CN115154482B - Application of ferric sulfide nano enzyme in resisting human papilloma virus - Google Patents
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
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Abstract
The invention discloses an application of ferric sulfide nano enzyme in resisting human papilloma virus. The invention provides an effective realization way for preventing and treating human papillomavirus infection diseases, in particular to preventing and treating genital warts, squamous intraepithelial lesions, cervical intraepithelial neoplasia, cervical cancer, vulva cancer or other gynecological precancerous lesions.
Description
Technical Field
The invention relates to the field of prevention and treatment of human papilloma virus infection diseases, in particular to application of ferric sulfide nanoenzyme in preventing or treating human papilloma virus infection diseases.
Background
Cervical cancer has become one of the ten major malignancies worldwide, and the affected population is becoming increasingly young.
In 2007, our scientist found Fe 3 O 4 Magnetic nanoparticles have peroxidase-like activity and enzymatic properties of nanomaterials have been systematically studied from an enzymatic point of view, such nanomaterials mimicking enzymes being subsequently defined as nanomesh enzymes (nanozymes). In terms of antibiosis, the nano-enzyme-based peroxidase-like enzyme, oxidase-like enzyme and other enzyme activities can clear bacterial biofilms, so that antibiosis activity is exerted. In 2020, the university of Yangzhou's Shuoshi thesis "preparation of iron/carbon composite material" and research of its bacteriostasis"Jiu" discloses Fe 7 S 8 The preparation method of the nano-sheet and researches the antibacterial property and the antibacterial mechanism of the nano-sheet. In terms of virus detection, nanoezymes have been applied to detection of Respiratory Syncytial Virus (RSV), human Immunodeficiency Virus (HIV), novel coronavirus (covd-19), and the like. In terms of antivirus, research has found that silver nanoparticles, ferric oxide nanoparticles and the like have the activity of resisting HIV, HSV, HCV, H1N1 and the like, and the action mechanism of nano enzyme against influenza virus is disclosed, namely: after the iron-based nano enzyme contacts with influenza virus particles, lipid peroxidation is catalyzed by an enzymatic reaction to the virus envelope, and oxidation products further collapse hemagglutinin protein and neuraminidase protein, so that the structure and the function of the influenza virus are destroyed, and the virus loses invasion and replication capacity.
Human papillomavirus (Human Papilloma Virus, HPV) belongs to the family Papovaviridae. HPV is a DNA virus, the outer layer has no envelope, and DNA molecules can be integrated with host cell chromosome after the HPV invades the host cell, so that certain gene functions of the host cell are inactivated, and the HPV can cause human skin mucosa hyperplasia lesions, and is an important 'basic value' of female lower genital tract infection, cervical cancer and precancerous lesions. HPV shares over 100 subtypes, direct skin-to-skin contact being the most common transmission pathway for HPV. According to the possibility of causing cervical cancer, the international agency for research on cancer (IARC) classified 40 HPV subtypes related to genital tract infection into high-risk type, suspected high-risk type and low-risk type in 2012. High-risk type and suspected high-risk type HPVs are related to cervical cancer, high-level vulva, vagina, cervical Squamous Intraepithelial Lesions (SIL) and the like, and low-risk type HPVs are related to genital warts, low-level vulva, vagina, cervical SIL and the like. Common high-risk HPV includes more than 10 subtypes of HPV-16, HPV-18, HPV-31 and HPV-33, and HPV-16 and HPV-18 can lead to about 70% of cervical cancer cases. Common low-risk HPV types include: HPV-6, HPV-11, HPV-40, HPV-42, etc. As a non-envelope double-stranded circular DNA virus, HPV is low in immunogenicity, is easy to form persistent infection, and the infection only stays in local skin and mucous membrane and does not enter blood circulation to produce viremia. Moreover, for HPV infection diseases (genital warts, squamous intraepithelial lesions, cervical intraepithelial neoplasias, cervical cancers or vulva cancers, etc.), the efficacy of the existing treatment means (laser, microwave, freezing, immunotherapy, etc.) is not satisfactory, and vaccines are almost the only prevention and control means against HPV infection. However, HPV vaccines have long presented significant patient accessibility problems due to the complex manufacturing process and long manufacturing cycle constraints.
Therefore, the development of drugs for directly killing or inhibiting HPV is significant for patients suffering from HPV infection diseases, and is also an urgent pursuit for those skilled in the relevant drug development field.
Disclosure of Invention
Through many years of research, the inventor obtains a great breakthrough in the field of metal nano material antivirus, namely: the inventor uses a scientific control research method to prove that the ferric sulfide nano-enzyme has obvious killing effect on human papilloma virus. Accordingly, the present invention provides a method for preventing or treating human papillomavirus infection diseases by using ferric sulfide nanoenzyme.
In particular to application of ferric sulfide nano-enzyme in preparing medicaments for resisting human papilloma virus infection diseases.
Preferably, the invention provides application of ferric sulfide nano-enzyme in preparing a medicament for preventing or treating human papilloma virus infection diseases.
Preferably, the invention provides application of ferric sulfide nano-enzyme in preparing a medicament for preventing or treating female lower genital tract human papillomavirus infection.
Wherein, the human papillomavirus infection diseases comprise: genital warts (e.g., condyloma acuminatum), squamous intraepithelial lesions, cervical intraepithelial neoplasia, cervical cancer, vulvar cancer, or other pre-cancerous lesions of gynaecology based on infection by human papillomavirus.
Wherein, the iron sulfide nano enzyme can utilize conventional preparation means to make Fe 7 S 8 The nanoenzyme can be made into oral preparation, injection or external preparation, etc., and can be administered to people in need by conventional route such as oral administration, injection, smearing, and washing, preferably suppository, gel, foam, and washingAgents, etc. For example, fe 7 S 8 Adding nanometer enzyme powder into purified water, adding adjuvant, mixing, and packaging to obtain Fe with specific concentration (such as 0.1mg/g, 0.25mg/g, 0.5mg/g, 1.0mg/g or 2.0 mg/g) 7 S 8 Nano enzyme gel.
The human papillomavirus is high-risk type HPV, suspected high-risk type HPV or low-risk type HPV, the high-risk type human papillomavirus is preferably HPV-16, HPV-18 or HPV-33, and the low-risk type human papillomavirus is preferably HPV-6.
Wherein, the iron sulfide nano enzyme is preferably Fe 7 S 8 Nanoenzyme or Fe 3 S 4 Nano enzyme.
Wherein, the dosage of the anti-human papillomavirus infection disease medicine can be 1-500 mg/day, preferably 5-100 mg/day, more preferably 10-50 mg/day, or is determined according to factors such as the type, severity and the like of human papillomavirus infection disease.
In addition, the invention provides a method for preparing the ferric sulfide nano enzyme by utilizing a hydrothermal (solvothermal) reaction method, which comprises the step of preparing the ferric sulfide nano enzyme by utilizing an iron-containing compound and sulfide under a weak alkaline condition. Of course, the iron sulfide nanoenzymes of the present invention may also be prepared by any other known method, for example: coprecipitation, microemulsion, microwave irradiation, and the like.
Based on the technical scheme, the invention has the following beneficial effects:
(1) The invention has the concentration of Fe of 0.1-2.0mg/ml proved by scientific experiments 7 S 8 The nano enzyme solution has definite inactivating effect on high-risk human papilloma virus HPV-16, HPV-18, HPV-33 and low-risk human papilloma virus HPV-6; further, fe is 0.5mg/ml or more 7 S 8 The inactivating rate of the nano enzyme solution to the human papillomavirus subtype is up to more than 99%.
(2) The invention provides and proves that the iron sulfide nano enzyme, in particular Fe, for the first time 7 S 8 Application of nano-enzyme in resisting human papilloma virus infection diseases, and is for human prevention and treatmentThe effective realization way is provided for treating human papillomavirus infection diseases, in particular preventing and treating genital warts, squamous intraepithelial lesions, cervical intraepithelial neoplasia, cervical cancer, vulvar cancer or other gynecological precancerous lesions.
Drawings
Fig. 1: a transmission electron microscope image of the seven-iron octasulfide nano enzyme;
fig. 2: XRD pattern of seven iron octasulfide nanoenzyme.
Detailed Description
The specific embodiments of the present invention are provided merely to illustrate possible embodiments of the invention and should not be construed as limiting the invention in any way. The raw materials, the auxiliary materials, the reagents, the instruments and the like related to the embodiment of the invention are all purchased commercially.
Example 1 Fe 7 S 8 Preparation method of nano enzyme
(1) 8.2 g (0.03 mol) of ferric trichloride hexahydrate is weighed, put into a 500ml beaker, 400ml of ethylene glycol is added, and stirred at room temperature until the ferric trichloride is completely dissolved, and marked as A solution;
(2) 24.6 g (0.30 mol) of anhydrous sodium acetate is weighed and added into the solution A, stirred until the solution A is completely dissolved, and marked as solution B; cooling the solution B in an ice bath, and performing ultrasonic treatment for 30min;
(3) 10.0 g (0.058 mol) of diallyl disulfide is weighed and added into the solution B, and marked as solution C;
(4) Pouring the solution C into a 500ml hydrothermal kettle, and reacting for 12 hours at 220 ℃;
(5) After the reaction is finished, naturally cooling, discarding supernatant, pouring the residual feed liquid into a centrifuge tube, and centrifugally separating;
(6) Washing with water and absolute ethanol for 3 times, and centrifuging;
(7) Placing the obtained wet product in a 60 ℃ blast drying oven, and drying to obtain Fe 7 S 8 2.78 g of nano enzyme powder, and the molar yield is 99.0% (calculated by ferric trichloride), and the transmission electron microscope and XRD patterns are respectively shown in figures 1 and 2.
Example 2 Fe 7 S 8 Nanometer enzyme HPV virus resistance experiment
1. Nanometer enzyme anti-HPV virus experimental method
(1) Weigh the Fe prepared in example 1 7 S 8 Adding nano enzyme powder into water, vibrating and uniformly mixing to prepare a nano enzyme solution with the concentration of 2 times as high as the following concentration: 0.1mg/ml, 0.25mg/ml, 0.5mg/ml, 1.0mg/ml, 2.0mg/ml.
(2) Vero-E6 cells were rapidly thawed in warm water at 37℃and transferred to culture flasks containing 10ml of DMEM medium. The growth of cells was observed daily, and when cells were full of monolayers, they were diluted to about 4X 10 with DMEM medium 5 ～8×10 5 Cell suspension at individual/ml concentration.
(3) HPV virus (HPV-16, HPV-18, HPV-6 and HPV-33) are respectively inoculated in cell bottles containing 10ml of cell suspension, cultured at 37 ℃ and observed, when 3/4 cells are diseased, the cells are broken by ultrasonic waves (or repeated freeze thawing) under ice bath condition, the cells are centrifuged at 6000r/min for 15min, and the supernatant is the virus suspension.
(4) And uniformly mixing the nano enzyme solution and the virus suspension according to a ratio of 1:1, and taking the mixed solution after 2 hours of action as a reaction solution of a test article. Sterile deionized water is used for replacing the nano enzyme solution in the synchronous operation to prepare the reference substance reaction solution.
(5) Filtering the reaction liquid obtained in the step (4) by using a sterile filter element, adding a proper amount of neutralizing agent (1.0% Tween 80+0.1% lecithin+0.5% sodium thiosulfate) into the reaction liquid, and then performing serial dilution by using a DMEM culture medium at a ratio of 1:10. 100 μl of each dilution was added to a 96-well plate containing 100 μl of cell suspension, and the plates were incubated at 37deg.C with 5% CO 2 Culturing in an incubator, and observing day by day; on day 4, 50 μl fresh DMEM medium was added to each reaction well; on day 7, cytopathic effects were observed and recorded well by well.
(6) And (3) measuring the virus titer, and calculating the inactivation logarithmic value and the inactivation rate.
2. Virus titer determination and inactivation rate calculation
(1) End point dilution method
TCID 50 Log value = log value + distance ratio of group dilutions with lesion rate higher than 50%
Wherein, TCID 50 Refers to half the dose of cell infection. Disease of the patientThe group with the variability higher than 50% refers to the lowest group with the lesion rate higher than 50%, which is hereinafter referred to as "group higher than 50%; the group with a lesion rate lower than 50% means the highest group with a lesion rate lower than 50%, hereinafter referred to as "group lower than 50%.
Distance ratio = (disease rate of more than 50% group-50)/(disease rate of more than 50% group-disease rate of less than 50% group)
(2) Average inactivation log value calculation: setting the average TCID of the positive control group 50 With a value of N 0 Test group average TCID 50 The value is Nx.
Average inactivation log number = log No-log Nx
(3) Inactivation rate calculation
HPV viral inactivation rate= (N 0 -Nx)/N 0 ×100％
3. Nano enzyme anti HPV virus experimental result
It is found from the calculation that the test groups have Fe at various concentrations 7 S 8 The nano enzyme solution has definite inactivating effect on HPV-16, fe of more than 0.5mg/ml 7 S 8 The inactivation rate of the nano enzyme solution to HPV-16 is up to 99% or more, and the specific experimental results are shown in the following table 1.
Table 1 Fe 7 S 8 Nano enzyme anti-HPV-16 activity
For HPV-18, HPV-6 and HPV-33, the test groups were tested for each concentration of Fe 7 S 8 The nano enzyme solution also has definite inactivating effect, fe of more than 0.5mg/ml 7 S 8 The inactivating rate of the nano enzyme solution to HPV-18, HPV-6 and HPV-33 is as high as 99% or more, and the experimental results are summarized in Table 2.
Table 2 Fe 7 S 8 Nanoenzyme anti-HPV-18, HPV-6, HPV-33 Activity
Claims (8)
1. Application of ferric sulfide nano enzyme in preparing medicament for treating human papilloma virus infection diseases, wherein the ferric sulfide is Fe 7 S 8 And Fe 7 S 8 The XRD pattern of the nanoenzyme is shown in FIG. 2.
2. The use according to claim 1, wherein the medicament for treating human papilloma virus infection disease is a medicament for preventing or treating human papilloma virus infection disease.
3. The use according to claim 1, wherein the human papillomavirus infection is a female lower genital tract human papillomavirus infection.
4. The use according to claim 1, wherein the human papillomavirus infection disease is genital warts, squamous intraepithelial lesions, cervical intraepithelial neoplasias, cervical cancer, vulvar cancer.
5. The use according to claim 1, wherein the medicament for treating human papilloma virus infection disease is an injection, an oral preparation or an external preparation.
6. The use according to claim 5, wherein the external preparation is a suppository, a gel, a foam or a rinse.
7. The use according to any one of claims 1 to 6, wherein the human papillomavirus is a high risk HPV, a suspected high risk HPV or a low risk HPV.
8. The use according to claim 7, wherein the high-risk type HPV is HPV-16, HPV-18 or HPV-33 and the low-risk type HPV is HPV-6.
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