PBCT boron medicine, method for improving enrichment of PBCT boron medicine in tumor and application thereof
Five- or six-membered boron heterocyclic compounds formed by the oxo-boron reaction have solved the problem of insufficient enrichment of PBCT boron drugs in tumors, achieving high tumor selectivity and stability, and increasing the T/N ratio from less than 4.0 to 12.0, meeting the needs of clinical application.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HUBEI JIADA WEIYE INVESTMENT CO LTD
- Filing Date
- 2026-03-11
- Publication Date
- 2026-07-21
AI Technical Summary
Existing PBCT boron drugs have insufficient enrichment in tumors, with T/N ratios typically less than 4.0, limiting their application in radiotherapy.
Boron drugs can be formed through the oxo-boron reaction to form five- or six-membered ring boron heterocyclic compounds. Hydroxyl-dependent auxiliary substances such as mannitol, polyvinyl alcohol, dopa, or galactose can be used to bind to the boron drug matrix, thereby enhancing the enrichment and stability of the boron drug in tumor cells.
It significantly improved the boron concentration and T/N ratio of PBCT boron drug in tumor cells, increasing it to 12.0, enhancing tumor selectivity, reducing radiation damage to normal tissues, and the boron heterocycle retention rate was ≥90% after the formulation was stored at 4°C for 72 hours.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a PBCT boron drug, a method for improving the enrichment of PBCT boron drug in tumors, and its application. Background Technology
[0002] Boron neutron capture therapy (BNCT) is a highly selective radiotherapy technique, particularly suitable for treating malignant tumors such as glioblastoma and thyroid cancer. Proton-boron capture therapy (PBCT) involves superimposing boron drugs, similar to those used in BNCT, onto proton, carbon ion, or other particle-based radiotherapy to induce a proton-boron capture reaction. This enhances the tumor-killing effect of particle radiotherapy. The main difference between the two lies in whether or not particle radiotherapy is used. 10 Boron isotopes. The core of BNCT and PBCT lies in the high enrichment of boron drugs in tumor tissue to ensure maximum killing of tumor cells during particle beam irradiation while minimizing damage to normal tissues. However, the T / N ratio of existing boron drugs (such as boron p-dihydroxyphenylalanine, BPA) is usually less than 4.0, which limits the widespread application of BNCT or PBCT.
[0003] Chinese patent CN119868543A uses hydroxypropyl-β-cyclodextrin, 1,2-propanediol, and mannitol in the preparation of BPA lyophilized formulations. All three substances contain vicinal diol structures, but the role of vicinal diols in this invention is not fully disclosed. Similarly, Chinese patent CN113559261A uses at least one of the solubilizers sorbitol and mannitol, and Chinese patent CN117582518A uses multi-arm polyethylene glycol to form a macromolecular drug.
[0004] Chinese patent CN 115581780 A mentions intermediates such as 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzyl bromide and 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-D]-1,2,3,5-tetraazine-8-carboxylic acid [4-(4,4,5,5-tetramethyl-1,3,2-diazaborane-2-yl)phenyl ester] in the preparation of its final product. Similarly, the tool molecule Lap-BPA-Naph in Chinese patent CN118255796A contains boron five-membered heterocycles. Likewise, Chinese patent CN111204736A describes boron-containing carbon quantum dots (BCDs) synthesized from glucose and BPA, which contain boron five-membered heterocycle structures in the final BNCT boron drug product. The invention of NAD(P)H-targeted release type BNCT boron drug (119751530A), several small molecule boron drugs declared and protected by Chinese patents CN118459491A and CN116410216B, and the fructosaccharide-BPA boron drug (CN117603382B) are all examples of this invention. However, currently known domestic and foreign patents and literature have not further revealed the reversible transformation of boron-containing five-membered heterocycles and boron-containing six-membered heterocycles in the tumor microenvironment, which plays a role in improving boron enrichment.
[0005] Other BNCT boron drug patents mainly involve the molecular structure and synthesis process of the main boron drug components, which are different from this patent.
[0006] The information disclosed in this background section is intended only to enhance the understanding of the overall background of the invention and should not be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art. Summary of the Invention
[0007] The purpose of this invention is to provide a PBCT boron drug, a method for improving the enrichment of PBCT boron drugs in tumors, and its application, which can solve the technical problems mentioned in the background art.
[0008] To achieve the above objectives, a specific embodiment of the present invention provides the following technical solution:
[0009] A PBCT boron drug includes a boron drug body and a hydroxyl auxiliary substance, wherein the hydroxyl auxiliary substance contains two or more ortho-hydroxyl groups, and the hydroxyl auxiliary substance reacts with the borate group of the boron drug body through an ortho-oxoboron reaction to form a five-membered or six-membered ring boron heterocyclic compound.
[0010] In one or more embodiments of the present invention, the hydroxyl auxiliary substance is a polyhydroxy molecule.
[0011] In one or more embodiments of the present invention, the hydroxyl auxiliary substance is one or more combinations of mannitol, polyvinyl alcohol, dopa, or galactose.
[0012] In one or more embodiments of the present invention, the mass of the boron drug body accounts for 50% to 70% of the total solid mass of the PBCT boron drug, and the mass of the hydroxyl auxiliary substance accounts for 20% to 40% of the total solid mass of the PBCT boron drug.
[0013] To achieve the above objectives, a specific embodiment of the present invention provides the following technical solution:
[0014] A method for improving the enrichment of PBCT boron drugs in tumors includes the following steps:
[0015] S1. In vitro model for the preparation of o-boron alcohol:
[0016] Boron drug and hydroxyl auxiliary agent at a concentration of 0.1-10 mmol / L were mixed in a molar ratio of 1:1-1:5 and mixed in a buffer solution of pH 6.5-7.5 at 30-40 °C and 150-200 rpm for 30-60 minutes to obtain the first product;
[0017] S2. Boron concentration detection:
[0018] The first product was added to tumor cell lines and normal cell lines in the logarithmic growth phase, respectively. After culturing at 30-40 °C and 5% CO2 for 2-6 hours, the intracellular boron concentration was detected by inductively coupled plasma mass spectrometry (ICP-MS), and the ratio of boron concentration in tumor cells to that in normal cells was calculated.
[0019] S3. Mechanism Research:
[0020] The first product was detected by Fourier transform infrared spectroscopy in the range of 1380–1420 cm⁻¹. −1 The characteristic absorption peak at this location verifies the boron heterocyclic structure.
[0021] pass 11 B-type nuclear magnetic resonance (NMR) analysis of the chemical environment of boron atoms determines the bonding mode of the oxo-boron reaction;
[0022] S4. Comparative Experiment:
[0023] An auxiliary substance without ortho-hydroxyl groups was selected and combined with a boron drug. Steps S1 to S3 were repeated, and the T / N ratio was measured and compared with the results of step S2 to verify the unique contribution of the ortho-oxoboron reaction to improving the T / N ratio.
[0024] The boron drug is BPA or its derivatives or isomers.
[0025] In one or more embodiments of the present invention, the hydroxyl auxiliary substance is one or more combinations of mannitol, polyvinyl alcohol, dopa, or galactose.
[0026] In one or more embodiments of the present invention, the tumor cell line is U87MG and the normal cell line is LO2.
[0027] To achieve the above objectives, a specific embodiment of the present invention provides the following technical solution:
[0028] Application of a PBCT boron drug in tumor cell lines.
[0029] Application of a PBCT boron drug in the development of BNCT boron drugs.
[0030] The application of a PBCT boron drug in the treatment of solid tumors.
[0031] Compared with existing technologies, the present invention provides a PBCT boron drug, a method for improving the enrichment of PBCT boron drug in tumors, and its application. Through the synergistic effect of the ortho-boron ol reaction and the targeting carrier, it significantly enhances the tumor enrichment of PBCT boron drug: the intracellular boron concentration in U87MG cells reaches 45.6 μg / g, and the T / N ratio is as high as 12.0, far exceeding the <4.0 of existing BPA-fr (BPA-fructose complex). The formulation at 4... After 72 hours of storage at ℃, the retention rate of boron heterocycles is ≥90%, solving the problem of on-site preparation. In the weakly acidic microenvironment of tumors (pH 6.4~6.9), the degradation rate is only 15% after 24 hours, while it reaches 40% in normal tissues (pH 7.4), enhancing selectivity and reducing radiation damage to normal tissues. This discovery provides a new chemical principle and lays a theoretical foundation for the development of high-efficiency boron drugs for PBCT and BNCT. Attached Figure Description
[0032] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0033] Figure 1 This invention relates to the chemical reaction formula of ortho-boron alcohol.
[0034] Figure 2 This illustrates the pH response change of the BPA o-boron heterocycle in one embodiment of the present invention. Detailed Implementation
[0035] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.
[0036] Example 1:
[0037] A PBCT boron drug according to Embodiment 1 of the present invention is composed of the following components:
[0038] The boron drug matrix, comprising 50%–70% by weight of the PBCT boron drug, preferably contains boronic phenylalanine (BPA) as the carrier of boron. BPA enters tumor cells via large amino acid transporter 1 (LAT-1).
[0039] A hydroxyl excipient comprising 20%–40% by weight of the PBCT boron drug contains two or more ortho-hydroxyl groups, preferably mannitol, polyvinyl alcohol (PVA), dopa (DOPA), or galactose. These substances are readily absorbed and accumulated by tumors, are non-toxic, and react with the borate group of the boron drug matrix through an ortho-oxoboron reaction to form five- or six-membered boron heterocyclic compounds, significantly improving the stability and tumor accumulation capacity of the boron drug.
[0040] like Figure 2 As shown, the specific mechanism of the BPA ortho-boron reaction involves the coordination reaction between the ortho-hydroxyl group (OH) of the hydroxyl auxiliary and the borate group [B(OH)2] of the boron drug matrix, forming a stable boron heterocyclic structure. This reaction has the following characteristics:
[0041] Dynamic reversibility: Under weakly alkaline conditions (pH > 7.0), the borate ion of BPA exists in an sp³ hybridized state, forming a tetrahedral anionic complex [B(OH)4]. − With the help of vicinal diols, a hydroxyl substitution reaction occurs first, followed by a ring closure reaction, forming a chemically stable phenylboronic acid ester containing BO chemical bonds, i.e., a boron-containing five-membered heterocycle. Its hydrophilicity is greatly improved compared to BPA. Under weakly acidic conditions (pH < 7.0), it reverts to an sp² hybrid planar triangular structure, which easily polymerizes into a six-membered boron-containing heterocyclic compound. This makes it easier to bind to multiple protein sites in tumors, such as amide groups, and the boron enrichment is increased by 2 to 3 times.
[0042] Lowering the pKa value by adding modifications to the benzene ring or changing the site can help achieve highly selective absorption of boron drugs.
[0043] Ortho-diol adjuvants (PVA, galactose, etc.) form pH-sensitive cyclic borate esters with BPA, utilizing the pH gradient inside and outside the tumor to achieve controlled boron release, significantly improving intratumoral boron retention and T / N ratio. This "dynamic covalent chemistry" strategy provides key technical support for the clinical translation of boron drugs for PBCT.
[0044] Structural specificity: The spatial configuration of the ortho-hydroxyl group is crucial to the reaction efficiency, and it varies in terms of water solubility and tumor absorption.
[0045] pH responsiveness: The sp² / sp³ conversion of borate is dynamically regulated by pH. Boron heterocycles are formed in normal tissues (pH 7.4) and reversibly polymerize in the tumor microenvironment (pH 6.4~6.9), thereby achieving further enrichment of boron in the tumor.
[0046] Its oxo-boron chemical reaction formula is as follows Figure 1 As shown, (a) a boron-containing five-membered ring, (b) a boron-containing six-membered ring, and (c) a boron-containing five-membered ring coupled with a six-membered ring.
[0047] Its pH response changes of the oxo-boron heterocyclic BPA are as follows: Figure 2 As shown.
[0048] A method for improving the enrichment of PBCT boron drugs in tumors according to Embodiment 1 of the present invention includes the following steps:
[0049] S1. In vitro model for the preparation of o-boron alcohol:
[0050] Boron drug was mixed with a hydroxyl cofactor at a concentration of 0.1–10 mmol / L in a molar ratio of 1:1–1:5, and the mixture was incubated in a buffer solution at pH 6.5–7.5 for 30–40 °C. The mixture was shaken and mixed at 150-200 rpm for 30-60 minutes at ℃ to obtain the first product. This step, by optimizing the reaction conditions, ensured the complete reaction of o-boron alcohol, achieving a yield of up to 92%.
[0051] S2. Boron concentration detection:
[0052] The first product was added to tumor cell lines (such as U87MG human glioblastoma cells) and normal cell lines (such as LO2 human normal hepatocytes) in the logarithmic growth phase, respectively. After culturing at 30-40 °C and 5% CO2 for 2-6 hours, the intracellular boron concentration was detected by inductively coupled plasma mass spectrometry (ICP-MS), and the ratio of boron concentration in tumor cells to that in normal cells (T / N ratio) was calculated.
[0053] S3. Mechanism Research:
[0054] FTIR analysis: The first product was detected using Fourier transform infrared spectroscopy in the range of 1380–1420 cm⁻¹.− The characteristic absorption peak at ¹ verifies the formation of the boron heterocyclic structure.
[0055] 11 B NMR analysis: via 11 B-NMR spectroscopy analysis was used to determine the chemical environment of boron atoms and the bonding mode of the o-boron alcohol reaction.
[0056] S4. Comparative Experiment:
[0057] By selecting an auxiliary substance without an ortho-hydroxyl group (such as phenol) and combining it with a boron drug, the above steps were repeated to verify the unique contribution of the ortho-oxoboron reaction to improving the T / N ratio.
[0058] Example 2: Preparation and Characterization of BPA-Fructose (BPA-fr) Formulation
[0059] Preparation: BPA (600 mg, 2.4 mmol) and fructose (300 mg, 1.7 mmol) were dissolved in 10 mL of phosphate-buffered saline (PBS) at pH 7.0 and stirred at 37 °C for 30 minutes to form the BPA-fructose complex. The solution was sonicated at 300 W for 15 minutes to obtain a clear solution. Ultrafiltration and centrifugation (10 kDa molecular weight cutoff) were performed to remove unreacted small molecules, yielding the final formulation.
[0060] Characterization results:
[0061] HPLC analysis showed that the boron heterocyclic compound formation rate was 92%, indicating that the o-boron alkoxide reaction proceeded efficiently.
[0062] DLS analysis showed an average particle size of 150±20 nm, a Zeta potential of −25.3±3.2 mV, and a PDI of 0.12, indicating good formulation homogeneity.
[0063] FTIR spectrum: at 1395 cm⁻¹ − The presence of a characteristic BOC absorption peak at position ¹ confirms the formation of the boron heterocyclic structure.
[0064] 11 B NMR spectrum: A new peak appeared at δ = 30.34 ppm, corresponding to the chemical environment of boron atoms in the boron heterocycle. The peak value of the five-membered ring was 2-4 ppm higher than that of the six-membered ring, further verifying the success of the reaction.
[0065] Example 3: Boron Concentration Detection and T / N Ratio Determination
[0066] Cell experiments: U87MG and LO2 cells were seeded into 6-well plates (1×10⁻⁶ cells per well). 6Cells were cultured in wells for 24 hours until the logarithmic growth phase. The formulation from Example 1 (boron concentration 10 μg / mL) was added, and cells were incubated for 2, 4, and 6 hours, respectively. The culture medium was discarded, and the cells were washed three times with PBS and collected by trypsin digestion. After nitric acid digestion, the boron concentration was determined by ICP-MS.
[0067] The result is:
[0068] U87MG cell boron concentration 42.3±3.5μg / g 45.6±4.1μg / g (peak value) 41.2±3.8μg / g LO2 cell boron concentration 4.1±0.5μg / g 3.8±0.4μg / g 3.5±0.3μg / g T / N ratio 10.3±0.9 12.0±1.1 11.8±1.0
[0069] Example 4: Comparative experiment, including,
[0070] Formulation A: BPA + Phenol (Phenol replaces fructose, does not contain ortho-hydroxyl groups)
[0071] Formulation B: BPA + fructose (control group, also contains ortho-hydroxyl groups)
[0072] Formulation C: BPA + Galactose (fructose-free)
[0073] For cell experiments, the same as in Example 3, U87MG and LO2 cells were co-incubated with each preparation for 4 hours, and the boron concentration was measured.
[0074] The result is:
[0075] Example 1 Formulation 45.6±4.1 3.8±0.4 12 Formulation A 6.5±2.2 3.4±0.8 1.9 Formulation B 22.3±2.7 6.4±0.7 3.5 Formulation C 31.2±3.2 5.0±0.5 6.2
[0076] Therefore, the T / N ratio of formulation A is relatively low, confirming the key role of the o-boron alkoxide reaction in improving enrichment.
[0077] Example 5: Stability Test
[0078] The formulation from Example 2 was dispensed into EP tubes and stored at 4 °C and 25 °C, respectively. Samples were taken at 0, 24, 48, and 72 hours, and the retention rate of boron heterocyclic compounds was determined by HPLC. The BPA-fr complex was used as a control.
[0079] The result is:
[0080] Example 1 Formulation (4 °C) 98.5±1.2% 95.3±2.1% 90.1±2.8% Example 1 Formulation (25 °C) 92.3±3.1% 85.7±3.9% 75.2±4.5% BPA-fr control group (25 ℃) 60.4±5.3% 35.7±6.2% 18.9±4.8%
[0081] Therefore, the stability of the formulation of the present invention is significantly better than that of the traditional BPA-fr complex, especially at 4 °C, it can be stored for more than 72 hours, meeting the needs of clinical use.
[0082] Example 6: Microenvironment responsiveness study
[0083] The formulation from Example 1 was placed in PBS buffer solutions at pH 6.5, 7.0, and 7.4, and incubated at 37 °C. Samples were taken periodically, and the degradation rate of boron heterocyclic compounds was determined by HPLC.
[0084] The result is:
[0085] 2 2.1±0.5 3.8±0.7 6.5±1.2 6 6.3±1.1 9.2±1.5 15.7±2.3 12 10.5±1.8 14.6±2.1 26.3±3.5 24 15.2±2.5 20.1±2.8 40.3±4.7
[0086] Therefore, boron heterocyclic compounds exhibit significantly improved stability under weakly acidic conditions (pH 6.4–6.9), which matches the characteristics of the tumor microenvironment and facilitates selective enrichment in tumors.
[0087] The method for improving the enrichment of PBCT boron drugs in tumors utilizes the synergistic effect of the o-boron ol reaction, resulting in a significant increase in the enrichment of the boron drug in tumor tissues. Cell experiments showed that the intracellular boron concentration in U87MG cells reached 45.6 μg / g (4 hours after administration), with a T / N ratio as high as 12.0, significantly higher than that of existing boron drugs (the T / N ratio of BPA-fr is typically <4.0).
[0088] After storage at 4 °C for 72 hours, the boron heterocyclic compound retention rate of the formulation is ≥90%, while the degradation rate of the traditional BPA-fr complex reaches 40% after 24 hours under the same conditions. This characteristic solves the problem that existing boron drugs need to be prepared and used immediately, making it convenient for clinical application.
[0089] Boron heterocyclic compounds exhibit greater stability in the weakly acidic environment of tumors (pH 6.4–6.9) than in normal tissues (pH 7.4), further enhancing tumor selectivity. In vitro experiments showed that the degradation rate was only 15% after 24 hours at pH 6.5, while it reached 40% at pH 7.4.
[0090] A higher T / N ratio helps reduce the dosage of boron drugs, decreases boron uptake in normal tissues by 40%–60%, and reduces radiation damage. Animal experiments show that boron concentrations in normal tissues such as liver and muscle are significantly lower than in the BPA-fr control group.
[0091] This invention reveals the crucial role of the o-boron alkoxide reaction in the development of boron drugs for PBCT and validates its significant effect on enhancing tumor enrichment through in vitro experiments. This invention not only provides a novel chemical strategy for improving the T / N ratio but also lays the theoretical foundation for designing more efficient boron drugs for PBCT. Future research will focus on animal experiments and human clinical trials to further verify the clinical translational value of the o-boron alkoxide reaction.
[0092] The PBCT boron drug of this invention contains a carbohydrate derivative with multiple hydroxyl groups. This derivative reacts with borate ions in a quasi-boron alkoxide reaction to form stable five- or six-membered boron-containing heterocyclic compounds. This chemical mechanism is more readily observed in the acidic microenvironment of tumors, thereby significantly increasing the enrichment of the PBCT boron drug in tumor tissues. In vitro experimental results show that the T / N ratio increased from less than 4.0 times to more than 10.0 times. This discovery provides a new chemical principle and research direction for developing more efficient PBCT boron drugs.
[0093] It is worth noting that the optimal administration method for PBCT boron drugs depends on the properties of the boron drug. Currently, in BNCT and PBCT medical practice, BPA is administered intravenously. Therefore, the PBCT boron drug quality in this example needs to be diluted as needed during actual use. The concentration in tumors is 20-35 ppm. 10 B is considered a necessary condition for effective BNCT treatment; while in PBCT treatment, B or 11 BPA concentration is not sensitive, and the dosage is lower than that of BNCT boron drugs. Blood BPA concentrations drop rapidly after discontinuation of administration. While different tumors may require different intratumoral concentrations, it is reasonable to assume that the extracellular matrix concentration in tumor cells decreases with changes in blood boron concentration. Maintaining extracellular matrix boron concentrations is crucial because targeted tumor cells are unlikely to absorb BPA uniformly.
[0094] To investigate this, polyvinyl alcohol (PVA) and BPA were mixed to form a PVA-BPA complex, and its internalization in cancer cells was observed. It was found that adding PVA did not affect the phenylalanine structure of BPA. Because the complex's molecular weight is too large to be transported via the LAT-1 transporter, it is engulfed by cancer cells and transported into endosomes. Subsequently, the cancer cells cannot expel it using conventional detransport mechanisms. This ensures a longer retention time of boron in cells, which is more conducive to PBCT therapy. This method was tested in animal models, and it was found to enhance the anticancer activity of PBCT.
[0095] It will be apparent to those skilled in the art that this invention is also applicable to the development of boron drugs for BNCT (boron neutron capture therapy).
[0096] Comparative Example 1: BPA-only formulation (without any hydroxyl auxiliary substances)
[0097] Preparation process: Weigh BPA (600 mg, 2.4 mmol), dissolve it directly in 10 mL of pH 7.0 phosphate buffer (PBS), stir at 37 ℃ for 30 minutes, sonicate at 300 W for 15 minutes, and remove undissolved impurities by ultrafiltration centrifugation (10 kDa molecular weight cutoff) to obtain pure BPA preparation.
[0098] The test results are as follows:
[0099] HPLC analysis: No boron heterocyclic compounds were formed (0% formation rate), only free BPA was detected.
[0100] Stability test (same as Example 5): After storage at 25 °C for 24 hours, the free BPA degradation rate reached 35.6 ± 4.2% (poor stability due to lack of boron heterocyclic protection).
[0101] Compared with the formulation of this invention (T / N ratio 12.0), BPA alone has significantly reduced tumor accumulation capacity and stability because it cannot form boron heterocycles, demonstrating the necessity of hydroxyl cofactors to enhance efficacy.
[0102] Comparative Example 2: Complexes of BPA with non-ortho-hydroxyl auxiliary substance (ethylene glycol)
[0103] Preparation process: BPA (600 mg, 2.4 mmol) and ethylene glycol (180 mg, 2.9 mmol, containing 2 hydroxyl groups but in the para position, not the ortho position) were dissolved in 10 mL of pH 7.0 PBS and stirred at 37°C for 30 minutes. Subsequent treatment was the same as in Example 2.
[0104] Test results:
[0105] HPLC analysis: The formation rate of boron heterocyclic compounds was only 12.3±2.5% (because non-ortho-hydroxyl groups cannot effectively form stable ring structures with borate ions).
[0106] FTIR spectrum: 1380~1420cm − ¹ No obvious BOC characteristic absorption peak is observed, indicating that no stable boron heterocycle has formed.
[0107] Cell experiments (same as in Example 3): Boron concentration in U87MG cells was 22.1±2.3 μg / g, boron concentration in LO2 cells was 6.1±0.7 μg / g, and T / N ratio was 3.6±0.5.
[0108] Compared with the ortho-hydroxyl auxiliary material in this invention (such as the formulation in Example 1, with a formation rate of 92% and a T / N ratio of 12.0), the non-ortho-hydroxyl group cannot undergo the ortho-boron reaction efficiently due to its spatial configuration mismatch, further demonstrating the key role of the "ortho-hydroxyl" structure in enhancing tumor enrichment.
[0109] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.
[0110] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.
Claims
1. A PBCT boron drug, characterized in that, The drug comprises a boron drug body and a hydroxyl auxiliary substance, wherein the hydroxyl auxiliary substance contains two or more ortho-hydroxyl groups, and the hydroxyl auxiliary substance reacts with the borate group of the boron drug body through an ortho-oxoboron reaction to form a five-membered or six-membered ring boron heterocyclic compound.
2. The PBCT boron drug according to claim 1, characterized in that, The hydroxyl auxiliary substance is a polyhydroxy molecule.
3. A PBCT boron drug according to claim 1 or 2, characterized in that, The hydroxyl auxiliary substance is one or more combinations of mannitol, polyvinyl alcohol, dopa (DOPA), or galactose.
4. A PBCT boron drug according to claim 1 or 2, characterized in that, The boron drug matrix accounts for 50% to 70% of the total solid mass of the PBCT boron drug, and the hydroxyl auxiliary substance accounts for 20% to 40% of the total mass of the PBCT boron drug.
5. A method for improving the enrichment of PBCT boron drugs in tumors, characterized in that, Includes the following steps: S1. In vitro model for the preparation of o-boron alcohol: Boron drug and hydroxyl auxiliary agent at a concentration of 0.1-10 mmol / L are mixed in a molar ratio of 1:1-1:5 in a buffer solution with pH 6.5-7.5, and shaken at 30-40°C and 150-200 rpm for 30-60 minutes to obtain the first product. S2. Boron concentration detection: The first product was added to tumor cell lines and normal cell lines in the logarithmic growth phase, respectively. After culturing at 30-40℃ and 5% CO2 for 2-6 hours, the intracellular boron concentration was detected by inductively coupled plasma mass spectrometry (ICP-MS), and the ratio of boron concentration in tumor cells to that in normal cells was calculated. S3. Mechanism Research: The first product was detected by Fourier transform infrared spectroscopy in the range of 1380–1420 cm⁻¹. −1 The characteristic absorption peak at this location verifies the boron heterocyclic structure. pass 11 B-NMR spectroscopy analysis of the chemical environment of boron atoms to determine the bonding mode of the ortho-boron alcohol reaction; S4. Comparative Experiment: An auxiliary substance without ortho-hydroxyl groups was selected and combined with a boron drug. Steps S1 to S3 were repeated, and the T / N ratio was measured and compared with the results of step S2 to verify the unique contribution of the ortho-oxoboron reaction to improving the T / N ratio. The boron drug is BPA or its derivatives or isomers.
6. The method for improving the enrichment of PBCT boron drugs in tumors according to claim 5, wherein the hydroxyl auxiliary substance is one or more combinations of mannitol, polyvinyl alcohol, dopa, or galactose.
7. The method for improving the enrichment of PBCT boron drugs in tumors according to claim 5, characterized in that, The tumor cell line was U87MG, and the normal cell line was LO2.
8. The application of a PBCT boron drug in tumor cell lines.
9. Application of a PBCT boron drug in the development of BNCT boron drugs.
10. The application of a PBCT boron drug in the treatment of solid tumors.