Bi2te3-biomimetic composite in-vivo stable deposition material and preparation method thereof

Abstract

The application relates to the application material field and discloses a tellurium-bismuth-biomineralization in-vivo stable deposition material and a preparation method, which comprises a nano core with a particle size of 20-100 nm, a PEG modification layer with a molecular weight of 2000-10000 Da and a calcium phosphate mineralization shell with a thickness of 5-15 nm. The tellurium-bismuth-biomineralization in-vivo stable deposition material provided by the application can be stably present in the body, has good targeting property and low toxicity.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of application materials, in particular to a bismuth telluride-biomineralization composite in-vivo stable deposition material and a preparation method. BACKGROUND

[0002] At present, with the rapid development of biomedical materials and nanotechnology, thermoelectric materials have shown great application potential in energy recovery, solid-state refrigeration and precise sensing due to their unique energy conversion characteristics. Among them, bismuth telluride (Bi2Te3) and its alloys have excellent thermoelectric properties (ZT≈1) near room temperature, and have become one of the most promising thermoelectric material systems, which have attracted much attention in wearable device power supply, industrial waste heat power generation and other fields. At present, in the related technical solutions of in-vivo deposition materials, the commonly used materials are mainly based on calcium salt or bilirubin calculus model. Such materials have obvious defects, they cannot simulate the actual behavior of functional thermoelectric materials in the body, and are difficult to meet the needs of emerging applications such as in-vivo thermoelectric power generation and micro-refrigeration; moreover, their deposition position and form are difficult to control accurately, and they cannot act on the target organs or tissues accurately; at the same time, they lack long-term stability, are easily absorbed or excreted by the body, and cannot continuously play a role. In addition, some studies have tried to use heavy metals such as lead (Pb) as deposition materials, but these materials are highly toxic (LD50<50mg / kg), and lack effective stability control means, which can cause long-term toxicity accumulation in the body and seriously threaten human health. For bismuth telluride materials themselves, although they exhibit good thermoelectric properties in vitro, they face many challenges in physiological environments. In physiological pH conditions (pH<7), the Te2- ions in bismuth telluride are easily oxidized to Te4+ ions, which leads to rapid disintegration of the material structure and a dissolution rate as high as >30% / 24h; unmodified bismuth telluride has a very short half-life in the body, usually <6 hours, and is difficult to maintain an effective action time; and it has poor targeting, making it difficult to achieve selective deposition in specific organs or tissues, which greatly limits its application in the field of in-vivo medical treatment. Therefore, it is urgent to develop a thermoelectric deposition material that can exist stably in the body, has good targeting and low toxicity. The present application carries out research on these problems, which has important scientific significance and application value. SUMMARY

[0003] The present application aims to provide a bismuth telluride-biomineralization composite in-vivo stable deposition material to achieve the purpose of stable existence in the body, good targeting and low toxicity.

[0004] In order to achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0005] Scheme one: a bismuth telluride-biomineralization composite in-vivo stable deposition material, comprising: ​​​The nanocore has a particle size of 20-100 nm; a PEG-modified layer has a molecular weight of 2000-10000 Da; a calcium phosphate mineralized shell has a thickness of 5-15 nm; the grafting rate of the PEG-modified layer is ≥80%; the calcium phosphate mineralized shell is doped with 0.1-2 mol% of rare earth elements, which are uniformly distributed in the mineralized shell.

[0006] Beneficial effects: It defines the basic composition and key parameter range of the composite material. The appropriate particle size range allows the nanocore to maintain thermoelectric properties while facilitating dispersion, transport, and function in vivo; the PEG modification layer with a specific molecular weight can effectively improve the biocompatibility of the material and reduce immune rejection; the calcium phosphate mineralized shell of a certain thickness enhances the stability of the material in the physiological environment and prevents the material from degrading too quickly.

[0007] Clearly define the grafting rate requirements for the PEG-modified layer. A higher grafting rate can more effectively improve the biocompatibility of the material, reduce immune clearance, prolong the circulation time of the material in vivo, enable the material to function better, and further enhance the stability and effectiveness of the material in vivo.

[0008] Preferably, the It has a cubic crystal system and XRD shows characteristic peaks at 27.5° and 37.8°.

[0009] Beneficial effects: Clarifying the crystal structure characteristics of bismuth telluride nanocores helps to accurately identify and prepare the composite material, ensuring that the material has the expected thermoelectric and physicochemical properties, and providing a reliable guarantee for subsequent applications.

[0010] Preferably, it further comprises a liposome encapsulation layer with a phospholipid:cholesterol ratio of 7:3.

[0011] Beneficial effects: Increasing the liposome encapsulation layer can further improve the material's targeting, enabling it to accurately reach the target organ or tissue; at the same time, it controls the drug release rate, achieving continuous and stable drug release and enhancing the material's therapeutic effect in vivo.

[0012] Preferably, the PEG-modified layer is a double-ended functionalized PEG, with a carboxyl group at one end and a targeting peptide RGD at the other end; and the grafting rate of the targeting peptide is 10-20%.

[0013] Beneficial effects:

[0014] Option 2: This invention also provides a method for preparing an in-situ stable depositional material of bismuth telluride-biomineralization composite, used to prepare the in-situ stable depositional material of bismuth telluride-biomineralization composite described in the aforementioned option, comprising the following steps: solvothermal synthesis Nanoparticles; PEGylation modification; calcium phosphate mineralization coating; optional liposome encapsulation.

[0015] Beneficial effects: It provides a complete and scientific preparation process. The solvothermal method can effectively control the particle size and crystal form of nanoparticles; PEGylation modification enhances the biocompatibility of materials; calcium phosphate mineralization coating improves the stability of materials; and the selectable liposome encapsulation step meets the needs of different application scenarios, ensuring that the prepared composite materials have good performance.

[0016] Preferably, the solvothermal synthesis The nanoparticle step also includes adding 0.05-0.2 mmol of hexadecyltrimethylammonium bromide to the reaction system as a morphology control agent, and the reaction heating rate is 5 °C / min.

[0017] Beneficial effects: In the solvothermal synthesis In the nanoparticle manufacturing process, CTAB was innovatively introduced as a morphology control agent, and the heating rate was strictly controlled. This approach allows for precise regulation of the process. The increased exposure ratio of crystal faces in nanoparticles significantly improves the exposure rate of active crystal faces, which has a profound impact on the subsequent PEG modification grafting efficiency and the uniformity of the mineralization layer. Compared with the traditional solvothermal method, this method effectively solves the performance fluctuation problem caused by uneven particle morphology, significantly improves the accuracy and controllability of the preparation process, and lays the foundation for obtaining high-quality, stable materials.

[0018] Preferably, in the PEGylation modification step, a microwave-assisted reaction with a power of 300-500W and a temperature of 40-50℃ is used, and mPEG-COOH reacts with... The mass ratio of nanoparticles is 1:3-1:8.

[0019] Beneficial effects: A groundbreaking microwave-assisted reaction was employed in the PEGylation modification step, and the reaction between mPEG-COOH and... The mass ratio range of nanoparticles. Microwave-assisted processing drastically reduced the reaction time from the conventional 12 hours to 1.5 hours, greatly improving production efficiency. Simultaneously, by rationally adjusting the mass ratio, the degradation of thermoelectric properties caused by excessive PEG chain encapsulation was successfully avoided while ensuring the grafting rate, achieving a balance between efficient modification and performance preservation, representing a significant breakthrough in the preparation process.

[0020] Preferably, in the calcium phosphate mineralization coating step, the alternating soaking... Add 5-10 mmol / L of magnesium ions to the solution, and purge with nitrogen gas at a flow rate of 0.5 L / min for 5 min after each soaking.

[0021] Beneficial effects: In the calcium phosphate mineralization coating step, by... Magnesium ions were added to the solution, followed by nitrogen purging. The addition of magnesium ions simulated bone mineral composition, and nitrogen purging removed surface-adsorbed air bubbles. The synergistic effect of these two processes significantly improved the Ca / P ratio stability of the mineralized layer and its bonding strength with the core. In vitro degradation experiments showed that this method effectively reduced the material degradation rate, solving the key problem of easy detachment of traditional mineralized layers, and is crucial for ensuring the long-term stability of the material in vivo.

[0022] Preferably, in the liposome encapsulation step, a combined thin-film ultrasonic-extrusion method is used, with an ultrasonic power of 200W and a time of 3min, and the pore sizes of the extruded membrane are 400nm, 200nm and 100nm respectively.

[0023] Beneficial Effects: In the liposome encapsulation step, a combined thin-film ultrasonic-extrusion method was employed, with clearly defined parameters such as ultrasonic power, time, and extruded membrane pore size. This method effectively reduces the liposome particle size distribution coefficient, improves encapsulation efficiency, and makes the liposome membrane structure more compact, achieving long-term sustained release of the material. This improvement plays an indispensable role in enhancing the targeted delivery efficiency and controlled drug release effect of the material in vivo, providing strong support for the in vivo application of the material.

[0024] Preferably, the obtained material is deposited in vivo using a specific method; the specific method for depositing the material in vivo includes one of the following: local injection into the renal pelvis or gallbladder; intravenous injection combined with a high-oxalate diet; the deposition process using the aforementioned method further includes an ultrasound-assisted step, with a frequency of 0.5-2MHz and an intensity of .

[0025] Beneficial Effects: Two different in vivo deposition methods are presented. Local injection enables local deposition of materials in specific cavities and organs, meeting local treatment needs. Intravenous injection combined with a high-oxalate diet promotes material deposition at specific sites in the body through systemic administration and dietary regulation, providing diversified options for different disease treatments and application scenarios. The introduction of an ultrasound-assisted procedure utilizes the physical effects of ultrasound, such as altering local tissue permeability and promoting material diffusion, to further improve the deposition efficiency and accuracy, enabling more precise deposition at the target location and enhancing therapeutic effects.

[0026] The advantages of this invention are:

[0027] High stability: Through a unique core-shell structure design, the inner PEG-modified layer reduces immune clearance, while the outer calcium phosphate mineralized shell mimics bone mineral composition, enhancing physiological stability. The solubility in pH 6.0 buffer is <5% after 7 days, the in vivo half-life is extended to >14 days, and 15% residue remains after 90 days, demonstrating significantly improved stability compared to traditional materials.

[0028] Excellent targeting: Employing a multimodal controlled deposition technique combining local and intravenous injection with chemical induction and physical assistance, and further enhancing targeting through liposome encapsulation, this technology enables precise deposition of materials in specific organs or tissues in vivo. For example, in a rat kidney deposition model, the deposition foci volume reached [missing information] after 7 days. .

[0029] Low toxicity:

[0030] The material has low toxicity, with an LD50 > 200 mg / kg, and no significant organ toxicity (normal blood biochemical indicators). It is highly safe for in vivo application, reducing potential threats to human health.

[0031] Multifunctionality: It has excellent imaging properties, with a CT value >2000HU, which facilitates in vivo imaging and monitoring; at the same time, based on its good thermoelectric properties, it can be widely used in thermoelectric power generation, micro-refrigeration, biosensing and other fields, laying an important material foundation for the development of new medical devices. Attached Figure Description

[0032] Figure 1 This is a flowchart of an embodiment of the present invention. Detailed Implementation

[0033] The following detailed description illustrates the specific implementation method:

[0034] This invention relates to a bismuth telluride-biomineralization composite material with stable in vivo deposition, comprising: The composite material consists of a nanocore (20-100 nm in diameter), a PEG-modified layer (2000-10000 Da molecular weight), and a calcium phosphate mineralized shell (5-15 nm thick). This structure defines the basic composition and key parameter range of the composite material. A suitable particle size range allows the nanocore to maintain thermoelectric properties while facilitating dispersion, transport, and function within the body. The PEG-modified layer with a specific molecular weight effectively improves the material's biocompatibility and reduces immune rejection. The calcium phosphate mineralized shell of a certain thickness enhances the material's stability in physiological environments and prevents rapid degradation.

[0035] Among them, the The bismuth telluride nanocore exhibits a cubic crystal system and characteristic peaks at 27.5° and 37.8° in XRD. Clarifying the crystal structure characteristics of the bismuth telluride nanocore facilitates accurate identification and preparation of the composite material, ensuring its expected thermoelectric and physicochemical properties and providing a reliable guarantee for subsequent applications.

[0036] This invention relates to a bismuth telluride-biomineralization composite material for stable in vivo deposition, further comprising a liposome encapsulation layer with a phospholipid:cholesterol ratio of 7:3. Adding the liposome encapsulation layer further enhances the material's targeting ability, enabling it to precisely reach the target organ or tissue; simultaneously, it controls the drug release rate, achieving sustained and stable drug release and improving the material's therapeutic effect in vivo.

[0037] This invention relates to a bismuth telluride-biomineralization composite material for stable in vivo deposition, comprising a PEG-modified layer with a grafting rate ≥80%. The defined grafting rate requirement for the PEG-modified layer is crucial; a higher grafting rate can more effectively improve the material's biocompatibility, reduce immune clearance, prolong the material's circulation time in vivo, and allow the material to function better, further enhancing its stability and effectiveness in vivo.

[0038] Among them, the calcium phosphate mineralization shell is doped with 0.1-2 mol% of rare earth elements (selected from...). , or Furthermore, the rare earth elements are uniformly distributed within the mineralization shell (verified via EDS surface scanning). By precisely doping specific rare earth elements into the calcium phosphate mineralization shell, not only is the physiological stability of the mineralization shell preserved, but new functional properties are also endowed to the material. For example, Doping can enhance the MRI imaging performance of materials, forming a multimodal imaging capability in combination with the original CT imaging function; and Doping further suppresses the dissolution rate of calcium phosphate, reducing the dissolution rate of the material to <3% after 7 days in an acidic environment of pH 5.0, an improvement of more than 40% compared to the undoped system. This doping design breaks through the limitation of traditional mineralization layers that only pursue stability, achieving a synergy between functional expansion and performance enhancement, and is of significant innovation.

[0039] The PEG-modified layer is a bi-terminal functionalized PEG (one end is a carboxyl group, and the other end is a targeting peptide RGD), with a targeting peptide grafting rate of 10-20% (quantitatively analyzed by HPLC). This invention innovatively introduces a targeting peptide into the PEG-modified layer, enabling the material to possess both biocompatibility and active targeting capabilities. The RGD peptide can specifically recognize integrin receptors on the surface of tumor cells. In a mouse tumor model, the material's accumulation at the tumor site was 2.3 times higher than that of the PEG-modified group alone. The bi-terminal functionalization design solves the compatibility problem between the targeting molecule and PEG, and the 10-20% grafting rate balances targeting efficiency and material stability, avoiding the PEG chain aggregation problem caused by high grafting rates. This design has outstanding and substantial characteristics in targeting modification strategies.

[0040] The liposome encapsulation layer is modified with a polyethylene glycol-polylysine block copolymer, exhibiting a zeta potential of -5 to 5 mV (measured using a Malvern particle size analyzer). By introducing the amphoteric block copolymer onto the liposome surface, the material possesses both "invisibility" properties in blood circulation (reducing macrophage recognition) and the ability to undergo charge reversal under specific pH conditions (such as the tumor microenvironment at pH 6.5), enhancing its interaction with the cell membrane. Experiments show that this modification extends the material's blood circulation time to >24 hours, a 1.8-fold increase compared to the unmodified liposome group, while simultaneously improving tumor penetration efficiency by 3 times. This intelligent responsive surface design overcomes the efficiency bottleneck of traditional liposome targeted delivery.

[0041] like Figure 1 As shown, the present invention also provides a method for preparing an in-situ stable depositional material of bismuth telluride-biomineralization composite, used to prepare the in-situ stable depositional material of bismuth telluride-biomineralization composite described in the aforementioned scheme, comprising the following steps:

[0042] Step 1: Solvothermal synthesis Nanoparticles;

[0043] The second step is PEGylation modification and calcium phosphate mineralization coating.

[0044] The third step is to encapsulate the product with an optional liposome.

[0045] This invention provides a complete and scientific preparation process. The solvothermal method can effectively control the particle size and crystal form of nanoparticles; PEGylation modification enhances the biocompatibility of the material; calcium phosphate mineralization coating improves the stability of the material; and the selectable liposome encapsulation step meets the needs of different application scenarios, ensuring that the prepared composite material has good performance.

[0046] The first step involves the solvothermal synthesis method. The nanoparticle step also includes adding 0.05-0.2 mmol of hexadecyltrimethylammonium bromide (CTAB) to the reaction system as a morphology control agent, and the reaction heating rate is 5 °C / min. By introducing the CTAB morphology control agent and controlling the heating rate, the reaction can be precisely controlled. The increased exposure ratio of the nanoparticle crystal faces led to an increase in the exposure rate of the (111) active crystal faces to over 60% (calculated by XRD texture coefficient), which is 2.5 times higher than the group without control agent. This significantly enhanced the grafting efficiency of subsequent PEG modification (increased to 92%) and the uniformity of the mineralized layer (thickness deviation <1nm), solving the performance fluctuation problem caused by the uneven particle morphology in the traditional solvothermal method, and greatly improving the accuracy and controllability of the preparation process.

[0047] In the PEGylation modification step, a microwave-assisted reaction (power 300-500W, temperature 40-50℃) is used, and mPEG-COOH reacts with... The mass ratio of nanoparticles is 1:3-1:8. This invention innovatively applies microwave-assisted technology to PEGylation modification, shortening the reaction time from 12 hours to 1.5 hours. Simultaneously, by optimizing the mass ratio range, it avoids the degradation of thermoelectric properties caused by excessive PEG chain encapsulation (ZT value retention rate increased from 70% to 90%) while maintaining a grafting rate (≥88%). This method achieves a balance between efficient modification and performance retention, representing a breakthrough in both production efficiency and performance control compared to traditional room temperature stirring methods.

[0048] In the calcium phosphate mineralization coating step, the alternating soaking Magnesium ions at a concentration of 5-10 mmol / L were added to the solution, and nitrogen purging was performed after each soaking (flow rate 0.5 L / min, time 5 min). By introducing magnesium ions to simulate bone mineral composition and combining this with nitrogen purging to remove surface-adsorbed air bubbles, the Ca / P ratio stability of the mineralized layer (deviation <0.05) and the bonding strength with the core (peeling rate reduced to <2%) were significantly improved. In vitro degradation experiments showed that the material's degradation rate in simulated body fluid was <10% after 30 days, a 60% reduction compared to the group without magnesium ions, solving the key problem of easy detachment of traditional mineralized layers. The process design is original.

[0049] In the liposome encapsulation step, a combined thin-film ultrasonic-extrusion method was employed, with an ultrasonic power of 200W and a duration of 3 minutes. The pore sizes of the extruded membranes were 400nm, 200nm, and 100nm, respectively. By optimizing the physical processing parameters for liposome encapsulation, the particle size distribution index (PDI) of the liposomes was reduced to below 0.12, and the encapsulation efficiency was increased to over 90% (a 35% improvement compared to the simple thin-film method). More importantly, the multilayer extrusion process resulted in a denser liposome membrane structure, with a release rate of <15% in serum at 37°C after 48 hours, achieving long-term sustained release of the material. This process significantly improves the efficiency and stability of liposome encapsulation.

[0050] After obtaining the material using the aforementioned preparation method, in vivo deposition is induced through one of the following methods: local injection into the renal pelvis or gallbladder; or intravenous injection combined with a high-oxalate diet. Two different in vivo deposition methods are presented: local injection allows for local deposition of the material in specific cavities, meeting local treatment needs; while intravenous injection combined with a high-oxalate diet promotes material deposition at specific sites in the body through systemic administration combined with dietary regulation, providing diverse options for different disease treatments and application scenarios.

[0051] During the in-bulk deposition of materials, a simultaneous ultrasonic-assisted step was employed, with a frequency of 0.5-2 MHz and an intensity of [missing information]. Introducing ultrasound-assisted procedures utilizes the physical effects of ultrasound, such as altering local tissue permeability and promoting material diffusion, to further improve the deposition efficiency and accuracy of materials, enabling more precise deposition at the target location and enhancing the therapeutic effect.

[0052] Specifically,

[0053] Example 1

[0054] The preparation of the bismuth telluride-biomineralization composite material in this embodiment includes the following:

[0055] Nanoparticle synthesis: 2 mmol and 3 mmol Dissolved in 50 mL of ethylene glycol, the mixture was reacted at 180 °C for 12 hours. After the reaction, the mixture was washed (using alternating washes of ethanol and water three times) by centrifugation (8000 rpm for 10 minutes) to remove impurities, and then dried in a vacuum drying oven at 60 °C for 12 hours to obtain the desired product. Nanoparticles. TEM analysis showed the particle size to be 50±5 nm.

[0056] PEGylation modification: mPEG-COOH (molecular weight 6000) was reacted with the above-prepared... Nanoparticles were mixed at a 1:5 mass ratio and added to an EDC / NHS catalyst system (5 mmol EDC, 5 mmol NHS). The mixture was stirred at room temperature for 12 hours in pH 7.4 PBS buffer. After the reaction was complete, unreacted mPEG-COOH and the catalyst were removed by dialysis (dialysis bag with a molecular weight cutoff of 3500 Da, dialysis time 24 hours, dialysis buffer changed 3 times) to obtain PEGylated modified [product name missing]. Nanoparticles. FTIR analysis showed that... The presence of the νC-OC characteristic peak confirms successful PEG grafting, with a grafting rate of ≥85% as determined by measurement.

[0057] Biomimetic mineralization: Biomimetic mineralization was carried out using an alternating immersion method, where PEGylated modified... Nanoparticles were alternately immersed in 10mM Solution and 10mM The particles were soaked in the solution for 1 hour each time, and the cycle was repeated 3 times. After soaking, the particles were placed in simulated body fluid (SBF) at 37°C for 24 hours to form a calcium phosphate mineralization shell with a thickness of 5-10 nm (verified by TEM), thus obtaining a stable in vivo deposition material of bismuth telluride-biomineralization composite.

[0058] The material prepared above was used to conduct 10 repeated preparation experiments. During each preparation process, the amount of raw materials, reaction conditions, and operating procedures were strictly controlled. The particle size, PEG grafting rate, and mineralized shell thickness of the materials obtained in each preparation were measured. The results showed that... The nanoparticles have a diameter between 48 and 52 nm, the PEG grafting rate is ≥85%, and the thickness of the calcium phosphate mineralization shell is in the range of 5-10 nm, indicating that the preparation method has good repeatability and stability and can prepare stable in-vivo deposition materials of bismuth telluride-biomineralization composite with consistent performance.

[0059] The performance comparison between the material in this embodiment and the unmodified bismuth telluride material is shown in Table 1.

[0060] Table 1

[0061]

[0062] As shown in Table 1, this embodiment solves the core problems of traditional bismuth telluride materials, namely easy degradation in physiological environments (dissolution rate decreased from >30% to <5% after 7 days) and short half-life (extended from <6 hours to >14 days), through a core-shell structure design of "PEG modification + calcium phosphate mineralization". Compared with single PEG-modified materials, the introduction of the mineralization layer nearly doubled the in vivo residue rate after 90 days, proving that the synergistic effect of the two modifications is not obvious—it cannot be achieved by simply adding existing technologies, but by overcoming the stability bottleneck through structural design.

[0063] Compared to existing technologies, this embodiment differs significantly in material design: Existing technologies have not effectively addressed the challenges of applying bismuth telluride materials in physiological environments, and traditional material design approaches have not combined polyethylene glycol modification with calcium phosphate mineralization to construct a core-shell structure. This invention creatively designs this unique structure, fundamentally solving the problems of easy oxidation and degradation and short half-life of bismuth telluride, resulting in a significant improvement in stability—something that cannot be conceived by those skilled in the art through conventional techniques or simple combinations. Regarding the preparation method: traditional preparation methods lack a systematic process for comprehensive control of material properties. The preparation method developed in this invention, from solvothermal synthesis to biomimetic mineralization, involves tightly coordinated steps with precise parameters. Through innovative optimization of raw materials, reaction conditions, and post-treatment, the realization of material properties is guaranteed. This systematic preparation process represents a breakthrough from traditional methods and is not readily apparent.

[0064] Example 2

[0065] This embodiment is an in vivo deposition experiment of the material obtained in Example 1, including the following:

[0066] Local injection group: Six healthy rats were selected, and after anesthesia, the left renal pelvis was exposed. 10 μL of a 15 mg / mL solution was injected using a 27G minimally invasive injection needle. @PEG-CaP material. Seven days later, Micro-CT imaging revealed that the deposition foci volume was... This demonstrates that the material can be effectively deposited in the renal pelvis. In the intravenous injection group, six healthy rats were injected via the tail vein at a dose of 5 mg / kg. Simultaneously, the rats were given 0.5% sodium oxalate in their drinking water for chemical induction. After 14 days, the amount of material deposited in the kidneys was detected by ICP-MS, and the result was 3.2 ± 0.5 μg / mg tissue, indicating that intravenous injection combined with chemical induction can effectively deposit the material in the kidneys.

[0067] Table 2 shows a comparison of the targeting and efficiency of different deposition methods in this embodiment and existing technologies.

[0068] Table 2

[0069]

[0070] As shown in Table 2, the multimodal deposition strategy (precise local injection + combined intravenous injection and chemical induction) of this embodiment significantly improves targeting and deposition efficiency. Compared with traditional materials, the amount of kidney deposition is increased by 6.4 times, and the targeting index is increased by 3-7 times, proving that it solves the problems of "difficult to control the deposition location and poor targeting" in the prior art. This synergistic design that integrates physical injection and chemical induction is not a conventional choice for those skilled in the art and has outstanding substantial characteristics.

[0071] Compared to existing technologies, this embodiment differs significantly in its in vivo deposition technique: existing in vivo deposition techniques struggle to precisely control the deposition location and morphology. The multimodal controlled deposition technique established in this embodiment integrates chemically induced and physically-assisted methods, combined with the material's own targeted design, to achieve precise targeted deposition. This technique differs fundamentally from traditional techniques in its principles and implementation, and is not easily foreseen or implemented by those skilled in the art.

[0072] Example 3

[0073] Unlike Example 1, this example describes the preparation and performance verification of bismuth telluride-biomineralization composite material doped with rare earth elements.

[0074] Material preparation: In the biomimetic mineralization step of Example 1, 10 mM Add 0.1 mmol / L to the solution (Maintaining a rare earth element doping level of 0.5 mol%), while keeping the remaining steps consistent. Verification was performed using EDS surface scanning. It is evenly distributed in the calcium phosphate mineralization crust.

[0075] Performance testing: The material was placed in a pH 5.0 buffer solution and allowed to stand for 7 days; the solubility was measured to be 2.8%. MRI imaging showed that the relaxation rate (r1) was 1.6 times higher than that of the undoped group. These results indicate that rare earth element doping enhances stability while also imparting MRI imaging capabilities to the material.

[0076] The effects of rare earth doping on material properties in this embodiment and in the prior art are shown in Table 3.

[0077] Table 3

[0078]

[0079] As can be seen from Table 3, rare earth doping (such as...) This invention not only reduces the solubility in acidic environments by 40% (from 4.7% to 2.8%), but also endows the material with MRI imaging capabilities (relaxation rate close to that of traditional contrast agents), achieving a synergistic improvement in both stability and imaging performance. Traditional contrast agents are easily degraded in physiological environments (solubility > 20%), while this invention solves this problem through mineralization layer protection. Its integrated functional effect cannot be achieved by simple combinations of existing technologies, resulting in superior performance.

[0080] Example 4

[0081] Unlike Example 1, this example involves the synergistic preparation of bi-terminal functionalized PEG modification and liposome smart encapsulation.

[0082] PEGylation modification: Using existing microwave-assisted methods, double-ended functionalized PEG (carboxyl-terminated PEG) is modified... RGD (with exposed peptide ends) was mixed with nanoparticles at a mass ratio of 1:5 and reacted at 400W power and 45℃ for 1.5 hours. The RGD grafting rate was determined to be 15% by HPLC.

[0083] Liposome encapsulation: According to the thin-film ultrasonic-extrusion method of claim 17, the above material is mixed with phospholipid-cholesterol (7:3), ultrasonicated at 200W for 3 minutes, and then extruded sequentially through 400nm, 200nm and 100nm membranes. The zeta potential was measured to be 0mV.

[0084] In vivo targeted experiment: The material was injected into the tail vein of a mouse tumor model. The accumulation in the tumor site was detected 24 hours later. It was 2.3 times higher than that of the PEG-modified group alone, and the blood circulation time was extended to 26 hours.

[0085] The targeting performance of this embodiment, which combines dual-terminal functionalized PEG with liposome modification, is compared with that of existing technologies, as shown in Table 4.

[0086] Table 4

[0087]

[0088] As shown in Table 4, the synergistic design of dual-terminated functionalized PEG (RGD targeting peptide) and liposome intelligent encapsulation increased tumor accumulation by 2.3 times and prolonged blood circulation time by 1.8 times, solving the problems of traditional liposomes being "easily cleared and having weak penetration ability." The 10-20% RGD grafting rate balanced targeting and material stability, avoiding aggregation caused by high grafting rates. This precise regulation is uncommon in this field.

[0089] Example 5

[0090] Unlike Example 1, this example is an optimized preparation process based on CTAB regulation and magnesium ion enhancement.

[0091] Nanoparticle synthesis: In the solvothermal synthesis step of Example 1, 0.1 mmol CTAB was added and the temperature was increased to 180°C at a rate of 5°C / min. XRD analysis showed that the (111) crystal plane exposure rate reached 62%.

[0092] Calcium phosphate mineralization: in Add 8 mmol / L to the solution After each soaking, nitrogen was purged for 5 minutes at a rate of 0.5 L / min. TEM analysis showed that the mineralization layer thickness deviation was 0.8 nm, and the 30-day simulated body fluid degradation rate was 8.5%.

[0093] Performance integration: After PEGylation modification (grafting rate of 92%), the ZT value retention rate of this material reaches 90%, which meets the synergistic requirements of thermoelectric performance and stability.

[0094] Table 5 shows a comparison of the impact of the optimized process and the existing process on material properties in this embodiment.

[0095] Table 5

[0096]

[0097] As shown in Table 5, by controlling the crystal facet exposure rate (increasing from 20% to 62%) using CTAB and enhancing the mineralization layer bonding force with magnesium ions (reducing the peeling rate from 22% to <2%), the material simultaneously achieves "high thermoelectric performance retention (ZT value of 90%)" and "high stability (30-day degradation rate of 8.5%)". Traditional processes cannot achieve both simultaneously, but this invention overcomes this contradiction through multi-parameter synergistic optimization, demonstrating its process innovation.

[0098] This invention achieves a unified "stability-targeting-functional integration" that is impossible to achieve with existing technologies through material structure design (core-shell structure, functional modification), process optimization (multi-step synergistic control), and application strategies (multimodal deposition). The performance improvement (e.g., 80% reduction in solubility and 6-fold improvement in targeting) far exceeds conventional improvements, and the technical problems solved (e.g., in vivo degradation of bismuth telluride and molding of high-fiber materials) are long-standing industry challenges, thus representing a significant breakthrough and progress.

[0099] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A bismuth telluride-biomineralization composite material with stable in-situ deposition, characterized in that, The core-shell structure from the inside out is as follows: The nanocore has a particle size of 20-100nm and is cubic in crystal form; the PEG-modified layer has a molecular weight of 2000-10000Da and a grafting rate of ≥80%. The PEG-modified layer is a double-ended functionalized PEG, with a carboxyl group at one end and a targeting peptide RGD at the other end; the calcium phosphate mineralization shell has a thickness of 5-15nm and is tightly wrapped around the outside of the PEG-modified layer. The calcium phosphate mineralization shell is doped with 0.1-2mol% of rare earth elements, which are uniformly distributed in the mineralization shell.

2. The bismuth telluride-biomineralization composite in vivo stable deposition material according to claim 1, characterized in that, The The XRD pattern has characteristic peaks at 27.5° and 37.8°.

3. The bismuth telluride-biomineralization composite in vivo stable deposition material according to claim 1, characterized in that, It also contains a liposome encapsulation layer, which is composed of phospholipids:cholesterol = 7:

3.

4. The bismuth telluride-biomineralization composite in vivo stable deposition material according to claim 1, characterized in that, The target peptide grafting rate of the PEG-modified layer is 10-20%.

5. A method for preparing bismuth telluride-biomineralization composite material with stable in-situ deposition, characterized in that, The preparation of the bismuth telluride-biomineralization composite in vivo stable deposition material as described in any one of claims 1-4 comprises the following steps: solvothermal synthesis Nanoparticles; PEGylation modification; calcium phosphate mineralization coating; optional liposome encapsulation.

6. The method for preparing bismuth telluride-biomineralization composite in vivo stable deposition material according to claim 5, characterized in that, The solvothermal synthesis The nanoparticle step also includes adding 0.05-0.2 mmol of hexadecyltrimethylammonium bromide to the reaction system as a morphology control agent, and the reaction heating rate is 5 °C / min.

7. The method for preparing bismuth telluride-biomineralization composite in vivo stable deposition material according to claim 5, characterized in that, In the PEGylation modification step, a microwave-assisted reaction with a power of 300-500W and a temperature of 40-50℃ is used, and mPEG-COOH reacts with... The mass ratio of nanoparticles is 1:3-1:

8.

8. The method for preparing bismuth telluride-biomineralization composite in vivo stable deposition material according to claim 5, characterized in that, In the calcium phosphate mineralization coating step, alternating soaking Add 5-10 mmol / L of magnesium ions to the solution, and purge with nitrogen gas at a flow rate of 0.5 L / min for 5 min after each soaking.

9. The method for preparing bismuth telluride-biomineralization composite in vivo stable deposition material according to claim 5, characterized in that, In the liposome encapsulation step, a combined ultrasonic-extrusion method was used, with an ultrasonic power of 200W and a time of 3min. The pore sizes of the extruded membranes were 400nm, 200nm, and 100nm, respectively.

10. The method for preparing bismuth telluride-biomineralization composite in vivo stable deposition material according to claim 5, characterized in that, The resulting material is deposited in vivo using a specific method; this specific method includes one of the following: local injection into the renal pelvis or gallbladder; intravenous injection combined with a high-oxalate diet; the deposition process also includes an ultrasound-assisted step with a frequency of 0.5-2 MHz and an intensity of .

Images