Fat-targeted photo-thermal weight-losing light diagnosis and treatment agent and application thereof

Abstract

The invention discloses a fat-targeted photo-thermal weight-losing light diagnosis and treatment agent and application thereof, and belongs to the technical field of nano biomedical diagnosis and treatment. The end group of the light diagnosis and treatment agent is modified with six water-soluble cations, the core skeleton of the light diagnosis and treatment agent is a conjugated near-infrared two-zone dye, the light diagnosis and treatment agent with an adipocyte enrichment function is obtained by directly dissolving ionic water-soluble light diagnosis and treatment small molecules in water, the retention time of the light diagnosis and treatment agent in adipose tissues is prolonged, and the weight losing function is achieved after fat illumination.

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., excessive accumulation of adipose tissue) is a rising public health problem that is associated with many fatal diseases, including type 2 diabetes, fatty liver, stroke, myocardial infarction, and certain types of cancer. Common methods for treating obesity include diet control, weight loss drugs, and bariatric surgery, but these methods require strict self-management or have significant side effects on the human body. In response to the obesity epidemic, there is an urgent need to discover promising methods to achieve safe and effective weight loss. Recently, researchers have achieved weight loss by activating beige fat in mice and humans through local heating of the neck and back fat, but existing materials used for fat heating have the disadvantages of lacking targeting, wavelengths in the visible light range, and no imaging function.

[0003] Near-infrared light above 800 nanometers has a better traditional depth for biological tissues, which can effectively enhance the effect of photothermal treatment for obesity. Near-infrared zone II fluorescence imaging of 1000-1700 nanometers has low autofluorescence and weaker scattering in biological tissues, which can effectively obtain high signal-to-noise ratio fluorescence imaging information of adipose tissue in vivo. However, organic molecules with near-infrared zone II fluorescence imaging characteristics currently have defects such as low water solubility and insufficient fat-targeted enrichment ability. Summary of the invention

[0004] The purpose of the present invention is to overcome the deficiencies in the prior art, provide a fat-targeted photothermal weight loss phototherapeutic agent and its application, improve the water solubility and fat-targeting ability of the phototherapeutic agent, and enhance 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 6 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 comprises 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-tri ((6-bromohexyl) oxy) phenyl) -1,3,2-dioxaborane, and tetrakis (triphenylphosphine) palladium to a solvent, mixing and uniformly stirring, heating the mixture to react, adding an aqueous potassium carbonate 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 dropping a trimethylamine THF solution, and continuously stirring; after stirring, placing the mixture in a constant temperature oil bath for reaction, evaporating the solvent under vacuum to obtain a water-soluble ionic organic molecule.

[0015] Furthermore, the mixed solution after the trimethylamine THF solution is added dropwise is placed in a constant temperature oil bath pot, the temperature is maintained at 45-55° C., and after reacting 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 phototherapeutic agent, which comprises 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 1.0~10 mg / mL 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 above-mentioned water-soluble ionic organic molecule acceptable gel, microneedle or excipient.

[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, and can be combined with two-zone fluorescence imaging to achieve effective identification of adipose 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 optical diagnostic and therapeutic agent, wherein the water-soluble ionic organic molecules are directly dissolved in water and assembled in an aqueous solution. The preparation method is simple and can be used as an optical diagnostic and therapeutic 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 with the near-infrared zone II fluorescent imaging characteristics in the prior art, and has higher water solubility, smaller size, better fat targeted enrichment ability, up to one month of in vivo fat enrichment and stronger near-infrared excited photothermal ability, which greatly improves 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 microscope image of the aqueous solution of the photothermal weight loss phototherapy agent in Example 1 of the present invention;

[0031] Figure 5 This is an absorption and emission spectrum diagram 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-nanometer laser excitation of an aqueous solution of a photothermal weight loss phototherapy 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 of 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 solution of the present invention, and cannot be used to limit the protection scope 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-benzene (5-bromo-4 (2-octyldodecyl) benzo[1,2,5]thiadiazole (BBTD) (73.19 mg, 100 μmol) and 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 stirrer;

[0043] b. After vacuuming and bubbling nitrogen with double-row tubes, heat to 60°C in the dark, react for 30 minutes, and add 2.5 ml of 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 stopped, 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 purified by column chromatography to obtain a green powder product BBTD-3C (159.1 mg, yield 74%).

[0046] e. Under nitrogen protection, the product BBTD-3C (50 mg, 23.3 μmol) of the previous step was added to a 5 mL round-bottom flask containing 2 mL of tetrahydrofuran (THF) solution. The reaction solution was placed in an acetone dry ice system for cooling for 20 minutes, and trimethylamine THF solution (25 wt%, 1 mL) was slowly added dropwise, and stirring was continued 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. By testing the transmission electron microscopy images of these three photothermal weight loss phototherapeutic agents, it can be found 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, the absorption and emission spectra of the photothermal weight loss phototherapy agent of test example 1 show that its ultraviolet-near infrared absorption is in the range of 600-900 nanometers, while the emission peak is above 1000 nanometers, with an obvious near-infrared second zone emission signal.

[0056] like Figure 6As shown, the photothermal effect diagram of the photothermal weight loss phototherapy agent of test example 2 shows 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 3 photothermal weight loss phototherapeutic agent was subcutaneously injected 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 adipose tissue has an 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 As shown in the figure, the weight loss effect diagram of the photothermal weight loss phototherapy agent of test example 3 was selected. High-fat fed mice were subcutaneously injected with 100 microliters of 5.0 mg / ml Example 3 photothermal weight loss phototherapy agent. It can be seen from the figure that after 808 nanometer laser irradiation for 20 minutes, twice a week, and 60% high-fat diet for four weeks, the expansion of fat tissue was significantly reduced. The body weight increased from 37.8±0.5 grams to 40.7±1.3 grams, with 11 mice in each group; while after subcutaneous injection of ordinary solvent, after 808 nanometer laser irradiation for 20 minutes, the body weight increased from 37.8±0.4 grams to 48.3±1.3 grams, with 11 mice in each 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. A water-soluble ionic organic molecule, 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: Formula (I).

2. The water-soluble ionic organic molecule according to claim 1, characterized in that The water-soluble ionic organic molecule conjugated structure core is a near-infrared second-zone fluorescent dye, and the near-infrared second-zone fluorescent dye is 4,8-benzene (5-bromo-4 (2-octyldodecyl) benzobenzo [1,2,5] thiadiazole.

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

4. A fat-targeted photothermal weight loss phototherapy agent, characterized in that: The fat-targeted photothermal weight loss phototherapy agent comprises the water-soluble ionic organic molecule described in any one of claims 1 to 3.

5. The method for preparing the fat-targeted photothermal weight loss phototherapy agent according to claim 4, characterized in that: The water-soluble ionic organic molecule according to any one of claims 1 to 3 is dissolved in water.

6. The method for preparing the fat-targeted photothermal weight loss phototherapy agent according to claim 5, characterized in that: The concentration of water-soluble ionic organic molecules is 1.0~10 mg / mL.

7. Use of the water-soluble ionic organic molecules described in any one of claims 1 to 3 or the fat-targeted photothermal weight loss phototherapeutic agent described in claim 4 in the preparation of a weight loss phototherapeutic agent.

8. The use according to claim 7, characterized in that: The weight loss phototherapy agent comprises a gel, microneedle or excipient acceptable to water-soluble ionic organic molecules as described in any one of claims 1-3.

9. The use according to claim 8, characterized in that The slimming phototherapy agent is used to reduce the degree of expansion of adipose tissue.

10. The use according to claim 9, characterized in that: The weight loss phototherapy agent is an injection.

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