area with radiation, and realizing the controllable release of metal ions under radiation.

[0041] The functional metal ions doped in the ultra-small hafnium oxide matrix include, but are not limited to, one or more of the following metal ions: Cu, Fe, Co, Mn, and Ce. It should be noted that the metal ions covered here include any functional metal ion that can be doped into the hafnium oxide support. The total doping amount of functional metal ions is 5-30% of the molar amount of Hf metal in the hafnium oxide matrix. To further enhance the material's functional properties, a multi-metal ion synergistic doping strategy can be adopted. The doping ratio of each metal ion can be adjusted as needed according to the target sensitization function, achieving functional complementarity through multi-ion synergy.

[0042] The aforementioned schemes, which introduce functional metal elements such as Cu, Fe, and Co into ultra-small hafnium oxide matrices, can trigger non-apoptotic death pathways in tumor cells, such as copper death, ferroptosis, and inflammatory pyroptosis, respectively, and form a synergistic effect with Hf-mediated physical sensitization, thereby significantly enhancing the overall killing effect of radiotherapy. If elements such as Ga and Mo are introduced, the material can be endowed with multimodal imaging capabilities, providing support for precise positioning and real-time monitoring during radiotherapy. Furthermore, the incorporation of elements such as Ce, Pt, Au, Mn, Ag, and Mo can further improve the efficiency and targeting of radiotherapy sensitization by relying on their unique enzyme-like catalytic activity.

[0043] Surface modifiers include, but are not limited to: anionic surfactants (sodium hexametaphosphate (SHMP), sodium pyrophosphate, sodium citrate, sodium dodecyl sulfate (SDS), sodium dodecylbenzene sulfonate (SDBS)), nonionic surfactants (polyethylene glycol (PEG) and its derivatives (PEG, molecular weight 2-5kDa), poloxamer series (Pluronic F68 / F127), polyglycerol fatty acid esters, alkyl glycosides (APG)), polyvinylpyrrolidone (PVP), Tween series (Tween-20 / 40 / 80)), amphoteric surfactants (lecithin, betaines (such as carboxybetaine), phosphorylcholine, sulfobetaine), natural hydrophilic polymers (hyaluronic acid (HA, molecular weight 50-200kDa), chitosan and its derivatives, sodium alginate, bile salts (such as sodium cholate)).

[0044] The above scheme significantly improves the dispersion stability of ultra-small hafnium oxide-based nanoradiotherapy sensitizers in aqueous solutions and physiological media, reduces nanoparticle aggregation, and enhances biocompatibility.

[0045] Modification methods for surfactants in ultra-small hafnium oxide nano-radiotherapy sensitizers include, but are not limited to: non-covalent modification (by wet ball milling and blending or solution stirring and adsorption modification), covalent modification (surface activation pretreatment or covalent coupling modification), and composite modification.

[0046] The crystal form of ultra-small metal ion-doped hafnium oxide is a monoclinic phase, or a mixture of monoclinic and tetragonal phases, wherein the mass proportion of the monoclinic phase is not less than 50%, or there is no lattice structure.

[0047] The above modification methods can achieve target-oriented surfactant modification on the surface of ultra-small nanomaterials.

[0048] Secondly, this invention provides a method for preparing surfactant-modified ultrasmall metal ion-doped hafnium oxide materials, such as... Figure 18 As shown, the steps include: Preparation of hafnium trifluoroacetate: Hafnium source was dissolved in anhydrous ethanol, then sufficient trifluoroacetic acid was added and stirred at a constant temperature. Hafnium trifluoroacetate powder was then obtained by vacuum rotary evaporation. Preparation of ultra-small metal ion-doped hafnium oxide: The prepared trifluoroacetic acid hafnium, an organic solution containing metal ions that can be doped into the ultra-small hafnium oxide matrix, and oleylamine were added to a container and stirred. Under vacuum or alternating inert gas protection, the temperature was increased by a programmed process and kept constant for a period of time. After cooling to room temperature, excess ethanol was added to the container to precipitate the product. The precipitate was washed and dried. Then, the organic matter on the surface of the dried powder was removed to obtain ultra-small metal ion-doped hafnium oxide, which can be used as an ultra-small nano-radiotherapy sensitizer.

[0049] In some specific implementation examples, a method for preparing an SHMP-modified ultrasmall metal ion-doped hafnium oxide material (US-HfO2:M@SHMP) is as follows: Step (1): Preparation of hafnium trifluoroacetate ( Hafnium trifluoroacetic acid precursor. The specific steps include completely dissolving the hafnium source in anhydrous ethanol, adding sufficient trifluoroacetic acid, stirring at a constant temperature for several hours, and finally drying by vacuum rotary evaporation to obtain hafnium trifluoroacetic acid precursor powder.

[0050] Step (2): Preparation of ultra-small metal ion-doped hafnium oxide ( The hafnium trifluoroacetate obtained in step (1), the metal ion organic solution that can be doped into the ultra-small hafnium oxide matrix, and oleylamine were placed in a round-bottom flask and stirred. Under vacuum or alternating inert gas protection, the temperature was increased by a programmed process and kept constant for a period of time to allow the reaction system to cool naturally to room temperature. After that, excess ethanol was added to the round-bottom flask to precipitate the product. The product was centrifuged and washed several times with an organic solvent, then washed with water and dried. The dried powder was calcined in air for several hours to remove surface organic matter, and finally, ultra-small metal ion doped hafnium oxide material was obtained. Step (3): Preparation of metal ion-doped hafnium oxide material modified with surfactant (SHMP) ( ).Will The powder and surfactant were dry-milled in a mortar for several minutes to obtain a mixture. This mixture, along with deionized water and grinding balls, was then added to a ball mill jar and wet-milled in a planetary ball mill at a specific speed for several hours. After centrifugation, the mixture was washed several times with water to thoroughly remove unbound surfactant, finally yielding the product. The product is preserved as an aqueous dispersion suspension.

[0051] In the above scheme, the ultrasmall metal ion doped material prepared by the present invention is prepared by precursor preparation, ultrasmall metal ion nanomaterial preparation and further surfactant modification to prepare surfactant-modified ultrasmall metal ion doped hafnium oxide material. The nanomaterial prepared by this method has uniform particle size, regular morphology and high structural stability.

[0052] Specifically, the hafnium sources used in step (1) above include hafnium chloride, hafnium nitrate (Hf(NO3)4), tetraethoxyhafnium (Hf(OC2H5)4), hafnium sulfate (Hf(SO4)2) and tetrabutoxyhafnium (Hf(OC4H9)4).

[0053] In step (1) above, the constant temperature stirring temperature is 40~60℃.

[0054] The time in step (1) above is 5 to 12 hours, and in some specific embodiments the stirring time is 6 hours.

[0055] In step (1) above, the molar ratio of hafnium source to trifluoroacetic acid is 1:(4~5) to ensure complete coordination of hafnium ions and avoid residual unreacted hafnium source affecting the subsequent formation of ultra-small hafnium oxide matrix and the uniformity of metal ion doping.

[0056] In step (1) above, the vacuum drying temperature is 50~70℃, and in some specific embodiments, the drying temperature is 60℃.

[0057] The functional metal ion raw materials in step (2) above include, but are not limited to: inorganic metal ion raw materials (chlorides, nitrates, sulfates, oxides) or organic metal ion raw materials (acetylacetone salts, carboxylates), and in some specific embodiments, copper chloride.

[0058] The organic solutions containing metal ions in step (2) above include, but are not limited to, anhydrous ethanol, n-octanol, octadecanol, n-hexane, etc., and in some specific embodiments, anhydrous ethanol.

[0059] In step (2) above, the functional metal ion is any metal ion M that can be doped into the ultra-small hafnium oxide matrix, including but not limited to Cu, Fe, Co, Mn, Ce, Mo, Pt, Zn, Ag and metal ions of different valence states, preferably Cu, Fe, Co, Mn and Ce in some specific embodiments.

[0060] In step (2) above, the molar ratio of metal ion M to Hf in trifluoroacetic acid is 1:(1-10), and in some specific implementation examples, the molar ratio is 1:2.

[0061] In step (2) above, the molar ratio of hafnium trifluoroacetate and oleylamine is 1:(20~60), and in some specific implementation examples the molar ratio is 1:40.

[0062] In step (2) above, the gradient heating program involves heating from room temperature to 100-120°C, maintaining the temperature under vacuum for 40-60 minutes, then heating to 310-330°C for 20-40 minutes and maintaining the temperature for 1-2 hours. This stage is the crystallization process, and the corresponding temperature and time will affect the growth and size of the grains. The selection of temperature and time in this step can optimize the grain growth and size of the ultra-small hafnium oxide matrix.

[0063] In step (2) above, the inert gas can be argon or nitrogen. In some specific implementation examples, the inert gas is argon.

[0064] The washing solvents in step (2) above include toluene, cyclohexane, and anhydrous ethanol.

[0065] In step (2) above, the calcination temperature is 400~900℃, and in some specific implementation examples, the calcination temperature is 550℃.

[0066] In the above scheme, In step (3) above, the surfactant includes a mass ratio of US-HfO2:M powder to surfactant of 1:(0.5-3), and in some specific implementation examples, the mass ratio is 1:1. The selected feeding ratio can effectively improve the water dispersibility of the material, while avoiding excessive modification that may lead to potential biotoxicity.

[0067] The surface modifiers in step (3) above include, but are not limited to: anionic surfactants (sodium hexametaphosphate (SHMP), sodium pyrophosphate, sodium citrate, sodium dodecyl sulfate (SDS), sodium dodecylbenzene sulfonate (SDBS)), nonionic surfactants (polyethylene glycol (PEG) and its derivatives (PEG, molecular weight 2-5kDa), poloxamer series (Pluronic F68 / F127), polyglycerol fatty acid esters, alkyl glycosides (APG)), polyvinylpyrrolidone (PVP), Tween series (Tween-20 / 40 / 80)), amphoteric surfactants (lecithin, betaines (such as carboxybetaine), phosphorylcholine, sulfobetaine), natural hydrophilic polymers (hyaluronic acid (HA, molecular weight 50-200kDa), chitosan and its derivatives, sodium alginate, bile salts (such as sodium cholate)). In some specific implementation examples, the surfactant used is sodium hexametaphosphate (SHMP).

[0068] In step (3) above, the dry grinding time ranges from 5 to 60 minutes, and in some specific implementation examples, it is 15 minutes. Dry ball milling aims to improve the mixing uniformity of materials and surfactants. Too short a time can only achieve physical doping, while too long a time may result in excessive coating and waste of time. The appropriate time ensures that the material agglomerates are broken down, while helping the surfactant to contact the material more uniformly. Studies have shown that if the grinding time is less than 5 minutes, the mechanical force is insufficient, and the surfactant can only physically mix with the surface of the nanoparticles, failing to form a continuous adsorption layer. The agglomerates of nanoparticles are not effectively broken, resulting in a wide particle size distribution and poor dispersibility, which directly affects the efficiency of subsequent wet ball milling. Therefore, 5 minutes is the minimum threshold for effective grinding, ensuring that the system reaches the basic state of "initial particle dispersion + local adsorption of surfactant". When the grinding time is greater than 60 minutes, two major defects will occur: distortion of the crystal structure of nanoparticles or molecular chain breakage and functional group decomposition of surfactant due to mechanical shear force and local temperature rise, resulting in loss of dispersion and stabilization and instead causing secondary hard agglomeration of particles. Therefore, setting an upper limit of 60 minutes can avoid the deterioration of material properties caused by excessive grinding.

[0069] In step (3) above, the ball milling speed is 100~600 r / min, and in some specific implementation examples, the ball milling speed is 550 r / min. Regarding the ball milling speed: if the ball milling speed is too low, the surface modification may not be complete, and if the speed is too high, it will affect the material lattice structure. Studies have shown that setting a lower limit (100 r / min) can ensure the effective impact and shear of the ball milling media. The core function of the ball milling speed is to drive the grinding balls to generate impact, grinding, and shearing forces, so as to achieve the refinement and uniform dispersion of nanoparticles. If the speed is <100 r / min, the kinetic energy of the grinding balls is insufficient, and they can only slide rather than fall, which cannot effectively break up the particle agglomerates; material stratification will also occur in wet ball milling, resulting in uneven grinding. Setting an upper limit (600 r / min) is to avoid system failure caused by high rotation speed. When the rotation speed is greater than 600 r / min, the grinding balls will stick tightly to the inner wall of the ball mill jar due to excessive centrifugal force, losing the impact grinding effect. At the same time, the severe friction generated by high rotation speed will cause the system temperature to rise sharply (especially wet ball milling), destroying the surfactant structure and causing nanoparticle agglomeration or crystal transformation. Excessive rotation speed will also aggravate the wear between the grinding balls and the jar wall, introduce impurities to contaminate the nano-sensitizer, and affect its biocompatibility.

[0070] In step (3) above, the wet ball milling time is 2-12 hours, and in some specific implementation examples, the ball milling time is 6 hours. Regarding the ball milling time: the ball milling time will affect the water dispersion performance and lattice structure of the ultra-small hafnium oxide matrix. If the time is too short (1-3 hours), the surface modification will be incomplete, and if the time is too long (12-24 hours), it may destroy the material lattice structure and thus affect the material performance. Setting a lower limit (2 h) can achieve sufficient particle refinement and dispersion. If the time is <2 h, the particle refinement is insufficient, and there are still a large number of micron-sized agglomerates. The surfactant cannot form a dense double electric layer structure on the particle surface, the dispersion has poor stability, and it is easy to settle after standing. 2 h is the minimum time for the particle size to tend to stabilize, which can meet the basic dispersion requirements of the nano sensitizer. Setting an upper limit (24 h) can control process costs and avoid over-grinding; when the time exceeds 24 h, the particle size has reached its limit, and further extending the time cannot further refine the particle size, but instead increases energy consumption and production costs; prolonged ball milling will cause the liquid medium to evaporate (if not sealed), increase the system viscosity, and cause particle agglomeration; at the same time, the wear of the grinding balls will be accelerated, and the impurity content will exceed the standard. The preferred value of 6 h is based on a comprehensive consideration of particle size stability, dispersion shelf life, and production costs.

[0071] To meet the needs of actual clinical applications, the dosage forms of the sensitizers used in tumor radiotherapy include powder, suspension, emulsion or liposome dosage forms.

[0072] Preferably, the suspension formulation is the preferred formulation of this invention due to its advantages such as good dispersion stability, high bioavailability, and convenient administration.

[0073] Based on the requirements of clinical drug safety and physiological compatibility, the suspension dosage form preferably uses an isotonic system, which may include sodium chloride isotonic suspension, glucose isotonic suspension and phosphate buffer isotonic suspension. By precisely maintaining the osmotic pressure balance inside and outside the cell, the normal transmembrane transport of water and electrolytes is ensured, thereby maintaining the stability of the body's physiological functions and avoiding local tissue irritation or systemic adverse reactions caused by osmotic pressure imbalance.

[0074] To achieve optimal isotonicity and synergistic sensitizing activity, the concentration ranges and preferred values ​​for each isotonic system are as follows: Furthermore, the concentration of the sodium chloride solution is 0.5~1 w / v%, preferably 0.9 w / v%, which perfectly matches the osmotic pressure of human body fluids and has optimal biocompatibility; the concentration of the glucose solution is 3~8 w / v%, preferably 5 w / v%, which has both isotonic regulation and energy replenishment effects; the concentration of the phosphate buffer solution is 0.005~0.015M, preferably 0.01M, with stable pH buffering capacity, which can maintain the integrity of the sensitizer nanostructure.

[0075] The preferred concentrations used in the embodiments of the present invention conform to the standard concentrations of clinical buffer solutions, are isotonic to human body fluids, and ensure biocompatibility.

[0076] 1. Physiological saline: Concentrations below 0.5 w / v% result in excessively low osmotic pressure, which can lead to cell swelling and rupture (hemolysis / cell lysis). If used for in vivo administration of nano-sensitizers, this can cause local tissue edema, and the nanoparticles are prone to surface charge disorder and aggregation due to osmotic pressure imbalance. Concentrations above 1 w / v% result in excessively high osmotic pressure, causing cell dehydration and shrinkage. Simultaneously, high ionic strength can compress the double layer thickness of nanoparticles, damaging the surfactant coating layer and leading to sensitizer structural dissociation and loss of radiosensitizing activity. 0.9 w / v% is the preferred value, widely used in injectable formulations and cell experimental systems, ensuring the structural stability and biosafety of nano-sensitizers (such as NBTXR3 and HfO2:Cu) during in vivo and in vitro applications. Sodium chloride solutions in the 0.5–1 w / v% range have moderate ionic strength, preventing specific interactions with nanomaterials and interference with the targeted binding of sensitizers to tumor cells. Excessively high chloride ion concentrations may trigger electrolyte salting-out effects on the nanoparticle surface, leading to particle aggregation and sedimentation.

[0077] 2. Glucose solution: The osmotic pressure of a 5 w / v% glucose solution is basically the same as that of human body fluids, and it is an isotonic solution with isotonic adaptability. If the concentration is lower than 3 w / v%, the osmotic pressure is insufficient and cannot maintain an isotonic environment. In addition, the glucose content is too low and it is difficult to achieve effective energy supplementation. If the concentration is higher than 8 w / v%, the osmotic pressure of the solution is too high, which will cause cell dehydration. At the same time, high concentrations of glucose will promote non-enzymatic glycation of proteins and may cross-link with the functional groups on the surface of nano-sensitizers, destroying their nanostructure.

[0078] 3. Phosphate buffer solution: If the concentration is below 0.005 M, the total amount of buffer is insufficient to resist pH fluctuations (such as dissociation of functional groups on the surface of nanomaterials or introduction of external acid and alkali impurities). pH drift will disrupt the surface charge balance of nanoparticles, causing aggregation or structural dissociation. If the concentration is above 0.015 M, the ionic strength is too high, compressing the double layer thickness of nanoparticles and weakening the steric hindrance effect of surfactants, leading to particle aggregation. At the same time, high concentrations of phosphate ions may react with metal ions (such as Hf) on the surface of nanoparticles. 4+ It exhibits weak coordination, altering the surface activity of the material; 0.01 M is the preferred value, as this concentration provides sufficient buffering capacity to maintain pH stability, and the ionic strength is mild, without interfering with the crystal structure and surface coating integrity of the nano-sensitizer.

[0079] Regarding the concentration of the active ingredient in the sensitizer, to ensure the full realization of the radiotherapy sensitization effect, the concentration range of the active ingredient in the sensitizer suspension containing ultra-small metal ion-doped hafnium oxide is set at 30~100 mg / mL. -1 50mg / mL -1 The optimal concentration is one that allows for the effective enrichment of the sensitizer in tumor tissue while avoiding the risk of nanoparticle aggregation or toxicity due to excessively high concentrations.

[0080] Thirdly, the ultra-small metal ion-doped hafnium oxide nanoradiosensitizer described in this invention has application scenarios covering the entire process of tumor radiotherapy and multi-dimensional treatment needs, specifically including the following core application directions, and each application direction can be implemented individually or in combination.

[0081] The sensitizer described in this invention can be used to prepare adjuvant drugs for radiotherapy targeting conventional cancers and radiation-resistant cancers. It has a good radiosensitizing effect on different tumors, resulting in a significant reduction in tumor volume. The categories include: conventional cancer types, including but not limited to: pancreatic cancer, breast cancer, cervical cancer, prostate cancer, esophageal cancer, gastric cancer, thyroid cancer, oral cancer, nasopharyngeal cancer, bladder cancer, etc.; primary sites of radiation-resistant solid tumors include: triple-negative breast cancer, advanced non-small cell lung cancer, pancreatic cancer, primary liver cancer, colorectal cancer, bile duct cancer, ovarian cancer, melanoma, glioblastoma, etc.; metastatic sites of radiation-resistant solid tumors include: bone metastases, lung metastases, and brain metastases of triple-negative breast cancer; brain metastases, liver metastases, and bone metastases of non-small cell lung cancer; liver metastases and lung metastases of colorectal cancer; peritoneal metastases of pancreatic cancer; lymph node metastases, brain metastases of melanoma; lung metastases and bone metastases of renal cancer, etc.; and special types of cancer include: AIDS-related malignant skin tumors, germ cell tumors originating in the central nervous system, neuroblastoma in children, T-cell lymphoma in adults, multiple myeloma, acute myeloid leukemia, etc.

[0082] The sensitizers described in this invention are adaptable to various key stages of tumor radiotherapy, including: Initial radiotherapy: For newly diagnosed primary tumors that have not previously received radiotherapy, it can be used as a radiosensitizer to increase the sensitivity of tumor cells to radiation, reduce the initial radiotherapy dose, and improve local control rates; Re-radiotherapy: For tumors that relapse, progress, or develop acquired radiation resistance after initial radiotherapy, it can reverse the radiation resistance phenotype of tumor cells, restore their sensitivity to radiotherapy, and solve the clinical problem of poor re-radiotherapy efficacy; Palliative radiotherapy: For advanced, incurable tumors, it can be used in palliative radiotherapy to relieve pain and control tumor progression, enhancing the symptom control effect of radiotherapy and improving the patient's quality of life.

[0083] The sensitizers can also cover the following specific clinical needs: Advanced tumors that cannot be surgically removed: For tumors located in special locations (such as near major blood vessels or the central nervous system), are too large, or have multiple metastases that make surgery impossible, sensitizers can enhance the effectiveness of radiotherapy and achieve tumor control; Prevention and treatment of tumor metastasis: It can be used to prevent secondary metastasis after primary tumor treatment, especially for tumors such as melanoma, lung cancer, kidney cancer, and breast cancer that are prone to central nervous system metastasis. By optimizing blood-brain barrier permeability, it can reduce the risk of brain metastasis; Pediatric and elderly cancer patients: For pediatric cancer patients (such as Wilm's tumor, neuroblastoma, and Ewing sarcoma) and elderly and frail patients, sensitizers can reduce the radiotherapy dose, ensuring efficacy while reducing radiotherapy-related toxic side effects.

[0084] The sensitizer described in this invention can be used in combination with various clinical tumor treatment methods to form a synergistic treatment plan, specifically including: Combined with tumor surgery: It can be used as a neoadjuvant therapy drug before surgery to reduce tumor volume and improve surgical resection rate; or used as an adjuvant therapy drug after surgery to sensitize residual microlesions to radiotherapy and reduce the risk of recurrence; Combined with chemotherapy: It can be used in combination with commonly used chemotherapy drugs such as platinum-based drugs (cisplatin, carboplatin), taxane-based drugs (paclitaxel, docetaxel), and antimetabolites (fluorouracil, gemcitabine), through "chemotherapy killing + radiotherapy..." The synergistic effect of radiosensitization enhances the efficiency of tumor cell clearance; when combined with immunotherapy: it can be used in combination with immune checkpoint inhibitors such as PD-1 / PD-L1 inhibitors and CTLA-4 inhibitors. The tumor antigens released during radiosensitization can enhance the anti-tumor immune response of immunotherapy, achieving the dual effect of "sensitization + immune activation"; when combined with targeted therapy: it can be used in combination with targeted drugs such as EGFR inhibitors, HER-2 inhibitors, and VEGF inhibitors. The specific molecular targets of tumor cells complement the radiosensitization mechanism, improving the precision of treatment.

[0085] And / or, the sensitizer for tumor radiotherapy is used in combination with one or more of the clinical tumor surgery, chemotherapy and immunotherapy methods.

[0086] Furthermore, the sensitizers used for tumor radiotherapy can be used at any point during radiotherapy, such as as neoadjuvants (before cancer surgery) or as adjuvants (after surgery), and can also be used for advanced tumors that cannot be surgically removed.

[0087] The radiotherapy method suitable for the sensitizer described in this invention is ionizing radiation radiotherapy, wherein the radiation source includes, but is not limited to, X-rays, α-rays, β-rays, γ-rays, electron beams, neutron beams, proton beams, heavy ion beams, and radiation generated by the decay of radioactive isotopes. From the perspective of clinical practicality and sensitization effect, X-rays or γ-rays are particularly preferred excitation sources.

[0088] Specifically, the key parameters for radiotherapy radiation are as follows: Radiation voltage: typically 2~25000keV, with linear accelerator sources preferably at 2~6000keV, cobalt-60 sources preferably at 2~1500keV, and proton beam radiotherapy sources preferably at 100~250MeV; Total radiation dose: can be adjusted according to tumor type, stage, and treatment purpose, ranging from 30~80Gy, with conventional radical radiotherapy preferably at 50~70Gy, palliative radiotherapy preferably at 10~30Gy, and re-radiotherapy preferably at 30~50Gy; Fractionated dose: conventional radiotherapy fractionated dose is 1.0~2.0Gy / fraction, stereotactic radiotherapy fractionated dose is 3~10Gy / fraction, and sensitizers can be adapted to various fractionated dose regimens, and can further reduce damage to normal tissues in high-fractionated radiotherapy.

[0089] The administration methods of the sensitizers include, but are not limited to, the following types, and can be selected for use alone or in combination depending on the tumor location, size, and pathological type: Intratumoral injection: Suitable for primary solid tumors or superficial metastases. Direct intratumoral injection allows the sensitizer to accumulate locally in the tumor, preferably 1-24 hours before radiotherapy. Intravenous injection: Suitable for deep tumors, multiple metastatic tumors, or tumors where intratumoral injection is not possible. It can be administered via intravenous drip, preferably 2-6 hours before radiotherapy to ensure that the sensitizer reaches peak concentration in the tumor tissue during radiotherapy. Topical application: Suitable for malignant skin tumors (such as melanoma and basal cell carcinoma) and superficial tumors. It forms a drug film through topical application, which can continuously release the sensitizer during radiotherapy. It can be applied 1-2 times daily. Targeted drug delivery: By modifying the surface of the sensitizer nanoparticles with tumor-targeting ligands (such as RGD peptides and Herceptin antibodies), active targeting of tumor cells can be achieved. It can be administered via intravenous injection and is suitable for precision treatment needs. Intracavitary drug delivery: Suitable for tumors of hollow organs such as esophageal cancer, cervical cancer, and bladder cancer. It is administered via intracavitary instillation under the guidance of esophagoscopy, colposcopy, or cystoscopy, allowing the sensitizer to come into direct contact with the tumor mucosa.

[0090] The frequency of administration can be adjusted according to the radiotherapy cycle. The usual administration is once a day or once per radiotherapy fraction, and it is used continuously until the end of radiotherapy. For patients undergoing re-radiotherapy, it can be adjusted to once every other day according to the tumor regression. The total course of administration is 2 to 6 weeks.

[0091] The sensitizer described in this invention is suitable for radiotherapy of tumors in various mammals, including humans, mice, rats, rabbits, dogs, and monkeys. In human tumor treatment, it is suitable for patients of all ages, and in animal experimental studies, it can serve as a standard sensitizer tool for tumor radiotherapy research, providing data support for clinical translation.

[0092] The application scope and usage specifications of the sensitizers described in this invention are not limited to the specific examples above. Any application method that achieves sensitization effects throughout the entire tumor radiotherapy process based on ultra-small metal ion-doped hafnium oxide radiosensitization therapy falls within the protection scope of this invention. For tumor types, radiotherapy regimens, or administration methods not explicitly listed, if the sensitizers described in this invention are used to achieve radiosensitization effects, they also fall within the scope of this protection.

[0093] Example 1: Ultra-small copper ion-doped hafnium oxide nanosensitizer ( The preparation steps of ).

[0094] (1) Precursor The specific steps include: Dissolved in anhydrous ethanol, then added with sufficient trifluoroacetic acid, and stirred at 50°C for 6 hours, finally dried under vacuum at 60°C for 1 hour to obtain the final product. powder.

[0095] (2) Powder preparation. 2 mmol of the precursor from step (1), 1 mmol of CuCl2 in ethanol solution, and 80 mmol of oleylamine were added to a round-bottom flask, and a gradient heating was performed. First, the solution was heated to 110°C over 5 minutes and vacuum-treated for 30 minutes. Then, under argon protection, the temperature was slowly increased to 330°C and maintained for 1 hour until the reaction was complete. The reaction system was then allowed to cool naturally to room temperature. Excess ethanol was added to the round-bottom flask to precipitate the product, which was then centrifuged. The resulting precipitate was washed three times alternately with cyclohexane and ethanol, and then redispersed in cyclohexane to obtain… Dispersed in cyclohexane like Figure 1 As shown in ab, the particle size of the spherical structure revealed by transmission electron microscopy is approximately 10 nm, which is consistent with the results of dynamic light scattering.

[0096] (3) Preparation of US-HfO2:Cu@SHMP. In step (2), the precipitated product was washed three times alternately with cyclohexane and ethanol, then washed with water, centrifuged and dried. The dried powder was then calcined in air at 530°C for 3 hours to remove surface organic matter. To improve the water dispersion concentration of the material, wet ball milling was performed: 200mg of... The powder was dry-milled with 200 mg of sodium hexametaphosphate (SHMP) at a mass ratio of 1:1 for 15 minutes to obtain a mixture. This mixture, along with 20 mL of deionized water and 20 g of 1 mm diameter mortar beads, was then added to a ball mill jar and ball-milled at 500 r / min for 6 hours. After ball milling, the product was centrifuged and washed three times with water to thoroughly remove unbound SHMP. The final product was stored as an aqueous suspension until use. The target product US-HfO2:Cu@SHMP was characterized, and the relevant results are as follows: Figure 2As shown. Characterization confirmed that US-HfO2:Cu@SHMP exhibits a near-spherical morphology, with Cu and Hf elements uniformly dispersed in the material, and the particle size did not change significantly after SHMP modification. High-resolution transmission electron microscopy (HRTEM) determined the lattice fringe spacing of US-HfO2:Cu@SHMP to be 0.317 nm, a value that is basically consistent with the characteristic parameters of the (-111) crystal plane of monoclinic HfO2 (JCPDS standard card number: 06-0318), indicating its stable crystal structure. X-ray photoelectron spectroscopy (XPS) analysis further confirmed the presence of a characteristic Cu-O chemical structure in US-HfO2:Cu@SHMP, indicating that the Cu-O bond is firmly embedded in the HfO2 lattice system; and Cu mainly exists as Cu... 2+ The existence of valence states, through lattice substitution, forms a stable doping configuration, providing a good structural basis for the regulation of material properties.

[0097] Example 2: Dispersion performance of ultra-small copper ion-doped hafnium oxide nanosensitizer (US-HfO2:Cu@SHMP).

[0098] Characteristic such as Figure 3 The Zeta potential confirmed that the SHMP-modified US-HfO2:Cu@SHMP surface exhibited significant electronegativity, directly verifying the effective modification of the material surface by SHMP. This lays the foundation for the good dispersibility of US-HfO2:Cu@SHMP. Furthermore, 20 mg of US-HfO2:Cu@SHMP was dispersed in 2 mL of 5% glucose solution (5% GS), 2 mL of physiological saline, 2 mL of PBS, 2 mL of body fluid simulation solution (CM), or 2 mL of DMEM. The material exhibited excellent dispersibility in all of these solvent systems. Meanwhile, at a concentration of 70 mg / mL... -1 The US-HfO2:Cu@SHMP aqueous dispersion suspension exhibits good stability.

[0099] Example 3: Cell safety evaluation of ultrasmall copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP.

[0100] To evaluate the acute cytotoxicity of US-HfO2:Cu@SHMP in Example 1 against normal cells (human bronchial epithelioid cells BEAS-2B, human immortalized keratinocytes HaCaT, human umbilical vein endothelial cells HUVEC, mouse mammary epithelial cells HC11, and rat small intestinal crypt epithelial cells IEC-6) and acquired radiation-resistant 4T1R cells, 3000-5000 cells per well were seeded in 96-well plates and incubated for 8 hours until cell attachment. Then, US-HfO2:Cu@SHMP (0-800 μg / mL) was added. -1After co-incubating the materials and cells for 24 hours, cell viability was tested. Figure 4 It can be seen that US-HfO2:Cu@SHMP at 800 μg mL -1 Cell viability remained above 80% at all concentrations, indicating that US-HfO2:Cu@SHMP had no significant toxicity to normal cells in the experiment.

[0101] Example 4: Evaluation of the in vitro therapeutic mechanism of ultrasmall copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP.

[0102] (1) To evaluate the cell proliferation inhibition ability of US-HfO2:Cu@SHMP combined with external beam radiotherapy (BT) or brachytherapy (EBRT) in Example 1, 150 μg mL of the solution was added to a 6-well plate containing 1000 adherent 4T1R radiation-resistant tumor cells per well. -1 US-HfO2:Cu@SHMP and co-incubated for 6 hours before X-ray or... 192 Ir-γ ray irradiation (0, 2, 4, or 6 Gy) was performed, followed by incubation for 4–7 days until a distinct cell population was observed. The cell populations were fixed with paraformaldehyde, stained with Giemsa stain, and counted. The experimental results (…) Figure 5 The results showed that, compared with EBER, US-HfO2:Cu@SHMP combined with BT had the most significant inhibitory effect on the proliferation of acquired radiation-resistant 41TR cells, and its inhibitory effect was significantly different from that of EBRT combined with BT.

[0103] Example 5: Comparative experiment on the inhibition of cell proliferation by ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP or ultra-small hafnium oxide nanosensitizer US-HfO2@SHMP combined with BT.

[0104] 800 4T1R radiation-resistant tumor cells per well were seeded into six-well plates. After cell attachment, the culture medium was replaced with a solution containing 150 μg mL of [unclear text - likely a specific substance or solution]. -1 Cells were incubated in US-HfO2:Cu@SHMP or US-HfO2@SHMP medium for 8 hours, followed by BT irradiation at 0, 1, 2, or 3 Gy. During irradiation, a circular guide pin was placed in the center of each well to ensure complete coverage of the plate. After irradiation, cells were cultured until cell colonies formed, then fixed with 4% paraformaldehyde and stained using Giemsa stain. Experimental results ( Figure 6This study verified that, under the same dose of BT irradiation, copper-doped US-HfO2:Cu@SHMP exhibited a stronger inhibitory effect on the proliferation of acquired radiation-resistant 41TR cells than US-HfO2@SHMP alone. Furthermore, the radiosensitization ratio of US-HfO2:Cu@SHMP was 1.91, while that of US-HfO2@SHMP was only 1.27, indicating that copper ions play a crucial role in inhibiting 4T1R proliferation. These results demonstrate that the ultra-small copper ion-doped hafnium oxide US-HfO2:Cu@SHMP of this invention shows better radiosensitization potential in 4T1R acquired radiation-resistant tumor cells.

[0105] Example 6: Verification of copper-induced cell death and nuclear DNA damage induced by ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP combined with BT.

[0106] In a large dish inoculated with 41TR to obtain radiation-resistant tumor cells, 500 mg / mL of the solution was incubated. -1 In Example 1, the ultrasmall copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP was irradiated with 6 Gy BT for 6 h, and then cultured for another 24 h before cell collection and protein quantification. Western blotting was then performed to detect the expression of copper death-related proteins in the cells. The results showed that after US-HfO2:Cu@SHMP combined with BT treatment, intracellular copper death-related iron-sulfur cluster proteins (ferredoxin 1FDX1, lipoyl synthase LIAS, cis-aconitase 2ACO2, and DNA polymerase δ1POLD1) were significantly downregulated; in addition, DNA double-strand breaks (γH2AX) were also observed, such as… Figure 7 As shown. Simultaneously, immunofluorescence assays yielded conclusions consistent with Western blotting: US-HfO2:Cu@SHMP combined with BT treatment significantly downregulated intracellular ferredoxin FDX1 expression and showed marked accumulation of dihydrolipoamide S-acetyltransferase DLAT.

[0107] Example 7: Evaluation of the in vivo tumor treatment efficacy of ultrasmall copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP combined with BT.

[0108] On day 0 and day 6, 5 × 10⁵ ions were implanted into the right and left sides of the back of 6-week-old BALB / c mice, respectively. 5 4T1R-derived radiation-resistant cells were used to evaluate the therapeutic efficacy of primary and distant metastatic lesions, when the volume of the right-sided primary tumor reached approximately 140 mm. 3 Mice were randomly divided into 6 treatment groups: 2 groups received intratumoral injection of US-HfO2:Cu@SHMP, and the other 2 groups received US-HfO2:Cu@SHMP (concentration of 50 mg / mL for both groups).-1 Mice in the first two groups received 30 μL of PBS, while the remaining two groups received 30 μL of PBS. Six hours after injection, the primary tumors of mice in the two drug-treated groups and one PBS-treated group were irradiated with a single 2 Gy BT treatment, as illustrated in the diagram. Figure 8 As shown in ab. The treatment regimen includes a single drug injection, followed by 2 Gy irradiation daily for 3 consecutive days, with bilateral tumor volume monitored every two days until the tumor volume reaches 1.5 cm. 3 The testing was terminated. Treatment results ( Figure 8 c) showed that the primary tumor growth in mice treated with US-HfO2:Cu@SHMP combined with BT was significantly inhibited, and the treatment effect was significantly stronger than that in the US-HfO2:Cu@SHMP alone group and the BT alone group. Furthermore, H&E staining or Ki67 pathological analysis was performed on tumor samples from different treatment groups on day 3 of treatment. Results are as follows... Figure 8 As shown in Figure d, the primary tumors of mice treated with US-HfO2:Cu@SHMP combined with BT exhibited extensive cell condensation, nuclear fragmentation, and disordered tissue structure, with the most severe tumor cell necrosis. Simultaneously, the positive rate of the proliferation marker Ki67 was significantly reduced in this group, indicating that tumor cell proliferation was significantly inhibited. These results demonstrate that US-HfO2:Cu@SHMP combined with BT treatment has a significant inhibitory effect on tumor proliferation in mice.

[0109] Example 8: Evaluation of the remote effect of ultrasmall copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP combined with BT therapy.

[0110] Changes in the left distal tumor in Example 7 were monitored every two days, and the results were as follows: Figure 9As shown in the figure, when BT alone was used to treat the primary tumor, the distant metastatic lesions in the mice in this treatment group maintained a relatively rapid proliferation rate, and no obvious growth arrest was observed. When US-HfO2:Cu@SHMP was administered intratumorally alone, its effect on distant tumors was also weak, and the volume of distant lesions continued to increase with the extension of monitoring time. In stark contrast to the above groups, the mice treated with US-HfO2:Cu@SHMP combined with BT showed excellent remote tumor growth. The growth curve of distant tumors in this treatment group showed a significantly flattened trend, and the growth rate slowed down significantly. It was calculated that the tumor growth inhibition rate of the US-HfO2:Cu@SHMP alone treatment group was 12.57%, the tumor growth inhibition rate of the BT alone treatment group was 18.94%, while the tumor growth inhibition rate of US-HfO2:Cu@SHMP combined with BT treatment was 81.56%. This result fully confirms the clear synergistic effect between US-HfO2:Cu@SHMP and BT treatment, and that this combined treatment regimen can effectively activate the body's inhibitory mechanism against distant metastatic tumors.

[0111] Example 9: Evaluation of the inhibitory effect of ultrasmall copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP on lung tumor metastasis. The PBS group, the BT alone group, and the US-HfO2:Cu@SHMP treatment group served as control groups, while the US-HfO2:Cu@SHMP combined with BT group served as the experimental group. In all groups, after treatment of the primary lesion, CD8 counts were performed on lung tissue at the treatment endpoint. + Pathological section staining and statistical analysis of tumor metastatic lesion area. Experimental results are as follows: Figure 10 As shown in ab, at the treatment endpoint, large areas of metastatic tumor nodules were observed in the lungs of mice in the control group after dissection. While the number of lung metastases was relatively small in the BT treatment group and the US-HfO2:Cu@SHMP treatment group, a small number of local metastases still occurred. However, the US-HfO2:Cu@SHMP combined with BT treatment group exhibited significant anti-lung tumor metastasis performance, with no obvious metastatic lesions observed in the lungs of mice in this group. Simultaneously, immunohistochemical results confirmed a significant increase in the number of CD8+ cytotoxic T lymphocytes infiltrating the lung tissue of mice in the US-HfO2:Cu@SHMP combined with BT group. Figure 10 (cd). This result fully demonstrates the unique advantage of US-HfO2:Cu@SHMP in blocking distant lung metastasis of tumors.

[0112] Example 10: Organ safety evaluation of ultra-small copper ion-doped hafnium oxide nanosensitizer US-HfO2:Cu@SHMP.

[0113] In a 6-week-old BALB / c mouse model of acquired radiation-resistant breast cancer 4T1R, a single intratumoral injection of 50 μl (30 mg / mL) was administered. -1 US-HfO2:Cu@SHMP nanoradiosensitizer was used, and samples were taken, fixed, and H&E stained from major organs (heart, liver, spleen, lung, and kidney) on days 7 and 14 after administration. Pathological staining results were used to analyze the results. Figure 11 It can be seen that intratumoral injection of US-HfO2:Cu@SHMP did not cause significant damage to the major organs of mice.

[0114] Example 11: Preparation steps of ultra-small cerium ion-doped hafnium oxide nanosensitizer (US-HfO2:Ce).

[0115] (1) The precursor Hf(CF3COO)4 is prepared by dissolving HfCl4 in anhydrous ethanol, adding sufficient trifluoroacetic acid, stirring at 50°C for 6 hours, and finally drying under vacuum at 60°C for 1 hour to obtain Hf(CF3COO)4 powder.

[0116] (2) Preparation of US-HfO2:Ce powder. 2 mmol of the precursor from step (1), 1 mmol of CeCl3 in ethanol solution, and 80 mmol of oleylamine were added to a round-bottom flask, and the temperature was gradually increased. The solution was first heated to 110°C within 5 minutes and then vacuum-treated for 30 minutes. Subsequently, under argon protection, the temperature was slowly increased to 330°C and maintained for 1 hour until the reaction was complete. The reaction system was then allowed to cool naturally to room temperature. Excess ethanol was added to the round-bottom flask to precipitate the product, which was then centrifuged. The precipitate was washed three times alternately with cyclohexane and ethanol, and then redispersed in cyclohexane to obtain US-HfO2:Ce. The product US-HfO2:Ce was characterized, and the relevant results are as follows: Figure 12 As shown. X-ray diffraction (XRD) analysis results show clear crystal diffraction peaks in US-HfO2:Ce, and its crystal structure is consistent with the standard hafnium oxide spectrum (JCPDS standard card number: 04-002-0612). High-resolution X-ray photoelectron spectroscopy (XPS) analysis further confirms the effective doping of Ce ions in US-HfO2:Ce, and that Ce is the dominant ion. 4+ exist.

[0117] (3) Preparation of US-HfO2:Ce@SHMP. The precipitate in step (2) was washed three times with alternating cyclohexane and ethanol, then washed with water, centrifuged and dried. The dried powder was then calcined in air at 530°C for 3 hours to remove surface organic matter. To improve the water dispersion concentration of the material, wet ball milling was performed: 200 mg of US-HfO2:Ce powder and 200 mg of sodium hexametaphosphate (SHMP) were first dry-milled at a mass ratio of 1:1 for 15 minutes to obtain a mixture. Then, the mixture, 20 mL of deionized water and 20 g of 1 mm diameter mortar beads were added to a ball mill jar and ball-milled in a planetary ball mill at a speed of 500 r / min for 6 hours. After ball milling, the mixture was centrifuged and washed with water three times to fully remove unbound SHMP. US-HfO2:Ce@SHMP was finally stored in the form of an aqueous suspension until use.

[0118] Example 12: Preparation steps of ultra-small iron ion-doped hafnium oxide nanosensitizer (US-HfO2:Fe).

[0119] (1) The precursor Hf(CF3COO)4 is prepared by dissolving HfCl4 in anhydrous ethanol, adding sufficient trifluoroacetic acid, stirring at 50°C for 6 hours, and finally drying under vacuum at 60°C for 1 hour to obtain Hf(CF3COO)4 powder.

[0120] (2) Preparation of US-HfO2:Fe powder. 2 mmol of the precursor from step (1), 1 mmol of FeCl2 in ethanol solution, and 80 mmol of oleylamine were added to a round-bottom flask, and the temperature was gradually increased. The solution was first heated to 110°C within 5 minutes and then vacuum-treated for 30 minutes. Subsequently, under argon protection, the temperature was slowly increased to 330°C and maintained for 1 hour until the reaction was complete. The reaction system was then allowed to cool naturally to room temperature. Excess ethanol was added to the round-bottom flask to precipitate the product, which was then centrifuged. The precipitate was washed three times alternately with cyclohexane and ethanol, and then redispersed in cyclohexane to obtain US-HfO2:Fe. The product US-HfO2:Fe was characterized, and the relevant results are as follows: Figure 13 As shown. X-ray diffraction (XRD) analysis results show that US-HfO2:Fe has clear crystal diffraction peaks, and its crystal structure is consistent with the standard hafnium oxide spectrum (JCPDS standard card number: 01-075-6426); high-resolution X-ray photoelectron spectroscopy (XPS) analysis further confirms that Fe in US-HfO2:Fe is in the form of Fe... 3+ It is effectively doped into the HfO2 matrix.

[0121] (3) Preparation of US-HfO2:Fe@SHMP. The precipitate in step (2) was washed three times with alternating cyclohexane and ethanol, then washed with water, centrifuged and dried. The dried powder was then calcined in air at 530°C for 3 hours to remove surface organic matter. To improve the water dispersion concentration of the material, wet ball milling was performed: 200 mg of US-HfO2:Fe powder and 200 mg of sodium hexametaphosphate (SHMP) were first dry-milled at a mass ratio of 1:1 for 15 minutes to obtain a mixture. Then, the mixture, 20 mL of deionized water and 20 g of 1 mm diameter mortar beads were added to the ball mill jar and ball-milled in a planetary ball mill at a speed of 500 r / min for 6 hours. After ball milling, the mixture was centrifuged and washed with water three times to fully remove unbound SHMP. US-HfO2:Fe@SHMP was finally stored in the form of an aqueous suspension until use.

[0122] Example 13: Preparation steps of ultra-small manganese ion-doped hafnium oxide nanosensitizer (US-HfO2:Mn).

[0123] (1) The precursor Hf(CF3COO)4 is prepared by dissolving HfCl4 in anhydrous ethanol, adding sufficient trifluoroacetic acid, stirring at 50°C for 6 hours, and finally drying under vacuum at 60°C for 1 hour to obtain Hf(CF3COO)4 powder.

[0124] (2) Preparation of US-HfO2:Mn powder. 2 mmol of the precursor from step (1), 1 mmol of ethanol solution of MnCl2, and 80 mmol of oleylamine were added to a round-bottom flask, and the temperature was gradually increased. The solution was first heated to 110°C within 5 minutes and then vacuum-treated for 30 minutes. Subsequently, under argon protection, the temperature was slowly increased to 330°C and maintained for 1 hour until the reaction was complete. The reaction system was then naturally cooled to room temperature. Excess ethanol was added to the round-bottom flask to precipitate the product, which was then centrifuged. The precipitate was washed three times alternately with cyclohexane and ethanol, and then redispersed in cyclohexane to obtain US-HfO2:Mn. The product US-HfO2:Mn was characterized, and the relevant results are as follows: Figure 14 As shown. X-ray diffraction (XRD) analysis results show that US-HfO2:Mn has clear crystal diffraction peaks, and its crystal structure is consistent with the standard hafnium oxide spectrum (JCPDS standard card number: 01-075-6426); high-resolution X-ray photoelectron spectroscopy (XPS) analysis further confirms that Mn in US-HfO2:Mn is in the form of Mn2. 2+ It is effectively doped into the HfO2 matrix.

[0125] (3) Preparation of US-HfO2:Mn@SHMP. The precipitate in step (2) was washed three times with alternating cyclohexane and ethanol, then washed with water, centrifuged and dried. The dried powder was then calcined in air at 530°C for 3 hours to remove surface organic matter. To improve the water dispersion concentration of the material, wet ball milling was performed: 200 mg of US-HfO2:Mn powder and 200 mg of sodium hexametaphosphate (SHMP) were first dry-milled at a mass ratio of 1:1 for 15 minutes to obtain a mixture. Then, the mixture, 20 mL of deionized water and 20 g of 1 mm diameter mortar beads were added to a ball mill jar and ball-milled in a planetary ball mill at a speed of 500 r / min for 6 hours. After ball milling, the mixture was centrifuged and washed with water three times to fully remove unbound SHMP. US-HfO2:Mn@SHMP was finally stored in the form of an aqueous suspension until use.

[0126] Example 14: Validation of cell activation and p-STING expression induced by ultra-small manganese ion-doped hafnium oxide nanosensitizer (US-HfO2:Mn@SHMP) combined with external irradiation radiotherapy (RT).

[0127] 4T1R cells were seeded into culture dishes containing climbing smears. After adhesion, the culture medium was replaced with US-HfO2:Mn@SHMP medium, and a series of immunofluorescence assays were performed. Results are as follows: Figure 15 As shown, in the US-HfO2:Mn@SHMP combined with RT treatment group, p-STING protein in 41TR cells exhibited significant fluorescent signal enrichment, mainly located in the cytoplasm. In some cells, the fluorescent signal showed accumulation towards the perinuclear region, with significantly higher fluorescence intensity than the control group. In contrast, no specific fluorescent signal accumulation was observed in the cytoplasm of the control group cells. These results suggest that US-HfO2:Mn@SHMP combined with external beam radiation therapy may activate the cGAS-STING-related pathway in cells.

[0128] Example 15: Preparation steps of ultra-small cobalt ion doped hafnium oxide nanosensitizer (US-HfO2:Co).

[0129] (1) The precursor Hf(CF3COO)4 is prepared by dissolving HfCl4 in anhydrous ethanol, adding sufficient trifluoroacetic acid, stirring at 50°C for 6 hours, and finally drying under vacuum at 60°C for 1 hour to obtain Hf(CF3COO)4 powder.

[0130] (2) Preparation of US-HfO2:Co powder. 2 mmol of the precursor from step (1), 1 mmol of ethanol solution of CoCl2, and 80 mmol of oleylamine were added to a round-bottom flask, and the temperature was gradually increased. The solution was first heated to 110°C within 5 minutes and then vacuum-treated for 30 minutes. Subsequently, under argon protection, the temperature was slowly increased to 330°C and maintained for 1 hour until the reaction was complete. The reaction system was then allowed to cool naturally to room temperature. Excess ethanol was added to the round-bottom flask to precipitate the product, which was then centrifuged. The precipitate was washed three times alternately with cyclohexane and ethanol, and then redispersed in cyclohexane to obtain US-HfO2:Co. The product US-HfO2:Co was characterized, and the relevant results are as follows: Figure 16 As shown. X-ray diffraction (XRD) analysis results show that US-HfO2:Co has clear crystal diffraction peaks, and its crystal structure is in perfect agreement with the standard hafnium oxide spectrum (JCPDS standard card number: 01-075-6426); high-resolution X-ray photoelectron spectroscopy (XPS) analysis further confirms that Co in US-HfO2:Co is in the form of Co 2+ It is effectively doped into the HfO2 matrix.

[0131] (3) Preparation of US-HfO2:Co@SHMP. The precipitate in step (2) was washed three times with alternating cyclohexane and ethanol, then washed with water, centrifuged and dried. The dried powder was then calcined in air at 530°C for 3 hours to remove surface organic matter. To improve the water dispersion concentration of the material, wet ball milling was performed: 200 mg of US-HfO2:Co powder and 200 mg of sodium hexametaphosphate (SHMP) were first dry-milled at a mass ratio of 1:1 for 15 minutes to obtain a mixture. Then, the mixture, 20 mL of deionized water and 20 g of 1 mm diameter mortar beads were added to a ball mill jar and ball-milled in a planetary ball mill at a speed of 500 r / min for 6 hours. After ball milling, the mixture was centrifuged and washed with water three times to fully remove unbound SHMP. US-HfO2:Co@SHMP was finally stored in the form of an aqueous suspension until use.

[0132] (4) The US-HfO2:Co surface modification SHMP step is the same as step (3) in Example 1, and finally US-HfO2:Co@SHMP is obtained.

[0133] Example 16: Validation of cell death morphology induced by ultra-small cobalt ion-doped hafnium oxide nanosensitizer (US-HfO2:Co@SHMP) combined with external irradiation radiotherapy (RT).

[0134] In a large dish inoculated with 41TR radiation-resistant tumor cells, 500 mg / mL was administered. -1The ultra-small cobalt ion-doped hafnium oxide nanosensitizer US-HfO2:Co@SHMP in Example 15 was co-incubated for 6 hours, then irradiated with 6 Gy X-rays, followed by cell collection, fixation, and biological transmission electron microscopy analysis of cell morphology. The results are as follows: Figure 17 As shown in the analysis, the cells in the PBS treatment group, X-ray treatment group, and US-HfO2:Co@SHMP treatment group all maintained normal morphology and structure, with intact and continuous cell membranes, clear organelle structures such as mitochondria and endoplasmic reticulum, intact nuclear membranes, and uniform chromatin distribution, without significant structural abnormalities. Only the US-HfO2:Co@SHMP combined with X-ray treatment group showed obvious morphological characteristics of cell damage: complete disruption of cell membrane integrity, leakage of cytoplasmic contents, severe fragmentation of organelle structures, and complete disintegration of the overall cell morphology. This is consistent with the characteristics of late pyroptosis, suggesting that US-HfO2:Co@SHMP combined with external beam radiation therapy may induce pyroptosis.

[0135] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A kind of ultra-small nano-radiotherapy sensitizer, characterized in that, This includes ultra-small hafnium oxide matrices doped with functional metal ions.

2. The ultra-small nano-radiotherapy sensitizer according to claim 1, characterized in that, The ultra-small hafnium oxide matrix doped with functional metal ions has a surface modification layer.

3. The ultra-small nano-radiotherapy sensitizer according to claim 2, characterized in that, The surface modification layer is formed by modifying the surface of the ultra-small hafnium oxide matrix doped with functional metal ions using a surface modifier.

4. The ultra-small nano-radiotherapy sensitizer according to claim 3, characterized in that, The surface modifiers include, but are not limited to: anionic surfactants, nonionic surfactants, amphoteric surfactants, and natural hydrophilic polymers; the methods for modifying the surface of the ultrasmall hafnium oxide matrix using surface modifiers include, but are not limited to: non-covalent modification, covalent bonding modification, and composite modification; the functional metal ions are one or more of Cu ions, Fe ions, Co ions, Mn ions, Ce ions, Ga ions, Mo ions, Pt ions, Au ions, and Ag ions.

5. The ultra-small nano-radiotherapy sensitizer according to any one of claims 1 to 4, characterized in that, The particle size of the ultra-small hafnium oxide matrix doped with functional metal ions is 3~20nm; the crystal form of the ultra-small hafnium oxide matrix doped with functional metal ions is monoclinic phase, or a mixture of monoclinic and tetragonal phases, or a latticeless structure; wherein, the mass proportion of monoclinic phase in the mixture is not less than 50%.

6. The ultra-small nano-radiotherapy sensitizer according to any one of claims 1 to 4, characterized in that, The total doping amount of the functional metal ions is 5-30% of the molar amount of Hf metal in the hafnium oxide matrix.

7. The ultra-small nano-radiotherapy sensitizer according to any one of claims 1 to 4, characterized in that, The dosage form of the ultra-small nano-radiotherapy sensitizer is powder, suspension, emulsion or liposome.

8. A method for preparing an ultra-small nano-radiotherapy sensitizer, comprising the following steps: Preparation of hafnium trifluoroacetate: Hafnium source was dissolved in anhydrous ethanol, then sufficient trifluoroacetic acid was added and stirred at a constant temperature. Hafnium trifluoroacetate powder was then obtained by vacuum rotary evaporation. Preparation of ultra-small metal ion-doped hafnium oxide: The prepared trifluoroacetic acid hafnium, an organic solution containing metal ions that can be doped into the ultra-small hafnium oxide matrix, and oleylamine were added to a container and stirred. Under vacuum or alternating inert gas protection, the temperature was increased by a programmed process and kept constant for a period of time. After cooling to room temperature, excess ethanol was added to the container to precipitate the product. The precipitate was washed and dried. Then, the organic matter on the surface of the dried powder was removed to obtain ultra-small metal ion-doped hafnium oxide, which can be used as an ultra-small nano-radiotherapy sensitizer.

9. The method according to claim 8, characterized in that, The surface of the ultra-small metal ion-doped hafnium oxide was modified with a surface modifier to obtain ultra-small metal ion-doped hafnium oxide with a surface modification layer, which can be used as an ultra-small nano-radiotherapy sensitizer.

10. The application of the ultra-small nano-radiosensitizer according to claim 1 in the preparation of adjuvant drugs for tumor radiotherapy.

Images