Method for producing boron carbide quantum dots

Abstract

FIELD: medicine.SUBSTANCE: invention can be used in the creation of therapeutic agents for boron neutron capture therapy and fluorescent markers of cancer cells in vivo and in vitro. A method for producing water-soluble boron carbide quantum dots using boron carbide powder as a precursor involves ultrasonic treatment of boron carbide powder in water for 8 hours using an ultrasonic disperser with a frequency of 25 kHz and a power of 900 W. Then, the resulting dispersion is subjected to solvothermal treatment at a temperature of 160-200 °C for 6–12 hours. The invention allows the creation of hydrophilic quantum dots that are stable over time in a simple manner.EFFECT: functionalization of boron carbide with hydroxyl groups formed during ultrasonic and solvothermal treatment allows for further modification of quantum dots with polymer compounds and conjugation with protein molecules to create therapeutic agents for boron neutron capture therapy.1 cl, 3 dwg

Description

[0001] The invention relates to nanotechnology, specifically to a method for producing hydrophilic boron carbide quantum dots, which can be used to create therapeutic agents for boron neutron capture therapy. The boron carbide quantum dots are synthesized from boron carbide powder using a combination of ultrasonic and solvothermal treatment methods. This production method can also be used to create fluorescent markers for cancer cells in vivo and in vitro, and to solve problems in optics, photovoltaics, and sensorics.

[0002] The traditionally used combination of radiation therapy and chemotherapy is the first line of treatment for cancer in developed countries. The main drawback of these methods is the possible occurrence of side effects due to the fact that not only cancer cells but also nearby healthy cells are destroyed [Polymer-Coated Nanoparticles for Therapeutic and Diagnostic Non-10B Enriched Polymer-Coated Boron Carbon Oxynitride (BCNO) Nanoparticles as Potent BNCT Drug / C.-W. Chiang, Y.-C. Chien, W.-J. Yu [et al.] / / Nanomaterials. - 2021. - Vol. 11. - No. 11. - P. 2936]. Malignant tumors are the most aggressive and resistant neoplasms that remain incurable with the current level of development of radiation therapy, surgery and chemotherapy.Boron neutron capture therapy is a promising alternative to traditional cancer treatments because it allows for the selective destruction of cells containing isotope-containing drugs. 10 B, without causing significant damage to healthy tissues [In silico assessments of the small molecular boron agents to pave the way for artificial intelligence-based boron neutron capture therapy / Y. Zhang, J. Cai, NS Hosmane, Y. Zhu / / European Journal of Medicinal Chemistry. - 2024. - Vol. 279. - P. 116841].

[0003] Clinically approved drugs for boron neutron capture therapy have a number of disadvantages, including low specificity for cancer cells, low boron content, and low solubility in water [Pre-targeting with ultra-small nanoparticles: boron carbon dots as drug candidates for boron neutron capture therapy / IVJ Feiner, KR Pulagam, KB Uribe [et al.] / / Journal of Materials Chemistry B. - 2021. - Vol. 9. - Pre-targeting with ultra-small nanoparticles. - No. 2. - P. 410-420]. Currently, research is underway to create therapeutic agents with a high specific boron content, high selectivity and retention time in cancer cells, as well as the ability to non-invasively visualize the distribution of the drug in the body.Boron-containing nanomaterials are among the most promising agents due to the ability to flexibly tune their physicochemical properties to create therapeutic agents with the required properties for boron neutron capture therapy. In addition to these advantages, quantum dots possess fluorescent properties, potentially enabling non-invasive visualization of drug distribution in the body.

[0004] Boron carbide is a promising boron-containing material, characterized by biocompatibility, low toxicity, and high content. Boron carbide quantum dots can be synthesized using laser ablation, ball milling, microwave assisted synthesis, ultrasonic treatment, solvothermal treatment, chemical vapor deposition, pyrolysis, and other methods.

[0005] Methods are known for producing boron carbide nanoparticles by high-temperature synthesis from boron powder and a carbon precursor (graphite, graphene, carbon nanotubes, activated carbon or acetylene soot) in a molar ratio of (1-10):1. The powder mixture and the transition metal salt used as a catalyst are dispersed by ultrasound for 10-20 minutes in absolute ethyl alcohol. The resulting suspension is dried in an oven (temperature 30-300°C) for 0.2-12 hours, calcined in a gas atmosphere (air, oxygen, carbon dioxide, helium or argon) at 700-1600°C for 0.1-6.0 hours, then annealed at a temperature of 300-900°C for 1-12 hours, washed with a 20% acid solution (sulfuric, hydrochloric or nitric) and centrifuged. The resulting precipitate is dried in an oven at 30-200°C for 0.2-12 hours to obtain boron carbide nanoparticles. The diameter of the obtained nanoparticles is 50-100 nm.(Patent CN111377449A "Preparation method of boron carbide nanoparticles", priority date 28.12.2018, CN112573520A "Preparation method of boron carbide nanoparticles", priority date 29.12.2020, EP4223694A1 "Method of obtaining boron carbide nanoparticles", priority date 07.02.2022). The disadvantages of this method include time-consuming, relatively large nanoparticle sizes and insolubility in water, which necessitates the functionalization of boron carbide for use in biological applications.

[0006] A known method for producing functionalized boron carbide nanoparticles by grinding boron carbide powder in a ball mill in an air atmosphere. Boron carbide powder (average size of 300 nm) is ground in a ball mill at 200 rpm for 96 hours. During grinding in an air atmosphere, boron carbide nanoparticles are functionalized with amino groups as a result of interaction with nitrogen from the air. The size of the resulting nanoparticles is 45 nm (Patent WO2005094884A2 "Boron containing nanoparticles", priority date 02.03.2004). The disadvantages of this method include the duration of grinding of boron carbide powder in a ball mill and the relatively large size of the resulting nanoparticles, which limits their use in the creation of therapeutic agents for boron neutron capture therapy.

[0007] A known method for producing boron nitride quantum dots by ball milling and ultrasonic treatment. Boron nitride powder weighing 50-200 g is ground in a ball mill in a gas atmosphere (fluorine, chlorine, ammonia, oxygen, or nitrogen) at 200-400 rpm for 10-100 hours and treated with ultrasound (frequency 40 kHz, power 600 W) in anhydrous ethyl alcohol for 24-48 hours (Patent CN110357049A "Method for preparing boron nitride quantum dots by ball milling process", priority date July 25, 2019). The disadvantages of this method include the duration of ball milling and ultrasonic treatment and the low yield of the product. In addition, quantum dots obtained using this approach are characterized by low fluorescence quantum yield.

[0008] A known method for producing water-soluble boron quantum dots is via ultrasonic treatment (frequency 80 kHz, power from 200 to 500 W) of a dispersion of amorphous or crystalline boron powder with a concentration of 0.5 - 5 mg / ml in deionized water at a temperature of -10 to 15°C for 10 to 30 hours. The size of the resulting boron quantum dots ranges from 1 to 10 nm (Patent CN113697822A "Boron quantum dot as well as preparation method and application thereof", priority date 05 / 20 / 2020). The disadvantage of the described approach is the duration of ultrasonic treatment and the low yield of the product. In addition, the quantum dots obtained in water are not characterized by pronounced fluorescent properties, which does not allow their use in visualizing their distribution in the body.

[0009] The proposed method for producing boron carbide quantum dots is based on a sequential combination of ultrasonic and solvothermal treatments of boron carbide powder in deionized water. This combination allows for the production of quantum dots with a fluorescence emission band at 390 nm (Fig. 1). Functionalization of boron carbide with hydroxyl groups formed during ultrasonic and solvothermal treatments enables further modification of the quantum dots with polymer compounds and conjugation with protein molecules to create therapeutic agents for boron neutron capture therapy.

[0010] To implement this method, a 1.00 g sample of boron carbide powder is dispersed in 1000 ml of deionized water for 8.0 hours using an ultrasonic disperser (frequency 25 kHz, power 900 W). The resulting dispersion is transferred to an autoclave with a Teflon insert and maintained at a temperature of 160 - 200 °C for 6 - 12 hours. Boron carbide quantum dots are purified by dialysis against deionized water for 1 - 2 days. The hydrodynamic size of the obtained quantum dots, measured by dynamic light scattering, is 84 nm (Fig. 2). The zeta potential of the quantum dots, determined by electrophoretic light scattering, is -31.8 mV (Fig. 3). The advantages of this method are the production of stable water-soluble boron carbide quantum dots and the possibility of their further functionalization.

[0011] The technical result of the proposed method consists of producing boron carbide quantum dots using boron carbide powder as a precursor through a sequential combination of ultrasonic and solvothermal treatment of a boron carbide dispersion. This enables the creation of stable hydrophilic quantum dots. The synthesis and purification process is simple and scalable. Functionalization of the surface of boron carbide quantum dots enables surface modification with polymer compounds and conjugation with specifically targeted biovectors for targeted drug delivery to cancer cells.

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