High-selectivity sensitizer for solid tumor radiotherapy and preparation method thereof

Abstract

The invention belongs to the field of biological medicine, and particularly relates to a high-selectivity sensitizer for solid tumor radiotherapy and a preparation method thereof.The sensitizer comprises two newly-designed modified compounds: a derivative based on a diamino-anthraquinone structure and capable of enhancing radiation energy deposition and relieving tumor hypoxia; and the other one is a cystamine derivative containing a diselenide bond, and can effectively consume overexpressed glutathione in tumor cells and enhance the generation of active oxygen. The preparation method comprises the following steps: dissolving the two modified compounds and the biodegradable polymer in an organic solvent to form an organic phase, dissolving phospholipid polyethylene glycol amino in warm water, blending with a stabilizer in a buffer solution to form a water phase, dropwise adding the organic phase into the water phase through a nano-precipitation method, self-assembling to form nano-particles, and filtering and purifying to obtain a final product. The sensitizer can specifically target tumor tissues, the radiotherapy effect is remarkably improved through a multiple synergistic mechanism, meanwhile, the damage to normal tissues is reduced, the preparation process is simple and convenient, and the reproducibility is good.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a highly selective sensitizer for radiotherapy of solid tumors and its preparation method. Background Technology

[0002] Radiotherapy for solid tumors, as one of the core treatment methods in clinical oncology, plays an irreplaceable role in controlling local lesions. However, its therapeutic effect is always severely constrained by the inherent characteristics of the tumor microenvironment. Solid tumors generally have insufficient blood perfusion and abnormally proliferating vascular networks, leading to low oxygen delivery efficiency and thus forming large-scale hypoxic areas. This hypoxic state significantly reduces the killing efficacy of radiation on tumor cells, because radiation-induced DNA damage is more easily repaired under hypoxic conditions. At the same time, to adapt to oxidative stress, tumor cells usually overexpress a series of endogenous antioxidants, among which the glutathione system is the most prominent. High concentrations of glutathione can efficiently scavenge reactive oxygen free radicals generated by radiation, providing a strong self-protective barrier for tumor cells. The two major factors of hypoxia and high antioxidant levels together constitute the core mechanism of tumor radioresistance, forcing clinical practice to increase radiation doses to pursue therapeutic effects, but this also increases the risk of damage to surrounding normal tissues, severely limiting the therapeutic window of radiotherapy.

[0003] To overcome these challenges, the scientific community has developed various types of radiosensitizers, but these existing technologies all have significant limitations. One widely studied class of sensitizers relies on high atomic number metal elements, which physically enhance the killing effect by increasing the deposition of local radiation energy. However, these materials are difficult to metabolize in vivo, raising questions about their long-term biosafety, and they cannot improve the hypoxic microenvironment. Another strategy uses hypoxia-activated prodrugs. These compounds are reduced to cytotoxic substances in hypoxic regions, but their sensitizing effect is limited by the degree of hypoxia and they have no effect on glutathione, which is highly expressed in tumors. Furthermore, although some studies have attempted to develop nanomaterials with glutathione depletion functions, they often lack tumor specificity and may simultaneously weaken the antioxidant defense capabilities of normal cells, leading to systemic toxic side effects. Common problems with existing sensitizers include single functional mechanisms, insufficient target specificity, poor biocompatibility, and complex preparation processes, making it difficult for them to achieve an ideal risk-benefit ratio in clinical applications.

[0004] Therefore, there is an urgent need in this field to develop a novel radiosensitizer that can simultaneously solve multiple technical challenges. An ideal product should possess the following characteristics: effectively improve the hypoxic microenvironment of tumors, fundamentally reversing radioresistance; specifically consume glutathione overexpressed in tumor cells, weakening their self-repair capabilities; significantly enhance the deposition efficiency of radiation energy without damaging normal tissues; and also possess good biodegradability and in vivo safety. Furthermore, from an industrialization perspective, the raw materials for this sensitizer should be readily available, and the preparation process should be simple and controllable to ensure product quality stability and reproducibility. Currently, there are no mature products on the market that simultaneously meet all of the above requirements, and this technological gap severely restricts further improvements in radiotherapy efficacy. The purpose of this invention is to provide an innovative solution to this pressing technical challenge. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a highly selective sensitizer for radiotherapy of solid tumors and its preparation method.

[0006] In a first aspect, the present invention provides a method for preparing a highly selective sensitizer for radiotherapy of solid tumors, comprising the steps of:

[0007] S1. Dissolve polylactic acid-glycolic acid copolymer in acetonitrile to obtain an organic phase; add 2,3-dihydroxypropyl-1,4-diaminoanthraquinone and N,N'-bis(2-seleno-1-carboxyethyl)cystamine to the organic phase and sonicate to obtain an organic phase mixture; dissolve 1,2-distearate-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino in deionized water at 58-62℃ and sonicate to obtain a solution; add the solution and Pronnic F-68 to a phosphate buffer solution and mix to obtain an aqueous phase; add the organic phase mixture dropwise to the aqueous phase while stirring, and continue stirring after the addition is complete to obtain a suspension;

[0008] S2. The suspension is first pre-filtered through a sieve, then aseptically filtered through a microporous membrane; finally, it is concentrated using a tangential flow ultrafiltration system and dispensed.

[0009] In this invention, the construction of the nano-sensitizer is based on multiple mechanisms of molecular self-assembly and interface stabilization. When the organic phase is slowly injected into the aqueous phase, the biodegradable polymer undergoes rapid phase separation at the interface, forming a nanoscale core framework. Two functional compounds are effectively encapsulated within the nanoparticles through hydrophobic interactions and π-π stacking effects. The anthraquinone derivative interacts strongly with the polymer chains through its planar aromatic structure, while the selenocysteine ​​derivative is positioned at the interface region through its amphiphilic characteristics. Surfactant molecules spontaneously migrate to the interface during nanoparticle formation, with their hydrophobic ends anchored on the particle surface and their hydrophilic segments extending into the aqueous phase to form a three-dimensional protective layer. Notably, the phospholipid polyethylene glycol amino derivative, after preheating, exhibits a more extended molecular conformation, enabling it to more uniformly coat the nanoparticle surface and form a dense hydrophilic protective layer. This structure not only prevents particle aggregation through steric hindrance but also provides active sites for subsequent targeted molecular modification with its terminal amino groups. The entire assembly process involves precise control of stirring speed and time, allowing the organic solvent to gradually diffuse into the aqueous phase, ultimately forming a stable nano-dispersion system with a core-shell structure and uniform particle size. This multi-level self-assembly mechanism ensures the correct positioning of each functional component and the effective synergistic effect.

[0010] As a preferred embodiment of the present invention, in step S1, the stirring time is 12-14 hours.

[0011] As a preferred embodiment of the present invention, in step S2, the particle size of the sieve is 350-450 mesh.

[0012] As a preferred embodiment of the present invention, the preparation method of 2,3-dihydroxypropyl-1,4-diaminoanthraquinone includes: A1, dissolving 1,4-diaminoanthraquinone in anhydrous N,N-dimethylformamide, adding potassium carbonate, adding 3-chloro-1,2-propanediol dropwise, reacting under nitrogen protection at 84-86°C to obtain a reaction mixture; A2, cooling the reaction mixture to room temperature, precipitating it in ice water, adjusting the pH to neutral with hydrochloric acid, filtering and collecting the precipitate, washing the precipitate with water and ethanol, and drying it under vacuum at 38-42°C.

[0013] In this invention, the preparation of 2,3-dihydroxypropyl-1,4-diaminoanthraquinone is based on the nucleophilic substitution reaction mechanism between aromatic amines and haloalcohols. Using 1,4-diaminoanthraquinone as the parent nucleus, its two amino groups in its molecular structure endow it with strong nucleophilic properties. In an anhydrous environment, potassium carbonate, as a highly efficient acid-binding agent, neutralizes the hydrogen chloride generated in the reaction, shifting the reaction equilibrium to the right. When 3-chloro-1,2-propanediol is added to the system as an alkylating agent, its chlorine atom is activated by the adjacent hydroxyl group, making it more susceptible to nucleophilic attack by the amino group. Under strictly controlled mass ratios, a single-sided substitution reaction mainly occurs, where one amino group forms a stable carbon-nitrogen covalent bond with the chloromethyl group of the propylene glycol chain, while retaining the chemical reactivity of the other amino group, reserving space for subsequent functionalization modifications. During the reaction, nitrogen protection effectively prevents the oxidative degradation of the anthraquinone structure, while a suitable reaction temperature ensures both the reaction rate and avoids the formation of byproducts. The final product can be efficiently separated into modified anthraquinone derivatives with amphiphilic structures through acid-base neutralization precipitation and solvent washing. The retained hydroxyl and amino groups together constitute multiple interaction sites, laying the molecular foundation for subsequent nano-assembly and functionalization.

[0014] As a preferred embodiment of the present invention, in step A1, the mass ratio of 1,4-diaminoanthraquinone, potassium carbonate and 3-chloro-1,2-propanediol is 1:0.75:0.8.

[0015] As a preferred embodiment of the present invention, in step A2, the vacuum drying time at 38-42°C is 12-14 hours.

[0016] As a preferred technical solution of the present invention, the preparation method of N,N'-bis(2-seleno-1-carboxyethyl)cystamine includes: B1, suspending cystamine dihydrochloride in tetrahydrofuran, adding triethylamine, cooling to 0-2°C in an ice-water bath, and then adding a tetrahydrofuran solution containing selenoacetic acid succinimide ester; B2, after the addition is complete, raising the temperature to room temperature for reaction, filtering after the reaction is complete, concentrating the filtrate by rotary evaporation, and then recrystallizing with ethyl acetate.

[0017] In this invention, the preparation of N,N'-bis(2-seleno-1-carboxyethyl)cystamine is based on a synergistic reaction mechanism of amide condensation and disulfide selenization substitution. Cystamine dihydrochloride is used as the starting material, with the disulfide bond and the two amino groups at both ends forming the key functional units. In an organic solvent, triethylamine first undergoes a neutralization reaction with the cystamine hydrochloride, releasing free amino groups and significantly enhancing its nucleophilic reactivity. Subsequently, selenoacetic acid succinimide ester is added as an active acylation reagent; its succinimide ester group, as an excellent leaving group, is readily subjected to nucleophilic attack from the amino groups in the cystamine molecule. Under strictly controlled mass ratios and low-temperature reaction conditions, the amino groups at both ends of the cystamine undergo amidation reactions with two molecules of selenoacetic acid succinimide ester, respectively, forming a symmetrical diamide structure. During this process, the selenium atom in the selenoacetic acid molecule is successfully introduced into the cystamine backbone, replacing the original sulfur atom function and forming a more reactive selenium-sulfur hybrid structure. This structural transformation allows the final product to retain the redox response characteristics of disulfide bonds while introducing the glutathione peroxidase-mimicking activity unique to selenium, enabling it to achieve dual antioxidant defense functions in the tumor microenvironment.

[0018] As a preferred embodiment of the present invention, in step B1, the mass ratio of cystamine dihydrochloride, triethylamine and selenoacetic acid succinimide ester is 1:1.0:1.5.

[0019] As a preferred embodiment of the present invention, in step B2, the reaction time at room temperature is 12-14 hours.

[0020] In a second aspect, the present invention provides a method for preparing a highly selective radiosensitizer for solid tumor radiotherapy, comprising the following raw materials in parts by weight: 3-8 parts by weight of 2,3-dihydroxypropyl-1,4-diaminoanthraquinone; 2-5 parts by weight of N,N'-bis(2-seleno-1-carboxyethyl)cystamine; 8-15 parts by weight of polylactic acid-glycolic acid copolymer; 1-3 parts by weight of 1,2-distearate-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino; 1-4 parts by weight of Pronic F-68; and 60-80 parts by weight of phosphate buffer solution.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] This invention achieves precise targeting and multiple synergistic sensitization of tumor tissue, significantly improving the efficacy and safety of radiotherapy. Through the perfect combination of two rationally designed functional compounds and a nanocarrier system, this sensitizer can exert multiple synergistic effects in the complex tumor microenvironment. Specifically, the anthraquinone-based derivative not only serves as a highly efficient radiation energy deposition center, enhancing the damage effect of radiation on tumor cell DNA, but its unique diol structure also catalyzes the decomposition of endogenous hydrogen peroxide at the tumor site to generate oxygen, effectively alleviating the tumor hypoxia problem that plagues traditional radiotherapy and fundamentally improving radiotherapy resistance. Simultaneously, another cystamine derivative containing a diselenoylene bond acts as a disruptor of the intracellular antioxidant defense system. It can efficiently consume overexpressed glutathione in tumor cells, weakening the tumor cells' self-repair ability, and releasing selenides with strong radiosensitizing effects in the process, further amplifying the killing effect of reactive oxygen species generated by radiation. These three mechanisms—enhancing radiation deposition, improving the hypoxic microenvironment, and consuming antioxidants—are not simply additive; rather, they promote each other and work synergistically to form a three-dimensional, multi-layered sensitization system, resulting in an unprecedented increase in the sensitivity of tumor cells to radiation.

[0023] The sensitizers of this invention exhibit remarkable innovation and selectivity in molecular structure and formulation process, minimizing potential damage to normal tissues. This high selectivity stems primarily from their unique nanoscale effect and surface properties. By precisely controlling the rate of organic phase injection into the aqueous phase and the stirring time during the preparation process, the formed nanoparticles are ensured to have a uniform particle size distribution and good dispersibility, enabling them to specifically accumulate within tumor tissues through enhanced penetration and retention effects. More importantly, the design concept of the two functional compounds fully considers the specificity of the tumor microenvironment. The cystamine derivative containing a diselenylene bond contains a chemical bond that is sensitive to the high concentration of glutathione in tumor cells. This acts as a smart biological switch, ensuring that its functions of consuming glutathione and enhancing reactive oxygen species are mainly activated within tumor cells, while remaining relatively inert in healthy tissues with normal glutathione levels. Furthermore, a unique process, which involves first pretreating the phospholipid polyethylene glycol amino derivative by dissolving it in hot water at a specific temperature before mixing it with other aqueous components, ensures that this key surface modifier can be uniformly distributed on the surface of nanoparticles, forming a stable hydrophilic protective layer. This not only prolongs the circulation time of the particles in the blood but also further enhances their targeted enrichment ability at tumor sites, thereby achieving precise control over the spatial distribution of the sensitizing effect.

[0024] This invention demonstrates excellent practicality and safety in terms of raw material selection, preparation process, and biocompatibility, and has broad prospects for clinical translation. All raw materials involved in the reaction are commercially available standard chemicals, which not only ensures the stability of production supply but also greatly controls raw material costs, avoiding the high costs and supply chain risks associated with using specially customized raw materials. The entire preparation process, from the synthesis of the two core functional compounds to the final assembly of the nano-sensitizer, employs classic and mature reactions and processes in the fields of organic synthesis and nano-formulation, such as nanoprecipitation, filtration sterilization, and tangential flow ultrafiltration concentration. These methods are simple to operate, mild, and highly reproducible, making them very suitable for large-scale industrial production in the future. Regarding biosafety, all components have been carefully screened. The polymeric carrier is a biodegradable material approved by regulatory agencies for use in medical products. The two functional compounds are expected to be metabolized or excreted after exerting their effects. The Pluronic stabilizer and phospholipid polyethylene glycol derivative are both widely used and safe excipients in formulations. In summary, this sensitizer successfully solves the key bottlenecks of traditional radiotherapy sensitizers, such as limited functionality, poor targeting, and high toxicity, providing a novel and highly promising solution for achieving efficient and low-toxicity tumor radiotherapy. Detailed Implementation

[0025] To facilitate understanding of the present invention, the following embodiments are provided. Those skilled in the art should understand that these embodiments are merely illustrative and should not be construed as limiting the scope of the invention.

[0026] The sources of some components in the examples and comparative examples are as follows:

[0027] The 1,2-distearate-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino compound was purchased from Chongqing Yusi Pharmaceutical Technology Co., Ltd.

[0028] The Prnik F-68 was purchased from BASF AG.

[0029] The 1,4-diaminoanthraquinone was purchased from Henan Wokas Biotechnology Co., Ltd.

[0030] The potassium carbonate was purchased from Henan Yilu Chemical Technology Co., Ltd.

[0031] The 3-chloro-1,2-propanediol was purchased from Changzhou Ditong Chemical Co., Ltd.

[0032] The cystamine dihydrochloride was purchased from Beijing Solarbio Technology Co., Ltd.

[0033] The triethylamine was purchased from Tianjin Xiens Biochemical Technology Co., Ltd.

[0034] The selenoacetic acid succinimide ester was purchased from Shanghai Jinjinle Industrial Co., Ltd.

[0035] Example 1

[0036] This embodiment provides a highly selective radiosensitizer for radiotherapy of solid tumors and its preparation method. First, 2,3-dihydroxypropyl-1,4-diaminoanthraquinone is prepared: 10.0 g of 1,4-diaminoanthraquinone is accurately weighed and placed in a 500 mL three-necked flask, and 200 mL of anhydrous N,N-dimethylformamide is added. The mixture is stirred in a 40°C water bath until completely dissolved. Then, 7.5 g of potassium carbonate is added as a catalyst, and the mixture is stirred at 300 rpm under nitrogen protection. 8.0 g of 3-chloro-1,2-propanediol is slowly added dropwise using a constant-pressure dropping funnel, controlling the dropping rate at 1 mL per minute. After the addition is complete, the reaction system is heated to 85°C and reacted under a nitrogen atmosphere. The reaction should be carried out for 6 hours, during which the reaction progress should be monitored by thin-layer chromatography. After the reaction is completed, the reaction mixture is cooled to 25°C and poured into a beaker containing 500g of crushed ice while stirring. The pH value is adjusted to 7.0 with 1mol / L hydrochloric acid solution, at which point a large amount of dark red precipitate is formed. The precipitate is collected by filtration through a Buchner funnel and washed three times each with 100mL of deionized water and 100mL of anhydrous ethanol. The obtained solid is placed in a vacuum drying oven and dried at 40°C for 12 hours to obtain a dark red crystalline solid product, 2,3-dihydroxypropyl-1,4-diaminoanthraquinone.

[0037] Next, N,N'-bis(2-seleno-1-carboxyethyl)cystamine was prepared: 5.0 g of cystamine dihydrochloride was accurately weighed and placed in a 250 mL round-bottom flask, and 100 mL of anhydrous tetrahydrofuran was added. The mixture was stirred at 200 rpm at 25 °C to form a suspension. 5.0 g of triethylamine was added as an acid-binding agent, and the reaction flask was placed in an ice-water bath to cool to 0 °C. 7.5 g of selenoacetic acid succinimide ester was weighed and dissolved in 50 mL of anhydrous tetrahydrofuran. The solution was slowly added dropwise to the reaction system at a rate of 2 mL per minute using a constant-pressure dropping funnel. After the addition was complete... Afterward, remove the ice-water bath and allow the reaction system to naturally heat to 25°C. Continue stirring the reaction for 12 hours. After the reaction is complete, filter the generated triethylamine hydrochloride using a sintered glass funnel. Transfer the filtrate to a rotary evaporator and concentrate it under reduced pressure to one-third of its original volume at a water bath temperature of 40°C. Add 100 mL of ethyl acetate to the concentrate and let it stand at 4°C for 12 hours for recrystallization. Collect the precipitated pale yellow crystals by vacuum filtration and wash twice with 20 mL of cold ethyl acetate to obtain N,N'-bis(2-seleno-1-carboxyethyl)cystamine.

[0038] Finally, a highly selective sensitizer was prepared: 10.0 g of polylactic acid-glycolic acid copolymer was accurately weighed and placed in a 250 mL beaker, 50 mL of acetonitrile was added, and the mixture was sonicated in a 25 °C water bath for 30 minutes until completely dissolved; 5.0 g of the 2,3-dihydroxypropyl-1,4-diaminoanthraquinone and 3.0 g of N,N'-bis(2-seleno-1-carboxyethyl)cystamine were added to this organic phase, and sonication was continued for 30 minutes to obtain a homogeneous organic phase mixture; 2.0 g of 1,2-distearate-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino was placed in a 50 mL beaker, 10 mL of deionized water at 60 °C was added, and the mixture was sonicated for 20 minutes until completely dissolved; this solution was then mixed with 2 0.0g of Prönkel F-68 was added to a 500mL three-necked flask containing 70g of phosphate buffer solution. The mixture was stirred at 400rpm for 30 minutes at 25°C to obtain a homogeneous aqueous phase. Under continuous stirring, the organic phase mixture was slowly added dropwise to the aqueous phase at a rate of 3mL per minute using a peristaltic pump over a period of 20 minutes. After the addition was complete, stirring was continued for 12 hours to ensure complete evaporation of the organic solvent, resulting in a milky white suspension. This suspension was pre-filtered through a 400-mesh stainless steel sieve and then aseptically filtered through a 0.22μm microporous membrane. Finally, it was concentrated to a final volume of 50mL using a tangential flow ultrafiltration system at a pressure of 0.1MPa and dispensed into 10mL sterile glass vials to obtain the final product.

[0039] Example 2

[0040] This embodiment provides another highly selective sensitizer for radiotherapy of solid tumors and its preparation method. First, 2,3-dihydroxypropyl-1,4-diaminoanthraquinone is prepared: 8.0 g of 1,4-diaminoanthraquinone is accurately weighed and placed in a 500 mL three-necked flask, and 160 mL of anhydrous N,N-dimethylformamide is added. The mixture is stirred in a 40 °C water bath until completely dissolved. Then, 6.0 g of potassium carbonate is added as a catalyst, and the mixture is stirred at 300 rpm under nitrogen protection. 6.4 g of 3-chloro-1,2-propanediol is slowly added dropwise using a constant pressure dropping funnel at a rate of 0.8 mL per minute. After the addition is complete, the reaction system is heated to 85 °C under a nitrogen atmosphere. The reaction was carried out for 6 hours, during which the reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction mixture was cooled to 25°C and poured into a beaker containing 400g of crushed ice while stirring. The pH was adjusted to 7.0 with 1mol / L hydrochloric acid solution, at which point a large amount of dark red precipitate was formed. The precipitate was collected by filtration through a Buchner funnel and washed three times each with 80mL of deionized water and 80mL of anhydrous ethanol. The obtained solid was placed in a vacuum drying oven and dried at 40°C for 12 hours to obtain a dark red crystalline solid product, 2,3-dihydroxypropyl-1,4-diaminoanthraquinone.

[0041] Next, N,N'-bis(2-seleno-1-carboxyethyl)cystamine was prepared: 4.0 g of cystamine dihydrochloride was accurately weighed and placed in a 250 mL round-bottom flask, and 80 mL of anhydrous tetrahydrofuran was added. The mixture was stirred at 200 rpm at 25 °C to form a suspension. 4.0 g of triethylamine was added as an acid-binding agent, and the reaction flask was placed in an ice-water bath to cool to 0 °C. 6.0 g of selenoacetic acid succinimide ester was weighed and dissolved in 40 mL of anhydrous tetrahydrofuran. The solution was slowly added dropwise to the reaction system at a rate of 1.6 mL per minute using a constant-pressure dropping funnel. After the addition was complete... The ice-water bath was then removed, and the reaction system was allowed to naturally heat to 25°C. The reaction was continued with stirring for 12 hours. After the reaction was completed, the generated triethylamine hydrochloride was removed by filtration through a sintered glass funnel. The filtrate was transferred to a rotary evaporator and concentrated under reduced pressure to one-third of its original volume at a water bath temperature of 40°C. 80 mL of ethyl acetate was added to the concentrate, and the solution was allowed to stand at 4°C for 12 hours for recrystallization. The precipitated pale yellow crystals were collected by vacuum filtration and washed twice with 16 mL of cold ethyl acetate to obtain the target product N,N'-bis(2-seleno-1-carboxyethyl)cystamine.

[0042] Finally, a highly selective sensitizer was prepared: 8.0 g of polylactic acid-glycolic acid copolymer was accurately weighed and placed in a 250 mL beaker, 40 mL of acetonitrile was added, and the mixture was sonicated in a 25 °C water bath for 30 minutes until completely dissolved; 3.0 g of the 2,3-dihydroxypropyl-1,4-diaminoanthraquinone and 2.0 g of N,N'-bis(2-seleno-1-carboxyethyl)cystamine prepared above were added to this organic phase, and sonication was continued for 30 minutes to obtain a homogeneous organic phase mixture; 1.0 g of 1,2-distearate-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino was placed in a 50 mL beaker, 5 mL of deionized water at 60 °C was added, and the mixture was sonicated for 20 minutes until completely dissolved; this solution was then mixed with 1.0 g of acetonitrile-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino. The organic phase was added to a 500 mL three-necked flask containing 60 g of phosphate buffer solution and stirred at 400 rpm for 30 minutes at 25 °C to obtain a homogeneous aqueous phase. While stirring continuously, the organic phase mixture was slowly added dropwise to the aqueous phase at a rate of 2.4 mL per minute using a peristaltic pump over a period of 18 minutes. After the addition was complete, stirring was continued for 12 hours to ensure complete evaporation of the organic solvent, resulting in a milky white suspension. This suspension was pre-filtered through a 400-mesh stainless steel sieve and then aseptically filtered through a 0.22 μm microporous membrane. Finally, it was concentrated to a final volume of 40 mL using a tangential flow ultrafiltration system at 0.1 MPa pressure and dispensed into 10 mL sterile glass vials to obtain the final product.

[0043] Example 3

[0044] This embodiment provides another highly selective sensitizer for radiotherapy of solid tumors and its preparation method. First, 2,3-dihydroxypropyl-1,4-diaminoanthraquinone is prepared: 12.0 g of 1,4-diaminoanthraquinone is accurately weighed and placed in a 500 mL three-necked flask, and 240 mL of anhydrous N,N-dimethylformamide is added. The mixture is stirred in a 40 °C water bath until completely dissolved. Then, 9.0 g of potassium carbonate is added as a catalyst, and the mixture is stirred at 300 rpm under nitrogen protection. 9.6 g of 3-chloro-1,2-propanediol is slowly added dropwise using a constant pressure dropping funnel, controlling the dropping rate at 1.2 mL per minute. After the addition is complete, the reaction system is heated to 85 °C under a nitrogen atmosphere. The reaction was carried out for 6 hours, during which the reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction mixture was cooled to 25°C and poured into a beaker containing 600g of crushed ice while stirring. The pH was adjusted to 7.0 with 1mol / L hydrochloric acid solution, at which point a large amount of dark red precipitate was formed. The precipitate was collected by filtration through a Buchner funnel and washed three times each with 120mL of deionized water and 120mL of anhydrous ethanol. The obtained solid was placed in a vacuum drying oven and dried at 40°C for 12 hours to obtain a dark red crystalline solid product, 2,3-dihydroxypropyl-1,4-diaminoanthraquinone.

[0045] Next, N,N'-bis(2-seleno-1-carboxyethyl)cystamine was prepared: 6.0 g of cystamine dihydrochloride was accurately weighed and placed in a 250 mL round-bottom flask, and 120 mL of anhydrous tetrahydrofuran was added. The mixture was stirred at 200 rpm at 25 °C to form a suspension. 6.0 g of triethylamine was added as an acid-binding agent, and the reaction flask was cooled to 0 °C in an ice-water bath. 9.0 g of selenoacetic acid succinimide ester was weighed and dissolved in 60 mL of anhydrous tetrahydrofuran. The solution was slowly added dropwise to the reaction system at a rate of 2.4 mL per minute using a constant-pressure dropping funnel. After the addition was complete... The ice-water bath was then removed, and the reaction system was allowed to naturally heat to 25°C. The reaction was continued with stirring for 12 hours. After the reaction was completed, the triethylamine hydrochloride was removed by filtration through a sintered funnel. The filtrate was transferred to a rotary evaporator and concentrated under reduced pressure to one-third of the original volume at a water bath temperature of 40°C. 120 mL of ethyl acetate was added to the concentrate, and the mixture was allowed to stand at 4°C for 12 hours for recrystallization. The precipitated pale yellow crystals were collected by vacuum filtration and washed twice with 24 mL of cold ethyl acetate to obtain the target product N,N'-bis(2-seleno-1-carboxyethyl)cystamine.

[0046] Finally, a highly selective sensitizer was prepared: 15.0 g of polylactic acid-glycolic acid copolymer was accurately weighed and placed in a 250 mL beaker, 75 mL of acetonitrile was added, and the mixture was sonicated in a 25 °C water bath for 30 minutes until completely dissolved; 8.0 g of the 2,3-dihydroxypropyl-1,4-diaminoanthraquinone and 5.0 g of N,N'-bis(2-seleno-1-carboxyethyl)cystamine were added to this organic phase, and sonication was continued for 30 minutes to obtain a homogeneous organic phase mixture; 3.0 g of 1,2-distearate-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino was placed in a 50 mL beaker, 15 mL of deionized water at 60 °C was added, and the mixture was sonicated for 20 minutes until completely dissolved; this solution was then combined with 4... 0g of Prönkel F-68 was added to a 500mL three-necked flask containing 80g of phosphate buffer solution. The mixture was stirred at 400rpm for 30 minutes at 25°C to obtain a homogeneous aqueous phase. Under continuous stirring, the organic phase mixture was slowly added dropwise to the aqueous phase at a rate of 3.6mL per minute using a peristaltic pump over a period of 22 minutes. After the addition was complete, stirring was continued for 12 hours to ensure complete evaporation of the organic solvent, resulting in a milky white suspension. This suspension was pre-filtered through a 400-mesh stainless steel sieve and then aseptically filtered through a 0.22μm microporous membrane. Finally, it was concentrated to a final volume of 60mL using a tangential flow ultrafiltration system at a pressure of 0.1MPa and dispensed into 10mL sterile glass vials to obtain the final product.

[0047] Comparative Example 1

[0048] The difference between this comparative example and Example 1 is that this comparative example provides a comparative formulation that does not contain 2,3-dihydroxypropyl-1,4-diaminoanthraquinone.

[0049] Preparation of N,N'-bis(2-seleno-1-carboxyethyl)cystamine: Accurately weigh 5.0 g of cystamine dihydrochloride and place it in a 250 mL round-bottom flask. Add 100 mL of anhydrous tetrahydrofuran and stir at 200 rpm at 25 °C to form a suspension. Add 5.0 g of triethylamine as an acid-binding agent and cool the reaction flask to 0 °C in an ice-water bath. Weigh 7.5 g of selenoacetic acid succinimide ester and dissolve it in 50 mL of anhydrous tetrahydrofuran. Slowly add the ester dropwise to the reaction system at a rate of 2 mL per minute using a constant-pressure dropping funnel. After the addition is complete, transfer the solution to the appropriate container. The reaction system was heated to 25°C naturally by de-icing in a water bath, and the reaction was continued with stirring for 12 hours. After the reaction was completed, the triethylamine hydrochloride was removed by filtration through a sintered glass funnel. The filtrate was transferred to a rotary evaporator and concentrated under reduced pressure to one-third of the original volume at a water bath temperature of 40°C. 100 mL of ethyl acetate was added to the concentrate, and the mixture was allowed to stand at 4°C for 12 hours for recrystallization. The precipitated pale yellow crystals were collected by vacuum filtration and washed twice with 20 mL of cold ethyl acetate to obtain the target product N,N'-bis(2-seleno-1-carboxyethyl)cystamine.

[0050] Preparation of the comparative formulation: Accurately weigh 15.0 g of polylactic acid-glycolic acid copolymer into a 250 mL beaker, add 50 mL of acetonitrile, and sonicate in a 25 °C water bath for 30 minutes until completely dissolved; add 3.0 g of N,N'-bis(2-seleno-1-carboxyethyl)cystamine to this organic phase, and continue sonicating for 30 minutes to obtain a homogeneous organic phase mixture; separately, place 2.0 g of 1,2-distearate-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino into a 50 mL beaker, add 10 mL of 60 °C deionized water, and sonicate for 20 minutes until completely dissolved; add this solution together with 2.0 g of Pranic F-68 to a solution containing... A homogeneous aqueous phase was prepared by stirring 70g of phosphate buffer solution in a 500mL three-necked flask at 25°C and 400rpm for 30 minutes. While continuously stirring, the organic phase mixture was slowly added dropwise to the aqueous phase at a rate of 3mL per minute using a peristaltic pump over a period of 18 minutes. After the addition was complete, stirring was continued for 12 hours to ensure complete evaporation of the organic solvent, resulting in a milky white suspension. This suspension was pre-filtered through a 400-mesh stainless steel sieve and then aseptically filtered through a 0.22μm microporous membrane. Finally, it was concentrated to a final volume of 50mL using a tangential flow ultrafiltration system at 0.1MPa pressure and dispensed into 10mL sterile glass vials to obtain the control formulation.

[0051] Comparative Example 2

[0052] The difference between this comparative example and Example 1 is that this comparative example provides a comparative formulation that does not contain N,N'-bis(2-seleno-1-carboxyethyl)cystamine.

[0053] Preparation of 2,3-dihydroxypropyl-1,4-diaminoanthraquinone: Accurately weigh 10.0 g of 1,4-diaminoanthraquinone and place it in a 500 mL three-necked flask. Add 200 mL of anhydrous N,N-dimethylformamide and stir in a 40 °C water bath until completely dissolved. Then add 7.5 g of potassium carbonate as a catalyst and stir at 300 rpm under nitrogen protection. Slowly add 8.0 g of 3-chloro-1,2-propanediol dropwise using a constant pressure dropping funnel, controlling the dropping rate at 1 mL per minute. After the addition is complete, heat the reaction system to 85 °C and react under a nitrogen atmosphere. The reaction was carried out for 6 hours, during which the reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction mixture was cooled to 25°C and poured into a beaker containing 500g of crushed ice while stirring. The pH was adjusted to 7.0 with 1mol / L hydrochloric acid solution, at which point a large amount of dark red precipitate was formed. The precipitate was collected by filtration through a Buchner funnel and washed three times each with 100mL of deionized water and 100mL of anhydrous ethanol. The obtained solid was placed in a vacuum drying oven and dried at 40°C for 12 hours to obtain a dark red crystalline solid product, 2,3-dihydroxypropyl-1,4-diaminoanthraquinone.

[0054] Preparation of the comparative formulation: Accurately weigh 13.0 g of polylactic acid-glycolic acid copolymer into a 250 mL beaker, add 50 mL of acetonitrile, and sonicate in a 25 °C water bath for 30 minutes until completely dissolved; add 5.0 g of 2,3-dihydroxypropyl-1,4-diaminoanthraquinone to this organic phase, and continue sonicating for 30 minutes to obtain a homogeneous organic phase mixture; separately, take 2.0 g of 1,2-distearate-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino and place it into a 50 mL beaker, add 10 mL of 60 °C deionized water, and sonicate for 20 minutes until completely dissolved; add this solution together with 2.0 g of Pranic F-68 to a solution containing 7 In a 500 mL three-necked flask containing 0 g of phosphate buffer solution, the mixture was stirred at 400 rpm for 30 minutes at 25 °C to obtain a homogeneous aqueous phase. While continuously stirring, the organic phase mixture was slowly added dropwise to the aqueous phase at a rate of 3 mL per minute using a peristaltic pump over a period of 18 minutes. After the addition was complete, stirring was continued for 12 hours to ensure complete evaporation of the organic solvent, resulting in a milky white suspension. This suspension was pre-filtered through a 400-mesh stainless steel sieve and then aseptically filtered through a 0.22 μm microporous membrane. Finally, it was concentrated to a final volume of 50 mL using a tangential flow ultrafiltration system at 0.1 MPa pressure and dispensed into 10 mL sterile glass vials to obtain the control formulation.

[0055] Comparative Example 3

[0056] The difference between this comparative example and Example 1 is that this comparative example provides a comparative formulation that does not contain the two modified compounds.

[0057] Preparation of the comparative formulation: Accurately weigh 18.0 g of polylactic acid-glycolic acid copolymer into a 250 mL beaker, add 50 mL of acetonitrile, and sonicate in a 25 °C water bath for 30 minutes until completely dissolved to obtain an organic phase mixture; Separately, place 2.0 g of 1,2-distearate-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino into a 50 mL beaker, add 10 mL of 60 °C deionized water, and sonicate for 20 minutes until completely dissolved; Add this solution together with 2.0 g of Prönkel F-68 into a 500 mL three-necked flask containing 70 g of phosphate buffer solution, and sonicate in a 25 °C water bath for 30 minutes until completely dissolved. A homogeneous aqueous phase was prepared by stirring at 400 rpm for 30 minutes at 5°C. Under continuous stirring, the organic phase mixture was slowly added dropwise to the aqueous phase at a rate of 3 mL per minute using a peristaltic pump, with the addition time controlled at 18 minutes. After the addition was completed, stirring was continued for 12 hours to ensure complete evaporation of the organic solvent, resulting in a milky white suspension. This suspension was pre-filtered through a 400-mesh stainless steel sieve and then aseptically filtered through a 0.22 μm microporous membrane. Finally, it was concentrated to a final volume of 50 mL using a tangential flow ultrafiltration system at a pressure of 0.1 MPa and dispensed into 10 mL sterile glass vials to obtain the control formulation.

[0058] According to national and industry standard testing specifications, the highly selective sensitizers for solid tumor radiotherapy obtained in Examples 1-3 and Comparative Examples 1-3 were systematically evaluated for performance. For cell experiments, human non-small cell lung cancer A549 cell line and mouse fibroblast L929 cell line were used to represent tumor cells and normal cells, respectively. Cells were cultured in DMEM medium containing 10% fetal bovine serum and incubated at 37°C in a 5% CO2 incubator. Logarithmic growth phase cells were seeded at a density of 5 × 10³ cells per well in 96-well plates. After 24 hours of culture, sample solutions from Examples 1-3 and Comparative Examples 1-3 were added at different concentration gradients of 0.1 mg / mL, 0.5 mg / mL, and 1.0 mg / mL, with six replicates for each concentration. A control group without the sample was also included. After sample addition, the cells were cultured for another 24 hours. h, cell viability was detected using the CCK-8 assay. 10 μL CCK-8 reagent was added to each well, and after incubation for 2 h, the absorbance at 450 nm was measured using a microplate reader. For the radiosensitization effect test, cells were grouped into a blank control group, a radiotherapy-only group, Examples 1-3 groups, and Comparative Examples 1-3 groups, with 6 replicates per group. The sample groups were pre-incubated with cells for 4 h before irradiation with 6 MV X-rays at doses of 2 Gy, 4 Gy, and 6 Gy. Cell viability was then measured after 24 h of post-irradiation culture. The intracellular glutathione consumption capacity test was performed using the DTNB method. Cells after sample treatment were collected, a protein precipitant was added, and the supernatant was collected by centrifugation. After the DTNB reagent reaction, the absorbance at 412 nm was measured. The hypoxia improvement capacity test used a hypoxia indicator, and changes in intracellular oxygen content were assessed by fluorescence intensity changes. Intracellular reactive oxygen species (ROS) levels were detected using a DCFH-DA fluorescent probe, and fluorescence intensity was measured by flow cytometry. For nanoparticle stability testing, samples were placed in PBS buffer and cultured at 37°C with shaking. Particle size distribution and zeta potential were measured at 0h, 6h, 12h, 24h, and 48h. For in vivo antitumor efficacy testing, a xenograft model was established by subcutaneously inoculating A549 cells into BALB / c nude mice. Once the tumor volume reached 100 mm³, the animals were randomly grouped. Six mice were used in each group. Each group received a tail vein injection of saline, samples from Examples 1-3, and Comparative Examples 1-3, respectively. Twenty-four hours after injection, the mice underwent local X-ray irradiation at a dose of 6 Gy, twice a week for two consecutive weeks. Tumor volume and mouse weight were measured every three days. For tissue distribution experiments, a separate group of animals received a tail vein injection of Cy5.5-labeled samples. The distribution was observed using in vivo imaging at different time points. After sacrifice, major organs and tumor tissues were collected to measure fluorescence intensity. Statistical analysis was performed using SPSS 22.0 software. Data are expressed as mean ± standard deviation. One-way ANOVA was used for comparisons between groups, and P < 0.05 was considered statistically significant.

[0059] The performance test data above are shown in Table 1.

[0060] Table 1 Performance Test Results

[0061] Test Project Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Tumor cell survival rate (%) 25.3±2.1 28.7±2.4 26.9±2.3 45.6±3.2 52.3±3.8 85.4±4.7 Normal cell survival rate (%) 89.5±3.5 87.2±3.8 88.3±3.6 86.3±3.9 88.7±4.1 92.1±4.3 Sensitization ratio (SER value) 2.45±0.15 2.32±0.13 2.38±0.14 1.65±0.11 1.52±0.10 1.08±0.08 GSH consumption rate (%) 78.6±4.2 75.3±4.0 76.8±4.1 72.5±3.9 35.2±2.8 8.5±1.2 Oxygen generation rate (μmol / L·min) 12.5±1.1 11.8±1.0 12.1±1.0 5.3±0.6 10.7±0.9 2.1±0.3 Enhancement factor of reactive oxygen species 3.85±0.25 3.62±0.23 3.74±0.24 2.45±0.18 2.13±0.16 1.25±0.12 Survival rate (%) after 2 Gy irradiation 35.2±2.8 38.7±3.0 36.8±2.9 55.3±3.5 61.2±3.8 78.5±4.1 4 Gy irradiation survival rate (%) 22.5±2.1 25.8±2.3 24.1±2.2 42.6±3.1 48.7±3.4 65.8±3.7 Survival rate (%) after 6 Gy irradiation 15.3±1.8 18.2±1.9 16.7±1.9 35.8±2.8 40.3±3.0 52.4±3.3 Average particle size (nm) 158.3±5.2 162.7±5.8 160.5±5.5 165.3±6.1 163.8±5.9 170.2±6.5 PDI 0.125±0.015 0.132±0.016 0.128±0.015 0.141±0.017 0.138±0.016 0.152±0.018 Zeta potential (mV) -18.5±1.2 -17.8±1.3 -18.2±1.2 -17.5±1.3 -17.9±1.3 -16.8±1.4 48 h stability (particle size change %) 8.5±0.7 9.2±0.8 8.8±0.7 10.3±0.9 9.8±0.8 12.7±1.1 Tumor inhibition rate (%) 82.5±4.3 78.6±4.1 80.3±4.2 55.3±3.8 48.7±3.5 15.2±2.1 Tumor tissue targeting index 8.65±0.45 8.32±0.43 8.51±0.44 6.87±0.38 7.25±0.40 3.25±0.25 Survival extension rate (%) 75.3±4.1 71.8±3.9 73.2±4.0 48.5±3.2 42.3±3.0 18.7±2.2 Weight loss rate (%) 8.5±0.9 9.2±1.0 8.8±0.9 12.3±1.2 13.7±1.3 5.2±0.7

[0062] As can be seen from the above, Examples 1-3 comprehensively solved the technical problems that this invention aims to overcome compared to Comparative Examples 1-3. In overcoming tumor radioresistance, the Example groups showed significant advantages. Example 1 achieved a radiosensitization ratio of 2.45, with tumor cell survival reduced to 25.3%, far superior to Comparative Example 1's 1.65 and 45.6% survival rate, demonstrating that the synergistic effect of the two modified compounds can effectively enhance radiosensitivity. Regarding improving the hypoxic tumor microenvironment, Example 1 achieved an oxygen generation rate of 12.5 μmol / L·min, significantly higher than Comparative Example 1's 5.3 μmol / L·min and Comparative Example 2's 10.7 μmol / L·min. This indicates that the oxygen-carrying function of dihydroxypropyl diaminoanthraquinone and the synergistic effect of diselenocarboxyethylcysteine ​​are crucial for alleviating tumor hypoxia. In regulating the intracellular antioxidant defense system of tumor cells, Example 1 achieved a GSH consumption rate of 78.6%, while Comparative Example 2 only achieved 35.2%, highlighting the unique role of diselenocarboxyethylcysteine ​​in consuming glutathione. In terms of targeting and safety, the tumor targeting index of the example group reached 8.65, while the survival rate of normal cells remained above 89.5%, and the weight loss rate was controlled at 8.5%, which were far superior to the targeting index and safety indicators of the comparative group, proving that it can accurately act on tumor tissue and reduce damage to normal tissue. Performance at different radiation doses further confirmed the stability of the example group. Under irradiation conditions of 2 Gy, 4 Gy, and 6 Gy, the tumor cell survival rates of Example 1 were 35.2%, 22.5%, and 15.3%, respectively, showing a dose-dependent increase and consistently significantly lower than those of the comparative groups. Nanoparticle characteristic data showed that the example group had better particle size control (158.3 nm), distribution uniformity (PDI 0.125), and stability (8.5% particle size change over 48 hours). These physical properties ensured its long-term circulation and tumor accumulation capacity in vivo. Finally, animal experimental results showed that Example 1 achieved a tumor inhibition rate of 82.5% and a survival extension rate of 75.3%, comprehensively surpassing the comparative group, demonstrating its excellent effect in practical treatment scenarios. These data fully demonstrate that the present invention, through the synergistic effect of two modified compounds, successfully solves the technical bottlenecks of traditional radiosensitizers in overcoming tumor hypoxia, consuming glutathione, enhancing radiosensitivity, and improving targeting, thereby achieving a highly efficient and low-toxicity tumor radiosensitizing effect.

Claims

1. A process for the preparation of a highly selective radiosensitizer for solid tumor radiotherapy, characterized by the steps of include: S1. Dissolve the polylactic acid-glycolic acid copolymer in acetonitrile to obtain the organic phase; 2,3-Dihydroxypropyl-1,4-diaminoanthraquinone and N,N'-bis(2-seleno-1-carboxyethyl)cystamine were added to the organic phase and sonicated to obtain an organic phase mixture. 1,2-distearate-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino was first dissolved in deionized water at 58-62℃ and sonicated to obtain a solution. The solution was then added to a phosphate buffer solution with Pluronic F-68 and mixed to obtain an aqueous phase. The organic phase mixture was added dropwise to the aqueous phase with stirring. After the addition was complete, stirring was continued to obtain a suspension. S2. The suspension is first pre-filtered through a sieve, then aseptically filtered through a microporous membrane; finally, it is concentrated using a tangential flow ultrafiltration system and dispensed.

2. The method for preparing a highly selective radiosensitizer for solid tumor radiotherapy according to claim 1, characterized in that, In step S1, the stirring time continues for 12-14 hours.

3. The method for preparing a highly selective radiosensitizer for solid tumor radiotherapy according to claim 1, characterized in that, In step S2, the particle size of the sieve is 350-450 mesh.

4. The method for preparing a highly selective radiosensitizer for solid tumor radiotherapy according to claim 1, characterized in that, The preparation method of the 2,3-dihydroxypropyl-1,4-diaminoanthraquinone includes: A1, dissolving 1,4-diaminoanthraquinone in anhydrous N,N-dimethylformamide, adding potassium carbonate, adding 3-chloro-1,2-propanediol dropwise, reacting under nitrogen protection at 84-86℃ to obtain a reaction mixture; A2, cooling the reaction mixture to room temperature, precipitating it in ice water, adjusting the pH to neutral with hydrochloric acid, filtering and collecting the precipitate, washing the precipitate with water and ethanol, and drying it under vacuum at 38-42℃.

5. The method for preparing a highly selective radiosensitizer for solid tumor radiotherapy according to claim 4, characterized in that, In step A1, the mass ratio of 1,4-diaminoanthraquinone, potassium carbonate, and 3-chloro-1,2-propanediol is 1:0.75:0.

8.

6. The method for preparing a highly selective radiosensitizer for solid tumor radiotherapy according to claim 4, characterized in that, In step A2, the vacuum drying time at 38-42℃ is 12-14 hours.

7. The method for preparing a highly selective radiosensitizer for solid tumor radiotherapy according to claim 1, characterized in that, The preparation method of N,N'-bis(2-seleno-1-carboxyethyl)cystamine includes: B1, suspending cystamine dihydrochloride in tetrahydrofuran, adding triethylamine, cooling to 0-2°C in an ice-water bath, and then adding a tetrahydrofuran solution containing succinimide selenoacetate dropwise; B2, after the addition is complete, raising the temperature to room temperature for reaction, filtering after the reaction is complete, concentrating the filtrate by rotary evaporation, and then recrystallizing with ethyl acetate.

8. The method for preparing a highly selective radiosensitizer for solid tumor radiotherapy according to claim 7, characterized in that, In step B1, the mass ratio of cystamine dihydrochloride, triethylamine, and selenoacetic acid succinimide ester is 1:1.0:1.

5.

9. The method for preparing a highly selective radiosensitizer for solid tumor radiotherapy according to claim 7, characterized in that, In step B2, the reaction time to room temperature is 12-14 hours.

10. A highly selective radiosensitizer for radiotherapy of solid tumors prepared by the method of any one of claims 1-9. The raw materials include the following parts by weight: 3-8 parts by weight of 2,3-dihydroxypropyl-1,4-diaminoanthraquinone; 2-5 parts by weight of N,N'-bis(2-seleno-1-carboxyethyl)cystamine; 8-15 parts by weight of polylactic acid-glycolic acid copolymer; 1-3 parts by weight of 1,2-distearyl-sn-glycerol-3-phosphoacetamide-polyethylene glycol-amino; 1-4 parts by weight of Pronic F-68; and 60-80 parts by weight of phosphate buffer solution.