CN115475244B - Metal organic framework nano-composite and preparation method and application thereof - Google Patents
Metal organic framework nano-composite and preparation method and application thereof Download PDFInfo
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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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
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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
- A61K47/6949—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 inclusion complexes, e.g. clathrates, cavitates or fullerenes
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y111/00—Oxidoreductases acting on a peroxide as acceptor (1.11)
- C12Y111/01—Peroxidases (1.11.1)
- C12Y111/01007—Peroxidase (1.11.1.7), i.e. horseradish-peroxidase
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention belongs to the technical field of antibacterial materials, and particularly relates to a metal-organic framework nano-composite and a preparation method and application thereof. The invention utilizes UiO-66 as a carrier to load TMB and HRP to form H in order to improve the accuracy of the antibacterial treatment of the nano material 2 O 2 And NIR light cascade response characteristics, and exhibit excellent photothermal bacterial inactivation characteristics.
Description
Technical Field
The invention belongs to the technical field of antibacterial materials, and particularly relates to a metal-organic framework nano-composite and a preparation method and application thereof.
Background
Bacterial infection is severely threatening human life and health. Antibiotics are traditional drugs for the treatment of bacterial infections, which save lives of countless people. However, at the same time of using antibiotics, bacterial drug resistance is also caused, which greatly reduces the therapeutic effect of the antibiotics and even makes the antibiotics ineffective. Whereas in recent years the abuse of antibiotics has accelerated the development of bacterial resistance. Unfortunately, the rate of development of new antibiotics is far less than the rate of development of bacterial resistance. According to World Health Organization (WHO) reports, about 70 tens of thousands of people die worldwide each year due to drug-resistant bacterial infections. If no effective measures are taken, 1000 tens of thousands of people die annually from drug-resistant bacterial infections are expected to die by 2050. In the face of such severe situations, on the one hand, the development of antibiotics is accelerated while avoiding abuse of antibiotics; on the other hand, new antimicrobial strategies are urgently needed.
Nanoparticle-mediated physical stimulation therapy is a promising bacterial treatment strategy that may partially replace antibiotics. The strategy is to take nano particles as media, and convert physical stimulation signals into forms such as heat energy or free radicals so as to inactivate bacteria. For example, most noble metal nanoparticles, nanocarbon materials, magnetic nanomaterials, some nanomaterials, etc. can be heated under light, magnetism, ultrasound or other physical stimuli to generate high temperatures for sterilization purposes; photosensitizers and nano semiconductor materials (such as titanium dioxide, bismuth vanadate, quantum dots and the like) can generate free radicals under the irradiation of light, X rays and even ultrasonic waves, and are used for bacterial inactivation. Among these strategies, the photothermal strategy has the obvious advantages of easy acquisition of light sources, high bacterial inactivation efficiency, low toxic and side effects and the like. In addition, photothermal treatment is not likely to cause bacterial resistance. Accordingly, photothermal antimicrobial treatment has received a great deal of attention in recent years and has made great progress in this field. Realizing efficient antibiosis is no longer a main problem of a photo-thermal method, and improving the treatment accuracy is based on the development trend of the photo-thermal antibiosis treatment research field. Although modification of targeting molecules such as antibodies and antimicrobial peptides can improve accuracy of nano photothermal treatment to a certain extent, the method has the problem of high cost and the like.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a metal-organic framework nano-composite, which utilizes UiO-66 as a carrier to load TMB and HRP to form H in order to improve the accuracy of antibacterial treatment of nano-materials 2 O 2 And NIR light cascade response characteristics, and exhibit excellent photothermal bacterial inactivation characteristics.
In order to achieve the technical purpose, the technical scheme of the invention is as follows:
a metal organic framework nano-composite takes metal organic framework MOF as a nano-carrier and is loaded with tetramethyl benzidine TMB and horseradish peroxidase HRP.
The metal organic framework nanocomposite has H 2 O 2 And NIR light cascade response characteristics.
The metal organic framework nano-composite has a photothermal antibacterial effect
The preparation method of the metal-organic framework nano-composite comprises the following steps:
step 1, uniformly mixing zirconium propoxide solution, DMF and acetic acid, carrying out oil bath to 130 ℃, carrying out heat preservation and stirring for 2 hours, and then cooling to room temperature, wherein the color of the solution is changed from colorless to yellow; finally, adding 1, 4-dicarboxyl benzene for ultrasonic dispersion, stirring at room temperature for 18 hours, and then centrifugally washing to obtain a UiO-66 carrier; the UiO-66 carrier is dispersed in water;
and 2, incubating and synthesizing the UiO-66 with TMB and HRP to obtain the metal-organic framework nano-composite.
The metal organic framework nano-composite is used in the antibacterial field,
the metal organic framework nano-composite is used in the field of wound treatment, and is particularly used in the field of skin wound infection treatment.
From the above description, it can be seen that the present invention has the following advantages:
1. the invention utilizes UiO-66 as a carrier to load TMB and HRP to form H in order to improve the accuracy of the antibacterial treatment of the nano material 2 O 2 And NIR light cascade response characteristics, and exhibit excellent photothermal bacterial inactivation characteristics.
2. In the use process, the high oxidation state of the bacterial infection microenvironment can trigger the nano-carrier to generate enzyme catalytic reaction, so that the charge transfer compound with near infrared photothermal effect is generated, and the carrier has near infrared photothermal antibacterial activity.
Drawings
FIG. 1 is a characterization map of UiO-66 and supported TMB and HRP (UiO-66@TMB-HRP, UTH) prepared in the examples; wherein a) TEM of MOF (UiO-66), b) XRD of UiO-66D, c) size distribution of MOF and obtained nanocomposite UiO-66@TMB-HRP (UTH), D) zeta potential of MOF and obtained nanocomposite UiO-66@TMB-HRP (UTH).
FIG. 2 is nanocomposite pair H in example 1 2 O 2 Wherein a) UTH and H 2 O 2 Absorption spectra before and after incubation; b) UTH-H 2 O 2 Absorption at 650nm in the system over time.
FIG. 3 is a nano-scale of example 1Photothermal effect of the nanocomposite wherein a) 0.2mg/mLUTH (i), 0.05mg/mLUTH+ mMH 2 O 2 (ii)、0.1mg/mLUTH+1mMH 2 O 2 (iii) And 0.2mg/mLUTH+1mMH 2 O 2 (iv) Photothermal effect under 900nmNIR light irradiation. b) a, corresponding thermal imaging map. c) 0.2mg/mLUTH+1mMH 2 O 2 On-off temperature change under 900nm light irradiation. d) Linear cooling time data and negative natural logarithm of-Ln (θ) and driving force temperature, ts= 172.63933s.
FIG. 4 is a photograph of colony of Escherichia coli and Staphylococcus aureus (0.4 mg/mLUTH+ mMH) of the nanocomposite of example 1 irradiated with 900nm light under various conditions 2 O 2 )。
FIG. 5 shows the bacteriostatic activity of the nanocomposite of example 1, wherein a) H 2 O 2 E.coli and Staphylococcus aureus colonies treated with UTH at different concentrations at a concentration of 1 mM. b) The corresponding bacterial viability was obtained by (a) counting. c) Under 900nm light irradiation, under H 2 O 2 Fluorescence images of E.coli (stained with SYTO9 and PI) before (left) and after (right) treatment with UTH in the presence.
Figure 6 is the therapeutic effect of the nanocomposite prepared in example 1 on wound infection (caused by staphylococcus aureus) in mice under different conditions.
Description of the embodiments
One embodiment of the present invention will be described in detail with reference to fig. 1 to 6, but does not limit the claims of the present invention in any way.
Examples
A metal organic framework nano-composite takes metal organic framework MOF as a nano-carrier and is loaded with tetramethyl benzidine TMB and horseradish peroxidase HRP.
The preparation method of the metal-organic framework nano-composite comprises the following steps:
step 1, MOFUiO-66 is prepared by using zirconium propoxide as zirconium source and terephthalic acid as chelating ligand, and forming the final product with specific morphology by coordinationMOF material of (a). The method comprises the following specific steps: a1, 3.5 mM LDMF,2mL acetic acid (2.1 g,35 mmol) and 30.5. Mu.L 70% zirconium propoxide [ Zr (OnPr) 4 ]The solution (in n-propanol) (26 mg,0.079 mmol) was mixed in a 10mL glass bottle; a2, heating the mixed solution to 130 ℃ through an oil bath, then preserving heat and stirring for 2 hours, and then cooling to room temperature, wherein the mixed solution turns from colorless to yellow; a3, adding 37.5mg of 1, 4-dicarboxybenzene into the solution after oil bath, carrying out ultrasonic treatment at the frequency of 40kHz for 30 seconds at room temperature, and then stirring for 18 hours at room temperature; a4, centrifugally separating the solution, washing the solution with DMF and water for a plurality of times, and finally dispersing the solution in water to obtain white emulsion solution with the concentration of 4.2 mg/mL.
Step 2, the nano-composite is prepared by adsorbing TMB in the pore canal through the porous characteristic and pi bond interaction of UiO-66, and adsorbing HRP on the surface of the UiO-66 through the nano-surface effect of the UiO-66 and the action of HRP. The method comprises the following specific steps: TMB was added to 5mL of 5mg/mLUiO-66 solution to give a final TMB concentration of 0.5mM, and after incubation for 3h, 25U was added
HRP, stirring at 4 ℃ for 8h; then, the above-mentioned products were centrifuged and washed several times with water, and finally dispersed in water, and the final concentrations of TMB and HRP in the resulting nanocomposite were 0.5mM and 10U/mL, respectively, and the appearance state of the solution was still a white emulsion solution.
And (3) performance detection:
the prepared UiO-66 is milky white and has good stability and dispersibility in water. As shown in fig. 1a, the TEM characterization results show that UiO-66 size is around 100nm and good dispersibility; as shown in FIG. 1b, crystallization and phase information were studied by powder X-ray diffraction (XRD), and the appearance of peaks in the XRD pattern indicated that UIO-66 had good crystallinity. As shown in FIGS. 1c and 1d, of the dimensions and zeta potential of UiO-66 and UiO-66 loaded with TMB and HRP (UiO-66@TMB-HRP, UTH), the UiO-66 major dimension was around 110nm, and after TMB and HRP loading, the resulting nanocomposite UTH showed a larger dimension around 210 nm. In addition, uiO-66 has a positive zeta potential of 26.3mV, which increases to 46.1mV after TMB and HRP are loaded. The changes in size and zeta potential clearly indicate successful preparation of nanocomposite UTH.
As shown in FIG. 2, nanocomposite pair H 2 O 2 Has response characteristics, the nanocomposite UTH contains enzyme (HRP) and substrate (TMB), and is characterized in that H 2 O 2 In the presence of HRP will catalyze H 2 O 2 An intermediate is produced that can oxidize TMB to a colored state. As shown in fig. 2a, the color of the nanocomposite solution changed from light opal to dark turquoise, while the uv absorption spectrum clearly indicated the production of TMB oxidation products; warp H 2 O 2 After the treatment, two strong absorption peaks appear around 650nm and around 900 nm. The intensity of the absorption peak increases with increasing nanocomposite concentration. As shown in fig. 2b, H 2 O 2 As low as 0.1mM, the color change of the nanocomposite material can be obviously caused in a short time, indicating that the nanocomposite material is resistant to H 2 O 2 Has higher responsiveness. Meanwhile, the photothermal effect of the nanomaterial is often closely related to the intensity of its absorption peak, which means that the oxidized nanocomposite is likely to generate a strong photothermal effect under irradiation of near infrared light (900 nm).
As shown in fig. 3, the nanocomposite has excellent photo-thermal effect, and as shown in fig. 3a and 3b, the temperature rise of the 0.2mg/mLUTH solution under 900nm light irradiation is very slight. However, in the presence of 1mMH 2 O 2 In the case of (C), even a low concentration of UTH (0.05 mg/mL) was rapidly heated by irradiation with 900nm light. The rate of temperature rise and the maximum temperature increase with increasing nanocomposite concentration. 0.2mg/mLUTH and 1mMH 2 O 2 The temperature of the solution can reach more than 45 ℃ within 3min under 900nm light irradiation, which obviously shows the excellent photo-thermal effect. It should be noted that H in the bacterial infection area 2 O 2 The concentration is usually around 1 mM. Furthermore, during light irradiation, the local temperature of the nanoparticle surface is much higher than the solution temperature. These indicate that the nanoparticle is an infected area pair H 2 O 2 Provides the necessary basis for sensitive reactions and efficient antimicrobial. As shown in fig. 3c and 3d, the photo-thermal efficiency was calculated by detecting the heating and cooling rates, and the result showed that the nanocomposite material UTH at H 2 O 2 The photo-thermal efficiency in the presence reaches 18%.
The nanocomposite has a photothermal antibacterial effect. The cascading antibacterial efficiency (measured using plate counting) was studied by selecting E.coli and Staphylococcus aureus as gram negative and positive bacterial models, respectively. As shown in FIG. 4, the results indicate that in the presence of H only 2 O 2 In the case of (1 mM) or UTH, NIR light irradiation does not cause significant antibacterial activity.
At H 2 O 2 And UTH, the near infrared light irradiation can cause obvious antibacterial activity, and the antibacterial activity is increased along with the increase of the concentration of UTH. As shown in fig. 5a and 5b, when H 2 O 2 At a concentration of 1mM, the IC50 of UTH for E.coli and Staphylococcus aureus was about 150 and 450 μg/mL, respectively, under NIR light irradiation; this demonstrates that it has a remarkable antibacterial effect against both gram positive and negative bacteria, indicating that such cascade nanosystems have broad-spectrum antibacterial properties. LIVE/DEAD staining was performed using LIVE/DEAD bacterial viability kit to investigate the antibacterial mechanism of the nanosystems. In this process, green fluorescence (SYTO 9 dye) indicates live bacteria and red fluorescence (PI dye) indicates dead bacteria with damaged cell walls. As shown in fig. 5c, most treated bacteria have intense red fluorescence, suggesting that cascading nanosystems can cause damage to the cell wall and kill the bacteria.
In the mouse skin infection model, hair in the back portion area of the mouse was removed with depilatory cream, and a small piece of back skin was cut off to construct a wound model. Staphylococcus aureus bacteria with a 10 mu LOD600 of 1 were dripped into the wound for infection. The infected wound was instilled with 10. Mu. LUTH once daily for the first three days, and then irradiated with 900nm light for 5 minutes. Wounds were photographed daily and changes recorded. As shown in fig. 6, after near infrared light irradiation or UTH treatment, the skin wound of the mice infected with staphylococcus aureus showed symptoms such as obvious suppuration, and the wound healing was slow. Ten days later, the wound still had significant dents. However, after UTH and NIR light irradiation treatment, the wound has fewer suppuration symptoms and can heal faster. Ten days later, the wound healed substantially. These results indicate that the cascade nanosystems have good therapeutic effect on skin wound infection.
To sum up, the H-containing material prepared by the technical scheme 2 O 2 And NIR light cascade response characteristics have excellent photothermal antimicrobial activity. Nanocomposite pair H 2 O 2 The reaction is sensitive and rapid. Color of nanocomposite at H 2 O 2 The composite material turns into dark green turquoise in the presence, and meanwhile, a strong absorption peak appears in a near infrared region near 900nm, and the oxidized nanocomposite material can convert near infrared photons into heat energy with the efficiency of 18 percent. The nano system has strong inactivation effect on gram negative bacteria and positive bacteria. At 1mM hydrogen peroxide and 0.5W/cm 2 The IC50 of the MOF nanocomposite against E.coli and Staphylococcus aureus was 150 and 450. Mu.g/mL, respectively, under NIR light intensity conditions. The cascade reaction nano-drug also shows a strong therapeutic effect on a mouse skin wound infection model.
It is to be understood that the foregoing detailed description of the invention is merely illustrative of the invention and is not limited to the embodiments of the invention. It will be understood by those of ordinary skill in the art that the present invention may be modified or substituted for elements thereof to achieve the same technical effects; as long as the use requirement is met, the invention is within the protection scope of the invention.
Claims (6)
1. A metal organic framework nanocomposite characterized by: using metal organic framework MOF as nano carrier, loading tetramethyl benzidine TMB and horseradish peroxidase HRP; the metal organic framework nanocomposite has H 2 O 2 And NIR light cascade response characteristics; the nano composite adsorbs TMB in the pore canal through the porous characteristic and pi bond interaction of UiO-66, and adsorbs HRP on the surface of the UiO-66 through the nano surface effect of the UiO-66 and the action of HRP.
2. A metal-organic framework nanocomposite as claimed in claim 1 wherein: the metal organic framework nano-composite has a photothermal antibacterial effect.
3. A method of preparing a metal organic framework nanocomposite as claimed in claim 1 wherein: the preparation method of the metal-organic framework nano-composite comprises the following steps:
step 1, uniformly mixing zirconium propoxide solution, DMF and acetic acid, carrying out oil bath to 130 ℃, carrying out heat preservation and stirring for 2 hours, and then cooling to room temperature, wherein the color of the solution is changed from colorless to yellow; finally, adding 1, 4-dicarboxyl benzene for ultrasonic dispersion, stirring at room temperature for 18 hours, and then centrifugally washing to obtain a UiO-66 carrier; the UiO-66 carrier is dispersed in water;
and 2, incubating and synthesizing the UiO-66 with TMB and HRP to obtain the metal-organic framework nano-composite.
4. The use of a metal organic framework nanocomposite according to claim 1 for the preparation of a medicament for the antibacterial field.
5. Use of a metal-organic framework nanocomposite according to claim 1 for the preparation of a medicament in the field of wound therapy.
6. Use of a metal-organic framework nanocomposite according to claim 5 for the preparation of a medicament for the treatment of skin wound infections.
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