Functionalized boron nitride nano-drug as well as preparation method and application thereof

Abstract

The invention provides a functionalized boron nitride nano-drug as well as a preparation method and application thereof, and belongs to the technical field of nano-medicines. The boron nitride nano-drug is composed of three parts, namely a 10B-enriched boron nitride (10BN) nano-crystal serving as a core, a bridging molecule and a targeting molecule. The preparation method comprises the following steps: carrying out heat treatment on boron nitride nanocrystals and nitric acid to obtain hydroxylated boron nitride; reacting the hydroxylated boron nitride with sodium hydroxide and sodium chloroacetate to obtain carboxylated boron nitride; carrying out chemical coupling on the hydroxylated or carboxylated boron nitride and polyethylene glycol to obtain PEGylated boron nitride; pEGylated boron nitride is chemically coupled with targeting molecules, such as arginyl-glycyl-aspartic acid and sialic acid, so that the boron nitride nano-drugs 10BN-PEG-RGD and 10BN-PEG '-SA are prepared, and the boron nitride nano-drugs are small in particle size, high in breast cancer targeting, high in wettability and long in retention time and are ideal boron reagents for boron neutron capture therapy.

Description

Technical Field

[0001] The present invention relates to the technical field of functional nano-drugs, and in particular to a functionalized boron nitride nano-drug and a preparation method and application thereof. Background Art

[0002] Boron neutron capture therapy (BNCT) is a promising precision radiotherapy for cancer treatment that utilizes 10 B atoms capture thermal neutrons, producing alpha particles and recoil with high linear energy transfer 7 Li nuclei selectively kill cancer cells enriched with boron reagents. 7 Li particles have a short propagation distance of only 5-9 μm, so BNCT can only destroy cancer cells enriched with boron reagents, while surrounding normal cells will not be affected. 10 Boron reagents, including borophenylalanine (BPA) and borosulfate sodium (BSH), have been approved for clinical BNCT, but their tumor enrichment and retention abilities are insufficient. Boron reagents for BNCT are generally required to meet the following requirements: (1) low toxicity and good biocompatibility; (2) high enrichment in tumor tissues; 10 The boron concentration must be ≥20 μg / g, and the ratio of the boron concentration in tumors to that in normal tissues (T / N or T / B) must be no less than 3; (3) The residence time in the blood and normal tissues is short, but the residence time in tumors is long, requiring at least several hours.

[0003] Boron nitride nanomaterials have excellent biocompatibility and can therefore be used in cosmetic additives, drug delivery, boron neutron capture therapy for cancer, and other fields. It is worth noting that the high boron content (50 mol%) of boron nitride makes it a potential boron reagent for BNCT therapy and is expected to be used in clinical BNCT. Boron nitride needs to have good dispersibility and high biocompatibility for use in biomedicine. In previous patents, we have developed a method for preparing ultrafine boron nitride nanocrystals (patent authorization number CN113753866B), but its application in BNCT still requires solving problems such as the targeted enrichment of boron nitride nanomedicines in tumor tissues.

[0004] In this regard, it is considered to introduce targeting molecules into boron reagents, and to construct the tumor targeting function of boron reagents through the specific recognition between targeting molecules and related receptors highly expressed on the surface of tumor cells. At present, commonly used targeting molecules include antibodies, peptides, aptamers, functional small molecules, etc. For example, folic acid (FA) and its derivatives are ligands of FA receptors, and arginyl-glycyl-aspartic acid (RGD) can specifically target integrin adhesion molecules α that are highly expressed in tumors. v β 3, L-selectin and Siglec-1 are receptors for sialic acid (SA). Compared with macromolecules such as antibodies, small molecule targeting molecules have the advantages of relatively simple synthesis, separation and purification processes, stability, and high biosafety, so they are widely used in active targeted drug design. At present, there are few reports on the introduction of targeting molecules into boron nitride nanomedicines. And not all targeting molecules are suitable for boron nitride nanomedicines.

[0005] Based on this, the present invention designs a functionalized boron nitride nanomedicine and a preparation method and application thereof. Summary of the invention

[0006] Aiming at the problems that currently available BNCT boron reagents in clinical practice are few in variety, low tumor-to-blood ratio, limited tumor targeting and retention, etc., the present invention provides a functionalized boron nitride nanomedicine and a preparation method and application thereof.

[0007] In order to achieve the above-mentioned purpose, the embodiment of the present invention provides a functionalized boron nitride nanomedicine and its preparation method and application. The present invention proposes a class of functionalized boron nitride nanomedicine based on 10 BN is the active core, and after functional modification, a boron reagent with high tumor targeting, high infiltration and long retention and a preparation method thereof are obtained.

[0008] An embodiment of the present invention provides a functionalized boron nitride nanomedicine, comprising: 10 BN is the core;

[0009] It also includes bridging molecules and targeting molecules;

[0010] in, 10 BN and the bridging molecule, and the bridging molecule and the targeting molecule are linked by chemical bonds.

[0011] Furthermore, the core structure is 10 B-enriched boron nitride nanoparticles, with a size ranging from 2 to 20 nm, 10 The abundance of B isotope is 19.5% to 100%.

[0012] Furthermore, the bridging molecule is polyethylene glycol, with an average molecular weight of 200 to 8000K Da, and a carboxyl or amino group at the end.

[0013] Furthermore, the targeting molecule is arginyl-glycyl-aspartic acid peptide or sialic acid.

[0014] Based on an overall concept of the invention, an embodiment of the present invention provides a method for preparing the above-mentioned functionalized boron nitride nanomedicine, the preparation method comprising the following steps:

[0015] S1: Referring to the preparation method disclosed in authorization number CN113753866B, select10 Preparation of Boron Source with B Isotope Abundance of 19.5%-100% 10 BN nanoparticle powder;

[0016] S2: Take 10 Add nitric acid (8M) to BN nanoparticle powder, disperse by ultrasonic for no less than 1 hour, and stir and react at 50-90°C for 12 hours to obtain hydroxylated boron nitride. 10 BN-OH;

[0017] S3: Take 10 BN-OH is coupled with dicarboxyl polyethylene glycol to obtain glycolized boron nitride with carboxyl terminal groups. 10 BN-PEG-COOH;

[0018] S4: 10 Boron nitride nanoparticles were prepared by coupling BN-PEG-COOH with arginyl-glycyl-aspartic acid peptides 10 BN-PEG-RGD;

[0019] S5: 10 BN-PEG-RGD was washed by centrifugation with deionized water and dialyzed with deionized water to obtain the purified functionalized boron nitride nanodrug;

[0020] Alternatively, the preparation method comprises the following steps:

[0021] S1: Referring to the preparation method disclosed in authorization number CN113753866B, select 10 Preparation of Boron Source with B Isotope Abundance of 19.5%-100% 10 BN nanoparticle powder;

[0022] S2: Take 10 Add nitric acid (8M) to BN nanoparticle powder, disperse by ultrasonic for no less than 1 hour, and stir and react at 50-90°C for 12 hours to obtain hydroxylated boron nitride. 10 BN-OH;

[0023] S3: Take 10 BN-OH was ultrasonically dispersed under alkaline conditions for no less than 1 hour, sodium chloroacetate was added and stirred for 12 hours, and after the reaction was completed, dilute hydrochloric acid was added to adjust the pH value to 1-4, and then centrifuged and washed to obtain carboxylated boron nitride. 10 BN-COOH;

[0024] S4: Take 10 BN-COOH is coupled with diaminopolyethylene glycol to obtain glycolized boron nitride with amino terminal groups. 10 BN-PEG'-NH 2 ;

[0025] S5: 10 BN-PEG'-NH 2 Boron nitride nanomedicine was prepared by coupling with sialic acid 10 BN-PEG′-SA;

[0026] S6: 10 The BN-PEG'-SA was washed by centrifugation with deionized water and dialyzed with deionized water to obtain the purified functionalized boron nitride nanomedicine.

[0027] Further, the alkaline condition is achieved by adding sodium hydroxide solution, 10 The mass ratio of BN to NaOH is 1:(0.1~5), 10 The mass ratio of BN to sodium chloroacetate is 1:(0.2~10).

[0028] Furthermore, the centrifugal speed is not less than 8000 r / min, and the centrifugal time is not less than 5 min.

[0029] Further, the boron source includes but is not limited to boric acid- 10 B is a boron source;

[0030] Furthermore, the 10 The mass ratio of BN-OH to dicarboxy polyethylene glycol is 1:0.2 to 1:10; 10 The mass ratio of BN-COOH to diaminopolyethylene glycol is 1:0.2 to 1:10.

[0031] Furthermore, the 10 The mass ratio of BN-PEG-COOH to arginyl-glycyl-aspartic acid peptide was 1:0.2 to 1:10.

[0032] Furthermore, the 10 BN-PEG-NH 2 The mass ratio to sialic acid is 1:0.2 to 1:10.

[0033] Furthermore, the activators used in the coupling process are 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS).

[0034] The embodiments of the present invention also provide the use of the above functionalized boron nitride nanomedicine or the functionalized boron nitride nanomedicine obtained by the above preparation method in the preparation of boron reagents for boron neutron capture therapy.

[0035] Furthermore, the boron nitride nanomedicine has a small particle size, high targeting to breast cancer, strong invasiveness, and long retention time, and is an ideal boron reagent for boron neutron capture therapy. In particular, it has a targeted enrichment effect on breast cancer.

[0036] The above scheme of the present invention has the following beneficial effects:

[0037] The present invention is based on chemical functional modification of boron nitride nanoparticles, coupling polyethylene glycol molecules to stabilize its in vivo circulation, coupling targeting molecules to achieve targeted enrichment of breast cancer tissues, and finally obtaining high-targeting, high-infiltration and high-retention boron nitride nanomedicines, which can be used in biomedical fields such as boron neutron capture therapy. Polyethylene glycol modification can make the boron nitride core have better in vivo stability and longer blood circulation. The raw materials used in the present invention are easy to obtain, cost-controllable, simple in equipment, fewer synthesis steps, and higher yields. After purification by centrifugation, dialysis, etc., it can be used directly. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0039] Figure 1 This is a schematic diagram of the structure of the functionalized boron nitride nanomedicine obtained in an embodiment of the present invention;

[0040] Figure 2 For Examples 1 and 3 of the present invention, 10 BN-PEG-RGD and 10 IR spectrum of BN-PEG'-SA;

[0041] Figure 3 The obtained examples 1 and 3 of the present invention 10 BN-PEG-RGD and 10 Boron content in different tissues and organs 12 hours after BN-PEG'-SA was injected via tail vein;

[0042] Figure 4 The obtained examples 1 and 3 of the present invention 10 BN-PEG-RGD and 10 Drug distribution and metabolism of BN-PEG'-SA in mouse tissues and organs at different times after tail vein injection;

[0043] Figure 5 The obtained examples 2 and 4 of the present invention 10 BN-PEG-RGD and 10 Drug distribution of BN-PEG'-SA in mouse tissues and organs 24 hours after tail vein injection. DETAILED DESCRIPTION

[0044] In order to make the technical problems, technical solutions and advantages to be solved by the present invention more clear, a detailed description will be given below with reference to the accompanying drawings and specific embodiments.

[0045] Unless otherwise defined, all professional terms used below have the same meanings as those generally understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention.

[0046] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0047] In view of the existing problems, the present invention provides a functionalized boron nitride nanomedicine. The structural schematic diagram of the functionalized boron nitride nanomedicine is shown in FIG. Figure 1 As shown, including: 10 BN is the core;

[0048] It also includes bridging molecules and targeting molecules;

[0049] in, 10 BN and the bridging molecule, and the bridging molecule and the targeting molecule are linked by chemical bonds.

[0050] Furthermore, the core structure is 10 B-enriched boron nitride nanoparticles, with a size ranging from 2 to 20 nm, 10 The abundance of B isotope is 19.5% to 100%.

[0051] Furthermore, the bridging molecule is polyethylene glycol, with an average molecular weight of 200 to 8000K Da, and a carboxyl or amino group at the end.

[0052] Furthermore, the targeting molecule is arginyl-glycyl-aspartic acid peptide or sialic acid.

[0053] Based on an overall concept of the invention, an embodiment of the present invention provides a method for preparing the above-mentioned functionalized boron nitride nanomedicine, the preparation method comprising the following steps:

[0054] S1: Referring to the preparation method disclosed in authorization number CN113753866B, select 10 Preparation of Boron Source with B Isotope Abundance of 19.5%-100% 10 BN nanoparticle powder;

[0055] S2: Take 10 Add nitric acid (8M) to BN nanoparticle powder, disperse by ultrasonic for no less than 1 hour, and stir and react at 50-90°C for 12 hours to obtain hydroxylated boron nitride. 10 BN-OH;

[0056] S3: Take 10 BN-OH is coupled with dicarboxyl polyethylene glycol to obtain glycolized boron nitride with carboxyl terminal groups. 10 BN-PEG-COOH;

[0057] S4: 10 Boron nitride nanoparticles were prepared by coupling BN-PEG-COOH with arginyl-glycyl-aspartic acid peptides 10 BN-PEG-RGD;

[0058] S5: 10 BN-PEG-RGD was washed by centrifugation with deionized water and dialyzed with deionized water to obtain the purified functionalized boron nitride nanodrug;

[0059] Alternatively, the preparation method comprises the following steps:

[0060] S1: Referring to the preparation method disclosed in authorization number CN113753866B, select 10 Preparation of Boron Source with B Isotope Abundance of 19.5%-100% 10 BN nanoparticle powder;

[0061] S2: Take 10 Add nitric acid (8M) to BN nanoparticle powder, disperse by ultrasonic for no less than 1 hour, and stir and react at 50-90°C for 12 hours to obtain hydroxylated boron nitride. 10 BN-OH;

[0062] S3: Take 10 BN-OH was ultrasonically dispersed under alkaline conditions for no less than 1 hour, sodium chloroacetate was added and stirred for 12 hours, and after the reaction was completed, dilute hydrochloric acid was added to adjust the pH value to 1-4, and then centrifuged and washed to obtain carboxylated boron nitride. 10 BN-COOH;

[0063] S4: Take 10 BN-COOH is coupled with diaminopolyethylene glycol to obtain glycolized boron nitride with amino terminal groups. 10 BN-PEG'-NH 2 ;

[0064] S5: 10 BN-PEG'-NH 2 Boron nitride nanomedicine was prepared by coupling with sialic acid 10 BN-PEG′-SA;

[0065] S6: 10 The BN-PEG'-SA was washed by centrifugation with deionized water and dialyzed with deionized water to obtain the purified functionalized boron nitride nanomedicine.

[0066] Further, the alkaline condition is achieved by adding sodium hydroxide solution, 10 The mass ratio of BN to NaOH is 1:(0.1~0.5), 10 The mass ratio of BN to sodium chloroacetate is 1:(0.2~10).

[0067] Furthermore, the centrifugal speed is not less than 8000 r / min, and the centrifugal time is not less than 5 min.

[0068] Further, the boron source includes but is not limited to boric acid- 10 B is a boron source;

[0069] Furthermore, the 10 The mass ratio of BN-OH to dicarboxy polyethylene glycol is 1:0.2 to 1:10; 10 The mass ratio of BN-COOH to diaminopolyethylene glycol is 1:0.2 to 1:10.

[0070] Furthermore, the 10 The mass ratio of BN-PEG-COOH to arginyl-glycyl-aspartic acid peptide was 1:0.2 to 1:10.

[0071] Furthermore, the 10 BN-PEG-NH 2 The mass ratio to sialic acid is 1:0.2 to 1:10.

[0072] Furthermore, the activators used in the coupling process are 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS).

[0073] The embodiments of the present invention also provide the use of the above functionalized boron nitride nanomedicine or the functionalized boron nitride nanomedicine obtained by the above preparation method in the preparation of boron reagents for boron neutron capture therapy.

[0074] Furthermore, the boron nitride nanomedicine has a small particle size, high targeting to breast cancer, strong invasiveness, and long retention time, and is an ideal boron reagent for boron neutron capture therapy. In particular, it has a targeted enrichment effect on breast cancer.

[0075] The following is a detailed description through specific embodiments.

[0076] Example 1

[0077] 10 Preparation and evaluation of BN-PEG-RGD

[0078] Step 1: Add 0.03 mol of melamine to a beaker containing 250 mL of deionized water, heat and stir, set the heater temperature to 100°C, and add 0.06 mol of boric acid ( 10 B abundance is 19.8%) to obtain a completely clear and transparent precursor solution, keep heating and stirring until precipitation begins to precipitate, then put it into ice water for rapid cooling and precipitation to obtain a white flocculent boric acid-melamine co-precipitate, put it into an oven and dry it at 80°C overnight to obtain a white boric acid-melamine precursor powder.

[0079] Step 2: Weigh 2.04g of the white precursor powder obtained in the first step, lay it into a reaction bed with a thickness of 1cm, and heat treat it in a muffle furnace at a temperature of 1000℃, a heating rate of 10℃ / min, and a holding time of 1 hour. After heat treatment, 0.53g of white boron nitride nanoparticles were obtained. Ethanol and deionized water were used for multiple centrifugal washing and membrane filtration to obtain a hexagonal boron nitride nanocrystal dispersion; then freeze-dried to obtain a hexagonal boron nitride nanocrystal powder ( 10 BN).

[0080] Step 3: Weigh 10 mg of the product from step 2 10 BN, add 5 mL of 8 M nitric acid, ultrasonicate for 1 hour, stir at 70 ° C in the dark for 12 hours, and wash with aqueous solution by centrifugation at a centrifugal speed of 10000 r / min to obtain hydroxylated boron nitride ( 10 BN-OH).

[0081] Step 4: Weigh 10 mg of dicarboxyl polyethylene glycol (average molecular weight 600 Da) and add it to 5 mL of water, add 9 mg of EDC and 2.25 mg of NHS and ultrasonicate for 1 hour to activate the carboxyl group, then add the hydroxylated boron nitride solution in step 3 and react for 12 hours, centrifuge and wash at a centrifugal speed of 10000 r / min to obtain PEGylated boron nitride ( 10 BN-PEG-COOH).

[0082] Step 5: Weigh 10 mg of arginyl-glycyl-aspartic acid (RGD) and add it to the 10 The BN-PEG-COOH dispersion was reacted for 12 hours, and the dispersion was dialyzed for 24 hours using a dialysis bag with a molecular weight cutoff of 8000-14000 to obtain the purified 10 BN-PEG-RGD.

[0083] The 10 BN-PEG-RGD was subjected to infrared spectrum analysis, and the results are as follows Figure 2 As shown, 10 BN has been coupled to PEG and RGD molecules.

[0084] The prepared 10 The distribution and metabolism of BN-PEG-RGD in 4T1 tumor-bearing mice were evaluated. The mice were killed and dissected 24 hours after tail vein injection, and the boron content of different tissues and organs was analyzed and statistically analyzed. The results are shown in Figure 3 As shown, 10 The boron content of BN-PEG-RGD in the tumor site was 71 ppm, and the tumor-to-blood ratio was 5.0. Figure 4 It can be seen that 10 BN-PEG-RGD is mainly enriched in tumor tissues, where it remains for more than 72 hours, while those in other organs and tissues are basically metabolized after 72 hours.

[0085] Example 2

[0086] The boric acid ( 10 B abundance is 19.8%) to boric acid- 10 B( 10 B abundance is 99.8%), other conditions remain unchanged. Figure 5 It can be seen that 10 BN-PEG-RGD is mainly enriched in tumor tissues, and its 24-hour distribution in the body is consistent with that in Example 1.

[0087] Example 3

[0088] 10 Preparation and evaluation of BN-PEG'-SA

[0089] In Example 1, the first three steps prepared hydroxyboron nitride ( 10 BN-OH), the fourth step: weigh 10 mg of sodium hydroxide and dissolve it in 5 mL of water, add the sodium hydroxide obtained in the third step 10 BN-OH, after ultrasonication for 2 hours, 33 mg of sodium chloroacetate was added to react for 12 hours, and after the reaction, dilute hydrochloric acid was added to adjust the pH of the solution to ~2, and centrifuged and washed to obtain carboxylated boron nitride ( 10 BN-COOH).

[0090] Step 5: Take the results from step 4 10 9 mg EDC and 2.25 mg NHS were added to the BN-COOH aqueous solution, and the carboxyl groups were activated by ultrasonication for 1 hour. Then 10 mg diamino polyethylene glycol (PEG', average molecular weight of 5000 Da) was added, and the reaction was continued for 12 hours. The reaction was centrifuged and washed to obtain PEGylated boron nitride ( 10 BN-PEG'-NH 2 ).

[0091] Step 6: Weigh 10 mg of sialic acid (SA) and dissolve it in 5 mL of deionized water. Add 9 mg of EDC and 2.25 mg of NHS and sonicate for 1 hour. Add the solution obtained in step 5.10 BN-PEG'-NH 2 The reaction was continued for 12 hours, and the dispersion was dialyzed for 24 hours using a dialysis bag with a molecular weight cutoff of 8000-14000 to obtain the purified 10 BN-PEG′-SA.

[0092] The 10 BN-PEG'-SA was subjected to infrared spectrum analysis, and the results are as follows Figure 2 As shown, 10 BN has been coupled to PEG and SA molecules.

[0093] The prepared 10 The distribution and metabolism of BN-PEG'-SA in 4T1 tumor-bearing mice were evaluated. The mice were killed and dissected 24 hours after tail vein injection, and the boron content of different tissues and organs was analyzed and statistically analyzed. The results are shown in Figure 3 As shown, 10 The boron content of BN-PEG'-SA in the tumor site was 182 ppm, and the tumor-to-blood ratio was 3.4. Figure 4 It can be seen that 10 BN-PEG'-SA is mainly enriched in tumor tissues, where it remains for more than 72 hours, while those in other organs and tissues are basically metabolized after 72 hours.

[0094] Example 4

[0095] The boric acid ( 10 B abundance is 19.8%) to boric acid- 10 B( 10 B abundance is 99.8%), other conditions remain unchanged. Figure 5 It can be seen that 10 BN-PEG-SA is mainly enriched in tumor tissues, and its 24-hour distribution in the body is consistent with that in Example 3.

[0096] Embodiment 5, 6, 7

[0097] The third step in Example 2 10 The mass of BN was changed to 5 mg, 15 mg and 20 mg, and other conditions remained unchanged.

[0098] Embodiment 8, 9, 10, 11

[0099] The reaction temperatures in the third step of Example 2 were changed to 50°C, 60°C, 80°C, and 90°C, respectively, while the others remained unchanged.

[0100] Embodiment 12, 13, 14

[0101] The mass of dicarboxyl polyethylene glycol (PEG) in the fourth step of Example 2 was changed to 5 mg, 15 mg and 20 mg, and 4.5 mg EDC and 1.1 mg NHS, 13.5 mg EDC and 3.4 mg NHS, and 18.0 mg EDC and 4.5 mg NHS were weighed to activate the carboxyl group, respectively, while other conditions remained unchanged.

[0102] Embodiment 15, 16, 17

[0103] The mass of arginyl-glycyl-aspartic acid (RGD) in the fifth step of Example 2 was changed to 5 mg, 15 mg, and 20 mg, while other conditions remained unchanged.

[0104] Embodiments 18, 19, 20, 21

[0105] The mass of sodium hydroxide in the fourth step in Example 2 was changed to 5 mg, 15 mg, 20 mg, and 30 mg, while other conditions remained unchanged.

[0106] Embodiment 22, 23, 24

[0107] The mass of carboxylated boron nitride in the fifth step of Example 4 was changed to 5 mg, 15 mg and 20 mg, and 4.5 mg EDC and 1.1 mg NHS, 13.5 mg EDC and 3.4 mg NHS, and 18.0 mg EDC and 4.5 mg NHS were weighed to activate the carboxyl groups, respectively, while other conditions remained unchanged.

[0108] Embodiment 25, 26, 27

[0109] The mass of sialic acid (SA) in the sixth step of Example 4 was changed to 5 mg, 15 mg and 20 mg, and 4.5 mg EDC and 1.1 mg NHS, 13.5 mg EDC and 3.4 mg NHS and 18.0 mg EDC and 4.5 mg NHS were weighed to activate the carboxyl groups, respectively, while other conditions remained unchanged.

[0110] The functional boron nitride drugs described in Examples 1-27 were subjected to infrared spectrum analysis, all of which showed 10 BN has been coupled to PEG molecules and to RGD or SA molecules.

[0111] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A functionalized boron nitride nanomedicine, characterized in that: include: by 10 BN is the core; It also includes bridging molecules and targeting molecules; in, 10 BN and the bridging molecule, and the bridging molecule and the targeting molecule are linked by chemical bonds.

2. The functionalized boron nitride nanomedicine according to claim 1, characterized in that: The core structure is 10 B-enriched boron nitride nanoparticles, with a size ranging from 2 to 20 nm, 10 The abundance of B isotope is 19.5% to 100%.

3. The functionalized boron nitride nanomedicine according to claim 1, characterized in that: The bridging molecule is polyethylene glycol, with an average molecular weight between 200 and 8000K Da, and a carboxyl or amino group at the end.

4. The functionalized boron nitride nanomedicine according to claim 1, characterized in that: The targeting molecule is an arginyl-glycyl-aspartic acid peptide or sialic acid.

5. The method for preparing the functionalized boron nitride nanomedicine according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: S1: Referring to the preparation method disclosed in authorization number CN113753866B, select 10 Preparation of Boron Source with B Isotope Abundance of 19.5%-100% 10 BN nanoparticle powder; S2: Take 10 BN nanoparticle powder was added with nitric acid, ultrasonically dispersed, and stirred for reaction to obtain 10 BN-OH; S3: Take 10 BN-OH was coupled with dicarboxy polyethylene glycol to obtain 10 BN-PEG-COOH; S4: 10 BN-PEG-COOH was prepared by coupling with arginyl-glycyl-aspartic acid peptide 10 BN-PEG-RGD; S5: 10 BN-PEG-RGD was washed by centrifugation with deionized water and purified by dialyzing with deionized water to obtain functionalized boron nitride nanoparticles. 10 BN-PEG-RGD; Alternatively, the preparation method comprises the following steps: S1: Referring to the preparation method disclosed in authorization number CN113753866B, select 10 Preparation of Boron Source with B Isotope Abundance of 19.5%-100% 10 BN nanoparticle powder; S2: Take 10 BN nanoparticle powder was added with nitric acid, ultrasonically dispersed, and stirred for reaction to obtain 10 BN-OH; S3: Take 10 BN-OH reacts with sodium chloroacetate under alkaline conditions to obtain 10 BN-COOH; S4: Take 10 BN-COOH was coupled with diaminopolyethylene glycol to obtain 10 BN-PEG′-NH2; S5: 10 BN-PEG'-NH2 was prepared by coupling with sialic acid 10 BN-PEG′-SA; S6: 10 BN-PEG'-SA was washed by centrifugation with deionized water and purified by dialyzing with deionized water to obtain functionalized boron nitride nanoparticles. 10 BN-PEG′-SA.

6. The preparation method according to claim 5, characterized in that: Said 10 The mass ratio of BN-OH to dicarboxyl polyethylene glycol is 1:0.2 to 1:10; 10 The mass ratio of BN-COOH to diaminopolyethylene glycol is 1:0.2 to 1:

10.

7. The preparation method according to claim 5, characterized in that: Said 10 The mass ratio of BN-PEG-COOH to arginyl-glycyl-aspartic acid peptide was 1:0.2 to 1:

10.

8. The preparation method according to claim 5, characterized in that: Said 10 The mass ratio of BN-PEG-NH2 to sialic acid is 1:0.2 to 1:

10.

9. The preparation method according to claim 5, characterized in that: The activators used in the coupling process are 1-ethyl-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide.

10. Use of the functionalized boron nitride nanomedicine according to any one of claims 1 to 4 or the functionalized boron nitride nanomedicine obtained by the preparation method according to any one of claims 5 to 9 in the preparation of boron reagents for boron neutron capture therapy.

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