CN109966489B - Nano composite material with photodynamic and photothermal combined treatment function and preparation method and application thereof - Google Patents

Nano composite material with photodynamic and photothermal combined treatment function and preparation method and application thereof Download PDF

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CN109966489B
CN109966489B CN201711457320.XA CN201711457320A CN109966489B CN 109966489 B CN109966489 B CN 109966489B CN 201711457320 A CN201711457320 A CN 201711457320A CN 109966489 B CN109966489 B CN 109966489B
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刘湘梅
韩艺蕃
蒋嘉洋
邹亮
田康
赵强
刘淑娟
黄维
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Nanjing University of Posts and Telecommunications
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Abstract

A nano composite material with photodynamic and photothermal combined treatment functions and a preparation method and application thereof belong to the technical field of nano material preparation and special materials. The composite nano material takes mesoporous silica nanoparticles as a carrier, and simultaneously modifies an organic photosensitizer iridium complex, a nano copper sulfide photo-thermal reagent and bovine serum albumin. The nano composite material with the photo-thermal and photo-dynamic treatment functions has the technical advantages of high biocompatibility, high-efficiency singlet oxygen generating photo-dynamic effect, near infrared light absorption to generate heat, simple preparation process, low cost, high photo-thermal conversion efficiency, good photo-dynamic effect, wide application range and the like, and has important application prospect in the aspect of tumor treatment.

Description

Nano composite material with photodynamic and photothermal combined treatment function and preparation method and application thereof
Technical Field
The invention belongs to the technical field of nano material preparation technology and special materials, and particularly relates to a nano composite material with photodynamic and photothermal combined treatment functions, and a preparation method and application thereof.
Background
Cancer has become one of the major life threatening factors for humans over the last centuries. On one hand, the conventional diagnosis method is relatively low in specificity and sensitivity, so that the detection is difficult in the early stage of tumor occurrence, and when the diagnosis is confirmed, tumor cells are already transferred, so that the optimal time for treatment is missed, and the current situations that the cancer is found late and the cure is difficult are further caused. On the other hand, the treatment methods for cancer mainly comprise traditional surgical excision, chemotherapy, radiotherapy, traditional Chinese medicine treatment and the like at present, but the treatments still have defects, such as killing cancer cells and normal cells, damaging immune systems to a certain extent, causing large side effects and even possibly causing secondary cancer of organisms. Therefore, the development of new methods for treating tumors with high efficiency and low side effects is not easy.
In recent years, with the continuous development of nanotechnology, the fluorescent nanoprobe has been widely used in the fields of chemistry, biology, medicine, etc., especially in the diagnosis, imaging and treatment of tumor cells. The nano tumor medicine formed by combining nano technology and tumor medicine is an emerging important field in nano medicine, and brings new hope for early diagnosis and treatment of cancer. At present, a photosensitizer is a fluorescent probe with diagnosis and treatment effects, the distribution and the uptake of the photosensitizer in tissues can be monitored through the fluorescence of the photosensitizer, and normal tissues and pathological tissues can be effectively distinguished, so that the cancer can be diagnosed and analyzed. The photosensitizer can also absorb the energy of light with specific wavelength and transmit the energy to the surrounding oxygen molecules to generate singlet oxygen with strong activity, and the generated singlet oxygen and adjacent biological macromolecules generate oxidation reaction to generate cytotoxicity effect, thereby causing cell damage and even cell death. The metal iridium complex photosensitizer has the characteristics of large Stokes shift, adjustable absorption spectrum and fluorescence spectrum, high fluorescence quantum yield, long phosphorescence life and the like, and can reach a triplet state through intersystem crossing after being excited by proper light due to the heavy atom effect of metal iridium, transfer energy to oxygen molecules to generate singlet oxygen, and further can be used for photodynamic therapy of tumor cells.
In photodynamic therapy, the desired therapeutic effect cannot be achieved because the penetration of the photosensitizer is limited and prolonged treatment is followed by severe local hypoxia due to tissue oxygen consumption, which prevents further procedures. The excessive heat energy generated by the laser absorbed by the photothermal therapy may cause unnecessary heating effect on normal tissues, and the photothermal therapy effect is limited by limiting the power of the irradiated laser and the possibility of recurrence of the photothermal therapy. Therefore, materials with photo-thermal and photodynamic treatment effects are combined, the materials are simple to prepare, high in specific surface area, large in porosity and good in biocompatibility and stability, and the materials are usually selected as excellent carrier silicon dioxide nano materials for receptors and chromophores for co-treatment, so that the treatment effect can be improved, the dosage of reagents is reduced, the treatment light energy is reduced, the risk of over-treatment is reduced, and a new thought and means are provided for tumor diagnosis and treatment.
Disclosure of Invention
The technical problem to be solved is as follows: aiming at the problems in the prior art, the invention provides a nano composite material with photodynamic and photothermal combined treatment functions and a preparation method and application thereof.
The technical scheme is as follows: a nano composite material with photodynamic and photothermal combined treatment functions comprises a mesoporous silica nano material with sulfydryl on the surface, an organic iridium complex, copper sulfide and bovine serum albumin.
The mesoporous silica nano material has a particle size of 50-80nm, a mesoporous structure and a pore diameter of 2-6 nm;
the organic matterThe structural formula of the iridium complex is
Figure BDA0001529475890000021
The organic iridium complex, copper sulfide and bovine serum albumin BSA are sequentially modified on the mesoporous silica nano material with sulfydryl on the surface.
Another technical scheme of the present invention is a method for preparing the nanocomposite material with the combined photodynamic and photothermal therapy function, wherein the method comprises the following steps:
step one, synthesizing an organic photosensitizer Ir complex, wherein the synthetic route is as follows:
Figure BDA0001529475890000022
firstly, mixing benzothiophene-2-boric acid, 1-chloroisoquinoline and palladium tetratriphenylphosphine, introducing nitrogen, adding toluene, ethanol and sodium carbonate aqueous solution, refluxing and stirring overnight, extracting, decompressing and spin-drying, and then purifying by a column to obtain a compound 1
Figure BDA0001529475890000031
Then mixing the compound 1 with iridium chloride trihydrate, introducing nitrogen, adding ethylene glycol ethyl ether and water, refluxing and stirring uniformly, filtering and drying to obtain a compound 2
Figure BDA0001529475890000032
Then mixing the compound 2 with 3-hydroxy-2-picolinic acid and sodium carbonate, introducing nitrogen, adding ethylene glycol ethyl ether, refluxing and stirring, extracting, performing reduced pressure spin drying, and purifying by a column to obtain an iridium complex Ir-OH compound 3
Figure BDA0001529475890000033
Mixing the compound 3 with 3-bromopropylene and sodium carbonate, stirring for reaction, extracting, performing reduced pressure spin drying, and purifying by a column to obtain an iridium complex Ir-double bond compound 4
Figure BDA0001529475890000034
Step two, synthesizing a mesoporous silica nano material with sulfydryl on the surface, mixing water, ethanol, diethanol amine and a hexadecyl trimethyl ammonium chloride aqueous solution, stirring for reaction, then adding tetraethoxysilane and 3-mercaptopropyl trimethoxy silane, continuing stirring for reaction, after the reaction is finished, centrifugally washing by using a mixed solution of ethanol and water, then dispersing in a solution of concentrated hydrochloric acid and ethanol, then stirring for reaction, and finally, centrifugally washing by using a mixed solution of ethanol and water to obtain the mesoporous silica nano material mSiO O with sulfydryl on the surface2NPs；
Step three, synthesizing mSiO2/CuS NPs, preparation of mSiO in step two2NPs are dispersed in water, the pH value of the solution is adjusted to be alkaline, then copper chloride solution is added, stirring reaction is carried out overnight, the pH value is adjusted to be acidic, sodium sulfide solution is added, reaction is carried out, and the target product copper sulfide modified mesoporous silica nano material mSiO with sulfydryl on the surface is obtained2/CuS NPs；
Step four, synthesizing mSiO2The preparation method comprises the steps of mixing the iridium complex Ir-double bond compound 4 prepared in the step one, 3-mercaptopropyltrimethoxysilane and tetrahydrofuran, adding benzoin dimethyl ether, illuminating under an ultraviolet lamp, and mixing the mSiO O prepared in the step three2dispersing/CuS NPs in ethanol, adjusting pH to alkalinity, adding the solution after illumination into the solution adjusted to alkalinity, heating for overnight reaction to obtain a target product mSiO2/CuS/Ir NPs；
Step five, synthesizing mSiO2(CuS/Ir/BSA NPs) bovine serum albumin BSA and mSiO prepared in step four2Dispersing the/CuS/Ir NPs material in water, and reacting at room temperature to obtain a target product mSiO2/CuS/Ir/BSA NPs。
Preferably, the preparation method comprises the following steps:
firstly, mixing benzothiophene-2-boric acid, 1-chloroisoquinoline and palladium tetratriphenylphosphine, introducing nitrogen, adding toluene, ethanol and sodium carbonate aqueous solution, refluxing and stirring overnight, extracting, decompressing and spin-drying, and then passing through a columnPurification to obtain compound 1
Figure BDA0001529475890000041
Then mixing the compound 1 with iridium chloride trihydrate, introducing nitrogen, adding ethylene glycol ethyl ether and water, refluxing and stirring for 24 hours, filtering and drying to obtain a compound 2
Figure BDA0001529475890000042
Then mixing the compound 2 with 3-hydroxy-2-picolinic acid and sodium carbonate, introducing nitrogen, adding ethylene glycol ethyl ether, refluxing and stirring for 10-24h at the temperature of 100-120 ℃, extracting, decompressing and spin-drying, purifying by a column to obtain an iridium complex Ir-OH compound 3
Figure BDA0001529475890000043
Mixing the compound 3 with 3-bromopropylene and sodium carbonate, stirring for 12h at 30 ℃, extracting, performing reduced pressure spin drying, and purifying by a column to obtain an iridium complex Ir-double bond compound 4
Figure BDA0001529475890000044
Step two, synthesizing a mesoporous silica nano material with sulfydryl on the surface, mixing water, ethanol, diethanol amine and a hexadecyl trimethyl ammonium chloride aqueous solution, stirring and reacting for 0.5h at 60 ℃, then adding tetraethoxysilane and 3-mercaptopropyl trimethoxy silane, continuously stirring and reacting for 3h, after the reaction is finished, centrifugally washing for 2-5 times by using a mixed solution of ethanol and water, then dispersing in a solution of concentrated hydrochloric acid and ethanol, stirring and reacting for 24h at 60 ℃, and finally centrifugally washing for 2-5 times by using a mixed solution of ethanol and water to obtain the mesoporous silica nano material with sulfydryl on the surface, namely mSiO O2NPs；
Step three, synthesizing mSiO2/CuS NPs, preparation of mSiO in step two2Dispersing NPs in water, adjusting the pH value of the solution to be alkaline, then adding a copper chloride solution, stirring for reaction overnight, adjusting the pH value to be acidic, adding a sodium sulfide solution, and reacting at 90 ℃ for 1h to obtain a target product copper sulfide modified mesoporous silica nano material mSiO with sulfydryl on the surface2/CuSNPs；
Step four, synthesizing mSiO2and/CuS/Ir NPs, mixing an iridium complex Ir-double bond compound 4, 3-mercaptopropyltrimethoxysilane and tetrahydrofuran, then adding benzoin dimethyl ether, illuminating for 15-60 min under an ultraviolet lamp, and carrying out the step three to prepare the mSiO2dispersing/CuS NPs in ethanol, adjusting the pH value to be alkaline, then adding the solution after illumination into the solution adjusted to be alkaline, heating at 25-60 ℃ for overnight reaction to obtain a target product mSiO2/CuS/Ir NPs；
Step five, synthesizing mSiO2(ii)/CuS/Ir/BSA NPs, bovine serum albumin BSA and mSiO prepared in step four2Dispersing the/CuS/Ir NPs material in water, and reacting at room temperature to obtain a target product mSiO2/CuS/Ir/BSA NPs。
Preferably, in the first step, the compound 2, 3-hydroxy-2-picolinic acid and sodium carbonate are mixed, nitrogen is introduced, ethylene glycol ethyl ether is added, reflux and stirring are carried out at 110 ℃ for 12 hours, extraction is carried out, decompression and spin drying are carried out, and the iridium complex Ir-OH, namely the compound 3, is obtained by column purification
Figure BDA0001529475890000051
Mixing the compound 3 with 3-bromopropylene and sodium carbonate, stirring for 12h at 30 ℃, extracting, decompressing, spin-drying, and purifying the iridium complex Ir-double bond by passing through a column to obtain a compound 4
Figure BDA0001529475890000052
Preferably, in the fourth step, the mSiO prepared in the third step is irradiated for 40min under an ultraviolet lamp2dispersing/CuS NPs in ethanol, adjusting pH to alkalinity, adding the solution after illumination into the solution after alkalinity adjustment, heating at 50 ℃ overnight for reaction to obtain a target product mSiO2/CuS/Ir NPs。
The nanometer composite material with the combined treatment function of photodynamic and photothermal is applied to the preparation of the medicine for preventing and treating tumor diseases.
Furthermore, the nano composite material with the combined treatment function of photodynamic and photothermal is applied to the preparation of the medicament for photodynamic treatment of tumor diseases.
Further, the nano composite material with the combined photodynamic and photothermal treatment function is applied to preparing a medicine for treating tumor diseases by using photothermal treatment.
Furthermore, the nano composite material with the combined photodynamic and photothermal treatment function is applied to preparing a medicine for treating tumor diseases by combining photodynamic and photothermal treatment.
Has the advantages that:
1. mSiO of the invention2the/CuS/Ir/BSA material has the advantages of higher specific surface, large loading capacity and good biocompatibility, and is easy to enter cells.
2. The mSiO of the invention2The preparation method of the/CuS/Ir/BSA NPs material has the technical advantages of simple preparation process, low cost, obvious effect, wide application range and the like.
3. mSiO of the invention2the/CuS/Ir/BSA NPs material has high photo-thermal conversion efficiency (the material in the patent is 31.2 percent under 808nm laser irradiation; Cu;)2-xSe nanocrystals (-22%, 808nm laser irradiation); cu9S5Nanocrystals (25.7%, 980nm laser irradiation)), good photodynamic effect (bpy)3Ru2+The complex (0.87) and the Ir complex is 1.3), can be applied to cell imaging and living body imaging, and has good application prospect in the treatment of cancers and tumor cells.
Drawings
FIG. 1. mSiO prepared in example 12SEM pictures of NPs;
FIG. 2 mSiO prepared in example 12SEM image of/CuS NPs;
FIG. 3 mSiO prepared in example 12SEM image of/CuS/Ir NPs;
FIG. 4. mSiO prepared in example 12SEM picture of/CuS/Ir/BSA NPs;
FIG. 5 mSiO prepared in example 12A stability comparison graph of/CuS/Ir/BSA NPs in different solvents;
FIG. 6 mSiO prepared in example 22UV-visible absorption spectra of/CuS/Ir NPs;
FIG. 7 mSiO prepared in example 32SEM picture of/CuS/Ir/BSA NPs;
FIG. 8 different Cu in photothermal testing in example 42+The temperature of the material with the concentration changes with time after being irradiated by laser;
FIG. 9-for Ir complex and mSiO in example 52In vitro photodynamic test pattern of/CuS/Ir/BSA NPs.
FIG. 10. mSiO in example 62Cytotoxicity (MTT) profile of/CuS/Ir/BSA NPs;
FIG. 11. mSiO in example 62Imaging plot of/CuS/Ir/BSA NPs in HeLa cells;
FIG. 12 mSiO in example 62Apoptosis pattern of/CuS/Ir/BSA NPs in HeLa cells;
FIG. 13 mSiO in example 72Graph of change in volume of the/CuS/Ir/BSA NPs after treatment in vivo after injection;
FIG. 14 is a schematic structural diagram of the nanocomposite material with photodynamic and photodynamic combined therapy functions according to the present invention.
Detailed Description
The following is a detailed description of the embodiments of the present invention, which is implemented on the premise of the technical solution of the present invention, and detailed implementation manners and specific operation procedures are given, but the scope of the present invention is not limited to the following examples.
Example 1
Step one, synthesis of metal Ir complex
Figure BDA0001529475890000071
I) adding 1g of benzothiophene-2-boric acid, 0.9g of 1-chloroisoquinoline and 0.3g of palladium tetratriphenylphosphine into a 250mL single-mouth bottle with a stirrer, introducing nitrogen, then adding 60mL of toluene, 20mL of ethanol and 20mL of 2M aqueous solution of sodium carbonate, refluxing and stirring overnight, extracting, performing reduced pressure spin drying, and purifying by a column to obtain white powder, namely the iridium complex Ir-1 compound 1
Figure BDA0001529475890000072
II) adding 500mg of the product obtained in the step I and 340mg of iridium chloride trihydrate into a 100mL single-neck bottle with a stirrer, introducing nitrogen, then adding 30mL of ethylene glycol ethyl ether and 10mL of water, refluxing and stirring for 24h, filtering, and drying to obtain a brick red powder compound 2
Figure BDA0001529475890000073
III) putting 680mg of the product obtained in the step II, 130mg of 3-hydroxy-2-picolinic acid and 300mg of sodium carbonate into a 100mL single-mouth bottle with a stirrer, introducing nitrogen, adding 30mL of ethylene glycol ethyl ether, refluxing and stirring for 10h at 120 ℃, extracting, drying in a spinning way, purifying by a column to obtain red powder, namely the iridium complex Ir-OH compound 3
Figure BDA0001529475890000074
Yield: 42 percent.1H NMR(400MHz,DMSO-d6)δ(ppm):13.4(s,1H)；8.978(d；1H；J＝8.4Hz)；8.922(d；1H；J＝8.4Hz)；8.424(d；1H；J＝6.8Hz)；8.167(m,1H)；7.953(m,6H)；7.790(d；1H；J＝6.4Hz)；7.640(d；1H；J＝6.4Hz)；7.587(dd；1H；J1＝0.8Hz,J2＝8.8Hz)；7.465(m,2H)；7.160(m,3H)；6.784(t；1H；J＝8Hz)；6.671(t；1H；J＝8Hz)；6.266(d；1H；J＝8.8Hz)；5.976(d；1H；J＝8Hz)；5.303(t；1H；J＝5.2Hz).
IV) taking the product 110mg, 130 mu L of 3-bromopropylene and 260mg of sodium carbonate obtained in the step III, stirring the mixture in a 100mL flask at the temperature of 30 ℃ for 12 hours, extracting the mixture, performing reduced pressure spin drying, and purifying the mixture by a column to obtain red powder, namely the iridium complex Ir-double bond compound 4
Figure BDA0001529475890000081
The yield was 64%.1H NMR(400MHz,DMSO)δ(ppm):8.96(dd；J1＝17.6Hz；J2＝8Hz；2H)；8.55(d；J＝6.8Hz；1H)；8.16(dd；J1＝7.2Hz；J2＝2Hz；2H)；7.95(m；6H)；7.77(m；2H)；7.63(d；J＝10.4Hz；1H)；7.48(m；2H)；7.19(m；2H)；7.13(t；J＝7.6Hz；1H)；6.79(t；J＝7.6Hz；1H)；6.67(t；J＝7.6Hz；1H)；6.29(d；J＝8Hz；1H)；5.99(d；J＝8Hz；1H)；5.58(dd；J1＝2Hz；J2＝17.6Hz；1H)；4.68(m；1H)；3.63(s；2H)；
Step two, synthesizing mesoporous silicon dioxide nano material mSiO with sulfydryl on surface2NPs
64mL of water, 11.25mL of ethanol, 0.2g of diethanolamine and 10.4mL of a 25 wt.% aqueous solution of cetyltrimethylammonium chloride CTAC were mixed uniformly and reacted at 60 ℃ for 30min, then 7mL of a mixture of tetraethoxysilane TEOS and 0.6mL of 3-mercaptopropyltrimethoxysilane was added and the reaction was continued with stirring for 3 h. After the reaction was completed, the mixture was washed 2-5 times by centrifugation, and then redispersed in 120mL of a 37 wt% solution of concentrated hydrochloric acid and 15mL of ethanol, followed by stirring the reaction at 60 ℃ for 24 hours, and finally, washed 2-5 times by centrifugation with a mixture of ethanol and water. The SEM image obtained by the test is shown in figure 1, and the particle size is about 50-80nm, the SEM image has a mesoporous structure, and the pore diameter is about 2-6 nm.
Step three, synthesizing mSiO2/CuS NPs
Taking the mSiO prepared in the step two2Dispersing 20mg of NPs in 20mL of water, adjusting the pH value of the solution to be alkaline, adding 200 mu L of 0.1M copper chloride solution, stirring for reaction overnight, adjusting the pH value to be acidic, adding 400 mu L of 0.1M sodium sulfide solution, and reacting for 1h at 90 ℃ to obtain a target product, namely copper sulfide modified mesoporous silica nano material mSiO O with sulfydryl on the surface2(ii)/CuS NPs. The SEM image of the product obtained by the test is shown in fig. 2.
As can be seen from fig. 1 to 2, the particle size of the mesoporous silica modified with copper sulfide is slightly changed, and the particle structure thereof is not damaged.
Step four, synthesizing mSiO2/CuS/Ir NPs
Uniformly mixing 3mg of Ir complex, 1.5 mu L of 3-mercaptopropyltrimethoxysilane and 1.5mL of tetrahydrofuran, adding 2.3 mu L of 0.1M of uniformly mixed benzoin dimethyl ether tetrahydrofuran solution, illuminating for 15min under an ultraviolet lamp, dispersing the material obtained in the step three in 20mL of ethanol, adjusting the pH value to be alkaline, adding the illuminated solution into the solution, and heating at 60 ℃ overnight to obtain the target product. The SEM image of the product obtained by the test is shown in fig. 3.
As can be seen from a comparison of fig. 3 and fig. 2, the dispersibility of the nanoparticles after modification of the Ir complex is not much different from that before modification, and there is no free Ir complex outside the nanoparticles.
Step five, synthesizing mSiO2/CuS/Ir/BSA NPs
Dispersing 200mg BSA and the material obtained in the fourth step into 20mL water, and then stirring at room temperature for reaction for 3h to obtain the target product mSiO2The structural diagram of the target product of the/CuS/Ir/BSA NPs is shown in FIG. 14. The SEM image obtained by the test is shown in FIG. 4, and the image of the material dispersed in different solvents before and after the modification of BSA is shown in FIG. 5.
In the figure, a is that materials before BSA modification are ultrasonically dispersed in ultrapure water, PBS and DMEM cell culture solution respectively; b, ultrasonically dispersing the material before BSA modification in ultrapure water, PBS and DMEM cell culture solution respectively and standing for a period of time; c, ultrasonically dispersing the material modified with BSA in ultrapure water, PBS and DMEM cell culture solution respectively; d is that the material after BSA modification is ultrasonically dispersed in ultrapure water, PBS and DMEM cell culture solution respectively and stands for a period of time. From the graphical comparison, the modified BSA material was stable in both PBS and culture.
Example 2
The difference from example 1 is in step III and step four in step 1.
III) in the step 1), putting 680mg of the product obtained in the step II, 130mg of 3-hydroxy-2-picolinic acid and 300mg of sodium carbonate into a 100mL single-neck bottle with a stirrer, introducing nitrogen, adding 30mL of ethylene glycol ethyl ether, refluxing and stirring for 24h at 100 ℃, extracting, spin-drying, purifying by a column to obtain red powder, namely the iridium complex Ir-OH compound 3
Figure BDA0001529475890000091
Yield: 45 percent.
Step four, synthesizing mSiO2/CuS/Ir NPS, 3mg Ir complex, 1.5. mu.L 3-mercaptopropyltrimethoxysilane and 1.5mL tetrahydrofuran are mixed uniformly, 2.3. mu. L0.1M of the uniformly mixed benzoin bis-methyl ether tetrahydrofuran solution is added, and the mixture is put under an ultraviolet lampAnd (3) irradiating for 60min, dispersing the material obtained in the third step in 20mL of ethanol, adjusting the pH value to be alkaline, adding the irradiated solution into the solution, and heating at 25 ℃ overnight to obtain the target product. The ultraviolet absorption pattern of the product obtained by the test is shown in FIG. 6. The CuS and Ir complexes are modified on the mesoporous silica nanoparticles by ultraviolet absorption.
Example 3
The difference from example 1 is in step III and step four in step 1.
III) in the step 1), putting 680mg of the product obtained in the step II, 130mg of 3-hydroxy-2-picolinic acid and 300mg of sodium carbonate into a 100mL single-neck bottle with a stirrer, introducing nitrogen, adding 30mL of ethylene glycol ethyl ether, refluxing and stirring for 12h at 110 ℃, extracting, spin-drying, purifying by a column to obtain red powder, namely the iridium complex Ir-OH compound 3
Figure BDA0001529475890000101
Yield: and 55 percent.
Step four, synthesizing mSiO2The preparation method comprises the following steps of/CuS/Ir NPS, uniformly mixing 3mg of Ir complex, 1.5 mu L of 3-mercaptopropyltrimethoxysilane and 1.5mL of tetrahydrofuran, adding 2.3 mu L0.1M of the uniformly mixed benzoin bis-methyl ether tetrahydrofuran solution, irradiating for 40min under an ultraviolet lamp, dispersing the material obtained in the third step in 20mL of ethanol, adjusting the pH value to be alkaline, adding the irradiated solution into the solution, and heating at 50 ℃ overnight to obtain a target product. The SEM image obtained from the test is shown in FIG. 7. Compared with examples 1 and 2, the Ir complex in example 3 has higher synthesis yield and more amount of the modified CuS and Ir complex.
Example 4
Using the mSiO obtained in example 32The material is/CuS/Ir/BSA NPs, and an in-vitro photothermal test is carried out.
The material obtained in example 1 was formulated into an aqueous solution to make Cu2+Respectively at concentrations of 0, 1.5625, 3.125, 6.25, 12.5 and 50, using a laser at 808nm and 0.72W/cm2The power of the light is irradiated for 5min, and the temperature change curve of the obtained materials with different concentrations along with the time is shown in figure 8.
As can be seen from fig. 8, the prepared material has a significant photothermal function, and the temperature rise of the material becomes more significant as the illumination time is prolonged. And under the irradiation of the laser with the same power, the higher the concentration of the material is, the higher the temperature rise is. The photo-thermal conversion efficiency of the existing photosensitive material is as follows: under the irradiation of 808nm laser, the gold rod is about 21.0 percent; cu2-xSe nanocrystal-22%; cu9S5Nanocrystal 25.7% (see Dalton Trans, 2015,44, 10343-.
The photothermal conversion efficiency of the nanocomposite prepared by the present invention was calculated according to the Roper's method, and it was found that the photothermal conversion efficiency was 31.2%.
Example 5
Using the mSiO obtained in example 32The material is/CuS/Ir/BSA NPs, and the in-vitro photodynamic test is carried out. By 1, 3-Diphenylisobenzofuran (DPBF)1O2The indicator produced was of Ru (bpy)3 2+(the yield of active oxygen molecules in methanol was 0.87) as a reference photosensitizer. Determination of pure Ir Complex and mSiO2Method for producing/CuS/Ir/BSA NPs in methanol1O2Quantum yield. Using a 475nm xenon lamp at 5mW/cm2And (3) after illumination is carried out under power, an ultraviolet-visible spectrophotometer is used for testing, the change of the ultraviolet absorption spectrum of the DPBF is observed, the ultraviolet absorption value at 414nm can be obtained from the absorption spectrum, and the graph 9 is obtained by using the difference value between the absorption value of the illumination curve at 414nm each time and the value when the graph is not illuminated (illumination is 0 s).
From the figure, Ir complexes and mSiO2the/CuS/Ir/BSA NPs all produce singlet oxygen according to
Figure BDA0001529475890000102
Figure BDA0001529475890000111
Formula (b) in which the ruthenium complex Ru (bpy)3 2+For reference, the subscript x represents the sample, std represents the ruthenium complex, S represents the slope of the line consisting of the descending dots of the indicator, F represents the absorption correction factor for the sample and the ruthenium complex, F ═ 1 to 10-ODOD represents the ruthenium complexThe ultraviolet absorption value of the compound at an irradiation wavelength of 475nm was calculated to give Φ Δ (Ir complex) ═ 1.3.
Example 6
Using the mSiO obtained in example 32the/CuS/Ir/BSA NPs material, tested in HeLa cells.
(1) Cytotoxicity test
The cytotoxicity test was determined by MTT cell activity standard assay for the HeLa cell line. Seeding the cells in a 96-well plate, controlling the cell density in each well at 1X 104Left and right, and cultured for 24 h. The plates were grouped and separately added to different concentrations (0, 20, 40, 60, 80, 100, 120. mu.g/mL) of mSiO2DMEM cell culture medium of/CuS/Ir/BSA NPs 150. mu.L each was put in 3 well plates. The cells were cultured for 4h under normal conditions, and the photothermal effect was measured at 720mW/cm using a 808nm laser2The power of the light source is 5min, and the photodynamic effect is realized by using a 520nm xenon lamp at the power of 30mW/cm2The power of (3) for 30min, the combined effect is respectively illuminated by the above 2 conditions, and then the culture is continued for 20 h. Thereafter, MTT-containing PBS was added to each well plate, and the plate was shaken with a shaker for 10 min. The cytotoxicity (MTT) calculated finally is shown in FIG. 10. It can be seen from the figure that the dark toxicity of the material increases with increasing material concentration, but the phototoxicity of the material also increases, and the dark toxicity of the material is greater at concentrations above 80 μ g/mL, and it can be seen that the effect of the combined treatment of PDT and PTT is greater than the effect of the treatment of PTT, and greater than the effect of the treatment of PDT.
(2) Confocal luminescent imaging
HeLa cells were incubated in culture dishes for 24h, and mSiO at 80. mu.g/mL was added2DMEM culture medium of/CuS/Ir/BSA NPs was incubated at 37 ℃ for 4 hours, washed 2 times with PBS and then confocal imaged as shown in FIG. 11.
mSiO is available from the figure2the/CuS/Ir/BSA NPs can well enter cells.
(3) HeLa imaging test of calcein (AM) coloration
HeLa cells were incubated in 3 dishes for 24h, and 3 portions of mSiO at 80. mu.g/mL were added2DMEM culture solution of/CuS/Ir/BSA NPs, and incubating for 4h in an incubator at 37 DEG CPDT treatment using a 520nm xenon lamp at 30mW/cm after washing 2 times with PBS2The power of the laser is 30min, and the laser with the wavelength of 808nm for the treatment of the PTT is 720mW/cm2The power of (3) for 5min, and the PDT and PTT combined treatment is respectively irradiated by the above 2 conditions. In the illumination process, one half of the culture dish is covered by tinfoil paper, and the other half of the culture dish is in direct contact with a light source, and an AM indicator is added after illumination to carry out confocal imaging, as shown in figure 12.
In the figure, the left side of a dotted line is covered by tinfoil paper, the right side of the dotted line is directly contacted with a light source, AM is stained with living cells (green fluorescence can be seen), AM is of an unstained color (namely green fluorescence cannot be seen) after the cells die, the picture is converted into a black-and-white image, green corresponds to white dots (representing the living cells), the dead cells cannot be seen, and the number of the white dots on the right side can be seen, so that the treatment effect is better (cells originally appearing on the image are stained with AM, have green fluorescence, the number of the green fluorescence on the right side is smaller, the number of the living cells is smaller, and the treatment effect is better). As can be seen from the figure, the treatment effect of PTT is better than that of PDT, but the effect of the combination treatment is the best.
Example 7
Using the mSiO obtained in example 32(ii)/CuS/Ir/BSA NPs material, in vivo.
Purchasing nude mice with tumor until the tumor grows to 200mm3At the time, experiments were started and they were randomly divided into the following groups: (1) a PBS group; (2) PBS + PDT + PTT light group; (3) a material group; (4) material + PDT illumination set; (5) material + PTT light group; (6) the change in tumor volume after 15 days of treatment in the material + PDT + PTT light group is shown in figure 13.
From the figure, the material + PDT illumination group has the effect of inhibiting the growth of the tumor, the material + PTT illumination group can eliminate the tumor, and the material + PDT + PTT illumination group can completely eliminate the tumor.

Claims (8)

1. A nano composite material with photodynamic and photothermal combined therapy functions is characterized in that the nano composite material comprises a mesoporous silica nano material with sulfydryl on the surface, an organic iridium complex, copper sulfide and bovine serum albumin,
the mesoporous silica nano material has a particle size of 50-80nm, a mesoporous structure and a pore diameter of 2-6 nm;
the structural formula of the organic iridium complex is shown in the specification
Figure DEST_PATH_IMAGE002
；
The organic iridium complex, copper sulfide and bovine serum albumin are sequentially modified on a mesoporous silica nano material with sulfydryl on the surface, and the preparation method of the nano composite material comprises the following steps:
step one, synthesizing an organic photosensitizer Ir complex, mixing benzothiophene-2-boric acid, 1-chloroisoquinoline and palladium tetratriphenylphosphine, introducing nitrogen, adding toluene, ethanol and a sodium carbonate aqueous solution, refluxing and stirring overnight, performing reduced pressure spin drying after extraction, and then performing column purification to obtain a compound 1
Figure DEST_PATH_IMAGE004
Then mixing the compound 1 with iridium chloride trihydrate, introducing nitrogen, adding ethylene glycol ethyl ether and water, refluxing and stirring uniformly, filtering and drying to obtain a compound 2
Figure DEST_PATH_IMAGE006
Then mixing the compound 2 with 3-hydroxy-2-picolinic acid and sodium carbonate, introducing nitrogen, adding ethylene glycol ethyl ether, refluxing and stirring, extracting, performing reduced pressure spin drying, and purifying by a column to obtain an iridium complex Ir-OH compound 3
Figure DEST_PATH_IMAGE008
Mixing the compound 3 with 3-bromopropylene and sodium carbonate, stirring for reaction, extracting, decompressing, spin-drying, purifying by a column to obtain the iridium complex Ir-double bond compound 4
Figure DEST_PATH_IMAGE010
；
Step two, synthesizing a mesoporous silicon dioxide nano material with sulfydryl on the surface, and mixing water, ethanol, diethanol amine and decaMixing hexaalkyltrimethyl ammonium chloride aqueous solution, stirring for reaction, adding tetraethoxysilane and 3-mercaptopropyl trimethoxy silane, continuing stirring for reaction, after the reaction is finished, centrifugally washing by using mixed solution of ethanol and water, dispersing in solution of concentrated hydrochloric acid and ethanol, stirring for reaction, and finally centrifugally washing by using mixed solution of ethanol and water to obtain mesoporous silica nano material mSiO O with sulfydryl on surface2 NPs；
Step three, synthesizing mSiO2/CuS NPs, preparation of mSiO in step two2NPs are dispersed in water, the pH value of the solution is adjusted to be alkaline, then copper chloride solution is added, stirring reaction is carried out overnight, the pH value is adjusted to be acidic, sodium sulfide solution is added, reaction is carried out, and the target product copper sulfide modified mesoporous silica nano material mSiO with sulfydryl on the surface is obtained2 /CuS NPs；
Step four, synthesizing mSiO2The preparation method comprises the steps of mixing the iridium complex Ir-double bond compound 4 prepared in the step one, 3-mercaptopropyltrimethoxysilane and tetrahydrofuran, adding benzoin dimethyl ether, illuminating under an ultraviolet lamp, and mixing the mSiO O prepared in the step three2dispersing/CuS NPs in ethanol, adjusting pH to alkalinity, adding the solution after illumination into the solution adjusted to alkalinity, heating for overnight reaction to obtain a target product mSiO2 /CuS/Ir NPs；
Step five, synthesizing mSiO2(ii)/CuS/Ir/BSA NPs, bovine serum albumin BSA and mSiO prepared in step four2Dispersing the/CuS/Ir NPs material in water, and reacting at room temperature to obtain a target product mSiO2 /CuS/Ir/BSA NPs。
2. The nanocomposite material with combined photodynamic and photothermal therapy function according to claim 1, wherein the preparation method of the nanocomposite material comprises the following steps:
step one, synthesizing an organic photosensitizer Ir complex, mixing benzothiophene-2-boric acid, 1-chloroisoquinoline and palladium tetratriphenylphosphine, introducing nitrogen, adding toluene, ethanol and a sodium carbonate aqueous solution, refluxing and stirring overnight, extracting, decompressing and spin-drying, and purifying by a column to obtain the organic photosensitizer Ir complexCompound 1
Figure DEST_PATH_IMAGE012
Then mixing the compound 1 with iridium chloride trihydrate, introducing nitrogen, adding ethylene glycol ethyl ether and water, refluxing and stirring for 24 hours, filtering and drying to obtain a compound 2
Figure DEST_PATH_IMAGE014
Then mixing the compound 2 with 3-hydroxy-2-picolinic acid and sodium carbonate, introducing nitrogen, adding ethylene glycol ethyl ether, refluxing and stirring for 10-24h at the temperature of 100-120 ℃, extracting, decompressing and spin-drying, purifying by a column to obtain an iridium complex Ir-OH compound 3
Figure DEST_PATH_IMAGE016
Mixing the compound 3 with 3-bromopropylene and sodium carbonate, stirring for 12h at 30 ℃, extracting, decompressing, spin-drying, purifying by a column to obtain the iridium complex Ir-double bond compound 4
Figure DEST_PATH_IMAGE018
；
Step two, synthesizing a mesoporous silica nano material with sulfydryl on the surface, mixing water, ethanol, diethanol amine and a hexadecyl trimethyl ammonium chloride aqueous solution, stirring and reacting for 0.5h at 60 ℃, then adding tetraethoxysilane and 3-mercaptopropyl trimethoxy silane, continuously stirring and reacting for 3h, after the reaction is finished, centrifugally washing for 2-5 times by using a mixed solution of ethanol and water, then dispersing in a solution of concentrated hydrochloric acid and ethanol, stirring and reacting for 24h at 60 ℃, and finally centrifugally washing for 2-5 times by using a mixed solution of ethanol and water to obtain the mesoporous silica nano material with sulfydryl on the surface, namely mSiO O2 NPs；
Step three, synthesizing mSiO2/CuS NPs, preparation of mSiO in step two2Dispersing NPs in water, adjusting the pH of the solution to be alkaline, then adding a copper chloride solution, stirring for reaction overnight, adjusting the pH to be acidic, adding a sodium sulfide solution, and reacting at 90 ℃ for 1h to obtain a target product copper sulfide modified mesoporous silica nano with sulfydryl on the surfaceRice material mSiO2 /CuS NPs；
Step four, synthesizing mSiO2and/CuS/Ir NPs, mixing an iridium complex Ir-double bond compound 4, 3-mercaptopropyltrimethoxysilane and tetrahydrofuran, then adding benzoin dimethyl ether, illuminating for 15-60 min under an ultraviolet lamp, and carrying out the step three to prepare the mSiO2dispersing/CuS NPs in ethanol, adjusting the pH value to be alkaline, then adding the solution after illumination into the solution adjusted to be alkaline, heating at 25-60 ℃ for overnight reaction to obtain a target product mSiO2 /CuS/Ir NPs；
Step five, synthesizing mSiO2(ii)/CuS/Ir/BSA NPs, bovine serum albumin BSA and mSiO prepared in step four2Dispersing the/CuS/Ir NPs material in water, and reacting at room temperature to obtain a target product mSiO2 /CuS/Ir/BSA NPs。
3. The nanocomposite with photodynamic and photothermal combined therapy function according to claim 2, wherein in the first step, the compound 2 is mixed with 3-hydroxy-2-picolinic acid and sodium carbonate, nitrogen is introduced, ethylene glycol ethyl ether is added, reflux stirring is carried out for 12 hours at 110 ℃, after extraction, reduced pressure spin drying is carried out, and column purification is carried out to obtain the iridium complex Ir-OH, namely the compound 3
Figure DEST_PATH_IMAGE020
Mixing the compound 3 with 3-bromopropylene and sodium carbonate, stirring for 12h at 30 ℃, extracting, decompressing, spin-drying, purifying by a column to obtain the iridium complex Ir-double bond compound 4
Figure DEST_PATH_IMAGE022
。
4. The nanocomposite with combined photodynamic and photothermal therapy function according to claim 2, wherein the mSiO prepared in the third step is irradiated under an ultraviolet lamp for 40min in the fourth step2dispersing/CuS NPs in ethanol, adjusting pH to alkalinity, adding the solution after illumination to the solution adjusted to alkalinity, addingHeating at 50 ℃ for overnight reaction to obtain a target product mSiO2 /CuS/Ir NPs。
5. Use of the nanocomposite material with combined photodynamic and photothermal therapy function according to claim 1 for the preparation of a medicament for the prevention and treatment of tumor diseases.
6. Use of the nanocomposite material with combined photodynamic and photothermal therapy function according to claim 1 for the preparation of a medicament for photodynamic therapy of tumor diseases.
7. Use of the combined photodynamic and photothermal therapy nanocomposite material as claimed in claim 1 for the preparation of a medicament for the photothermal therapy of neoplastic diseases.
8. Use of the photodynamic and photothermal combination therapy functional nanocomposite material as claimed in claim 1 for preparing a medicament for photodynamic and photothermal combination therapy of tumor diseases.
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