Nucleoside drug gelation method
By grafting lipoic acid onto nucleoside drugs and performing ring-opening polymerization, nucleoside drug gels or microparticles were prepared, which solved the problems of insufficient stability and functionality of nucleoside drugs in antiviral therapy and achieved a significant improvement in antioxidant performance.
Patent Information
- Application Number
- CN202511090442.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-05
- Publication Date
- 2025-12-09
AI Technical Summary
Existing nucleoside analogues face problems such as drug resistance, unsatisfactory pharmacokinetic properties, and insufficient functionality in antiviral therapy. Furthermore, existing delivery systems suffer from issues such as uncontrollable drug dispersion and release rate, and the need to introduce photosensitizers for photothermal therapy.
Nucleoside drugs can be prepared into gels or microparticles by grafting lipoic acid onto them and then performing ring-opening polymerization, thereby improving their antioxidant properties and stability.
It significantly improved the antioxidant properties and functionality of nucleoside analogues, enhanced their stability and functionality, and achieved a clearance rate far higher than that of unmodified drugs.
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Figure CN121086237A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a method for gelling nucleoside drugs. Background Technology
[0002] Nucleoside analogues work by mimicking the structure of natural nucleosides, primarily by interfering with viral nucleic acid synthesis. Their antiviral activity mainly relies on the following core processes: selective phosphorylation, competitive inhibition with natural substrates, and chain termination reactions. Antiherpesvirus drugs are one of the most successful applications of nucleoside analogues, with representative drugs including acyclovir and ganciclovir. These drugs exhibit high selectivity, relying on activation by virus-encoded kinases to significantly reduce toxicity to host cells. They inhibit viral DNA replication and, in conjunction with the host immune system, clear the virus, leading to widespread clinical application and in-depth research. However, drugs like acyclovir and ganciclovir still face challenges such as drug resistance, unsatisfactory pharmacokinetic properties, and insufficient functionality, necessitating improvements in their stability and functionality.
[0003] Currently, commonly used methods to enhance the efficacy of nucleoside analogues mainly include drug delivery systems using carriers such as gels, DNA tetrahedra, and nanomaterials; combining with photothermal dynamics therapy; or improving drug penetration in the human body by promoting drug absorption through osmosis. In developing this invention, the inventors discovered at least the following problems in the prior art: This method of drug loading or combining with other treatment methods often introduces new problems, such as the drug itself lacking multifunctional properties, like antioxidant properties; using carriers to load drugs usually faces problems such as uncontrollable drug dispersion and release rate; combining with photothermal dynamics usually requires the introduction of photosensitizers and light sources; and while osmosis-enhancing drugs can improve the permeability of nucleoside analogues to some extent, they cannot avoid the potential harm to the human body. Summary of the Invention
[0004] The technical problem to be solved by the present invention is to provide a method for gelling nucleoside drugs, which addresses the shortcomings of the prior art.
[0005] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is: to provide a method for gelling nucleoside drugs, comprising:
[0006] Provides nucleoside analogues grafted with thioctic acid;
[0007] The nucleoside drug grafted with thioctic acid is subjected to ring-opening polymerization to complete the gelation of the nucleoside drug.
[0008] Compared with the prior art, the present invention has the following advantages:
[0009] 1. This invention provides a method for improving the efficacy of nucleoside analogues. By grafting lipoic acid onto nucleoside analogues and inducing ring-opening polymerization, drug gels or drug microparticles are obtained. The drug gels or drug microparticles have significantly improved DPPH and ABTS free radical scavenging rates. The method of this invention can improve the antioxidant properties of nucleoside analogues and has the characteristics of enhancing drug stability and functionality.
[0010] 2. In the method of the present invention, thioctic acid, nucleoside drugs and esterification catalyst are mixed and grafted in a reaction solvent to obtain thioctic acid-grafted nucleoside drugs. The thioctic acid-grafted nucleoside drugs are dispersed in an organic solvent to obtain a dispersion. The dispersion is dropped into hot water to induce ring-opening polymerization and obtain a nucleoside drug gelation product, thereby achieving structural and performance improvement based on the drug itself.
[0011] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description
[0012] Figure 1 The equation and 1H NMR spectrum of acyclovir grafted with lipoic acid in Example 1 are shown.
[0013] Figure 2 The mass spectrum of acyclovir grafted with lipoic acid in Example 1 is shown.
[0014] Figure 3 This is a scanning electron microscope image of acyclovir nanogel from Example 1;
[0015] Figure 4 The mass spectrum of acyclovir nanogel in Example 1 is shown below.
[0016] Figure 5 This is a scanning electron microscope image of acyclovir nanoparticles from Example 2;
[0017] Figure 6 The equation and 1H NMR spectrum of ganciclovir grafted with lipoic acid in Example 3 are shown.
[0018] Figure 7 The mass spectrum of ganciclovir grafted with thioctic acid in Example 3 is shown.
[0019] Figure 8 This is a scanning electron microscope image of ganciclovir nanogel from Example 3;
[0020] Figure 9 This is a scanning electron microscope image of ganciclovir nanofibers from Example 4;
[0021] Figure 10 This is a schematic diagram showing the antioxidant performance test results of acyclovir grafted with lipoic acid in step one of Example 1.
[0022] Figure 11 This is a schematic diagram of the rheological test results of acyclovir nanogel in Example 1;
[0023] Figure 12 This is a schematic diagram of the antioxidant performance test results of acyclovir nanogel in Example 1. Detailed Implementation
[0024] The technical solution will now be clearly and completely described with reference to the embodiments of this application. Obviously, the described embodiments are only a part of the embodiments of this application, not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this application without creative effort are within the scope of protection of this application.
[0025] In the following description, the term "and / or" is used to describe the relationship between related objects, indicating that there can be three relationships. For example, A and / or B can mean: A exists alone, B exists alone, and A and B exist simultaneously. A and B can be singular or plural.
[0026] In the following description, the terms “including,” “containing,” “having,” and “containing” are open-ended terms, meaning that they include but are not limited to.
[0027] Those skilled in the art should understand that, in the following description of the embodiments of this application, the sequence of numbers does not imply the order of execution. Some or all steps may be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of this application.
[0028] Those skilled in the art will understand that the numerical ranges in the embodiments of this application should be understood to specifically disclose each intermediate value between the upper and lower limits of the range. Each smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this application. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.
[0029] Unless otherwise stated, the technical / scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. While this application describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this application. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.
[0030] The technical principle adopted in this invention is as follows: using lipoic acid as a grafting group, it combines with the hydroxyl group in nucleoside drugs to modify the nucleoside drugs, thereby obtaining lipoic acid-grafted nucleoside drugs. The lipoic acid-grafted nucleoside drugs are then used to prepare drug nanogel materials through ring-opening polymerization.
[0031] On the one hand, a method for gelling nucleoside analogues is provided, comprising:
[0032] Provides nucleoside analogues grafted with thioctic acid;
[0033] The nucleoside drug grafted with thioctic acid is subjected to ring-opening polymerization to complete the gelation of the nucleoside drug.
[0034] Nucleoside drugs were polymerizable by using lipoic acid, and then induced to undergo ring-opening polymerization to obtain nucleoside drug nanogel materials with high antioxidant properties.
[0035] In some embodiments, the nucleoside drug gelation product includes nucleoside drug nanogels and / or nucleoside drug nanoparticles, wherein the nucleoside drug nanoparticles include nucleoside drug nanoparticles or nucleoside drug nanofibers, wherein the nucleoside drug nanoparticles have a particle size of 200–350 nm; and the nucleoside drug nanofibers have a width of 200–400 nm and an aspect ratio of 1.5–3.
[0036] Nanogels typically refer to gel materials with crosslinked particle sizes ranging from 1 to 1000 nm. This invention creatively proposes a method for gelling nucleoside drugs, based on the grafting of nucleoside drugs and subsequent ring-opening polymerization to form nanogel materials. The gelation product structure includes nanogels, nanoparticles, or nanofibers. The morphology of the nanoparticles or nanofibers shows no adhesion between particles or fibers, while the nanogels show highly crosslinked nanoparticles or nanofibers.
[0037] In some embodiments, the nucleoside analogue includes acyclovir or ganciclovir.
[0038] In some embodiments, the lipoic acid-grafted acyclovir has the following structural formula:
[0039]
[0040] In some embodiments, the thioctic acid-grafted ganciclovir has the following structural formula:
[0041]
[0042] In some embodiments, providing a lipoic acid-grafted nucleoside drug involves mixing lipoic acid, a nucleoside drug, and an esterification catalyst, and then performing a grafting reaction in a reaction solvent to obtain the lipoic acid-grafted nucleoside drug. In some specific embodiments, the molar ratio of lipoic acid, the nucleoside drug, and the esterification catalyst is 1:(1-2):(3-6), and the grafting reaction is a stirred grafting reaction for 12-24 hours; preferably, the grafting time is 12 hours. In some specific embodiments, the esterification catalyst is 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 4-dimethylaminopyridine; in some preferred embodiments, the molar ratio of 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 4-dimethylaminopyridine is 1:1. In some specific embodiments, the reaction solvent is dimethyl sulfoxide or dimethylformamide.
[0043] In some embodiments, the ring-opening polymerization includes: dispersing the lipoic acid-grafted nucleoside drug in an organic solvent to obtain a dispersion; adding the dispersion dropwise to hot water at 80–100°C; and stirring and polymerizing for 2–24 hours; preferably, the hot water temperature is 90°C, and the stirring and polymerization time is 2–12 hours; the concentration of the lipoic acid-grafted nucleoside drug in the dispersion is 1–5 mg / mL; the organic solvent is dimethyl sulfoxide or dimethylformamide; preferably, when obtaining nucleoside drug nanogels, the stirring and polymerization time is 12 hours, and the concentration of the lipoic acid-grafted nucleoside drug in the dispersion is 5 mg / mL; under the above polymerization time and lipoic acid-grafted nucleoside drug concentration conditions, the free radical scavenging rate of the obtained nucleoside drug nanogels exceeds 50%, which is much higher than that of the drug itself; when obtaining nucleoside drug nanoparticles or nucleoside drug nanofibers, the stirring and polymerization time is 2 hours, and the concentration of the lipoic acid-grafted nucleoside drug in the dispersion is 1 mg / mL;
[0044] Lipoic acid has a carboxyl group at one end and a dithiopental ring at the other. Through esterification, the carboxyl group of lipoic acid is coupled to the hydroxyl group of nucleoside drug molecules to obtain nucleoside drugs with polymerization and antioxidant capabilities.
[0045] In this invention, the structural formula of acyclovir is shown below:
[0046]
[0047] The structural formula for ganciclovir is shown below:
[0048]
[0049] Prior to this application, a series of experiments were conducted. Some of the experimental results are listed below to provide a more detailed description of the invention. The following is a detailed description in conjunction with the embodiments.
[0050] Example 1
[0051] This embodiment provides a method for preparing acyclovir nanogel, including:
[0052] Step 1: Mix and dissolve 1 mmol lipoic acid, 3 mmol esterification catalyst and 1 mmol acyclovir in 20 mL dimethyl sulfoxide, stir at room temperature for 12 h to obtain acyclovir grafted with lipoic acid; wherein, the esterification catalyst is 1.5 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 1.5 mmol 4-dimethylaminopyridine;
[0053] Step 2: Disperse the above-mentioned acyclovir grafted with thioctic acid in dimethyl sulfoxide to obtain a dispersion with a concentration of 5 mg / mL of acyclovir grafted with thioctic acid in the dispersion. Drop the dispersion into hot water at 90°C and stir at 90°C for 12 h to allow ring-opening polymerization, thereby obtaining acyclovir nanogel.
[0054] Example 2
[0055] This embodiment provides a method for preparing acyclovir nanoparticles, which is the same as in Example 1, except that step two involves dispersing the above-mentioned acyclovir grafted with thioctic acid in dimethyl sulfoxide to obtain a dispersion with a concentration of 1 mg / mL of acyclovir grafted with thioctic acid in the dispersion. The dispersion is then dropped into hot water at 90°C and stirred at 90°C for 2 hours to induce ring-opening polymerization, thereby obtaining acyclovir nanoparticles.
[0056] Example 3
[0057] This embodiment provides a method for preparing ganciclovir nanogel, including:
[0058] Step 1: Mix and dissolve 1 mmol lipoic acid, 6 mmol esterification catalyst and 2 mmol ganciclovir in 20 mL dimethyl sulfoxide, stir at room temperature for 12 h to obtain ganciclovir grafted with lipoic acid; wherein, the esterification catalyst is 3 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 3 mmol 4-dimethylaminopyridine.
[0059] Step 2: Disperse the grafted thioctic acid ganciclovir in dimethyl sulfoxide to obtain a dispersion with a concentration of 5 mg / mL. Drop the dispersion into hot water at 90°C and stir for 12 h at 90°C to induce ring-opening polymerization, thereby obtaining ganciclovir nanogel.
[0060] Example 4
[0061] This embodiment provides a method for preparing ganciclovir nanofibers, which is the same as in Example 1, except that step two involves dispersing the above-mentioned ganciclovir grafted with thioctic acid in dimethyl sulfoxide to obtain a dispersion. The concentration of ganciclovir grafted with thioctic acid in the dispersion is 1 mg / mL. The dispersion is then dropped into hot water at 90°C and stirred at 90°C for 2 hours to induce ring-opening polymerization, thereby obtaining ganciclovir nanofibers.
[0062] Performance Evaluation
[0063] The product from step one of Example 1 was subjected to NMR detection. The proton spectrum and mass spectrum are shown in [reference 1]. Figures 1-2 As can be seen from the figure, the grafting of lipoic acid was successful, and the molecular weight of the target product was 413.
[0064] Scanning electron microscope image of acyclovir nanogel in Example 1 is shown below. Figure 3 As shown, it exhibits a cross-linked network structure, and the presence of nanoparticles in the framework can be observed, forming a gel network formed by the cross-linking of nanoparticles. The mass spectrometry analysis results of the acyclovir nanogel are as follows: Figure 4 As shown, the molecular weight of the gel in this embodiment is 826, which matches the molecular weight of the two thioctic acid-grafted acyclovir molecules, indicating that this embodiment achieves ring-opening polymerization from a monomer to a dimer.
[0065] Scanning electron microscopy was performed on the acyclovir nanoparticles of Example 2, such as... Figure 5 As shown, the nanoparticles obtained in this step have a particle size between 200 and 350 nm and are mostly spherical.
[0066] The product from step one of Example 3 was subjected to NMR detection. The proton spectrum and mass spectrum are shown in [reference 1]. Figures 6-7 As can be seen from the figure, the grafting of lipoic acid was successful, and the molecular weight of the target product was 631.
[0067] Scanning electron microscope image of ganciclovir nanogel in Example 3 is shown below. Figure 8 As shown, it exhibits a cross-linked network structure, and the presence of nanofibers in the framework can be observed, which is a gel network formed by the cross-linking of nanofibers.
[0068] Scanning electron microscopy was performed on the ganciclovir nanofiber product of Example 4, as shown in the results. Figure 9 As can be seen, the nanofibers obtained in this step are long and thin, with a fiber width of 200-400 nm and an aspect ratio of 1.5-3.
[0069] Example 1: The antioxidant performance test results of acyclovir grafted with lipoic acid in step one are as follows: Figure 10As shown, acyclovir was used as a comparison. The DPPH clearance test method included mixing 300 μL of 0.1 mM DPPH ethanol solution, 200 μL of 1 mg / mL drug solution and 2700 μL of anhydrous ethanol, and measuring the absorbance (517 nm) at different times (every 5 min, for a total of 30 min) using an ELISA reader. The antioxidant capacity was calculated according to the following formula: Antioxidant capacity = [(Ab-As) / Ab] × 100%, where Ab is the absorbance of the DPPH ethanol solution and As is the absorbance at each time point after drug treatment. The ABTS test method includes: placing 0.946 mg of potassium persulfate (K2S2O8) in 1 mL of 7 mM ABTS aqueous solution and stirring thoroughly to obtain an ABTS ion solution; mixing 100 μL of the ABTS ion solution, 200 μL of a 1 mg / mL drug solution, and 2900 μL of deionized water; and then measuring the absorbance (714 nm) at different times (every 5 min, for a total of 30 min) using an ELISA reader. The calculation formula is consistent with the DPPH calculation formula. Figure 10 The results of a 30-minute antioxidant performance test, combined with Figure 10 As can be seen from a, the DPPH radical scavenging rate of acyclovir grafted with lipoic acid in this invention reaches 60%, which is much higher than the 15% of acyclovir. Figure 10 As can be seen from b, the scavenging rate of ABTS free radicals in acyclovir grafted with lipoic acid of the present invention is 54%, which is much higher than that of acyclovir at 13%. This may be because the disulfide bonds in acyclovir grafted with lipoic acid can react with reactive oxygen species to achieve the purpose of scavenging DPPH free radicals and ABTS free radicals.
[0070] Example 1: Rheological test results of acyclovir nanogel are as follows Figure 11 As shown, the storage modulus is higher than the energy loss, and the method of the present invention successfully prepared acyclovir nanogel.
[0071] The antioxidant performance test results of acyclovir nanogel in Example 1 and ganciclovir nanogel in Example 3 are as follows: Figure 12 As shown, the test method is the same as the above test method for the antioxidant properties of acyclovir grafted with thioctic acid. The results show that the DPPH free radical scavenging rate of acyclovir nanogel reached 58%, and the ABTS free radical scavenging rate was 49%, which is basically consistent with the antioxidant properties of the corresponding grafted thioctic acid drug and is much higher than that of the corresponding drug itself.
Claims
1. A method for gelling nucleoside analogues, characterized in that, include: Provides nucleoside analogues grafted with thioctic acid; The nucleoside drug grafted with thioctic acid is subjected to ring-opening polymerization to complete the gelation of the nucleoside drug.
2. The method for gelling nucleoside analogues according to claim 1, characterized in that, The nucleoside drug gelation product includes nucleoside drug nanogels and / or nucleoside drug nanoparticles, wherein the nucleoside drug nanoparticles include nucleoside drug nanoparticles or nucleoside drug nanofibers.
3. The method for gelling nucleoside drugs according to claim 2, characterized in that, The nucleoside drug nanoparticles have a particle size of 200–350 nm.
4. The method for gelling nucleoside drugs according to claim 2, characterized in that, The nucleoside drug nanofibers have a width of 200–400 nm and an aspect ratio of 1.5–3.
5. The method for gelling nucleoside analogues according to claim 1, characterized in that, The nucleoside analogues include acyclovir or ganciclovir.
6. The method for gelling nucleoside drugs according to claim 5, characterized in that, The structural formula (1) of the thioctic acid-grafted acyclovir or the structural formula (2) of the thioctic acid-grafted ganciclovir are as follows:
7. The method for gelling nucleoside analogues according to claim 1, characterized in that, The method of providing thioctic acid-grafted nucleoside drugs involves mixing thioctic acid, a nucleoside drug, and an esterification catalyst, and then performing a grafting reaction in a reaction solvent to obtain thioctic acid-grafted nucleoside drugs.
8. The method for gelling nucleoside analogues according to claim 7, characterized in that, The molar ratio of lipoic acid, nucleoside analogue and esterification catalyst is 1:(1-2):(3-6), and the grafting reaction is a stirred grafting reaction for 12-24 hours.
9. The method for gelling nucleoside drugs according to claim 1, characterized in that, The ring-opening polymerization includes: dispersing the thioctic acid-grafted nucleoside drug in an organic solvent to obtain a dispersion, dropping the dispersion into hot water at 80-100°C, and stirring and polymerizing for 2-24 hours.
10. The method for gelling nucleoside drugs according to claim 9, characterized in that, The concentration of the lipoic acid-grafted nucleoside drug in the dispersion is 1–5 mg / mL.