CN115245566A - Application of mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material in preparation of medicine for treating periodontitis through photo-thermal treatment and preparation method - Google Patents
Application of mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material in preparation of medicine for treating periodontitis through photo-thermal treatment and preparation method Download PDFInfo
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
A mesoporous silicon loaded nitrogen-doped graphene nanocomposite material is applied to preparation of a medicine for photo-thermal periodontitis treatment, mesoporous silicon nanospheres are synthesized, then the mesoporous silicon nanospheres are used for loading nitrogen-doped graphene quantum dots, chlorhexidine is fixed on the MSN @ NGQDs nanocomposite material, and an MSN @ NGQDs-CHX nanocomposite system is obtained. Then, the pathological part is irradiated by light, heat is generated to kill pathogenic bacteria through the unique photo-thermal conversion performance of the nano composite material, the nano composite material has an ultra-large specific surface area, and a good drug slow release effect can be realized, so that small dose of chlorhexidine can be slowly released, and further, the bacteriostatic action is continuously exerted after the photo-thermal treatment, and the pathogenic bacteria at the deep tissue layer are thoroughly eradicated.
Description
Technical Field
The invention relates to the technical field of periodontitis treatment, and in particular relates to application of a mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material in preparation of a medicine for treating periodontitis through photo-thermal treatment and a preparation method of the mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material.
Background
Chronic periodontitis is a chronic inflammatory disease which is clinically characterized by taking a plaque biological membrane as an initiating factor and periodontal tissue destruction as a clinical characteristic, is a main reason for tooth loss of adults, is hard to endure pain during the onset of the chronic inflammatory disease, and is a main oral disease which harms human teeth and the general health. If gingivitis is not treated timely, inflammation can diffuse from the gingiva to the deep layer to the periodontal ligament, alveolar bone and cementum, and periodontitis can develop. Because early stage has no obvious subjective symptoms and is easy to ignore, the symptoms are serious and even teeth can not be kept. The incidence rate of periodontitis in China exceeds 50 percent, and the incidence rate of people aged 60 to 74 years is up to 70 to 90 percent. The global economic burden due to periodontitis is about $ 4.16 billion annually per year, and will increase year by year as the population grows and the life expectancy of the population increases. The traditional clinical treatment of periodontitis mainly aims at removing bacterial plaque and biological membranes by using special instruments so as to remove bacterial plaque and control infection. However, periodontal pathogens are hidden in the root bifurcation or implanted deep in the periodontal pocket to form a biofilm due to the complex periodontal anatomy structure, and bacteria are easy to re-implant, which is difficult to completely remove. Although the combined treatment of antibiotics can better improve the bacterial inhibition rate, the drug resistance problem caused by repeated and excessive use of antibiotics causes long-term chronic infection and repeated inflammation of periodontal tissues, and influences the normal life of patients. Mechanical intervention is even more likely to negatively affect periodontal tissue regeneration. High concentration use of antibiotics can also cause side effects such as liver and kidney injury, oral cavity and digestive tract flora imbalance, and the like.
In the existing treatment of periodontitis, the simple photothermal therapy is limited by the complexity of periodontal anatomy, the size of laser light spot and the penetration depth of near infrared light, so that deep residual bacteria cannot be completely eradicated.
Disclosure of Invention
In order to overcome the defects and shortcomings of periodontitis treatment in the current oral clinic, the invention provides an application of a mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material in preparation of a medicine for treating periodontitis through photo-thermal treatment and a preparation method thereof.
The technical solution adopted by the invention is as follows: the mesoporous silicon-loaded nitrogen-doped graphene nanocomposite is prepared from a mesoporous silicon @ nitrogen-doped graphene material (MSN @ NGQDs) through a physical electrostatic adsorption method and a pi-pi stacking effect loaded Chlorhexidine (CHX).
The Chlorhexidine (CHX) is chlorhexidine acetate.
The mesoporous silicon @ nitrogen-doped graphene material (MSN @ NGQDs) in the mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material is spherical or ellipsoidal, wherein the diameter of the mesoporous silicon is 100-200 nm, and nitrogen-doped graphene quantum dots are accumulated in mesopores of the mesoporous silicon material.
The concentration of the mesoporous silicon-loaded nitrogen-doped graphene nanocomposite in the medicine for treating periodontitis through photothermal therapy is 200 mug/mL.
The medicine for treating periodontitis by photo-thermal is excited under the condition of 808 nm near infrared, and the power is 1.5W/cm 2 。
A preparation method of a mesoporous silicon loaded nitrogen-doped graphene nanocomposite material comprises the following steps:
(1) Preparing Mesoporous Silicon Nanospheres (MSN) by a template method: 0.3-1 g hexadecyl trimethyl ammonium bromide (CTAB) aqueous solution and 2M NaOH react for 30 min at 60-80 ℃, then TEOS of 2.5-10 mL is added at a titration speed of 30-90 mul/min to stir 2 h, after being cleaned and centrifuged by deionized water and ethanol, the obtained product and ammonium nitrate are mixed in absolute ethanol according to a mass ratio of 2:5-5:2, and are continuously stirred at 60 ℃ for 6-24 h, so that the mesoporous silicon nanosphere material is obtained;
(2) Synthesizing carboxylated nitrogen doped graphene quantum dots (NGQDs) by a hydrothermal method: quickly and uniformly mixing 20-100 mg citric acid solution and 800-1200 mu L ammonia water, transferring into a lining of a high-pressure kettle, reacting at 200 ℃ for 1-6 h, naturally cooling to room temperature, and dialyzing a product by using a cellulose dialysis bag for 72 h for later use;
(3) The amide method is used for synthesizing the MSN @ NGQDs nano composite material: mixing and stirring 30-100 mg mesoporous silicon nano material and 0.5-2.0 mL APTES for 6-24 h to obtain aminated mesoporous silicon nanospheres, then activating nitrogen-doped graphene quantum dots rich in carboxyl by adopting EDC and NHS for 30 min, and finally mixing and reacting the activated carboxylated nitrogen-doped quantum dots with aminated mesoporous silicon at 4 ℃ for 10-20 h to obtain the MSN @ NGQDs nano composite material;
(4) Preparing the MSN @ NGQDs-CHX nano composite material: stirring 10 mg/mL MSN @ NGQDs and 1.0-10 mg/mL chlorhexidine acetate (CHX) at room temperature for 24 h, and centrifuging and cleaning to obtain the MSN @ NGQDs-CHX nanocomposite.
The molecular weight cut-off of the cellulose dialysis bag in the step (2) is 100-500 Da.
The medicine comprises a mesoporous silicon-loaded nitrogen-doped graphene nanocomposite (MSN @ NGQDs-CHX), and is prepared from the mesoporous silicon-loaded nitrogen-doped graphene nanocomposite (MSN @ NGQDs) loaded with Chlorhexidine (CHX) through a physical electrostatic adsorption method and pi-pi stacking effect.
The invention has the beneficial effects that: the invention provides an application of a mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material in preparation of a medicine for treating periodontitis by photo-thermal treatment and a preparation method thereof. Then, the pathological part is irradiated by light, heat is generated to kill pathogenic bacteria through the unique photo-thermal conversion performance of the nano composite material, the nano composite material has an ultra-large specific surface area, and a good drug slow release effect can be realized, so that small dose of chlorhexidine can be slowly released, and further, the bacteriostatic action is continuously exerted after the photo-thermal treatment, and the pathogenic bacteria at the deep tissue layer are thoroughly eradicated.
Drawings
FIG. 1 (a) is a technical scheme for preparing the MSN @ NGQDs-CHX nano-composite system of the present invention, and (b) is a schematic diagram of the nano-composite system constructed by the present invention for treating periodontitis.
Fig. 2 is a transmission electron microscope image of (a) mesoporous silicon, (b) nitrogen-doped graphene, and (c) mesoporous silicon-loaded nitrogen-doped graphene nanocomposite.
FIG. 3 is the photo-thermal temperature-rise curves of the prepared MSN @ NGQDs nanocomposite respectively at (a) different concentrations and (b) different near-infrared light radiation powers.
FIG. 4 shows the inhibitory effect of the invented MSN @ NGQDs-CHX nano composite system on methicillin-resistant Staphylococcus aureus. "NIR-" is a group to which no near infrared light irradiation is applied, and "NIR +" is a group to which 1.5W/cm is applied 2 808 nm near infrared light irradiation for 10 min treatment group.
FIG. 5 is a graph showing the results of different days of treatment of the inventive MSN @ NGQDs-CHX nano-complex in the skin abscess region of a mouse imitating periodontal abscess.
Detailed Description
The present invention is further described below in conjunction with the following embodiments and the accompanying drawings, it being understood that the drawings and the following embodiments are illustrative of the invention only and are not limiting thereof.
Example 1 preparation of Mesoporous Silica Nanospheres (MSN) by template method
0.3-1 g hexadecyl trimethyl ammonium Bromide (CTAB) water solution and 2M NaOH with different volumes are respectively reacted for 30 min at different temperatures (60-80 ℃), then TEOS (2.5-10 mL) is added into the mixture at different titration speeds (30-90 muL/min) to stir 2 h, the mixture is mixed with ammonium nitrate according to the mass ratio (2:5, 1:1 and 5:2) respectively after being washed and centrifuged by deionized water and ethanol, and the mixture is continuously stirred at 60 ℃ for different times (6-24 h) to obtain the appropriate mesoporous silicon nanosphere material.
Example 2 Synthesis of carboxylated Nitrogen-doped graphene Quantum dots (NGQDs) by hydrothermal method
20-100 mg citric acid solution and ammonia water with different volumes (800, 1000, 1200 mu L) are quickly and uniformly mixed, transferred into an autoclave liner of 50 mL polytetrafluoroethylene, reacted at 200 ℃ for different times (1, 3, 6 h), naturally cooled to room temperature, and the product is dialyzed by a cellulose dialysis bag (molecular weight cutoff is 100-500 Da) for 72 h for later use.
Example 3 Synthesis of MSN @ NGQDs nanocomposite by amide Process
30-100 mg mesoporous silicon nanometer material and APTES with different volumes (0.5-2.0 mL) are mixed and stirred for different times (6-24 h) to obtain the aminated mesoporous silicon nanosphere. And then, activating the carboxyl-rich nitrogen-doped graphene quantum dots for 30 min by adopting EDC and NHS, and finally, mixing and reacting the activated carboxyl nitrogen-doped quantum dots with the aminated mesoporous silicon at 4 ℃ for 10-20 h to obtain the MSN @ NGQDs nano composite material.
Example 4 preparation of MSN @ NGQDs-CHX nanocomposite systems by physical electrostatic adsorption of mesoporous structures to chlorhexidine and pi-pi stacking between large pi bonds on graphene quantum dots and chlorhexidine aromatic rings
10 mg/mL MSN @ NGQDs was stirred with chlorhexidine acetate (CHX) at various concentrations (1.0-10 mg/mL) at room temperature for 24 h. And centrifugally cleaning to obtain the MSN @ NGQDs-CHX nano composite system.
Results of the experiment
As can be seen from FIG. 1, mesoporous silicon nanospheres are synthesized first and then used for loading nitrogen-doped graphene quantum dots. Then the chlorhexidine is fixed on the MSN @ NGQDs nano composite material to obtain the MSN @ NGQDs-CHX nano composite system. The prepared nano composite system has better water phase dispersibility, and can be directly injected into periodontitis parts to slowly permeate into the deep of tooth sockets. Then, the pathological part is irradiated by light, and the heat is generated to kill pathogenic bacteria through the unique photo-thermal conversion performance of the nano composite material. The nano composite material has an ultra-large specific surface area, can realize a good drug slow release effect, and enables small dose of chlorhexidine to be slowly released, so that after the introduction of photothermal therapy, the nano composite material further continuously plays a role in bacteriostasis, and thoroughly eradicates pathogenic bacteria at the deep layer of a tissue.
As can be seen from FIG. 2, the mesoporous silicon prepared by the invention is in a porous nanosphere structure, and becomes a spherical or ellipsoidal MSN @ NGQDs nanocomposite after the graphene quantum dots are deposited. The diameter of the mesoporous silicon is about 100-200 nm, and the nitrogen-doped graphene quantum dots can be effectively accumulated in mesopores of the mesoporous silicon material.
As can be seen from FIG. 3, the photothermal temperature rise curves of the MSN @ NGQDs nanocomposites with different concentrations under different powers of near infrared (808 nm) excitation are obviously different. The power adopted by the invention is 1.5W/cm 2 The concentration of the nano composite material is 200 mug/mL, the irradiation time is 10 min, and the final temperature can exceed 50 ℃.
As can be seen from FIG. 4, the synthesized MSN @ NGQDs-CHX nano composite system has a remarkable antibacterial effect. When the MSN @ NGQDs are simply used, the nano composite material does not show obvious bacteriostatic effect. After the MSN @ NGQDs nano composite material group is irradiated by near infrared light, the antibacterial effect is effectively enhanced, and the survival rate of bacteria is reduced to about 60 percent. And after the MSN @ NGQDs-CHX nano composite system is irradiated by near infrared light, the antibacterial effect is obviously enhanced, and 100 percent of bacteria are killed after 6 h.
As can be seen from figure 5, the MSN @ NGQDs-CHX nano composite system synthesized by the invention is applied to a mouse skin abscess model imitating periodontal abscess, and shows excellent treatment effect after being irradiated by near infrared light. The control group and the non-nano material illumination group have no wound healing at 15 days, ulcer tissues are arranged below the scab blocks, and the inflammatory reaction is severe. The recovery condition of MSN @ NGQDs nanocomposite illumination group compares obvious improvement with the contrast group, explains the good optothermal performance of nanocomposite, has realized the suppression to pathogenic bacterium certain degree, but in 15 days, still can see the small wound, explains still that there is the pathogenic bacterium to remain. After the MSN @ NGQDs-CHX nano composite system is applied to photo-thermal treatment, the inflammation condition is well controlled on the 7 th day, and no wound or inflammation residue is observed in 15 days after the treatment, so that the nano composite system synthesized by the invention can effectively inhibit periodontitis pathogenic bacteria and effectively treat periodontitis lesions.
In conclusion, the MSN @ NGQDs-CHX nano complex system disclosed by the invention has an excellent photothermal bacteriostasis effect under the excitation of near infrared light, can realize a 100% inhibition rate on drug-resistant staphylococcus aureus under the enhancement of a small amount of drugs, and has good biocompatibility and small toxic and side effects. The material has the advantages of simple preparation method, good biocompatibility, high-efficiency photothermal/photodynamic/drug synergistic antibacterial capability under near-infrared radiation, capability of effectively and efficiently killing common gram-positive pathogenic bacteria of periodontitis, namely drug-resistant staphylococcus aureus, small local dosage, small side effect, no influence on oral health periodontal tissues, high safety, capability of promoting healing of periodontal infection regions in a short time, high safety, small side effect and the like.
The skilled person should understand that: although the present invention has been described in terms of the above-described embodiments, the inventive concept is not limited thereto, and any modification that utilizes the inventive concept is intended to be included within the scope of the appended claims.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (8)
1. The application of the mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material in preparation of drugs for photo-thermal treatment of periodontitis is characterized in that the mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material is prepared from a mesoporous silicon @ nitrogen-doped graphene material (MSN @ NGQDs) loaded with Chlorhexidine (CHX) through a physical electrostatic adsorption method and a pi-pi stacking effect.
2. Use according to claim 1, characterized in that said Chlorhexidine (CHX) is chlorhexidine acetate.
3. The application of claim 1, wherein the mesoporous silicon @ nitrogen doped graphene material (MSN @ NGQDs) in the mesoporous silicon loaded nitrogen doped graphene nanocomposite material is spherical or ellipsoidal, wherein the diameter of the mesoporous silicon is 100-200 nm, and the nitrogen doped graphene quantum dots are accumulated in mesopores of the mesoporous silicon material.
4. The use according to claim 1, wherein the concentration of the mesoporous silicon-loaded nitrogen-doped graphene nanocomposite in the medicine for photothermal treatment of periodontitis is 200 μ g/mL.
5. The use of claim 1, wherein the photothermal periodontitis inhibiting drug is excited under the near infrared condition of 808 nm with a power of 1.5W/cm 2 。
6. The preparation method of the mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material of claim 1, which is characterized by comprising the following steps:
(1) Preparing Mesoporous Silicon Nanospheres (MSN) by a template method: 0.3-1 g hexadecyl trimethyl ammonium bromide (CTAB) aqueous solution and 2M NaOH react for 30 min at 60-80 ℃, then TEOS of 2.5-10 mL is added at a titration speed of 30-90 mul/min to stir 2 h, after being cleaned and centrifuged by deionized water and ethanol, the obtained product and ammonium nitrate are mixed in absolute ethanol according to a mass ratio of 2:5-5:2, and are continuously stirred at 60 ℃ for 6-24 h, so that the mesoporous silicon nanosphere material is obtained;
(2) Synthesizing carboxylated nitrogen doped graphene quantum dots (NGQDs) by a hydrothermal method: quickly and uniformly mixing 20-100 mg citric acid solution and 800-1200 mu L ammonia water, transferring into a lining of a high-pressure kettle, reacting at 200 ℃ for 1-6 h, naturally cooling to room temperature, and dialyzing a product by using a cellulose dialysis bag for 72 h for later use;
(3) The amide method is used for synthesizing the MSN @ NGQDs nano composite material: mixing and stirring 30-100 mg mesoporous silicon nano material and 0.5-2.0 mL APTES for 6-24 h to obtain aminated mesoporous silicon nanospheres, then activating nitrogen-doped graphene quantum dots rich in carboxyl by adopting EDC and NHS for 30 min, and finally mixing and reacting the activated carboxylated nitrogen-doped quantum dots with aminated mesoporous silicon at 4 ℃ for 10-20 h to obtain the MSN @ NGQDs nano composite material;
(4) Preparing the MSN @ NGQDs-CHX nano composite material: stirring 10 mg/mL MSN @ NGQDs and 1.0-10 mg/mL chlorhexidine acetate (CHX) at room temperature for 24 h, and centrifuging and cleaning to obtain the MSN @ NGQDs-CHX nanocomposite.
7. The method of claim 6, wherein the cellulose dialysis bag of step (2) has a molecular weight cut-off of 100 to 500 Da.
8. The medicine for treating periodontitis by photo-thermal is characterized by comprising a mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material (MSN @ NGQDs-CHX), wherein the mesoporous silicon-loaded nitrogen-doped graphene nanocomposite material is prepared by loading Chlorhexidine (CHX) on the mesoporous silicon @ nitrogen-doped graphene material (MSN @ NGQDs) through a physical electrostatic adsorption method and a pi-pi stacking effect.
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| CN103655207A (en) * | 2013-12-04 | 2014-03-26 | 上海纳米技术及应用国家工程研究中心有限公司 | Drug-loaded mesoporous-silica-reinforced dental binder and preparation method thereof |
| US20180000559A1 (en) * | 2014-12-22 | 2018-01-04 | Richard Titlebaum | System and method for introducing photosensitive dyes via an insert into a root canal in a tooth, method for producing said dye impregnated insert and method of using said dye-impregnated insert |
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| US20180000559A1 (en) * | 2014-12-22 | 2018-01-04 | Richard Titlebaum | System and method for introducing photosensitive dyes via an insert into a root canal in a tooth, method for producing said dye impregnated insert and method of using said dye-impregnated insert |
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