Bismuth-based nanomaterial, preparation method thereof and photodiagnosis and treatment reagent

Abstract

The application provides a bismuth-based nanomaterial and a preparation method and a photodiagnosis and treatment reagent thereof, wherein the preparation method comprises the following steps: S1, mixing a bismuth source precursor and a reducing agent to obtain a mixed solution; and S2, performing hydrothermal reaction on the mixed solution to obtain a bismuth-doped bismuth-based nanomaterial Bi / Bi compound, wherein the Bi compound comprises any one or more of Bi2Se3, Bi2S3 and Cu3BiS3. According to the preparation method, the plasmonic resonance peak is regulated to the near-infrared two region through bismuth doping, and the bismuth-based nanodiagnosis and treatment material can be self-enriched in a lesion area. The material has strong absorption, reflection and scattering characteristics under a system imaging light source, and has the functions of enhancing imaging effect and improving treatment efficiency.

Description

Technical Field

[0001] This invention belongs to the field of phototherapy reagent preparation technology, and more specifically, relates to a bismuth-based nanomaterial and its preparation method, as well as a phototherapy reagent. Background Technology

[0002] According to the latest statistics from the International Agency for Research on Cancer (IARC) of the World Health Organization, there were 19.29 million new cancer cases and 9.96 million cancer deaths globally in 2020. Breast cancer, lung cancer, and colorectal cancer all ranked among the top three in terms of new cases worldwide, seriously endangering human health and attracting significant attention from researchers. Early diagnosis and treatment are crucial for cancer patients. Colorectal cancer (CRC), in particular, is considered a marker of socioeconomic development and has garnered widespread attention in biomedical research.

[0003] Among diagnostic methods, considering the limitations of endoscopic lesion locations, endoscopic catheter-based endoscopic imaging systems have been widely reported. Optical coherence tomography (OCT), as an important optical imaging method in clinical diagnosis, has been widely used in many fields, including ophthalmology, cardiology, and dermatology. OCT achieves high-speed and high-resolution imaging of subsurface tissues by acquiring the interference of backscattered light and reference light, enabling real-time "optical biopsy." Through integrated microcatheters, OCT can perform precise in vivo imaging, providing high-resolution depth tomographic imaging of lesion areas. However, living tissue exhibits multiple light scattering characteristics, and some lesion sites require OCT contrast agents to improve imaging contrast.

[0004] On the other hand, surgical resection and adjuvant radiotherapy and chemotherapy are the main treatment methods for colorectal cancer, which can prolong patient survival and inhibit cancer metastasis. However, due to the severe toxicity, multidrug resistance, and adverse side effects caused by radiotherapy and chemotherapy, treatment efficiency is low or fails. To address these issues, efforts are being made to find effective diagnostic and treatment strategies for colorectal cancer. Among these, phototherapy strategies are receiving increasing attention.

[0005] Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), transfers the light energy absorbed by the phototherapy agent to oxygen or converts it into heat energy. This induces tumor cell apoptosis through the generation of reactive oxygen species or localized hyperthermia. It can also cause thrombosis by damaging blood vessels within the tumor, indirectly leading to tissue necrosis due to ischemia or loss of nutrients. Interventional photothermal therapy (IPTT) can achieve precise treatment with catheter assistance and overcomes the limitations of previous phototherapy methods, which were limited to superficial tumors and inflammatory lesions. Currently, IPTT has shown good therapeutic effects in in situ abdominal tumor models such as pancreatic cancer and bladder cancer.

[0006] Various inorganic photothermal agents have been extensively reported in the field of tumor therapy, including noble metal nanomaterials (gold nanorods); carbon nanomaterials (carbon nanotubes); transition metal sulfides or oxides (ferric oxide); and other two-dimensional materials (black phosphorus nanosheets). Most of these nanomaterials utilize molecular engineering to modulate near-infrared absorption, such as supramolecular self-assembly, DAD conjugation, plasmon resonance, and π-π stacking.

[0007] However, to date, there have been no reports of integrating photodiagnosis and phototherapy. Summary of the Invention

[0008] Through research, the inventors have discovered that the prerequisite for achieving integrated diagnosis and treatment is to develop materials that simultaneously possess therapeutic and imaging-enhancing properties and have self-accumulation characteristics at the lesion site.

[0009] On the one hand, an excellent OCT contrast agent should have good biocompatibility, a high molar extinction coefficient in the near-infrared region, and a small size (less than 150 nm).

[0010] On the other hand, bismuth-based compounds are widely used as drugs to treat gastrointestinal diseases such as indigestion, gastric ulcers, and Helicobacter pylori infection. For example, bismuth subsalicylate (BSS) and ranitidine citrate (RBC) have been approved for clinical use. In recent years, the medical applications of bismuth-based nanomaterials have further expanded to multiple fields such as the treatment of viral and multidrug-resistant microbial infections, tumor treatment, and biosensing. Bismuth, as a high atomic number metal, is green and non-toxic, inexpensive, and has high X-ray attenuation capability (5.74 cm⁻¹). 2 g -1 With its high photothermal efficiency (at 100 keV) and biocompatibility, bismuth-based nanomaterials have great potential for application in the field of tumor radiotherapy. As an effective novel photothermal agent, bismuth-based nanomaterials have been extensively studied in recent years. Currently, research on PTT agents mainly focuses on Bi₂Se₃, Bi₂S₃, Cu₃BiS₃, and Bi NPs, all of which exhibit high photothermal conversion efficiency and excellent in vivo PTT effects under near-infrared laser irradiation.

[0011] However, the scattering properties of bismuth-based materials have not yet been reported for use in OCT imaging.

[0012] Through repeated research and practice, the inventors have prepared a multifunctional bismuth-based nano-therapeutic reagent. By doping, the plasma resonance peak is modulated to the near-infrared II region. It also has photothermal conversion properties and scattering characteristics. It can be used as an OCT contrast agent for OCT imaging and can also be used for OCT-mediated photothermal therapy.

[0013] In view of this, the purpose of this invention is to provide novel bismuth-based nanomaterials, their preparation methods, and phototherapy reagents.

[0014] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0015] A method for preparing bismuth-based nanomaterials according to a first aspect of the present invention includes:

[0016] Step S1: Mix the bismuth source precursor with a reducing agent to obtain a mixture;

[0017] Step S2: The mixture is reacted to obtain bismuth-doped bismuth-based nanomaterials Bi / Bi compounds, wherein the Bi compounds include any one or more of Bi2Se3, Bi2S3, and Cu3BiS3.

[0018] Furthermore, the bismuth source precursor includes bismuth nitrate pentahydrate, the reducing agent is a mixture of 1-dodecathiol and oleylamine, wherein the volume ratio of 1-dodecathiol to oleylamine in the mixture is 1:5 to 5:1, and the Bi compound is Bi2S3.

[0019] Furthermore, step S1 includes:

[0020] Bismuth nitrate pentahydrate was added to a mixture of 1-dodecyl mercaptan and oleylamine and stirred for a predetermined time to ensure thorough mixing, thereby obtaining the mixture.

[0021] Furthermore, the volume ratio of 1-dodecyl mercaptan to oleylamine in the mixture is 1:1.

[0022] Further, step S2 includes:

[0023] Step S21: Argon gas is passed through the mixture for a predetermined time to perform inert gas replacement, and the replaced mixture is obtained.

[0024] Step S22: Transfer the substituted mixture to a reaction vessel and perform a hydrothermal reaction for 6-18 hours to generate the bismuth-based nanomaterial.

[0025] The bismuth-based nanomaterials according to the second aspect of the present invention are prepared by the preparation method of any of the first aspects described above.

[0026] The phototherapy reagent according to a third aspect of the present invention includes the bismuth-based nanomaterials described in the second aspect of the present invention.

[0027] Furthermore, in the phototherapy reagent, the bismuth-based nanomaterial is modified with a targeting group on its surface, and the targeting group includes any one or more of hyaluronic acid, folic acid, transferrin, interleukin, and microRNA.

[0028] Furthermore, the phototherapy reagent is used as a contrast agent and photothermal agent for optical coherence tomography imaging.

[0029] Furthermore, the photothermal transducer is a photothermal agent used for near-infrared II window photothermal therapy.

[0030] The above-described technical solution of the present invention has at least one of the following beneficial effects:

[0031] According to the preparation method of the present invention, the plasma resonance peak is tuned to the near-infrared II region by bismuth doping, and a bismuth-based nano-therapeutic material that can self-accumulate in the lesion area is produced. This material has strong absorption, reflection and scattering characteristics under the system imaging excitation source, and has the function of enhancing the imaging effect and improving the treatment efficiency. Attached Figure Description

[0032] Figure 1 Absorption spectra of bismuth-based nanomaterials with different compositions in aqueous dispersions;

[0033] Figure 2 The XRD pattern of Bi / Bi2Se31:1 is shown.

[0034] Figure 3 OCT images of Bi / Bi2Se3NPs solution;

[0035] Figure 4 The images are OCT images taken at different time points after a mouse model of orthotopic colorectal cancer was injected via the tail vein with Bi / B Bi2Se3 NPs. (a) is immediately after injection, (b) is 4 hours after injection, and (c) is 6 hours after injection. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.

[0037] The preparation method of bismuth-based nanomaterials according to embodiments of the present invention is described in detail below, including:

[0038] Step S1: Mix the bismuth source precursor with the reducing agent to obtain a mixed solution;

[0039] Step S2 involves subjecting the mixture to a hydrothermal reaction to obtain bismuth-doped bismuth-based nanomaterials, specifically Bi / Bi compounds. The Bi compounds include any one or more of Bi₂Se₃, Bi₂S₃, and Cu₃BiS₃. In other words, the Bi / Bi compounds can be Bi / Bi₂Se₃, Bi / Bi₂S₃, Bi / Cu₃BiS₃, or a mixture of one or more of these compounds.

[0040] In other words, in the preparation method of the present invention, in order to adjust the plasma resonance peak of bismuth-based nanomaterials, bismuth source precursors and sulfur-containing reducing agents are used as starting materials to prepare bismuth-doped bismuth-based nanomaterials.

[0041] It should be noted that, depending on the bismuth-based material, a corresponding bismuth source precursor and a corresponding reducing agent can be selected. Preferably, the bismuth-based nanomaterial is Bi / Bi₂S₃, meaning the Bi compound is preferably Bi₂S₃.

[0042] Accordingly, in some embodiments of the present invention, the bismuth source precursor includes bismuth nitrate pentahydrate, and the reducing agent is a mixture of 1-dodecathiol and oleylamine, wherein the volume ratio of 1-dodecathiol to oleylamine in the mixture is 1:5 to 5:1, preferably, for example, 1:2 to 5:1, and more preferably 1:2 to 2:1.

[0043] Both 1-dodecathiol and oleylamine possess reducing properties. When mixed with the bismuth source precursor, and by adjusting the volume ratio of 1-dodecathiol to oleylamine, Bi / Bi₂S₃ nanomaterials with varying bismuth doping levels can be obtained. These nanomaterials exhibit both excellent scattering and photothermal conductivity properties. Preferably, in the mixture of the sulfur-containing reducing agent, 1-dodecathiol and oleylamine, the volume ratio of 1-dodecathiol to oleylamine is 1:1. The final mixture obtained at this volume ratio exhibits a significant absorption peak in the near-infrared II region, resulting in better imaging performance when used as an OCT contrast agent.

[0044] In some embodiments of the present invention, step S1 includes:

[0045] Bismuth nitrate pentahydrate is added to a mixture of 1-dodecyl mercaptan and oleylamine, and stirred for a predetermined time to ensure thorough mixing, for example, stirring at 500-800 rpm for 10 min-1 h to obtain the mixture. Stirring ensures more thorough mixing, resulting in more uniform and stable bismuth-doped bismuth-based nanomaterials in the subsequent hydrothermal reaction.

[0046] In some embodiments of the present invention, step S2 includes:

[0047] Step S21: Argon gas is passed through the mixture for a predetermined time to perform inert gas replacement, resulting in a replaced mixture.

[0048] By exchanging the mixture with argon gas, the risk of oxidation of the reducing agent can be reduced, and better and more stable Bi / Bi2S3 nanomaterials can be obtained in the subsequent hydrothermal reaction.

[0049] Step S22: Transfer the substituted mixture to a reaction vessel and perform a hydrothermal reaction for 6-18 hours to generate the bismuth-based nanomaterial.

[0050] Furthermore, the hydrothermal reaction temperature can be selected, for example, at 150-250°C. Of course, this can be appropriately chosen based on the solvent, precursor, etc.

[0051] The bismuth-based nanomaterials prepared by the above method have both light scattering and photothermal conduction properties. When injected into the lesion area through OCT, they can achieve OCT imaging and phototherapy effects.

[0052] In order to achieve better targeting of the lesion area, the bismuth-based nanomaterials can be modified with targeting groups. The targeting groups can be different depending on the characteristics of the lesion. For example, for rectal cancer, the targeting groups can include any one or more of hyaluronic acid, folic acid, transferrin, interleukin, and microRNA.

[0053] The preparation method of this application will be further described in detail below with reference to specific embodiments.

[0054] Example 1: Preparation of Bismuth-based Nanomaterials

[0055] Bismuth nitrate pentahydrate (1 mmol) was added to a mixed solution (30 mL) containing 1-dodecyl mercaptan (DDT) and oleylamine (OAm) in different proportions (v / v, 1:2, 1:1, 2:1, 5:1). The mixture was magnetically stirred at 600 rpm for 30 minutes, followed by purging with argon gas for 5 minutes. The solution was then transferred to a 50 mL polytetrafluoroethylene liner and hydrothermally reacted at 200 °C for 12 h. The crude product was washed twice with ethanol (8000 rpm, 5 min), followed by vacuum distillation to obtain solid samples, designated as Bi / Bi₂S₃ (1:2), Bi / Bi₂S₃ (1:1), Bi / Bi₂S₃ (2:1), and Bi / Bi₂S₃ (5:1).

[0056] Figure 1 Absorption spectra of four types of Bi / Bi2S3 nanoparticles in aqueous dispersions are shown: Bi / Bi2S3 (1:2), Bi / Bi2S3 (1:1), Bi / BBi2S3 (2:1), and Bi / Bi2S3 (5:1). Figure 1It can be seen that, except for Bi / Bi2S3(1:2), there are absorption peaks in the 1100-1300nm range, with the absorption peak of Bi / B Bi2S3(1:1) being more obvious.

[0057] XRD analysis was performed on the above Bi / Bi2S3(1:1), and the XRD pattern is shown in the figure. Figure 2 XRD data showed that the main diffraction peaks of the Bi / Bi2S3 (1:1) sample corresponded to Bi (JCPDS:44-1246) and Bi2S3 (JCPDS:17-0302), proving that the synthesized product was composed of elements Bi and Bi2S3.

[0058] Example 2: Folic acid-modified bismuth-based nanomaterials

[0059] Add 15 mg of Bi / Bi2S3 (1:1) powder prepared in Example 1 and 30 mg of DSPE-PEG2000-FA to 10 mL of chloroform and stir for 1 hour until Bi / Bi2S3 and DSPE-PEG2000-FA are completely dissolved.

[0060] Then, the above solution was added dropwise to deionized water (80℃, 20 mL). After the chloroform evaporated, the solution was purified by centrifugation and filtration through a 0.22 μm pore membrane to remove excess substances.

[0061] Finally, the dispersion was lyophilized for further use and designated as folic acid-modified Bi2S3 nanoparticles (Bi / Bi2S3NPs).

[0062] An OCT catheter was inserted into a Bi / Bi2S3 NPs solution to acquire OCT images. The results are as follows: Figure 3 As shown in the figure, the sample exhibits strong scattering properties.

[0063] Bi / Bi2S3 NPs (3 mg / kg) were injected intravenously into a mouse model of orthotopic colorectal cancer. An OCT catheter was inserted into the intestinal lumen of the mice at different time points to collect signals for OCT imaging. The results are shown in Figure 4.

[0064] Figure 4 In the image, the raised area indicated by the arrow represents a colorectal cancer tumor. From... Figure 4 It can be seen that the strongest scattering signal was observed within the tumor 4 hours after drug injection, further demonstrating the material's tumor-targeting capability. As the time was extended to 6 hours, the photothermal effect became apparent, the colorectal cancer tumor was treated, and the scattering signal within the tumor weakened.

[0065] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing bismuth-based nanomaterials, characterized in that, include: Step S1: Mix the bismuth source precursor with the reducing agent to obtain a mixture; the bismuth source precursor includes bismuth nitrate pentahydrate, and the reducing agent is a mixture of 1-dodecathiol and oleylamine, wherein the volume ratio of 1-dodecathiol to oleylamine in the mixture is 1:2 to 2:

1. Step S2: The mixture is reacted to obtain bismuth-doped bismuth-based nanomaterials Bi / Bi compounds, wherein the Bi compound is Bi2S3.

2. The preparation method according to claim 1, characterized in that, Step S1 includes: Bismuth nitrate pentahydrate was added to a mixture of 1-dodecyl mercaptan and oleylamine, and stirred for a predetermined time to ensure thorough mixing, thereby obtaining the mixture.

3. The preparation method according to claim 1, characterized in that, Step S1 includes: Bismuth nitrate pentahydrate was added to a mixture of 1-dodecyl mercaptan and oleylamine, and stirred at 500-800 rpm for 10 min-1 h to obtain the mixture.

4. The preparation method according to claim 1, characterized in that, The volume ratio of 1-dodecyl mercaptan to oleylamine in the mixture is 1:

1.

5. The preparation method according to claim 1, characterized in that, Step S2 includes: Step S21: Argon gas is passed through the mixture for a predetermined time to perform inert gas replacement, and the replaced mixture is obtained. Step S22: Transfer the substituted mixture to a reaction vessel and perform a hydrothermal reaction for 6-18 hours to generate the bismuth-based nanomaterial.

6. The preparation method according to claim 5, characterized in that, The temperature of the hydrothermal reaction is 150-250℃.

7. A bismuth-based nanomaterial, characterized in that, It is prepared according to any one of claims 1 to 6.

8. A phototherapy reagent, characterized in that, Including the bismuth-based nanomaterials as described in claim 7.

9. The phototherapy reagent according to claim 8, characterized in that, The bismuth-based nanomaterial is modified with a targeting group on its surface, and the targeting group includes any one or more of hyaluronic acid, folic acid, transferrin, interleukin, and microRNA.

10. The phototherapy reagent according to claim 8 or 9, characterized in that, The phototherapy reagent is used as a contrast agent and / or photothermal agent for optical coherence tomography imaging.

11. The phototherapy reagent according to claim 10, characterized in that, The photothermal reagent is a photothermal reagent used for near-infrared II window photothermal therapy.

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