An organic small-molecule radical photothermal material, a preparation method and application thereof

Abstract

The application discloses an organic small-molecule radical photothermal material taking croconic acid as a receptor unit and a preparation method and application thereof. The organic small-molecule radical photothermal material has the structure shown in the figure. The organic small-molecule radical photothermal material prepared by the application has an absorption peak of about 850 nm in a solution, and an absorption of about 2000-2500 nm in a solid state, has super-wide solar spectrum absorption and high photothermal conversion efficiency, and can be applied to solar-driven water volatilization, photothermal-electric conversion, photoacoustic imaging and photothermal therapy and the like, and has very wide application prospects.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic functional molecules, in particular, to an organic small molecule radical photothermal material and a preparation method and application thereof. BACKGROUND

[0002] Organic functional molecules have wide application value in the fields of energy, information, and biological medicine. In the field of medicine, organic near-infrared absorbing dyes are a very promising diagnostic and therapeutic agent for tumor diagnosis and treatment. In the near-infrared spectral range, the spontaneous fluorescence of organ tissues is low, and the light scattering is low, so the near-infrared fluorescence imaging has higher sensitivity and lower background. In addition, the near-infrared light has a deeper tissue penetration ability, and the near-infrared absorbing organic functional molecules with photothermal conversion energy can also be used as photothermal agents for photoacoustic imaging and photothermal therapy, so it is of great significance to design and prepare organic functional molecules with near-infrared absorption.

[0003] At present, there are various materials with near-infrared absorption and photothermal conversion. Noble metal nanoparticles such as Au, Pt, etc. have high photothermal conversion efficiency but are expensive; carbon materials such as graphene, carbon nanotubes, etc. have high photothermal conversion efficiency, but have poor near-infrared absorption and are not easy to metabolize in the body; metal and non-metal compounds such as CuS, ZnS, etc. have high photothermal conversion efficiency but are not easy to metabolize and are harmful to the body. Compared with the above-mentioned materials, organic small molecule photothermal materials have better biocompatibility, potential biodegradability, simple processing method, and easy adjustment of structure and performance. Therefore, through reasonable structure design, the absorption wavelength of the organic molecule can be conveniently and effectively regulated to obtain an organic small molecule material with near-infrared absorption. SUMMARY

[0004] The technical problem solved by the present application is to provide a series of structures of D-A-D type organic near-infrared absorbing organic small molecule photothermal systems based on croconic acid acceptor units, and a preparation method and application thereof.

[0005] Croconic acid, as a five-membered ring molecule, has strong electron-withdrawing property. According to reports, the absorption of 1,3-symmetrically substituted croconic acid derivatives is mostly around 800 nm, which has good near-infrared absorption. Therefore, croconic acid is an effective acceptor unit for preparing organic molecules with infrared absorption. When a donor unit is introduced on croconic acid to construct a molecule with a donor-acceptor (D-A) structure, the aggregation state of the double free radical characteristics and intramolecular electron transfer can be induced, and the electronic energy gap can be reduced to promote the red shift of the spectrum of the organic molecule.

[0006] The organic small molecule described in the present application has the characteristics of aggregation state stable double free radical, excellent near-infrared absorption, and high-efficiency photothermal conversion efficiency, and has good biocompatibility and stability.

[0007] In the technical solution provided by the present application, the small molecule with the characteristics of organic near-infrared absorption and photothermal conversion is a series of 1,3-substituted croconic acid derivatives with electron-donating D units as substituents and croconic acid as A unit. The series of derivatives are formed by condensation of croconic acid A unit and D unit with electron-donating ability. The present application also provides a preparation method and application of the organic photothermal small molecule containing a croconic acid nucleus.

[0008] One of the objectives of the present application is to provide an organic small molecule radical photothermal material with the following structure shown in formula (I):

[0009]

[0010] wherein n is 0 or 1 or 2 or 3, D is a conjugated unit with electron-donating ability; R1 is hydrogen, alkyl or alkoxy; X is a heteroatom such as nitrogen (N), oxygen (O), sulfur (S), selenium (Se), tellurium (Te) and the like.

[0011] In the D-A-D type near-infrared organic photothermal small molecule based on the croconic acid nucleus of the present application, the five-membered heterocycle is a π-connection unit.

[0012] Preferably, R1 is hydrogen, C1-C24 alkyl or C1-C24 alkoxy; more preferably, R1 is hydrogen, C1-C12 alkyl or C1-C12 alkoxy.

[0013] Preferably, D can have the following structure:

[0014]

[0015] wherein R2 is H, -C m H 2m+1 , -OC m H 2m+1 , -SC m H 2m+1 ; m is an integer of 1-24, preferably an integer of 1-12.

[0016] Specifically, R2 can be a linear or branched alkyl group, an alkoxy group and the like, for example, can be the following structure:

[0017]

[0018] When D has the following structure: , specifically can be the following structure:

[0019]

[0020] wherein R2 is H, -C m H2m+1 -OC m H 2m+1 -SC m H 2m+1 .

[0021] The second object of the present application is to provide a preparation method of the organic small molecule radical photothermal material, which comprises reacting a compound containing an electron-donating D group with a croconic acid monomer.

[0022] The compound containing the electron-donating D group has the following structure shown in formula (II):

[0023]

[0024] wherein n is 0 or 1 or 2 or 3, D is a conjugated unit having an electron-donating ability; R1 is hydrogen, an alkyl group or an alkoxy group; X is nitrogen, oxygen, sulfur, selenium or tellurium.

[0025] Preferably, R1 is hydrogen, a C1-C24 alkyl group or a C1-C24 alkoxy group; more preferably, R1 is hydrogen, a C1-C12 alkyl group or a C1-C12 alkoxy group.

[0026] The molar ratio of the compound containing the electron-donating D group to the croconic acid is (2-2.5):1, preferably (2.1-2.3):1.

[0027] The preparation method of the D-A-D type near-infrared absorbing organic small molecule radical photothermal system based on the croconic acid core of the present application has the following reaction route:

[0028]

[0029] The preferred reaction conditions are as follows: under anhydrous and anaerobic conditions, the compound containing the electron-donating D group, the croconic acid and the mixed solution of toluene / n-butanol are mixed, and reacted at 80-140℃ for 1-12h to obtain the organic small molecule radical photothermal material.

[0030] In the mixed solution of toluene / n-butanol, the volume ratio of toluene to n-butanol is 1:(0.5-2), more preferably 1:(1-1.5).

[0031] According to a preferred embodiment of the present application, the molar ratio of the electron-donating D group substituted thiophene to the croconic acid is (2-2.5):1, and under anhydrous and anaerobic conditions, toluene / n-butanol mixed solution is added, and refluxed at 100-135℃ for 1-12h, and the solvent is concentrated to obtain the target product.

[0032] The separation method can use column chromatography and other common separation methods.

[0033] The third object of the present application is to provide the application of the D-A-D type of the small molecule organic radical photothermal material based on croconic acid in the field of seawater desalination, such as solar-driven water evaporation.

[0034] The fourth object of the present application is to provide the application of the D-A-D type of the small molecule organic radical photothermal material based on croconic acid in the field of photoacoustic imaging (PA).

[0035] The fifth object of the present application is to provide the application of the D-A-D type of the small molecule organic radical photothermal material based on croconic acid in the field of photothermal therapy (PTT).

[0036] The sixth object of the present application is to provide the application of the D-A-D type of the small molecule organic radical photothermal material based on croconic acid in the field of photothermal electric conversion, such as the heat collection of solar thermal generator.

[0037] Compared with the prior art, the small molecule organic radical photothermal system of the present application is prepared by reacting croconic acid as an acceptor unit A with different electron donor units D, and has the advantages of simple and convenient preparation method, and various structures easy to adjust. The small molecule organic radical photothermal material has the characteristics of double radicals, enhanced non-radiative transition, more red-shifted absorption spectrum, and absorption range reaching the near-infrared region, and has excellent photothermal conversion performance.

[0038] The small molecule organic radical photothermal material prepared by the present application has an absorption peak of about 850 nm in solution, and an absorption of about 2000-2500 nm in solid state, and has super-wide solar spectrum absorption and high-efficiency photothermal conversion efficiency.

[0039] The D-A-D type of the small molecule organic radical photothermal system based on croconic acid is used for photoacoustic imaging and photothermal therapy, so that the mouse tumor cells have very strong photoacoustic signals, and good treatment effect can be achieved, and the problems of large toxicity or difficulty in being discharged from the biological body of precious metals, carbon materials and metal-nonmetal composite materials are solved, and the croconic acid D-A-D type of the small molecule organic radical photothermal material has good application prospect.

[0040] The small molecule organic radical photothermal system containing croconic acid of the present application is used as a water evaporation heat source, and the water mass loss can reach 1.2 kg / m 2 under the light intensity of 1000 W / m 2 . The small molecule organic radical photothermal system is used as a heat generating material for a thermoelectric generator, and has high heat generation and good stability. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 is the product of example 11 HNMR spectrum.

[0042] Figure 2 HNMR spectrum of the product of Example 2. 1 HNMR spectrum.

[0043] Figure 3 HNMR spectrum of the product of Example 3. 1 HNMR spectrum.

[0044] Figure 4 HNMR spectrum of the product of Example 4. 1 HNMR spectrum.

[0045] Figure 5 Solution absorption spectrum of D-A-D type organic small molecule radical photothermal system of Examples 1-5.

[0046] Figure 6 Solid powder absorption spectrum of D-A-D type organic small molecule radical photothermal system of Examples 1-5.

[0047] Figure 7 Variable-temperature electron paramagnetic resonance spectrum of D-A-D type organic radical small molecule CR-DPA-T solid powder.

[0048] Figure 8 Temperature rise curve of D-A-D type organic small molecule radical photothermal system of Examples 1-5 under 808 nm laser irradiation of 1.2 W / cm 2

[0049] Figure 9 4T1 cell toxicity test results.

[0050] Figure 10 Under 808 nm near-infrared light irradiation of 0.8 W / cm 2

[0051] Figure 11 Mouse tumor pictures.

[0052] Figure 12 Output performance of flexible solar photothermal electric generator covered with CR-DPA-T molecule under five sun irradiation.

[0053] Figure 13 Charging performance of lithium ion battery by flexible solar photothermal electric generator covered with CR-DPA-T molecule under five sun irradiation. DETAILED DESCRIPTION

[0054] ​​The preparation and application of the preparation and application of the D-A-D type near-infrared absorbing organic small molecule radical photothermal system based on croconic acid of the present application will be described in detail below in conjunction with specific embodiments. It is necessary to point out here that the following embodiments are only used to further illustrate the present application and cannot be understood as limiting the protection scope of the present application. Some non-essential improvements and adjustments made by those skilled in the art to the present application according to the content of the present application still fall within the protection scope of the present application.

[0055] The raw materials used in the examples and comparative examples, if not specifically limited, are disclosed in the prior art, for example, can be directly purchased or prepared according to the preparation method disclosed in the prior art.

[0056] Example 1:

[0057]

[0058] 1 mmol of croconic acid and 2.2 mmol of 4,4-dimethoxydiphenylamine thiophene were added to a two-necked flask, ensuring anhydrous and oxygen-free environment, 50 ml of a mixed solution of toluene / n-butanol with a volume ratio of 1:1 was added, the solution was refluxed at 110°C for 12 hours, the organic solvent was distilled off under vacuum, and the target product CR-DPA-T was separated by silica gel column chromatography.

[0059] Example 2:

[0060]

[0061] 1 mmol of croconic acid and 2.2 mmol of 2TPE-OMe-T were added to a two-necked flask, ensuring anhydrous and oxygen-free environment, 50 ml of a mixed solution of toluene / n-butanol with a volume ratio of 1:1 was added, the solution was refluxed at 110°C for 1 hour, the organic solvent was distilled off under vacuum, and the target product CR-2TPE-2OMe-SF was separated by silica gel column chromatography.

[0062] Example 3:

[0063]

[0064] 1 mmol of croconic acid and 2.2 mmol of TPE-Ph-T-1 were added to a two-necked flask, ensuring anhydrous and oxygen-free environment, 50 ml of a mixed solution of toluene / n-butanol with a volume ratio of 1:1 was added, the solution was refluxed at 110°C for 12 hours, the organic solvent was distilled off under vacuum, and the target product CR1 was separated by silica gel column chromatography.

[0065] Example 4:

[0066]

[0067] Into a two-necked flask, 1 mmol of ketonic acid and 2.2 mmol of TPE-Ph-T-2 were added, and 50 ml of a 1:1 mixture of toluene / n-butanol was added to ensure anhydrous and oxygen-free environment. The solution was refluxed at 110°C for 12 hours. The organic solvent was distilled under vacuum, and the target product CR2 was separated by silica gel column chromatography.

[0068] Example 5

[0069] A 1 cm wide quartz cuvette was selected, 3 ml of 10 -5 The THF solutions of the ketonic acid-based D-A-D organic small molecule radical photothermal systems in Example 1, Example 2, Example 3, and Example 4 of M were tested for UV-Vis absorption spectrum. As shown in Figure 5 The maximum solution absorption of the series of ketonic acid-based D-A-D type organic small molecule radical photothermal systems was in the range of 450 nm-1100 nm, and the maximum absorption was around 860 nm. Figure 6 For the solid state powder of the series of molecules, the absorption edge was as long as about 1950 nm.

[0070] Example 6

[0071] The ketonic acid-based D-A-D type organic small molecule powder in Example 1 was treated for water and oxygen removal at temperatures of 195 K, 175 K, 155 K, 135 K, 115 K, and 95 K, and its paramagnetic resonance spectrum was tested. As shown in Figure 7 The small molecule showed obvious carbon radical signal, and the paramagnetic signal increased with the decrease of temperature, showing high spin characteristics.

[0072] Example 7

[0073] The ketonic acid-based D-A-D organic small molecule radical photothermal systems in Example 1, Example 2, Example 3, and Example 4 were irradiated with 0.8 W / cm 2 The 808 nm laser as a light source, and the temperature change was recorded by an infrared camera to test the photothermal conversion performance of each molecule. As shown in Figure 8 The series of ketonic acid-based D-A-D type organic small molecule radical photothermal systems reached the highest temperature within 20 s, and the highest temperature was as high as 140°C.

[0074] Example 8

[0075] The organic radical small molecule of Example 3 was prepared into nanoparticles and its cytotoxicity was tested. In order to study the killing effect of free drug and drug-loaded carriers on tumor cells, we studied the effect of different concentration gradients of free drug and drug-loaded nanoparticles on tumor cells after administration, and also studied the cytotoxicity of drug-loaded nanoparticles with different degrees of modification and under different pH conditions. The results of 4T1 cell toxicity test are as follows Figure 9 .

[0076] According to the results Figure 9 , we can see that the toxicity of free chemotherapy drug GA to 4T1 cells is very large, and the IC50 value is as low as 0.3081. The toxicity of drug-loaded nanoparticles formed by loading GA into amphiphilic polymers is much lower than that of free drug, with an IC50 of 2.5621. The toxicity of drug-loaded nanoparticles after polymer loading has a significant gradient toxicity compared to free drug. After polymer loading, the particle size of the drug nanoparticles increases, endocytosis decreases, and toxicity decreases. The toxicity of free photothermal molecules and empty micelles is very low, which proves that the biological safety of polymer carriers and photothermal molecules is good, reducing the toxic side effects in treatment. The toxicity of PEG-modified drug-loaded nanoparticles is not as good as that of unmodified ones. This may be because the PEG wrapping shields the positive charge on the surface of the drug-loaded nanoparticles, reducing the electrostatic interaction between the drug-loaded nanoparticles and the negatively charged cells, and reducing the internalization of the drug-loaded nanoparticles in the tumor. At pH 6.8, due to the breakage of the Schiff base under acidic conditions and the protonation of the amine group, the PEG and iRGD on the surface of the drug-loaded nanoparticles fall off, exposing the positive charge on the surface of the carrier, increasing the internalization of the drug-loaded nanoparticles in tumor cells. The toxicity of the modified drug-loaded nanoparticles is greater than that at pH 7.2.

[0077] Example 9

[0078] In the process of chemotherapy-photothermal synergistic inhibition of tumor tissue growth in tumor-bearing mice, we used 0.8 W / cm 2 of 808 nm near-infrared light for photothermal treatment of the tumor tissue of mice, and used a thermal imaging camera to detect the temperature change of the tumor site. The temperature rise effect of the tumor site during irradiation is as follows Figure 10 .

[0079] From Figure 10 we can see that the photothermal nanoparticles can be well enriched in the tumor site after being injected into the mouse body through the tail vein, and under the irradiation of 0.8 W / cm 2 of 808 nm near-infrared light, a good photothermal heating effect can be achieved, and finally a platform temperature of 50°C is reached. For the nanocarriers without photothermal molecules, under the irradiation of 0.8 W / cm 2808 nm near-infrared light for 10 min and then kept at 37 °C, the normal body temperature, which also verified the low-power near-infrared light irradiation has no side effects on normal tissues, and can be used for the photothermal therapy to increase the safety of the treatment.

[0080] From the change of tumor volume during the treatment, the tumor volume of the photothermal therapy group decreased significantly. At the second heat exchange treatment, the tumor collapsed and became a small black pit. After 24 h of irradiation, the tumor site became a hard black scab. During the subsequent continuous treatment, the tumor cells of the photothermal group did not have the opportunity to relapse. For the pure chemotherapy group, the tumor volume of the overall chemotherapy group increased very slowly. After the treatment, the tumor of the mouse hardly grew. The low-dose administration can inhibit the growth of the tumor and play a certain control role in clinical treatment to prevent the growth of the tumor. Then, the photothermal therapy is performed to control the cell growth and find the tumor location. Finally, the chemotherapy and photothermal therapy are combined to eliminate the tumor cells synergistically. Figure 11 From the above, we can see that the chemotherapy-photothermal synergistic therapy can indeed inhibit the growth of the tumor.

[0081] Example 10

[0082] First, the commercial 1.5 mm x 1.5 mm x 3 mm semiconductor thermoelectric elements (TE) were arranged in a 7 x 10 array in a polytetrafluoroethylene mold with a spacing of 2.5 mm between adjacent elements. Then, Ecoflex 00-50A / B (Smooth-On) was poured into the mold and cured to fix the TE elements. The Ecoflex layer with the TE column embedded after curing was taken out of the mold. Next, 65 μm thick Cu thin films were cut into individual electrodes and soldered to the TE column array in series. Then, 40 mg of the CR-DPA-T organic photothermal molecule in Example 1 and 42 mg of triformylmethane molecules were dissolved in 2 ml of dichloromethane solution, and the above solution was mixed with 2 g of amino-terminated polymethylsiloxane (NH2-PDMS-NH2) uniformly, poured into a polytetrafluoroethylene mold and left for 4 hours to form a film. The film was covered on one side of the Ecoflex layer with the series TE column embedded, and the other side of the layer was poured with an Ecoflex 00-50A / B (Smooth-On) / AlN with an AlN powder volume content of 26% and cured. Finally, the three-layer solar thermoelectric device was cut into a solar thermoelectric device with a size of 4.3 cm x 4 cm. After the three solar thermoelectric devices were connected in series, the output power curve was tested under 5 suns, as shown in FIG. 8, and the maximum output power reached 13.75 mW. Figure 12

[0083] Example 11

[0084] ​The solar thermoelectric generator prepared in Example 10 was connected across a commercial lithium-ion battery after being boosted by a transformer to achieve charging of the lithium-ion battery, as shown in Figure 13 FIG. 6.

Claims

1. An organic small molecule radical photothermal material, having the following structure shown in formula (I): wherein n is 1, R1 is hydrogen, and X is sulfur. （I）， wherein 2. A preparation method of the organic small molecule radical photothermal material according to claim 1, comprising reacting a compound containing an electron-donating D group with croconic acid. D is wherein R2is H, -OC m H 2m+1 m is an integer from 1 to 12; or, D is wherein R2is OCH3; or, D is wherein R2is OCH3. The compound containing the electron-donating D group has the following structure shown in formula (II):

3. The preparation method according to claim 2, characterized in that: (I), (II), wherein, n, D, R 1、 X are identical with n, D, R1, X of claim 1. The molar ratio of the compound containing the electron-donating D group to croconic acid is (2-2.5):

1.

4. The preparation method according to claim 3, characterized in that: The molar ratio of the compound containing the electron-donating D group to croconic acid is (2.1-2.3):

1.

5. The preparation method according to any one of claims 2-4, characterized in that: The compound containing the electron-donating D group, croconic acid, and a mixed solution of toluene / n-butanol are mixed under anhydrous and anaerobic conditions, and reacted at 80-140℃ for 1-12h to obtain the organic small molecule radical photothermal material.

6. The application of the organic small molecule radical photothermal material according to claim 1 in the field of seawater desalination, which is solar-driven water evaporation.

7. The application of the organic small molecule radical photothermal material according to claim 1 in the field of photoacoustic imaging, which is not related to the diagnosis and treatment of diseases.

8. The application of the organic small molecule radical photothermal material according to claim 1 in the field of photo-thermal-electric conversion, which is not related to the diagnosis and treatment of diseases.

9. The application according to claim 8, characterized in that: The application is the application of a solar thermal generator for heat collection. ​

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