Covalent organic framework material loaded with boron drug compound as well as preparation method and application of covalent organic framework material

Abstract

The invention relates to the technical field of medicines, in particular to a covalent organic framework material loaded with a boron drug compound as well as a preparation method and application of the covalent organic framework material. The covalent organic framework material loaded with the boron drug compound comprises bortezomib and a loading body, and the loading body is prepared from a covalent organic framework material modified by folic acid. The pore size regulation of the triazinyl COF is matched with the molecular size of the boron drug, and the topological structure design (AA stacking mode) of the COF is combined with the dynamic simulation of drug molecules, so that the ultrahigh drug loading capacity (42.7%) and the high retention rate gt of the drug within 72 hours are realized; moreover, folic acid molecules are connected through thioether bonds, so that gt is realized while the COF crystallinity is kept; and the FA surface coverage rate is 85%. The three-in-one design of'structure adaptive drug loading, chemical stable targeting and accurate environment release 'is realized for the first time, an efficient drug delivery platform is provided for advanced therapies such as boron neutron capture therapy (BNCT) and the like, and cross development of anti-cancer drugs from'extensive chemotherapy' to'molecular-level accurate regulation and control 'is promoted.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to covalent organic framework materials for loading boron drug compounds, their preparation methods, and applications. Background Technology

[0002] Boron neutron capture therapy (BNCT) is a type of radiotherapy that selectively kills tumor cells. After a boron delivery agent with a specific affinity for tumor cells enters the body, it selectively accumulates within the tumor cells. (The text then repeats the description of a non-radioactive isotope.) 10 When boron (B) captures a low-energy thermal neutron (0.025 eV), it undergoes nuclear fission to produce alpha particles (4He) and recoil lithium-7 nuclei (7Li). This high linear energy transfer kills tumor cells. The alpha particle's path length (5–9 μm, approximately the diameter of a cell) is very short, limiting its destructive effect to boron-containing cells and not affecting adjacent normal cells, thus minimizing damage to surrounding tumor tissues. Therefore, boron-neutral radiotherapy (BNCT) is a binary, cellular-scale, highly targeted radiotherapy with high energy density, making it one of the best methods for achieving precise radiotherapy.

[0003] From a clinical treatment perspective, due to the limitations of existing boron drug delivery technologies, the efficacy of BNCT treatment is not ideal, and many patients fail to achieve effective tumor control. Existing anticancer drug delivery systems have certain shortcomings: First, traditional carriers have low drug loading efficiency; for example, doxorubicin liposomes only load 15-25% of the drug, and drug leakage easily leads to systemic toxicity. COF, through the dual effects of π-π stacking and pore adsorption, increases the drug loading to 42.7%. While mesoporous silica has a high specific surface area (1000 m² / g), its rigid pores cause delayed drug release, resulting in a bortezomib loading rate of less than 20%. PLGA-PEG polymer micelle systems can achieve a loading capacity of up to 30% for hydrophobic boron drugs, but the in vivo circulation time is short (t1 / 2 < 6 h). Second, there are limitations in targeted modification technology. For example, while trastuzumab-modified nanoparticles can target HER2-positive cells, the large molecular weight of the antibody (~150 kDa) results in a carrier size exceeding 200 nm, significantly reducing tumor penetration ability (Nat. Biotechnol. 2020, 38, 420-432). Amide bond linkages can disrupt COF crystallinity, leading to a decrease in specific surface area of ​​over 50% (J. Am. Chem. Soc. 2021, 143, 12129-12137). Third, there is insufficient precision in release control. For instance, the polyacrylic acid (PAA) modified system has a release rate of 65% at pH 5.5, but 40% of the drug is still released prematurely at pH 6.8. In addition, the release efficiency of matrix metalloproteinase (MMP) responsive carriers in tumor tissue is only 50-60%.

[0004] Despite this, researchers have offered some promising research ideas: A team at the Max Planck Institute for Intelligent Systems in Germany developed an upconversion nanoparticle-covalent organic framework (UCNP-COF) core-shell microrobot (Adv. Mater. 2021, 202418425). This microrobot utilizes COF to absorb upconversion luminescence (UCL) and convert it into thermoelastic vibrations, generating high-contrast photoacoustic signals. Further, by sputtering a nickel-gold layer, the UCNP-COF microrobot is endowed with a magnetically controlled Janus structure, enabling real-time navigation in cerebral blood vessels with blood flow velocities up to 50 mm / s. Combining photoacoustic imaging and magnetic navigation, this platform is the first to integrate diagnostic, therapeutic, and manipulative functions into a single particle, overcoming the functional limitations of traditional nanocarriers. Teams from Southwest Medical University and Southern Medical University reported a hypoxia-responsive COF that in situ encapsulates the chemotherapy drug gambogeylic acid (GA).

[0005] However, during the experiments conducted by the inventors of this application on the relevant prior art, it was discovered that the above-mentioned technology still has the problem of low delivery efficiency of BNCT boron drug. Summary of the Invention

[0006] In view of this, the purpose of the present invention is to provide covalent organic framework materials for loading boron drug compounds, their preparation methods and applications, so as to at least solve the problem of low delivery efficiency of boron drugs by BNCT in the prior art.

[0007] The following is a summary of this disclosure to provide a basic understanding of some aspects. This summary is not intended to identify key or important elements, nor is it intended to limit the implementation or any aspects of the claims. Furthermore, this summary provides a simplified overview of some aspects that may be described in more detail in other parts of this disclosure.

[0008] The present invention solves the above-mentioned technical problems through the following technical means:

[0009] In a first aspect, embodiments of this application provide a covalent organic framework material for loading boron drug compounds, including bortezomib, and a support for loading bortezomib, said support being made of a folic acid-modified covalent organic framework material.

[0010] Furthermore, the mass ratio of bortezomib to the support is 1:3 to 7.

[0011] Furthermore, the mass ratio of folic acid to covalent organic framework material is 1:1.5 to 2.0.

[0012] Furthermore, the covalent organic framework material is an amino-functionalized COF, and the raw materials for preparing the amino-functionalized COF include 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid, wherein the molar ratio of 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid is 2:3.

[0013] Secondly, embodiments of this application provide a method for preparing a covalent organic framework material loaded with boron drug compounds, comprising the following steps:

[0014] Folic acid was dissolved in dimethyl sulfoxide, and EDC / NHS was added and activated at room temperature for 2–5 h to obtain an activation solution. The amino-functionalized COF was dispersed in the activation solution and reacted at 55–65 °C for 16–48 h under nitrogen protection. After cooling to room temperature, the mixture was centrifuged at 9000–12000 rpm for 3–6 min, washed 3–5 times by alternating centrifugation with DMF / ethanol, and dried under vacuum at 50–60 °C to obtain FA-COF.

[0015] Bortezomib was dissolved in PBS buffer, FA-COF was added, and the mixture was soaked for 36–60 h under ultrasonic assistance. The boron-loaded FA-COF material was then separated by centrifugation or filtration, washed with deionized water, and then vacuum dried at 40–60 °C for 6–12 h to obtain the boron-loaded and dried FA-COF carrier, which was stored in the dark.

[0016] Furthermore, the preparation method of the amino-functionalized COF is as follows:

[0017] Weigh 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid separately, add them to a mixed solvent of acetonitrile / acetic acid and stir until homogeneous. Then keep the mixture at 110-130 °C for 12-72 h. After cooling to room temperature, collect the amino-functionalized COF and centrifuge at 9000-12000 rpm for 3-6 min. Wash the COF with ethanol and distilled water alternately 3-5 times for later use.

[0018] Furthermore, the molar ratio of 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid is 2:3.

[0019] Furthermore, in the activation solution, the molar ratio of folic acid to dimethyl sulfoxide is 1:11.

[0020] Furthermore, the FA-COF carrier is stored at 3–5 °C in the dark.

[0021] Thirdly, the embodiments of this application also provide the application of the covalent organic framework material of the boron-loaded drug compound described in the first aspect above, or the covalent organic framework material of the boron-loaded drug compound prepared by the preparation method described in the second aspect above, in the preparation of targeted anticancer drugs.

[0022] One or more technical solutions provided in the embodiments of this application have at least the following technical effects or advantages:

[0023] The covalent organic framework material for loading boron drug compounds of this invention achieves ultra-high drug loading (42.7%) by matching the pore size of the triazine-based COF to the size of the boron drug molecule, combining the topological design of the COF (AA ​​stacking mode) with drug molecular dynamics simulation. Furthermore, by using thioether bonds to connect folic acid molecules, it achieves a FA surface coverage of >85% while maintaining the crystallinity of the COF. This invention is the first to achieve a three-in-one design of "structure-adaptive drug loading - chemically stable targeting - precise environmental release," providing a highly efficient drug delivery platform for advanced therapies such as boron neutron capture therapy (BNCT), and promoting the leap from "extensive chemotherapy" to "molecular-level precise regulation" in anticancer drug development. Attached Figure Description

[0024] Figure 1 The concentration of bortezomib in mice is the concentration of samples prepared in different embodiments. Detailed Implementation

[0025] Reference will now be made to exemplary embodiments, examples of which are shown in the detailed description, implementation, and examples. It should be understood that other implementations may be utilized, and structural and functional changes may be made. Furthermore, features of various implementations may be combined or modified. Therefore, the following description is presented by way of illustration only and should not in any way limit the various alternatives and modifications that may be made to the illustrated implementations. Numerous specific details in this disclosure provide a comprehensive understanding of the subject matter of this disclosure. It should be understood that aspects of this disclosure may be practiced through other implementations, etc., that do not necessarily include all aspects described herein.

[0026] As used herein, the expressions “example” and “exemplary” are intended to indicate an example or illustration. The expressions “example” and “exemplary” do not indicate a key or preferred aspect or implementation. Unless the context otherwise requires, the expression “or” is intended to be inclusive rather than exclusive.

[0027] The abbreviations used in this application are defined as follows:

[0028] DMSO: Dimethyl sulfoxide; BNCT: Boron neutron capture therapy; COF: Covalent organic framework; Tp: 2,4,6-tricarboxyloyl phloroglucinol; Pa-NH2: 2,5-diaminoterephthalic acid; FA: Folic acid; EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; NHS: N-hydroxysuccinimide; FA-COF: Folic acid-modified covalent organic framework; DMF: N,N-dimethylformamide; NH2-COF: Aminofunctionalized COF.

[0029] The covalent organic framework material for loading boron drug compounds in this application includes bortezomib and a support for loading bortezomib, wherein the support is made of a folic acid-modified covalent organic framework material. The mass ratio of bortezomib to the support is 1:3–7; the mass ratio of folic acid to the covalent organic framework material is 1:1.5–2.0; the covalent organic framework material is an amino-functionalized COF, and the raw materials for preparing the amino-functionalized COF include 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid, with a molar ratio of 2:3 between 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid.

[0030] The preparation method of the covalent organic framework material for loading boron drug compounds in this application is as follows:

[0031] (1) Preparation of amino-functionalized COF

[0032] According to a molar ratio of 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid of 2:3, 2,4,6-tricarboxymethyl phloroglucinol (Tp) and 2,5-diaminoterephthalic acid (Pa-NH2) were weighed separately and added to an acetonitrile / acetic acid mixed solvent and stirred until homogeneous. The mixture was then placed in a hydrothermal reactor and maintained at 110–130 °C for 12–72 h. After cooling to room temperature, the resulting NH2-COF was collected, centrifuged at 9000–12000 rpm for 3–6 min, and washed 3–5 times alternately with ethanol and distilled water for later use. The volume ratio of acetonitrile to acetic acid in the acetonitrile / acetic acid mixed solvent was 1:3.

[0033] (2) Preparation of FA-COF

[0034] Folic acid (FA) was dissolved in DMSO at a mass ratio of 1:1:2:11, and EDC / NHS was added and activated at room temperature for 2–5 h to obtain an activated solution. NH2-COF was dispersed in the activated solution at a mass ratio of 1:1.5–2.0, and reacted at 55–65 °C for 16–48 h under nitrogen protection. After cooling to room temperature, the mixture was centrifuged at 9000–12000 rpm for 3–6 min, washed 3–5 times alternately by centrifugation with DMF and ethanol, and then vacuum dried at 50–60 °C to obtain the FA-COF support.

[0035] (3) Boron-loaded drug compounds

[0036] Bortezomib was dissolved in PBS buffer at a mass ratio of 1:13 to bortezomib and then FA-COF was added at a mass ratio of 1:3 to 7 to bortezomib and ultrasonically assisted for 36 to 60 h. After loading, the FA-COF material loaded with boron was separated by centrifugation or filtration and washed multiple times with deionized water to remove unadsorbed boron on the surface. The loaded product was then vacuum dried at 40 to 60 °C for 6 to 12 h to obtain the boron-loaded and dried FA-COF support, i.e., the covalent organic framework material of the boron compound, and stored at 3 to 5 °C in the dark.

[0037] The above technical solution will be described in detail below through specific embodiments:

[0038] Example 1

[0039] The preparation method of the covalent organic framework material loaded with boron drug compound in this embodiment is as follows:

[0040] (1) Preparation of amino-functionalized COF

[0041] According to the molar ratio of 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid of 2:3, 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid were weighed separately and added to a mixed solvent of acetonitrile / acetic acid (volume ratio of acetonitrile and acetic acid of 1:3). The mixture was stirred evenly and then placed in a hydrothermal reactor and kept at 110 °C for 72 h. After cooling to room temperature, the obtained NH2-COF was collected, centrifuged at 9000 rpm for 6 min, and washed three times alternately with ethanol and distilled water for later use.

[0042] (2) Preparation of FA-COF

[0043] Folic acid (FA) was dissolved in DMSO at a mass ratio of 1:1:2:11 with folic acid, EDC, NHS, and DMSO. EDC / NHS was added and the mixture was activated at room temperature for 2 h to obtain an activated solution. NH2-COF was dispersed in the activated solution at a mass ratio of 1:1.5 with folic acid. The mixture was reacted at 55 °C for 48 h under nitrogen protection. After cooling to room temperature, the mixture was centrifuged at 12,000 rpm for 3 min, washed three times by alternating centrifugation with DMF and ethanol, and dried under vacuum at 60 °C to obtain the FA-COF support.

[0044] (3) Boron-loaded drug compounds

[0045] Bortezomib was dissolved in PBS buffer at a mass ratio of 1:13 to bortezomib and then FA-COF was added at a mass ratio of 1:3 to bortezomib and the support. The mixture was then soaked for 36 hours under ultrasonic assistance. After loading, the FA-COF material loaded with boron was separated by centrifugation or filtration and washed multiple times with deionized water to remove unadsorbed boron on the surface. The loaded product was then vacuum dried at 40°C for 12 hours to obtain the boron-loaded and dried FA-COF support, which is a covalent organic framework material for loading boron compounds. It was stored at 3–5°C in the dark.

[0046] Example 2

[0047] The preparation method of the covalent organic framework material loaded with boron drug compound in this embodiment is as follows:

[0048] (1) Preparation of amino-functionalized COF

[0049] According to the molar ratio of 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid of 2:3, 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid were weighed separately and added to a mixed solvent of acetonitrile / acetic acid (volume ratio of acetonitrile and acetic acid of 1:3). The mixture was stirred evenly and then placed in a hydrothermal reactor and kept at 120 °C for 36 h. After cooling to room temperature, the obtained NH2-COF was collected, centrifuged at 10,000 rpm for 4 min, and washed 4 times alternately with ethanol and distilled water for later use.

[0050] (2) Preparation of FA-COF

[0051] Folic acid (FA) was dissolved in DMSO at a mass ratio of 1:1:2:11, and EDC / NHS was added and activated at room temperature for 4 h to obtain an activated solution. NH2-COF was dispersed in the activated solution at a mass ratio of 1:1.6, and reacted at 60 °C for 32 h under nitrogen protection. After cooling to room temperature, the mixture was centrifuged at 10,000 rpm for 4 min, washed four times alternately by centrifugation with DMF and ethanol, and dried under vacuum at 60 °C to obtain the FA-COF support.

[0052] (3) Boron-loaded drug compounds

[0053] Bortezomib was dissolved in PBS buffer at a mass ratio of 1:13 to bortezomib and then FA-COF was added at a mass ratio of 1:5 to bortezomib and the support. The mixture was then soaked for 48 hours under ultrasonic assistance. After loading, the FA-COF material loaded with boron was separated by centrifugation or filtration and washed multiple times with deionized water to remove unadsorbed boron on the surface. The loaded product was then vacuum dried at 50°C for 8 hours to obtain the boron-loaded and dried FA-COF support, which is a covalent organic framework material for loading boron compounds. It was stored at 3–5°C in the dark.

[0054] Example 3

[0055] The preparation method of the covalent organic framework material loaded with boron drug compound in this embodiment is as follows:

[0056] (1) Preparation of amino-functionalized COF

[0057] According to the molar ratio of 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid of 2:3, 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid were weighed separately and added to a mixed solvent of acetonitrile / acetic acid (volume ratio of acetonitrile and acetic acid of 1:3). The mixture was stirred evenly and then placed in a hydrothermal reactor and kept at 130 °C for 12 h. After cooling to room temperature, the obtained NH2-COF was collected, centrifuged at 12000 rpm for 6 min, and washed 5 times alternately with ethanol and distilled water for later use.

[0058] (2) Preparation of FA-COF

[0059] Folic acid (FA) was dissolved in DMSO at a mass ratio of 1:1:2:11, and EDC / NHS was added and activated at room temperature for 3 h to obtain an activated solution. NH2-COF was dispersed in the activated solution at a mass ratio of 1:2.0 to folic acid, and reacted at 65 °C for 16 h under nitrogen protection. After cooling to room temperature, the solution was centrifuged at 9000 rpm for 5 min, washed four times alternately by centrifugation with DMF and ethanol, and dried under vacuum at 50 °C to obtain the FA-COF support.

[0060] (3) Boron-loaded drug compounds

[0061] Bortezomib was dissolved in PBS buffer at a mass ratio of 1:13 to bortezomib and then FA-COF was added at a mass ratio of 1:6 to bortezomib and the loading agent. The mixture was then soaked for 60 h under ultrasonic assistance. After loading, the FA-COF material loaded with boron was separated by centrifugation or filtration and washed multiple times with deionized water to remove unadsorbed boron on the surface. The loaded product was then vacuum dried at 60 °C for 6 h to obtain the boron-loaded and dried FA-COF support, i.e., the covalent organic framework material of the boron compound, which was stored at 3–5 °C in the dark.

[0062] Example 4

[0063] The preparation method of the covalent organic framework material loaded with boron drug compound in this embodiment is as follows:

[0064] (1) Preparation of amino-functionalized COF

[0065] According to the molar ratio of 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid of 2:3, 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid were weighed separately and added to a mixed solvent of acetonitrile / acetic acid (volume ratio of acetonitrile and acetic acid of 1:3). The mixture was stirred evenly and then placed in a hydrothermal reactor and kept at 110 °C for 48 h. After cooling to room temperature, the obtained NH2-COF was collected, centrifuged at 11000 rpm for 5 min, and washed three times alternately with ethanol and distilled water for later use.

[0066] (2) Preparation of FA-COF

[0067] Folic acid (FA) was dissolved in DMSO at a mass ratio of 1:1:2:11, and EDC / NHS was added and activated at room temperature for 5 h to obtain an activated solution. NH2-COF was dispersed in the activated solution at a mass ratio of 1:2.0 to folic acid, and reacted at 55 °C for 24 h under nitrogen protection. After cooling to room temperature, the mixture was centrifuged at 11,000 rpm for 5 min, washed three times alternately by centrifugation with DMF and ethanol, and dried under vacuum at 50 °C to obtain the FA-COF support.

[0068] (3) Boron-loaded drug compounds

[0069] Bortezomib was dissolved in PBS buffer at a mass ratio of 1:13 to bortezomib and then FA-COF was added at a mass ratio of 1:7 to bortezomib and the support. The mixture was then soaked for 56 hours under ultrasonic assistance. After loading, the FA-COF material loaded with boron was separated by centrifugation or filtration and washed multiple times with deionized water to remove unadsorbed boron on the surface. The loaded product was then vacuum dried at 55°C for 9 hours to obtain the boron-loaded and dried FA-COF support, which is a covalent organic framework material for loading boron compounds. It was stored at 3–5°C in the dark.

[0070] Comparative Example 1

[0071] This comparative example uses traditional liposome-loaded bortezomib, as detailed below:

[0072] Bortezomib was dissolved in PBS buffer, and conventional liposomes were added. The mixture was then soaked for 48 hours under ultrasonic assistance. After loading, the liposomes loaded with boron were separated by centrifugation or filtration. The liposomes were washed multiple times with deionized water to remove unadsorbed boron on the surface. The loaded product was then vacuum dried at 40°C for 8 hours to obtain the liposomes loaded with boron, which were stored at 3–5°C in the dark.

[0073] Comparative Example 2

[0074] This comparative example uses mesoporous silica-supported bortezomib, as detailed below:

[0075] Bortezomib was dissolved in PBS buffer, and mesoporous silica was added. The mixture was immersed in the solution for 48 hours under ultrasonic assistance. After loading, the boron-loaded mesoporous silica was separated by centrifugation or filtration. The silica was washed several times with deionized water to remove unadsorbed boron on the surface. The loaded product was then vacuum dried at 40°C for 8 hours to obtain boron-loaded mesoporous silica, which was stored at 3–5°C in the dark.

[0076] Performance testing:

[0077] (1) Using the covalent organic framework material of the boron-loaded drug compound prepared in Example 2, the liposome of the boron-loaded drug prepared in Comparative Example 1, and the mesoporous silica of the boron-loaded drug prepared in Comparative Example 2 as samples, the drug loading, pH 5.5 release rate and tumor accumulation rate were detected by conventional methods under the same conditions. The detection results are shown in Table 1:

[0078]

[0079] Table 1

[0080] (2) The covalent organic framework materials of boron-loaded drug compounds prepared in Examples 1-4, the liposomes of boron-loaded drug prepared in Comparative Example 1, and the mesoporous silica of boron-loaded drug prepared in Comparative Example 2 were used as targeted anticancer drugs for drug loading performance testing. Specifically, the test samples were dissolved in physiological saline to ensure no precipitate and a clear solution to guarantee the stability of the formulation during storage and use. The samples were injected intravenously into artificially induced liver cancer mice. The injection dose was adjusted according to factors such as mouse weight, tumor type, and size, generally 3 mg of test sample per kilogram of body weight. After injection into artificially induced liver cancer mice, the test samples, through surface-modified targeting groups, specifically recognized and bound receptors on the surface of tumor cells, thereby accumulating in the tumor region. By detecting the boron-10 concentration in the target region, it can be demonstrated that the corresponding sample can be effectively enriched in the treatment area. The results are shown in Table 2 and... Figure 1 As shown:

[0081]

[0082] Table 2

[0083] Combining Table 1 and Table 2, and Figure 1 The data show that the covalent organic framework material for loading boron drug compounds of the present invention has excellent boron drug loading and targeting performance.

[0084] The folic acid-modified COF boron-loaded drug system developed in this invention successfully overcomes the technical bottlenecks of traditional drug delivery systems through a three-pronged innovation of "molecular-level structure design, precise modification of chemical bonds, and intelligent responsive release." Compared with existing technologies, this system achieves a leapfrog improvement in the following dimensions: First, it revolutionizes drug loading performance, setting a new record for boron drug carriers with a drug loading capacity of 42.7%, and significantly reducing off-target toxicity with a pH-responsive release ratio of 6:1; Second, it upgrades targeted delivery, with folic acid modification that stabilizes thioether bonds increasing the tumor accumulation rate to 12.8% ID / g, laying a material foundation for precision treatment.

[0085] The COF design strategy developed in this invention is compatible with a variety of hydrophobic drugs (paclitaxel, doxorubicin, etc.) and provides an ideal boron carrier for boron neutron capture therapy (BNCT).

[0086] The folic acid-modified covalent organic framework (FA-COF) loaded boron compound targeted anticancer drug prepared by this invention combines the topological design of COF (AA ​​stacking mode) with drug molecular dynamics simulation to achieve precise matching of "pore size-drug diffusion rate-release kinetics", which solves the core problem of low delivery efficiency of boron drugs in BNCT and is expected to reduce neutron irradiation dose by 50%.

[0087] The foregoing description includes examples from this specification. Of course, for the purposes of describing this specification, it is impossible to describe every conceivable combination of components or methods; however, those skilled in the art will understand that many other combinations and arrangements are possible. Therefore, this specification is intended to cover all such changes, modifications, and variations that fall within the spirit and scope of the appended claims. Furthermore, with regard to the use of the term "comprising" in the detailed description or claims, the term is intended to be inclusive in a manner similar to the term "including," as interpreted when "comprising" is used as a transitional word in the claims.

[0088] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications and substitutions should be covered within the scope of the claims of the present invention. Technical aspects, shapes, and structures not described in detail in this invention are all well-known technologies.

Claims

1. A covalent organic framework material loaded with boron drug compounds, characterized in that, This includes bortezomib and a support for loading bortezomib, said support being made of a folic acid-modified covalent organic framework material.

2. The covalent organic framework material for loading boron drug compounds according to claim 1, wherein, The mass ratio of bortezomib to the support is 1:3 to 7.

3. The covalent organic framework material for loading boron drug compounds according to claim 1, wherein, The mass ratio of folic acid to covalent organic framework material is 1:1.5 to 2.

0.

4. The covalent organic framework material for loading boron drug compounds according to claim 1, wherein, The covalent organic framework material is an amino-functionalized COF. The raw materials for preparing the amino-functionalized COF include 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid, and the molar ratio of 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid is 2:

3.

5. A method for preparing covalent organic framework materials loaded with boron drug compounds, characterized in that, Includes the following steps: Folic acid was dissolved in dimethyl sulfoxide, and EDC / NHS was added and activated at room temperature for 2–5 h to obtain an activation solution. The amino-functionalized COF was dispersed in the activation solution and reacted at 55–65 °C for 16–48 h under nitrogen protection. After cooling to room temperature, the mixture was centrifuged at 9000–12000 rpm for 3–6 min, washed 3–5 times by alternating centrifugation with DMF / ethanol, and dried under vacuum at 50–60 °C to obtain FA-COF. Bortezomib was dissolved in PBS buffer, FA-COF was added, and the mixture was soaked for 36–60 h under ultrasonic assistance. The boron-loaded FA-COF material was then separated by centrifugation or filtration, washed with deionized water, and then vacuum dried at 40–60 °C for 6–12 h to obtain the boron-loaded and dried FA-COF carrier, which was stored in the dark.

6. The preparation method according to claim 5, wherein, The preparation method of the amino-functionalized COF is as follows: Weigh 2,4,6-tricarboxymethyl phloroglucinol and 2,5-diaminoterephthalic acid separately, add them to a mixed solvent of acetonitrile / acetic acid and stir until homogeneous. Then keep the mixture at 110-130 °C for 12-72 h. After cooling to room temperature, collect the amino-functionalized COF and centrifuge at 9000-12000 rpm for 3-6 min. Wash the COF with ethanol and distilled water alternately 3-5 times for later use.

7. The preparation method according to claim 6, wherein, The molar ratio of 2,4,6-tricarboxymethyl phloroglucinol to 2,5-diaminoterephthalic acid is 2:

3.

8. The preparation method according to claim 5, wherein, In the activation solution, the molar ratio of folic acid to dimethyl sulfoxide is 1:

11.

9. The preparation method according to claim 5, wherein, The FA-COF carrier was stored at 3–5 °C in the dark.

10. The covalent organic framework material of the boron-loaded drug compound according to any one of claims 1-4, or the covalent organic framework material of the boron-loaded drug compound prepared by the preparation method according to any one of claims 5-9, in the preparation of targeted anticancer drugs.

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