A rhenium phthalocyanine complex, its preparation method and application

Abstract

The present invention discloses a rhenium phthalocyanine complex, a preparation method thereof and an application thereof. The molecular formula of the rhenium phthalocyanine complex is Re2Pc, and the structural formula is shown in Formula I. The synthetic route is shown in Formula II, including: drying the Schlenk flask by roasting with a flame under a nitrogen atmosphere, evacuating and filling with nitrogen, cooling to room temperature, quickly adding the α-(ButO)8Pc ligand and Re2(CO) 10 , evacuating and filling with nitrogen, adding ortho-dichlorobenzene, heating the reaction mixture to reflux until the reaction is complete; cooling the reaction solution to room temperature, dissolving it with a small amount of dichloromethane, recrystallizing with petroleum ether, and a large amount of precipitation is generated; centrifuging the precipitate, retaining the centrifuged liquid and standing for 1-3 h, collecting the purple product, repeating the purification to obtain the Re2Pc complex, which can convert near-infrared light into heat energy, has good thermal stability and high photothermal conversion efficiency, can be used as or in the preparation of a photothermal conversion reagent for photothermal therapy, and the reaction steps are simple and the purification process is convenient and easy to operate.

Description

Technical Field

[0001] The invention relates to the field of nanomaterials, and in particular to a phthalocyanine-rhenium complex and a preparation method and application thereof. Background Art

[0002] Cancer is usually cured by surgery, radiotherapy, chemotherapy, hormone therapy, immunotherapy, etc. However, these treatments may damage healthy cells and disrupt the immune system, leading to a second cancer. In recent years, there has been an increased focus on the development of nanomaterials for photothermal therapy (PTT), a minimally invasive and selective method for treating cancer. PTT, also known as photothermal ablation, is a thermal therapy method that uses light-absorbing materials to burn cancer cells through heat generated by light energy. In particular, PTT based on near-infrared (NIR, λ = 700-1100nm) lasers is preferred because NIR light has the highest transmittance to biological tissues (hemoglobin and water) and the typical penetration depth of NIR light can reach several centimeters in biological tissues. Optimal intratumoral delivery nanomaterials for PTT should be small enough to pass through the pores of the vasculature, but large enough (>5nm) to avoid rapid clearance. However, it remains challenging to synthesize nanomaterials below 100 nm to meet all the requirements, including tunable near-infrared wavelength, high light absorption coefficient, good biocompatibility, nontoxicity, and the material should be easily functionalized to modify other molecules on its surface, such as drug molecules, photosensitizers, etc.

[0003] Since the rise of photothermal therapy, the first generation of materials are precious metal nanoparticles represented by gold and silver, which have the advantage of high photothermal conversion efficiency, but are relatively expensive. With the development of carbon materials, graphene, carbon nanorods, etc. have become representatives of the second generation of photothermal materials. They have a large photothermal conversion area, but poor absorption capacity in the near-infrared region, cannot reach the near-infrared light region required for treatment, and have weak tissue penetration depth. Recently, metal and non-metal compounds represented by CuS and ZnS, and organic dye substances represented by indocyanine green and Prussian blue have become a research trend for photothermal materials.

[0004] The complexes formed by the noble metal rhenium and phthalocyanine show excellent photophysical properties due to their metal-ligand charge transfer triplet states, such as large Stokes shift, adjustable absorption and emission spectra, high fluorescence quantum yield and long phosphorescence lifetime, especially in the metal rhenium complexes, the heavy atoms rhenium atoms can induce strong spin inductive coupling, which enhances the inter-gap crossing efficiency between the excited singlet state and the excited triplet state. The energy of the metal rhenium complex reaching the excited triplet state is released in the form of phosphorescence, while the energy transfer or charge transfer to the ground state oxygen generates active oxygen or singlet oxygen, which expands the application range of metal rhenium complexes to the field of photodynamic therapy. Therefore, the metal rhenium complexes have unique advantages in optics. In addition, phthalocyanine rhenium complexes are stable in the air, have good chemical stability and photothermal stability, high photothermal conversion efficiency, low toxicity to organisms and biological tissues, and the phthalocyanine rhenium complexes themselves are easy to functionalize, and other molecules such as drug molecules can be modified on their surface. These advantages make it an excellent photothermal conversion material. In the foreseeable future, phthalocyanine rhenium complexes will attract more and more attention from researchers.

[0005] However, most of the current rhenium complexes are still in the ultraviolet region, not reaching the biological light region of 650-1100nm for biological treatment. The metal-ligand charge transfer triplet state exhibits excellent photophysical properties. Therefore, by adjusting and modifying the ligand and introducing precious metal atoms, the absorption of the complex can be changed from the near-infrared region 1 (650-900nm) to the near-infrared region 2 (1000-1700nm). As we all know, ultraviolet light has certain damage to human skin and is not conducive to the application of biological diagnosis and treatment. In order to expand the light source of metal rhenium complex photothermal therapy to visible light, researchers are developing new photosensitizers with better penetration depth. Summary of the invention

[0006] In view of the problems existing in the prior art, the main purpose of the present invention is to provide a phthalocyanine rhenium complex (Re 2 The complex has different absorption in different solvents and can realize absorption from near-infrared region 1 to near-infrared region 2. It can convert near-infrared light into thermal energy very well and has good thermal stability. It is an excellent photothermal conversion agent in photothermal therapy technology.

[0007] Another object of the present invention is to provide a method for preparing the above-mentioned phthalocyanine rhenium complex

[0008] Another object of the present invention is to provide the use of the above-mentioned rhenium phthalocyanine complex as or in the preparation of a photothermal conversion agent for photothermal therapy.

[0009] To achieve the above object, the present invention adopts the following technical solution:

[0010] The present invention provides a phthalocyanine rhenium complex, the molecular formula of which is Re 2 Pc, the structural formula is shown in Formula I:

[0011]

[0012] The present invention provides a method for preparing the above-mentioned phthalocyanine rhenium complex, and its synthesis route is shown in Formula II:

[0013]

[0014] Specifically, the steps include:

[0015] Step 1: Flame dry the Schlenk flask under nitrogen atmosphere, evacuate and refill with nitrogen three times, and then cool to room temperature under vacuum;

[0016] Step 2: Remove the flask and quickly add α-(ButO) 8 Pc ligand (69 mg, 0.0632 mmol) and Re 2 (CO) 10 (61.9 mg, 0.0948 mmol), evacuate and fill with nitrogen three times, add 2.2 mL of o-dichlorobenzene, and heat the reaction mixture under reflux for more than 31 h. Meanwhile, ultraviolet-visible absorption spectroscopy (UV-vis) was used to monitor the reaction until the reaction was complete;

[0017] Step 3: The reaction solution is cooled to room temperature, then a small amount of dichloromethane is used to dissolve the reaction solution, and then a sufficient amount of petroleum ether (petroleum ether and dichloromethane are recrystallized) is added to produce a large amount of precipitation;

[0018] Step 4: centrifuge to remove the precipitated material and retain the centrifuged liquid;

[0019] Step 5: The liquid collected by centrifugation is allowed to stand for 1-3 hours, and the purple product is collected;

[0020] Step 6: The solid precipitated in step 3 is dissolved again with a small amount of dichloromethane, petroleum ether is added to precipitate the solid again, and the solid is washed by centrifugation with petroleum ether for 2-3 times until the centrifuged liquid is colorless. UV-vis is used to monitor whether the liquid obtained by centrifugation is the desired product. If so, the liquid is collected and spun dry to obtain a partial product;

[0021] Step 7: Dissolve the solid precipitated in step 6 with dichloromethane. If it is colorless, it means that the product has been completely dispersed in petroleum ether and washed clean;

[0022] Step 8: Combine the partial products collected in steps 5 and 6 to obtain the target product Re 2 Pc complex.

[0023] The present invention also provides the use of the above-mentioned phthalocyanine rhenium complex as or in the preparation of a photothermal conversion agent for photothermal therapy.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. The phthalocyanine rhenium complex of the present invention has good absorption at about 950nm, can well convert near-infrared light into thermal energy, and has good thermal stability.

[0026] 2. The preparation method of the phthalocyanine rhenium complex of the present invention has simple reaction steps and a convenient and easy-to-operate purification process, thus avoiding complex and expensive purification methods.

[0027] 3. The phthalocyanine rhenium complex of the present invention has high photothermal conversion efficiency. Under the excitation of 808nm laser, the temperature can rise to 60°C within 15 minutes, which can effectively kill cancer cells. It is an excellent photothermal conversion agent in photothermal therapy technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Re in the embodiment 2 1HNMR spectrum of Pc.

[0029] Figure 2 Re in the embodiment 2 UV absorption diagram of Pc in dichloromethane.

[0030] Figure 3 Re in the embodiment 2 Fourier transform ion cyclotron resonance mass spectrometry of Pc (Maldi source).

[0031] Figure 4 Re in the embodiment 2 Crystal structure diagram of Pc.

[0032] Figure 5 In the embodiment, 0.8w / cm 2 Re in DMF solvent at laser power density 2 Photothermal curve of Pc. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solution and advantages of the embodiment of the present invention clearer, the technical solution of the embodiment of the present invention will be clearly and completely described in conjunction with the drawings of the embodiment of the present invention. Obviously, the described embodiment is a part of the embodiment of the present invention, not all of the embodiments. Based on the described embodiment of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0034] In the following examples, butoxy-substituted phthalocyanine is taken as an example to further illustrate the present invention.

[0035] Example 1

[0036] (1)Re 2 Preparation of Pc

[0037] 1. Flame dry the Schlenk flask under nitrogen atmosphere. Flame dry the Schlenk flask, evacuate and fill with nitrogen three times, and then cool to room temperature under vacuum.

[0038] 2. Remove the flask and quickly add α-(ButO) 8 Pc ligand (138 mg) and Re 2 (CO) 10 (123.8 mg), and then evacuate and fill with nitrogen three times, add 2.2 mL of o-dichlorobenzene, and heat the reaction mixture under reflux for more than 31 h. Monitor the reaction with UV-vis until the reaction is complete.

[0039] (2)Re 2 Purification of PC

[0040] 1. Cool to room temperature, then dissolve the reaction solution with a small amount of dichloromethane, and then add enough petroleum ether (petroleum ether and dichloromethane recrystallization), and a large amount of precipitation will be generated.

[0041] 2. Use centrifugation to centrifuge the precipitated material and retain the centrifugal liquid.

[0042] 3. After the liquid collected by centrifugation is left to stand for about 2 hours, some purple products will come out. Collect this part of the product.

[0043] 4. Dissolve the solid precipitated in step 1 again with a small amount of dichloromethane, add petroleum ether to precipitate the solid again, and wash it by centrifugation with petroleum ether 2-3 times until the centrifuged liquid is colorless. Monitor the liquid obtained by centrifugation with UV-vis to see if it is the desired product. If so, collect the liquid and spin dry it to obtain partial product.

[0044] 5. Dissolve the solid precipitated in step 4 with dichloromethane. If it is colorless, it means that the product has been completely dispersed in petroleum ether and washed clean.

[0045] 6. Combine the products from step 3 and step 4 to obtain the target product Re 2 Pc complex.

[0046] Example 2

[0047] (1)Re 2 Preparation of Pc

[0048] 1. Flame dry the Schlenk flask under nitrogen atmosphere. Flame dry the Schlenk flask, evacuate and fill with nitrogen three times, and then cool to room temperature under vacuum.

[0049] 2. Remove the flask and quickly add α-(ButO) 8 Pc ligand (138 mg) and Re 2 (CO) 10 (123.8 mg), and then evacuate and fill with nitrogen three times, add 2.2 mL of decahydronaphthalene, and heat the reaction mixture to 200°C for more than 27 hours. The reaction was monitored by UV-vis until the reaction was complete.

[0050] (2)Re 2 Purification of PC

[0051] 1. Cool to room temperature, then dissolve the reaction solution with a small amount of dichloromethane, and then add enough petroleum ether (petroleum ether and dichloromethane recrystallization), and a large amount of precipitation will be generated.

[0052] 2. Use centrifugation to centrifuge the precipitated material and retain the centrifuged liquid.

[0053] 3. After the liquid collected by centrifugation is left to stand for about 2 hours, some purple products will come out. Collect this part of the product.

[0054] 4. Dissolve the solid precipitated in step 1 again with a small amount of dichloromethane, add petroleum ether to precipitate the solid again, and wash it by centrifugation with petroleum ether 2-3 times until the centrifuged liquid is colorless. Monitor the liquid obtained by centrifugation with UV-vis to see if it is the desired product. If so, collect the liquid and spin dry it to obtain part of the product.

[0055] 5. Dissolve the solid precipitated in step 4 with dichloromethane. If it is colorless, it means that the product has been completely dispersed in petroleum ether and washed clean.

[0056] 6. Combine the products from step 3 and step 4 to obtain the target product Re 2 Pc complex.

[0057] Example 3

[0058] (1)Re 2 Preparation of Pc

[0059] 1. Flame dry the Schlenk flask under nitrogen atmosphere. Flame dry the Schlenk flask, evacuate and fill with nitrogen three times, and then cool to room temperature under vacuum.

[0060] 2. Remove the flask and quickly add α-(ButO) 8 Pc ligand (69 mg) and Re 2 (CO)10 (61.9 mg), and then evacuate and fill with nitrogen three times, add 2.2 mL of o-dichlorobenzene, and heat the reaction mixture under reflux for more than 31 h. Monitor the reaction with UV-vis until the reaction is complete.

[0061] (2)Re 2 Purification of PC

[0062] 1. Cool to room temperature, then dissolve the reaction solution with a small amount of dichloromethane, and then add sufficient amount of n-hexane (n-hexane and dichloromethane recrystallization), and a large amount of precipitate will be produced.

[0063] 2. Use centrifugation to centrifuge the precipitated material and retain the centrifugal liquid.

[0064] 3. After the collected liquid is left to stand for about 2 hours, some purple products will come out. Collect this part of the product.

[0065] 4. Dissolve the solid precipitated in step 1 again with a small amount of dichloromethane, then add n-hexane to precipitate the solid again, and wash it with n-hexane by centrifugation 2-3 times until the centrifuged liquid is colorless. Monitor the liquid obtained by centrifugation with UV-vis to see if it is the desired product. If so, collect the liquid and spin dry it to obtain part of the product.

[0066] 5. Dissolve the solid precipitated in step 4 with dichloromethane. If it is colorless, it proves that the product has been completely dispersed in n-hexane and washed clean.

[0067] 6. Combine the products from step 3 and step 4 to obtain the target product Re 2 Pc complex.

[0068] The above description of the embodiments is to facilitate the understanding and use of the present invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments. Improvements and modifications made by those skilled in the art based on the principles of the present invention without departing from the scope of the present invention should be within the protection scope of the present invention.

Claims

1. A phthalocyanine rhenium complex, whose molecular formula is Re 2 Pc, the structural formula is shown in Formula I:

2. The method for preparing the phthalocyanine rhenium complex according to claim 1, It is characterized in that Its synthetic route is shown in Formula II: The following steps are involved: Step 1: Flame dry the Schlenk flask under nitrogen atmosphere, evacuate and refill with nitrogen three times, and then cool to room temperature under vacuum; Step 2: Remove the flask and quickly add Pc ligand and Re 2 (CO) 10 , evacuate and fill with nitrogen three times, add o-dichlorobenzene, and heat the reaction mixture under reflux for more than 31 hours, while monitoring the reaction by UV-visible absorption spectroscopy until the reaction is complete; Step 3: The reaction solution is cooled to room temperature, then a small amount of dichloromethane is used to dissolve the reaction solution, and then a sufficient amount of petroleum ether is added for recrystallization, and a large amount of precipitation is generated; Step 4: centrifuge to remove the precipitated material and retain the centrifuged liquid; Step 5: The liquid collected by centrifugation is allowed to stand for 1-3 hours, and the purple product is collected; Step 6: The solid precipitated in step 3 is dissolved again with a small amount of dichloromethane, petroleum ether is added to precipitate the solid again, and the solid is washed by centrifugation with petroleum ether for 2-3 times until the centrifuged liquid is colorless. The ultraviolet-visible absorption spectrum is used to monitor whether the liquid obtained by centrifugation is the desired product. If so, the liquid is collected and spin-dried to obtain a partial product; Step 7: Dissolve the solid precipitated in step 6 with dichloromethane. If it is colorless, it means that the product has been completely dispersed in petroleum ether and washed clean; Step 8: Combine the partial products collected in steps 5 and 6 to obtain the target product Re 2 Pc complex; Among them, Pc ligand, Re 2 (CO) 10 The molar volume ratio of o-dichlorobenzene is 0.0632mmol:0.0948mmol:2.2mL.

3. Use of the rhenium phthalocyanine complex according to claim 1 in the preparation of a photothermal conversion agent for photothermal therapy.

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