CN115554397A - Application of nano piezoelectric material in preparation of in-situ vaccine for resisting bacterial infection - Google Patents
Application of nano piezoelectric material in preparation of in-situ vaccine for resisting bacterial infection Download PDFInfo
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
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Abstract
The invention provides application of a nano piezoelectric material in preparation of an anti-bacterial infection in-situ vaccine. The nano piezoelectric material comprises but is not limited to barium titanate, barium titanate with metal nano particles loaded on the surface, lithium niobate, hydroxyapatite, polylactic acid, collagen or two-dimensional MoS 2 A nano-material. The specific application method is as follows: dispersing the nano piezoelectric material in a dispersing reagent, preparing into a solution with the concentration of 5mg/mL, injecting, and then performing ultrasonic power of 0.1-2.5W/cm 2 And carrying out ultrasonic treatment for 2-5min under the ultrasonic frequency of 0.1 Hz. The nano piezoelectric particles can show excellent piezoelectric catalysis effect under the ultrasonic condition to generate a large amount of Reactive Oxygen Species (ROS), the ROS can destroy bacterial structures to release a large amount of PAMP antigens, related immune cells of an organism are activated to generate immune effect, infection can be cleared in situ, control of ectopic infection can be realized, and reinfection of bacteria can be effectively prevented.
Description
Technical Field
The invention relates to application of a nano piezoelectric material in preparation of an anti-bacterial infection in-situ vaccine, belonging to the technical field of immune medicine.
Background
Bacterial infections are a major cause of high global morbidity and mortality, and bacteria can cause infections in almost all host tissues. It is well known that bacterial infectious diseases such as pneumonia, skin and soft tissue infections, invasive blood infections and surgical wound infections are more and more common, and seriously threaten the health and civilization of human beings. There is increasing evidence that bacterial infections may also indirectly contribute to the development and progression of other diseases, such as cancer.
Bacterial infectious diseases are currently treated clinically mainly by local or systemic use of antibiotics, but extensive use and even abuse of antibiotics causes the bacteria to develop resistance, and some pathogenic bacteria have developed into highly resistant strains, such as staphylococcus aureus, streptococcus pneumoniae, escherichia coli, and mycobacterium tuberculosis. Infection by drug-resistant bacteria is more and more common, which leads to higher medical cost, increased medical difficulty and increased death population. And the permeability of antibiotics in bacterial biofilms is so poor that the antibiotics cannot exert the drug effect sufficiently. In addition, the development period of antibiotics is long and even not faster than the development speed of bacterial drug resistance. The number of approved new antibiotic classes is decreasing and there is increasing concern for humans over traditional antibiotic therapy for the control of diseases infected by drug-resistant bacteria. Therefore, human health faces a great threat, and there is a need to develop an effective novel drug-resistant vaccine to solve the current challenges.
The vaccine can prevent the occurrence of infectious diseases, cut off the transmission path of the diseases and reduce the generation of drug resistance of bacteria. Resistant vaccines are also being developed, and include mainly attenuated live vaccines, inactivated vaccines, protein vaccines, polysaccharide conjugate vaccines, synthetic conjugate vaccines, biological conjugate vaccines, outer membrane vesicle vaccines, and the like. Although these vaccines have more immune targets than antibiotics and bacteria need to generate more mutations to develop resistance to the vaccine, rapid variation of bacteria still causes great difficulty in vaccine development. Therefore, the development of effective anti-infectious vaccines remains a significant challenge.
The inactivated vaccine is generated in situ at the bacterial infection part, the pathogenic bacteria become vaccine while killing bacteria, and then the whole body anti-infection immune effect is stimulated, so that the vaccine is a new path for activating immunity to resist bacterial infection, and the advantages of simple operation, high safety, universality and the like are displayed in anti-infection diseases. The nano piezoelectric material has high piezoelectric catalysis efficiency, and can convert mechanical vibration such as ultrasound and the like into electric energy to drive electrochemical reaction, generate active oxygen and kill pathogenic bacteria. The strategy for preparing the in-situ bacterial infection therapeutic vaccine by inactivating the bacteria generated by the active oxygen sterilization treatment not only can avoid the harsh and complicated preparation method of the in-vitro conventional vaccine, but also can greatly expand the application range of the bacterial immunotherapy.
At present, no report of the nano piezoelectric material in the development of in-situ therapeutic vaccines for resisting bacterial infection is found.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the application of the nano piezoelectric material in preparing the anti-bacterial infection in-situ vaccine. The nano piezoelectric particles can generate a large amount of reactive oxygen species ROS by showing an excellent piezoelectric catalysis effect under an ultrasonic condition, the ROS can destroy a bacterial structure to release a large amount of pathogen-associated pattern molecules (PAMP) antigens, and activate body-associated immune cells to generate an immune effect in a body (the immune mechanism is shown in figure 1).
Interpretation of terms:
vaccine induction adjuvant: also called vaccine adjuvant, refers to a class of substances that can nonspecifically alter or enhance the body's specific immune response to antigens, exerting an adjuvant effect; the vaccine adjuvant can induce the organism to generate long-term and high-efficiency specific immune response, improve the protective capability of the organism, reduce the dosage of immune substances and reduce the production cost of the vaccine.
The purpose of the invention is realized by the following technical scheme:
the application of the nano piezoelectric material in resisting bacterial infection.
The application of the nano piezoelectric material in preparing the anti-bacterial infection in-situ vaccine.
According to the invention, the nano piezoelectric material is preferably used as a vaccine induction adjuvant for preparing in-situ vaccines for resisting bacterial infection.
According to the present invention, the nano-piezoelectric material includes, but is not limited to, barium titanate with metal nanoparticles loaded on the surface, lithium niobate, hydroxyapatite, polylactic acid, collagen or two-dimensional MoS 2 A nanomaterial; further preferably, the nano piezoelectric material is barium titanate or barium titanate with metal nanoparticles loaded on the surface, and the metal nanoparticles are Au, pt, pd, al or Ni nanoparticles; more preferably, the nano piezoelectric material is barium titanate nanoparticles with Au nanoparticles loaded on the surface.
According to the invention, the particle size of the nano piezoelectric material is preferably 30-300nm.
According to the invention, the preferable specific application method is as follows: dispersing the nano piezoelectric material in a dispersing reagent, preparing into a solution with the concentration of 5mg/mL, injecting, and then performing ultrasonic power of 0.1-2.5W/cm 2 Carrying out ultrasonic treatment for 2-5min under the ultrasonic frequency of 0.1 Hz;
further preferably, the dispersing agent is a PBS solution, physiological saline or Tris buffer; the concentration of the PBS solution is 0.01mol/L, the pH value is 7.4, the concentration of the Tris buffer solution is 0.01mol/L, and the pH value is 7.4.
According to the invention, the ultrasound is probe type ultrasound, and a coupling agent is coated on the probe.
According to the invention, the preparation method of the nano piezoelectric material is the prior art.
The invention has the technical characteristics and the beneficial effects compared with the prior art that:
1. the antibacterial infection in-situ vaccine prepared by using the nano piezoelectric material has deep tissue penetrability, and can more thoroughly eliminate bacterial infections such as subcutaneous abscess and the like; the nano piezoelectric material can be used as a vaccine induction adjuvant to activate the whole body immunity while killing bacteria in situ, and shows that the antibacterial infection in situ vaccine prepared from the nano piezoelectric material has dual functions of treatment and immunity.
2. The ultrasonic-activated in-situ vaccine for resisting bacterial infection, which is prepared from the nano piezoelectric material, is a novel in-situ therapeutic vaccine form, and compared with the traditional treatment means and the conventional vaccine method, the vaccine method can realize the advantages of personalized treatment, independence on antibiotics, no generation of drug resistance, non-invasive treatment, activation of autoimmunity and the like; the nano piezoelectric material can show excellent piezoelectric catalysis effect under the ultrasonic condition to generate a large amount of reactive oxygen species ROS, ROS can destroy the bacterial structure to release a large amount of PAMP antigens, and activate relevant immune cells of an organism to generate immune effect, so that ectopic infection can be controlled while infection can be cleared in situ, and the reinfection of bacteria can be effectively prevented.
Drawings
FIG. 1 shows the mechanism of action principle of nano piezoelectric material for preparing in situ vaccine.
FIG. 2 shows ectopic infection of rat in example 1, wherein the nano-piezoelectric material only sonicates right-side abscess of rat, and the size of the abscess on both sides of the treatment time point changes.
FIG. 3 shows ectopic infection of rats in example 1, and data output of abscess size change at different time points.
FIG. 4 shows the infection of subcutaneous abscesses at different time points for different treatments at the time of primary infection of rats in example 2.
FIG. 5 is the data output of the change of the size of the subcutaneous abscess infection area of the nano-piezoelectric material at different time points of ultrasonic treatment when the rat in example 2 is infected for the first time.
FIG. 6 shows the subcutaneous abscess of the nano-piezoelectric material treated by ultrasound at different time points when the rat is infected again in situ in example 2.
FIG. 7 is the data output of the change of the size of the subcutaneous abscess infection area of the nano-piezoelectric material at different time points of the ultrasonic treatment when the rat is infected again in situ in example 2.
Detailed Description
The invention is further illustrated by the following specific examples and the accompanying drawings. The examples of the present invention are for better understanding of the present invention to those skilled in the art, and do not limit the present invention in any way.
Meanwhile, the experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
The nano piezoelectric material used in the embodiment is a barium titanate nano piezoelectric material with Au nano particles loaded on the surface, and is prepared according to the following preparation method:
(1) Dispersing 40mg of barium titanate in 40mL of absolute ethyl alcohol, adding 400uL (3-mercaptopropyl) trimethoxysilane, uniformly stirring, ultrasonically shaking for 30min under the condition that the ultrasonic frequency is 40kHz, centrifuging for 10min under the condition that the rotating speed is 5000rmp to obtain a precipitate, washing the obtained precipitate with absolute ethyl alcohol for 3 times, and drying for 5h at 60 ℃ to obtain the mercapto barium titanate.
(2) 10mg of barium mercaptide titanate was dispersed in 10mL of deionized water, and 10mL of 20mmol/L HAuCl was added 4 The solution was mixed with 10mL of 20% (v/v) methanol aqueous solution using 0.5mol/L K 2 CO 3 The pH value of the system is adjusted to 9.7 by the solution; and (2) carrying out ultrasonic treatment for 60min at the temperature of 0 ℃ and the ultrasonic frequency of 40kHz to obtain a mixture, centrifuging the obtained mixture for 10min at the rotation speed of 10000rmp to obtain a precipitate, washing the obtained precipitate for 3 times by using water, and drying at 80 ℃ for 7h to obtain the barium titanate nano piezoelectric material with the surface loaded with Au nano particles, wherein the particle size is 100nm and is marked as BTO @ Au.
The rats used in the examples were Wistar rats, 6 weeks male, purchased from sbeful (beijing) biotechnology limited.
The sonication conditions described in the examples are as follows: coupling of the smear with a hand-held ultrasound apparatus (model WED-100)The probe of the agent is attached to the infected tissue at an ultrasonic power of P =1W/cm 2 And carrying out ultrasonic treatment on the injection infection part for 3min under the condition of the ultrasonic frequency of 0.1 Hz.
Example 1
To evaluate the possibility of bto @ au as an anti-infective vaccine and to prepare an ultrasonically activated in situ vaccine against bacterial infection, we explored whether bto @ au could induce activation of systemic immunity under ultrasonic conditions, and performed the following experiments.
The method comprises the following steps: preparing all required articles one day before the experiment, and performing high-temperature high-pressure steam sterilization treatment on the required surgical instruments; on the day of the experiment: and (4) turning on an ultraviolet lamp in the operating room to irradiate for 30min, and sterilizing all equipment and laboratory supplies in the operating room.
Step two: dipping 2cm with sterile cotton swab 2 Putting single colony staphylococcus aureus with the area into 10mL of LB culture medium, uniformly mixing, and then adjusting the concentration of the bacteria liquid to OD600= 0.5-0.7 (about 1 × 10) 8 CFU/mL), and shaking uniformly for later use. Rats were anesthetized with isoflurane inhalation and then skin preparation was performed on the back. After the iodophor cotton ball is sterilized, 100 mu L of 1X 10 iodine cotton balls are respectively injected into the two sides of the back by subcutaneous injection by a 1mL disposable syringe 8 And (3) normally breeding the CFU/mL staphylococcus aureus liquid for 24 hours, and establishing a bilateral subcutaneous bacterial infection model of the rat.
Step three: the rat subcutaneous bacterial infection model was randomly divided into 4 groups: an ultrasonic group: ultrasonic treatment is carried out without injecting nano piezoelectric material; group of nano-piezoelectric materials: injecting the nano piezoelectric material without ultrasonic treatment; bto @ au + sonication: injecting a nano piezoelectric material, and carrying out ultrasonic treatment; blank group: the right side was injected subcutaneously with 100uL of 5 ten thousand units of penicillin, 8 h/time, for 4 days. The specific operation is as follows: an ultrasonic group: sonication was performed on the right side, applying frequency: 8 h/time, and continuously treating for 4d; group of nano-piezoelectric materials: injecting 100uL 5mg/mL nano piezoelectric material normal saline solution into the abscess on the right side; nano piezoelectric material + ultrasonic group: injecting 100 mu L of 5mg/mL nano piezoelectric material normal saline solution into the right-side abscess in situ, and performing ultrasonic treatment at the application frequency: 8 h/time, and continuously treating for 4d; the left side of each group was not treated. Each group of experimental animals was sacrificed by cutting off the neck, and after the back skin was cut off, the subcutaneous abscess tissue was completely peeled off, and the abscess tissue was photographed and measured, and the results thereof are shown in fig. 2 and 3.
As can be seen from FIGS. 2-3, subcutaneous abscess models are simultaneously established on both sides of the back of the mouse, the right piezoelectric nanomaterial group is subjected to ultrasonic treatment, the left side is not subjected to any treatment, and the infection area on the left side is reduced to 32.60mm 2 Right side infected area reduced to 22.59mm 2 Far below the other controls. The nano-piezoelectric material can be used as a vaccine to kill bacteria, and can be used as a vaccine induction adjuvant to activate the systemic immunity.
Example 2
In order to investigate whether the nano piezoelectric material has the potential to be used as a vaccine against bacterial infection, the nano piezoelectric material is used for treating an abscess model of a rat infected for the first time under the ultrasonic condition, and the specific experimental steps are as follows:
the method comprises the following steps: establishment of rat subcutaneous bacterial infection model
Rats were anesthetized with isoflurane inhalation and then the backs were prepared for skin preparation. After the iodophor tampon was sterilized, 100. Mu.L of 1X 10 was subcutaneously injected into the back using a 1mL disposable syringe 8 CFU/mL bacterial liquid, after normally breeding for 24h, establishing a rat subcutaneous bacterial infection model.
Step two: preparing all required articles one day before the experiment, and performing high-temperature high-pressure steam sterilization treatment on the required surgical instruments; on the day of the experiment, an operating room ultraviolet lamp is turned on to irradiate for 30min, and all equipment and experimental articles in the operating room are sterilized.
Step three: the rat subcutaneous bacterial infection model was randomly divided into 4 groups: blank group: no treatment is carried out; an ultrasonic group: ultrasonic treatment is carried out without injecting nano piezoelectric materials; BTO @ Au group: injecting the nano piezoelectric material without ultrasonic treatment; bto @ au + sonication: injecting nano piezoelectric material, and performing ultrasonic treatment. After rats are inhaled and anesthetized with isoflurane, and the iodophor cotton balls are disinfected, 100 mu L of 5mg/mL nano piezoelectric material normal saline solution is respectively injected into subcutaneous abscess in situ according to groups, and the ultrasonic treatment applying frequency is as follows: 8 h/time. Each group was sacrificed at random neck-cut of 5 patients at treatment 0d (no ultrasonic treatment), 1d (treatment 3 times), 2d (treatment 6 times), 3d (treatment 9 times), and 4d (treatment 12 times), and after the skin of the back was cut out, subcutaneous abscess tissue was completely peeled off, and the abscess tissue was photographed and measured, and the results thereof are shown in fig. 4 and 5.
As can be seen from figures 4 and 5, the infected area of the BTO @ Au + ultrasonic group after 4 days of ultrasonic treatment is 101.28mm 2 Reduced to 11.92mm 2 As the ultrasound time was prolonged, the infected area gradually decreased (1d 2 ，2d：52.54mm 2 ，3d：27.2mm 2 ) The other control group had almost no change in the infected area. The antibacterial infection in-situ therapeutic vaccine prepared from the nano piezoelectric material can kill bacteria and has the function of in-situ treatment.
Step four: then, the mice were kept normally for 40 days, infected again at the first infected site, kept without any treatment for 24 hours, and the size of the area of abscess infection was measured for each group of mice. As can be seen from FIGS. 6-7, the area of abscess in re-infection of BTO @ Au + sonication group was much smaller than that of other groups, and the in situ infection experiment showed good immune effect. The antibacterial infection in-situ therapeutic vaccine prepared from the nano piezoelectric material plays a role in activating immune memory effect and preventing reinfection.
Claims (9)
1. The application of the nano piezoelectric material in resisting bacterial infection.
2. The application of the nano piezoelectric material in preparing the anti-bacterial infection in-situ vaccine.
3. The use according to claim 2, wherein said nano-piezoelectric material is used as a vaccine inducing adjuvant for the preparation of in situ vaccines against bacterial infections.
4. The use according to any one of claims 1 to 3, wherein the nano-piezoelectric material is barium titanate, barium titanate with metal nano-particles loaded on the surface, lithium niobate, hydroxyapatitePolylactic acid, collagen or two-dimensional MoS 2 A nanomaterial; the grain diameter of the nano piezoelectric material is 30-300nm.
5. The use according to claim 4, wherein the nano-piezoelectric material is barium titanate or barium titanate with metal nanoparticles loaded on the surface.
6. The use according to claim 4 or 5, wherein the metal nanoparticles are Au, pt, pd, al or Ni nanoparticles.
7. The use according to claim 4 or 5, wherein the nano-piezoelectric material is barium titanate nanoparticles with Au nanoparticles loaded on the surface.
8. The use according to any one of claims 1 to 3, characterized in that the specific application method is as follows: dispersing the nano piezoelectric material in a dispersing reagent, preparing into a solution with the concentration of 5mg/mL, injecting, and then performing ultrasonic power of 0.1-2.5W/cm 2 And carrying out ultrasonic treatment for 2-5min under the ultrasonic frequency of 0.1 Hz.
9. The use of claim 8, wherein the dispersing agent is a PBS solution, physiological saline or Tris buffer; the concentration of the PBS solution is 0.01mol/L, the pH value is 7.4, the concentration of the Tris buffer solution is 0.01mol/L, and the pH value is 7.4.
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