A fluorinated zinc phthalocyanine derivative and its preparation method and application

Abstract

The present invention discloses a fluorinated zinc phthalocyanine derivative and its preparation method and application. The fluorinated zinc phthalocyanine derivative is obtained by chemically covalently linking trithiocarbonate to the four amino groups of tetraaminoperfluorophthalocyanine zinc. The fluorinated zinc phthalocyanine derivative can be used as a star-shaped RAFT chain transfer agent to induce hydrophobic methacrylate monomers and / or hydrophilic acrylate monomers to prepare four-arm star-shaped random copolymers through near-infrared light-controlled reversible addition-fragmentation chain transfer polymerization. The star-shaped polymer prepared by the above method has a narrow molecular weight distribution and can form polymer micelles with uniform hydrodynamic diameter in an aqueous solution below its critical aggregation concentration. In addition, the above polymer micelles have a high singlet state yield and good oxygen carrying capacity, and can be used for two-photon photodynamic therapy of hypoxic tumors.

Description

Technical Field

[0001] The present invention relates to the technical fields of polymer preparation and photodynamic tumor therapy, and specifically to a fluorinated zinc phthalocyanine derivative and a preparation method and application thereof. Background Art

[0002] Near-infrared light has the advantages of deep tissue penetration and strong remote controllability, which can overcome the many contraindications and serious adverse reactions associated with surgical resection, radiotherapy, chemotherapy, and other therapies. Currently, nanocarrier-mediated tumor phototherapy has made great progress, especially in photothermal therapy and photodynamic therapy, which are non-invasive, precise, and have minimal side effects. Compared with photothermal therapy, photodynamic therapy (PDT) has the advantages of low photosensitizer concentration, low light dose, and long-lasting therapeutic effect, thus having a higher safety.

[0003] Typically, photodynamic therapy (PDT) requires photosensitizer molecules (PSs), light, and oxygen to generate toxic reactive oxygen species (ROS) that mediate cancer cell death. However, most small-molecule photosensitizers have low extinction coefficients and emission quantum yields, absorb at low wavelengths in the visible spectrum, and have poor solubility in aqueous media, leading to aggregation. This results in a decrease in singlet oxygen production in tumor tissue and renders the treatment ineffective. In contrast, nanoparticle-based photosensitizers can overcome the limitations of small-molecule dyes and improve the anti-tumor efficiency of PDT. Nanoparticles have the following advantages for PDT: (1) large extinction coefficients and emission quantum yields; (2) the ability to encapsulate hydrophobic photosensitizers and maintain their monomeric form, preserve their photosensitizing activity, improve their solubility, and maximize their singlet oxygen yield under physiological conditions; (3) easy control of the size and structure of the nanoparticles to maximize the surface-to-volume ratio and optimize the loading efficiency of PSs molecules; (4) the ability to increase their accumulation in solid tumors through passive targeting via enhanced permeability and retention (EPR); (5) established surface modification chemistry to attach targeting ligands and functional groups to improve pharmacokinetics, biodistribution, specificity, and cellular uptake to enhance the efficacy of PDT in vivo; and (6) the rational design of multifunctional nanocomposites by integrating various photosensitizers with chemotherapeutic drugs and multimodal molecular imaging agents. In recent years, polymeric micelle nanomaterials have received extensive attention. Compared with small molecule compounds, polymeric micelles have the advantages of easily adjustable structure and long blood circulation time. The hydrophilic / hydrophobic structure of single-molecule micelles is stabilized by covalent bonds and will not disintegrate due to changes in concentration, temperature and other factors. Their size is 10-20 nanometers, making it easy to avoid capture by the immune system and penetrate deep into diseased tissues. Therefore, they have unique advantages in the biomedical field.

[0004] Traditional single-photon excitation of PSs requires the absorption of a single photon equal to the band gap energy of the PSs, while two-photon excitation (TPE) occurs when two low-energy infrared light photons are absorbed by PSs, and the sum of the photon energies is equal to the energy band gap, resulting in deeper light penetration and lower photobleaching of PS molecules in tissues. A key feature of TPE is the nonlinearity of photon absorption, which makes it possible to activate PSs at the focus of the laser beam. This allows for better three-dimensional control of PS activation during PDT and reduces off-target damage to surrounding healthy tissues. Common two-photon photosensitizers include 5-aminolevulinic acid, dihydrochlorin e6, and tetrasulfonic acid aluminum phthalocyanine.

[0005] In addition, the hypoxic state within the tumor is not conducive to the implementation of photodynamic therapy, and generally, intracellular oxygen supplementation is required. Based on this, the present invention provides a method for simply and rapidly synthesizing oxygen-carrying polymer micelles, which can be used for two-photon photodynamic therapy. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a fluorinated zinc phthalocyanine derivative and its preparation method and application. The fluorinated zinc phthalocyanine derivative can be used as a star-shaped RAFT chain transfer agent to induce acrylate monomers to prepare four-arm star-shaped random copolymers through near-infrared light-controlled reversible addition-fragmentation chain transfer polymerization. The star polymer prepared by the above method has a narrow molecular weight distribution, and the star polymer containing hydrophilic monomers can form stable polymer micelles with uniform diameter in aqueous solution. The polymer micelles have both two-photon photodynamic therapy performance and oxygen-carrying function.

[0007] The first aspect of the present invention provides a fluorinated zinc phthalocyanine derivative, the structure of which is shown below:

[0008]

[0009] The second aspect of the present invention provides a method for preparing the fluorinated zinc phthalocyanine derivative described in the first aspect, comprising reacting zinc tetraaminoperfluorophthalocyanine with 4-cyano-4-(ethyltrithiocarbonate)pentanoic acid-active ester in the presence of a solvent to obtain the fluorinated zinc phthalocyanine derivative.

[0010] Furthermore, the solvent may be selected from one of chloroform, N,N-dimethylformamide and dichloromethane.

[0011] Furthermore, the reaction temperature is 0-30°C, and the reaction time is 24-72h.

[0012] Furthermore, the molar ratio of the tetraaminoperfluorophthalocyanine zinc to the 4-cyano-4-(ethyltrithiocarbonate)pentanoic acid-active ester is 1:4-32.

[0013] In some preferred embodiments, a portion of 4-cyano-4-(ethyltrithiocarbonate)pentanoic acid-active ester is first dissolved in chloroform and stirred in an ice bath. Then, a DMF solution containing zinc tetraaminoperfluorophthalocyanine is added dropwise. After the addition is complete, the mixture is reacted in an ice bath for 1 hour. After the temperature is raised to room temperature, the reaction is continued for 24 hours. Then, the remaining portion of the chloroform solution containing zinc tetraaminoperfluorophthalocyanine-active ester is added and the reaction is continued for 24 hours to obtain the fluorinated zinc phthalocyanine derivative.

[0014] A third aspect of the present invention provides a use of a fluorinated zinc phthalocyanine derivative as a RAFT chain transfer agent in a near-infrared light-controlled reversible addition-fragmentation chain transfer polymerization reaction.

[0015] Furthermore, the wavelength of the near-infrared light is 690-850 nm.

[0016] A fourth aspect of the present invention provides a method for synthesizing a star polymer, comprising the following steps:

[0017] Under near-infrared irradiation, an acrylate monomer and a chain transfer agent are reacted in the presence of a co-catalyst and a solvent to obtain the star polymer;

[0018] The chain transfer agent is the fluorinated zinc phthalocyanine derivative according to claim 1;

[0019] The co-catalyst is selected from one or more of triethylamine, triethanolamine, and dimethylaminoethyl acrylate, and is more preferably triethanolamine.

[0020] Furthermore, the near-infrared irradiation wavelength is 690-850 nm, for example 730 nm.

[0021] Furthermore, the acrylate monomers may be hydrophilic acrylate monomers and / or hydrophobic methacrylate monomers, wherein the hydrophilic acrylate monomers include polyethylene glycol monomethyl ether acrylate, such as M n =480 g / mol of polyethylene glycol monomethyl ether acrylate; hydrophobic methacrylate monomers include pentafluorophenyl methacrylate, 1H,1H-perfluoroheptyl methacrylate, 1H,1H-perfluorooctyl methacrylate, etc.

[0022] Furthermore, the molar ratio of the acrylic acid ester monomer to the chain transfer agent and the co-catalyst is 10-40:0.05:1-4; in some preferred embodiments, when the acrylic acid ester monomer is a hydrophilic acrylic acid ester monomer, the molar ratio of the hydrophilic acrylic acid ester monomer, the chain transfer agent and the co-catalyst is 10-40:0.05:1-4, for example, 20:0.05:2; when the acrylic acid ester monomer comprises a hydrophilic acrylic acid ester monomer and a hydrophobic methacrylic acid ester monomer, the molar ratio of the hydrophilic acrylic acid ester monomer, the hydrophobic methacrylic acid ester monomer, the chain transfer agent and triethanolamine is 15-25:0.05-2:0.05:1-4.

[0023] Furthermore, the solvent is selected from one or more of N,N'-dimethylformamide, N,N'-dimethylacetamide, and dimethyl sulfoxide, more preferably dimethyl sulfoxide.

[0024] Furthermore, the reaction temperature is preferably 20-90°C, more preferably 20-30°C; when the acrylic acid ester monomer comprises pentafluorophenyl methacrylate, the reaction temperature is more preferably 70-90°C, for example 80°C.

[0025] Furthermore, the reaction time of the reaction is preferably 1-24 hours; when the acrylate monomers contain only hydrophilic acrylate monomers, the reaction time is more preferably 16-24 hours; when the acrylate monomers contain hydrophilic acrylate monomers and hydrophobic methacrylate monomers, the reaction time is preferably 1-21 hours.

[0026] The present invention uses the aforementioned fluorinated zinc phthalocyanine derivative as a star-shaped RAFT chain transfer agent to conduct near-infrared light-controlled reversible addition-fragmentation chain transfer (RAFT) polymerization. The fluorinated zinc phthalocyanine derivative not only acts as a chain transfer agent but also as a photocatalyst, inducing polymerization under the combined action of triethanolamine. This method avoids the use of transition metals in the polymerization reaction and replaces the heat energy used in traditional polymerization with near-infrared light, enabling the polymerization reaction to proceed at room temperature. This mild reaction conditions also reduce the occurrence of side reactions during the polymerization process.

[0027] The fifth aspect of the present invention provides a star polymer prepared by the synthesis method described in the fourth aspect.

[0028] Furthermore, the star polymer includes compounds represented by formula (2) and formula (3):

[0029]

[0030]

[0031] Wherein, n is an integer from 17 to 75;

[0032] a is 1 or 2;

[0033] c is an integer from 7 to 10;

[0034] R1 is

[0035] R2 is

[0036] The sixth aspect of the present invention provides a polymer micelle, which is obtained by dissolving the star polymer described in the fifth aspect in an organic solvent and dialyzing it with deionized water; the acrylate monomer used to prepare the star polymer contains a hydrophilic acrylate monomer.

[0037] Furthermore, the star polymer is preferably a compound represented by the above formula (2) or formula (3).

[0038] Furthermore, the mass volume ratio of the star polymer to the organic solvent is less than 0.5 mg / mL; and the organic solvent is selected from one or more of tetrahydrofuran and N,N-dimethylformamide.

[0039] Furthermore, the particle size of the polymer micelles is preferably 10-18 nm.

[0040] The seventh aspect of the present invention provides a use of the polymer micelles described in the sixth aspect in the preparation of a drug for photodynamic hypoxic tumor treatment.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] 1. The present invention provides a fluorinated zinc phthalocyanine derivative, which is obtained by chemically covalently linking a trithiocarbonate to the four amino groups of tetraaminoperfluorophthalocyanine zinc. The fluorinated zinc phthalocyanine derivative undergoes an energy level transition from the ground state to the excited state under near-infrared (NIR) light irradiation. A cocatalyst (e.g., triethanolamine) quenches singlet oxygen, generating more efficient O2 ˙- , which then generates hydrogen peroxide through electron transfer. The excited tetrasubstituted perfluorophthalocyanine zinc reduces the hydrogen peroxide to hydroxyl radicals, which then undergo reversible chain transfer with a chain transfer reagent, successfully synthesizing a star polymer with a narrow molecular weight distribution in an organic phase. The synthesis and use of the tetrasubstituted perfluorophthalocyanine zinc described in this invention fills a gap in the polymerization methods for NIR-controlled RAFT star polymers.

[0043] 2. The present invention uses the above-mentioned fluorinated zinc phthalocyanine derivative as a chain transfer agent to prepare an oxygen-carrying single-molecule micelle that can be used for two-photon photodynamic therapy through a near-infrared light-controlled RAFT polymerization reaction. The preparation method is simple and efficient, not only avoiding the problems of additional catalyst addition, physical embedding leakage of photosensitizers, or post-modification in the prior art, but also overcoming the problem that tumor cell hypoxia affects the effectiveness of photodynamic therapy in practical applications. The uniform and stable polymer micelles constructed by the above method have excellent two-photon photodynamic performance, high singlet oxygen yield, and good biocompatibility, providing a new type of single-molecule polymer micelle material for the current field of two-photon photodynamic tumor therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is the MALDI-TOF MS test result of tetraaminoperfluorophthalocyanine zinc;

[0045] Figure 2 The fluorescence spectra of tetraaminoperfluorophthalocyanine zinc and tetrasubstituted perfluorophthalocyanine zinc;

[0046] Figure 3 GPC elution curves of star polymers PPEGA (a), PPFC-b-PPEA (b) and PFHMA-b-PPEGA (c);

[0047] Figure 4 DLS test results of PPEGA (a) and PFHMA-b-PPEGA (b) star-shaped polymer micelles;

[0048] Figure 5 Critical aggregation concentration (CAC) test results of PPEGA (a) and PFHMA-b-PPEGA (b) star-shaped polymeric micelles;

[0049] Figure 6 TEM test results of PPEGA (T-3) star-shaped polymer micelles, (a) is multimolecular micelle, (b) is unimolecular micelle;

[0050] Figure 7 TEM test results of PFHMA-b-PPEGA(H-3) star-shaped polymer micelles, (a) is multimolecular micelle, (b) is unimolecular micelle;

[0051] Figure 8 The photodynamic test results of PPEGA (T-3) and PPFC-b-PPEGA (F-1, F-2, F-3), (a) is T3, (b) is F-1, (c) is F-2, and (d) is F-3;

[0052] Figure 9The oxygen carrying capacity test results of PPFC-b-PPEGA (a) and PFHMA-b-PPEGA (b). DETAILED DESCRIPTION

[0053] 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.

[0054] 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.

[0055] In the following examples, the monomers used included polyethylene glycol monomethyl ether acrylate (PEGA), pentafluorophenyl methacrylate (PFMA), 1H,1H-perfluoroheptyl methacrylate (FHMA), or 1H,1H-perfluorooctyl methacrylate (FOMA), which were passed through a neutral alumina column before use. Other reagents were obtained from commercial sources and used directly.

[0056] The test methods involved are as follows:

[0057] 1. Number average molecular weight of polymer (M n , GPC) and molecular weight distribution (M w / M n ) was measured by TOSOH HLC-8320 gel permeation chromatography (GPC), which was equipped with a TOSOH differential refractive index detector, a guard column (4.6×20 mm, TSKgelguard column SuperMP-N) and two test columns (4.6×150 mm, TSKgelSupermultiporeHZ-N). The molecular weight range of the testable 2 to 5×10 5 g / mol. During the test, DMF (0.1wt% LiBr) was used as the mobile phase, the temperature was 40°C, and the flow rate was 0.35mL / min. The sample was drawn up by a TOSOH automatic sampler for testing, and the linear PS purchased from TOSOH was selected as the standard sample when analyzing the data. The preparation process of the sample for GPC test is as follows: take 20μL of the polymer mixed solution, freeze-dry it, remove the solvent, and then dissolve the polymer with DMF (0.1wt% LiBr), pass the polymer solution through a small column of neutral alumina and a syringe equipped with a 0.45μm filter head, and finally inject the pure polymer solution into the test bottle.

[0058] 2. The H NMR spectra of small molecule compounds and polymers were obtained by testing with a Bruker 300 MHz NMR spectrometer using deuterated reagent CDCl3 as solvent and tetramethylsilane (TMS) as internal standard.

[0059] 3. The hydrodynamic diameter of micelles was measured by dynamic light scattering (DLS, NanoBrook 90Plus) with the micelles dispersed in water at a test temperature of 25°C.

[0060] 4. The morphology of micelles was obtained using a FEI Tecnai G22 transmission electron microscope (TEM) at an accelerating voltage of 120 kV. 20 μL of a 0.1 mg / mL micelle solution was dropped onto a 200-mesh copper grid and allowed to stand for 30 seconds.

[0061] Example 1

[0062] This embodiment relates to a tetrasubstituted perfluorophthalocyanine zinc (ZnF 12 The synthesis of Pc-4) is as follows:

[0063]

[0064] The specific preparation process is as follows:

[0065] (1) Synthesis of 4-cyano-4-(ethyl trithiocarbonate) pentanoic acid-active ester (CEPTA-NHS):

[0066] Sodium hydroxide (6.44 g, 0.161 mol) and 100 mL of anhydrous ether were added to a three-necked flask, stirred under argon protection, and ethanethiol (10.00 g, 0.161 mol) was slowly added via a constant pressure dropping funnel under ice-water bath conditions. The mixture was stirred overnight at room temperature, followed by the addition of carbon disulfide (12.25 g, 0.161 mol) in portions, and stirring continued for 2 hours. The reaction solution was washed twice with n-hexane, and the solvent was removed by rotary evaporation to obtain sodium trithiocarbonate salt. Sodium trithiocarbonate salt (10.00 g, 0.062 mol) was added to 150 mL of anhydrous ether, followed by the addition of iodine (7.93 g, 0.031 mol) in portions, and stirred at room temperature for 3 hours. The filtrate was then collected by filtration, washed sequentially with a 5 wt% aqueous sodium dithionite solution, purified water, and a sodium chloride solution, and dried over anhydrous sodium sulfate. After filtration, the product bis(ethylsulfanylthiocarbonyl) disulfide was obtained by rotary evaporation, and the next step of the reaction was continued without purification. Take bis(ethylsulfanylthiocarbonyl) disulfide (7.93g, 0.031mol) and azobiscyanovaleric acid (7.1g, 0.025mol) and dissolve them in 100mL of ethyl acetate, pass through argon protection, heat to 80°C, react for 12 hours, add azobiscyanovaleric acid (7.1g, 0.025mol) and ethyl acetate (100mL), and continue to react for 12 hours. The crude product 3 was obtained by rotary evaporation, and petroleum ether / ethyl acetate (1 / 0 to 20 / 1) was used as the developing agent to pass through the column to obtain 8.4g of pure product with a yield of 64.1%. 1 The structure of the product was confirmed by H NMR and was labeled as CEPTA. 1 H NMR(300MHz,CDCl3)δ(ppm fromTMS):1.35-1.37(3H,t,CH3-CH2),1.88(3H,s,CH3-C),2.38-2.56(2H,m,CH2-CH2-COOH),2.67-2.69(2H,t,C-CH2-CH2),3.33-3.37(2H,b,CH3-CH2-S).

[0067] Dissolve 1.05 g (4 mmol) of 4-cyano-4-(ethyltrithiocarbonate)pentanoic acid and 0.46 g (4 mmol) of N-hydroxysuccinimide in 100 mL of chloroform and stir in an ice bath (0°C). Add 0.87 g (4.2 mmol) of N,N'-dicyclohexylcarbodiimide and stir in an ice bath for 1 hour. Then, raise the temperature to room temperature and allow the reaction to proceed for 22 hours. Filter the filtrate, remove the solvent by rotary evaporation, and dry to obtain a yellow powder (CEPTA-NHS). The product is used directly in the next step without purification.

[0068] (2) Tetraaminoperfluorophthalocyanine zinc (ZnF 12Synthesis of Pc-NH2):

[0069] 10.0 g of 3,4,5,6-tetrafluorophthalonitrile was dissolved in 50 mL of acetonitrile. 20 mL of 28% ammonium hydroxide was added dropwise with stirring, and the mixture was stirred for 3 hours in an ice bath. The reaction temperature was then warmed to room temperature and stirred for an additional 3 hours. The mixture was then extracted with acetonitrile, and after evaporation of the solvent, the mixture was recrystallized from isopropyl alcohol to obtain a pale yellow solid (4-amino-3,5,6-trifluorophthalonitrile, AF3, 60.9% yield).

[0070] In a 100 mL round-bottom flask, 1.60 g (8 mmol) of 4-amino-3,5,6-trifluorophthalonitrile, 0.37 g (2 mmol) of anhydrous zinc acetate, and 30 mL of n-pentanol were added in sequence. The mixture was sealed and filled with argon and reacted at 120°C for 10 minutes. Then, 3 mL of 1,8-diazabicycloundecene-7-ene was added, the temperature was raised to 140°C, and refluxed for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and 200 mL of a mixture of water and methanol (V 甲醇 :V 水 =3:1), stirred for 15 minutes and then centrifuged to obtain the precipitate. The precipitate was further washed and purified with 1.0M hydrochloric acid and 1.0M sodium hydroxide respectively. Finally, the product was washed with deionized water and precipitated, and dried to obtain a blue-green product (tetraaminoperfluorophthalocyanine zinc, ZnF 12 Pc-NH2, yield 62.8%).

[0071] The MALDI-TOF MS test results of tetraaminoperfluorophthalocyanine zinc prepared in this example are as follows: Figure 1 As shown in the figure, it can be seen that the test value is consistent with the calculated value.

[0072] (3) Tetrasubstituted perfluorophthalocyanine zinc (ZnF 12 Synthesis of Pc-4)

[0073] 8.43g (32mmol) of 4-cyano-4-(ethyl trithiocarbonate) pentanoic acid-active ester was dissolved in 300mL of chloroform and stirred in an ice bath. 80mL of a DMF solution containing 2.73g of tetraaminoperfluorophthalocyanine zinc (3.2mmol) was added dropwise to the above solution. After completion of the dropwise addition, the mixture was reacted for 1 hour under ice bath conditions. The temperature was raised to room temperature and the mixture was reacted for 24 hours. Then, 50mL of a CHCl solution containing 4.22g of 4-cyano-4-(ethyl trithiocarbonate) pentanoic acid-active ester (16mmol) was added and the mixture was reacted for another 24 hours at room temperature. The solvent was removed by washing with water and rotary evaporation. The mixture was freeze-dried and then chromatographed with ethyl acetate to obtain a green powder (tetrasubstituted perfluorophthalocyanine zinc, ZnF 12 Pc-4, yield: 34.1%).

[0074] Figure 2Figure 2 is the fluorescence spectrum of tetraaminoperfluorophthalocyanine zinc and tetrasubstituted perfluorophthalocyanine zinc. It can be seen from the figure that tetraaminoperfluorophthalocyanine zinc and tetrasubstituted perfluorophthalocyanine zinc both have two-photon fluorescence characteristics.

[0075] Example 2

[0076] This embodiment relates to the synthesis of star-shaped homopolymer PPEGA, and the specific preparation process is as follows:

[0077] The polymerization was carried out in an ampoule under air atmosphere. PEGA was used as a model monomer to illustrate the polymerization process. The polymerization process for other monomers was the same. The initial molar ratio of the raw materials was [PEGA]0 / [TEOA]0 / [ZnF 12 Pc-4]0=20 / 2 / 0.05, PEGA (0.50mL, 1.18mmol), TEOA (17.68mg, 0.118mmol), ZnF 12 Pc-4 (5.44 mg, 0.00295 mmol) was added to a 2.0 mL ampoule equipped with a magnetic stirrer and dried, and 0.5 mL of DMSO was added as the polymerization solvent. The mouth of the ampoule was then wrapped with plastic wrap to prevent monomer volatilization and contaminants. The ampoule was placed in a magnetic stirrer at room temperature and heated under a NIR LED light (66.3 mW·cm) with a central wavelength of 730 nm. -2 ) was irradiated and the polymerization reaction was set for a time. After the polymerization reaction was completed, the reaction mixture was taken out and dissolved in THF (2.0 mL), and then precipitated using 180 mL of petroleum ether. The polymer product was collected by filtration and dried at 30 ° C under vacuum to constant weight. The molecular weight distribution of the sample was tested by GPC, as shown in Table 1:

[0078] Table 1 Polymerization test results at different polymerization times

[0079] serial number Time (h) <![CDATA[ c M n，GPC (g / mol)]]> <![CDATA[ c M w / M n ]]> T-1 16 10000 1.27 T-2 18 18000 1.32 T-3 21 27000 1.31 T-4 24 38000 1.28

[0080] As can be seen from Table 1, the molecular weight distribution of the star-shaped homopolymer PPEGA prepared in this example is always kept within a narrow range. Figure 3 (a) is the GPC elution curve of the star-shaped homopolymer PPEGA with different molecular weights prepared in this example, wherein the reaction time corresponding to the curve from right to left is successively extended, and the polymers prepared at different polymerization times all show a unimodal distribution.

[0081] Example 3

[0082] This embodiment relates to the synthesis of a star-shaped random copolymer PPFC-co-PPEGA, and the specific preparation process is as follows:

[0083] Perfluorocarbon monomers PFC were selected from three types: pentafluorophenyl methacrylate (PFMA), 1H,1H-perfluoroheptyl methacrylate (FHMA), or 1H,1H-perfluorooctyl methacrylate (FOMA). When the hydrophobic monomers were FHMA and FOMA, polymerization was carried out in an ampoule under air atmosphere. The initial molar ratio of the raw materials was [PEGA]0 / [PFC]0 / [TEOA]0 / [ZnF 12 Pc-4]0=18 / 2 / 2 / 0.05, PEGA (0.435mL, 1.06mmol), TEOA (15.88mg, 0.106mmol), ZnF 12 Pc-4 (4.86 mg, 0.00295 mmol) was added to a 2.0 mL ampoule equipped with a magnetic stirrer and dried, and 0.5 mL of DMSO was added as the polymerization solvent. The mouth of the ampoule was then wrapped with plastic wrap to prevent monomer volatilization and contaminants. The ampoule was placed in a magnetic stirrer at room temperature and heated under a NIR LED light (66.3 mW·cm) with a central wavelength of 730 nm. -2 ) was irradiated and the polymerization reaction was set for a time. After the polymerization reaction was completed, the reaction mixture was taken out and dissolved in THF (2.0 mL), and then precipitated using 180 mL of petroleum ether. The polymer product was collected by filtration and dried at 30 ° C under vacuum to constant weight. When the hydrophobic monomer was PFMA, the polymerization was carried out in an ampoule under an argon atmosphere, and the initial molar ratio of the raw materials was [PEGA]0 / [PFMA]0 / [AIBN]0 / [ZnF 12 Pc-4]0=18 / 2 / 0.05 / 0.05, PEGA (0.435mL, 1.06mmol), PFMA (26.72mg, 0.106mmol), AIBN (0.435mg, 0.00265mmol), ZnF 12 Pc-4 (4.86 mg, 0.00265 mmol), polymerization temperature 80 ° C, polymerization time 1 hour, other conditions remain unchanged. The molecular weight distribution of the sample was tested by GPC, as shown in Table 2:

[0084] Table 2 Test results of random copolymerization of different perfluorocarbon monomers with PEGA

[0085] serial number Time (h) <![CDATA[ c M n，GPC (g / mol)]]> <![CDATA[ c M w / M n ]]> F-1 1 25000 1.32 F-2 21 25000 1.30 F-3 21 25000 1.28

[0086] As shown in Table 2, the molecular weight distribution of the star-shaped random copolymer PPFC-co-PPEGA prepared in this example is always kept within a narrow range. Figure 3 (b) is the GPC elution curve of different star-shaped random copolymers prepared in this example, wherein the reaction time corresponding to the curves from right to left increases successively, and the different star-shaped random copolymers all present a unimodal distribution.

[0087] Example 4

[0088] This embodiment relates to the synthesis of a star-shaped random copolymer PFHMA-co-PPEGA, and the specific preparation process is as follows:

[0089] Perfluorocarbon monomer PFC was selected from 1H,1H-perfluoroheptyl methacrylate (FHMA), and the initial molar ratio of the raw materials was [PEGA]0 / [PFC]0 / [TEOA]0 / [ZnF 12 Pc-4]0 was polymerized in an ampoule under air atmosphere. For example, TEOA (15.88 mg, 0.106 mmol) and ZnF12Pc-4 (4.86 mg, 0.00295 mmol) were added to a 2.0 mL ampoule equipped with a magnetic stirrer and dried, and 0.5 mL of DMSO was added as the polymerization solvent. The mouth of the ampoule was then wrapped with plastic wrap to prevent monomer volatilization and contaminants, and placed in a magnetic stirrer at room temperature under an NIR LED light (66.3 mW·cm) with a central wavelength of 730 nm. -2 ) was irradiated and the polymerization reaction was set for a time. After the polymerization reaction was completed, the reaction mixture was taken out and dissolved in THF (2.0 mL), and then precipitated using 180 mL of petroleum ether. The polymer product was collected by filtration and dried at 30° C. under vacuum to constant weight. The molecular weight distribution of the sample was tested by GPC, as shown in Table 3:

[0090] Table 2 Test results of polymerization under different feed molar ratios

[0091] serial number Proportion Time (h) <![CDATA[ c M n，GPC (g / mol)]]> <![CDATA[ c M w / M n ]]> H-1 15 / 5 / 2 / 0.05 21 19000 1.25 H-2 16.5 / 3.5 / 2 / 0.05 21 20000 1.27 H-3 18 / 2 / 2 / 0.05 21 25000 1.30 H-4 19 / 1 / 2 / 0.05 21 20000 1.32 H-5 19.5 / 0.5 / 2 / 0.05 21 24000 1.30

[0092] As shown in Table 3, the molecular weight distribution of the star-shaped random copolymer PFHMA-co-PPEGA prepared in this example is always kept in a narrow range. Figure 3 (c) is the GPC elution curve of different star-shaped random copolymers PFHMA-co-PPEGA prepared in this example, wherein the reaction time corresponding to the curves from right to left increases successively, and the different star-shaped random copolymers PFHMA-co-PPEGA all show a unimodal distribution.

[0093] Example 5

[0094] This embodiment relates to the preparation of star-shaped polymer micelles, and the specific preparation process is as follows:

[0095] Weigh a certain amount of the star polymer PPEGA (M) prepared in the experimental groups No. T-3 of Example 2 and No. H-3 of Example 4. n,GPC =27000 g / mol, M w / M n=1.31) and PFHMA-b-PPEGA (M n,GPC =25000 g / mol, M w / M n =1.30) was dissolved in 5 mL of THF to prepare solutions with concentrations ranging from 1.0 mg / mL to 0.01 mg / mL, and 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 a micellar solution. The critical aggregation concentration of the micellar solution was determined using pyrene fluorescence, the particle size of the unimolecular micelles was measured by DLS, and the morphology of the unimolecular micelles was observed by TEM. The test results are shown below:

[0096] Figure 4 The DLS test results of PPEGA (a) and PFHMA-b-PPEGA (b) micelle solutions prepared at different concentrations can be seen from the figure. When the concentration of PPEGA polymer micelle solution is high (1.0 mg / mL), both multi-molecular associated micelles and unimolecular micelles exist, while when the concentration is low (below 0.50 mg / mL), only unimolecular micelles exist; when the concentration of PFHMA-b-PPEGA polymer micelle solution is high (1.0 mg / mL), both multi-molecular associated micelles and unimolecular micelles exist, while when the concentration is low (below 0.047 mg / mL), only unimolecular micelles exist. The micelle particle size does not decrease with decreasing concentration.

[0097] Figure 5 The critical aggregation concentration (CAC) test results of PPEGA (a) and PFHMA-b-PPEGA (b) star polymer micelles are shown in the figure. The critical aggregation concentration of PPEGA polymer micelles is 0.504 mg / mL, and the critical aggregation concentration of PFHMA-b-PPEGA polymer micelles is 0.047 mg / mL, which is consistent with the results of the previous study. Figure 4 This is consistent with the test results, which means that when the micelle concentration is greater than this value, there will be multi-molecular associated micelles, and when the micelle concentration is less than this value, only single-molecule micelles exist in the solution.

[0098] Figure 6 、 7 These are the TEM test results of multimolecular micelles and unimolecular micelles of PPEGA and PFHMA-b-PPEGA star polymers. As can be seen from the figure, the unimolecular micelles have uniform particle size and small diameter.

[0099] Example 6

[0100] This example tests the photodynamics and oxygen carrying capacity of polymer micelles formed by different star polymers, as follows:

[0101] (1) Photodynamic testing

[0102] With a wavelength of 740nm LED light (50mW / cm 2 ) as a light source, and the 1O2 generated by irradiating the photosensitizer can be measured by the singlet oxygen scavenger DPBF (1 mg / mL). The specific operation is as follows:

[0103] 20 μL of DPBF was added to 1 mL of a 0.20 mg / mL aqueous solution of self-assembled star polymer micelles containing PPEGA (T-3), PPFMA-b-PPEGA (F-1), PFHMA-b-PPEGA (F-2), and PFOMA-b-PPEGA (F-3). The singlet oxygen yield of each material was determined. The degradation rate of DPBF was measured by irradiating the solution with a 740 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.

[0104] Figure 8 (a)-(d) show the photodynamic measurement results of PPEGA (T-3) and PPFC-b-PPEGA (F-1, F-2, F-3) star polymer micelles, respectively. As shown in the figures, under 740 nm illumination, the change in DPBF absorption at 417 nm gradually decreases with increasing illumination time. After 5 minutes, DPBF absorption at 417 nm is essentially absent, indicating that these star polymer micelles have a high singlet yield and can rapidly generate singlet oxygen for two-photon photodynamic tumor therapy.

[0105] (2) Oxygen carrying capacity test

[0106] The oxygen carrying capacity of the polymer micelles is measured by a dissolved oxygen meter, and the specific operation is as follows:

[0107] 5 mL of a 0.20 mg / mL aqueous solution of self-assembled PPFC-b-PPEGA and PFHMA-b-PPEGA star polymer micelles was taken and oxygen was bubbled through the solution for 30 minutes. The oxygen was removed, and the solution was stirred openly for 10 minutes. The oxygen loading of the materials was then measured using a dissolved oxygen meter. Each experiment lasted 800 seconds. A blank control group was run with water replacing the materials, while all other conditions remained unchanged. Three parallel experiments were performed for each group.

[0108] Figure 9The oxygen-carrying capacity test results for PPFC-b-PPEGA(a) and PFHMA-b-PPEGA(b) star polymer micelles show that all possess a certain oxygen-carrying capacity, with Example 4, No. F-2, and Example 5, No. H-3, showing the highest oxygen-carrying capacity and slow release over 800 seconds. These results demonstrate that the polymer micelles provided by the present invention possess oxygen-carrying capacity and can be used for two-photon photodynamic therapy of hypoxic tumors.

[0109] 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 zinc phthalocyanine derivative, characterized in that The structure of the fluorinated zinc phthalocyanine derivative is shown below: 。 2. A method for preparing the fluorinated zinc phthalocyanine derivative according to claim 1, characterized in that: Tetraaminoperfluorophthalocyanine zinc is reacted with 4-cyano-4-(ethyltrithiocarbonate)pentanoic acid-activated ester in the presence of a solvent to obtain the fluorinated phthalocyanine zinc derivative.

3. The preparation method according to claim 2, characterized in that The reaction temperature is 0-30°C and the reaction time is 24-72 h.

4. Use of the fluorinated zinc phthalocyanine derivative according to claim 1 as a RAFT chain transfer agent in near-infrared light-controlled reversible addition-fragmentation chain transfer polymerization.

5. A method for synthesizing a star polymer, characterized in that: The following steps are involved: Under near-infrared irradiation, an acrylate monomer and a chain transfer agent are reacted in the presence of a co-catalyst and a solvent to obtain the star polymer; The chain transfer agent is the fluorinated zinc phthalocyanine derivative according to claim 1; The co-catalyst is selected from one or more of triethylamine, triethanolamine and dimethylaminoethyl acrylate.

6. The synthesis method according to claim 5, characterized in that The acrylic acid ester monomers include one or more of polyethylene glycol monomethyl ether acrylate, pentafluorophenyl methacrylate, 1H,1H-perfluoroheptyl methacrylate, and 1H,1H-perfluorooctyl methacrylate; The molar ratio of the acrylic acid ester monomer to the chain transfer agent and the co-catalyst is 10-40: 0.05:1-4； The reaction temperature of the reaction is 20-90° C., and the reaction time is 1-24 h.

7. A star polymer, characterized in that The compound is prepared by the synthesis method according to claim 5 or 6.

8. A polymer micelle, characterized in that The star-shaped polymer according to claim 7 is dissolved in an organic solvent and dialyzed with deionized water to obtain the polymer micelles; the acrylate monomers used to prepare the star-shaped polymer include hydrophilic acrylate monomers.

9. The polymer micelle according to claim 8, characterized in that The star polymer is a compound represented by formula (2) or formula (3): ， ， Wherein, n is an integer from 17 to 75; a is 1 or 2; b is an integer from 7 to 10; R1 is ; R2 is 、 or .

10. Use of the polymer micelle according to claim 8 or 9 in preparing a drug for photodynamic hypoxic tumor treatment.

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