A fluorinated tin phthalocyanine derivative and its preparation method and application

Abstract

The present invention discloses a fluorinated tin phthalocyanine derivative, its preparation method, and application. The fluorinated tin phthalocyanine derivative is prepared by chemically covalently linking a perfluorocarbon to a tin phthalocyanine side chain. Compared with tin phthalocyanine, the fluorinated tin phthalocyanine derivative not only has an oxygen-carrying function but also effectively improves the singlet oxygen yield and photostability of tin phthalocyanine. The present invention also provides a nanophotosensitizer. The fluorinated tin phthalocyanine derivative is PEGylated to form a PEGylated fluorinated tin phthalocyanine derivative that can self-assemble in water to form nanoparticles. The nanophotosensitizer exhibits excellent performance in terms of singlet oxygen yield, photostability, solution stability, and oxygen carrying capacity, and has good application prospects in photodynamic tumor therapy.

Description

Technical Field

[0001] The present invention relates to the technical field of photosensitizer synthesis and photodynamic tumor therapy, and in particular to a fluorinated tin phthalocyanine derivative and a preparation method and application thereof. Background Art

[0002] Photodynamic therapy (PDT) has attracted considerable attention due to its minimally invasive nature and high spatiotemporal precision. Photosensitizers, as a key component of PDT, transfer absorbed energy to ambient oxygen and generate reactive oxygen species (ROS), which then react with nearby biomacromolecules (e.g., lipids, proteins, DNA) to kill cancer cells and complete PDT. Therefore, effective accumulation of photosensitizers at the tumor site is a prerequisite for PDT in cancer patients, and their tumor retention directly determines whether the treatment is accurate and effective. However, during in vivo PDT, most organic small molecule photosensitizers are rapidly cleared from the bloodstream, typically within hours or even minutes. This prevents the photosensitizers from being effectively accumulated and retained at the tumor site, resulting in low PDT efficiency. Therefore, increasing the retention time of photosensitizers at the tumor site is urgent. Nanoparticle-based photosensitizers can overcome the limitations of small molecule dyes and improve the anti-tumor efficacy of PDT.

[0003] Designing photosensitizers into nanosystems, such as organic polymer nanoparticles, liposomes, and nanoinorganic materials, has been reported to prolong blood circulation and enhance tumor retention. The physicochemical properties of nanosystems (i.e., size, shape, and charge) can be well controlled to optimize tumor retention, and tumor retention can be further enhanced by exploiting "passive targeting" effects. Numerous photosensitizers have been reported or commercially available, but most suffer from limitations, such as low photostability, structural instability, or a limited range of solvent conditions. The development of new photosensitizers that are highly efficient, photostable, and widely applicable under a wide range of conditions would be highly beneficial. Good photostability under repeated excitation is highly desirable. Photobleaching is often considered a drawback of photosensitizers because the formation of photodegradation products complicates the interpretation of experimental results and reduces the efficiency of ROS generation. Therefore, researchers have been investigating the design of a new generation of nanomaterial-based photosensitizers (nanophotosensitizers) with improved photostability and higher singlet oxygen generation efficiency, as well as methods to improve the performance of existing photosensitizers.

[0004] However, most current clinical photodynamic therapy drugs are based on a Type-II photosensitization mechanism, which is highly oxygen-dependent, resulting in a very limited effectiveness of PDT against hypoxic solid tumors. Therefore, achieving effective therapeutic effects of photosensitizers within hypoxic solid tumors remains a major challenge in the clinical application of PDT. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a fluorinated tin phthalocyanine derivative and its preparation method and application. The present invention prepares a fluorinated tin phthalocyanine derivative with oxygen-carrying function through nucleophilic substitution and solid-phase synthesis, wherein perfluorocarbon is chemically covalently linked to the tin phthalocyanine side chain, so that the prepared fluorinated tin phthalocyanine derivative has oxygen-carrying function, and the singlet oxygen yield and photostability are effectively improved. In addition, by pegylation of the fluorinated tin phthalocyanine derivative, it can self-assemble in water to form stable nanoparticles, and exhibits excellent performance in terms of singlet oxygen yield, photostability, solution stability and oxygen carrying capacity, and has good application prospects in hypoxic photodynamic tumor treatment.

[0006] The first aspect of the present invention provides a fluorinated tin phthalocyanine derivative having the following general structural formula:

[0007]

[0008] Where R is x is an integer from 5 to 7.

[0009] The present invention covalently links a perfluorocarbon (R) to a tin phthalocyanine side chain, resulting in a photosensitizer with oxygen-carrying functionality, high singlet oxygen yield, and excellent photostability. The main reasons for this are as follows: 1. The strong binding affinity between the fluorine atoms in the perfluorocarbon and oxygen gives the fluorinated tin phthalocyanine derivative prepared in this invention its oxygen-carrying capacity; 2. The fluorine atoms alter the electron cloud density on the phthalocyanine ring. Fluorination modification along the phthalocyanine axis, with its highly electronegative fluorine atoms, sensitizes the fluorescence quantum yield and extends the fluorescence lifetime, facilitating the binding of excited-state phthalocyanine with oxygen, thereby increasing singlet oxygen yield. 3. Singlet oxygen attack on phthalocyanine is the primary factor affecting its stability. The conjugated π-bond system of the phthalocyanine ring is sensitive to oxygen molecules, which can react with the bridging nitrogen atoms. In the absence of light, the phthalocyanine molecule does not oxidize. However, upon illumination, the excited-state molecular reactivity is sufficiently high to promote oxidation of the phthalocyanine, forming phthalimide. Furthermore, the presence of a benzene ring and an electron donor accelerates the decomposition of phthalocyanine. Therefore, the fluorinated tin phthalocyanine derivative provided by the present invention not only has an oxygen-carrying function, but also effectively improves the singlet oxygen yield and photostability.

[0010] The second aspect of the present invention provides a method for preparing the fluorinated tin phthalocyanine derivative described in the first aspect, comprising the following steps:

[0011] (1) reacting perfluorocarbon with 4-nitrophthalonitrile in the presence of an inorganic base and an organic solvent to obtain a precursor;

[0012] (2) grinding and mixing the precursor prepared in step (1) and stannous chloride uniformly, and then heating and reacting them in an oxygen-free environment to obtain the fluorinated tin phthalocyanine derivative;

[0013] The structure of the precursor is shown below:

[0014]

[0015] Among them, the perfluorocarbon R-OH and the R in the precursor are x is an integer from 5 to 7.

[0016] Furthermore, in step (1), the perfluorocarbon R—OH may be pentafluorophenol, perfluoro-1-heptanol or perfluoro-1-octanol.

[0017] Furthermore, in step (1), the inorganic base is preferably anhydrous potassium carbonate and / or lithium hydroxide, more preferably lithium hydroxide.

[0018] Furthermore, in step (1), the organic solvent is selected from one or more of acetonitrile, dimethyl sulfoxide, and N,N'-dimethylformamide.

[0019] Furthermore, in step (1), the reaction temperature is preferably 40-60°C, such as 55°C, and the reaction time is preferably 24-48h, such as 38h.

[0020] Furthermore, in step (1), the molar feed ratio of 4-nitrophthalonitrile to perfluorocarbon is preferably 1:1-1.5, for example 1:1.2.

[0021] Furthermore, in step (2), the reaction temperature of the heating reaction is preferably 250-280° C., such as 275° C., and the reaction time is preferably 6-12 h, such as 8 h.

[0022] Furthermore, in step (2), the molar feed ratio of the precursor to stannous chloride is preferably 4-8:1, for example 4:1.

[0023] Furthermore, the fluorinated tin phthalocyanine derivative, a product of the heating reaction, was washed and purified using 1 M hydrochloric acid and 1 M sodium hydroxide in sequence.

[0024] The third aspect of the present invention provides a nano photosensitizer, wherein the preparation method of the nano photosensitizer comprises the following steps:

[0025] S1: reacting the fluorinated tin phthalocyanine derivative described in the first aspect with polyethylene glycol in the presence of an acid-binding agent and a solvent to obtain a PEGylated fluorinated tin phthalocyanine derivative;

[0026] S2: self-assembling the PEGylated fluorinated tin phthalocyanine derivative prepared in S1 in water to obtain the nano photosensitizer.

[0027] Furthermore, in S1, the acid binding agent is selected from one or more of pyridine, anhydrous potassium carbonate, and sodium hydride, more preferably sodium hydride.

[0028] Furthermore, in S1, the solvent is selected from one or more of toluene, 1,3-bis(trifluoromethyl)benzene, and N,N'-dimethylformamide.

[0029] Furthermore, the general structural formula of the polyethylene glycol is as follows:

[0030]

[0031] Wherein, n is an integer of 111-444; For example, the polyethylene glycol may be methoxy PEG 5000 Hydroxyl, methoxy PEG 10000 Hydroxyl, methoxy PEG 20000 One or more of the hydroxyl groups, more preferably methoxy PEG 5000 Hydroxyl.

[0032] Furthermore, in S1, the molar feed ratio of the fluorinated tin phthalocyanine derivative to polyethylene glycol is preferably 1:4-10, for example 1:8.

[0033] Furthermore, in S1, the reaction temperature of the reaction is preferably 120-160° C., and the reaction time is preferably 8-24 h. In some preferred embodiments, the reaction temperature is 160° C., and the reaction time is 14 h.

[0034] Furthermore, in S2, a co-solvent dialysis method is used to make the PEGylated fluorinated tin phthalocyanine derivative self-assemble in water to obtain the nano photosensitizer; the co-solvent dialysis method is specifically: dissolving the PEGylated fluorinated tin phthalocyanine derivative in tetrahydrofuran and dialyzing it with deionized water to obtain the nano photosensitizer.

[0035] The fourth aspect of the present invention provides a use of the fluorinated tin phthalocyanine derivative described in the first aspect or the nano photosensitizer described in the third aspect in the preparation of a drug for hypoxic photodynamic tumor therapy.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] 1. The present invention provides a fluorinated tin phthalocyanine derivative, which is obtained by chemically covalently linking a perfluorocarbon to a tin phthalocyanine side chain, so that the prepared fluorinated tin phthalocyanine derivative has an oxygen-carrying function; each tin phthalocyanine molecule contains four perfluorocarbons, thereby meeting the oxygen-carrying requirement while avoiding the grafting efficiency problems caused by post-modification; in addition, the introduction of perfluorocarbons improves the singlet oxygen yield and photostability of the tin phthalocyanine.

[0038] 2. The present invention utilizes a nucleophilic substitution reaction between a hydroxyl-containing perfluorocarbon and phthalonitrile to prepare a precursor, and then prepares the above-mentioned fluorinated tin phthalocyanine derivative through a solid-phase reaction between the precursor and stannous chloride. The preparation method is simple, efficient, and suitable for batch preparation.

[0039] 3. The present invention also provides a nano photosensitizer, which is obtained by self-assembling the above-mentioned fluorinated tin phthalocyanine derivative in water after polyethylene glycolization; based on the fluorine-fluorine interaction on the side chain of the fluorinated tin phthalocyanine, the polyethylene glycolized fluorinated tin phthalocyanine derivative can self-assemble in water to form stable nanoparticles, thereby preparing a functional nano photosensitizer that meets different application requirements. The preparation method of the above-mentioned nano photosensitizer is simple, and it shows excellent performance in terms of singlet oxygen yield, photostability, solution stability and oxygen carrying capacity. The nano photosensitizer provided by the present invention overcomes the limitations faced by many photosensitizers that have been reported or commercially available, such as low photostability, unstable structure or limited range of available solvent conditions. It also avoids the problem that the high oxygen dependence of type II photosensitizers leads to limited PDT for hypoxic solid tumors and reduced therapeutic effect, and has good application prospects in hypoxic photodynamic tumor treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The MALDI-TOF MS test results of the three fluorinated tin phthalocyanines prepared in Example 1, (a): SnF 20 Pc, (b): SnF 52 Pc, (c): SnF 60 Pc;

[0041] Figure 2 The UV absorption spectra of three fluorinated tin phthalocyanines prepared in Example 1 are shown;

[0042] Figure 3 GPC elution curves of three polyethylene glycolated fluorinated tin phthalocyanines prepared in Example 2;

[0043] Figure 4 The UV absorption spectra of three polyethylene glycol fluorinated tin phthalocyanines prepared in Example 2, (a): SnF 20 Pc and SnF 20 Pc-PEG, (b): SnF 52 Pc and SnF52 Pc-PEG, (c): SnF 60 Pc and SnF 60 Pc-PEG;

[0044] Figure 5 The DLS test results of the three nanophotosensitizers prepared in Example 2;

[0045] Figure 6 SnF after self-assembly 60 TEM test results of Pc-PEG nanophotosensitizer;

[0046] Figure 7 SnF after self-assembly 60 Mapping test results of Pc-PEG nanophotosensitizer;

[0047] Figure 8 The photodynamic test results of three fluorinated tin phthalocyanines prepared in Example 1 are as follows: (a) SnF 20 Pc, (b): SnF 52 Pc, (c): SnF 60 Pc;

[0048] Figure 9 The photodynamic test results of three nano photosensitizers prepared in Example 2, (a): SnF 20 Pc-PEG nanophotosensitizer, (b): SnF 52 Pc-PEG nanophotosensitizer, (c): SnF 60 Pc-PEG nanophotosensitizer;

[0049] Figure 10 The oxygen carrying capacity test results of the three nano-photosensitizers prepared in Example 2;

[0050] Figure 11 The photostability test results of three fluorinated tin phthalocyanines prepared in Example 1 are as follows: (a) SnF 20 Pc, (b): SnF 52 Pc, (c): SnF 60 Pc. DETAILED DESCRIPTION

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. The terms used in this specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0052] The present invention will be further described below with reference to the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it. However, the embodiments are not intended to limit the present invention.

[0053] Example 1

[0054] This embodiment relates to the preparation of three fluorinated tin phthalocyanines, and the specific preparation process is as follows:

[0055] (1) Preparation of precursor:

[0056] Preparation of the precursor PFP-DCA: 4.48 g (26 mmol) of pale yellow 4-nitrophthalonitrile, 5.52 g (30 mmol) of pentafluorophenol, and 30 mL of N,N'-dimethylformamide were added to a 100 mL three-necked flask. 0.8 g of lithium hydroxide was added in batches over two hours. The mixture was heated and stirred continuously at 55°C under an argon atmosphere for 38 hours. After 38 hours, the reaction mixture was poured into 100 mL of 10% sodium chloride solution and magnetically stirred for 1 hour. The mixture was then vacuum-filtered and dried to obtain a yellow solid (4-pentafluorophenoxyphthalonitrile, PFP-DCA, yield: 55.8%). GCT-TOF MS: m / z = 310.02 ([C 14 H3F5N2O] calculated value: 310.02), the structural formula is shown below:

[0057]

[0058] Preparation of the precursor FH-DCA: To a 100 mL three-necked flask, 2.01 g (11.56 mmol) of pale yellow 4-nitrophthalonitrile, 5.03 g (14.37 mmol) of perfluoro-1-heptanol, and 30 mL of N,N'-dimethylformamide were added. 0.8 g of lithium hydroxide was added in batches over two hours. The mixture was heated and stirred continuously at 55°C under an argon atmosphere for 38 hours. After 38 hours, the reaction mixture was poured into 100 mL of 10% sodium chloride solution and magnetically stirred for 1 hour. The mixture was then vacuum-filtered and dried to obtain a yellow solid (4-(perfluoro-1-heptanoxy)phthalonitrile, FH-DCA, yield: 79.6%). GCT-TOF MS: m / z = 476.02 ([C 15 H5F 13 N2O] calculated value: 476.02), the structure is shown below:

[0059]

[0060] Preparation of the precursor FO-DCA: To a 100 mL three-necked flask, 1.92 g (10.98 mmol) of pale yellow 4-nitrophthalonitrile, 4.92 g (12.3 mmol) of perfluoro-1-octanol, and 30 mL of N,N'-dimethylformamide were added. 0.8 g of lithium hydroxide was added in batches over two hours. The mixture was heated and stirred continuously at 55°C under an argon atmosphere for 38 hours. After 38 hours, the reaction mixture was poured into 100 mL of 10% sodium chloride solution and magnetically stirred for 1 hour. The mixture was then vacuum-filtered and dried to obtain a yellow solid (4-(perfluoro-1-octanyloxy)phthalonitrile, FO-DCA, yield: 72.0%). GCT-TOF MS: m / z = 526.02 ([C 16 H5F 15 N2O] calculated value: 526.02), the structure is shown below:

[0061]

[0062] (2) Preparation of fluorinated tin phthalocyanine:

[0063] FWf 20 Preparation of Pc: 620.04 mg (2 mmol) of PFP-DCA and 95 mg (0.5 mmol) of anhydrous stannous chloride were ground and mixed evenly, placed in a 20 mL ampoule, evacuated and sealed, and reacted at 275 ° C for 8 hours. The resulting solid was then washed three times with 1 M dilute hydrochloric acid and 1 M sodium hydroxide to obtain a blue-green solid (tetrakis(pentafluorophenoxy)phthalocyanine tin, SnF 20 Pc, yield: 67.4%). MALDI-TOF MS: m / z = 1452.11 ([C 56 H 12 Cl2F 20 N8O4Sn] calculated value: 1429.91+Na + ), the structure is as follows:

[0064]

[0065] FWf 52 Preparation of Pc: 952.04 mg (2 mmol) of FH-DCA and 95 mg (0.5 mmol) of anhydrous stannous chloride were ground and mixed uniformly, placed in a 20 mL ampoule, evacuated and sealed, and reacted at 275 ° C for 8 hours. The resulting solid was then washed three times with 1 M dilute hydrochloric acid and 1 M sodium hydroxide to obtain a blue-green solid (tetrakis(perfluoro-1-heptyloxy)phthalocyanine tin, SnF 52 Pc, yield: 45.9%). MALDI-TOF MS: m / z = 2023.74 ([C 60 H 20Cl2F 52 N8O4Sn] calculated value: 2093.92-2Cl - ), the structure is as follows:

[0066]

[0067] FWf 60 Preparation of Pc: 1.05 g (2 mmol) of FO-DCA and 95 mg (0.5 mmol) of anhydrous stannous chloride were ground and mixed uniformly, placed in a 20 mL ampoule, evacuated and sealed, and reacted at 275 ° C for 8 hours. The resulting solid was then washed three times with 1 M dilute hydrochloric acid and 1 M sodium hydroxide to obtain a blue-green solid (tetrakis(perfluoro-1-octyloxy)phthalocyanine tin, SnF 60 Pc, yield: 78.9%). MALDI-TOF MS: m / z = 2258.45 ([C 64 H 20 Cl2F 60 N8O4Sn] calculated value: 2293.90-Cl - ), the structure is as follows:

[0068]

[0069] The MALDI-TOF MS test results of the three fluorinated phthalocyanine tin compounds are as follows: Figure 1 As shown in the figure, it can be seen that the test results are consistent with the calculation results, indicating that the target product can be prepared by the above method.

[0070] Figure 2 This is the ultraviolet absorption spectrum of the three fluorinated tin phthalocyanines prepared in this example. It can be seen from the figure that the best absorption peaks of the three fluorinated tin phthalocyanines are all around 700nm.

[0071] Example 2

[0072] This embodiment involves the preparation of three nano-photosensitizers, and the specific preparation process is as follows:

[0073] (1) Preparation of polyethylene glycol-fluorinated tin phthalocyanine

[0074] FWf 20 Preparation of Pc-PEG: 206.85 mg (0.142 mmol) of tetrakis(pentafluorophenoxy)phthalocyanine tin, methoxy PEG 5000Hydroxyl 5.69g (1.139mmol), N, N'-dimethylformamide 30mL and 20mg sodium hydride were heated to reflux continuously at 140 ° C in an argon atmosphere for 12 hours. After evaporating the solvent, it was dissolved with about 50mL of chloroform and filtered. The filtrate was collected, the solvent was evaporated, and it was fully dissolved with a small amount of N, N'-dimethylformamide and dialyzed with water for 72 hours. After freeze-drying, a green solid (polyethylene glycol tetrakis (pentafluorophenoxy) phthalocyanine tin, SnF 20 Pc-PEG, yield: 45.6%), the structure is shown below:

[0075]

[0076] FWf 52 Preparation of Pc-PEG: 298.29 mg (0.142 mmol) of tetrakis(perfluoro-1-heptyloxy)phthalocyanine tin, methoxy PEG 5000 5.69g (1.139mmol) of hydroxyl group, 30mL of toluene and 20mg of sodium hydride were heated to reflux continuously at 140°C in an argon atmosphere for 12 hours. After evaporating the solvent, the mixture was dissolved in about 50mL of chloroform and filtered. The filtrate was collected, the solvent was evaporated, and the mixture was fully dissolved in a small amount of N,N'-dimethylformamide and dialyzed with water for 72 hours. After freeze-drying, a green solid (polyethylene glycol tetrakis (perfluoro-1-heptyloxy) phthalocyanine tin, SnF 52 Pc-PEG, yield: 58.5%), the structure is shown below:

[0077]

[0078] FWf 60 Preparation of Pc-PEG: 335.26 mg (0.142 mmol) of tetrakis(perfluoro-1-octyloxy)phthalocyanine tin, methoxy PEG 5000 5.69g (1.139mmol) of hydroxyl group, 30mL of toluene and 20mg of sodium hydride were heated to reflux continuously at 140°C in an argon atmosphere for 12 hours. After evaporating the solvent, the mixture was dissolved in about 50mL of chloroform and filtered. The filtrate was collected, the solvent was evaporated, and the mixture was fully dissolved in a small amount of N,N'-dimethylformamide and dialyzed with water for 72 hours. After freeze-drying, a green solid (polyethylene glycol tetrakis (perfluoro-1-octyloxy) phthalocyanine tin, SnF 60 Pc-PEG, yield: 65.6%), the structure is shown below:

[0079]

[0080] The GPC elution curves of the three polyethylene glycol fluorinated phthalocyanine tins are as follows: Figure 3 As shown in the figure, it can be seen that the molecular weights of the three polyethylene glycol fluorinated tin phthalocyanines are all around 7000-9000 g / mol, indicating that the three fluorinated tin phthalocyanines are all monosubstituted with polyethylene glycol.

[0081] Figure 4 This is the ultraviolet absorption spectra of the three polyethylene glycol fluorinated tin phthalocyanines prepared in this example. As can be seen from the figure, the best absorption peaks of the three polyethylene glycol fluorinated tin phthalocyanines are all around 700nm, which is consistent with that of fluorinated tin phthalocyanine, indicating that their structures are not destroyed.

[0082] (2) Preparation of nanophotosensitizers

[0083] 1 mg of each of the three PEGylated fluorinated tin phthalocyanines was dissolved in 5 mL of THF to a concentration of 0.20 mg / mL. The solution was stirred at room temperature for 12 hours. The solution was transferred to a dialysis bag with a molecular weight cutoff of 3500 g / mol and dialyzed against deionized water for 48 hours to remove the THF, yielding the three nanophotosensitizers.

[0084] Figure 5 Three nano-photosensitizers SnF prepared 20 Pc-PEG nanophotosensitizer, SnF 52 Pc-PEG nanophotosensitizer, SnF 60 DLS test results of Pc-PEG nanophotosensitizers. As can be seen from the figure, the particle sizes of the three nanophotosensitizers are all around 200-250nm.

[0085] Figure 6 SnF 60 TEM image of Pc-PEG nano-photosensitizer. It can be observed from the image that the particle size is uniform. The mapping test results ( Figure 7 ) It can be seen that the nanoparticles contain C, N, O, Cl, and F elements, and each element is uniformly dispersed in the nanoparticles.

[0086] Example 3

[0087] The photodynamics, oxygen carrying capacity or photostability of the three fluorinated tin phthalocyanines prepared in Example 1 and the three nano-photosensitizers prepared in Example 2 were tested. The specific test process and results are shown below:

[0088] (1) Photodynamic testing

[0089] With a wavelength of 690nm LED light (50mW / cm 2 ) as a light source, through which the photosensitizer is irradiated 1 O2, and then the yield is determined by singlet oxygen capture agent DMA (organic phase) and DPBF (aqueous phase), the specific operation is as follows:

[0090] Take 1mL of self-assembled SnF with a concentration of 0.20mg / mL 20 Pc-PEG, SnF 52 Pc-PEG and SnF 60 Pc-PEG nanophotosensitizer aqueous solution and 10 μg / mL SnF 20 Pc, SnF 52 Pc and SnF 60 A solution of PC in DMF was pipetted with 20 μL of DPBF or 20 μL of DMA to measure the singlet oxygen yield of each material. The degradation rate of DPBF was measured by irradiating the solution with a 690 nm LED light for 30 seconds. The optical density at 417 nm was monitored using a UV-visible spectrophotometer until the optical density at 417 nm stabilized. A blank control was performed with water replacing the material, while all other conditions remained unchanged. Three parallel experiments were performed for each group.

[0091] Figure 8 、 Figure 9 The photodynamic test results for three fluorinated tin phthalocyanines and three nanophotosensitizers are shown. As can be seen from the figure, under 690nm wavelength illumination, the change in DPBF absorption at 417nm gradually decreases with increasing illumination time. After 5 minutes, DPBF absorption at 417nm is essentially absent, indicating that all three fluorinated tin phthalocyanines and three nanophotosensitizers have high singlet yields and can rapidly generate singlet oxygen for photodynamic tumor therapy.

[0092] (2) Oxygen carrying capacity test

[0093] The oxygen carrying capacity of the nano-photosensitizer is measured by a dissolved oxygen meter. The specific operation is as follows:

[0094] Take 5mL of self-assembled SnF with a concentration of 0.20mg / mL 20 Pc-PEG, SnF 52 Pc-PEG and SnF 60 Aqueous solutions of Pc-PEG nanophotosensitizers were aerated with oxygen for 30 minutes. The oxygen was removed, and the solution was stirred open for 10 minutes. The oxygen loading of the materials was measured using a dissolved oxygen meter. Each experiment lasted 800 seconds. A blank control group was run with water substituted for the materials, while other conditions remained unchanged. Three parallel experiments were performed for each group.

[0095] Figure 10 The oxygen carrying capacity test results of three nano-photosensitizers are shown in the figure. 20 Pc-PEG, SnF 52 Pc-PEG and SnF 60The oxygen carrying capacity of the Pc-PEG nano-photosensitizer aqueous solution is significantly higher than that without the above-mentioned nano-photosensitizer, and oxygen can be released slowly within 800 seconds. It can be seen that the nano-photosensitizer has good oxygen-carrying function and can be used for photodynamic hypoxic tumor treatment.

[0096] (3) Light stability test

[0097] With a wavelength of 690nm LED light (50mW / cm 2 ) as a light source, and determine whether its absorbance at around 700 nm decreases by UV-visible spectroscopy. The specific operation is as follows:

[0098] Take 1mL of 10μg / mL SnF 20 Pc, SnF 52 Pc and SnF 60 A DMF solution of Pc was added to a quartz cuvette. Irradiation was performed using a 690 nm LED light for 10-minute intervals. The absorbance at 700 nm was monitored using a UV-visible spectrophotometer to measure the degradation rate of fluorinated tin phthalocyanine. A blank control was performed using water instead of the sample, while other conditions remained unchanged. Three parallel experiments were performed for each group.

[0099] Figure 11 The results of the photostability test of three fluorinated tin phthalocyanines are shown in the figure. As can be seen from the figure, under 690nm wavelength light, with the increase of illumination time, the absorbance of the three fluorinated tin phthalocyanines at around 700nm has a downward trend, but SnF 60 The absorbance of Pc at around 700 nm decreased slowly. After 60 minutes, only a small part of it was photodegraded. 60 Pc has high photostability and is a photostable material that can be used in hypoxia photodynamic therapy.

[0100] The above embodiments are merely preferred embodiments for the purpose of fully illustrating the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are within the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

Claims

1. A fluorinated tin phthalocyanine derivative, characterized in that The fluorinated tin phthalocyanine derivative has the following general structural formula: ， Where R is or , x is an integer from 5 to 7.

2. A method for preparing the fluorinated tin phthalocyanine derivative according to claim 1, characterized in that: The following steps are involved: (1) reacting perfluorocarbon R-OH with 4-nitrophthalonitrile in the presence of an inorganic base and an organic solvent to obtain a precursor; (2) grinding and mixing the precursor prepared in step (1) and stannous chloride uniformly, and then heating and reacting them in an oxygen-free environment to obtain the fluorinated tin phthalocyanine derivative; The structure of the precursor is shown below: ， Among them, the perfluorocarbon R-OH and the R in the precursor are or , x is an integer from 5 to 7.

3. The preparation method according to claim 2, characterized in that In step (1), the inorganic base is anhydrous potassium carbonate and / or lithium hydroxide; The organic solvent is selected from one or more of acetonitrile, dimethyl sulfoxide, and N,N'-dimethylformamide.

4. The preparation method according to claim 2, characterized in that In step (1), the reaction temperature is 40-60 °C and the reaction time is 24-48 h.

5. The preparation method according to claim 2, characterized in that In step (2), the reaction temperature of the heating reaction is 250-280 °C, and the reaction time is 6-12 h.

6. A nano photosensitizer, characterized in that: The preparation method of the nano photosensitizer comprises the following steps: S1: The fluorinated tin phthalocyanine derivative according to claim 1 is mixed with a compound of formula The compound shown is reacted in the presence of an acid-binding agent and a solvent to obtain a polyethylene glycol-containing fluorinated tin phthalocyanine derivative; wherein n is an integer from 111 to 444; S2: self-assembling the PEGylated fluorinated tin phthalocyanine derivative prepared in S1 in water to obtain the nano photosensitizer.

7. The nano photosensitizer according to claim 6, characterized in that In S1, the acid binding agent is selected from one or more of pyridine, anhydrous potassium carbonate, and sodium hydride; The solvent is selected from one or more of toluene, 1,3-bis(trifluoromethyl)benzene, and N,N'-dimethylformamide.

8. The nano photosensitizer according to claim 6, characterized in that In S1, the reaction temperature is 120-160° C., and the reaction time is 8-24 h.

9. The nano photosensitizer according to claim 6, characterized in that In S2, a co-solvent dialysis method is used to make the PEGylated fluorinated tin phthalocyanine derivative self-assemble in water to obtain the nano photosensitizer; the co-solvent dialysis method is specifically: dissolving the PEGylated fluorinated tin phthalocyanine derivative in tetrahydrofuran and dialyzing it with deionized water to obtain the nano photosensitizer.

10. Use of the fluorinated tin phthalocyanine derivative according to claim 1 or the nano photosensitizer according to any one of claims 6 to 9 in the preparation of a drug for hypoxic photodynamic tumor therapy.

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