Boron-containing microspheres for neutron capture tumor therapy

Abstract

The invention discloses a boron-containing microsphere for neutron capture tumor therapy, which is characterized by comprising a 10B-containing compound and a microsphere skeleton, and the 10B-containing compound is distributed in the microsphere skeleton to form the microsphere. The invention also discloses a preparation method. Through loading of the boron medicine, the microspheres can be conveyed to a designated tumor area through an interventional catheter, and the targeting property of a selected focus area is enhanced. Therefore, the concentration of the therapeutic agent in the diseased tissue can be improved, and the accuracy and specificity of treatment can be improved. Meanwhile, the side effect of the therapeutic agent on normal tissues can be reduced, and the safety and effectiveness of treatment are improved. The boron-loaded microspheres disclosed by the invention have good stability and biocompatibility, the use efficiency and safety of a therapeutic agent in a living body are improved, and the pain and risk of a patient are reduced.

Description

Technical Field

[0001] The invention relates to a boron-containing microsphere used for neutron capture tumor treatment, belonging to the technical field of tumor interventional treatment. Background Art

[0002] Boron neutron capture therapy (BNCT) is a tumor-selective particle radiotherapy based on the administration of isotopes to tumor cells. 10 The molecules of B or their carriers are then irradiated with thermal or epithermal neutron beams. Figure 1 As shown, it can minimize damage to healthy tissues. However, the two boron carriers that have entered clinical research, borophenylalanine (BPA) and sodium thiochloride dodecacarbonate (BSH), have problems such as low boron content, poor in vivo stability, poor solubility, lack of targeting and imaging tracking function, resulting in the clinical treatment of BNCT not being widely used. Therefore, the development of a new generation of boron carriers or boron drugs that meet the requirements of BNCT has become the key to promoting the development of BNCT.

[0003] Chinese invention patent CN114949215A discloses a boron phenylalanine nanocrystal and its preparation method and its application in the preparation of boron neutron capture tumor treatment drugs. The boron phenylalanine solution is obtained by mixing the sodium hydroxide solution and hydrochloric acid solution of boron phenylalanine, and then the boron phenylalanine solution is mixed with polyvinyl pyrrolidone solution to obtain boron phenylalanine nanocrystals, which have good stability and significantly reduce the survival rate of tumor cells after thermal neutron irradiation. Chinese invention patent CN111204736A discloses the preparation of boron-containing carbon quantum dots and its application in tumor diagnosis and boron neutron capture therapy drugs. Boron-containing carbon quantum dots (BCDs) are synthesized with glucose and BPA as raw materials, and have in vivo and in vitro fluorescence properties similar to carbon quantum dots. It can target brain tumors and other tumor tissues and enrich them at the tumor site, while BCDs in healthy tissues can be quickly metabolized and excreted. This characteristic provides conditions for achieving excellent therapeutic effects of BNCT, and can realize the integration of tumor diagnosis and BNCT treatment. Chinese invention patent CN113318227A discloses a boron-doped tumor targeting drug and its preparation method and application. The boron-doped tumor targeting drug includes a polypeptide, a hydrophobic molecule located at the nitrogen end of the polypeptide, and disodium thiododecaborane located on the lysine of the polypeptide; the amino acids constituting the polypeptide include phosphorylated L-tyrosine, L-lysine and L-phenylalanine. The drug can achieve specific enrichment in tumor cells, and the enrichment amount per tumor cell can reach 3.73×10 10B atoms meet the needs of boron neutron capture therapy. Chinese invention patent CN109161530A discloses a method for separating circulating tumor cells based on phenylboronic acid, which uses the reaction of phenylboronic acid and sialic acid to capture circulating tumor cells. Taking advantage of the characteristic of overexpression of sialic acid on the surface of tumor cells, circulating tumor cells can be detected and enriched with high sensitivity and specificity.

[0004] Chinese invention patent CN118084998A discloses a β-galactose-modified chlorambucil-fluoroboron dipyrrole combined anti-tumor prodrug and its preparation method and application. The prodrug can be rapidly and selectively taken up by tumor cells. The glycosidic bond in the molecule will be cut by the β-galactosidase overexpressed in tumor cells, releasing the original drug chlorambucil and the photosensitizer fluoroboron dipyrrole, thereby achieving selective chemotherapy-photodynamic combined therapy. Chinese invention patent CN115737591A discloses a platelet carrier and its method and application for encapsulating bortezomib, which utilizes the natural targeting effect of platelets on tumor cells to enhance the tumor killing effect. Chinese invention patent CN108478779B authorizes a tumor-targeted nanomedicine and its preparation method and application, which is combined with mannose polymers through dynamic covalent bonds. In addition to chemotherapy through bortezomib, it can also perform photothermal therapy and photoacoustic imaging. Chinese invention patent CN107163097A discloses a cyclic adenosine monophosphate boric acid complex and its preparation method, as well as an anti-tumor drug and a boron agent for neutron capture therapy. By utilizing the characteristics of tumor cells absorbing boron agents and tumor cells needing a large amount of nucleosides for reproduction, the drug is enriched in sensitive targets such as tumor cell membranes and specifically kills tumor cells through neutron capture, greatly improving the efficiency of killing tumor cells.

[0005] In summary, current patents all use chemical synthesis of small molecule compounds or use boron-containing inorganic particles for tumor treatment. Different from the prior art, the present invention uses microfluidics technology to prepare boron-containing polymer microspheres for interventional embolization and neutron irradiation synergistic treatment of solid tumors. The boron therapeutic agent is delivered to the tumor feeding blood vessels for embolization through an interventional catheter, thereby improving the targeting and utilization of the boron therapeutic agent. Summary of the invention

[0006] The purpose of the present invention is to provide a boron-containing microsphere for neutron capture tumor therapy, which is used for interventional embolization and neutron irradiation coordinated therapy of solid tumors.

[0007] The technical solution adopted by the present invention is:

[0008] A boron-containing microsphere for neutron capture tumor therapy, comprising 10 The compound containing 10B is distributed in the microsphere skeleton to form microspheres.

[0009] Preferably, the 10The compound B is a water-soluble boron drug or a fat-soluble boron drug.

[0010] Preferably, the water-soluble boron drug refers to borophenylalanine (BPA) or sodium thiochloride dodecanone (BSH).

[0011] Preferably, the fat-soluble boron drug refers to boric acid, boride (such as boron carbide, boron nitride, etc.) or boron particles (boron nanoparticles, boron powder, etc.).

[0012] Preferably, the microsphere skeleton is gelatin, chitosan, hyaluronic acid, dextran, polycaprolactone (PCL), polylactic acid (PLA), polylactic acid / polycaprolactone blend, polylactic acid / polycaprolactone block copolymer or polylactic acid-glycolic acid copolymer.

[0013] The present invention also discloses a method for preparing the above-mentioned boron-containing microspheres. One or more of gelatin, chitosan, hyaluronic acid and dextran are mixed with a water-soluble boron drug to form an aqueous solution, preferably gelatin, and a surfactant is added. The mixture is placed in a microfluidic system as a dispersed phase (inner phase), and paraffin oil or C10-18 alkane is selected as the mobile phase (outer phase), preferably paraffin oil. The boron-containing microspheres are prepared by a microfluidic chip, and cross-linked by genipin or glutaraldehyde, or cross-linked by ultraviolet curing.

[0014] Preferably, the mass concentration of the gelatin, chitosan, hyaluronic acid or dextran in the aqueous solution is 1-10%, more preferably 2%, the mass concentration of the water-soluble boron drug in the aqueous solution is 2-10%, more preferably 10%, the surfactant is selected from vitamin E polyethylene glycol succinate (VE-TPGS), dehydrated sorbitan fatty acid ester (Span), dehydrated sorbitan fatty acid ester (Tween), polyoxyethylene-polyoxypropylene polymer (Pluronic), more preferably VE-TPGS, and the mass concentration of the surfactant in the system is 0.5-2%, more preferably 1%.

[0015] Preferably, the microfluidic system uses a microfluidic chip with a channel size of 10 to 300 μm, the dispersed phase flow rate of the microfluidic system is 0.1 to 20 mL / h, more preferably 1 mL / h, and the mobile phase flow rate is 1 to 200 mL / h, more preferably 15 mL / h.

[0016] The present invention also discloses a method for preparing the above-mentioned boron-containing microspheres, which comprises dissolving a fat-soluble boron drug and polycaprolactone (PCL), polylactic acid (PLA), a polylactic acid / polycaprolactone blend, a polylactic acid / polycaprolactone block copolymer or a polylactic acid-glycolic acid copolymer in an organic solvent, adding a surfactant, using the above-mentioned solution as the dispersed phase of a microfluidic system, and using water or an aqueous solution as the mobile phase, and preparing the boron-containing microspheres through a microfluidic chip.

[0017] Preferably, the organic solvent refers to dichloromethane, the concentration of the fat-soluble boron drug in the organic solvent is 1% to 50wt%, the mass concentration of polycaprolactone, polylactic acid, polylactic acid / polycaprolactone blend, polylactic acid / polycaprolactone block copolymer or polylactic acid-glycolic acid copolymer in the organic solvent is 2 to 10%, the surfactant is vitamin E polyethylene glycol succinate, the mass concentration of the surfactant in the system is 0.5-2%, the dispersed phase flow rate of the microfluidic system is 0.1 to 20 mL / h, and the mobile phase flow rate is 1 to 200 mL / h.

[0018] Beneficial effects of the present invention:

[0019] (1) Improving targeting of diseased tissues: By loading the boron drug, the microspheres of the present invention can be delivered to the designated area of ​​the tumor through an interventional catheter, thereby enhancing targeting of the selected area of ​​the lesion. This helps to increase the concentration of the therapeutic agent in the diseased tissue, improve the accuracy and specificity of the treatment. At the same time, it can also reduce the side effects of the therapeutic agent on normal tissues, and improve the safety and effectiveness of the treatment.

[0020] (2) Good stability and biocompatibility: The boron-loaded microspheres of the present invention have good stability and biocompatibility, which helps to improve the efficiency and safety of the therapeutic agent in living bodies and reduce the pain and risks of patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Schematic diagram of the principle of boron neutron capture therapy. Specific implementation methods

[0023] The present invention is further described below in conjunction with embodiments, but the description of the embodiments does not impose any limitation on the protection scope of the present invention.

[0024] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention, and the terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments, and are not intended to limit the present invention. In addition, although demonstrations of parameters containing specific values ​​may be provided herein, it should be understood that the parameters do not need to be exactly equal to the corresponding values, but can be approximated to the corresponding values ​​within an acceptable error tolerance or design constraint. The directional terms mentioned in the embodiments, such as "up", "down", "front", "back", "left", "right", etc., are only directions with reference to the accompanying drawings. Therefore, the directional terms used are used to illustrate rather than to limit the scope of protection of the present invention.

[0025] Unless otherwise specified, the materials and instruments used in the following examples can be obtained from conventional commercial channels.

[0026] Example 1

[0027] Will be rich in 10 2 g of BSH boron drug and 10 g of methacrylated gelatin (GelMA) were dissolved in 500 mL of water, and 5 g of VE-TPGS was added and mixed evenly. This was used as the internal phase of the microfluidic system at a flow rate of 1 mL / h.

[0028] Paraffin oil was used as the external phase of microfluidics at a flow rate of 15 mL / h, and microspheres containing BSH were prepared through a microfluidic chip with a flow channel size of 50 μm. The enriched microspheres were cured by ultraviolet light with a wavelength of 365 nm for 10 min, separated by centrifugation at 4000 rpm for 5 min, washed with ethanol three times, and freeze-dried to obtain microspheres loaded with BSH for BNCT.

[0029] Example 2

[0030] Will be rich in 10 2g of boric acid of B and 10g of PCL with a molecular weight of 60,000 were dissolved in 100mL of dichloromethane, and 2g of VE-TPGS was added and mixed evenly. The mixture was used as the inner phase of the microfluidic system at a flow rate of 1mL / h. Water was used as the outer phase of the microfluidic system at a flow rate of 15mL / h. The microspheres were enriched and evaporated by the solvent for 8h, then washed and freeze-dried to obtain the loaded microspheres. 10 Boric acid microspheres of B.

[0031] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with this technology to understand the contents of the present invention and implement them accordingly. They cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A boron-containing microsphere for neutron capture tumor therapy, characterized in that Including 10 B compound and microsphere skeleton, the containing 10 The compound of B is distributed in the microsphere skeleton to form microspheres.

2. The boron-containing microsphere according to claim 1, characterized in that: The said 10 The compound B is a water-soluble boron drug or a fat-soluble boron drug.

3. The boron-containing microspheres according to claim 2, characterized in that: The water-soluble boron drug refers to borophenylalanine or sodium thiochloride and sodium dodecacarbonate.

4. The boron-containing microspheres according to claim 2, characterized in that: The fat-soluble boron drug refers to boric acid, boron carbide, boron nitride, boron nanoparticles or boron powder.

5. The boron-containing microsphere according to claim 1, characterized in that: The microsphere skeleton is gelatin, chitosan, hyaluronic acid, dextran, polycaprolactone, polylactic acid, polylactic acid / polycaprolactone blend, polylactic acid / polycaprolactone block copolymer or polylactic acid-glycolic acid copolymer.

6. The method for preparing boron-containing microspheres according to any one of claims 1 to 5, characterized in that: One or more of gelatin, chitosan, hyaluronic acid, and dextran are mixed with a water-soluble boron drug to form an aqueous solution, a surfactant is added, and the mixture is placed in a microfluidic system as a dispersed phase. Paraffin oil or C10-18 alkane is selected as the mobile phase. Microspheres containing boron drugs are prepared through a microfluidic chip and cross-linked by genipin or glutaraldehyde, or cross-linked by ultraviolet light curing.

7. The method for preparing boron-containing microspheres according to claim 6, characterized in that: The mass concentration of the gelatin, chitosan, hyaluronic acid or dextran in the aqueous solution is 1-10%, the mass concentration of the water-soluble boron drug in the aqueous solution is 2-10%, the surfactant is selected from vitamin E polyethylene glycol succinate, dehydrated sorbitan fatty acid ester, dehydrated sorbitan fatty acid ester, polyoxyethylene-polyoxypropylene polymer, and the mass concentration of the surfactant in the system is 0.5-2%.

8. The method for preparing boron-containing microspheres according to claim 7, characterized in that: The microfluidic system adopts a microfluidic chip with a flow channel size of 10 to 300 μm. The dispersed phase flow rate of the microfluidic system is 0.1 to 20 mL / h, and the mobile phase flow rate is 1 to 200 mL / h.

9. The method for preparing boron-containing microspheres according to any one of claims 1 to 5, characterized in that: A lipophilic boron drug and polycaprolactone (PCL), polylactic acid (PLA), a polylactic acid / polycaprolactone blend, a polylactic acid / polycaprolactone block copolymer or a polylactic acid-glycolic acid copolymer are dissolved in an organic solvent, a surfactant is added, and the above solution is used as the dispersed phase of the microfluidic system, the mobile phase is water or an aqueous solution, and microspheres containing the boron drug are prepared by a microfluidic chip.

10. The method for preparing boron-containing microspheres according to claim 9, characterized in that: The organic solvent refers to dichloromethane, the concentration of the fat-soluble boron drug in the organic solvent is 1% to 50wt%, the mass concentration of polycaprolactone, polylactic acid, polylactic acid / polycaprolactone blend, polylactic acid / polycaprolactone block copolymer or polylactic acid-glycolic acid copolymer in the organic solvent is 2 to 10%, the surfactant is vitamin E polyethylene glycol succinate, the mass concentration of the surfactant in the system is 0.5-2%, the dispersed phase flow rate of the microfluidic system is 0.1 to 20mL / h, and the mobile phase flow rate is 1 to 200mL / h.

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