Albumin-bound manganese borate nanoparticles and their application in the preparation of tumor therapeutic drugs

Abstract

The present invention relates to the field of anti-tumor drug technology, and in particular to albumin-bound manganese borate nanoparticles and their use in the preparation of tumor therapeutic drugs. The technical solution comprises a manganese borate compound and an albumin shell, wherein the manganese borate compound binds to manganese ions via a coordination bond, and the albumin shell coats the manganese borate compound to form nanoparticles; wherein the average particle size of the nanoparticles is 100 nm to 300 nm, and the mass ratio of the albumin to the manganese borate compound is 10:1 to 1000:1. The albumin-bound manganese borate nanoparticles provided by the present invention not only synergistically enhance the inhibitory effect of boric acid on tumor cells, significantly inhibiting tumor growth in tumor-bearing mice, but also increase the proportion of tumor-infiltrating T cells, upregulate the level of immune killer factors, and activate the tumor immune system. These nanoparticles combine multiple benefits, including targeted delivery, image guidance, synergistic therapy, and immune sensitization, providing an efficient and precise innovative solution for tumor treatment.

Description

Technical Field

[0001] The present invention relates to the technical field of anti-tumor drugs, in particular to albumin-bound manganese borate nanoparticles and applications thereof in preparing tumor therapeutic drugs. Background Art

[0002] Cancer remains one of the greatest threats to human health. Boron Neutron Capture Therapy (BNCT), a cutting-edge targeted tumor treatment technology, has become widely available in clinical practice thanks to the availability of hospital-based neutron accelerators. BNCT works by injecting a boron-containing drug into the body, causing it to accumulate in tumor cells. Neutron beam irradiation then triggers a nuclear reaction, producing high-energy alpha particles and lithium ions that precisely destroy cancer cells, achieving cellular-level targeted therapy while minimizing damage to normal tissue.

[0003] Boron-containing drugs are central to achieving precision therapy. Ideally, boron-containing drugs should be dynamically monitored, have low toxicity, and be retained in tumor tissue for extended periods, absorbing at least 20 μg of 10B per gram of tumor tissue (equivalent to more than 109 10B atoms per tumor cell). Furthermore, boron-containing drugs should be rapidly metabolized in blood and normal tissues, with the 10B concentration ratios (T / N) between tumor and normal tissue, and T / B between tumor and blood, both exceeding 3. Currently, first-generation boron-containing drugs for BNCT, such as boric acid and its derivatives, have high boron content (up to a theoretical 17.5%). However, they exhibit poor specificity for tumor cells, resulting in a low tumor / normal tissue boron concentration ratio and unavoidable damage to normal tissues. This severely limits the selectivity and therapeutic window of neutron irradiation, leading to the failure of the first BNCT clinical trials. Second-generation BNCT drugs, such as boranophenylalanine (BPA), have demonstrated significant clinical efficacy thanks to their tumor-targeting advantage mediated by the L-type amino acid transporter (LAT1) and are currently approved by the US Food and Drug Administration for the clinical treatment of tumor BNCT. However, their boron atomic content is significantly reduced (approximately 3.8% by mass), requiring patients to receive high-dose injections (300-500 mg / kg) to achieve the required boron concentration (15-35 μg / g). This not only increases the metabolic burden on the liver and kidneys but may also induce systemic toxicities such as hypotension. Furthermore, BPA has a short retention time at the tumor site, likely due to the effects of LAT1's anti-transport mechanism on intracellular BPA molecules.

[0004] Therefore, current boron drugs used in BNCT suffer from problems such as low boron content, insufficient tumor targeting, and excessively high therapeutic doses, which limit their clinical application and fail to fully exert their anti-tumor immune effects. This application proposes albumin-bound manganese borate nanoparticles and their use in the preparation of tumor therapeutic drugs. Summary of the Invention

[0005] The purpose of the present invention is to address the problems of low boron content, insufficient tumor targeting and excessively high therapeutic doses in current boron drugs used in BNCT in the background art, and to propose albumin-bound manganese borate nanoparticles and their use in the preparation of tumor therapeutic drugs.

[0006] In a first aspect, the present application provides albumin-bound manganese borate nanoparticles, comprising:

[0007] a manganese borate compound that is bound to the manganese ion via a coordinate bond;

[0008] An albumin shell, coating the manganese borate compound to form nanoparticles;

[0009] The average particle size of the nanoparticles is 100 nm to 300 nm, and the mass ratio of the albumin to the manganese borate compound is 10:1 to 1000:1.

[0010] Optionally, the albumin is selected from one or more of serum albumin, ovalbumin, lactalbumin, myoalbumin, wheat albumin, and legumin, preferably human serum albumin.

[0011] Optionally, the average particle size of the nanoparticles is 150 nm to 250 nm.

[0012] Optionally, the mass ratio of the albumin to the manganese borate compound is 10:1.

[0013] Optionally, the nanoparticles are prepared by an ultrafiltration membrane with a molecular weight cut-off of 95-105 kDa and are formed by high-pressure homogenization at 2°C-6°C for 20-40 minutes.

[0014] In a second aspect, the present application provides a pharmaceutical composition comprising the albumin-bound manganese borate nanoparticles described in the first aspect and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is an intravenous injection preparation or a lyophilized powder injection.

[0015] In a third aspect, the present application provides the use of the albumin-bound manganese borate nanoparticles described in the first aspect in the preparation of tumor treatment drugs, wherein the tumor is selected from colon cancer, triple-negative breast cancer, malignant melanoma, non-small cell lung cancer, liver cancer, renal cell carcinoma, prostate cancer, ovarian cancer or gastric cancer.

[0016] Optionally, the albumin-bound manganese borate nanoparticles achieve tumor targeting through the following technical features:

[0017] a. Accumulates in tumor tissues through albumin-mediated transmembrane transport;

[0018] b. Release boric acid and manganese ions in response to the hydrogen peroxide (H2O2) concentration gradient in the tumor microenvironment, making the boron concentration ratio (T / N) of tumor tissue to normal tissue ≥3.

[0019] Optionally, the manganese ions released by the nanoparticles produce T1-weighted signal enhancement in magnetic resonance imaging (MRI), which is used to guide neutron beam positioning.

[0020] Optionally, the nanoparticles are obtained by the following preparation steps:

[0021] a. In an ice bath, manganese ions were introduced into the albumin solution and stirred at 450-550 rpm for 8-12 minutes;

[0022] b. Add sodium tetraborate solution and continue stirring for 5-15 minutes;

[0023] c. Buffer exchange and concentration through 80-120 kDa ultrafiltration membrane;

[0024] d. High pressure homogenization for 20-40 minutes to obtain the final nanoparticles.

[0025] Compared with the prior art, this application has at least one of the following beneficial technical effects:

[0026] The manganese in the nanosystem of the pharmaceutical composition of the present invention can induce MRI signal enhancement, thereby providing guidance for pre-treatment triage and neutron beam positioning.

[0027] The nanosystem of the pharmaceutical composition of the present invention has a synergistic effect. The synergistic effect of manganese ions not only significantly enhances the tumor cell damage induced by neutron irradiation, but also enhances the innate immune response activated by radiation.

[0028] The nanosystem of the pharmaceutical composition of the present invention has good tumor cell targeting, achieves efficient tumor cell enrichment through a specific transmembrane transport mechanism mediated by albumin, and then precisely releases boric acid and manganese ions in response to the H2O2 microenvironment, reducing toxic side effects on other normal tissues.

[0029] The nanosystem of the pharmaceutical composition of the present invention exhibits superior anti-tumor efficacy both via intratumoral injection and systemic administration, and synergizes with adoptive T cell immunotherapy and immune checkpoint inhibitors, providing an innovative solution to overcome the limitations of BNCT efficacy associated with tumor heterogeneity.

[0030] The albumin-bound manganese borate nanoparticles provided by the present invention can be targeted and enriched in tumor tissues through an albumin-mediated transmembrane transport mechanism, and release boric acid and manganese ions in response to the hydrogen peroxide concentration gradient in the tumor microenvironment (so that the boron concentration ratio between tumor and normal tissue is ≥3). The released manganese ions can also guide the precise positioning of the neutron beam by enhancing MRI signals; the nanoparticles can not only synergistically enhance the inhibitory effect of boric acid on tumor cells and significantly inhibit tumor growth in tumor-bearing mice, but also increase the proportion of tumor-infiltrating T cells, increase the level of immune killing factors, and activate the tumor immune system. It has multiple effects such as targeted delivery, image guidance, synergistic treatment and immune sensitization, providing an efficient and precise innovative solution for tumor treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a diagram showing the appearance of a pharmaceutical composition nanosystem;

[0032] Figure 2 Mn 2+ Figure 1 shows the synergistic effect of boric acid on inhibiting tumor cells;

[0033] Figure 3 It is the release of the drug composition nanosystem under the condition of H2O2 in vitro;

[0034] Figure 4 This is a statistical graph of the biodistribution of the drug composition nanosystem in tumor-bearing mice;

[0035] Figure 5 This is the MRI tracking signal diagram of the drug composition nanosystem in mice;

[0036] Figure 6 is a graph of the tumor volume of each group of mice in Example 8;

[0037] Figure 7 Graph showing the relative percentages of CD3+, CD8+, CD11c, and CD45+ T lymphocytes in the tumors of mice in each group in Example 9;

[0038] Figure 8 This is a statistical graph showing the levels of INF-β and CXCL10 in the tumors of each group of mice in Example 9. DETAILED DESCRIPTION

[0039] The technical solution of the present invention is further described below with reference to the accompanying drawings and specific embodiments.

[0040] Example 1: Preparation of manganese borate albumin nanoparticles

[0041] Under ice bath conditions, manganese ions were introduced into the albumin solution and stirred at 500 rpm for 10 minutes. Then, sodium tetraborate solution was quickly added to the mixture and stirred for another 10 minutes. The resulting solution was concentrated and buffer exchanged using a 100 kDa ultrafiltration membrane. The concentrated solution was homogenized at 4°C for 30 minutes to obtain the prepared pharmaceutical composition nanosystem (Albumin@MnB). The appearance of the preparation is shown in FIG. Figure 1 .

[0042] Example 2: Preparation of manganese borate albumin nanoparticles

[0043] Manganese ions were introduced into the transferrin solution in an ice bath and stirred at 500 rpm for 10 minutes. Sodium tetraborate solution was then quickly added to the mixture, and stirring continued for 10 minutes. The resulting solution was concentrated and buffer exchanged using a 100 kDa ultrafiltration membrane. The concentrated solution was then homogenized at 4°C for 30 minutes using high-pressure homogenization to obtain the prepared pharmaceutical nanocomposite (Albumin@MnB).

[0044] Example 3: Preparation of manganese borate albumin nanoparticles

[0045] Manganese ions were introduced into the trastuzumab solution in an ice bath and stirred at 500 rpm for 10 minutes. Sodium tetraborate solution was then quickly added to the mixture, and stirring continued for 10 minutes. The resulting solution was concentrated and buffer exchanged using a 100 kDa ultrafiltration membrane. The concentrated solution was then homogenized at 4°C for 30 minutes using high-pressure homogenization to obtain the prepared pharmaceutical nanocomposite (Albumin@MnB).

[0046] Example 4: Mn 2+ Can synergistically enhance the inhibitory effect of boric acid on tumor cells

[0047] Mn was determined by CCK-8 assay. 2+ Effects on the survival rate of B16 cells treated with BNCT, see Figure 2 . B16 cells were seeded in a 96-well plate at a density of 5×10³ cells per well. B16 cells were treated with different concentrations (0, 5, 10, 20, 40, 80, and 160µM) of Mn²⁺ for 24 hours. Six replicate wells were set up for each concentration of each metal ion, and the same volume of blank solvent was used as a control group. Subsequently, the culture medium was removed, and 100µL of DMEM culture medium containing 10% CCK-8 reagent was added to each cell well. After incubation for 1 hour, the absorbance (OD value) was measured at a wavelength of 450 nm using an automatic microplate reader.

[0048] Example 5: Release of the composition under H2O2 conditions in vitro

[0049] B16 cells were first treated with Alb@MnB and then exposed to H2O and different concentrations of H2O2 (1%, 0.1% and 0.01%) for 5 minutes, 15 minutes, 30 minutes, 60 minutes and 2 hours, respectively. After the cells were collected, the supernatant was obtained by centrifugation and the concentration of B10 in each sample was measured. The measurement results are shown in Figure 3 .

[0050] Example 6: Biodistribution of the Nanosystem of the Pharmaceutical Composition in Tumor-Bearing Mice

[0051] Male Balb / c mice weighing approximately 18-22g were selected to establish a subcutaneous melanoma (B16) transplant model. The biodistribution of the nanosystem in mice was studied using ICP-MS analysis. Five days after tumor inoculation, the drug composition nanosystem (5 mg / kg) was injected into the tail vein. At 3, 6, and 24 hours after administration, the mice were anesthetized with 2% sodium pentobarbital solution and the biodistribution of the drug composition nanosystem in vivo was tracked by ICP-MS ( Figure 4 The results showed that the drug composition nanosystem can achieve effective boron accumulation in tumor tissue, with the boron concentration ratio of tumor tissue to normal tissue exceeding 3, meeting the basic therapeutic threshold of BNCT.

[0052] Example 7: MRI tracking of the drug composition nanosystem in mice

[0053] Given that divalent manganese (Mn²⁺) itself has magnetic resonance imaging (MRI) signals, MRI can be used to clearly track the metabolic process of Mn²⁺ in mice after subcutaneous injection of Alb@MnB. The melanoma (B16) subcutaneous transplantation model mice established in Example 6 were selected and first received subcutaneous injections of equal doses of manganese MnCl2 and Alb@MnB, and then were anesthetized and fixed. MRI scans were performed 3 hours and 24 hours after injection to carefully observe the metabolic changes of Mn²⁺ in the mice. The results showed that after 3 hours, the mice in the Albumin@MnB group showed stronger t1-weighted imaging signals in the tumor area than those injected with MnCl2 ( Figure 5 This signal difference became more obvious at 12 h, indicating that the drug was gradually released intratumorally through H2O2-responsive dissociation in the tumor microenvironment.

[0054] Example 8: Evaluation of the anti-tumor efficacy of the drug composition nanosystem using a B16 tumor-bearing mouse model

[0055] Male Balb / c mice aged 6-7 weeks, weighing between 18-22 g, were selected to establish a mouse melanoma (B16) subcutaneous transplantation model to evaluate the anti-tumor effect of the pharmaceutical composition nanosystem (Albumin@MnB) prepared in Example 1. Five days after tumor inoculation (tumor size was approximately 80 mm 3 ), the mice were randomly divided into 5 groups (8-10 mice per group): ① control group: 5 mg / kg normal saline (iv); ② 5 mg / kg 4B (iv); ③ 5 mg / kg BPA (iv); ④ 5 mg / kg drug composition nanosystem (iv), and ⑤ 5 mg / kg drug composition nanosystem (it). Neutron beam irradiation began. The experiment lasted for 16 days. During the experiment, the tumor size was measured every other day for the first 4 days, and then every 2 days and the data were recorded. The tumor volume of mice in each group is shown in Figure 6 The results showed that compared with the saline control group, 4B showed no therapeutic effect, BPA exhibited moderate tumor inhibition but was not statistically significant, while Albumin@MnB (iv) significantly inhibited tumor growth, and intratumoral injection of Albumin@MnB (it) further enhanced the efficacy.

[0056] Example 9: Effects of drug composition nanosystem therapy on tumor-infiltrating T cells

[0057] The tumor tissues of the mice in the control group, BPA group, and Albumin@MnB (iv) group in Example 8 were sliced into 8 μm sections and fluorescently stained with anti-mouse CD3-Alexa Fluor antibody (Biolegend), anti-CD8-Alexa Fluor 594 antibody (Biolegend), anti-CD11c-Alexa Fluor 488 antibody, and anti-CD45-Alexa Fluor 488 antibody (Biolegend). + 、CD8 + , CD11c and CD45+ T cells, and the relative percentages of various T cells infiltrating the tumor tissues of mice in each group were quantified by immunofluorescence. Figure 7 The results showed that compared with the saline control group, both BPA and Albumin@MnB increased CD45 leukocyte recruitment, with comparable proportions of dendritic cells (CD11c-CD45). However, Albumin@MnB increased CD3 and CD8 T cell infiltration (P < 0.05 compared with saline), while BPA failed to increase CD8 T cell levels.

[0058] Example 10: Effect of drug composition nanosystem treatment on the level of immune killing factors in tumors

[0059] B16 cells were cultured at 2 × 10 5 Cells were seeded in 6-well culture plates at a density of 100 cells and treated with B, Mn, and Alb@MnB, respectively. After 24 hours, the cells were collected and centrifuged. Subsequently, the concentrations of INF-β and CXCL10 in the samples were detected using a mouse INF-β enzyme-linked immunosorbent assay (ELISA) kit and a mouse CXCL10 ELISA kit, respectively. The test results are shown in Figure 8 The results showed that the secretion of IFN-β and CXCL10 proteins in the tumor supernatant of the Albumin@MnB group was increased, indicating that the nanosystem of the drug composition can effectively activate the tumor immune system, significantly increase the level of toxic killing factors of effector T cells, and enhance the anti-tumor immune effect.

[0060] Example 11: Transcriptomic Analysis of the Anti-tumor Effect of the Nanosystem of the Pharmaceutical Composition

[0061] First, high-quality total RNA was extracted from the NC, B, and Albumin@MnB-treated groups, and RNA quality was assessed. Subsequently, cDNA libraries were constructed from qualified RNA samples. These libraries were sequenced using a high-throughput sequencing platform, generating extensive transcriptome sequence data. During the data analysis phase, differential expression analysis was performed using the DESeq2 software package. Genes with adjusted P values less than 0.05 and absolute log-2-fold changes greater than 1 were identified as differentially expressed genes. Furthermore, visualization tools such as volcano plots and boxplots were used to visually display the differentially expressed genes. Transcriptomic analysis revealed a striking mechanistic contrast: while conventional BNCT primarily activates pro-survival pathways (e.g., DNA replication and homologous recombination), Albumin@MnB-based BNCT shifted the transcriptomic landscape toward innate immunity. Key immune pathways—including TNF / NF-κB signaling, antigen processing, and interferon response—were significantly upregulated (P < 0.001). Concomitantly, DNA repair genes (PARP1, XRCC1) and the oxidative stress alleviator (TXNIP) were downregulated, indicating impaired damage resolution.

[0062] This invention leverages the natural biocompatibility and tumor-targeting properties of albumin (such as transmembrane transport mediated by albumin receptors highly expressed on tumor cells and the EPR effect), enabling nanoparticles to accumulate at tumor sites, minimizing damage to normal tissue. Example 6 demonstrates a boron concentration ratio of ≥3 in tumor tissue to normal tissue, meeting the core threshold for boron neutron capture therapy (BNCT), demonstrating significant targeted enrichment. Increased hydrogen peroxide (H2O2) concentrations in the tumor microenvironment trigger nanoparticle dissociation and the release of boric acid and manganese ions, achieving "on-demand release," further increasing local drug concentration within the tumor and reducing systemic toxicity.

[0063] It is worth noting that the released manganese ions (Mn²⁺) act as a T1-weighted contrast agent, enhancing the MRI signal in the tumor region. Example 7 shows that the tumor region signal in the Albumin@MnB group is significantly stronger than that of free MnCl₂, demonstrating its specific enrichment and sustained release properties in vivo. This provides real-time imaging guidance for neutron beam positioning and improves the accuracy of BNCT.

[0064] In this invention, boric acid, a key component of BNCT, generates high-energy alpha particles and lithium ions through neutron bombardment, selectively killing tumor cells (with a range of only a few micrometers, precisely damaging the DNA of adjacent cells). Manganese ions (Mn²⁺) synergistically enhance the anti-tumor effect of boric acid (CCK-8 assay in Example 4), potentially by modulating tumor cell metabolism or oxidative stress, thereby sensitizing tumor cells to BNCT. Examples 9-11 demonstrate that the nanoparticles significantly increase CD3⁺ / CD8⁺ T cell infiltration in tumors (cellular immune activation) and upregulate immune killer factors such as IFN-β and CXCL10 (humoral immune activation). Transcriptomic analysis also reveals that they induce activation of innate immune pathways (such as TNF / NF-κB signaling) and inhibit the expression of DNA repair genes. This dual mechanism of "direct killing + immune activation" synergistically enhances anti-tumor efficacy and reduces the risk of tumor recurrence and drug resistance.

[0065] In this invention, buffer exchange using an ultrafiltration membrane (100 kDa) and high-pressure homogenization are employed, resulting in a simple process with excellent reproducibility and suitability for large-scale production. The nanoparticles have an average particle size of 100-300 nm (preferably 150-250 nm), combining long circulation (avoiding rapid clearance by mononuclear macrophages) with tumor penetration (accumulation through the endothelial space). The wide range of albumin to manganese borate mass ratios (10:1 to 1000:1) allows for flexible adjustment of shell thickness and drug loading to meet diverse tumor treatment needs.

[0066] By providing intravenous injection preparations and lyophilized powder injections, the former is suitable for systemic targeted therapy, and the latter is easy to store and transport, broadening the clinical application scenarios. Example 8 shows that both intravenous injection and intratumoral injection can significantly inhibit tumor growth, especially the efficacy of intratumoral injection is further enhanced, proving that the dosage form has strong adaptability. Albumin, as a natural carrier, has low immunogenicity and high biodegradability, reducing the risk of allergic reactions. No obvious toxic reactions are mentioned in the examples, and by adjusting the mass ratio and particle size, the pharmacokinetic properties can be further optimized and the therapeutic window can be increased.

[0067] One of the current bottlenecks in BNCT is the inefficient accumulation of boron compounds within tumors. This approach significantly increases the boron concentration ratio through albumin nanoparticles, providing a key technological breakthrough for the clinical application of BNCT. This approach integrates nanomaterials, nuclear medicine, and immunology to achieve an integrated approach of "diagnosis-treatment-immunomodulation." This approach aligns with the development of precision medicine and personalized treatments, and has broad potential for technological expansion (e.g., combined with chemoradiotherapy and immune checkpoint inhibitors). By leveraging the multi-mechanism synergy of "targeted delivery-responsive release-image-guided-immune activation," this approach addresses the challenges of traditional BNCT, including insufficient drug accumulation and limited efficacy. This approach combines scientific and practical advantages with a forward-looking patent portfolio, providing an efficient and safe innovative strategy for precision cancer treatment.

[0068] The above specific embodiments are merely several optional embodiments of the present invention. Based on the technical solutions of the present invention and the relevant inspirations of the above embodiments, those skilled in the art may make various alternative improvements and combinations to the above specific embodiments.

Claims

1. Albumin-bound manganese borate nanoparticles, characterized in that: include: a manganese borate compound that is bound to the manganese ion via a coordinate bond; An albumin shell, coating the manganese borate compound to form nanoparticles; Wherein, the average particle size of the nanoparticles is 100 nm to 300 nm, and the mass ratio of the albumin to the manganese borate compound is 10:1; The manganese ions released by the nanoparticles produce T1-weighted signal enhancement in magnetic resonance imaging, which is used to guide neutron beam positioning; The nanoparticles are obtained by the following preparation steps: a. In an ice bath, manganese ions were introduced into the albumin solution and stirred at 450-550 rpm for 8-12 minutes; b. Add sodium tetraborate solution and continue stirring for 5-15 minutes; c. Buffer exchange and concentration through 80-120 kDa ultrafiltration membrane; d. High pressure homogenization for 20-40 minutes to obtain the final nanoparticles.

2. The albumin-bound manganese borate nanoparticles according to claim 1, characterized in that: The albumin is selected from one or more of serum albumin, ovalbumin, lactalbumin, myoalbumin, wheat albumin, and soy albumin.

3. The albumin-bound manganese borate nanoparticles according to claim 1, wherein The average particle size of the nanoparticles is 150 nm to 250 nm.

4. The albumin-bound manganese borate nanoparticles according to claim 1, wherein The nanoparticles are prepared by using an ultrafiltration membrane with a molecular weight cut-off of 95-105 kDa and are formed by high-pressure homogenization at 2° C.-6° C. for 20-40 minutes.

5. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the albumin-bound manganese borate nanoparticles according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is an intravenous injection preparation or a lyophilized powder injection.

6. Use of the albumin-bound manganese borate nanoparticles according to any one of claims 1 to 4 in the preparation of a drug for treating tumors, characterized in that: The tumor is malignant melanoma.

7. The use according to claim 6, characterized in that The albumin-bound manganese borate nanoparticles achieve tumor targeting through the following technical features: a. Accumulates in tumor tissues through albumin-mediated transmembrane transport; b. Release boric acid and manganese ions in response to the hydrogen peroxide concentration gradient in the tumor microenvironment, making the boron concentration ratio of tumor tissue to normal tissue ≥3.

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