Nitric oxide-driven nanomotor composition, preparation method and application thereof
By breaking chemical bonds in an inflammatory microenvironment through nitric oxide-driven nanomotor synthesis, combined with nanoparticle self-assembly technology, the complexity and stability issues in nanomedicine preparation are solved, enabling targeted drug release and improving drug stability.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- QINGDAO UNIV
- Filing Date
- 2025-12-19
- Publication Date
- 2026-06-19
AI Technical Summary
Existing nanomedicines and nanomedicine carriers are cumbersome to prepare, have low yields and poor stability, which affects drug release.
The synthesized nanomotors driven by nitric oxide achieve targeted drug release by breaking specific chemical bonds in an inflammatory microenvironment, and combine this with nanoparticle self-assembly technology to improve drug stability.
This approach achieves targeted drug release, increases drug concentration in the target area, reduces non-target distribution, minimizes adverse reactions, improves drug stability, and simplifies the preparation of drug-loaded nanomotors.
Smart Images
Figure CN121337772B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical technology, and specifically relates to a nitric oxide-driven nanomotor synthesis, its preparation method, and its application. Background Technology
[0002] Nanotechnology is an emerging science and technology that utilizes the properties of materials at the nanoscale to manufacture nanomaterials and nanodevices with specific functions, and then studies their properties and practical applications. Since its inception in the last century, nanotechnology has shown great promise in fields such as materials, chemical engineering, medicine, environment, and food.
[0003] In the field of biomedical research, the continuous development of nanotechnology has led to the development of various nanomedicines and nanomedicine carriers. Nanomotors are nanoscale components with self-propelled capabilities, converting various forms of energy, including electrical, magnetic, light, acoustic, and chemical energy, into mechanical energy for self-propulsion. Enzyme-driven nanomotors achieve autonomous movement through energy generated by enzymatic reactions under specific chemical environments. Utilizing exposed active sites, they respond to specific chemical signals, achieving chemotaxis at specific sites, making them particularly suitable for the biomedical field.
[0004] Currently, the preparation of nanomedicines and nanomedicine carriers using existing technologies is quite cumbersome, has low yield, and poor stability, which affects drug release. Summary of the Invention
[0005] To address the aforementioned problems, this invention provides a nitric oxide-driven nanomotor synthesis, its preparation method, and its applications. The provided nanomotor possesses unique chemical bonds that are sensitive to inflammatory microenvironments and are easily broken in inflammatory environments. This allows for targeted drug release from inflammatory environments, increasing drug concentration in the target area, reducing drug distribution in non-target regions, and minimizing adverse reactions.
[0006] This invention provides a nitric oxide-driven nanomotor synthesis, the structure of which is shown in the following formula:
[0007] .
[0008] This invention also provides a method for preparing a nitric oxide-driven nanomotor, comprising the following steps:
[0009] S1. Cyclodextrin and Boc-protected arginine were dissolved in anhydrous DMF, and EDC and DMAP were added. The mixture was reacted in a water bath under nitrogen. After dialysis, the mixture was freeze-dried to obtain the white product CD-Arg.
[0010] S2. Rapamycin and thioacetate were dissolved in anhydrous DMF, and EDC and DMAP were added. The mixture was reacted in a water bath under nitrogen. After dialysis, the mixture was freeze-dried to obtain the yellow product RAPA-TK.
[0011] S3. Dissolve CD-Arg and RAPA-TK in anhydrous DMF, then add EDC and DMAP; react in a water bath under nitrogen; the product is separated by dialysis and freeze-drying to obtain the nanomotor synthesis CD-Arg-TK-RAPA.
[0012] Furthermore, in steps S1 to S3, the water bath reaction temperature is 25-40℃ and the time is 12-30h.
[0013] Furthermore, in step S1, the molar ratio of the cyclodextrin to the Boc-protected arginine is 1:(3.5-4.5).
[0014] In step S2, the molar ratio of rapamycin to thioacetate is 1:(2.5-3.2).
[0015] In step S3, the molar ratio of CD-Arg to RAPA-TK is 1:(1-1.2).
[0016] Furthermore, the structural formula of the thioacetate is shown below:
[0017] .
[0018] Furthermore, the synthesis process of step S1 is shown in the following formula:
[0019] Formula I;
[0020] The synthesis process for step S2 is shown in the following formula:
[0021] Formula II;
[0022] The synthesis process for step S3 is shown in the following formula:
[0023] Formula III.
[0024] The present invention also provides the application of the above-described nitric oxide-driven nanomotor synthesis or the nanomotor synthesis obtained by any of the above preparation methods in the preparation of drugs to alleviate atherosclerosis.
[0025] Furthermore, the preparation of the drug for relieving atherosclerosis includes: self-assembling the active pharmaceutical ingredient and the nitric oxide-driven nanomotor synthesis into nanoparticles in solution, thereby encapsulating the active pharmaceutical ingredient to obtain the drug for relieving atherosclerosis.
[0026] The beneficial effects of this invention are:
[0027] The nitric oxide-driven nanomotor synthesis provided by this invention has special chemical bonds that are sensitive to inflammatory microenvironments and are easily broken in inflammatory environments, enabling targeted drug release, increasing the drug concentration in the target area, reducing its distribution in non-target areas, and reducing adverse reactions. Lipid-lowering drugs can self-assemble with the nanomotor in solution to form nanoparticles, achieving drug encapsulation and significantly improving drug stability. Furthermore, the preparation method of the drug-loaded nanomotor is simple in process and produces products with high stability. Attached Figure Description
[0028] Figure 1 This is a transmission electron microscope image of the drug-loaded nanomotor in an embodiment of the present invention.
[0029] Figure 2 This is a particle size distribution diagram of the drug-loaded nanomotor in an embodiment of the present invention.
[0030] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the drug-loaded nanomotor under the action of hydrogen peroxide in an embodiment of the present invention.
[0031] Figure 4 This is a Brownian motion trajectory and velocity distribution diagram of water, the solvent for the drug-loaded nanomotor, in an embodiment of the present invention.
[0032] Figure 5 This is a diagram showing the motion trajectory and velocity distribution of a drug-loaded nanomotor in an aqueous solution in an embodiment of the present invention.
[0033] Figure 6 The images show laser confocal images of nitric oxide generated when the drug-loaded nanomotor and control samples were co-incubated with endothelial cells and macrophages, respectively, in embodiments of the present invention. Detailed Implementation
[0034] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0035] This invention provides a nitric oxide-driven nanomotor synthesis, with the synthetic structure shown in general formulas I to III:
[0036] Formula I.
[0037] As shown in the above structural formula, where:
[0038] Synthesis of CD-Arg: Cyclodextrin (113.5 mg, 0.1 mmol) and Boc-protected arginine (200 mg, 0.4 mmol) were dissolved in 30 mL of anhydrous DMF. EDC (115 mg, 0.6 mmol, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and DMAP (10 mg, 0.08 mmol, 4-dimethylaminopyridine) were added. The mixture was heated in a water bath at 30 °C for 24 h under nitrogen atmosphere. The product was then dialyzed and freeze-dried to obtain the white product CD-Arg, with a yield of 79%. The chemical formula of CD-Arg is C0. 64 H 110 N8O 41 .
[0039] As shown in Equation II:
[0040] Formula II;
[0041] As shown in the above structural formula, where:
[0042] Synthesis of RAPA-TK: Rapamycin (200 mg, 0.2 mmol) and thioacetate (200 mg, 0.57 mmol) were dissolved in 30 mL of anhydrous DMF, and EDC (50 mg, 0.25 mmol) and DMAP (10 mg, 0.08 mmol) were added. The mixture was heated in a water bath at 30 °C for 24 h under nitrogen atmosphere. The product was then dialyzed and freeze-dried to obtain the yellow product RAPA-TK, with a yield of 69%. The chemical formula of RAPA-TK is C0. 70 H 95 NO 16 S2.
[0043] As shown in Equation III:
[0044] Formula III;
[0045] As shown in the above formula, where:
[0046] Synthesis of CD-Arg-TK-RAPA: CD-Arg (164.6 mg, 0.1 mmol) and RAPA-TK (152.2 mg, 0.1 mmol) were dissolved in 50 mL of anhydrous DMF, followed by the addition of EDC (50 mg, 0.25 mmol) and DMAP (10 mg, 0.08 mmol). The mixture was incubated in a water bath at 30 °C for 24 h under nitrogen atmosphere. The product was then dialyzed and freeze-dried to obtain the yellow product CD-Arg-TK-RAPA, with a yield of 49%. The chemical formula of CD-Arg-TK-RAPA is C0. 134 H 203 N9O 56 S2.
[0047] Furthermore, the present invention also provides the application of the above-described nitric oxide-driven nanomotor synthesis in the preparation of drugs for alleviating atherosclerosis.
[0048] Example 1
[0049] A method for preparing a nitric oxide-driven nanomotor is as follows:
[0050] Synthesis of CD-Arg: Cyclodextrin (113.5 mg, 0.1 mmol) and Boc-protected arginine (200 mg, 0.4 mmol) were dissolved in 30 mL of anhydrous DMF, and EDC (115 mg, 0.6 mmol) and DMAP (10 mg, 0.08 mmol) were added. The mixture was heated in a water bath at 30 °C for 24 h under nitrogen atmosphere. The product was then dialyzed and freeze-dried to obtain the white product CD-Arg with a yield of 79%. The chemical formula of CD-Arg is C2. 64 H 110 N8O 41 . 1 H NMR (600 MHz, DMSO-D6) δ 4.80 – 5.10 (m, 2H), 3.55 –3.85 (m, 2H), 3.45 – 3.65 (m, 2H), 3.25 – 3.45 (m, 2H). 2.82 (m, 4H). 2.58(m, 4H). 1.42 (s, 18H).
[0051] Synthesis of RAPA-TK: Rapamycin (200 mg, 0.2 mmol) and thioacetate (200 mg, 0.57 mmol) were dissolved in 30 mL of anhydrous DMF, and EDC (50 mg, 0.25 mmol) and DMAP (10 mg, 0.08 mmol) were added. The mixture was heated in a water bath at 30 °C for 24 h under nitrogen atmosphere. The product was then dialyzed and freeze-dried to obtain the yellow product RAPA-TK, with a yield of 69%. The chemical formula of RAPA-TK is C0. 70 H 95 NO 16 S2. 1 H NMR (600 MHz, DMSO-D6) δ 7.45 –7.75 (s, 1H). 6.15 – 6.45 (d,2H). 5.70 – 5.90 (m, 1H). 3.35 – 3.65 (m, 3H). 2.82 (m, 4H). 2.58 (m, 4H).1.59 (s, 6H). 0.8 – 0.9 (d, 9H).
[0052] Synthesis of CD-Arg-TK-RAPA: CD-Arg (164.6 mg, 0.1 mmol) and RAPA-TK (152.2 mg, 0.1 mmol) were dissolved in 50 mL of anhydrous DMF, followed by the addition of EDC (50 mg, 0.25 mmol) and DMAP (10 mg, 0.08 mmol). The mixture was incubated in a water bath at 30 °C for 24 h under nitrogen atmosphere. The product was then dialyzed and freeze-dried to obtain the yellow product CD-Arg-TK-RAPA, with a yield of 49%. The chemical formula of CD-Arg-TK-RAPA is C0. 134 H 203 N9O 56 S2. 1 H NMR (600 MHz, DMSO-D6) δ 7.45 –7.75 (s, 1H). 6.15 – 6.45 (d, 2H). 5.70 – 5.90 (m, 1H). 4.80 – 5.10 (m, 2H).3.55 – 3.85 (m, 2H), 3.45 – 0.8 – 0.9(d, 9H).
[0053] Figure 1 The transmission electron microscope image of the drug-loaded nanomotor in an embodiment of the present invention is shown. It can be seen that its morphology consists of uniformly dispersed spherical particles. Figure 2 The particle size distribution of the drug-loaded nanomotor in an embodiment of the present invention is shown, with an average particle size of 129.1 nm. Figure 3 This demonstrates the responsiveness of the present invention in an inflammatory microenvironment, enabling successful drug dissociation. Figure 4 and Figure 5 The Brownian motion of aqueous solvent molecules and the trajectory and velocity distribution of the drug-loaded nanomotor demonstrate that our drug-loaded nanomotor can achieve nitric oxide-driven motion, and the driving speed is 6 times the Brownian motion speed. Figure 6 (LPS, LPS+CDA, and LPS+CDATR refer to lipopolysaccharide, lipopolysaccharide+CD-Arg, and lipopolysaccharide+CD-Arg-TK-RAPA, respectively. Among them, CD-Arg-TK-RAPA is the drug-loaded nanomotor.) Further verification showed that the drug-loaded nanomotor exhibited the strongest green fluorescence and the highest nitric oxide production in inflammatory macrophages.
[0054] The nanomotor provided in this embodiment possesses unique chemical bonds that are sensitive to reactive oxygen species (ROS) in the inflammatory microenvironment. These bonds are easily broken in the presence of ROS, thereby enabling targeted drug release, increasing drug concentration in the target area, reducing its distribution in non-target areas, and minimizing adverse reactions. Simultaneously, the arginine modified on the nanomotor generates nitric oxide under the action of ROS and inducible nitric oxide synthase, regulating vasodilation and providing gas-driven propulsion.
[0055] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A nitric oxide-driven nanomotor synthesis, characterized in that, Its structure is shown in the following formula: 。 2. A method for preparing a nitric oxide-driven nanomotor as described in claim 1, characterized in that, Includes the following steps: S1. Cyclodextrin and Boc-protected arginine were dissolved in anhydrous DMF, and EDC and DMAP were added; the mixture was reacted in a water bath under nitrogen; after dialysis, it was freeze-dried to separate the product, giving a white product CD-Arg; the molar ratio of cyclodextrin to Boc-protected arginine was 1:(3.5-4.5). S2. Rapamycin and thioacetate were dissolved in anhydrous DMF, and EDC and DMAP were added; the mixture was reacted in a water bath under nitrogen; after dialysis, it was freeze-dried to separate the product, yielding a yellow product RAPA-TK; the molar ratio of rapamycin to thioacetate was 1:(2.5-3.2). S3. Dissolve CD-Arg and RAPA-TK in anhydrous DMF, then add EDC and DMAP; react in a water bath under nitrogen; the product is separated by dialysis and freeze-drying to obtain the nanomotor synthesis CD-Arg-TK-RAPA; the molar ratio of CD-Arg to RAPA-TK is 1:(1-1.2).
3. The method for preparing the nitric oxide-driven nanomotor synthesis according to claim 2, characterized in that, In steps S1 to S3, the water bath reaction temperature is 25-40℃ and the time is 12-30h.
4. The method for preparing the nitric oxide-driven nanomotor synthesis according to claim 2, characterized in that, The structural formula of the thioacetate is shown below: 。 5. The method for preparing the nitric oxide-driven nanomotor synthesis according to any one of claims 2-4, characterized in that, The synthesis process of step S1 is shown in the following formula: Formula I; The synthesis process for step S2 is shown in the following formula: Formula II; The synthesis process for step S3 is shown in the following formula: Formula III.
6. The use of a nitric oxide-driven nanomotor synthesis as described in claim 1 or a nanomotor synthesis obtained by any one of claims 2-5 in the preparation of drugs to alleviate atherosclerosis.
7. The application according to claim 6, characterized in that, The preparation of the drug for relieving atherosclerosis includes: self-assembling the active pharmaceutical ingredient and the nitric oxide-driven nanomotor compound into nanoparticles in solution, and encapsulating the active pharmaceutical ingredient to obtain the drug for relieving atherosclerosis.