CN113491770B - Composite material, preparation method thereof and application of composite material in treatment of deep tissue infection caused by pan-drug-resistant acinetobacter baumannii - Google Patents

Composite material, preparation method thereof and application of composite material in treatment of deep tissue infection caused by pan-drug-resistant acinetobacter baumannii Download PDF

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CN113491770B
CN113491770B CN202010270690.8A CN202010270690A CN113491770B CN 113491770 B CN113491770 B CN 113491770B CN 202010270690 A CN202010270690 A CN 202010270690A CN 113491770 B CN113491770 B CN 113491770B
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rare earth
doped
composite material
modifier
photosensitizer
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CN113491770A (en
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陈卓
刘雯珍
宋晓荣
陈学元
张宇翔
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Fujian Institute of Research on the Structure of Matter of CAS
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    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
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    • A61P31/10—Antimycotics

Abstract

The invention provides a composite material, a preparation method thereof and application thereof in treating deep tissue infection caused by pan-drug-resistant acinetobacter baumannii. The composite material comprises rare earth-doped up-conversion nanoparticles, a modifier and a photosensitizer, combines the advantages of the rare earth-doped up-conversion nanoparticles and photodynamic antibacterial chemotherapy, makes up the defect of poor tissue penetrability caused by the fact that the excitation wavelength of the traditional photosensitizer is in the visible light range, and can effectively treat bacterial or fungal infection in deep tissues, particularly infection caused by pan-drug-resistant acinetobacter baumannii.

Description

Composite material, preparation method thereof and application of composite material in treatment of deep tissue infection caused by pan-drug-resistant acinetobacter baumannii
Technical Field
The invention belongs to the technical field of up-conversion nanoparticles, and particularly relates to a composite material, a preparation method thereof and application of the composite material in treatment of deep tissue infection caused by pan-drug-resistant acinetobacter baumannii.
Background
Acinetobacter baumannii is an important pathogenic bacterium of hospital infection, is mainly harmful to severe patients, and can cause respiratory tract infection, septicemia, urinary system infection, secondary meningitis and the like. In recent years, there has been an increasing number of infections caused by acinetobacter baumannii, and since there is an inherent drug-resistant gene on the chromosome and the acinetobacter baumannii has a strong ability to take up the drug-resistant gene from the outside, the drug resistance of acinetobacter baumannii has been developed at a very high rate, and a wide range of drug-resistant acinetobacter baumannii has appeared. Therefore, there is an urgent need to develop new antibacterial agents or antibacterial methods to combat infections caused by such bacteria.
The development of photodynamic antibacterial chemotherapy has seen new promise. The basic principle of photodynamic antibacterial is as follows: after receiving the excitation of light with specific wavelength, the photosensitizer reacts with nearby oxygen to generate active oxygen, thereby destroying the basic structure of bacteria and leading the bacteria to die. However, the excitation wavelengths of the photosensitizers currently used are mostly in the visible range, the wavelengths of visible light are short, and some components of the organism such as: melanin, hemoglobin, and the like have high absorption and scattering of visible light, resulting in poor tissue penetration of visible light. And acinetobacter baumannii mainly infects patients suffering from severe trauma, burns or having undergone surgical operations and interventions, and thus, acinetobacter baumannii mainly colonizes tissues deeper in the infected host. The poor tissue penetration of the photosensitizer excitation light limits the use of photosensitizers in deep tissue infections caused by pan-resistant acinetobacter baumannii.
Disclosure of Invention
In order to improve the defects of the prior art, the invention provides a rare earth doped up-conversion nanoparticle photosensitizer composite material, a preparation method thereof and application thereof in treating bacterial or fungal infection, such as deep tissue infection caused by acinetobacter baumannii, particularly pan-drug-resistant acinetobacter baumannii. Rare earth-doped up-conversion nanoparticles (UCNPs) are widely used in biomedical research due to their unique luminescence characteristics, and can emit short-wave radiation light with high energy under the excitation of long-wave radiation light with low energy. Therefore, the composite material based on the rare earth doped up-conversion nanoparticles and the photosensitizer has the up-conversion function and the photodynamic action, can well solve the problem of poor tissue penetrability of exciting light in the traditional photodynamic antibacterial therapy, and can effectively treat bacterial or fungal infection, such as deep tissue infection caused by pan-drug resistant acinetobacter baumannii. The composite material can convert 980nm light into 668nm light and 550nm light under the excitation of near infrared light, and the 550nm light can activate a photosensitizer Rose Bengal (RB) to generate a large amount of Reactive Oxygen Species (ROS), or the 668nm light can activate a photosensitizer phthalocyanine to generate a large amount of Reactive Oxygen Species (ROS), so that the aim of killing target bacteria or fungi is fulfilled.
The purpose of the invention is realized by the following technical scheme:
a composite material comprising a rare earth-doped upconverting nanoparticle having a surface to which a modifier is attached via coordination, a modifier, and a photosensitizer adsorbed to the surface of the rare earth-doped upconverting nanoparticle to which the modifier is attached via electrostatic interaction.
According to the invention, the composite material has a core-shell structure, the core comprises rare earth doped up-conversion nanoparticles, the shell comprises a modifier and a photosensitizer, and the shell is coated on the outer surface of the core.
According to the invention, the rare earth doped up-conversion nanoparticles are solid structures.
According to the invention, the photosensitizer is adsorbed to the surface of the rare earth doped up-conversion nanoparticle to which the modifier is attached by electrostatic interaction between the negative charge of its surface and the positive charge of the surface of the rare earth doped up-conversion nanoparticle. The photosensitizer may be located within the modifier layer, may be located on the outer surface of the modifier layer, or both.
According to the present invention, the introduction of the modifier may increase the water solubility and biocompatibility of the rare earth doped upconversion nanoparticles.
According to the invention, the rare earth doped up-conversion nanoparticles have the chemical formula AREF 4 Yb, er; wherein A is an alkali metal element selected from one of lithium (Li), sodium (Na) and potassium (K)(ii) a RE is a rare earth element selected from one of yttrium (Y), scandium (Sc), lanthanum (La), gadolinium (Gd) and lutetium (Lu). For example, A is Na or Li, and RE is one of Y and Gd. Illustratively, the rare earth doped upconversion nanoparticles have a chemical formula of LiYF 4 :Yb,Er。
Wherein, in the rare earth doped up-conversion nanoparticles, AREF 4 As a substrate, ytterbium ion (Yb) 3+ ) As a sensitizer, erbium ion (Er) 3+ ) Is an activator.
According to the invention, the particle size of the rare earth doped up-conversion nanoparticles may be in the range of 10-100nm, such as 15-80nm,20-60nm.
According to the present invention, the modifier may be selected from a high molecular polymer type organic ligand, for example, one, two or more selected from Polyvinylpyrrolidone (PVP), chitosan, polyethyleneimine, polyacrylic acid, polyethylene glycol, and the like.
According to the present invention, the amount of the modifier used in the composite material is not particularly limited, and may be adjusted according to the water solubility and/or biocompatibility requirements of the rare earth doped upconversion nanoparticles.
According to the invention, the photosensitizer is a photosensitizer capable of absorbing visible light emitted by the rare earth doped up-conversion nanoparticles under near infrared light irradiation to generate singlet oxygen. Preferably, it is selected from phthalocyanines which can be excited under 668nm wavelength excitation light, or rose bengal which can be excited under 550nm wavelength excitation light.
According to the invention, the loading of the photosensitizer in the composite material is 0.1-5wt% (i.e. weight percent), such as 0.3-4wt%,0.5-3wt%,0.7-2wt%, such as 0.8wt%, 1.0wt%, 1.2wt%, 1.4wt%, 1.6wt% or 1.8wt%. The loading rate of the photosensitizer refers to the weight percentage of the photosensitizer in the composite material, and can be obtained by calculation of an absorbance value at a certain wavelength, or by calculation of an ultraviolet visible absorption spectrum, for example, the absorbance value at a wavelength of 550nm is tested, the loading rate of rose bengal can be tested, and the absorbance value at a wavelength of 668nm is also tested, and the loading rate of phthalocyanine can be tested.
According to the invention, the energy transfer between the rare earth doped up-conversion nanoparticles and the photosensitizer in the composite material is mainly realized by means of fluorescence resonance energy transfer, and the transfer efficiency is 31.11%. Using the composite material UCNPs-PVP-RB prepared in example 1 below as an example, the change in fluorescence lifetime was calculated as eta = 1-tau 1 /τ 0 In which τ is 1 、τ 0 Respectively Er ions in UCNPs-PVP-RB and UCNPs 4 S 3/2 Fluorescence lifetime of the energy level.
According to the invention, the particle size of the composite material may be in the range of 10-150nm, for example 15-120nm,20-100nm,20-80nm,20-60nm.
According to the invention, the zeta potential of the composite material may be in the range-10 to 50mV, for example 10 to 30mV,15 to 25mV, for example 23.1mV.
According to the invention, the composite material can convert 980nm wavelength light into 550nm wavelength light under the excitation of near infrared light, and the Er ion light is used for the conversion 4 S 3/2 → 4 I 15/2 The energy level transition between them, exactly matches the absorption of RB at 550nm wavelength. Therefore, under 980nm illumination, the rare earth doped up-conversion nanoparticles transmit light with a wavelength of 550nm to the RB, and the activated RB further reacts with ambient oxygen to generate a large amount of Reactive Oxygen Species (ROS), so that biomolecules such as protein and nucleic acid are rapidly oxidized, and target bacteria are effectively killed.
Similarly, the composite material can convert 980nm wavelength light into 668nm wavelength light under the excitation of near infrared light, and the Er ions are used for the conversion 4 F 9/2 → 4 I 15/2 The energy level transition between them results, exactly matching the absorption of phthalocyanine at 668nm wavelength. Therefore, under 980nm illumination, the rare earth doped up-conversion nanoparticles transmit 668nm wavelength light to the phthalocyanine, and the activated phthalocyanine further reacts with ambient oxygen to generate a large amount of Reactive Oxygen Species (ROS), so that biomolecules such as protein and nucleic acid are rapidly oxidized, and target bacteria are effectively killed.
The invention also provides a preparation method of the composite material, which comprises the following steps:
(1) Mixing the water-soluble rare earth-doped up-conversion nanoparticles with a modifier, and obtaining the rare earth-doped up-conversion nanoparticles with the surface modified with the modifier through coordination;
(2) And (2) mixing the rare earth-doped up-conversion nanoparticles with the surface modified with the modifier in the step (1) with a photosensitizer, and obtaining the composite material through electrostatic interaction.
According to the present invention, in step (1), the water-soluble rare earth-doped upconversion nanoparticles may be prepared according to a method known in the art, or may be prepared by:
and (3) carrying out acid washing on the oil-soluble rare earth-doped up-conversion nanoparticles to remove oleic acid and oleylamine coated on the surfaces of the oil-soluble rare earth-doped up-conversion nanoparticles.
Wherein the oil-soluble rare earth doped upconversion nanoparticles can be prepared according to methods known in the art, for example, by high temperature thermal decomposition.
The acid washing may be carried out with an inorganic acid such as hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, for example.
Wherein the acid washing is performed, for example, in an alcohol solvent, for example, by dispersing oil-soluble rare earth doped upconversion nanoparticles in an ethanol solution followed by acid washing with hydrochloric acid.
Wherein, the acid washing may further include water washing, for example, deionized water may be used to wash the rare earth doped up-conversion nanoparticles after the acid washing, so as to obtain water-soluble rare earth doped up-conversion nanoparticles.
According to the present invention, in step (1), the mixing may be carried out at room temperature and the mixing time may be from 4 to 12 hours, for example from 5 to 8 hours, such as 6 hours.
According to the present invention, in step (1), the mixing may be performed in an aqueous solution, for example, mixing the water-soluble rare earth doped upconversion nanoparticles, the modifier, and water.
According to the invention, in step (1), the weight ratio of the water-soluble rare earth doped up-conversion nanoparticles to the modifier may be 1 (5-20), for example 1 (8-15), such as 1.
According to the present invention, in step (1), the mixing may be performed, for example, under stirring conditions, and the stirring may be performed, for example, with a magnetic stirrer.
According to the invention, in the step (1), the modifier is a high molecular polymer type organic ligand, such as one, two or more selected from polyvinylpyrrolidone, chitosan, polyethyleneimine, polyacrylic acid and polyethylene glycol.
According to the invention, in the step (1), the step of separating and washing can be further included after the mixing is finished.
According to the invention, in step (2), the mixing may be carried out at room temperature and the mixing time may be 4 to 12 hours, for example 5 to 8 hours, such as 6 hours.
According to the present invention, in the step (2), the mixing may be performed in an aqueous solution, for example, mixing the rare earth-doped upconversion nanoparticle surface-modified with a modifier, a photosensitizer, and water.
According to the present invention, in the step (2), the weight ratio of the rare earth doped upconversion nanoparticle with the surface modification agent and the photosensitizer can be (5-15): 1, for example (8-12): 1, such as 10.
According to the invention, in step (2), the mixing can be carried out, for example, under stirring, which can be carried out, for example, with a magnetic stirrer.
According to the invention, in the step (2), the photosensitizer can be rose bengal and/or phthalocyanine.
According to the invention, in step (2), a separation and water washing step can be further included after the mixing is finished.
The invention also provides the application of the composite material, which is used for preparing a therapeutic agent for treating bacterial or fungal infection, such as a therapeutic agent for treating deep tissue infection caused by acinetobacter baumannii, particularly pan-drug-resistant acinetobacter baumannii.
The present invention also provides a method of treating bacterial or fungal infections in a human or animal comprising administering to a human or animal in need of such treatment a therapeutically effective amount of the above-described composite. Preferably, the bacterial or fungal infection is an infection caused by acinetobacter baumannii, in particular a deep tissue infection caused by pan-resistant acinetobacter baumannii.
The invention has the beneficial effects that:
the invention provides an up-conversion nanoparticle photosensitizer composite material based on rare earth doping, a preparation method thereof and application of the composite material in treating bacterial or fungal infection, in particular deep tissue infection caused by pan-drug-resistant acinetobacter baumannii. The invention combines the advantages of the rare earth doped up-conversion nanoparticles and the photodynamic antibacterial chemotherapy, the photodynamic antibacterial chemotherapy can easily kill drug-resistant bacteria, and after the bacteria under the photodynamic action are transferred and cultured for 10 generations, the bacteria still have no drug resistance to the photodynamic action. This has brought new hopes for the treatment of infections caused by drug-resistant bacteria. And the introduced rare earth doped up-conversion nanoparticles make up the defect of poor tissue penetrability caused by the fact that the excitation wavelength of the traditional photosensitizer is in the visible light range. Therefore, the composite material can effectively treat bacterial or fungal infection in deep tissues, particularly infection caused by pan-resistant acinetobacter baumannii.
Drawings
FIG. 1 is a schematic diagram of the preparation process and antibacterial principle of the composite material UCNPs-PVP-RB of the invention.
FIG. 2 is a rare earth doped upconversion nanoparticle UCNPs-LiYF of example 1 4 Transmission electron microscopy of Yb, er, where (a) is transmission electron microscopy of UCNPs at low resolution and (b) is transmission electron microscopy of UCNPs at high resolution.
FIG. 3 is the upconversion emission spectra of UCNPs, UCNPs-PVP and UCNPs-PVP-RB in example 1 (left ordinate is relative intensity of fluorescence under 980nm laser excitation) and the absorption spectrum of RB (right ordinate is absorbance), where "RB" refers to simple photosensitizer rose bengal and "UCNPs" refers to water-soluble rare earth doped upconversion nanoparticle LiYF 4 Yb and Er, UCNPs-PVP refers to rare earth doped up-conversion nano particles with PVP modified on the surface, and UCNPs-PVP-RB refers to rare earth doped up-conversion nano particle photosensitizer composite material.
FIG. 4 is a graph showing ROS production of UCNPs-PVP-RB of example 1, wherein "DCFH-DA" refers to an untreated aqueous solution containing only DCFH-DA (2 ',7' -dichlorofluorescein diacetate), "DCFH-DA +980nm" refers to an aqueous solution of DCFH-DA subjected to illumination at a wavelength of 980nm, "DCFH-DA + UCNPs-PVP-RB" refers to an aqueous solution containing DCFH-DA and UCNPs-PVP-RB, and "DCFH-DA + UCNPs-PVP-RB +980nm" refers to a mixed aqueous solution of DCFH-DA and UCNPs-PVP-RB subjected to illumination at a wavelength of 980 nm.
Fig. 5 is a graph of the in vitro antibacterial effect of UCNPs-PVP-RB on pan-resistant acinetobacter baumannii as described in example 2, and (a) in fig. 5 is a graph of the in vitro antibacterial effect at different concentrations of UCNPs-PVP-RB, wherein "UCNPs-PVP-RB" refers to rare earth doped up-conversion nanoparticle photosensitizer composite that is not excited with excitation light, and "UCNPs-PVP-RB +980nm" refers to rare earth doped up-conversion nanoparticle photosensitizer composite that is excited with light of 980nm wavelength; fig. 5 (b) is a graph comparing the in vitro antibacterial effect of UCNPs-PVP-RB with the pork tissue without blocking the excitation light, wherein "control" means that the upconversion nanoparticle photosensitizer composite material without blocking pork and without doping rare earth is simply irradiated with light with 980nm wavelength or 550nm wavelength, "550nm" means that the upconversion nanoparticle photosensitizer composite material with doping rare earth is excited with light with 550nm wavelength, and "980nm" means that the upconversion nanoparticle photosensitizer composite material with doping rare earth is excited with light with 980nm wavelength.
Fig. 6 is a graph of the therapeutic effect of UCNPs-PVP-RB on pan-resistant acinetobacter baumannii induced local wound infection in mice as described in example 2, wherein "control group" refers to untreated mice, "UCNPs-PVP-RB +550nm" refers to mice treated with the 550nm wavelength light-excited rare earth-doped upconversion nanoparticle photosensitizer composite, "UCNPs-PVP-RB +980nm" refers to mice treated with the 980nm wavelength light-excited rare earth-doped upconversion nanoparticle photosensitizer composite, "UCNPs-PVP-RB +550nm + pork tissue" refers to mice treated with the 550nm wavelength light-excited rare earth-doped upconversion nanoparticle photosensitizer composite with the pork tissue blocking the excitation light. "UCNPs-PVP-RB +980nm + pork tissue" refers to mice treated with 980nm wavelength light-excited rare earth doped upconversion nanoparticle photosensitizer composite under conditions where the pork tissue blocks the excitation light.
Detailed Description
The preparation method of the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the techniques realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.
Example 1: the preparation method comprises the following steps: rare earth doped upconversion nanoparticles LiYF 4 Preparation of Yb, er
(1) 0.78mmol of Y (CF) was weighed 3 COO) 3 ·4H 2 O、0.2mmol Yb(CF 3 COO) 3 ·4H 2 O、0.02mmol Er(CF 3 COO) 3 ·4H 2 O、1mmol CF 3 COOLi·H 2 Adding 8mL of oleic acid and 6mL of oleylamine into a 50mL three-neck flask, and uniformly mixing;
(2) Communicating nitrogen with the double-mouth flask filled with the mixed solution, placing the double-mouth flask in a heating sleeve, adjusting the voltage, heating to 120 ℃, stirring to obtain a clear solution, and keeping the temperature for half an hour so as to fully remove moisture and oxygen in the device;
(3) Then quickly raising the temperature of the clear solution to 325 ℃, and keeping the temperature to react for 1.5 hours;
(4) After the reaction is finished, the heating device is removed under the condition of keeping the nitrogen gas communication, so that the reaction system is quickly cooled to room temperature, and the reaction is carried outAdding absolute ethyl alcohol into the system until the clear solution turns turbid, subpackaging the solution into EP tubes at 12000rpm for 5min, pouring off the supernatant, adding cyclohexane for resuspension, adding absolute ethyl alcohol again, centrifuging at 12000rpm for 5min, and obtaining precipitates, namely the oil-soluble rare earth-doped upconversion nanoparticles LiYF 4 Yb and Er can be dissolved in cyclohexane and stored in refrigerator at-20 deg.C for a long period.
The second step: preparation of composite material UCNPs-PVP-RB
(1) Method for removing oil-soluble rare earth-doped up-conversion nanoparticles LiYF by acid pickling 4 Preparation of water-soluble rare earth doped up-converted nanoparticles LiYF from oleic acid and oleylamine on the surface of Yb, er 4 Yb, er. The method comprises the following specific steps: coating 20mg of oleic acid-coated nanoparticle LiYF 4 Yb and Er are dispersed in 2mL of absolute ethanol solution with the pH =1 (40 mu L of hydrochloric acid is added into 5mL of absolute ethanol to obtain the absolute ethanol solution with the pH = 1), ultrasonic treatment is carried out for 20min,13000 is rotated and centrifuged for 5min, and then the solution is resuspended in the absolute ethanol solution with the pH =1 and ultrasonic treatment is carried out for 20min.13000 rotating and centrifuging to obtain precipitate, respectively washing with anhydrous ethanol solution with pH =4 and pH =7 twice, finally washing the precipitate with pure water twice or more, removing the residual anhydrous ethanol, and finally centrifuging to obtain precipitate which is water-soluble rare earth doped up-conversion nano particle UCNPs-LiYF 4 :Yb,Er。
(2) The water-soluble rare earth doped up-conversion nanoparticles UCNPs-LiYF are added 4 Yb and Er were added to 2mL of an aqueous solution containing 100mg of PVP, the mixed solution was placed on a magnetic stirrer and stirred at room temperature for 6 hours, and the precipitate obtained after centrifugation at 13000 rpm was washed with pure water 3 times and dispersed in pure water. The rare earth doped up-conversion nanoparticles UCNPs-PVP with PVP modified on the surface can be obtained through the steps.
(3) 1mg of rose bengal was added to a solution of UCNPs-PVP dissolved in water, and the mixture was stirred continuously at room temperature in the dark for 6 hours, and the precipitate obtained after centrifugation at 13000 rpm was washed with pure water for 3 times and dispersed in pure water. The rare earth doped up-conversion nanoparticle photosensitizer composite material UCNPs-PVP-RB can be obtained through the steps, wherein the load rate of the RB is 1.8wt%.
Example 2: UCNPs-PVP-RB (u-carboxy terminal protein-poly (vinyl pyrrolidone) -RB) for antibacterial research of pan-drug-resistant acinetobacter baumannii
In vitro experiments: mu.L of pan-resistant A.baumannii stored in glycerol was taken out from a refrigerator at-80 ℃ and added to 2mL of LB (Luria-Bertani) medium for 12 hours, 2. Mu.L of the resulting suspension was aspirated and added again to 2mL of LB medium for 4 hours until the bacteria grew to the logarithmic phase (about 10.) 8 CFU/mL). Diluting the bacterial liquid to 10 6 Then, the UCNPs-PVP-RB of example 1 with different concentrations were added and incubated for 10min in dark, the mixed solution was irradiated with 980nm laser, 100. Mu.L of the solution was smeared on a solid agar plate and incubated overnight in a 37 ℃ incubator. And finally, investigating the in-vitro antibacterial effect of UCNPs-PVP-RB on pan-drug-resistant acinetobacter baumannii by a plate counting method. The results show that the antibacterial effect can reach 4.7log when the concentration reaches 50 mu g/mL 10 . In addition, the antibacterial capability of UCNPs-PVP-RB to pan-drug-resistant acinetobacter baumannii of deep tissues is investigated by using pork tissues with the thickness of 5mm to block 980nm laser, and the result shows that the 980nm laser can still excite the nano material to generate a photodynamic antibacterial effect under the shielding of the pork tissues.
Animal experiments: a mouse local wound tissue infection model was used to evaluate the therapeutic effect of the composite material UCNPs-PVP-RB of example 1 on the pan-resistant A.baumannii-induced deep tissue infection. First, a 1cm X1 cm piece of skin tissue was excised from the back of a mouse, and 20. Mu.L of 10-concentration skin tissue was aspirated 8 CFU/mL of bacteria was incubated for 10min at the wound site on the back of the mouse. Then, 20. Mu.L of the composite material with a concentration of 1mg/mL was aspirated and incubated at the wound site of the mouse, and after 10min, the wound site of the mouse (covered with 5mm pork tissue) was fixed and irradiated with 980nm laser for 10min. Finally, the mice were kept normally and were observed daily for wound healing. Meanwhile, a blank control group (physiological saline replaces composite materials), a UCNPs-PVP-RB +980nm group, a UCNPs-PVP-RB +550nm group and a UCNPs-PVP-RB +550nm + pork tissue group are set. The results show that in the presence of pork tissue, the 980nm laser can still activate RB to produce photodynamic action, kill bacteria on wounds and promoteAnd (5) healing the wound. The UCNPs-PVP-RB can effectively treat deep tissue infection caused by pan-drug resistant acinetobacter baumannii under the excitation of 980 nm.
FIG. 2 shows a rare earth doped upconversion nanoparticle LiYF of example 1 of the present invention 4 Transmission electron micrographs of Yb, er. As can be seen from FIG. 2, the synthesized LiYF 4 Yb and Er are tetragonal phase with size of 50 +/-5 nm multiplied by 35 +/-5 nm, and the nano particles are monodisperse and uniform in shape and size. The high-resolution transmission electron microscope picture shows obvious (101-plane) lattice stripes, and proves that the synthesized nano particles have better crystallization degree, and the distance between lattices is about 0.41nm.
FIG. 3 is a graph of upconversion spectra of UCNPs, UCNPs-PVP and UCNPs-PVP-RB of example 1 of the present invention. As can be seen from FIG. 3, under the irradiation of 980nm laser, the nanometer particle UCNPs have stronger luminescence near 550nm and 668nm, which is caused by Er ion 4 S 3/2 → 4 I 15/2 And 2 F 9/2 → 4 I 15/2 energy level transitions in between. The modification of the PVP layer does not influence the up-conversion luminescence of the nano material, and after the PVP layer is loaded on RB, the luminescence at 550nm is obviously reduced compared with the luminescence at 668nm, which shows that energy transfer occurs between the nano material and RB, because Er ions 4 S 3/2 → 4 I 15/2 The luminescence of (b) is exactly matched to the absorption of RB at 550nm, which is the basis for energy transfer to occur.
FIG. 4 is a graph showing the ROS yield of UCNPs-PVP-RB in example 1 of the present invention. Wherein the ordinate represents the fluorescence value of DCF at 520nm, and the generation level of active oxygen can be detected by using the fluorescence of DCF. DCFH-DA itself has no fluorescence and can be hydrolyzed to generate DCFH. Whereas DCFH without fluorescence can be oxidized by active oxygen to generate DCF with fluorescence. As can be seen from FIG. 4, the fluorescence value at 520nm increased with the increase of the irradiation time after the addition of UCNPs-PVP-RB. After 10min of irradiation, the fluorescence value of the drug-added illumination group (DCFH-DA + UCNPs-PVP-RB +980 nm) at 520nm was increased by 6.7 times (9374/1215-1 = 6.7) compared with the simple illumination group (DCFH-DA +980 nm), the simple drug-added group (DCFH-DA + UCNPs-PVP-RB) and the control group (DCFH-DA). It is shown that under 980nm illumination, UCNPs transmit 980nm light to RB, and further activated RB reacts with ambient oxygen to generate large amounts of ROS.
FIG. 5 is a graph showing the in vitro antibacterial effect of UCNPs-PVP-RB of example 2 of the present invention against pan-resistant A.baumannii. As can be seen from (a) in FIG. 5, under 980nm illumination, with the increasing concentration of UCNPs-PVP-RB, the survival number of bacteria is continuously reduced, and when the concentration reaches 50 mug/mL, the bactericidal effect of the UCNPs-PVP-RB reaches 4.72log 10 While the simple light and UCNPs-PVP-RB did not affect the survival number of the bacteria. Indicating that UCNPs-PVP-RB can generate a large amount of ROS to kill target bacteria under the illumination of 980 nm. As can be seen from (b) of fig. 5, in the case where the excitation light is not blocked by the pork tissue (i.e., in the case where the thickness of the pork tissue is 0 mm), both 550nm and 980nm light can activate UCNPs-PVP-RB to generate ROS to kill bacteria, whereas in the case where the excitation light is blocked by the pork tissue (i.e., in the case where the thickness of the pork tissue is 5 mm), the 550nm light cannot penetrate the pork tissue to activate UCNPs-PVP-RB to generate photodynamic action, and the 980nm light can penetrate the pork tissue to continue to activate UCNPs-PVP-RB to generate photodynamic action. Meanwhile, the control group shows that the pure laser irradiation with the wavelength of 550nm or 980nm does not produce the antibacterial effect. Shows that UNCPs-PVP-RB can kill pan-drug-resistant acinetobacter baumannii in deep tissues under the excitation of 980nm light.
FIG. 6 is a graph showing the therapeutic effect of UCNPs-PVP-RB of example 1 of the present invention on the local wound infection of mice caused by pan-resistant A.baumannii.
As can be seen from fig. 6, the wound healing speed of the mice in the group of "UCNPs-PVP-RB +550nm + pork tissue" is not significantly different from that of the control group, while the wound healing speed of the mice in the group of "UCNPs-PVP-RB +980nm", the group of "UCNPs-PVP-RB +550nm" and the group of "UCNPs-PVP-RB +550nm + pork tissue" is significantly increased compared with that of the control group, which indicates that, even if the pork tissue blocks the mouse wound healing speed, 980nm light can still activate the UCNPs-PVP-RB to generate photodynamic force, kill pan-resistant acinetobacter baumannii in deep tissues, and thus promote the healing of the mouse wound.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (9)

1. A composite material for treating an infection caused by acinetobacter baumannii, comprising rare earth-doped up-conversion nanoparticles, a modifier and a photosensitizer, wherein the surface of the rare earth-doped up-conversion nanoparticles is connected with the modifier through coordination, and the photosensitizer is adsorbed to the surface of the rare earth-doped up-conversion nanoparticles connected with the modifier through electrostatic interaction;
the composite material has a core-shell structure, the core comprises rare earth doped up-conversion nanoparticles, the shell comprises a modifier and a photosensitizer, and the shell is coated on the outer surface of the core;
the photosensitizer is rose bengal;
the chemical formula of the rare earth doped up-conversion nano particles is LiYF 4 :Yb,Er；
The modifier is selected from one, two or more of polyvinylpyrrolidone, chitosan, polyethyleneimine, polyacrylic acid and polyethylene glycol.
2. The composite of claim 1, wherein the photosensitizer is adsorbed to the surface of the rare earth doped up-conversion nanoparticle having a modifier attached thereto by electrostatic interaction between the negative charge of its surface and the positive charge of the surface of the rare earth doped up-conversion nanoparticle.
3. The composite of claim 2, wherein the photosensitizer is located within the modifier layer, or at the outer surface of the modifier layer, or both.
4. The composite material according to any one of claims 1 to 3, wherein the loading rate of the photosensitizer in the composite material is 0.1 to 5wt%;
the particle size of the composite material is 10-120 nm;
the zeta potential of the composite material is-10 mV to 50 mV.
5. A method of preparing a composite material as claimed in any one of claims 1 to 4, comprising the steps of:
(1) Mixing the water-soluble rare earth-doped up-conversion nanoparticles with a modifier, and obtaining the rare earth-doped up-conversion nanoparticles with the surface modified with the modifier through coordination;
(2) And (2) mixing the rare earth-doped up-conversion nanoparticles with the surface modified with the modifier in the step (1) with a photosensitizer, and obtaining the composite material through electrostatic interaction.
6. The preparation method according to claim 5, wherein in the step (1), the weight ratio of the water-soluble rare earth doped up-conversion nanoparticles to the modifier is 1 (5-20);
in the step (2), the weight ratio of the rare earth doped up-conversion nanoparticles with the surface modified by the modifier to the photosensitizer is (5-15): 1.
7. The method of claim 5, wherein the water-soluble rare earth doped upconversion nanoparticles of step (1) are prepared by:
and (3) carrying out acid washing on the oil-soluble rare earth-doped up-conversion nanoparticles, and removing oleic acid and oleylamine coated on the surfaces of the oil-soluble rare earth-doped up-conversion nanoparticles to obtain the oil-soluble rare earth-doped up-conversion nanoparticles.
8. Use of the composite material according to any one of claims 1 to 4 or obtained by the preparation process according to any one of claims 5 to 7 for the preparation of a therapeutic agent for the treatment of an infection caused by Acinetobacter baumannii.
9. The use according to claim 8 for the preparation of a therapeutic agent for the treatment of pan-resistant deep tissue infections caused by acinetobacter baumannii.
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