A fat-targeted photothermal weight loss phototherapy agent and its application

Abstract

This invention discloses a fat-targeted photothermal weight loss phototherapeutic agent and its application, belonging to the field of nanobiomedical diagnosis and treatment technology. This phototherapeutic agent is end-group modified with six water-soluble cations, and its core skeleton is a conjugated near-infrared region II dye. By directly dissolving an ionic, water-soluble phototherapeutic small molecule in water, a fat cell-enriching phototherapeutic agent is obtained. This increases the agent's retention time in adipose tissue and achieves weight loss after irradiation.

Description

Technical Field

[0001] The invention discloses a fat-targeted photothermal weight loss photodiagnostic agent and application thereof, belonging to the technical field of nano-biomedical diagnosis and treatment. Background Art

[0002] Obesity (i.e., the excessive accumulation of adipose tissue) is a growing public health concern and is associated with numerous fatal diseases, including type 2 diabetes, fatty liver disease, stroke, myocardial infarction, and certain types of cancer. Common treatments for obesity include diet control, weight-loss medications, and bariatric surgery, but these approaches require strict self-management or are significantly limited by side effects. To address the obesity epidemic, there is an urgent need to discover promising approaches for safe and effective weight loss. Recently, researchers have demonstrated weight loss in mice and humans by activating beige fat through localized heating of the dorsal neck fat. However, existing materials for fat heating suffer from shortcomings such as a lack of targeting, wavelengths in the visible light range, and a lack of imaging capabilities.

[0003] Near-infrared light above 800 nanometers has a greater depth of penetration into biological tissues than traditional light, effectively enhancing the effectiveness of photothermal therapy for obesity. Near-infrared second-zone fluorescence imaging in the 1000-1700 nanometer range offers low autofluorescence and weaker scattering in biological tissues, effectively enabling high signal-to-noise ratio fluorescence imaging of adipose tissue in vivo. However, currently, organic molecules targeted for near-infrared second-zone fluorescence imaging suffer from limitations such as low water solubility and insufficient fat-targeting enrichment. Summary of the Invention

[0004] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a fat-targeted photothermal weight loss phototherapeutic agent and its application, thereby improving the water solubility and fat-targeting ability of the phototherapeutic agent and enhancing the photothermal weight loss effect.

[0005] To achieve the above object, the present invention is implemented by adopting the following technical solutions:

[0006] A water-soluble ionic organic molecule, wherein the water-soluble ionic organic molecule is a compound of formula (I), and the structural formula of the compound of formula (I) is as follows:

[0007]

[0008] Formula (I).

[0009] Furthermore, the water-soluble ionic organic molecule conjugated structure core is a near-infrared second region fluorescent dye, and the near-infrared second region fluorescent dye is 4,8-benzene(5-bromo-4(2-octyldodecyl)benzo[1,2,5]thiadiazole (BBTD).

[0010] Furthermore, the water-soluble ionic organic molecule contains six water-soluble quaternary ammonium salt cationic side groups.

[0011] The present invention also provides a method for preparing the above-mentioned water-soluble ionic organic molecules, comprising the following steps:

[0012]

[0013]

[0014] Furthermore, the method includes the following steps: under nitrogen protection, adding 4,8-benzene (5-bromo-4 (2-octyldodecyl) benzobenzo [1,2,5] thiadiazole (BBTD), 4,4,5,5-tetramethyl-2- (3,4,5-tris ((6-bromohexyl) oxy) phenyl) -1,3,2-dioxaborolane, and tetrakis (triphenylphosphine) palladium to a solvent, mixing and uniformly stirring, heating the mixture to react, adding a potassium carbonate aqueous solution and further heating the mixture to react, stopping the reaction, extracting and rotary evaporating, and then purifying by column chromatography to obtain BBTD-3C; mixing BBTD-3C and a tetrahydrofuran solution, placing the reaction solution in an acetone dry ice system for cooling, slowly adding a trimethylamine THF solution dropwise, and continuously stirring; after stirring, placing the mixture in a constant temperature oil bath for reaction, and evaporating the solvent under vacuum to obtain a water-soluble ionic organic molecule.

[0015] Furthermore, the mixture after the trimethylamine THF solution is added dropwise is placed in a constant temperature oil bath, the temperature is maintained at 45-55° C., and the reaction is carried out for 70-80 hours. The solvent is evaporated under vacuum to obtain a water-soluble ionic organic molecule.

[0016] The present invention also provides a fat-targeted photothermal weight loss phototherapy agent, which includes the above-mentioned water-soluble ionic organic molecules.

[0017] Furthermore, the water-soluble ionic organic molecules are dissolved in water.

[0018] Furthermore, the concentration of the water-soluble ionic organic molecules is 1.0 to 10 mg / mL.

[0019] The present invention also provides the use of the above-mentioned water-soluble ionic organic molecules or the above-mentioned fat-targeted photothermal weight loss phototherapeutic agent in the preparation of a weight loss phototherapeutic agent.

[0020] Furthermore, the weight loss phototherapy agent includes the aforementioned water-soluble ionic organic molecule-acceptable gel, microneedles or excipients.

[0021] Furthermore, the weight loss phototherapy agent is used to reduce the degree of expansion of adipose tissue.

[0022] Furthermore, the weight loss phototherapy agent is an injection.

[0023] Beneficial effects

[0024] The present invention provides a near-infrared two-window water-soluble ionic organic molecule, which can target fat and accumulate in fat cells. Combined with two-zone fluorescence imaging, it can effectively identify fat tissue in the body. Near-infrared absorption and excellent photothermal effect enable it to have a good photothermal weight loss effect.

[0025] The present invention provides a method for preparing a fat-targeted water-soluble photothermal weight loss phototherapeutic agent, which directly dissolves the water-soluble ionic organic molecules in water and assembles them in an aqueous solution. The preparation method is simple and can be used as a phototherapeutic agent to achieve near-infrared photothermal weight loss for obesity.

[0026] The water-soluble ionic organic molecule in the present invention contains 6 water-soluble quaternary ammonium salt cationic side groups, and the core of the 6-arm water-soluble ionic organic molecule is a near-infrared zone II fluorescent molecule; the prepared photothermal weight loss photodiagnostic agent can track the state of fat compared to the near-infrared zone II fluorescence imaging characteristics in the prior art, has higher water solubility, smaller size, better fat targeted enrichment ability, up to one month of in vivo fat enrichment and stronger near-infrared excitation photothermal ability, greatly improving the weight loss effect on obese tissue. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a dynamic light scattering diagram of the aqueous solution of the photothermal weight loss phototherapy agent in Example 1 of the present invention;

[0028] Figure 2 This is a dynamic light scattering diagram of the aqueous solution of the photothermal weight loss phototherapy agent in Example 2 of the present invention;

[0029] Figure 3 This is a dynamic light scattering diagram of the aqueous solution of the photothermal weight loss phototherapy agent in Example 3 of the present invention;

[0030] Figure 4 This is a transmission electron microscopy image of an aqueous solution of the photothermal weight loss phototherapy agent in Example 1 of the present invention;

[0031] Figure 5 This is the absorption and emission spectra of the aqueous solution of the photothermal weight loss phototherapy agent in Example 1 of the present invention;

[0032] Figure 6 This is a photothermal effect diagram of the photothermal weight loss phototherapy agent according to Example 2 of the present invention;

[0033] Figure 7 This is a near-infrared second-zone fluorescence imaging image of adipose tissue under 808-nm laser excitation of an aqueous solution of a photothermal weight loss photodiagnostic agent according to Example 3 of the present invention;

[0034] Figure 8This is a diagram showing the changes in fat tissue after the aqueous solution of the photothermal weight loss phototherapy agent in Example 3 of the present invention is treated with 808 nm laser photothermal treatment. DETAILED DESCRIPTION

[0035] The present invention will be further described below in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention.

[0036] The present invention provides a water-soluble ionic organic molecule, the structural formula of the water-soluble ionic organic molecule is as follows:

[0037]

[0038] Formula (I)

[0039] Further description, the preparation method of the compound of formula (I) comprises the following steps:

[0040]

[0041]

[0042] a. Under nitrogen protection, add 4,8-phenyl(5-bromo-4(2-octyldodecyl)benzobenzo[1,2,5]thiadiazole (BBTD) (73.19 mg, 100 μmol), 4,4,5,5-tetramethyl-2-(3,4,5-tris((6-bromohexyl)oxy)phenyl)-1,3,2-dioxaborolane) (3C) (222.37 mg, 300 μmol), tetrakis(triphenylphosphine)palladium (Pd(pph3)4) (4.0 mg, 0.64 μmol), and anhydrous toluene (5.0 mL) into a 25 mL round-bottom flask and stir with a magnetic stir bar.

[0043] b. After evacuating the mixture with nitrogen using a double-row tube, heat the mixture to 60°C in the dark and allow it to react for 30 minutes before adding 2.5 ml of a potassium carbonate aqueous solution (K2CO3, 2 mol / L).

[0044] c. Further heating to 90°C and reacting for 10 hours;

[0045] d. After the reaction was terminated, the crude product was extracted three times with dichloromethane and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The product was then purified by column chromatography to obtain a green powder product BBTD-3C (159.1 mg, 74% yield);

[0046] e. Under nitrogen, add BBTD-3C (50 mg, 23.3 μmol), the product from the previous step, to a 5 mL round-bottom flask containing 2 mL of tetrahydrofuran (THF). Cool the reaction mixture in acetone / dry ice for 20 minutes. Slowly add trimethylamine (25 wt%, 1 mL) in THF dropwise, and continue stirring for 2 hours.

[0047] f. The reaction system was placed in a thermostatic oil bath at 50°C for 72 hours, and then the solvent was evaporated under vacuum to obtain product (I) (42.6 mg, yield 85%).

[0048] The present invention provides a method for preparing a photothermal weight loss phototherapy agent:

[0049] The product (I) water-soluble ionic organic molecules are directly dissolved in water to obtain a high-fat targeted photothermal weight loss phototherapy agent.

[0050] Example 1: The concentration of the prepared phototherapy agent is 1.0 mg / ml, that is, the concentration of the water-soluble ionic organic molecules is 1.0-10 mg / ml.

[0051] Example 2: The concentration of the prepared phototherapy agent is 5.0 mg / ml, that is, the concentration of the water-soluble ionic organic molecules is 1.0-10 mg / ml.

[0052] Example 3: The concentration of the prepared phototherapy agent is 10 mg / ml, that is, the concentration of the water-soluble ionic organic molecules is 1.0-10 mg / ml.

[0053] Benru Figure 1 、 Figure 2 and Figure 3 As shown, they are dynamic light scattering diagrams of the aqueous solutions of the photothermal weight loss phototherapy agents in Examples 1 to 3, respectively. According to the dynamic light scattering diagrams, the hydrodynamic diameters of the photothermal weight loss phototherapy agents in Examples 1, 2 and 3 are approximately 45.6, 30.1 and 24.2 nanometers, respectively.

[0054] like Figure 4 , is a transmission electron microscopy image of the aqueous solution of the photothermal weight loss phototherapeutic agent in Example 1. The transmission electron microscopy images of these three photothermal weight loss phototherapeutic agents show that the particle sizes of the photothermal weight loss phototherapeutic agents are all in the range of 10 to 50 nanometers, and are all spherical.

[0055] like Figure 5 As shown in the absorption and emission spectra of the photothermal weight loss phototherapy agent of Test Example 1, it can be seen that its ultraviolet-near infrared absorption is in the range of 600-900 nanometers, while the emission peak is above 1000 nanometers, with obvious near-infrared second region emission signals.

[0056] like Figure 6As shown in the photothermal effect diagram of the photothermal weight loss phototherapy agent of test example 2, it can be seen that the temperature of the aqueous solution rises significantly under the irradiation of 808 nm laser, and has a significant photothermal effect.

[0057] like Figure 7 As shown, the near-infrared zone II fluorescence imaging diagram of the fat-targeted enrichment of the photothermal weight loss phototherapeutic agent in test example three, high-fat fed mice, 100 μL of 5.0 mg / mL Example three photothermal weight loss phototherapeutic agent was injected subcutaneously in the groin, and the signal intensity change diagram of the fat position of the mice was observed using a near-infrared zone II imager. It can be seen from the figure that the fat tissue has obvious near-infrared zone II fluorescence signal, and the imaging signal shows that the phototherapeutic agent can be enriched in the fat for one month.

[0058] like Figure 8 The following figure shows the weight loss effect of the photothermal weight loss phototherapy agent in Example 3. High-fat-fed mice were subcutaneously injected with 100 μL of a 5.0 mg / mL dose of the photothermal weight loss phototherapy agent in Example 3. The figure shows that after 20 minutes of 808-nm laser irradiation twice a week for four weeks, followed by a 60% high-fat diet, adipose tissue expansion was significantly reduced. Body weight increased from 37.8 ± 0.5 g to 40.7 ± 1.3 g (11 mice per group). Subcutaneous injection of a standard solvent and 20 minutes of 808-nm laser irradiation increased body weight from 37.8 ± 0.4 g to 48.3 ± 1.3 g (11 mice per group).

[0059] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. The use of water-soluble ionic organic molecules in the preparation of a weight loss phototherapy agent, characterized in that: The water-soluble ionic organic molecule is a compound of formula (I), and the structural formula of the compound of formula (I) is as follows: 。 2. The use according to claim 1, characterized in that The water-soluble ionic organic molecule conjugated structure core is a near-infrared second-region fluorescent dye, and the near-infrared second-region fluorescent dye is 4,8-phenyl(5-bromo-4(2-octyldodecyl)benzo[1,2,5]thiadiazole.

3. The use according to claim 1, characterized in that The water-soluble ionic organic molecule contains six water-soluble quaternary ammonium salt cationic side groups.

4. The use according to claim 1, characterized in that The water-soluble ionic organic molecules are dissolved in water.

5. The use according to claim 4, characterized in that The concentration of water-soluble ionic organic molecules is 1.0~10mg / mL.

6. The use according to claim 1, characterized in that The weight loss phototherapy agent includes a gel, microneedle or excipient acceptable to the water-soluble ionic organic molecules.

7. The use according to claim 1, characterized in that The slimming phototherapy agent is used to reduce the degree of expansion of adipose tissue.

8. The use according to claim 1, characterized in that The weight loss phototherapy agent is an injection.

Images