CN116947792B - Aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity and preparation method and application thereof - Google Patents
Aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity and preparation method and application thereof Download PDFInfo
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- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 63
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- 239000001301 oxygen Substances 0.000 title claims abstract description 54
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- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 claims description 22
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- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical group [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention belongs to the technical field of biochemical materials, and particularly relates to an aggregation-induced emission (AIE) photosensitizer with I-type active oxygen and photo-thermal generation capacity, and a preparation method and application thereof. The AIE type photosensitizer with the I type active oxygen and photo-thermal generating capacity has a structure shown in a formula I. The AIE photosensitizer provided by the invention has large Stokes displacement, is positioned in the near infrared first region (NIR-I) emission, is beneficial to penetrating deep biological tissues and reduces photodamage to the biological tissues; meanwhile, the AIE type photosensitizer provided by the invention has stronger ROS and photo-thermal generation capability. From the results of the examples, it is shown that photosensitizers of the structure shown in formula I are expected to be useful as near infrared fluorescence mediated PDT/PTT co-therapies.
Description
Technical Field
The invention belongs to the technical field of biochemical materials, and particularly relates to an aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity, and a preparation method and application thereof.
Background
Cancer has become one of the diseases that severely threatens human health. The traditional methods of chemotherapy, operation and radiotherapy have great toxic and side effects, bring great pain to the body and mind of patients and are easy to relapse. Photodynamic therapy (PDT) and photothermal therapy (PTT) kill cancer cells by exciting photosensitizers with light to generate Reactive Oxygen Species (ROS) and heat, and have the advantages of non-invasiveness, good selectivity, low drug resistance, local treatment, and small side effects, and thus have been receiving a great deal of attention in anticancer. Among them, the type I free radical type active oxygen shows better therapeutic effect on hypoxic tumor than type II active oxygen (singlet oxygen) due to low oxygen concentration dependence. Aggregation-induced emission (AIE) photosensitizers have limited intramolecular movement in an aggregated state, are non-radiation-attenuated and radiation-enhanced, have fluorescence enhancement characteristics, and meanwhile, aggregation can also improve the ROS production efficiency, thereby providing a new opportunity for photodynamic anticancer application.
Photothermal therapy (PTT) is a process in which a photosensitizer absorbs light of a certain wavelength, and energy is converted into heat through vibration relaxation from a ground state to an excited state, and the generated heat increases the temperature of biological tissues to thereby kill cancer cells. PTT can promote immune cell activation and, with temperature changes, changes in both cell morphology and viability of biological tissue. For tumor cells, when the temperature is raised to 41 ℃, both the cell transmembrane diffusion and blood flow velocity are accelerated. At the temperature of 41-48 ℃, proteins in cells are aggregated, so that the sensitivity of the cells to radiotherapy and chemotherapy is increased, and the cells are seriously damaged by the temperature of Wen Chaoguo min. If the temperature is raised to 48-60 ℃, irreversible damage such as protein denaturation, DNA damage and the like can be caused to cells in a short time. The tumor tissue has poor heat tolerance compared with normal tissue due to the characteristic of poor blood supply, which is the basis of PTT for treating cancer.
PTT has similar light excitation characteristics as PDT and is therefore widely used in combination with PDT action to overcome the limitations of single PDT anticancer. The heat generated in the PTT process can not only cause the apoptosis of cancer cells, but also improve the blood flow in the tumor, thereby providing more oxygen for the PDT process. In addition, ROS generated in the PDT process can inhibit the generation of heat shock proteins, and the PTT can be better acted.
Currently, relatively few new AIE photosensitizers are reported that have both high ROS production capability and photothermal conversion efficiency.
Disclosure of Invention
The invention aims to provide an aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity, and a preparation method and application thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity, which has a structure shown in a formula I;
a formula I;
r in the formula I is:or->，/>X in (C) is O, S or Se.
Preferably, the compound has a structure shown in a formula I-1 or a formula I-2:
formula I-1;
formula I-2.
The invention provides a preparation method of an aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity, which comprises the following steps:
mixing a compound with a structure shown in a formula II, a compound with a structure shown in a formula III, piperidine and an organic solvent to perform a brain cell reaction to obtain an aggregation-induced emission type photosensitizer with a structure shown in a formula I and simultaneously having I-type active oxygen and photo-thermal generation capacity;
formula II, R-CHO formula III; r in formula III is: />Or->，X in (C) is O, S or Se.
Preferably, R in the structural compound of formula III isIn the process, the preparation method of the compound with the structure shown in the formula III comprises the following steps:
the compound with the structure shown in the formula IV, diphenylamine and Pd (dba) 3 Mixing tri-tert-butyl phosphorus tetrafluoroborate, sodium tert-butoxide and an organic solvent to perform a first substitution reaction to obtain a compound with a structure shown in a formula V;
a formula IV; />V, V; in formula IV and formula V: x is O, S or Se;
mixing a compound with a structure shown in a formula V, phosphorus oxychloride and an organic solvent for carrying out a second substitution reaction to obtain RA compound of the structure shown in formula III.
Preferably, the compound of the structure shown in the formula IV, diphenylamine and Pd (dba) 3 The molar ratio of the tri-tert-butyl phosphate tetrafluoroborate to the sodium tert-butoxide is 1.2:1:0.03:1.2:1.2; the temperature of the first substitution reaction is 110 ℃; the time for the first substitution was 15h.
Preferably, the molar ratio of the compound with the structure shown in the formula V to phosphorus oxychloride is 1:1.1; the temperature of the second substitution reaction is room temperature; the time for the second substitution was 10h.
Preferably, the molar ratio of the compound with the structure shown in the formula III to the compound with the structure shown in the formula II to the piperidine is 1:1:1; the temperature of the reaction of the brain Wen Ge is 40-70 ℃; the reaction time of the brain Wen Ge is 12-24 hours.
The invention provides an application of the aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity in preparing antitumor drugs or antitumor diagnostic reagents, wherein the aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity is prepared by the preparation method of the technical scheme.
The invention provides an aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capability, which is prepared by the technical scheme or the preparation method of the technical scheme, and the application of the aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capability in non-therapeutic cancer cell imaging.
The invention provides a preparation method of aggregation-induced emission type photosensitizer water-dispersible nano particles with I-type active oxygen and photo-thermal generation capacity, which comprises the following steps:
the aggregation-induced emission type photosensitizer with the I-type active oxygen and the photo-thermal generation capacity or the aggregation-induced emission type photosensitizer with the I-type active oxygen and the photo-thermal generation capacity prepared by the preparation method of the technical scheme is mixed with an organic solvent to obtain a mixed solution;
and mixing the mixed solution with water, and performing ultrasonic coprecipitation to obtain the aggregation-induced emission type photosensitizer water-dispersible nano particles with I-type active oxygen and photo-thermal generation capacity.
The invention provides an aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity, which has a structure shown in a formula I. The AIE provided by the invention has pi electron donor acceptor (D-A) interaction in the molecular structure, wherein the R group is an electron donor, which is favorable for red shift of the absorption and emission wavelength of the photosensitizer, increases the penetration depth of biological tissues and reduces the photodamage to the biological tissues; in addition, the photosensitizer provided by the invention has AIE property, AIE intramolecular movement is limited in an aggregation state, non-radiation is weakened, radiation is enhanced, so that the photosensitizer has fluorescence enhancement property, and meanwhile, the photosensitizer provided by the invention has stronger ROS and photo-thermal generation capability. The results of the examples show that the photosensitizer with the structure shown in the formula I is expected to be used for photodynamic photo-thermal synergistic anticancer by near infrared fluorescence imaging.
The invention also provides a preparation method of the aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity, which has the advantages of few steps, easy operation and suitability for industrial production.
Drawings
FIG. 1 shows TPA-TCF at various toluene volume fractions (f T ) The ratio of the real-time fluorescence intensity to the initial fluorescence intensity in the DMSO/toluene mixed solution is along with f T Is a change curve of (2);
FIG. 2 shows the DSP-TCF at various toluene volume fractions (f T ) The ratio of the real-time fluorescence intensity to the initial fluorescence intensity in the DMSO/toluene mixed solution is along with f T Is a change curve of (2);
FIG. 3 is a graph of UV absorption of TPA-TCF NPs and DSP-TCF NPs in the aqueous phase;
FIG. 4 is a graph of fluorescence emission of TPA-TCF NPs and DSP-TCF NPs in the aqueous phase;
FIG. 5 shows the TPA-TCF NPs, DSP-TCF NPs and hydroxyl radical (. OH) scavenger APF mixed solution under 660 nm laser irradiation (optical power: 0.1W/cm) 2 ) A plot of real-time fluorescence intensity versus initial fluorescence intensity versus time at 515 nm;
FIG. 6 shows TPA-TCF NPs, DSP-TCF NPs in aqueous phase mixed with hydrogen peroxide scavenger DHR 123 under 660 nm laser irradiation(optical power: 0.1W/cm) 2 ) A plot of real-time fluorescence intensity versus initial fluorescence intensity versus time at 525 nm;
FIG. 7 shows calculation of the photo-thermal properties of TPA-TCF NPs (molar concentration: 100. Mu.M) under 660 nm laser irradiation and their photo-thermal conversion efficiency (optical power: 0.4W/cm) 2 ）；
FIG. 8 shows the calculation of the photo-thermal properties of a DSP-TCF NPs solution (molar concentration: 100. Mu.M) under 660 nm laser irradiation and its photo-thermal conversion efficiency (optical power: 0.4W/cm) 2 ）；
FIG. 9 is a synthetic scheme of the compound of formula I-1 in example 1 of the present invention;
FIG. 10 is a synthetic scheme for compound 6 of example 2 of the present invention;
FIG. 11 is a synthetic scheme of the structural compound of formula I-2 in example 3 of the present invention.
Detailed Description
The invention provides an aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity, which has a structure shown in a formula I;
a formula I;
r in the formula I is:or->，/>X in (C) is O, S or Se.
In the present invention, R is、/>、/>Or (b)。
In the present invention, the aggregation-induced emission type photosensitizer having both type I active oxygen and photo-thermal generating capability is more preferably one having a structure represented by formula I-1 or formula I-2:
formula I-1;
formula I-2.
The invention provides a preparation method of an aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity, which comprises the following steps:
mixing a compound with a structure shown in a formula II, a compound with a structure shown in a formula III, piperidine and an organic solvent (hereinafter referred to as a first organic solvent) (hereinafter referred to as a first mixture) to perform a brain cell reaction to obtain an aggregation-induced emission type photosensitizer with a structure shown in a formula I and simultaneously having type I active oxygen and photo-thermal generation capability;
formula II, R-CHO formula III; r in formula III is: />Or->，X in (C) is O, S or Se.
In the present invention, all preparation materials/components are commercially available products well known to those skilled in the art unless specified otherwise.
In the present invention, a compound of formula IIIThe structural compound isOr->。
In the present invention, the structural compound represented by formula III is preferablyOr (b)。
In the present invention, R in the structural compound represented by formula III isIn the process, the preparation method of the compound with the structure shown in the formula III comprises the following steps:
the compound with the structure shown in the formula IV, diphenylamine and Pd (dba) 3 Mixing tri-tert-butyl phosphorus tetrafluoroborate, sodium tert-butoxide and an organic solvent (hereinafter referred to as a second organic solvent) (hereinafter referred to as a second mixture) to perform a first substitution reaction to obtain a compound having a structure shown in formula V;
a formula IV; />V, V; in formula IV and formula V: x is O, S or Se;
the compound having the structure shown in formula V, phosphorus oxychloride, and an organic solvent (hereinafter referred to as a third organic solvent) are mixed (hereinafter referred to as a third mixture) to perform a second substitution reaction, thereby obtaining a compound having the structure shown in formula III.
The invention uses the compound with the structure shown in the formula IV, diphenylamine and Pd (dba) 3 Tri-tert-butyl phosphorus tetrafluoroborate ((t-Bu) 3 PHBF 4 ) And carrying out a first substitution reaction on the second mixture of the tertiary sodium butoxide and a second organic solvent to obtain the compound with the structure shown in the formula V. At the position ofIn the present invention, in formula IV and formula V: x is preferably S. The second organic solvent is preferably toluene, and particularly preferably anhydrous anaerobic toluene. The compound with the structure shown in the formula IV, diphenylamine and Pd (dba) 3 The molar ratio of tri-tert-butyl phosphorus tetrafluoroborate to sodium tert-butoxide is preferably 1.2:1:0.03:1.2:1.2. The invention has no special requirement on the dosage of the second organic solvent, and ensures that the first substitution reaction is smoothly carried out. The second mixing is preferably: the compound with the structure shown in the formula IV, diphenylamine and Pd (dba) 3 Dissolving the tri-tert-butyl phosphorus tetrafluoroborate in part of the second organic solvent to obtain a first mixed solution; dissolving the sodium tert-butoxide in the residual second organic solvent to obtain a second mixed solution; and stirring and mixing the first mixed solution and the second mixed solution, wherein the stirring and mixing is performed under the protection of nitrogen, the temperature of stirring and mixing is preferably room temperature, and the time is preferably 30min. The temperature of the first substitution reaction is preferably 110 ℃; the time for the first substitution is preferably 15h. The present invention preferably uses a TLC plate (i.e., a thin layer chromatography spot plate) to monitor the first substitution reaction until the diphenylamine is completely eliminated, and the first substitution reaction is completed to obtain a first substitution reaction solution. In the present invention, the first substitution reaction solution is preferably subjected to post-treatment to obtain a compound having a structure represented by formula V. The post-treatment preferably comprises the steps of: concentrating the first substitution reaction liquid to obtain a concentrate; subjecting the concentrate to column chromatography to obtain a purified reactant; and mixing the purified reactant, dichloromethane and normal hexane for recrystallization, and carrying out solid-liquid separation to obtain the compound with the structure shown in the formula V. The specific embodiment of the concentration is not particularly limited, and a conventional concentration mode, such as rotary evaporation, is adopted. The eluent used in the column chromatography is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 10:1. The volume ratio of the dichloromethane to the n-hexane is preferably 1:10. The temperature of the recrystallization is preferably room temperature. The solid-liquid separation is preferably filtration.
After the compound with the structure shown in the formula V is obtained, the compound with the structure shown in the formula V, phosphorus oxychloride and a third organic solvent are mixed for a second substitution reaction to obtain the compound with the structure shown in the formula III. In the present invention, the third organic solvent is preferably N, N-Dimethylformamide (DMF). The molar ratio of the compound of the structure of formula V to phosphorus oxychloride is preferably 1:1.1. The invention has no special requirement on the dosage of the third organic solvent, and ensures that the second substitution reaction is smoothly carried out. The third mixture is preferably: the compound of the structure shown in the formula V and phosphorus oxychloride are dissolved in a third organic solvent. The temperature of the second substitution reaction is preferably room temperature; the time for the second substitution is preferably 10h. The present invention preferably uses a TLC plate (i.e., thin layer chromatography spot plate) to monitor the second substitution reaction until the compound of the structure represented by formula V is completely eliminated, and the second substitution reaction is completed to obtain a second substitution reaction solution. In the present invention, the second substitution reaction solution is preferably subjected to post-treatment to obtain a compound having a structure represented by formula III. The post-treatment preferably comprises the steps of: mixing and extracting the second substitution reaction liquid, dichloromethane and water to obtain a dichloromethane phase; concentrating the dichloromethane phase to obtain a concentrate; subjecting the concentrate to column chromatography to obtain a purified reactant; and mixing the purified reactant, dichloromethane and normal hexane for recrystallization, and carrying out solid-liquid separation to obtain the compound with the structure shown in the formula III. The specific embodiment of the concentration is not particularly limited, and a conventional concentration mode, such as rotary evaporation, is adopted. The eluent used in the column chromatography is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 10:1. The volume ratio of the dichloromethane to the n-hexane is preferably 1:10. The temperature of the recrystallization is preferably room temperature. The solid-liquid separation is preferably filtration.
In the present invention, the first organic solvent is preferably ethanol. The molar ratio of the compound with the structure shown in the formula III to the compound with the structure shown in the formula II to the piperidine is preferably 1:1:1. The invention has no special requirement on the dosage of the first organic solvent, and ensures that the brain Wen Ge reaction is smoothly carried out. The first mixing is preferably: the compound with the structure shown in the formula III, the compound with the structure shown in the formula II and piperidine are dissolved in a first organic solvent. In the present invention, the temperature of the reaction of the brain Wen Ge is preferably 40 to 70 ℃, more preferably 50 to 70 ℃, and even more preferably 60 ℃. The reaction time of the brain Wen Ge is preferably 12-24 hours, more preferably 12-h. The brain Wen Ge reaction is preferably carried out under a protective gas atmosphere, which is preferably nitrogen or argon, more preferably nitrogen. The present invention preferably uses a TLC plate (i.e., thin layer chromatography spot plate) to monitor the brain Wen Ge reaction until the compound of the structure of formula II is completely eliminated and the brain Wen Ge reaction is completed, resulting in a brain cell reaction solution. The invention carries out post-treatment on the brain Wen Ge reaction liquid to obtain the aggregation-induced emission type photosensitizer which has the structure shown in the formula I and simultaneously has the I-type active oxygen and photo-thermal generation capability. In the present invention, the post-treatment preferably includes the steps of: concentrating the brain Wen Ge reaction solution to obtain a concentrate; subjecting the concentrate to column chromatography to obtain a purified reactant; and mixing the purified reactant, dichloromethane and n-hexane for recrystallization, and carrying out solid-liquid separation to obtain the aggregation-induced emission photosensitizer with the structure shown in the formula I and simultaneously having the I-type active oxygen and photo-thermal generation capacity. The specific embodiment of the concentration is not particularly limited, and a conventional concentration mode, such as rotary evaporation, is adopted. The eluent used in the column chromatography is preferably dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is preferably 100:1. The volume ratio of the dichloromethane to the n-hexane is preferably 1:10. The temperature of the recrystallization is preferably room temperature. The solid-liquid separation is preferably filtration.
The invention provides an application of the aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity in preparing antitumor drugs or antitumor diagnostic reagents, wherein the aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity is prepared by the preparation method of the technical scheme.
The invention provides an aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capability, which is prepared by the technical scheme or the preparation method of the technical scheme, and the application of the aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capability in non-therapeutic cancer cell imaging.
The invention provides a preparation method of aggregation-induced emission type photosensitizer water-dispersible nano particles with I-type active oxygen and photo-thermal generation capacity, which comprises the following steps:
the aggregation-induced emission type photosensitizer with the I-type active oxygen and the photo-thermal generation capacity or the aggregation-induced emission type photosensitizer with the I-type active oxygen and the photo-thermal generation capacity prepared by the preparation method of the technical scheme is mixed with an organic solvent to obtain a mixed solution;
and mixing the mixed solution with water, and performing ultrasonic coprecipitation to obtain the aggregation-induced emission type photosensitizer water-dispersible nano particles with I-type active oxygen and photo-thermal generation capacity.
The aggregation-induced emission type photosensitizer with the I-type active oxygen and the photo-thermal generation capability or the aggregation-induced emission type photosensitizer with the I-type active oxygen and the photo-thermal generation capability prepared by the preparation method according to the technical scheme, a coating agent and an organic solvent (hereinafter referred to as a fourth organic solvent) are mixed to obtain a mixed solution. In the present invention, the coating agent is preferably methoxy polyethylene glycol amine, distearoyl phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG) 2000 ) One or more of phosphatidylethanolamine-polyethylene glycol 2000-maleimide, distearoyl phosphatidylethanolamine-polyethylene glycol-folic acid, distearoyl phosphatidylethanolamine-polyethylene glycol-mercapto, distearoyl phosphatidylacetamide-polyethylene glycol 2000-carboxylic acid, distearoyl phosphatidylethanolamine-polyethylene glycol 5000-azide, distearoyl ethanolamine-polyethylene glycol 2000-biotin, 1-palmitoyl-2-oleoylethanolamide, 1-stearoyl-2-oleoyl lecithin, dipalmitoyl phosphatidylethanolamine-polyethylene glycol 2000, and poloxamer F127. The fourth organic solvent is preferably Tetrahydrofuran (THF). The mass ratio of the aggregation-induced emission type photosensitizer and the coating agent with I-type active oxygen and photo-thermal generation capability is preferablyIs 1:5 to 10, more preferably 1:5 to 6. The dosage of the fourth organic solvent is not particularly required, and the aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity and the coating agent are ensured to be uniformly mixed.
After the mixed solution is obtained, the mixed solution is mixed with water, ultrasonic coprecipitation is carried out, and the aggregation-induced emission type photosensitizer water-dispersible nano particles with I-type active oxygen and photo-thermal generation capacity are obtained. In the present invention, the mixing is preferably to drop the mixed liquid into the water. The ultrasonic power of the ultrasonic coprecipitation is preferably 100-300W, more preferably 150W, and the ultrasonic time is preferably 2-10 min, more preferably 5 min.
The aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capacity is prepared into the water-dispersed nano particles, which is beneficial to near infrared fluorescence imaging of cancer cells.
The aggregation-induced emission type photosensitizers having both type I active oxygen and photo-thermal generating capabilities, and the preparation methods and applications thereof, which are provided by the present invention, are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
A compound of the structure shown in formula I-1 was prepared according to the synthetic scheme depicted in fig. 9:
compound 1 (compound of the structure shown in formula II, 200.0 mg,1 mmol), compound 2 (274.6 mg,1 mmol) and piperidine (85.5 mg,1 mmol) were dissolved in ethanol to obtain a mixture. The mixture was reacted overnight at 60 ℃, the progress of the reaction was monitored by TLC plate until the complete disappearance of compound 1, the reaction was concentrated, column chromatographed with Dichloromethane (DCM): methanol (MeOH) =100:1 (v: v) as eluent, recrystallised with a mixed solvent of dichloromethane: n-hexane=1:10 (v: v) to give a bluish violet powder, yield: 83, designated TPA-TCF.
The solid product obtained in this example was characterized and the specific nuclear magnetic data are as follows:
1 H NMR (500 MHz, CDCl 3 ) δ 7.58 (d, J = 16.1 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 4H), 7.20 (dd, J = 18.9, 7.5 Hz, 6H), 6.98 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 16.0 Hz, 1H), 1.76 (s, 6H)； 13 C NMR (151 MHz, CDCl 3 )：δ 175.77, 173.91, 152.52, 147.18, 145.67, 131.07, 129.84, 126.35, 125.91, 125.62, 119.89, 112.13, 111.33, 111.17, 110.84, 97.08, 96.79, 56.25, 26.63；HRMS [M+Na] + calcd 477.1691, found 477.1685。
from the above characterization data, it can be seen that the resulting aggregation-induced emission type photosensitizer TPA-TCF having both type I active oxygen and photo-thermal generating capability is a compound having the structure shown in formula I-1.
In order to enable TPA-TCF to be applied to biological environment water system, the embodiment uses TPA-TCF particles as photosensitizer and amphiphilic copolymer DSPE-PEG 2000 For coating the matrix, an ultrasonic method is adopted to prepare the modified photosensitizer nanoparticle aqueous dispersion. The preparation method comprises the following steps:
TPA-TCF and DSPE-PEG 2000 (TPA-TCF and DSPE-PEG) 2000 Mass ratio of 1:5) is dispersed and dissolved in THF to obtain a mixed solution, wherein the mass concentration of TPA-TCF in the mixed solution is 0.2 mg/mL, DSPE-PEG 2000 The mass concentration of (2) is 0.5mg/mL; the obtained mixed solution is rapidly dripped into water under the ultrasonic condition (ultrasonic power is 150W), and ultrasonic mixing is continued for 5min after the dripping is finished, so that the modified aqueous dispersion of TPA-TCF nano particles (marked as TPA-TCF NPs) is obtained.
Example 2
Compound 6 was prepared according to the synthetic scheme depicted in fig. 10:
compound 3 (195.6 mg,1.2 mmol), diphenylamine (Compound 4, 169.2 mg,1 mmol), pd (dba) 3 （28 mg，0.03 mmol）、(t-Bu) 3 PHBF 4 (348.2 mg,1.2 mmol) was dissolved in anhydrous and anaerobic toluene to obtain a mixed solution, and after adding anhydrous and anaerobic toluene-dissolved sodium tert-butoxide (115.3 mg,1.2 mmol), the mixture was stirred at room temperature under nitrogen protection for 30 minutes. The mixture was reacted overnight at 110℃and the progress of the reaction was monitored by TLC until the diphenylamine had completely disappeared, and the reaction solution was concentratedThe column chromatography was performed with Petroleum Ether (PE): ethyl Acetate (EA) =10:1 (v: v) as eluent, and recrystallized from a mixed solvent of dichloromethane: n-hexane=1:10 (v: v) to give compound 5 as a white solid, yield: 95%; compound 5 (251.3 mg,1 mmol) and phosphorus oxychloride (168.7 mg,1.1 mmol) were dissolved in anhydrous and oxygen-free DMF to obtain a mixture. The mixture was reacted overnight at room temperature, the progress of the reaction was monitored by TLC plate until the compound 5 was completely disappeared, the substitution reaction solution was extracted with dichloromethane and water to obtain a dichloromethane phase, the dichloromethane phase was concentrated, column chromatography was performed using Petroleum Ether (PE): ethyl Acetate (EA) =50:1 (v:v) as eluent, and recrystallization was performed using a mixed solvent of dichloromethane: n-hexane=1:10 (v:v) to obtain a yellow solid product, yield: 92%.
The solid product obtained in this example was characterized and the specific nuclear magnetic data are as follows:
1 H NMR (500 MHz, CDCl 3 )：δ 9.61 (s, 1H), 7.46 (d, J = 4.3 Hz, 1H), 7.37 (t, J = 8.2 Hz, 4H), 7.28 (d, J = 7.6 Hz, 4H), 7.22 (t, J = 7.4 Hz, 2H), 6.39 (d, J = 4.3 Hz, 1H)。
from the above-described nuclear magnetic characterization data, compound 6 in fig. 10 of this example was obtained.
A compound of the structure shown in formula I-2 was prepared according to the synthetic scheme depicted in fig. 11:
compound 1 (200 mg,1 mmol), compound 6 (279.4 mg,1 mmol) and piperidine (85.5 mg,1 mmol) were dissolved in ethanol to obtain a mixed solution. The mixture was reacted overnight at 60 ℃, the progress of the reaction was monitored by TLC plate until the compound 6 was completely disappeared, the reaction was concentrated, column chromatography was performed using Dichloromethane (DCM): methanol (MeOH) =100:1 (v: v) as eluent, and recrystallization was performed using a mixed solvent of dichloromethane: n-hexane=1:10 (v: v) to give a blue-black powder, yield: 79, designated DSP-TCF.
The solid product obtained in this example was characterized and the specific nuclear magnetic data are as follows:
1 H NMR (500 MHz, CDCl 3 ) δ 7.79 (d, J = 15.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 4H), 7.33 (t, J = 5.7 Hz, 6H), 7.29 (d, J = 4.4 Hz, 1H), 6.40 (d, J = 4.4 Hz, 1H), 6.05 (d, J = 15.1 Hz, 1H), 1.65 (s, 6H)； 13 C NMR (151 MHz, CDCl 3 )：δ 176.44, 172.83, 165.38, 145.16, 140.45, 140.26, 130.18, 127.74, 127.43, 125.80, 113.64, 112.98,
112.18, 112.03, 107.07, 96.21, 26.61；HRMS [M+Na] + calcd 483.1256, found 483.1254。
from the above characterization data, it is clear that the obtained aggregation-induced emission type photosensitizer DSP-TCF having both type I active oxygen and photo-thermal generating capability is a compound having a structure as shown in formula I-2.
In order to enable the DSP-TCF to be applied to a biological environment water system, the embodiment takes DSP-TCF particles as a photosensitizer and amphiphilic copolymer DSPE-PEG 2000 For coating the matrix, an ultrasonic method is adopted to prepare the modified photosensitizer nanoparticle aqueous dispersion. The preparation method comprises the following steps:
DSP-TCF and DSPE-PEG 2000 (TPA-TCF and DSPE-PEG) 2000 The mass ratio is 1:5) is dispersed and dissolved in THF to obtain a mixed solution, wherein the mass concentration of DSP-TCF in the mixed solution is 0.2 mg/mL, DSPE-PEG 2000 The mass concentration of (2) is 0.5mg/mL; and rapidly dripping the obtained mixed solution into water under ultrasonic conditions (ultrasonic power is 150W), and continuing ultrasonic mixing for 5min after dripping, so as to obtain an aqueous dispersion of modified DSP-TCF nano particles (marked as DSP-TCF NPs).
Performance test:
(1) AIE Property test of TPA-TCF: at different toluene volume fractions (f T ) Adding TPA-TCF or DSP-TCF DMSO solution (1 mM) to obtain 10 μm TPA-TCF or DSP-TCF solution, and measuring the change of the ratio of real-time fluorescence intensity to initial fluorescence intensity at 625 nm in the mixed solution with different toluene volume fractions by using 550 nm as excitation wavelength, wherein the test result is shown in FIG. 1.
FIG. 1 shows the fluorescence intensity ratio of TPA-TCF at 625 nm in DMSO/toluene mixed solutions of different toluene volume fractions, which varies with toluene volume fraction, from 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 99% in order from low to high, with excitation light wavelength of 550 nm. As can be seen from fig. 1, the ratio of the fluorescence emission intensities of TPA-TCF gradually increases with increasing toluene volume fraction until 99% reaches the maximum, indicating that TPA-TCF has AIE properties.
(2) The AIE property test of the DSP-TCF is carried out by the same specific steps as the test of TPA-TCF. The results are shown in FIG. 2.
FIG. 2 shows the fluorescence intensity ratio of DSP-TCF at 717 nm in DMSO/toluene mixed solutions of different toluene volume fractions, with the corresponding toluene volume fractions from low to high being 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 99% in order, with excitation light wavelengths of 624 nm. As can be seen from FIG. 2, the fluorescence emission intensity ratio of DSP-TCF gradually increases with increasing toluene volume fraction until 80% reaches the maximum intensity, which indicates that DSP-TCF has AIE properties.
(3) The ultraviolet absorption spectrum test of TPA-TCF NPs and DSP-TCF NPs comprises the following specific steps:
the aqueous solutions of TPA-TCF NPs and DSP-TCF NPs are respectively prepared into test concentrations of 10 mu M, and the test concentrations are placed in an ultraviolet spectrophotometer for ultraviolet absorption spectrum acquisition. The normalized results are shown in fig. 3, with maximum absorption values of 500 and 592, nm, respectively.
(4) The fluorescence spectrum test of TPA-TCF NPs and DSP-TCF NPs comprises the following specific steps:
the aqueous solutions of TPA-TCF NPs and DSP-TCF NPs are respectively prepared into test concentrations of 10 mu M, and are respectively excited by a fluorescence spectrometer by 500 and 592 and nm to collect fluorescence emission spectra. The normalized results are shown in fig. 4, with maximum emission values of 750, 745, nm, respectively, and stokes shifts of 250, 153, nm, respectively.
(5) The hydroxyl radical (. OH) generating capability test of TPA-TCF NPs and DSP-TCF NPs is carried out as follows:
detection of H in solution using aminophenyl fluorescein (APF) as an indicator 2 O 2 . When hydroxyl radicals are generated in the system, the APF will oxidize and fluoresce strongly at 515 nm. Will be10. Mu M TPA-TCF NPs or DSP-TCF NPs were dissolved in 2 mL PBS containing 1. Mu.L APF (concentration: 5 mM). The mixture was then placed in a cuvette and irradiated with 660 nm laser (0.1W/cm 2 ) And (5) irradiating. The change in fluorescence of the sample at 515 nm was recorded with a fluorescence spectrophotometer (excitation wavelength: 490 nm). The results are shown in FIG. 5.
FIG. 5 shows the fluorescence values of TPA-TCF NPs and DSP-TCF NPs in water mixed with hydroxyl radical scavenger APF at 515 and nm as a function of time of illumination. When the solution was exposed to 660 nm laser irradiation in the presence of these two nanoparticles, the fluorescence signal of the APF probe was greatly increased, indicating that the nanoparticles had hydroxyl radical generating capability.
(6) Hydrogen peroxide (H) of TPA-TCF NPs and DSP-TCF NPs 2 O 2 ) The production capability test comprises the following specific steps:
h in solution with dihydrorhodamine 123 (DHR 123) as indicator 2 O 2 . When H is generated in the system 2 O 2 When DHR 123 is oxidized, it emits strong fluorescence at 525 nm. 10. Mu.M 2TPA-PTCF NPs or 2DSP-PTCF NPs were dissolved in 2 mL PBS containing 5. Mu.L DHR 123 (concentration: 1 mM). The mixture was then placed in a cuvette and irradiated with 660 nm laser (0.1W/cm 2 ) And (5) irradiating. The change in fluorescence of the sample at 525 nm is recorded with a fluorescence spectrophotometer (excitation wavelength: 480 nm). The results are shown in FIG. 6.
FIG. 6 is a graph showing the fluorescence of TPA-TCF NPs and DSP-TCF NPs in water mixed with hydrogen peroxide scavenger DHR 123 at 525 nm as a function of time of illumination. When the solution was exposed to 660 nm laser irradiation in the presence of these two nanoparticles, the fluorescence signal of the DHR 123 probe was greatly increased, indicating that the nanoparticles had hydrogen peroxide generating capability.
(7) The photo-thermal conversion efficiency test of TPA-TCF NPs comprises the following specific steps:
photo-thermal property test: aqueous TPA-TCF NPs (100. Mu.M) at 0.4. 0.4W/cm 2 660 And irradiating the nm laser for 5min, and when the temperature reaches the platform, turning off the laser, and cooling the solution to room temperature. During this process, the solution temperature change was recorded. Results such asShown in fig. 7.
FIG. 7 shows TPA-TCF NPs at a concentration of 100. Mu.M under 660 nm laser irradiation (0.4W/cm 2 ) And (3) calculating the photo-thermal property and the photo-thermal conversion efficiency of the light-thermal energy. The light-heat conversion efficiency is 22%.
(8) The specific steps of the photo-thermal conversion efficiency test of the DSP-TCF NPs are the same as those of the TPA-TCF NPs. The results are shown in FIG. 8.
FIG. 8 shows that a DSP-TCF NPs with a concentration of 100. Mu.M was irradiated with 660 nm laser (0.4W/cm) 2 ) And (3) calculating the photo-thermal property and the photo-thermal conversion efficiency of the light-thermal energy. The light-heat conversion efficiency is 42%.
From the above examples, the aggregation-induced emission type photosensitizer provided by the invention has the advantages of simple synthesis steps, simple separation and purification operation, near infrared fluorescence generation, large stokes shift, excellent I-type active oxygen generation capability and high-efficiency photo-thermal conversion performance.
Although the foregoing embodiments have been described in some, but not all embodiments of the invention, other embodiments may be obtained according to the present embodiments without departing from the scope of the invention.
Claims (8)
1. An aggregation-induced emission type photosensitizer with I-type active oxygen and photo-thermal generation capability, which is characterized by having a structure shown in a formula I;
r in the formula I is:x in (C) is O, S or Se.
2. The aggregation-induced emission type photosensitizer having both type I active oxygen and photo-thermal generation capability according to claim 1, which has a structure represented by formula I-2:
3. the method for preparing an aggregation-induced emission type photosensitizer having both type I active oxygen and photo-thermal generating capability as set forth in claim 1 or 2, comprising the steps of:
mixing a compound with a structure shown in a formula II, a compound with a structure shown in a formula III, piperidine and an organic solvent to perform a brain cell reaction to obtain an aggregation-induced emission type photosensitizer with a structure shown in a formula I and simultaneously having I-type active oxygen and photo-thermal generation capacity;
R-CHO formula III; r in formula III is: />X in (C) is O, S or Se.
4. A process according to claim 3, wherein the process for the preparation of a compound of the structure of formula III comprises the steps of:
the compound with the structure shown in the formula IV, diphenylamine and Pd (dba) 3 Mixing tri-tert-butyl phosphorus tetrafluoroborate, sodium tert-butoxide and an organic solvent to perform a first substitution reaction to obtain a compound with a structure shown in a formula V;
in formula IV and formula V: x is O, S or Se;
mixing a compound with a structure shown in a formula V, phosphorus oxychloride and N, N-dimethylformamide for carrying out a second substitution reaction to obtain RA compound of the structure shown in formula III.
5. The process according to claim 4, wherein the compound of the formula IV, diphenylamine, pd (dba) 3 The molar ratio of the tri-tert-butyl phosphate tetrafluoroborate to the sodium tert-butoxide is 1.2:1:0.03:1.2:1.2; the temperature of the first substitution reaction is 110 ℃; the time for the first substitution was 15h.
6. The method according to claim 4, wherein the molar ratio of the compound of the structure represented by formula V to phosphorus oxychloride is 1:1.1; the temperature of the second substitution reaction is room temperature; the time for the second substitution was 10h.
7. The method according to claim 3, wherein the molar ratio of the compound of the structure represented by formula III, the compound of the structure represented by formula II, and the piperidine is 1:1:1; the temperature of the reaction of the brain Wen Ge is 40-70 ℃; the reaction time of the brain Wen Ge is 12-24 hours.
8. A method for preparing aggregation-induced emission type photosensitizer water-dispersible nanoparticles having both type I active oxygen and photo-thermal generation capabilities, comprising the steps of:
mixing the aggregation-induced emission type photosensitizer having both type I active oxygen and photo-thermal generating capability according to claim 1 or 2, a coating agent and an organic solvent to obtain a mixed solution;
and mixing the mixed solution with water, and performing ultrasonic coprecipitation to obtain the aggregation-induced emission type photosensitizer water-dispersible nano particles with I-type active oxygen and photo-thermal generation capacity.
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