CN111689955A - Naphthothiadiazole free radical type photosensitizer and preparation method and application thereof - Google Patents
Naphthothiadiazole free radical type photosensitizer and preparation method and application thereof Download PDFInfo
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- CN111689955A CN111689955A CN202010455239.3A CN202010455239A CN111689955A CN 111689955 A CN111689955 A CN 111689955A CN 202010455239 A CN202010455239 A CN 202010455239A CN 111689955 A CN111689955 A CN 111689955A
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- Prior art keywords
- naphthothiadiazole
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- derivative
- photosensitizer
- radical type
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Classifications
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K49/0032—Methine dyes, e.g. cyanine dyes
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
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Abstract
The invention belongs to the field of biomedical materials, and discloses a naphthothiadiazole free radical type photosensitizer as well as a preparation method and application thereof. The naphthothiadiazole derivative-based free radical type photosensitizer material has the following structure:
wherein the pi bridges are independently aromatic rings; x is independently an anion pair; r1Independently an aromatic ring derivative electron donating group; r2Independently is C1‑6An alkyl group. According to the invention, a derivative with a steric hindrance effect and a strong Charge Transfer (CT) effect is constructed on one side of a 4, 9-dibromonaphthothiadiazole element, so that the near infrared emission and AIE characteristics of the material are endowed. By further potentiating the CT effect of the corresponding derivatives and creating an electron rich environment, efficient activation of ISC channels is induced and efficient free radical type ROS generation is achieved. Finally, the synchronous improvement of the fluorescence efficiency and the ROS generation capacity of the material in the aggregation state is realized, and the method has good application prospect in fluorescence imaging mediated tumor photodynamic therapy.
Description
Technical Field
The invention belongs to the field of biomedical materials, and particularly relates to a naphthothiadiazole free radical-based photosensitizer as well as a preparation method and application thereof.
Background
Photodynamic therapy (PDT) mediated by fluorescence imaging has received much attention because of its high sensitivity and spatial and temporal resolution, low toxic side effects, minimal invasive and cooperativity. The PDT process includes three basic elements: light, a photosensitizer, and oxygen. The essence is that light irradiates the tumor tissue part, and the light and a photosensitizer retained in the tissue generate photophysical and photochemical reactions to generate Reactive Oxygen Species (ROS) with high oxidability, so that the tumor structure is destroyed to achieve the purpose of treatment. ROS can be finely divided into type I ROS mainly based on radical species (superoxide anion radical, hydroxyl radical, etc.) and type II ROS mainly based on singlet oxygen. At present, commercial photosensitizers (compounds such as porphyrin derivatives and metal phthalocyanine) mainly use singlet oxygen under the illumination condition, and the high oxygen dependence of the photosensitizers causes the decline of the treatment effect of the photosensitizers due to the hypoxic effect in the tumor microenvironment in long-term living tumor treatment. In addition, the hydrophobic rigid structure is easy to aggregate in a physiological environment, so that the fluorescence aggregation quenching and the active oxygen generation efficiency are reduced, and the development of the hydrophobic rigid structure in fluorescence imaging mediated living tumor treatment is extremely unfavorable.
An ideal photosensitizer should include several important characteristics: 1) have near infrared emission and enhanced fluorescence and ROS efficiency accumulation; 2) good biocompatibility and low toxic and side effects; 3) precise organelle targeting and low oxygen dependence. As a type I photosensitizer with high oxidizability, free radical ROS is a photosensitizer with extremely low oxygen dependence because free radical ROS can generate oxygen in situ spontaneously due to Fenton reaction in cells. Therefore, free radical type ROS can greatly overcome the problem of the reduction of the treatment efficiency of the traditional PDT caused by tumor hypoxia. However, the currently reported organic photosensitizer generating free radical type ROS is mainly rhodamine derivative, and its typical fluorescence-mediated quenching (ACQ) effect makes it difficult to realize fluorescence imaging mediated tumor photodynamic therapy.
In 2001, the present inventors proposed an Aggregation-induced emission (AIE) concept: in the single-molecule state, AIE molecules emit weak light, but when aggregated, the light emission of these molecules is significantly enhanced. Despite the significant aggregate luminescence enhancement advantages of AIE molecules, the presently reported photosensitizer material systems with AIE properties are still very poor, and the AIE-type photosensitizers with near infrared emission that can overcome hypoxic PDT treatment are more refractive.
Disclosure of Invention
In order to overcome the defects and shortcomings of the prior art, the invention mainly aims to provide a naphthothiadiazole free radical type photosensitizer material system with aggregation-induced emission performance.
Still another object of the present invention is to provide a method for preparing the above photosensitizer material, which is simple and effective, and has easily available raw materials and high yield.
It is yet another object of the present invention to achieve dynamic dual targeting of the photosensitizer materials described above for imaging of cellular mitochondrial and lysosomal fluorescence.
It is a further object of the present invention to model the above photosensitizer materials for cancer cell killing and live tumor therapy.
The free radical photosensitizer with AIE property developed by the invention is expected to solve the key problems of fluorescence aggregation quenching, tumor hypoxia treatment and the like in the traditional PDT, and has very important application prospect for noninvasive accurate clinical PDT treatment.
The purpose of the invention is realized by at least one of the following technical solutions.
The invention provides a free radical type photosensitizer based on naphthothiadiazole derivatives, which has the following structure:
wherein:
the pi bridges are independently aromatic rings; x is independently an anion pair; r1Independently an aromatic ring derivative electron donating group; r2Independently is an alkyl group.
Further, the pi bridge is one of a benzene ring, a pyridine ring, a thiophene ring and a furan ring.
Further, the anion pair is a common anion or an organic anion; the common anion includes iodide (I)-) Bromine ion (Br)-) Hydroxyl ion (OH)-) Tetrafluoroborate ion, nitrate ion, sulfate ion, hexafluorophosphate ion (PF)6-) (ii) a The organic anion comprises lactate and citrate.
Further, said R1Is one of the structures shown in the following formulas a-q:
wherein R' are the same or different hydrogen atoms, C1-8Alkyl, methoxy and diethylamino.
Further, said R1Is diethylaminophenyl, dimethylaminophenyl, carbazolylphenyl, phenothiazinyl, phenoxazinyl, 9, 10-dihydro-9, 9-dimethylazinyl, 9, 10-dihydro-9, 9-diphenylacridinyl, 10-H-spiro [ acridine-9, 9' -fluorene]A phenyl group, a diphenylamino group, a triphenylamino group, a diphenylaminothienyl group, a bithiophenyl group, a fused thienyl group, a thienocyclopentadienyl group, a naphthylaminophenyl group, or a bipyridinylamino group.
Further, said R2Is methyl, ethyl, propyl, butyl, isobutyl,T-butyl and cyclohexyl.
Preferably, the pi bridge is a benzene ring; the R is2Is methyl; the anion pair is iodide.
The preparation method of the free radical type photosensitizer based on the naphthothiadiazole derivative provided by the invention comprises the following steps: 4, 9-dibromo-naphthothiadiazole and aromatic ring derivatives are used as raw materials, and a unilateral substitution product is obtained through a Suzuki coupling reaction; then, obtaining a corresponding pi-bridge compound containing an aldehyde group through Suzuki coupling reaction; under the condition of organic alkali, the aldehyde group-containing pi-bridge compound reacts with an anion paraalkyl pyridinium to obtain the naphthothiadiazole derivative-based free radical type photosensitizer material (free radical photosensitizer with organic near-infrared fluorescence).
Further, the organic base is one of piperidine, tetramethylammonium hydroxide and tetrabutylammonium hydroxide.
The invention provides an application of a free radical photosensitizer based on naphthothiadiazole derivatives in cell lysosome and mitochondrial fluorescence imaging.
The invention provides application of a free radical photosensitizer based on naphthothiadiazole derivatives in preparation of photodynamic tumor treatment medicines.
According to the invention, a moving (rotating/vibrating) electron donor is introduced into the 4, 9-dibromonaphthothiadiazole in a single side, so that a strong Charge Transfer (CT) state is constructed, and meanwhile, the intermolecular pi-pi accumulation effect of molecules in an aggregation state is inhibited, thereby endowing the material with remarkable near infrared emission and AIE characteristics. In addition, diphenylethylene is used as a bridge on the other side of the corresponding derivative to introduce a stronger electron acceptor, so that the CT state of the product is enhanced. In addition, due to the strong degree of twist between the electron donor-acceptor, the separation of the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) is facilitated, thereby realizing a small singlet-triplet energy level difference (Δ E)st) Facilitating excitation of singlet energy gap crossing (ISC) to triplet states enables efficient ROS generation. Meanwhile, due to the limited molecular aggregation motion, the non-radiative excitation energy is effectively inhibited, the energy is promoted to dissipate in a radiative transition way, and the fluorescence efficiency is increased. Thus, it is possible to provideThe material has high-efficiency fluorescence quantum efficiency and ROS generation capacity, and has good application prospect in fluorescence imaging-mediated photodynamic tumor treatment.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the invention synthesizes and obtains a new free radical type photosensitizer material system with AIE performance based on naphthothiadiazole elements, so as to overcome the problem that the ACQ effect of the existing photosensitizer and the tumor treatment effect is reduced caused by tumor hypoxia;
(2) the synthetic method of the free radical type photosensitizer based on the naphthothiadiazole derivative is simple, raw materials are easy to obtain, the yield is high, and the obtained material is stable in structure;
(3) the free radical photosensitizer based on the naphthothiadiazole derivative provided by the invention realizes dynamic dual targeting on the fluorescence imaging of lysosomes and mitochondria in cells;
(4) the free radical type photosensitizer based on the naphthothiadiazole derivative provided by the invention has good fluorescence imaging effect on in vitro cells and living tumors; under the hypoxic condition, the composition has good killing property on cancer cells; but also has high curative effect on mouse living tumor.
Drawings
FIG. 1 is a fluorescence spectrum based on the materials obtained in example 1 and example 2 under different water content conditions;
FIG. 2 is a graph showing the identification of ROS species based on the materials obtained in example 1 and example 2;
FIG. 3 is a diagram of the imaging of TNZPy on targeted fluorescence of organelle lysosomes;
FIG. 4 is a graphical representation of the targeted fluorescence imaging of TNZPy on organelle mitochondria;
FIG. 5 is a graph of the targeted fluorescence imaging of MTNZPy to lysosomes of organelles;
FIG. 6 is a diagram of the imaging of MTNZPy on the target fluorescence of mitochondria of organelles;
fig. 7A is a graph of staining of live/dead HeLa cells for TNZPy molecular photodynamic therapy using calcein AM and propidium iodide fluorescent dyes under normal and hypoxic conditions, respectively;
fig. 7B is a graph of staining of live/dead HeLa cells for MTNZPy molecular photodynamic therapy using calcein AM and propidium iodide fluorochromes under normal and hypoxic conditions, respectively;
FIG. 8A is a diagram of fluorescence confocal and bright field cells irradiated after a T24 cell is independently reacted with an acridine orange AO dye, a diagram of fluorescence confocal and bright field cells not irradiated after a T24 cell is reacted with an AO dye and then respectively reacted with TNZPy and MTNZPy photosensitizers, and a diagram of fluorescence confocal and bright field cells irradiated after a T24 cell is simultaneously reacted with AO, TNZPy and MTNZPy;
FIG. 8B is a fluorescent confocal and bright field image of T24 cells after coaction with FITC and PI and only subjected to illumination, a fluorescent confocal and bright field image of T24 cells after coaction with FITC and PI and then TNZPy, a fluorescent confocal and bright field image of T24 cells after coaction with FITC and PI and respectively subjected to illumination under normal oxygen and hypoxic conditions and then subjected to TNZPy, and a partially enlarged view after illumination;
FIG. 8C is a fluorescent confocal and bright field image of T24 cells after coaction with FITC and PI and only subjected to illumination, a fluorescent confocal and bright field image of T24 cells after coaction with FITC and PI and then with MTNZPy, a fluorescent confocal and bright field image of T24 cells after coaction with FITC and PI respectively under normal oxygen and hypoxic conditions and then with MTNZPy and a local enlarged image after illumination;
FIG. 9A is a graph of tumor growth inhibition in control and after photodynamic therapy;
fig. 9B is a graph showing the change in body weight of the mice in the control group and the experimental group.
Detailed Description
The following examples are presented to further illustrate the practice of the invention, but the practice and protection of the invention is not limited thereto. It is noted that the processes described below, if not specifically described in detail, are all realizable or understandable by those skilled in the art with reference to the prior art. The reagents or apparatus used are not indicated to the manufacturer, and are considered to be conventional products available by commercial purchase.
EXAMPLE 1 preparation of a superoxide anion radical type photosensitizer (TNZPy)
The synthetic route is as follows:
(1) methyl iodide (2.13g,15mmol) was added dropwise to a solution of 4-methylpyridine (930mg,10mmol) to precipitate a solid, and then anhydrous ethyl acetate (10mL) was added thereto, followed by suction filtration to obtain a white solid powder 1. The yield was 89%.
(2) 4, 9-Dibromonaphthothiadiazole (682mg,2mmol), 4-triphenylamine borate (348mg,1.5mmol), and palladium tetratriphenylphosphine (115mg,0.1mmol) were placed in a dry reaction flask. Nitrogen-pump-nitrogen cycle 3 times (10 minutes each). An aqueous solution of potassium carbonate (2M,8mL) and tetrahydrofuran (12mL) were sparged with nitrogen for 30 minutes and injected into a reaction flask for reflux overnight. After the reaction was completed, the mixture was extracted with dichloromethane/water, dried over anhydrous magnesium sulfate for 12 hours, and purified by column chromatography to obtain a violet black powder 2 with a yield of 53%.
1HNMR(500MHz,CD2Cl2)(ppm):8.33(d,1H),8.07(d,1H),7.64(t,1H),7.55(d,2H),7.48(t,1H),7.41(t,4H),7.19-7.11(m,8H)。
(3) Intermediate 2(507mg,1mmol), 4-formylphenylboronic acid (225mg,1.5mmol), and tetrakistriphenylphosphine palladium (58mg,0.05mmol) were placed in a dry reaction flask. Nitrogen-pump-nitrogen cycle 3 times (10 minutes each). An aqueous potassium carbonate solution (2M,8mL) and tetrahydrofuran (12mL) were purged with nitrogen for 30 minutes, and then injected into a reaction flask to reflux for 12 hours. After the reaction, dichloromethane/water extraction was performed, anhydrous magnesium sulfate was dried for 12 hours, and purification by column chromatography gave a magenta powder 3 with a yield of 82%.
1HNMR(500MHz,CD2Cl2)(ppm):10.2(s,1H),8.19(d,1H),8.17(d,2H),7.92(d,1H),7.85(d,2H),7.56(d,2H),7.40(t,2H),7.35(t,4H),7.26(t,6H),7.11(t,2H)。
(4) Intermediate 3(270mg,0.5mmol) and intermediate 1(176mg,0.75mmol) were dissolved in a mixed solvent of ethanol/tetrahydrofuran (V/V ═ 5/15), and 5 drops of an ultra-dry piperidine organic base were added to the solution to react at room temperature for 12 hours. Purifying by column chromatography to obtain purple red powder TNZPy with a yield of 77%.
1HNMR(500MHz,d-DMSO)8.93-8.79(m,8H),8.05-7.95(m,5H),7.73(d,1H),7.55-7.50(m,5H),7.40(t,3H),7.20-7.14(m,6H),4.30(s,3H).
EXAMPLE 2 preparation of a superoxide anion radical type photosensitizer (MTNZPy)
The synthetic route is as follows:
(1) the intermediate 1 synthesis procedure was the same as described above.
(2) 4, 9-Dibromonaphthothiadiazole (682mg,2mmol), 4, 4' -dimethoxytriphenylamine borate (524mg,1.5mmol), and palladium tetratriphenylphosphine (115mg,0.1mmol) were placed in a dry reaction flask. Nitrogen-pump-nitrogen cycle 3 times (10 minutes each). An aqueous potassium carbonate solution (2M,8mL) and tetrahydrofuran (12mL) were purged with nitrogen for 30 minutes, and then injected into a reaction flask to reflux for 12 hours. After the reaction, dichloromethane/water extraction was performed, anhydrous magnesium sulfate was dried for 12 hours, and purification by column chromatography gave a violet black powder 2 with a yield of 55%.
1HNMR(500MHz,CD2Cl2)(ppm):8.42(d,1H),8.14(d,1H),7.68(t,1H),7.43(m,3H),7.22(t,4H),7.06(t,2H),6.93(t,4H),3.82(s,6H)。
(3) Intermediate 2(567mg,1mmol), 4-formylphenylboronic acid (225mg,1.5mmol), and tetrakistriphenylphosphine palladium (58mg,0.05mmol) were placed in a dry reaction flask. Nitrogen-pump-nitrogen cycle 3 times (10 minutes each). An aqueous potassium carbonate solution (2M,8mL) and tetrahydrofuran (12mL) were purged with nitrogen for 30 minutes, and then injected into a reaction flask to reflux for 12 hours. After the reaction, the mixture was extracted with dichloromethane/water, dried over anhydrous magnesium sulfate for 12 hours, and purified by column chromatography to obtain a purplish black powder 3 with a yield of 88%.
1HNMR(500MHz,CD2Cl2)10.2(s,1H),8.19(d,1H),8.17(d,2H),7.92(d,1H),7.85(d,2H),7.48(d,2H),7.40(d,2H),7.23(t,4H),7.10(d,2H),6.93(t,4H),3.81(s,6H)。
(4) Intermediate 3(297mg,0.5mmol) and intermediate 1(176mg,0.75mmol) were dissolved in a mixed solvent of ethanol/tetrahydrofuran (V/V ═ 5/15), and 5 drops of an ultra-dry piperidine organic base were added to the solution to react at room temperature for 12 hours. After purification by column chromatography, purple black powder MTNZPy is obtained with the yield of 79 percent.
1HNMR(500MHz,d-DMSO)8.94(d,2H),8.84(d,1H),8.33(d,1H),8.22(d,1H),8.09(d,1H),8.02(t,2H),7.97(m,2H),7.79(d,1H),7.72(d,1H),7.48(m,4H),7.20(d,4H),7.01-6.94(m,6H),4.30(s,3H),3.78(s,6H)。
Example 3 AIE characterization of naphthothiadiazole free radical photosensitizers (TNZPy and MTNZPy)
FIG. 1 is a fluorescence spectrum based on the materials obtained in example 1 and example 2 under different water content conditions. FIG. 1(A) is a graph with H2Increased O content TNZPy (10. mu.M) in DMSO/H2Fluorescence emission spectrum in O (v/v) mixed solvent, lambdaex498 nm; (B) is as follows H2Increased O content MTNZPy (10. mu.M) in DMSO/H2Fluorescence emission spectrum in O (v/v) mixed solvent, lambdaex523nm, where fw(vol%) represents the water content. As can be seen in fig. 1, both example materials did not substantially emit light in neat dimethylsulfoxide solvent, and fluorescence began to increase gradually with the addition of poor solvent water. When the water content is increased to 90%, the fluorescence intensity reaches the strongest state, which indicates that the TNZPy photosensitizer and the MTNZPy photosensitizer both have AIE characteristics. In addition, the fluorescence emission wavelengths of the materials obtained in example 1 and example 2 at 90% water content were 663nm and 682nm, respectively, indicating the property of near infrared fluorescence emission.
Example 4 ROS species identification of naphthothiadiazole free radical type photosensitizers (TNZPy and MTNZPy)
FIG. 2 shows the ROS species identification based on the materials obtained in example 1 and example 2. FIG. 2(A) is a graph demonstrating that TNZPy generates superoxide anion radical type ROS species using a DHR123 fluorescent probe; (B) to confirm that MTNZPy generates superoxide anion radical type ROS species using DHR123 fluorescent probes; (C) generating superoxide anion free radical signals for detecting TNZPy and MTNZPy using electron paramagnetic spectroscopy (EPR); (D) the degradation rate of ABDA (5. mu.M) solutions containing TNZPy (10. mu.M) and MTNZPy (10. mu.M) under white light irradiation. As can be seen from part a of fig. 2 and part B of fig. 2, when DHR123 fluorescent probe is used to detect radical-type ROS, DHR123 fluorescence intensity is significantly increased after adding photosensitizers (TNZPy and MTNZPy) and irradiating with white light, indicating that both TNZPy and MTNZPy can generate radical-type ROS; when a reducing agent Vc is further added, the fluorescence intensity is reduced to the self intensity of the DHR123 probe, which shows that the free radical type ROS is easily quenched by Vc, and the reverse side proves that the TNZPy and MTNZPy can generate the free radical type ROS. Part C of fig. 2 is a direct demonstration of TNZPy and MTNZPy producing free radical signals using electron paramagnetic resonance spectroscopy (EPR). 5-tert-Butoxycarbonyl-5-methyl-1-pyroline-N-oxide (BMPO) is used as a free radical trapping agent, three control groups of BMPO, BMPO + TNZPy and BMPO + MTNZPy have no free radical signals, and after light activation, obvious multiple splitting peaks indicate that TNZPy and MTNZPy can generate free radicals. To further verify that TNZPy and MTNZPy mainly generate type I ROS rather than type II singlet oxygen, by using a type II singlet oxygen probe (ABDA), the present inventors found that TNZPy and MTNZPy respond poorly to ABDA under light conditions (portion D of fig. 2), indicating that TNZPy and MTNZPy generate singlet states with low efficiency, mainly based on free radical type ROS.
Example 5 fluorescence imaging dynamic targeting of TNZPy photosensitizers to lysosomes and mitochondria
FIG. 3 is a diagram of the imaging of TNZPy on targeted fluorescence of organelle lysosomes. FIG. 3 shows the effect of TNZPy and Lysotracker green DND-26 on lysosome staining and co-staining of cells at different time points (A) for 4h, (B) for 6h, (C) for 12h, and (D) for 24 h. [ TNZPy ] ═ 5 μ M, Ex ═ 543nm, Em ═ 600 and 720nm, Laser 5%; [ lysotracergreen DND-26] (200 nM), Ex (488 nM), Em (500-. HeLa cells were cultured for 24 hours, and then added to a medium together with 5. mu.M TNZPy and 0.2. mu.M Lysotracker green (lysosome green fluorescent probe) in PBS, and after the incubation at 37 ℃ for 4 hours, 6 hours, 12 hours, and 24 hours, the cells were washed with PBS 3 times, and then characterized by imaging with a confocal laser microscope. From the results, it can be seen that when the culture time reaches 6h, the co-localization coefficient of TNZPy to lysosome is 81%; the culture time is continuously prolonged to 24h, and the co-localization coefficient is reduced to 64 percent.
FIG. 4 is a diagram of the imaging of TNZPy on the target fluorescence of mitochondria of organelles. FIG. 4 shows the effect of TNZPy and commercial Mitotracker green FM on mitochondrial staining and co-staining of cells at different time points (A) for 4h, (B) for 6h, (C) for 12h, and (D) for 24 h. [ TNZPy ] ═ 5 μ M, Ex ═ 543nm, Em ═ 600 and 720nm, Laser 5%; [ Mitotracker greenFM ] (200 nM), Ex (488 nM), Em (500) and 530nM. HeLa cells were cultured for 24 hours, and then added to a medium together with 5. mu.M TNZPy and 0.2. mu.M Mitotracker green (mitochondrial Green fluorescent Probe) in PBS, and after the cells were allowed to react at 37 ℃ for 4 hours, 6 hours, 12 hours, and 24 hours, they were washed with PBS 3 times, and then characterized by imaging with a confocal laser microscope. From the results, it can be seen that the co-localization coefficient of TNZPy to mitochondria continuously increases with the increase of the culture time, and the targeting efficiency to mitochondria reaches up to 88% after the culture time reaches 24 h.
As can be seen from the analysis in conjunction with fig. 3 and 4, the targeting behavior of TNZPy to two organelles (lysosome and mitochondria) is not two relatively independent processes, but one dynamic process. That is, as time goes on, TNZPy will "escape" from lysosomes and enter mitochondria, eventually achieving dynamic dual-targeting properties of lysosomal, mitochondrial fluorescence imaging.
Example 6 fluorescence imaging dynamic targeting of MTNZPy photosensitizers to lysosomes and mitochondria
FIG. 5 is a diagram of imaging of MTNZPy on targeted fluorescence of organelle lysosomes. FIG. 5 shows the results of the lysosome staining and co-staining of cells with MTNZPy and the commercial lysosome dye Lysotracker green DND-26 at different time points (A) for 4h, (B) for 6h, (C) for 12h, and (D) for 24 h. [ MTNZPy ] ═ 5 μ M, Ex ═ 543nm, Em ═ 600 and 720nm, Laser 5%; [ lysotracergreen DND-26] (200 nM), Ex (488 nM), Em (500-. HeLa cells were cultured for 24 hours, and then added to a medium with 5. mu.M MTNZPy and 0.2. mu.M Lysotracker green (lysosome green fluorescent probe) in PBS, and after exposure to 37 ℃ for 4 hours, 6 hours, 12 hours, and 24 hours, the cells were washed with PBS 3 times, and then characterized by imaging with a confocal laser microscope. From the results, it can be seen that when the culture time reaches 6h, the co-localization coefficient of MTNZPy to lysosome is 64%; the culture time is continuously prolonged to 24h, and the co-localization coefficient is reduced to 60%.
FIG. 6 is a diagram of the imaging of MTNZPy on the target fluorescence of organelle mitochondria. FIG. 6 shows the effect of MTNZPy and commercial mitochondrial dye Mitotracker green FM on mitochondrial staining and co-staining of cells at different time points (A) for 4h, (B) for 6h, (C) for 12h, and (D) for 24 h. [ MTNZPy ] ═ 5 μ M, Ex ═ 543nm, Em ═ 600 and 720nm, Laser 5%; [ Mitotracker greenFM ] (200 nM), Ex (488 nM), Em (500) and 530nM. HeLa cells were cultured for 24 hours, and then added to a medium together with 5. mu.M MTNZPy and 0.2. mu.M Mitotracker green (mitochondrial Green fluorescent Probe) in PBS, and after the cells were allowed to react at 37 ℃ for 4 hours, 6 hours, 12 hours, and 24 hours, they were washed with PBS 3 times, and then characterized by imaging with a confocal laser microscope. From the results, it can be seen that the co-localization coefficient of MTNZPy to mitochondria continuously increases with the increase of the culture time, and the targeting efficiency to mitochondria reaches as high as 84% after the culture time reaches 24 h.
As can be seen from the analysis of fig. 5 and fig. 6, the MTNZPy targets two organelles (lysosome and mitochondria) similarly to TNZPy, and both exhibit dynamic dual-targeting characteristic of lysosome and mitochondrial fluorescence imaging.
Example 7 evaluation of cytotoxicity of TNZPy and MTNZPy sensitizers
HeLa cells were used as the subject for evaluation of phototoxicity of TNZPy and MTNZPy under normoxic and hypoxic conditions. When the PI fluorescent red signal represents the cell death signal, the calcein fluorescent green signal represents the living cell signal. As shown in fig. 7A, when only light was applied and only TNZPy photosensitizer was applied, the cells exhibited green fluorescence, indicating that the survival status of the cells was good; when the light condition is added under the normoxic condition, obvious PI red fluorescence signals appear at the moment, which indicates that the cells die; even if light is added under hypoxic conditions, more cells still appear red, indicating that hypoxic conditions still have a phenomenon of cell death. As shown in fig. 7B, the photodynamic treatment efficiency of MTNZPy under normoxic and hypoxic conditions is similar to that of TNZPy, which indicates that both MTNZPy and TNZPy have good in vitro photodynamic treatment effect.
Example 8 photodynamic therapy mechanistic evaluation of TNZPy and MTNZPy photosensitizers
T24 human bladder cancer cells are taken as research objects, and the photodynamic killing mechanism of the two photosensitizers is researched by utilizing AO fluorescent probes. AO was co-cultured with photosensitizers TNZPy and MTNZPy in T24 cells. FIG. 8A is a diagram of fluorescence confocal and bright field cells treated by light after the T24 cell alone reacts with acridine orange AO dye, fluorescence confocal and bright field cells treated by light without the action of TNZPy and MTNZPy photosensitizers after the T24 cell reacts with AO dye, and fluorescence confocal and bright field cells treated by light after the T24 cell reacts with AO and TNZPy or MTNZPy, respectively, [ AO]＝5μM,Ex＝488nm,Em＝610–635nm,Laser 1.5％；Scale bar＝20μm.. As can be seen in fig. 8A, AO exhibited green fluorescence in the cytoplasm and nucleus, but orange red light (white arrows) in the lysosome, indicating that organelle lysosomes were still present prior to illumination. When subjected to photodynamic therapy, the orange-red light of AO disappears, indicating that the lysosome is disrupted thereby releasing AO into the cytoplasm. In addition, in the invention, in bright field pictures, macrophagic vesicles (red arrows) in the cells can be observed, indicating that mitochondria are also damaged. The simultaneous destruction of both organelles leads to apoptosis, consistent with the observation of the dual-specific targeting behavior of both photosensitizers to mitochondria and lysosomes in accordance with the present invention. In addition, the invention further evaluates the cell killing of fluorescein isothiocyanate FITC + propidium iodide PI under normal oxygen content and hypoxic conditions, the cell killing of MTNZPy under the hypoxic conditions is stronger than that of TNZPy, and the dominant action of free radical type ROS to cause cell apoptosis is illustrated again, as shown in FIG. 8B and FIG. 8C. FIG. 8B is the fluorescence confocal and bright field diagram of T24 cell after combined action with FITC and PI and only illuminated, and the fluorescence confocal and bright field diagram of T24 cell after combined action with FITC and PI and then combined action with TNZPyThe field diagram, the fluorescence confocal and bright field diagram of the T24 cell after the combined action with FITC and PI and the action with TNZPy under the normal oxygen and hypoxic condition respectively and after the illumination and the local enlarged view after the illumination; FIG. 8C is a fluorescent confocal and bright field image of T24 cells after coaction with FITC and PI and only subjected to illumination, a fluorescent confocal and bright field image of T24 cells after coaction with FITC and PI and then with MTNZPy, a fluorescent confocal and bright field image of T24 cells after coaction with FITC and PI respectively under normal oxygen and hypoxic conditions and then with MTNZPy and a local enlarged image after illumination; [ TNZPy]＝(10μM,24h),[MTNZPy]＝(10μM,24h),[Annexin V-FITC]＝(5μM,24h)，Ex＝488nm,Em＝500–530nm；[PI]＝(5μM,24h)，Ex＝488nm,Em＝600–620nm。
Example 9 evaluation of phototoxicity of TNZPy and MTNZPy photosensitizers in vivo tumors
T24 human bladder cancer cells are used as a model and are planted under the skin of a mouse to establish a tumor animal model. When the size of subcutaneous tumor of the mouse is 50mm3Thereafter, the evaluation of the photodynamic therapy effect of TNZPy and MTNZPy on the tumors of mice was started. By adopting the mode of intratumoral injection, the drug is administered once in two days, the drug concentration is 1mg/mL for each time, the drug is administered three times continuously, and white light treatment (150mW cm) is carried out on the tumor part after each drug administration-2) A total of three white light treatments were performed for 15 minutes. After the treatment period was completed, tumor volume and body weight changes of the mice were recorded every two days. After TNZPy and MTNZPy are injected into tumors for 24 hours, in vivo fluorescence imaging is obvious, the signal-to-noise ratio is low, and the two photosensitizers have good in vivo fluorescence imaging effect. As can be seen from fig. 9A, the tumor proliferation of the control group of mice that did not undergo photodynamic therapy was rapid, and the tumor growth was effectively inhibited after photodynamic therapy, indicating that TNZPy and MTNZPy still have good efficacy in the treatment of in vivo tumors. In addition, fig. 9B illustrates that the body weight growth trend of mice was the same in all experimental groups, indicating that the photodynamic-treated mice did not show any tumor growth inhibition due to other causes.
The above examples are only preferred embodiments of the present invention, which are intended to be illustrative and not limiting, and those skilled in the art should understand that they can make various changes, substitutions and alterations without departing from the spirit and scope of the invention.
Claims (10)
1. A free radical type photosensitizer based on naphthothiadiazole derivatives is characterized by having the following structure:
wherein the pi bridges are independently aromatic rings; x is independently an anion pair; r1Independently an aromatic ring derivative electron donating group; r2Independently is an alkyl group.
2. The naphthothiadiazole derivative-based radical photosensitizer according to claim 1, wherein the pi-bridge is one of a benzene ring, a pyridine ring, a thiophene ring and a furan ring.
3. The naphthothiadiazole derivative-based radical photosensitizer according to claim 1, wherein the anion pair is one of iodide, bromide, hydroxide, tetrafluoroborate, nitrate, sulfate, hexafluorophosphate, lactate, and citrate.
4. The naphthothiadiazole derivative-based radical type photosensitizer according to claim 1, wherein R is1Is one of the structures shown in the following formulas a-q:
wherein R' are the same or different hydrogen atoms, C1-8Alkyl, methoxy and diethylamino.
5. The naphthothiadiazole-based according to claim 4A photosensitizer of a free radical type, characterized in that R is1Is diethylaminophenyl, dimethylaminophenyl, carbazolylphenyl, phenothiazinyl, phenoxazinyl, 9, 10-dihydro-9, 9-dimethylazinyl, 9, 10-dihydro-9, 9-diphenylacridinyl, 10-H-spiro [ acridine-9, 9' -fluorene]A phenyl group, a diphenylamino group, a triphenylamino group, a diphenylaminothienyl group, a bithiophenyl group, a fused thienyl group, a thienocyclopentadienyl group, a naphthylaminophenyl group, or a bipyridinylamino group.
6. The naphthothiadiazole derivative-based radical type photosensitizer according to claim 1, wherein R is2Is one of methyl, ethyl, propyl, butyl, isobutyl, tertiary butyl and cyclohexyl.
7. A method for preparing the naphthothiadiazole derivative-based radical type photosensitizer of any one of claims 1 to 6, comprising the steps of: 4, 9-dibromo-naphthothiadiazole and aromatic ring derivatives are used as raw materials, and a unilateral substitution product is obtained through a Suzuki coupling reaction; then, obtaining an aldehyde group-containing pi-bridge compound through Suzuki coupling reaction; under the condition of organic base, the aldehyde group-containing pi-bridge compound reacts with the anion-alkyl pyridinium to obtain the naphthothiadiazole derivative-based free radical type photosensitizer material.
8. The method of claim 7, wherein the organic base is one of piperidine, tetramethylammonium hydroxide and tetrabutylammonium hydroxide.
9. Use of the naphthothiadiazole derivative-based radical type photosensitizer of any one of claims 1 to 6 for cell lysosome and mitochondrial fluorescence imaging.
10. Use of the naphthothiadiazole derivative-based radical photosensitizer of any one of claims 1 to 6 in the preparation of a photodynamic tumor treatment drug.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113200913A (en) * | 2021-04-08 | 2021-08-03 | 华南理工大学 | Light-activated type I photosensitizer and preparation method and application thereof |
| CN113234071A (en) * | 2021-05-17 | 2021-08-10 | 阜阳师范大学 | Triphenylamine methyl pyridine salt, synthetic method thereof, and application of triphenylamine methyl pyridine salt in CN-recognition and biological imaging |
| CN113480528A (en) * | 2021-08-16 | 2021-10-08 | 四川大学华西医院 | Imidazole photosensitizer specially targeting mitochondria and efficiently generating singlet oxygen and preparation method thereof |
| CN114106015A (en) * | 2021-10-11 | 2022-03-01 | 深圳大学 | Novel near-infrared two-region emission aggregation-induced luminescent material, and preparation method and application thereof |
| CN114195775A (en) * | 2021-12-28 | 2022-03-18 | 黄埔海关技术中心 | Fluorescent dye, preparation method thereof and application thereof in bacterial staining |
| CN114539239A (en) * | 2022-03-18 | 2022-05-27 | 华南理工大学 | AIE photosensitizer based on pyridinium salt and preparation method and application thereof |
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565606A (en) * | 2016-10-17 | 2017-04-19 | 华南理工大学 | Compound with aggregation induced luminescence property and preparation method and application thereof |
| CN107849441A (en) * | 2015-06-24 | 2018-03-27 | 香港科技大学 | AIE illuminators for visualization and the treatment of cancer |
| CN108055852A (en) * | 2015-07-16 | 2018-05-18 | 香港科技大学 | Emit red or yellow fluorescent aggregation inducing emitting biological probe |
| CN109336909A (en) * | 2018-11-07 | 2019-02-15 | 武汉大学深圳研究院 | Two area's fluorescent chemicals of near-infrared and preparation method, nanoparticle micella and its application with aggregation-induced emission property |
| CN109722237A (en) * | 2019-01-07 | 2019-05-07 | 华南理工大学 | A kind of fluorescence probe based on condensed ring oxidation of thiophene and its application in cell imaging |
| CN110407736A (en) * | 2018-04-27 | 2019-11-05 | 香港科技大学 | The preparation and application of near-infrared compound with strong two-photon absorption |
| CN111004624A (en) * | 2019-12-24 | 2020-04-14 | 南开大学 | Preparation of near-infrared fluorescent probe with PTT effect and aggregation-induced emission enhancement effect |
| CN111116574A (en) * | 2019-12-25 | 2020-05-08 | 渤海大学 | Viscosity fluorescent probe with mitochondrial targeting function and preparation method and application thereof |
-
2020
- 2020-05-26 CN CN202010455239.3A patent/CN111689955A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107849441A (en) * | 2015-06-24 | 2018-03-27 | 香港科技大学 | AIE illuminators for visualization and the treatment of cancer |
| CN108055852A (en) * | 2015-07-16 | 2018-05-18 | 香港科技大学 | Emit red or yellow fluorescent aggregation inducing emitting biological probe |
| CN106565606A (en) * | 2016-10-17 | 2017-04-19 | 华南理工大学 | Compound with aggregation induced luminescence property and preparation method and application thereof |
| CN110407736A (en) * | 2018-04-27 | 2019-11-05 | 香港科技大学 | The preparation and application of near-infrared compound with strong two-photon absorption |
| CN109336909A (en) * | 2018-11-07 | 2019-02-15 | 武汉大学深圳研究院 | Two area's fluorescent chemicals of near-infrared and preparation method, nanoparticle micella and its application with aggregation-induced emission property |
| CN109722237A (en) * | 2019-01-07 | 2019-05-07 | 华南理工大学 | A kind of fluorescence probe based on condensed ring oxidation of thiophene and its application in cell imaging |
| CN111004624A (en) * | 2019-12-24 | 2020-04-14 | 南开大学 | Preparation of near-infrared fluorescent probe with PTT effect and aggregation-induced emission enhancement effect |
| CN111116574A (en) * | 2019-12-25 | 2020-05-08 | 渤海大学 | Viscosity fluorescent probe with mitochondrial targeting function and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| QING WAN ET AL.: "Molecular Engineering for Boosting AIE-active Free Radical Photogenerator and Its High-performance in Hypoxia via Photodynamic Therapy", 《CHEMRXIV》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113200913A (en) * | 2021-04-08 | 2021-08-03 | 华南理工大学 | Light-activated type I photosensitizer and preparation method and application thereof |
| CN113234071A (en) * | 2021-05-17 | 2021-08-10 | 阜阳师范大学 | Triphenylamine methyl pyridine salt, synthetic method thereof, and application of triphenylamine methyl pyridine salt in CN-recognition and biological imaging |
| CN113234071B (en) * | 2021-05-17 | 2023-08-01 | 阜阳师范大学 | Triphenylamine methyl pyridine salt, synthesis method and application thereof in CN & lt- & gt identification and biological imaging |
| CN113480528A (en) * | 2021-08-16 | 2021-10-08 | 四川大学华西医院 | Imidazole photosensitizer specially targeting mitochondria and efficiently generating singlet oxygen and preparation method thereof |
| CN114106015A (en) * | 2021-10-11 | 2022-03-01 | 深圳大学 | Novel near-infrared two-region emission aggregation-induced luminescent material, and preparation method and application thereof |
| CN114195775A (en) * | 2021-12-28 | 2022-03-18 | 黄埔海关技术中心 | Fluorescent dye, preparation method thereof and application thereof in bacterial staining |
| CN114195775B (en) * | 2021-12-28 | 2023-11-03 | 黄埔海关技术中心 | Fluorescent dye, preparation method thereof and application thereof in bacterial staining |
| CN114539239A (en) * | 2022-03-18 | 2022-05-27 | 华南理工大学 | AIE photosensitizer based on pyridinium salt and preparation method and application thereof |
| CN116425739A (en) * | 2023-03-16 | 2023-07-14 | 浙江义氪生物科技有限公司 | Compound for tumor targeted imaging and photodynamic therapy and synthesis method and application thereof |
| CN116425739B (en) * | 2023-03-16 | 2024-08-20 | 浙江义氪生物科技有限公司 | Compound for tumor targeted imaging and photodynamic therapy and synthesis method and application thereof |
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