Core-shell structure piezoelectric composite material loaded NO donor nanoparticle and application thereof

Abstract

The invention belongs to the field of nano material synthesis, and particularly relates to a core-shell structure piezoelectric composite material loaded NO donor nano particle and application thereof.The core-shell structure piezoelectric composite material loaded NO donor nano particle comprises a core and a shell layer, the core is made of a layered bismuth-based piezoelectric material, the shell layer is made of a porous material, and the shell layer is made of a porous material. The nanoparticles with the core-shell structure are loaded with an NO donor drug. The nano-drug delivery system can be used as an eye drug delivery system based on ultrasonic mediation, and the first low-frequency ultrasonic response type nano-drug is provided for glaucoma treatment. By means of the innovative design of piezoelectric core / MOF drug loading / PDA sealing / PEG functionalization, the three problems that in glaucoma treatment, drug targeting is poor, release is uncontrollable, and frequent drug administration is needed are solved, and a safe, efficient and micro-intervention nanometer treatment new normal form is provided for irreversible blinding diseases.

Description

Technical Field

[0001] This invention belongs to the field of nanomaterial synthesis, specifically relating to a core-shell structured piezoelectric composite material loaded with NO donor nanoparticles and its applications. Background Technology

[0002] Glaucoma is the leading cause of irreversible blindness worldwide, with its core pathological mechanism being optic nerve damage caused by elevated intraocular pressure. Traditional drug treatments, such as prostaglandin analogs, and surgical interventions, such as trabeculectomy, suffer from poor compliance, significant trauma, or high risks of complications. Focused ultrasound (FUS), as a non-invasive or minimally invasive technique, has been successfully applied clinically in glaucoma treatment, such as trabeculoplasty and ciliary body ablation. FUS uses high-frequency sound waves (0.5-10 MHz) to precisely deposit energy in target tissues (trabecular meshwork, ciliary body), selectively ablating the ciliary body epithelium through localized high temperatures, thereby reducing aqueous humor secretion. However, as an invasive treatment, FUS carries the risk of postoperative hypotension due to over-ablation or persistent inflammation. More importantly, individual differences in the anterior chamber angle structure (such as trabecular meshwork thickness and ciliary body position) can lead to inaccurate energy deposition and unstable efficacy.

[0003] Low-frequency ultrasound (LFUS) has greater penetration and lower energy attenuation compared to high-intensity focused ultrasound (HIFU), allowing it to directly target key glaucoma sites while reducing the thermal side effects of ultrasound. Therefore, LFUS-mediated drug release has unique advantages in glaucoma treatment. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings and deficiencies of the existing technology and to provide a core-shell structured piezoelectric composite material loaded with NO donor nanoparticles and its application.

[0005] The technical solution adopted in this invention is as follows: a core-shell structured piezoelectric composite material for supporting NO donor nanoparticles, comprising core-shell structured nanoparticles composed of a core and a shell, wherein the core is made of layered bismuth-based piezoelectric material. The shell is a porous material, and the core-shell structured nanoparticles are loaded with NO donor drugs.

[0006] Preferably, the layered bismuth-based piezoelectric material It was synthesized using a hydrothermal method.

[0007] Preferably, the preparation process includes the following steps: dissolving a bismuth source in anhydrous ethanol to obtain solution A; dispersing PVP powder and solid NaOH in deionized water to obtain suspension B; adding the suspension B dropwise to solution A and heating at 100-140°C for 10-12 hours.

[0008] Preferably, the shell is a ZIF-8 metal-organic framework.

[0009] Preferably, the preparation process includes the following steps: preparing layered bismuth-based piezoelectric materials. and The methanol solution of the zinc salt and the methanol solution of the zinc salt are uniformly mixed and reacted at 30-50℃ in a layered bismuth-based piezoelectric material. In situ growth of ZIF-8 metal-organic frameworks.

[0010] Preferably, the outer shell has a polydopamine coating.

[0011] Preferably, it further includes a functionalized outer layer covering the polydopamine coating, wherein the functionalized outer layer is... .

[0012] Preferably, the preparation process includes the following steps: adding core-shell structured nanoparticles loaded with NO donor drug to a solution containing dopamine hydrochloride, stirring to form nanoparticles coated with a polydopamine coating; and then mixing the polydopamine-coated nanoparticles with... The solution is mixed and stirred to form nanoparticles with a functionalized outer layer.

[0013] Preferably, the NO donor drug is sodium nitroprusside.

[0014] The application of the core-shell structured piezoelectric composite material loaded with NO donor nanoparticles, as described above, in the preparation of drugs for treating glaucoma.

[0015] This invention provides a core-shell structured piezoelectric composite material loaded with NO donor nanoparticles, which has the following technical effects: (1) Layered bismuth-based piezoelectric materials With this as its core, its unique Multi-layer structure and The sandwich design endows the material with a permanent built-in electric field and strong piezoelectric catalytic activity, significantly enhancing the mechanical stress-charge conversion capability. The external ultrasonic excitation of the piezoelectric core generates an electrochemical signal, triggering the on-demand release of NO donor drugs. (2) A ZIF-8 metal-organic framework (MOF) shell with high specific surface area is used to efficiently load drugs using its porous structure, thereby further improving the drug loading capacity of the nano-drug delivery system. (3) Coating the ZIF-8 metal-organic framework (MOF) shell with a polydopamine (PDA) coating effectively blocks the non-specific leakage of SNPs, ensuring zero leakage during delivery and extending the cycle half-life. (4) Set up a functional outer layer It enhances the permeability of ocular mucus (extends corneal retention time to 6-8 hours) and improves biocompatibility.

[0016] The core-shell piezoelectric composite material-loaded NO donor nanoparticles provided by this invention achieve a three-in-one function of "ultrasound triggering-targeted retention-long-acting sustained release," serving as an ultrasound-mediated ocular drug delivery system and providing the first low-frequency ultrasound-responsive nanomedicine for glaucoma treatment. Ultrasound waves can penetrate ocular tissues such as the sclera and cornea; low-frequency ultrasound-mediated external devices can enhance drug penetration and reduce the need for injections. More importantly, by adjusting ultrasound parameters such as frequency, intensity, and time, the timing and dosage of drug release can be precisely determined. In summary, this invention, through its innovative design of "piezoelectric core / MOF drug loading / PDA sealing / PEG functionalization," solves three major challenges in glaucoma treatment: poor drug targeting, uncontrollable release, and the need for frequent administration, providing a safe, efficient, and minimally invasive new paradigm for nanotherapy of irreversible blinding diseases. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, obtaining other drawings based on these drawings without creative effort still falls within the scope of the present invention.

[0018] Figure 1 A schematic diagram illustrating the application of the SNP@BOC-MOF@PDA-PEG nanoparticles provided by this invention in the treatment of glaucoma; Figure 2 This is a schematic diagram of the process for preparing SNP@BOC-MOF@PDA-PEG nanoparticles in Example 1 of the present invention; Figure 3 This is a TEM image of the hydrothermally synthesized piezoelectric BOC core in SNP@BOC-MOF@PDA-PEG nanoparticles prepared in Example 1 of this invention. Figure 4 The XRD pattern of piezoelectric BOC-modified PEG in SNP@BOC-MOF@PDA-PEG nanoparticles prepared in Example 1 of this invention; Figure 5The image shows the PFM butterfly strain curve of the SNP@BOC-MOF@PDA-PEG nanoparticles prepared in Example 1 of this invention. Figure 6 The hydrated particle size diagram of the SNP@BOC-MOF@PDA-PEG nanoparticles prepared in Example 1 of this invention; Figure 7 TEM images and detailed magnified images of the final product of SNP@BOC-MOF@PDA-PEG nanoparticles prepared in Example 1 of this invention; Figure 8 SEM image and corresponding EDX elemental distribution spectrum of SNP@BOC-MOF@PDA-PEG nanoparticles prepared in Example 1 of this invention; Figure 9 The UV absorption spectra of SNP@BOC-MOF@PDA-PEG nanoparticles and free SNP prepared in Example 1 of this invention are shown below. Figure 10 The image shows the cytotoxicity of SNP@BOC-MOF@PDA-PEG nanoparticles to corneal epithelial cells prepared in Example 1 of this invention. Figure 11 This is a graph showing the in vitro NO release detection under ultrasonic conditions for SNP@BOC-MOF@PDA-PEG nanoparticles in Example 1 of this invention. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings.

[0020] Example 1: (1) Hydrothermal synthesis of small-particle-size piezoelectric : 0.252 g of bismuth source ( Dissolve the compound in 20 mL of anhydrous ethanol and stir until completely dissolved to form a solution. Add 5 mL of a mixed aqueous solution containing polyvinylpyrrolidone (PVP, molecular weight 5800) and NaOH (PVP concentration 50 mg / mL, NaOH concentration 1 M) to this solution and stir continuously for 30 minutes to form a suspension. Gently add the suspension dropwise to the above solution, and the solution changes from colorless to pale yellow. Transfer the mixed solution to a polytetrafluoroethylene-lined high-pressure reactor and hydrothermally react at 120 °C for 12 hours. After the reaction, centrifuge the product at 10000-15000 rpm, wash it three times each with deionized water and anhydrous ethanol, and finally dry it in a vacuum drying oven at 60 °C for 12 hours to obtain the product. Nanosheets; (2) In-situ encapsulation of MOF shell and NO donor loading: Take 50 mg of the product obtained in step (1) Nanosheets were dispersed in 20 mL of methanol and sonicated for 30 minutes. Then, 5 mL of a 100 mM 2-methylimidazolium methanol solution and 5 mL of a 100 mM [unclear - likely a specific compound or solution] were added. A methanol solution was mixed and reacted with stirring at 40°C for 24 hours. After the reaction, the product was collected by centrifugation and washed three times with methanol to obtain BOC@ZIF-8 core-shell nanoparticles (denoted as BOC-MOF); subsequently, sodium nitroprusside was prepared ( SNP (abbreviated as SNP) methanol solution (30-100 mg, 1 mL); then 100 mg of the above-synthesized BOC-MOF nanoparticles were mixed with the SNP solution and stirred overnight. The SNP@BOC-MOF product was collected by centrifugation and washed three times with methanol to finally obtain SNP@BOC-MOF nanoparticles. (3) Modification with dopamine and methoxy polyethylene glycol amino: 20 mg of SNP@BOC-MOF nanoparticles were dispersed in 20 mL of Tris-HCl buffer (pH=8.5), and 10 mg of dopamine hydrochloride was added. The mixture was stirred at room temperature for 24 hours to form a polydopamine (PDA) coating layer. The SNP@BOC-MOF@PDA nanoparticles were collected by centrifugation and washed three times with deionized water. The obtained SNP@BOC-MOF@PDA nanoparticles were then mixed with an equal mass (mass ratio 1:1) of methoxy polyethylene glycol amino (PGA) The nanoparticles (with a molecular weight of 2000) were dispersed together in 10 mL of deionized water and stirred for 12 hours. The product was separated by centrifugation and freeze-dried to obtain the final product, SNP@BOC-MOF@PDA-PEG nanoparticles.

[0021] Transmission electron microscope image as shown Figure 3 As shown, this confirms the piezoelectric nanorods It exhibits good dispersibility with a particle size of approximately 100 nm, as shown in the magnified image. Having the corresponding (020) and (220) crystal planes of typical bismuth-based piezoelectric materials, it is proven that Successful synthesis.

[0022] Figure 4 To modify PEG The XRD diffraction pattern confirms this. The nanoparticles correspond one-to-one with the diffraction peaks of the reference card, proving that the nanoparticles were obtained after hydrothermal synthesis. The crystalline black phosphorus nanoparticles have a thickness of 4.54 nm.

[0023] Figure 5The butterfly strain curve obtained by piezoelectric microscopy of the final product SBMP nanoparticles verifies that the SBMP nanoparticles retain good piezoelectric response properties, providing a prerequisite for ultrasound-induced SNP release.

[0024] Figure 6 The hydrated particle size distribution of the final product SBMP nanoparticles shows that the particle size is less than 200 nm and the PDI is less than 0.25, indicating that the final product has uniform size and good water solubility.

[0025] pass Figure 7 The TEM magnified spectrum of the final product reveals a clearly defined shell outside the nanorods, indicating the successful construction of the core-shell material.

[0026] Figure 8 The SEM and EDX spectra of the final product were used to further demonstrate the successful MOF shell coating and PDA modification on BOC nanorods by observing Bi, Zn, O, Cl, and C.

[0027] Figure 9 The UV-Vis spectra of the SNP solution and the final product at the same mass concentration are shown. By observing the characteristic absorption peak of SNP at 395 nm, it was found that the final product was significantly lower than the free SNP solution, which suggests that the SNP was successfully loaded into the final product.

[0028] Safety assessment of nanomedicines is a crucial guarantee for achieving effective therapeutic results. Figure 10 In the study, the biocompatibility of the final product was verified by cytotoxicity experiments. It was observed that the final product maintained a corneal epithelial cell (HCEC) cell viability of more than 90% under different concentration conditions (0, 12.5, 25, 50, 100 μg / mL) for 48 h.

[0029] Figure 11 This is an in vitro NO release detection graph of SNP@BOC-MOF@PDA-PEG nanoparticles under ultrasound conditions in Example 1 of the present invention. The groups in the graph are as follows: (1) Control; (2) US; (3) SBMP nanoparticles; (4) SBMP nanoparticles + US group, with an ultrasound power of 1.5 W / cm. 2The ultrasound frequency was 1 MHz and the ultrasound time was about 10 min. The release of NO gas was detected using a NO detection kit. Groups (1) and (2) were control groups, showing a background signal with no NO gas release. Compared with control groups (1) and (2), Group (3) showed that the SBMP nanoparticles did not release NO gas without ultrasound, indicating that the SBMP nanoparticles of the present invention can ensure zero leakage during delivery. Group (4) showed the release of SBMP nanoparticles under ultrasound. Compared with control groups (1) and (2), it showed an effective NO gas release effect, indicating that the SBMP nanoparticles of the present invention can release NO gas in a controllable manner under ultrasound, laying the foundation for in vivo targeted therapy.

[0030] The above description discloses only preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. Therefore, equivalent variations made in accordance with the claims of the present invention are still within the scope of the present invention.

Claims

1. A core-shell structured piezoelectric composite material loaded with NO donor nanoparticles, characterized in that: It comprises core-shell structured nanoparticles consisting of a core and a shell, wherein the core is made of layered bismuth-based piezoelectric material. The shell is a porous material, and the core-shell structured nanoparticles are loaded with NO donor drugs.

2. The core-shell structured piezoelectric composite material with NO donor nanoparticles according to claim 1, characterized in that: The layered bismuth-based piezoelectric material It was synthesized using a hydrothermal method.

3. The core-shell structured piezoelectric composite material with NO donor nanoparticles according to claim 2, characterized in that, The preparation process includes the following steps: dissolving bismuth source in anhydrous ethanol to obtain solution A; dispersing PVP powder and solid NaOH in deionized water to obtain suspension B; adding suspension B dropwise to solution A and heating at 100-140℃ for 10-12 hours.

4. The core-shell structured piezoelectric composite material with NO donor nanoparticles according to claim 1, characterized in that: The shell is a ZIF-8 metal-organic framework.

5. The core-shell structured piezoelectric composite material with NO donor nanoparticles according to claim 4, characterized in that, Its preparation process includes the following steps: layered bismuth-based piezoelectric materials and The methanol solution of zinc salt and the methanol solution of zinc salt are uniformly mixed and reacted at 30-50℃ in a layered bismuth-based piezoelectric material. In situ growth of ZIF-8 metal-organic frameworks.

6. The core-shell structured piezoelectric composite material with NO donor nanoparticles according to claim 1, characterized in that: The outer shell has a polydopamine coating.

7. The core-shell structured piezoelectric composite material with NO donor nanoparticles according to claim 6, characterized in that: It also includes a functionalized outer layer covering the polydopamine coating, wherein the functionalized outer layer is... .

8. The core-shell structured piezoelectric composite material with NO donor nanoparticles according to claim 7, characterized in that, The preparation process includes the following steps: adding core-shell structured nanoparticles loaded with NO donor drug, consisting of a core and a shell, to a solution containing dopamine hydrochloride, and stirring to form nanoparticles coated with polydopamine; then mixing the polydopamine-coated nanoparticles with… The solution is mixed and stirred to form nanoparticles with a functionalized outer layer.

9. The core-shell structured piezoelectric composite material with NO donor nanoparticles according to claim 1, characterized in that: The NO donor drug is sodium nitroprusside.

10. The use of the core-shell structured piezoelectric composite material loaded with NO donor nanoparticles as described in any one of claims 1-9 for the preparation of a drug for treating glaucoma.

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