Binary phthalocyanine with type i photosensitive reaction and photothermal synergistic effect and preparation and application thereof

Abstract

This invention discloses a binary phthalocyanine exhibiting type I photosensitivity and photothermal synergistic effects, its preparation, and its applications. The binary phthalocyanine is a silicon phthalocyanine-zinc phthalocyanine coupling compound or a zinc phthalocyanine-zinc phthalocyanine coupling compound, which can self-assemble in water. In water, the self-assembled binary phthalocyanine not only produces an effective type I photosensitivity reaction but also generates a photothermal effect, thus it can be used as a photosensitizer, photothermal agent, or photodynamic-photothermal combined drug. Furthermore, when used as a photodynamic-photothermal combined drug, it can generate a high amount of superoxide anions and a significant photothermal effect under near-infrared laser irradiation and hypoxic conditions, meaning it has high anticancer activity under both aerobic and anaerobic conditions, showing significant application prospects in the treatment of hypoxic tumors. In addition, in vivo experiments have demonstrated that the binary phthalocyanine can be cleared by the kidneys and excreted in urine, effectively avoiding potential biotoxicity caused by drug accumulation after treatment, thereby significantly improving biosafety.

Description

Technical Field

[0001] This invention belongs to the field of photodynamic therapy drugs and photothermal therapy drugs, specifically relating to a binary phthalocyanine, its preparation, and its application in the pharmaceutical field. Background Technology

[0002] Malignant tumors have become one of the major diseases affecting human health and threatening human life. However, traditional tumor treatments, including surgery and chemotherapy, have significant drawbacks and limitations, making tumor prevention and treatment an urgent problem to be solved. With the development of science and technology, some new treatment methods for malignant tumors are constantly emerging, including photodynamic therapy (PDT) and photothermal therapy (PTT). As non-invasive treatment methods, PDT and PTT have attracted much attention and anticipation due to their advantages such as fewer side effects, rapid efficacy, and no drug resistance with repeated use.

[0003] Photosensitizers (or photodynamic drugs) and photothermal agents (or photothermal drugs) are key factors determining the efficacy of photodynamic therapy and photothermal therapy, respectively. Photothermal therapy primarily works by using photothermal agents to absorb photon energy and convert it into heat energy, thereby destroying tumor cells and tissues. Photodynamic therapy involves photosensitizers undergoing a photosensitization reaction under photoexcitation, generating reactive oxygen species (ROS), which in turn destroy tumor cells and tissues. The mechanisms for generating ROS include type I and type II reactions. In the ground state (S0), the photosensitizer absorbs photon energy and transitions to the excited singlet state (S1). The excited singlet state then transitions to the relatively longer-lived excited triplet state (T1) via intersystem crossing. Subsequently, the photosensitizer in the excited triplet state generates superoxide anions (O2) through electron transfer and substrate interaction. ·－ Reactive oxygen species (ROS) are present in the atmosphere, and this process is called a type I reaction. Photosensitizers in the excited triplet state can also directly transfer energy to molecular oxygen in the ground state, producing highly reactive singlet oxygen. 1 This process, known as a type II reaction, involves the production of reactive oxygen species (ROS) (O2). Both type I and type II reactions generate ROS that can kill cancer cells and destroy tumor tissue. Most photosensitizers produce ROS through type II reactions; those with effective type I photosensitization are extremely rare. Type II reactions are highly dependent on ambient oxygen, while type I reactions are less dependent. Since hypoxia is a major characteristic of solid tumors, photosensitizers with type I reaction mechanisms have greater application value in photodynamic therapy against solid tumors. Furthermore, photothermal therapy does not require oxygen.

[0004] Phthalocyanines have attracted considerable attention as a new generation of photosensitizers due to their advantages such as strong absorption within the phototherapy window (600-900 nm), low dark toxicity, and ease of structural modification. Phthalocyanines belong to the benzozaporphyrin class of derivatives and are macrocyclic conjugated systems composed of 18 π electrons. Different structures and functions of phthalocyanines can be synthesized by introducing different pericyclic and axial substitutions, as well as changing different central ions. Currently, one phthalocyanine (Photosens) has been approved for clinical use, and three phthalocyanines (Pc4, CGP55847, and Foctisine) have entered clinical trials. However, all of these phthalocyanine photosensitizers are monophthalocyanines and function through a type II photosensitization mechanism with high oxygen dependence, limiting their effectiveness in photodynamic therapy of solid tumors. Covalently coupling two phthalocyanine molecules to form binary phthalocyanines holds promise for obtaining photosensitizers with superior performance; however, the application of binary phthalocyanines in photodynamic therapy has not yet been reported. Summary of the Invention

[0005] The purpose of this invention is to provide a binary phthalocyanine with type I photosensitivity and photothermal synergistic effect, its preparation method and application. This binary phthalocyanine can not only produce an effective type I photosensitivity and also produce a photothermal effect. After exerting its effect in vivo, it is easily cleared by the kidneys and excreted in urine, showing significant application prospects in photodynamic therapy of solid tumors.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] The binary phthalocyanine provided by this invention is a silicon phthalocyanine-zinc phthalocyanine coupling compound or a zinc phthalocyanine-zinc phthalocyanine coupling compound, which can undergo self-assembly in water.

[0008] The phthalocyanine silicon-phthalocyanine zinc coupling is specifically an axially asymmetric monocarboxyl-substituted phthalocyanine silicon-pericyclic asymmetric trisubstituted "nitrogen-bridged" morpholinotriethylene glycol phthalocyanine zinc coupling, with the following structural formula:

[0009]

[0010] The zinc phthalocyanine-zinc phthalocyanine coupling compound is specifically a pericyclic asymmetric trisubstituted "nitrogen-bridged" morpholino phthalocyanine zinc-pericyclic asymmetric trisubstituted "nitrogen-bridged" morpholino phthalocyanine zinc coupling compound, the structural formula of which is:

[0011]

[0012] The preparation method of the silicon phthalocyanine-zinc phthalocyanine coupling compound includes the following steps:

[0013] (1) The preparation structures are respectively Phthalonil derivatives containing morpholino groups and phthallonil derivatives containing triethylene glycol groups: using N-aminoethylmorpholine or triethylene glycol as reactants with 3-nitrophthalonitrile, and dimethyl sulfoxide purified by molecular sieves as solvent, the reaction was carried out at 20-80°C for 17-72 hours in the presence of triethylamine or anhydrous potassium carbonate and under nitrogen protection. The reaction was monitored by thin-layer chromatography and terminated when the 3-nitrophthalonitrile was basically consumed. The target product was purified by solvent method and column chromatography.

[0014] (2) Preparation of asymmetric trisubstituted morpholinotriethylene glycol zinc phthalocyanine: Using the morpholino-containing phthalonitrile derivative and the triethylene glycol-containing phthalonitrile derivative prepared in step (1) as reactants, n-octanol as solvent, the corresponding zinc chloride compound is added, and 1,8-diazabicyclo[5.4.0]undec-7-ene is used as catalyst. The reaction is stirred at 150-170℃ for 12-48 hours. The reaction endpoint is monitored by thin-layer chromatography to generate the corresponding zinc phthalocyanine. The target product is then purified by solvent method or chromatography.

[0015] (3) The preparation of the axially asymmetric monocarboxyl-substituted phthalocyanine silicon-pericyclic asymmetric trisubstituted "nitrogen bridge" morpholinotriethylene glycol phthalocyanine zinc coupling compound was carried out using axially asymmetric monocarboxyl-substituted silicon phthalocyanine and the pericyclic asymmetric trisubstituted "nitrogen bridge" morpholinotriethylene glycol phthalocyanine zinc prepared in step (2) as reactants. N,N-dimethylformamide was used as solvent, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added as condensing agent and 4-dimethylaminopyridine as catalyst. The reaction was stirred at 25-45℃ for 12-48 hours. The reaction endpoint was monitored by thin-layer chromatography. The target product was then purified by solvent method or chromatography to obtain the axially asymmetric monocarboxyl-substituted phthalocyanine silicon-pericyclic asymmetric trisubstituted "nitrogen bridge" morpholino phthalocyanine zinc coupling compound.

[0016] The molar ratio of the axially asymmetric monocarboxyl-substituted silicon phthalocyanine, the pericyclic asymmetric trisubstituted "nitrogen-bridged" morpholino phthalocyanine zinc, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine used is 1:1.2 to 1:1.2 to 5.7:1.9 to 7.5.

[0017] The structural formula of the axially asymmetric monocarboxyl-substituted silicon phthalocyanine is: The structural formula of the pericyclic asymmetric trisubstituted "nitrogen-bridged" morpholinotriethylene glycol phthalocyanine zinc is:

[0018] The preparation method of the zinc phthalocyanine-zinc phthalocyanine coupling compound includes the following steps:

[0019] (1) The prepared structure is Phthalonil coupling: Triethylene glycol and 3-nitrophthalonitrile were used as reactants, and dimethyl sulfoxide purified by molecular sieves was used as solvent. The reaction was carried out at 20-80℃ for 17-72 hours in the presence of anhydrous potassium carbonate and under nitrogen protection. The reaction was monitored by thin-layer chromatography and terminated when the 3-nitrophthalonitrile was basically consumed. The target product was purified by solvent method and column chromatography.

[0020] (2) Preparation of zinc phthalocyanine-zinc phthalocyanine coupling: Using the phthalonitrile coupling prepared in step (1) and the phthalonitrile derivative containing morpholino group prepared above as reactants, n-octanol as solvent, the corresponding zinc chloride compound is added, and 1,8-diazabicyclo[5.4.0]undec-7-ene is used as catalyst. The reaction is stirred at 150-170℃ for 12-48 hours. The reaction endpoint is monitored by thin-layer chromatography to generate the corresponding zinc phthalocyanine. The target product is then purified by solvent method or chromatography.

[0021] The binary phthalocyanine provided by this invention can be used in photodynamic drugs, photothermal drugs, photodynamic-photothermal combined drugs, photosensitizing agents, photothermal agents, photothermal imaging reagents, or photoacoustic imaging reagents. The photosensitizing agent, also referred to as a photosensitizer, photosensitive drug preparation, or photodynamic agent, is also called a photodynamic agent. The photothermal agent, also referred to as a photothermal agent, photothermal drug preparation, or photothermal agent, is also called a photothermal agent. The prepared photodynamic drugs or photosensitizing agents can be used in photodynamic therapy, photodynamic diagnosis, or photodynamic disinfection. The prepared photothermal drugs or photothermal agents can be used in photothermal therapy, photothermal diagnosis, or photodynamic disinfection. The treatment can be for malignant tumors, benign tumors, bone marrow purification therapy for leukemia, or non-cancer diseases. The non-cancer diseases can be bacterial infections, oral diseases, macular degeneration, arteriosclerosis, wound infections, skin diseases, or viral infections. The disinfection can be the sterilization and purification of blood or blood derivatives, the sterilization and disinfection of water, or the disinfection of medical or household utensils.

[0022] The method for preparing a photosensitizing (or photothermal) agent using the binary phthalocyanine described in this invention is as follows: Using water, or a mixture of water and other substances, wherein the mass fraction of the other substances is not higher than 10%, as a solvent, the binary phthalocyanine described in this invention is dissolved to prepare a photosensitizing (or photothermal) agent containing a certain concentration, the concentration of which is not higher than its saturation concentration. Antioxidants, buffers, and isotonic agents are added to the prepared solution as additives to maintain the chemical stability and biocompatibility of the photosensitizing (or photothermal) agent. The other substances are one or a mixture of several of the following: castor oil polyoxyethylene 35 ether, dimethyl sulfoxide, ethanol, glycerol, N,N-dimethylformamide, polyethylene glycol 300-3000, cyclodextrin, glucose, Tween, and polyethylene glycol monostearate. For formulations intended for topical administration, the binary phthalocyanine described in this invention can be dissolved in a penetrating solvent or injected into ointments, lotions, or gels. The preferred penetrating solvent is an aqueous solution of 5-35% (wt%) dimethyl sulfoxide.

[0023] The application of the binary phthalocyanine described in this invention in photodynamic (or photothermal) therapy, photodynamic (or photothermal) diagnosis, photodynamic (or photothermal) disinfection, and photodynamic (or photothermal) degradation of pollutants requires a suitable light source. The suitable light source can be provided by a common light source connected with a suitable filter or by a laser, LED lamp, or other light source of a specific wavelength, with a wavelength range of 600–900 nm.

[0024] The beneficial effects and outstanding advantages of this invention are:

[0025] (1) In water, the binary phthalocyanine and its self-assembled form described in this invention can not only produce an effective type I photosensitizing reaction but also a photothermal effect. Therefore, it can be used as a photosensitizer, photothermal agent, or photodynamic-photothermal combined drug. When used as a photodynamic-photothermal combined drug, it can generate a high amount of superoxide anions and a significant photothermal effect under near-infrared laser irradiation and hypoxic conditions. The type I photosensitizing mechanism it exhibits is not found in other types of phthalocyanine photosensitizers.

[0026] (2) Cellular experiments demonstrated that the photodynamic-photothermal combined drug prepared using the aforementioned binary phthalocyanine or its self-assembly exhibits high anticancer activity under both aerobic and anaerobic conditions, showing a high synergistic effect of photodynamic and photothermal therapy. Animal experiments showed that the aforementioned binary phthalocyanine or its self-assembly has good tumor targeting and photodynamic-photothermal combined therapeutic effects, and has significant application prospects in the treatment of hypoxic tumors.

[0027] (3) Animal experiments show that the binary phthalocyanine or its self-assembled form can be cleared by the kidneys and excreted in urine, which significantly improves biosafety.

[0028] (4) The binary phthalocyanine described in this invention can self-assemble in water, and the formation of the self-assembled body can enhance its type I photosensitivity and photothermal effect.

[0029] (5) The preparation process of the binary phthalocyanine of the present invention is simple to operate, has stable properties, is easy to store, and is conducive to large-scale preparation in industrial production, with good prospects for industrialization. Attached Figure Description

[0030] Figure 1 The electronic absorption spectra of the binary phthalocyanine (4 μM) obtained in Examples 3 and 4 in N,N-dimethylformamide, water, and 1% CEL aqueous solution are shown.

[0031] Figure 2 The particle size distribution and particle size stability diagrams of the binary phthalocyanine (10 μM) obtained in Examples 3 and 4 in water are shown. Detailed Implementation

[0032] To make the content of this invention easier to understand, the technical solution of this invention will be further described below with reference to specific embodiments, but this invention is not limited thereto.

[0033] Example 1

[0034] Pericyclic asymmetric trisubstituted "nitrogen bridge" morpholinotriethylene glycol zinc phthalocyanine Synthesis:

[0035] (1) Phthalonil derivative 1 Preparation:

[0036] Using 3-nitrophthalonitrile (10 mmol) and triethylene glycol (10-40 mmol, preferably 20 mmol) as reactants, and dimethyl sulfoxide (DMSO) (20-100 mL, preferably 30 mL) as solvent, the reaction was carried out under nitrogen protection in the presence of potassium carbonate (30-90 mmol, preferably 50 mmol) at 20-45°C (preferably 45°C) with stirring for 17-24 hours. The reaction endpoint was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was filtered through a Bush funnel and rotary evaporated. A small amount of dichloromethane was dissolved and passed through a silica gel column, and ethyl acetate was used as eluent. The solution was collected, rotary evaporated, and dried to give the product in 58% yield.

[0037] Characterization data: 1H NMR (300MHz, CDCl3, ppm):7.72-7.59(m,1H,Ar-H),7.37-7.26(m,2H,Ar-H),4.33-4.24(m,2H,CH2),3.90(dd, J=5.2,4.0Hz,2H,CH2),3.75-3.70(m,2H,CH2),3.68-3.62(m,4H,CH2),3.59-3.54(m,2H,CH2).HRMS(ESI):m / z calcd for C 14 H 17 N₂O₄[M+H] + ,277.1182; found 277.1187.Relative error:1.8ppm.HRMS(ESI):m / z calcd forC 14 H 16 N₂O₄Na[M+Na] + ,299.1002; found 299.1008.Relative error:2.01ppm.

[0038] (2) Phthalonil derivative 2 Preparation:

[0039] Using 3-nitrophthalonitrile (10 mmol) and N-aminoethylmorpholine (10-40 mmol, preferably 20 mmol) as reactants, and dimethyl sulfoxide (DMSO) (20-100 mL, preferably 30 mL) as solvent, the reaction was carried out under nitrogen protection in the presence of triethylamine (30-90 mmol, preferably 50 mmol) at 20-45°C (preferably 45°C) with stirring for 17-24 hours. The reaction endpoint was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was poured into 200 mL of an ice-water mixture, and a yellow precipitate formed. After standing overnight, the precipitate was filtered, washed with deionized water, and the filter cake was collected and dried to give a pale yellow solid. The solid was dissolved in dichloromethane, filtered through silica gel, eluted with dichloromethane, and the fraction exhibiting fluorescent absorption was collected. The fraction was then evaporated to dryness to give the product, with a yield of 38%.

[0040] Characterization data: 1HNMR(300MHz, CDCl3):7.56-7.39(m,1H,Ar-H),7.03(dd,J=7.5,0.8Hz,1H,Ar-H),6.89(d,J=8.7Hz,1H,Ar-H),5.82(s,1H ,NH),3.82-3.74(m,4H,CH2),3.33-3.23(m,2H,CH2),2.76-2.68(m,2H,CH2),2.59-2.49(m,4H,CH2).HRMS(ESI):m / zcalcd for C 14 H 17 N4O[M+H] + ,257.1402; found 257.1403.Relative error:0.39ppm.

[0041] (3) Preparation of the target zinc phthalocyanine complex: The above-mentioned phthalonitrile derivative 1 (1.0 mmol) and phthalonitrile derivative 2 (4-6 mmol, preferably 5.0 mmol) were used as reactants, and octanol (20-35 mL, preferably 30 mL) was used as solvent. Zinc chloride (1-4 mmol, preferably 2 mmol) was added, and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4-1.2 mL, preferably 0.6 mL) was used as catalyst. The reaction was stirred at 150-170 °C for 12-48 hours. The reaction endpoint was monitored by thin-layer chromatography to generate the corresponding zinc phthalocyanine complex. After the reaction was complete, the product was rotary evaporated to dryness, dissolved in a small amount of N,N-dimethylformamide (DMF), and passed through a silica gel column. Impurity bands were washed away using dichloromethane:methanol at a volume ratio of 1:1. Finally, the phthalocyanine band was washed off with DMF and collected. The organic solvent was removed by rotary evaporation, and a small amount of DMF was added to dissolve the product. The product was then passed through a Bio-Beads S-X3 DMF gel column, and the first phthalocyanine band was collected. The product was dissolved in a small amount of dichloromethane, poured into 300 mL of n-hexane, precipitated, filtered, washed with hexane, and dried to obtain the product with a yield of 21%.

[0042] Characterization data: 1 H NMR(300MHz,DMSO,ppm):9.47(s,1H,Pc-H α ),9.18-8.83(m,3H,Pc-H α ), 8.79-8.46(m,3H,Pc-H α ), 8.19-7.80(m,5H,Pc-H α),7.72(s,1H,OH),7.33(s,3H,NH),5.00(dd,J=12.1,13.7Hz,4H,CH2),4.59(s,2H,CH2),4.39(s,2H,CH2),4.29-4.03(m,5H,CH2),3. 78(dd,J=10.2,11.6Hz,14H,CH2),3.68-3.54(m,5H,CH2),3.48-3.34(m,8H,CH2),3.12(s,4H,CH2),2.79(s,4H,CH2).HRMS(ESI):m / z calcd for C 56 H 65 N 14 O7Zn[M+H] + ,1109.4446; found 1109.4457.Relative error:0.99ppm.HRMS(ESI):m / z calcd forC 56 H 64 N 14 O7ZnNa[M+Na] + ,1131.4266; found 1131.4285.Relative error:1.68ppm.

[0043] Example 2

[0044] Axially asymmetric monocarboxyl-substituted phthalocyanine silicon Synthesis:

[0045] The synthesis is carried out according to the existing patent (201410108985.X), and the specific steps are as follows:

[0046] Under nitrogen protection, dichlorosilyl phthalocyanine (100 mg, 0.164 mmol), p-hydroxyphenylpropionic acid (1.640-3.280 mmol, preferably 4.920 mmol), and NaH (0.01-0.02 mmol, preferably 0.016 mmol) were added to 7-15 ml (preferably 10 ml) of toluene and refluxed for 12-24 hours (preferably 12 hours). The solvent was removed by vacuum rotary evaporation, and the product was washed with water to obtain a blue crude product. The crude product was dissolved in a small amount of DMF, passed through a silica gel column, and eluted with a mixed solvent of DCM:EA = 1:10 (v / v). The blue phthalocyanine band was eluted, and the organic solvent was removed by rotary evaporation. A small amount of THF was added to dissolve the product, and it was passed through a Bio-Beads S-X3 gel column. The first blue phthalocyanine band was collected, and THF was removed by rotary evaporation. The same method was used (using EA as the eluent to collect the phthalocyanine band) to pass the product through a silica gel column again. The organic solvent was removed by rotary evaporation, and 10 mL of DMF was added to dissolve the product. The product was then added to 150 mL of deionized water to precipitate it. The product was filtered, washed with plenty of deionized water, and dried at 45 °C to obtain the product, with a yield of 17%.

[0047] Characterization data: 1 H NMR(400MHz,DMSO,ppm):9.81–9.63(m,8H,Pc-H α ),8.95(s,1H,OH),8.62–8.50(m,8H,Pc-H β ),5.98(d,J=8.0Hz,2H,Ar-H),5.45(d,J=8.0Hz,2H,Ar-H),5.15(d,J=8.0Hz,2H,Ar-H),2.25(d,J=7.9Hz,2H,Ar-H),1.86 (t,J=8.0Hz,2H,CH2),1.65(t,J=7.5Hz,2H,CH2),0.19(t,J=7.5Hz,2H,CH2),-0.48(t,J=7.5Hz,2H,CH2).HRMS(ESI):m / z calcd for C 50 H 34 N8O6Si[M] + ,870.2365; found 870.2369.

[0048] Example 3

[0049] Axially asymmetric monocarboxyl-substituted phthalocyanine silicon-pericyclic asymmetric trisubstituted "nitrogen-bridged" morpholinophthalocyanine zinc coupling Synthesis:

[0050] The axially asymmetric monocarboxyl-substituted phthalocyanine silicon (0.055 mmol) synthesized in Example 2 and the pericyclic asymmetric trisubstituted "nitrogen-bridged" morpholinotriethylene glycol phthalocyanine zinc (0.055 mmol) synthesized in Example 1 were used as reactants. EDCI (0.078-0.314 mmol, preferably 0.157 mmol) was used as the condensing agent and DMAP (0.102-0.410 mmol, preferably 0.205 mmol) as the catalyst. DMF (5-15 mL, preferably 10 mL) was used as the solvent. The reaction was stirred at 25-45 °C for 12-48 hours. The reaction endpoint was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was removed by rotary evaporation. A small amount of DCM was added to dissolve the solution and pass it through a silica gel column. Methanol was used as the eluent to remove impurity bands. The phthalocyanine bands were eluted with DMF, and the organic solvent was removed by rotary evaporation. A small amount of DMF was added to dissolve the solution and pass it through a Bio-Beads column. Using an S-X3 type gel column, the first blue phthalocyanine band was collected, the organic solvent was removed by rotary evaporation, a small amount of DCM was added to dissolve the product, a large amount of hexane was added to precipitate the product, and the filter cake was collected and dried under vacuum to obtain the product with a yield of 29%.

[0051] Characterization data: 1 H NMR(300MHz,DMSO,ppm):9.85-9.38(m,8H,Pc-H α ), 9.16-8.86(m,6H,Pc-H α ,Pc-H β ),8.76-8.31(m,8H,Pc-H β ), 8.16-7.95(m,4H,Pc-H β ),7.85(s,1H,Pc-H β ),7.74(s,1H,Pc-H β),7.64-7.30(m,3H,NH),5.96(d,J=8.3Hz,2H,Ar-H),5.45(d,J=8.2Hz,2H,Ar-H),5.13(d,J=8.5Hz,2H,Ar-H ),4.88(s,2H,CH2),4.39(s,4H,CH2),4.20(s,4H,CH2),4.07(s,4H,CH2),3.91-3.70(m,15H,CH2),3.60-3.4 9(m,9H,CH2),3.42(s,8H,CH2),3.08(dd,J=7.3,4.7Hz,2H,CH2),2.26(d,J=8.8Hz,2H,Ar-H),2.02(s,2H,CH 2),1.72(d,J=13.9Hz,2H,CH2),0.16(t,J=7.5Hz,2H,CH2),-0.53(t,J=7.5Hz,2H,CH2).HRMS(ESI):m / zcalcd for C 106 H 96 N 22 O 12 SiZn[M] + ,1960.6633; found 1960.6626.Relative error:0.36ppm.

[0052] Example 4

[0053] (1) Phthalonil coupling Preparation:

[0054] Using 3-nitrophthalonitrile (10 mmol) and triethylene glycol (0-10 mmol, preferably 5 mmol) as reactants, and dimethyl sulfoxide (DMSO) (20-100 mL, preferably 30 mL) as solvent, the reaction was carried out under nitrogen protection in the presence of potassium carbonate (30-90 mmol, preferably 50 mmol) at 20-45°C (preferably 45°C) with stirring for 17-24 hours. The reaction endpoint was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was poured into 200 mL of an ice-water mixture, and a yellow precipitate precipitated. After standing overnight, the precipitate was filtered, washed with deionized water, and the filter cake was collected and dried to give a white solid in a yield of 35%.

[0055] Characterization data: 1H NMR (300MHz, CDCl3, ppm):7.72-7.53(m,2H,Ar-H),7.38-7.11(m,4H,Ar-H),4.28-4.2 2(m,3H,CH2),3.89(dd,J=9.2,4.8Hz,3H,CH2),3.71-3.53(m,6H,CH2).HRMS(ESI):m / z calcd for C 22 H 18 N4O4Na[M+Na] + ,425.1220; found425.1227.Relativeerror:1.65ppm.

[0056] (2) Target zinc phthalocyanine-zinc phthalocyanine conjugate Preparation: The above-mentioned phthalonitrile coupling compound (1.0 mmol) and morpholinophthalonitrile derivative 2 containing a "nitrogen bridge" (6.0-12.0 mmol, preferably 10.0 mmol) were used as reactants. Octanol (20-35 mL, preferably 30 mL) was used as the solvent, and zinc chloride (1-4 mmol, preferably 2 mmol) was added. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4-1.2 mL, preferably 0.6 mL) was used as the catalyst. The reaction was stirred at 150-170 °C for 12-48 hours. The reaction endpoint was monitored by thin-layer chromatography to generate the corresponding zinc phthalocyanine complex. After the reaction was complete, the product was rotary evaporated to dryness, dissolved in a small amount of N,N-dimethylformamide (DMF), and passed through a silica gel column. Impurity bands were washed away using dichloromethane:methanol at a volume ratio of 1:1. Finally, phthalocyanine bands were washed off using DMF and collected. Organic solvent was removed by rotary evaporation, and a small amount of DMF was added to dissolve the product. The product was then passed through a Bio-Beads S-X3 DMF gel column, and the first phthalocyanine band was collected. A small amount of dichloromethane was added to dissolve the phthalocyanine band, and the product was poured into 300 mL of n-hexane to precipitate. The precipitate was filtered, washed with hexane, and dried to obtain the product with a yield of 21%.

[0057] Characterization data: 1 H NMR(300MHz,DMSO,ppm):9.30-8.89(m,5H,Pc-H α ), 8.87-8.54(m,5H,Pc-H) α ,Pc-H β ), 8.45-7.93(m,8H,Pc-H β ), 7.84-7.30(m,6H,Pc-H) β),4.58-4.29(m,10H,CH2),4.16-3.90(m,20H,CH2),3.87-3.67(m,14H,CH2),3.60-3.26(m,40H,CH2).HRMS(ESI):m / zcalcd for C 106 H 114 N 28 O 10 Zn2K[M+K] + ,2105.7487; found 2105.7544.Relative error:2.71ppm.

[0058] Example 5

[0059] The binary phthalocyanines prepared in Examples 1-4 were dissolved in DMSO to prepare a 1 mM stock solution. Their dispersion in different solutions, including DMF, 1% CEL, and pure water, was tested using a UV-Vis spectrophotometer. Detailed experimental procedures can be found in Eur. J. Med. Chem., 2016, 114, 380-389.

[0060] Test results show that the binary phthalocyanines obtained in Examples 3 and 4 exhibit strong and sharp Q bands in DMF and 1% CEL, indicating that the binary phthalocyanines exist as monomers in both DMF and 1% CEL. However, in pure water, they show broad and short Q bands, indicating that the binary phthalocyanines exist as aggregates in pure water. See [link to relevant documentation] for details. Figure 1 .

[0061] Example 6

[0062] The particle size distribution and stability of the binary phthalocyanines prepared in Examples 3 and 4 in water were determined using a particle size analyzer. Detailed experimental procedures can be found in J. Mater. Chem. B, 2021, 9, 2845.

[0063] Test results show that the binary phthalocyanines (10 μM) prepared in Examples 3 and 4 can both self-assemble in water to form uniform nanoparticles, and the formed nanoparticles all exhibit good stability. The nanoparticles formed by the silicon phthalocyanine-zinc phthalocyanine coupling compound obtained in Example 3 have a particle size of approximately 10 nm and can remain stable for 7 days; the nanoparticles formed by the zinc phthalocyanine-zinc phthalocyanine coupling compound obtained in Example 4 have a particle size of approximately 25 nm and can remain stable for 7 days. See [link to relevant documentation] for details. Figure 2 .

[0064] Example 7

[0065] The zinc phthalocyanine and silicon phthalocyanine complexes prepared in Examples 1 and 2, as well as the binary phthalocyanines prepared in Examples 3 and 4, were dissolved in DMF to prepare 1 mM stock solutions, which were then diluted in deionized water to test their total reactive oxygen species (ROS).

[0066] The total reactive oxygen species (ROS) assay used hydrolyzed 2,7-dichlorofluorescein diacetate (DCFH-DA) as a fluorescent probe. DCFH-DA is a commonly used probe for ROS detection; it is activated by oxygen to form dichlorofluorescein, which emits a fluorescent signal at a wavelength of 520 nm. The preparation method of 2,7-dichlorofluorescein protein acetate (DCF) is as follows: 2,7-dichlorofluorescein diacetate (DCFH-DA) is dissolved in methanol to prepare a 5 mM DCFH-DA solution, which is stored at -20 °C. Before testing, the DCFH-DA solution is mixed with 0.1 mol / L sodium hydroxide solution and reacted in the dark for 30 min, then diluted with pH 7.4 PBS solution to obtain a 200 μM stock solution.

[0067] Prepare a 2 mL deionized aqueous solution of phthalocyanine (4 μM) and the activated reactive oxygen species probe (5 μM) in a quartz cuvette, and test it using 655 nm light (15 mW / cm²). 2 Irradiate the control cuvette and measure the changes in fluorescence intensity of the reactive oxygen species (ROS) probe under different illumination times (488 nm excitation, fluorescence scan range of 500 nm-600 nm). Plot the relative fluorescence intensity (Ft-F0) at 522 nm against illumination time (T). The larger the Ft-F0 value per unit time, the stronger the ability to generate ROS.

[0068] The experimental results are shown in Table 1.

[0069] Table 1 Comparison of the total amount of reactive oxygen species generated in different samples

[0070]

[0071] As can be seen from the table, the silicon phthalocyanine-zinc phthalocyanine coupling compound has the strongest ability to generate ROS, which is 2.9 times that of the zinc phthalocyanine obtained in Example 1 and 21.5 times that of the silicon phthalocyanine obtained in Example 2. At the same time, the ability of the silicon phthalocyanine-zinc phthalocyanine coupling compound to generate ROS is also significantly higher than that of the common photosensitizer methylene blue, which is 2.2 times that of methylene blue.

[0072] Example 8

[0073] The zinc phthalocyanine and silicon phthalocyanine complexes prepared in Examples 1 and 2, as well as the binary phthalocyanines prepared in Examples 3 and 4, were dissolved in DMF to prepare 1 mM stock solutions, which were then diluted in deionized water. The production of superoxide anions (O2-) under normal oxygen conditions was then tested. ·-The ability of the binary phthalocyanines prepared in Cases 3 and 4 to generate superoxide anions (O2) under anaerobic conditions. ·- The ability to detect photosensitize is assessed. During the test, methylene blue (MB), a common photosensitizer, was used as a control group.

[0074] Dihydroethidium (DHE) was used as the probe for detecting superoxide anions. In the presence of superoxide anions, DHE is oxidized to ethidium bromide, which then binds to surrounding RNA or DNA, emitting bright red fluorescence (excitation wavelength around 500-510 nm, emission wavelength around 600 nm). The stronger the fluorescence, the greater the amount of superoxide anions produced. The specific steps are as follows: the desired phthalocyanine complex and its binary phthalocyanine conjugate (phthalocyanine concentration 4 μM), the DHE probe (25 μM), and calf thymus DNA (250 μg / mL) are added to deionized water and mixed thoroughly. The initial fluorescence intensity is measured, and then light at a wavelength of 655 nm (illuminance density 1 mW / cm²) is used. 2 After 12 minutes of illumination, the changes in probe fluorescence intensity were recorded using a fluorescence scaler to determine the generation of superoxide anions.

[0075] Method for testing superoxide anions under hypoxic conditions: Before the test, the purified water used was boiled for 20 minutes and sonicated to remove oxygen. Then, a large amount of nitrogen gas was introduced to prevent oxygen from entering. The oxygen content was measured using a Shanghai Leici JPB607A portable dissolved oxygen analyzer to check the hypoxic state of the water. Pre-prepared deoxygenated water (oxygen concentration 1.0-2.5 mg / L) was selected, and the required binary phthalocyanine (phthalocyanine concentration 4 μM), DHE probe (25 μM), and calf thymus DNA (250 μg / mL) were added and mixed thoroughly. Nitrogen gas was then introduced for a certain period, and the mixture was sealed. The fluorescence intensity was measured at the beginning, followed by testing with 655 nm light (illuminance 1 mW / cm²). 2 Irradiate for 12 minutes. During the irradiation period, nitrogen gas is continuously introduced through the prepared device to remove oxygen. Then, a fluorescence scaler is used to record the changes in probe fluorescence intensity to determine the generation of superoxide anions.

[0076] The experimental results are shown in Tables 2 and 3.

[0077] Table 2 Comparison of fluorescence intensity of superoxide anions generated by different samples under normal oxygen conditions

[0078]

[0079] Table 3 Comparison of fluorescence intensity of superoxide anions produced by different samples under hypoxic conditions

[0080]

[0081] As shown in Table 2, under normal oxygen conditions, the silicon phthalocyanine-zinc phthalocyanine coupling compound has the highest ability to generate superoxide anions, which is significantly higher than that of the common photosensitizer MB (3.9 times higher).

[0082] As shown in Table 3, the silicon phthalocyanine-zinc phthalocyanine coupling compound can also generate superoxide anions efficiently under hypoxic conditions, with a generation capacity close to that under aerobic conditions, and significantly higher than that of the common photosensitizer MB (2.8 times higher).

[0083] The above experimental results show that zinc phthalocyanine, by introducing a morpholino nitrogen bridge into the parent structure of the phthalocyanine photosensitizer, enables the conjugate to generate reactive oxygen species through electron transfer. This allows the binary phthalocyanine to effectively generate superoxide anions under both aerobic and anaerobic conditions, and the fluorescence intensity difference between the two conditions is small, indicating that the generation of superoxide anions is not significantly correlated with the oxygen concentration.

[0084] Example 9

[0085] The zinc phthalocyanine and silicon phthalocyanine complexes prepared in Examples 1 and 2, as well as the binary phthalocyanines prepared in Examples 3 and 4, were dissolved in DMSO to prepare 1 mM mother liquors, which were then diluted in deionized water to test their photothermal generation capabilities and photothermal conversion efficiency.

[0086] The temperature changes of phthalocyanine in pure water and under near-infrared light irradiation were tested using a photothermal imaging system. A prepared 1 mM phthalocyanine stock solution was diluted to 10 μM with deionized water, and 100 μL was added to a 96-well plate. The plate was then irradiated with an 808 nm laser (0.5 W / cm²). 2 Temperature changes were detected using a photothermal imager (ideally, the test should be conducted under similar room temperature and in darkness). ICG, a common photothermal agent, was used as a reference. The experimental conditions for photothermal conversion efficiency were consistent with those described above: first, the temperature rise after 10 minutes of illumination was measured; then, the temperature drop after 10 minutes of illumination was measured and recorded. The photothermal conversion efficiency was calculated by plotting temperature (°C) against time (t) and referring to relevant literature (Chem.Sci., 2018, 9, 2098).

[0087] Experimental results show that the phthalocyanine complexes prepared in Examples 1 and 2, and the zinc phthalocyanine-zinc phthalocyanine coupling prepared in Example 4, exhibit almost no photothermal effect in water. However, the silicon phthalocyanine-zinc phthalocyanine coupling prepared in Example 3 demonstrates a photothermal effect, reaching a temperature of 48.5°C under illumination, with a photothermal conversion efficiency of 15.6%. In contrast, the photothermal conversion efficiency of the reference material ICG is 5.6%. This indicates that the silicon phthalocyanine-zinc phthalocyanine coupling possesses a higher photothermal effect, with a significantly higher photothermal conversion efficiency than the common photothermal agent ICG.

[0088] Example 10

[0089] The method for preparing photosensitizers or phototherapy (photodynamic / photothermal therapy) drugs using the phthalocyanine silicon-phthalocyanine zinc coupling compound of the present invention is as follows: first, dissolve the phthalocyanine silicon-phthalocyanine zinc coupling compound in DMF or DMSO to prepare a 1-2 mM stock solution, and then dilute it with water to prepare a drug aqueous solution of a certain concentration.

[0090] The phthalocyanine silicon-phthalocyanine zinc coupling photosensitizer or phototherapy drug prepared in this invention requires a suitable light source during application. Suitable light sources can include 655nm and 808nm lasers, etc.

[0091] Example 11

[0092] The study investigated the superoxide anion production of the silicon phthalocyanine-zinc phthalocyanine conjugate in human hepatocellular carcinoma cells (HepG2) and mouse breast cancer cells (4T1) under normoxic and hypoxic conditions, as well as its phototherapy-induced anticancer activity.

[0093] Measurement of intracellular superoxide anion under normoxic and hypoxic conditions: Diethidium hydrogen phosphate (DHE) was used as a probe to detect the production of intracellular superoxide anions. 4T1 and HepG2 cells in logarithmic growth phase were seeded in culture plates containing clean, sterile coverslips (approximately 1 × 10⁻⁶ cells per plate). 5 (Each sample) was cultured at 37℃ under 5% CO2 (normative oxygen) or 3% O2, 5% CO2, and 92% N2 (hypoxia), respectively. After 24 hours, the culture medium was removed, and 400 μL of medium containing a binary phthalocyanine silicon-phthalocyanine zinc coupling photosensitizer was added. The samples were then cultured for another 2 hours. Afterward, PBS buffer was added twice to wash away the drug-containing medium, and the prepared probe DHE was added for further incubation for 30 minutes under 655 nm light (illuminance of 0.1 W / cm²). 2 The cells were exposed to light for 30 seconds, and then detected using a fluorescence confocal microscope with an excitation wavelength of 488 nm and fluorescence signals collected from 570 to 630 nm.

[0094] The phthalocyanine silicon-phthalocyanine zinc conjugate from Example 3 was dissolved in DMF to prepare a 1 mM stock solution, which was then diluted in cell culture medium to prepare cell culture media containing different concentrations of phthalocyanine silicon-phthalocyanine zinc conjugate. 4T1 cells in the logarithmic growth phase (approximately 1 × 10⁻⁶ cells per plate) were seeded into culture plates containing clean, sterile coverslips. 5Cells were cultured at 37°C under 5% CO2 (normative oxygen) or 3% O2, 5% CO2, and 92% N2 (hypoxia) for 24 hours. After 24 hours, the culture medium was removed, and the cancer cells were cultured for 2 hours in culture medium containing different concentrations of the conjugate. The culture medium was then discarded, and the cells were washed with PBS buffer before being added to fresh culture medium (without the aforementioned conjugate). For the light-induced experimental group, an excitation light source with a wavelength of 808 nm (0.5 W / cm²) was used. 2 ) and 655nm (0.1W / cm 2 The cells were exposed to light for 3 minutes in each group; in the unexposed group, the cells were placed in the dark for 6 minutes. The cell viability in both groups was assessed using the MTT assay. For detailed experimental procedures, please refer to Eur. J. Med. Chem., 2018, 155, 24-33.

[0095] Regardless of whether under normoxic or hypoxic conditions, the silicon phthalocyanine-zinc phthalocyanine conjugate prepared in Example 3 could elicit a response from the superoxide anion fluorescent probe in 4T1 and HepG2 cells. Moreover, the fluorescence intensity of the superoxide anion probe was almost the same under normoxic and hypoxic conditions, indicating that the silicon phthalocyanine-zinc phthalocyanine conjugate can effectively generate superoxide anions in cells and can also generate superoxide anions efficiently under hypoxic conditions.

[0096] The experimental results also showed that, without light irradiation, the phthalocyanine silicon-phthalocyanine zinc conjugates obtained in Example 3 had no killing or growth-inhibiting effects on 4T1 cells, indicating that the above-mentioned phthalocyanine silicon-phthalocyanine zinc conjugates had no dark toxicity. However, after light irradiation, the phthalocyanine silicon-phthalocyanine zinc conjugates obtained in Examples 5-8 all showed high photodynamic anticancer activity, exhibiting a dose-response relationship. These results demonstrate that the phthalocyanine silicon-phthalocyanine zinc conjugates prepared in this invention have high photodynamic anticancer activity against 4T1 cells under both normoxic and hypoxic conditions, with an IC50 value of [missing value]. 50 The value (median lethal concentration, i.e. the drug concentration required to kill 50% of cancer cells) is as low as 0.15 μM.

[0097] Example 12

[0098] The silicon phthalocyanine-zinc phthalocyanine conjugate from Example 3 was dissolved in DMF to prepare a 1 mM stock solution, which was then diluted with water to prepare a 200 μM aqueous solution of the photosensitizing agent. Its fluorescence and photothermal imaging effects on KM mice with solid tumors containing hepatocellular carcinoma cells (H22) were tested.

[0099] 100 μL of a 200 μM aqueous solution of the above-mentioned photosensitizing agent was injected via the tail vein into tumor-bearing mice containing H22. The accumulation of the drug at the tumor site was monitored using a small animal fluorescence imaging system. The mice were dissected 24 hours later, and the distribution of the drug in various tissues and organs was monitored using the same system. Detailed experimental procedures can be found in ACS Appl. Mater. Interfaces 2019, 11, 36435-36443.

[0100] 100 μL of a 200 μM aqueous solution of the above-mentioned photosensitizing agent was injected via the tail vein into tumor-bearing mice containing H22. The accumulation of the drug at the tumor site in the mice was monitored using a photoacoustic imaging system. For detailed experimental procedures, please refer to Bioconjugate Chem. 2020, 31, 1438-1448.

[0101] In vivo fluorescence imaging results showed that the silicon phthalocyanine-zinc phthalocyanine conjugate of Example 3 exhibited high tumor targeting. Fluorescence was observed at the tumor site 1 hour after intravenous injection of the photosensitizer, peaking at 2 hours, and was only visible at the tumor site. 24 hours later, mice were dissected to obtain various organs, and their fluorescence imaging was observed. It was found that, except for the tumor site, where significant fluorescence was observed, no obvious drug residues were found in other organs and tissues.

[0102] Photoacoustic experiments showed that after intravenous injection of the photosensitizer solution, the photoacoustic signal intensity at the tumor site gradually increased, reaching its maximum 2 hours after intravenous injection, and then gradually decreased. This also indicates that the silicon phthalocyanine-zinc phthalocyanine conjugate prepared in this invention has good accumulation at the tumor site in mice.

[0103] Example 13

[0104] The silicon phthalocyanine-zinc phthalocyanine conjugate from Example 3 was dissolved in DMSO to prepare a 1 mM stock solution, which was then diluted with water to prepare a 200 μM aqueous solution of the photosensitizing agent. Its in vivo clearance in KM mice with solid tumors containing hepatocellular carcinoma cells (H22) was tested.

[0105] 100 μL of a 200 μM aqueous solution of the above-mentioned photosensitizing agent was injected via the tail vein into tumor-bearing mice containing H22. The mice were dissected at 2 hours and 24 hours later, and the distribution of the drug in various tissues and organs was monitored using a small animal fluorescence imaging system. For detailed experimental procedures, please refer to ACS Appl. Mater. Interfaces 2019, 11, 36435-36443.

[0106] 100 μL of the above-mentioned photosensitizing agent aqueous solution at a concentration of 200 μM was injected into the tail vein of H22-bearing tumor-bearing mice. Urine and feces of the mice were collected at different time periods. The fluorescence of the drug in the urine and feces of the mice at different time periods was monitored using a small animal fluorescence imaging system, and the urine of the mice was characterized using high-resolution mass spectrometry.

[0107] In vitro organ fluorescence imaging results showed that, 2 hours after intravenous injection of the photosensitizer, significant fluorescence signals were observed in the liver, spleen, lungs, and kidneys. After 24 hours, only the tumor sites in mice showed relatively significant fluorescence; no significant drug residues were found in other organ tissues. Compared to the fluorescence signal intensity of the liver, spleen, lungs, and kidneys of mice dissected 2 hours prior, the fluorescence intensity values ​​of the liver, spleen, lungs, and kidneys of mice dissected 24 hours prior decreased by 2.5, 3.7, 6.9, and 6.2 times, respectively, indicating that the phthalocyanine silicon-phthalocyanine zinc conjugate of Example 3 can be cleared in mice. This avoids the potential biotoxicity caused by drug accumulation after treatment and improves biosafety.

[0108] In vitro urine fluorescence imaging results showed that fluorescence was detectable in mouse urine 2 hours after intravenous injection of the photosensitizer, and the fluorescence gradually decreased thereafter. 24 hours after tail vein injection, no fluorescence was detected in the mouse urine, indicating that the drug had been almost completely excreted from the body. Furthermore, no fluorescence was observed in the mouse feces during the testing period, indicating that the drug is primarily cleared by the kidneys and excreted in the urine. Simultaneously, high-resolution mass spectrometry detected a signal peak of the drug, further confirming that the drug is mainly cleared by the kidneys and excreted in the urine.

[0109] Example 14

[0110] The antitumor effect of phototherapy (photodynamic therapy / photothermal therapy) of the silicon phthalocyanine-zinc phthalocyanine conjugate in Example 3 was tested. KM mice with subcutaneously transplanted H22 hepatocellular carcinoma cells were established according to the literature method (ACS Appl. Mater. Interfaces 2019, 11, 36435-36443). The H22 tumor-bearing KM mice were divided into 8 experimental groups: drug administration alone, PBS alone, 655nm light irradiation alone, 808nm light irradiation alone, drug administration + 655nm light irradiation, drug administration + 808nm light irradiation, and drug administration + 808nm + 655nm light irradiation, with 5 mice in each group. Drug administration + laser irradiation was performed when the tumor grew to 60-100mm. 3 At the time of administration, 100 μL of a 200 μM aqueous solution of a binary phthalocyanine silicon-phthalocyanine zinc coupling compound was injected intravenously. Twenty-four hours later, the tumor site was irradiated for 5 minutes each with 808 nm and 655 nm light intensity (0.1 W / cm²). 2The light intensity at 808nm is 0.5W / cm². 2 After treating the mice as required, they were continued to be fed, and their condition was observed every other day. The mice's weight was measured, and the long and short diameters of the tumors were measured using calipers for a total of 14 days. The tumor inhibition rate was calculated according to the method described in the literature (ACS Appl. Mater. Interfaces 2019, 11, 36435-36443).

[0111] The photothermal treatment effect of the drug after tail vein injection in mice was monitored using a small animal photothermal imaging system. The imaging was performed using 655nm light (0.1W / cm²). 2 ) light and 808nm (light intensity 0.5W / cm) 2 The tumor sites of mice were continuously irradiated with light for 5 minutes, and the temperature changes of the tumor sites were continuously monitored using a small animal photothermal imaging device.

[0112] The experimental results showed that: (1) the drug administration group, the PBS group, the 655nm light group, and the 808nm group had no inhibitory effect on tumor growth in mice (the tumors grew by about 12 times). (2) the drug administration + 655nm light group showed a good inhibitory effect on tumor growth, with an inhibition rate of 53% (p<0.001), and the drug administration + 808nm + 655nm light group showed extremely high inhibitory activity on tumor growth, with an inhibition rate as high as 88% (p<0.001). This further proves that the two light irradiations can effectively induce photothermal and photodynamic effects, and the extremely high inhibition rate of the drug administration + 808nm + 655nm group should be the result of the synergistic effect of photodynamic therapy and photothermal effect of phthalocyanine silicon-phthalocyanine zinc conjugate. (3) The mice in the single-drug group, the drug + 655nm light group, the drug + 808nm light group, and the drug + 808nm + 655nm light group showed an increasing weight trend within 14 days, indicating that the silicon phthalocyanine-zinc phthalocyanine conjugate has no obvious toxicity to mice and has good biocompatibility.

[0113] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made within the scope of the claims of the present invention should be included in the scope of the present invention.

Claims

1. A binary phthalocyanine having a type I photosensitization reaction and a photothermal synergistic effect, characterized by: The binary phthalocyanine is a phthalocyanine silicon-phthalocyanine zinc conjugate, which can self-assemble in water; The phthalocyanine silicon-phthalocyanine zinc conjugate is an axially asymmetric monocarboxyl-substituted phthalocyanine silicon-peripheral asymmetric tri-substituted "nitrogen bridge" morpholinyl triethylene glycol phthalocyanine zinc conjugate, and a structural formula thereof is as follows: 。 2. A method for preparing a binary phthalocyanine having a type I photosensitization reaction and a photothermal synergistic effect according to claim 1, characterized by, The preparation method of the phthalocyanine silicon-phthalocyanine zinc conjugate comprises the following steps: (1) Preparation of morpholine-containing phthalonitrile derivatives and triethylene glycol-containing phthalonitrile derivatives with structures of and respectively: using N-aminoethyl morpholine or triethylene glycol as a reactant, dimethyl sulfoxide purified by molecular sieves as a solvent, stirring at 20-80 ℃ for 17-72 hours under the presence of triethylamine or anhydrous potassium carbonate and nitrogen protection, monitoring by thin layer chromatography, terminating the reaction when 3-nitrophthalonitrile is basically consumed, and purifying the target product by solvent method and column chromatography respectively; (2) Preparation of peripheral asymmetric tri-substituted "nitrogen bridge" morpholinyl triethylene glycol phthalocyanine zinc: the phthalonitrile derivative containing morpholinyl and the phthalonitrile derivative containing triethylene glycol prepared in step (1) are used as reactants, n-octanol is used as a solvent, the corresponding zinc chloride compound is added, 1,8-diazabicyclo[5.4.0]undec-7-ene is used as a catalyst, and the reaction is stirred at 150-170 ℃ for 12-48 hours; the reaction end point is monitored by thin layer chromatography; the corresponding phthalocyanine zinc is generated; and the target product is purified by a solvent method or a chromatographic method; (3) Preparation of axially asymmetric monosubstituted carboxyl phthalocyanine silicon-peripheral asymmetric trisubstituted "nitrogen bridge" morpholinyl triethylene glycol phthalocyanine zinc conjugate: using axially asymmetric monosubstituted carboxyl phthalocyanine silicon and the peripheral asymmetric trisubstituted "nitrogen bridge" morpholinyl triethylene glycol phthalocyanine zinc prepared in step (2) as reactants, using dimethylformamide as solvent, adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as condensing agent and 4-dimethylaminopyridine as catalyst, stirring at 25-45 ℃ for 12-48 hours, monitoring the end point of the reaction by thin layer chromatography, and then purifying the target product by solvent method or chromatography to obtain the axially asymmetric monosubstituted carboxyl phthalocyanine silicon-peripheral asymmetric trisubstituted "nitrogen bridge" morpholinyl triethylene glycol phthalocyanine zinc conjugate. N,N- dimethylformamide as solvent, adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as condensing agent and 4-dimethylaminopyridine as catalyst, stirring at 25-45 ℃ for 12-48 hours, monitoring the end point of the reaction by thin layer chromatography, and then purifying the target product by solvent method or chromatography to obtain the axially asymmetric monosubstituted carboxyl phthalocyanine silicon-peripheral asymmetric trisubstituted "nitrogen bridge" morpholinyl triethylene glycol phthalocyanine zinc conjugate. The molar ratio of the axially asymmetric monocarboxyl-substituted silicon phthalocyanine, the peripheral asymmetric tri-substituted "nitrogen bridge" morpholinyl triethylene glycol phthalocyanine zinc, the 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and the 4-dimethylaminopyridine is 1:1.2~1:1.2~5.7:1.9~7.

5. The structural formula of the axial asymmetric monocarboxyl-substituted silicon phthalocyanine is: The structural formula of the pericyclic asymmetric trisubstituted "nitrogen bridge" morpholinyl triethylene glycol phthalocyanine zinc is: .

3. Use of a binary phthalocyanine as claimed in claim 1, characterized in that: The binary phthalocyanine is used for preparing a drug for synergistic photodynamic therapy and photothermal therapy, or a photodynamic drug, or a photothermal drug, or a photothermal imaging reagent, or a photoacoustic imaging reagent.

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