A stimuli-responsive nanomedicine for low-temperature photothermal therapy

Abstract

Invention Name: A Stimuli-Responsive Nanomedicine for Low-Temperature Photothermal Therapy Abstract: The present invention provides a method for preparing and applying a nanomaterial with stimulus-responsive mild photothermal therapy for tumors. Provided are a micro-nanostructure having a structure represented by formula (I) or its isomers, pharmaceutically acceptable salts, hydrates or solvates self-assembled in an aqueous solution, as well as the preparation of its pharmaceutical composition and its application in mild photothermal therapy for tumors and stimulus-responsive drug release. The compound provided by the present invention can target tumors, and the material with high photothermal conversion efficiency generates heat under laser irradiation to achieve thermal ablation of tumor cells. Heat shock protein inhibitors (APOs) can inhibit overexpressed Hsp90 to reduce the heat resistance of tumor cells, reduce thermal damage to surrounding normal tissues due to heat diffusion, and achieve mild photothermal therapy for tumors. Stimuli-responsive linkers can respond to high levels of glutathione and hydrogen peroxide in tumors to achieve efficient and precise drug release.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a class of materials containing stimulus-responsive linkers, heat shock protein inhibitors and high photothermal conversion efficiency, a pharmaceutical composition for mild photothermal therapy of tumors, and its preparation method and application. Background Art

[0002] In the 21st century, even in developed countries, cancer, caused by environmental and other factors, remains a major health problem facing humanity. To date, in vivo tumor treatments, such as in vivo radiation, chemotherapy, biotherapy, and targeted therapy, have been widely explored. However, these treatments are subject to high surgical risks, significant postoperative adverse reactions, and the development of drug resistance to these drugs, significantly limiting their application. Selecting a safe and effective treatment approach is crucial. Photothermal therapy (PTT) is a promising tumor treatment technology based on the principle that photothermal materials absorb near-infrared (NIR) light and convert it into heat to treat tumors. NIR light, with wavelengths ranging from 700 nm to 1300 nm, has a penetration depth of up to 10–15 mm and can penetrate tissue well with little to no damage. It offers advantages such as minimal invasiveness, low side effects, specific targeting of tumor cells, and a lack of significant drug resistance.

[0003] Although photothermal therapy (PTT) has been recognized as a leading therapeutic strategy in both clinical and preclinical settings, it still faces several pressing challenges. Excessively high temperatures can increase cellular levels of heat shock proteins, leading to heat resistance in tumor cells and potentially significantly reducing PTT's efficacy. Furthermore, uncontrolled heat diffusion can pose a threat to surrounding healthy tissue. In certain tumor treatments (particularly in the brain), damage to surrounding normal tissue can lead to loss of critical bodily functions or even death. The difficulty in preventing heat diffusion can also trigger adverse inflammation. High-temperature thermal ablation can also produce several adverse biological effects. Firstly, because PTT operates above 50°C, it primarily forces cell death through necrosis, leading to the release of cell debris and intracellular biomolecules. This can cause severe local inflammation, further damage surrounding normal tissue, and increase the risk of tumor metastasis. Secondly, such excessively high temperatures can impair the immune responses of immune cells within the tumor microenvironment (TME) that stimulate anti-tumor immunity, potentially impairing the immune system's ability to conquer cancer. To overcome these problems, low-temperature PTT has been proposed. Most mild PPTs are performed at temperatures below 48°C. It eliminates bacteria or tumors without causing much damage to normal tissues and promotes wound healing at low temperatures. A large number of studies have shown that low-temperature PTT can achieve unique therapeutic effects, enabling it to be used in biomedicine.

[0004] Compared to normal tissues and organs, the tumor microenvironment exhibits unique characteristics: tumors are rich in hydrogen peroxide (H2O2), glutathione (GSH), acidic conditions (low pH), and lack oxygen. Stimuli-responsive linkers were selected as the linkers for the heat shock protein inhibitor APO and photosensitizer, which react with hydrogen peroxide and glutathione overexpressed in tumors, achieving on-demand release of APO and photosensitizer in tumor cells.

[0005] In view of the above advantages, a class of compounds containing stimulus-responsive linkers, heat shock protein inhibitors and photosensitizers were constructed. They have a high photosensitizer loading rate and can accurately attack tumor tissue without damaging surrounding normal tissues. By inhibiting overexpressed Hsp90, the heat resistance of tumor cells is reduced, and they can exhibit good mild photothermal therapy (MT-PTT) effects, reducing the thermal damage of high temperature to normal tissues around the tumor, greatly improving the tumor treatment effect. Summary of the Invention

[0006] The purpose of the present invention is to provide a pharmaceutical composition for mild photothermal therapy of tumors, which consists of a stimulus-responsive linker, a heat shock protein inhibitor, and a material with photothermal conversion properties. The compound can self-assemble into nanomicelles in an aqueous solution. The preparation process is simple and does not require the use of chemical reagents for cross-linking. It can efficiently load materials with photothermal conversion properties and heat shock protein inhibitors to form a pharmaceutical composition, achieve photothermal therapy under mild conditions (≤45°C), and achieve on-demand release at the tumor site. The pharmaceutical composition has the advantages of good stability, high tumor selectivity, and low toxic side effects.

[0007] The technical solution of the present invention is:

[0008] A stimuli-responsive compound for mild photothermal therapy of tumors, wherein the compound has a micro-nanostructure formed by self-assembly in aqueous solution of the structure represented by formula (I), its isomers, pharmaceutically acceptable salts, hydrates or solvates:

[0009]

[0010] In the above formula (I):

[0011] K is a stimulus response group, including:

[0012]

[0013] Z is a heat shock protein inhibitor, including: Apotozole, HSP70-IN-1, 17-AAG, VER-155008, SNX-5422, BIIB021,

[0014]

[0015] In the formula (I):

[0016] X2 is selected from O, S or -CR 20 R 20 '-;

[0017] Y3, Y4, and Y5 are each independently selected from H, a hydroxyl group, a halogen atom, a substituted or unsubstituted amino group, and an oxyalkyl group;

[0018] t1, t2, and t3 are each independently selected from integers of 0 to 5;

[0019] R 13 、R 13 '、R 14 Each independently selected from -CN, -CF3, F, -SO2CF3, -NO2, -COOEt, -SO2ph,

[0020] R 15 -(CH2) m -、 m is an integer from 0 to 5;

[0021] R 16 and R 17 Together they form one of the following connections: or R 16 、R 17 Together with X2, we form the following connection Among them, R a 、R b 、R c 、R d 、R e 、R f 、R g Each is independently selected from H, halogen, substituted or unsubstituted hydrocarbon, substituted or unsubstituted carboxyl, substituted or unsubstituted hydroxyl and substituted or unsubstituted amino;

[0022] R 18 、R 18 '、R 19 、R 20 and R 20 'are each independently selected from H, a halogen atom, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted ester group and a substituted or unsubstituted amino group;

[0023] In the above formula (I), when the group is substituted, the substituents are monosubstituted or polysubstituted.

[0024] Furthermore, in formula (I), t1 and t2 are both 1, t3 is 0; m is 3;

[0025] The R 13 、R 13 ' are -CN, R 14 -CN or

[0026] The R 18 、R 18 '、R 19 Each independently selected from H, -(CH2) q CH3, -(CH2) q CF3, -(CH2) q CHCH2, -(CH2) q CCH, -(CH2) q OH, -(CH2) q COOH, -(CH2) q NH2, -(CH2) q CHO, -(CH2) q CO(CH2) q 'CH3, -(CH2) q O(CH2) r 'CH3, wherein q and q' are independently selected from integers of 0-12; preferably, the R 19 is -CH2CH3;

[0027] Said Y3 and Y5 are both H;

[0028] Y4 is Cl, Br or -NR 21 R 21 '-, where R 21 、R 21 ' are each independently selected from H, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alcohol group, a substituted or unsubstituted ether group, a substituted or unsubstituted aldehyde group, a substituted or unsubstituted carboxyl group, a substituted or unsubstituted amide group, a substituted or unsubstituted ester group and a substituted or unsubstituted amino group; L1 is a carbon chain substituted or unsubstituted by an ester group.

[0029] Preferably, the micro-nano structure is formed by self-assembly of compound I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28 or I-29 in aqueous solution.

[0030] The particle size of the micro-nano structure is 1 nm to 500 nm, preferably 10 nm to 200 nm, and more preferably 30 nm to 150 nm.

[0031] The present invention also provides a method for preparing the micro-nano structure, comprising the following steps:

[0032] 1) dissolving the compound having the structure represented by formula (I), its isomer, pharmaceutically acceptable salt, hydrate or solvate in an organic solvent;

[0033] The organic solvent selected is a mixture of one or more of alkanes, olefins, aromatic hydrocarbons, alcohols, ketones, aldehydes, carboxylic acids, esters or ethers; specifically, the organic solvent is a mixture of one or more of dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, ethylene glycol, n-propanol, isopropanol, propylene glycol, glycerol, n-butanol, isobutanol, butanediol or polyethylene glycol, acetone, dichloromethane or acetonitrile; preferably ethanol.

[0034] 2) adding the dissolved solution into water to obtain a compound solution with a final concentration of 1 nM to 1 M;

[0035] The final concentration is preferably 100 nM to 500 μM; most preferably 0.46 μM to 300 μM.

[0036] 3) The compound self-assembles in aqueous solution to form micro-nanostructures.

[0037] The preparation method is simple, convenient and suitable for large-scale production.

[0038] The present invention also provides a pharmaceutical composition of a micro-nanostructure, comprising: a therapeutically effective dose of the micro-nanostructure and a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier comprises a diluent, a disintegrant, an excipient, a binder, a stabilizer, or a combination thereof.

[0039] The present invention also provides a pharmaceutical composition comprising:

[0040] 1) a therapeutically effective dose of a compound having the structure represented by formula (I) or its isomer, pharmaceutically acceptable salt, hydrate or solvate, and

[0041] 2) Pharmaceutically acceptable carrier.

[0042] Preferably, the pharmaceutically acceptable carrier comprises a diluent, a disintegrant, an excipient, a binder, a stabilizer or a combination thereof.

[0043] The pharmaceutical composition provided by the present invention can be prepared as an injection, comprising a therapeutically effective dose of the micro-nanostructures and an injection solvent or additive, or a combination thereof; wherein the injection solvent is one or a mixture of two or more of water for injection, ethanol, propylene glycol, glycerol, and polyethylene glycol. Preferably, the pharmaceutical composition can be prepared as an injection solution.

[0044] The micro-nano structure of the present invention is a nanodisc structure, and its pharmaceutical composition also includes a material with photothermal properties and a stimulus-responsive linker, wherein the linker includes: a monosulfide bond, a monoselenide bond, a monotellurium bond, a disulfide bond, a diselenide bond, a ditellurium bond, a thioketal bond, etc., and the linker is preferably a monosulfide bond. Furthermore, the micro-nano structure also includes a heat shock protein inhibitor, including Apotozole, HSP70-IN-1,17-AAG, VER-155008, SNX-5422, BIIB021, etc., preferably Apotozole.

[0045] In another aspect, the present invention further provides the use of the micro-nanostructure or its pharmaceutical composition in mild photothermal therapy for tumors, as well as its use as a photothermal material. The photothermal material is used to prepare a phototherapeutic drug. The phototherapeutic drug is a photothermal drug or a photoacoustic drug.

[0046] The present invention also provides the use of the micro-nanostructure or its pharmaceutical composition in treating solid tumor cancers, including esophageal cancer, non-small cell lung cancer, biliary tract cancer, brain tumors, Barrett's esophagitis, bladder cancer, colorectal cancer, pancreatic cancer, prostate cancer, ovarian cancer, breast cancer, or skin cancer.

[0047] The present invention also provides a method for performing light therapy on a target area of ​​a subject under mild conditions, comprising:

[0048] 1) Providing the micro-nano structure;

[0049] 2) administering the micro-nanostructure to a subject via intravenous injection;

[0050] 3) waiting for the micro-nanostructure to be enriched in the target area due to the EPR effect;

[0051] 3) Using light in the excitation band of the micro-nanostructure to irradiate the target area of ​​the subject, using 808nm light waves for irradiation, the preferred photothermal treatment temperature is lower than 48 degrees Celsius.

[0052] Beneficial effects of the present invention:

[0053] (1) The compounds provided by the present invention can self-assemble into micro-nanostructures in aqueous solution, can be enriched in tumor tissues through the EPR effect, and can release photosensitizers and heat shock protein inhibitors by stimulating the breaking of connecting bonds in the tumor microenvironment, with high tumor selectivity. Heat shock protein inhibitors can effectively inhibit the expression of heat shock proteins HSP90 and HSP70 in tumor cells, thereby reducing the heat resistance of tumor cells, increasing the thermosensitivity of tumor cells, promoting the apoptosis of tumor cells, and reducing the treatment temperature of photothermal therapy. Excellent photothermal anti-tumor effects can be achieved under mild temperature (43-45°C) treatment conditions, reducing the side effects caused by local overheating.

[0054] (2) The present invention provides a class of compounds containing stimuli-responsive linkers, high photothermal conversion materials, and heat shock protein inhibitors. The resulting micro-nanostructures have advantages such as good biocompatibility, high photothermal conversion efficiency, and good photothermal stability. They are effective, minimally invasive, and have few side effects for mild photothermal therapy of cancer in vivo, possessing great market value and broad economic prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 A roadmap for the preparation of compound I-1 provided by the present invention;

[0056] Figure 2 is the UV absorption spectrum of compound Ⅰ-1 in different polar solvents;

[0057] Figure 3 is the fluorescence emission spectrum of compound Ⅰ-1 in solvents of different polarity;

[0058] Figure 4 This is a transmission electron microscopy image of nanodiscs self-assembled by compound Ⅰ-1 in aqueous solution;

[0059] Figure 5 The particle size test results of the compound provided by the present invention in aqueous solution show that the entire molecule can self-assemble into a micro-nano structure after chemical bonding with the active targeting group;

[0060] Figure 6 The temperature change diagram of compound Ⅰ-1 with different concentrations under 808nm laser irradiation;

[0061] Figure 7 The photothermal effect and photothermal stability comparison of compound Ⅰ-1 before and after hydrogen peroxide (H2O2) and glutathione (GSH) stimulation response;

[0062] Figure 8 This is a microscopic image of nanodiscs assembled from compound Ⅰ-1 being engulfed by cells;

[0063] Figure 9 Fluorescence imaging of the dark toxicity and phototoxicity of HeLa cells by nanodiscs assembled from compound Ⅰ-1;

[0064] Figure 10 The photoacoustic imaging images of the whole body of mice with dual tumors at different time points after the nanodiscs assembled from compound I-1 were intravenously injected into the mice;

[0065] Figure 11 The photoacoustic imaging signal intensity of the whole body of mice at different time points after the nanodiscs assembled with compound I-1 were intravenously injected into mice with dual tumors;

[0066] Figure 12 Photothermal imaging of compound Ⅰ-1 in vivo photothermal therapy in mice;

[0067] Figure 13 This is a photothermal therapy experiment of compound Ⅰ-1 in mice;

[0068] Figure 14 This is a graph of tumor volume-time in tumor-bearing mice after intravenous injection of compound Ⅰ-1 and photothermal therapy; Figure 15 This is a graph showing the weight-time relationship of tumor-bearing mice after intravenous injection of compound Ⅰ-1;

[0069] Figure 16 Liver function and blood routine of tumor-bearing mice after intravenous injection of compound Ⅰ-1 and photothermal therapy;

[0070] Figure 17 H&E-stained images of heart, liver, spleen, lung, and kidney sections of tumor-bearing mice 22 days after intravenous injection of compound I-1 and photothermal therapy. DETAILED DESCRIPTION

[0071] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0072] The present invention provides certain specific examples of compounds, including compounds I-1 to I-29 shown in Table 1 below.

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079] The above compounds can be synthesized by the following reaction formula:

[0080]

[0081] The main synthetic steps include:

[0082] (1) providing compounds a, b, c, and d respectively;

[0083] Synthesis of compound a:

[0084]

[0085] Compound 1', compound 2' and magnesium ethoxide were dissolved in ethanol and reacted at 60°C for 24 hours. The solvent was evaporated under vacuum and the obtained solid was purified by column chromatography to obtain the target compound a.

[0086] Synthesis of compound b:

[0087]

[0088] Add dichloromethane and compound 4' to a flask under ice-cooling and stir. Add compound 5' at constant pressure and stir. Then add compound 3' and react at 80°C for 3 hours. After the reaction is complete, pour the product into crushed ice to quench the reaction and refrigerate overnight. Evaporate the solvent under vacuum to obtain the crude product, compound b, which is used directly in the next reaction without purification.

[0089] Synthesis of compound c:

[0090]

[0091] Compound 6' and compound 7' were added to acetonitrile and heated to 110°C for 24 hours under reflux. The solvent was evaporated under vacuum and the resulting solid was washed with ether three times to obtain compound c.

[0092] Compound d was purchased directly.

[0093] (2) Compound a and compound b were dissolved in ethanol, heated to reflux, and then compound c was added, heated to reflux, and the solvent was evaporated under vacuum. The obtained solid was purified by column chromatography. The obtained product was dissolved in dichloromethane with compound d, and EDC-HCl and DMAP were added. After reacting at room temperature overnight, the mixture was washed three times with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution. After removing water, the obtained solid was purified by column chromatography to obtain the product compound I.

[0094] Example 1 Synthesis of Compound Ⅰ-1 and its Fluorescence Properties

[0095] like Figure 1 As shown, the synthesis of compound I-1 includes the following steps:

[0096] 1) Synthesis of Compound 15: 2.04 g of Compound 6 and 2.86 g of iodoethanol were weighed and added to 50 mL of acetonitrile. The mixture was heated to 110° C. and refluxed for 10 hours. The solvent was evaporated under vacuum, and the resulting solid was washed three times with diethyl ether to obtain Compound 1.

[0097] 1 H NMR (400MHz, DMSO-d6): δ (ppm): 8.95 (d, J = 8.8 Hz, 1H), 8.12 (t, 1H), 7.44 (d, J =8.4Hz,1H),7.30(t,1H),4.23(m,3H),3.60(m,2H),1.44(s,6H),0.87(s,3H).

[0098] 2) Synthesis of Compound 9: 1.94 g of malononitrile and 1.24 g of magnesium ethoxide were weighed and added to 20 mL of anhydrous ethanol. 1.0 mL of 3-hydroxy-3-methylbutan-2-one was then added. The mixture was heated to 90°C for 10 hours. The solvent was evaporated under vacuum, and the resulting solid was purified by column chromatography to yield the title compound 9.

[0099] 1 H NMR (400MHz, CDCl3): δ (ppm): 2.36 (s, 3H), 1.63 (s, 6H).

[0100] 3) Synthesis of Compound 11: 20 mL of dichloromethane and 20 mL of DMF were added to a flask under ice-cooling and stirred. 17.5 mL of phosphorus oxychloride was added at constant pressure and stirred. 5.3 mL of cyclohexanone was then added, and the mixture was heated to 80°C for 3 hours. After the reaction was complete, the product was poured into crushed ice to quench the reaction, and the mixture was refrigerated overnight. The solvent was evaporated under vacuum to obtain the crude product, Compound 11, which was used directly in the next reaction without purification.

[0101] 4) Synthesis of Compound 12: 2.0 g of Compound 9 and 2.5 g of Compound 11 were added to 60 mL of ethanol, heated to 90° C. and refluxed for 10 hours. After cooling to room temperature, the crude product, Compound 12, was filtered and used directly in the next step without purification.

[0102] 5) Synthesis of Compound 16: 1.2 g of Compound 15 and 2.0 g of Compound 12 were dissolved in 60 mL of ethanol, heated to 100° C. and refluxed for 8 hours. The solvent was evaporated under vacuum, and the resulting solid was purified by column chromatography to obtain the target compound 16.

[0103] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.35 (d, J = 8.4Hz, 1H), 8.22 (d, J = 7.2Hz, 1H), 7.60 (t, 2H), 7.46 (s, 2H), 7.30 (t, 1H), 7.24 (d, J = 8 .8Hz,1H),6.08(s,1H),3.48(s,2H),5.82(d,J=13.6Hz,1H),2.66(t,4H),2.62(t,2H),1.81(m,1H),1.67(s,6H),1.59(m,6H).

[0104] 6) Synthesis of Compound 4: 0.48 mL of 3,5-bis(trifluoromethyl)benzaldehyde, 1.03 g of ammonium acetate, 0.44 g of 4-(aminomethyl)benzoic acid, and 0.60 g of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione were added to acetic acid (20 mL) and stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water, saturated aqueous NaHCO3, and saturated brine. The resulting mixture was purified by column chromatography to yield Compound 4.

[0105] 1 H NMR (400MHz, DMSO-d6): δ (ppm): 8.20 (s, 2H), 8.12 (s, 1H), 7.80 (d, J = 8.0Hz, 2H), 7.43 (d, J = 8.0Hz, 2 H),7.30(d,J=8.0Hz,2H),7.02(t,3H),6.84(d,J=8.0Hz,2H),5.27(s,2H),3.79(s,3H),3.72(s,3H).

[0106] 7) Synthesis of Compound 5: 0.73 g of ethanolamine was dissolved in 5 mL of dichloromethane, and 0.50 g of Compound 4 was added. After stirring for 30 minutes, 0.35 g of O-benzotriazole-tetramethyluronium hexafluorophosphate and 0.42 L of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature for 5 hours. The reaction was concentrated under reduced pressure, and the resulting mixture was purified by column chromatography to yield Compound 6.

[0107] 1H NMR (400MHz, CDCl3): δ (ppm): 8.05 (s, 2H), 7.82 (s, 1H), 7.70 (d, J = 8.0Hz, 2H), 7.50 (d, J = 8.0Hz, 2H), 7.16 (d, J = 8.0Hz,2H),6.90(m,4H),6.78(d,J=8.0Hz,2H),5.29(s,2H),5.10(s,2H),3.81(s,3H),3.76(s,5H),3.55(m,2H).

[0108] 8) Synthesis of Compound 6: 0.66 g of compound 5 was dissolved in 30 mL of dichloromethane, followed by the addition of 0.12 g of 2,2'-thiodiacetic acid. In an ice bath, 0.15 g of EDC·HCl and 0.12 g of DMAP were added. The reaction was stirred at room temperature for 12 hours. The resulting mixture was purified by column chromatography to obtain compound 6.

[0109] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.03 (s, 2H), 7.81 (s, 1H), 7.76 (d, J = 8.0Hz, 2H), 7.46 (d, J = 8.0Hz, 2H), 7.15 (d, J = 8.0Hz, 2H), 6 .90(m,4H),6.78(d,J=8.0Hz,2H),5.09(s,2H),4.20(t,2H),3.81(s,3H),3.76(s,3H),3.64(s,2H),3.47(t,2H),3.28(s,2H).

[0110] 9) Synthesis of Compound I-1: 0.37 g of Compound 6 and 0.25 g of Compound 16 were dissolved in 30 mL of dichloromethane, and 0.07 g of EDC·HCl and 0.05 g of DMAP were added. The mixture was allowed to react at room temperature overnight. The mixture was washed three times with saturated aqueous HCl and saturated brine, dried over anhydrous NaSO, and the solvent removed under reduced pressure. The resulting mixture was purified by column chromatography to yield Compound I-1.

[0111] 1H NMR (400MHz, CDCl3): δ (ppm): 8.52 (t, 1H), 8.36 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 2H), 8.12 (s, 1H), 8. 05(d,J=8.0Hz,1H),7.72(d,J=8.0Hz,2H),7.45(m,3H),7.30(m,4H),7.13(t,1H),7.00(t,4H), 6.84(d,J=8.0Hz,2H),6.21(d,J=8.0Hz,2H),5.26(s,2H),4.42(m,4H),4.11(t,2H),3.78(s,3 H),3.72(s,3H),3.45(t,2H),3.28(s,4H),2.62(m,4H),1.80(m,2H),1.63(s,6H),1.60(s,6H).

[0112] The UV absorption spectrum and fluorescence emission spectrum of compound Ⅰ-1 in water and methanol are shown as follows: Figure 2 and Figure 3 As shown, the ultraviolet absorption spectra and fluorescence emission spectra of compound I-1 in the two solvents are significantly different. The absorption spectrum distribution of I-1 in aqueous solution is wider and the fluorescence intensity of the emitted light is lower, indicating that the physical properties of compound I-1 in aqueous solution and organic solvent are different.

[0113] Example 2 Synthesis of Compounds I-2 to I-15

[0114] Compounds I-2 to I-15 can be prepared by a method similar to Example 1.

[0115] 1. Synthesis of Compound Ⅰ-2

[0116]

[0117] Compound 17 was used to replace compound 11 in Example 1. The remaining reagents and preparation methods were the same as steps 1 to 9 of Example 1 to prepare compound I-2.

[0118] 1HNMR (400MHz, CDCl3) δ (ppm): 8.81 (s, 1H), 8.64 (s, 2H), 7.84 (d, 2H), 7.55 (d, 4H), 7.34 (d, 2H), 7.22(d,2H),7.06(t,1H),7.03(d,4H),6.84(d,2H),6.72(t,1H),6.64(s,1H),6.51(s,2H),6.36 (d,1H),6.23(s,1H),5.79(s,2H),5.64(s,1H),4.48(t,2H),4.37(s,1H),4.16(t,2H),3.81(s, 6H),3.39(t,2H),3.34(s,4H),3.16(t,2H),2.84(m,1H),2.10(d,2H),1.79(s,6H),1.16(s,6H).

[0119] 2. Synthesis of Compound I-3

[0120]

[0121] Compound 19 was used to replace compound 15 in Example 1, and the remaining reagents and preparation methods were the same as steps 1-9 of Example 1 to prepare compound I-3;

[0122] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.71 (s, 1H), 8.64 (s, 2H), 8.33 (s, 1H), 7.96 (d, 2H), 7.84 (d ,2H),7.55(d,4H),7.42(d,1H),7.37(d,1H),7.34(d,2H),7.30(d,1H),7.03(d,4H),6.91 (d,1H),6.51(s,2H),5.79(t,2H),5.64(s,1H),4.48(t,2H),4.16(t,2H),3.81(s,6H),3. 39(t,2H),3.34(s,4H),3.16(t,2H),2.81(t,4H),1.85(s,6H),1.47(m,2H),1.16(s,6H).

[0123] 3. Synthesis of Compound I-4

[0124]

[0125] Compound 15 in Example 1 was replaced by compound 21, and the remaining reagents and preparation methods were the same as steps 1-9 of Example 1 to prepare compound I-4;

[0126] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.71 (s, 1H), 8.64 (s, 2H), 8.33 (s, 1H), 7.88 (d, 1H), 7.8 4(d,2H),7.56(d,1H),7.55(d,4H),7.48(t,1H),7.34(d,2H),7.29(t,1H),7.03(d,4H ),6.51(s,2H),6.23(s,1H),5.79(s,2H),5.46(s,1H),4.48(t,2H),4.16(t,2H),3.81 (s,6H),3.39(t,2H),3.34(s,4H),3.16(t,2H),2.81(t,4H),1.47(m,2H),1.16(s,6H).

[0127] 4. Synthesis of Compound I-5

[0128]

[0129] Compound 15 in Example 1 was replaced by compound 23, and the remaining reagents and preparation methods were the same as steps 1-9 of Example 1 to prepare compound I-5;

[0130] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.71 (s, 1H), 8.64 (s, 2H), 8.33 (s, 1H), 7.96 (d, 1H), 7.84 (d ,2H),7.82(d,1H),7.64(t,1H),7.62(d,1H),7.55(d,4H),7.45(t,1H),7.34(d,2H),7.03 (d,4H),6.51(s,2H),6.23(s,1H),5.89(s,1H),5.79(s,2H),4.48(t,2H),4.16(t,2H),3. 81(s,6H),3.39(t,2H),3.34(s,4H),3.16(t,2H),2.81(t,4H),1.47(m,2H),1.16(s,6H).

[0131] 5. Synthesis of Compound I-6

[0132]

[0133] Compound 25 is used to replace the compound 2,2'-thiodiacetic acid in Example 1, X can be selected from S, Se, Te, and the remaining reagents and preparation methods are the same as steps 1-9 of Example 1 to prepare compound I-6;

[0134] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.52 (t, 1H), 8.36 (d, 1H), 8.23 ​​(s, 2H), 8.12 (s, 1H), 8.05(d,1H),7.72(d,2H),7.45(m,3H),7.30(m,4H),7.13(t,1H),7.00(t,4H),6.84 (d,2H),6.21(d,2H),5.26(s,2H),4.42(m,4H),4.11(t,2H),3.78(s,3H),3.72(s, 3H),3.45(t,2H),3.28(s,4H),2.62(m,4H),1.80(m,2H),1.63(s,6H),1.60(s,6H).

[0135] 6. Synthesis of Compound I-7

[0136]

[0137] Compound 25 is substituted for the compound 2,2'-thiodiacetic acid in Example 1, and compound 17 is substituted for compound 11 in Example 1, X can be selected from S, Se, Te, and the remaining reagents and preparation methods are the same as steps 1-9 of Example 1 to prepare compound I-7;

[0138] 1 HNMR (400MHz, CDCl3) δ (ppm): 8.81 (s, 1H), 8.64 (s, 2H), 7.84 (d, 2H), 7.55 (d, 4H), 7.34 (d, 2H), 7.22(d,2H),7.06(t,1H),7.03(d,4H),6.84(d,2H),6.72(t,1H),6.64(s,1H),6.51(s,2H),6.36 (d,1H),6.23(s,1H),5.79(s,2H),5.64(s,1H),4.48(t,2H),4.37(s,1H),4.16(t,2H),3.81(s, 6H),3.39(t,2H),3.34(s,4H),3.16(t,2H),2.84(m,1H),2.10(d,2H),1.79(s,6H),1.16(s,6H).

[0139] 7. Synthesis of Compound I-8

[0140]

[0141] Compound 25 is substituted for the compound 2,2'-thiodiacetic acid in Example 1, and compound 19 is substituted for compound 11 in Example 1, X can be selected from S, Se, Te, and the remaining reagents and preparation methods are the same as steps 1-9 of Example 1 to prepare compound I-8;

[0142] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.71 (s, 1H), 8.64 (s, 2H), 8.33 (s, 1H), 7.96 (d, 2H), 7.84 (d ,2H),7.55(d,4H),7.42(d,1H),7.37(d,1H),7.34(d,2H),7.30(d,1H),7.03(d,4H),6.91 (d,1H),6.51(s,2H),5.79(t,2H),5.64(s,1H),4.48(t,2H),4.16(t,2H),3.81(s,6H),3. 39(t,2H),3.34(s,4H),3.16(t,2H),2.81(t,4H),1.85(s,6H),1.47(m,2H),1.16(s,6H).

[0143] 8. Synthesis of Compound I-9

[0144]

[0145] Compound 25 is substituted for the compound 2,2'-thiodiacetic acid in Example 1, and compound 21 is substituted for compound 11 in Example 1, X can be selected from S, Se, Te, and the remaining reagents and preparation methods are the same as steps 1-9 of Example 1 to prepare compound I-9;

[0146] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.71 (s, 1H), 8.64 (s, 2H), 8.33 (s, 1H), 7.88 (d, 1H), 7.8 4(d,2H),7.56(d,1H),7.55(d,4H),7.48(t,1H),7.34(d,2H),7.29(t,1H),7.03(d,4H ),6.51(s,2H),6.23(s,1H),5.79(s,2H),5.46(s,1H),4.48(t,2H),4.16(t,2H),3.81 (s,6H),3.39(t,2H),3.34(s,4H),3.16(t,2H),2.81(t,4H),1.47(m,2H),1.16(s,6H).

[0147] 9. Synthesis of Compound I-10

[0148]

[0149] Compound 25 is substituted for the compound 2,2'-thiodiacetic acid in Example 1, and compound 23 is substituted for the compound 11 in Example 1, X can be selected from S, Se, Te, and the remaining reagents and preparation methods are the same as steps 1-9 of Example 1) to prepare compound I-10;

[0150] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.71 (s, 1H), 8.64 (s, 2H), 8.33 (s, 1H), 7.96 (d, 1H), 7.84 (d ,2H),7.82(d,1H),7.64(t,1H),7.62(d,1H),7.55(d,4H),7.45(t,1H),7.34(d,2H),7.03 (d,4H),6.51(s,2H),6.23(s,1H),5.89(s,1H),5.79(s,2H),4.48(t,2H),4.16(t,2H),3. 81(s,6H),3.39(t,2H),3.34(s,4H),3.16(t,2H),2.81(t,4H),1.47(m,2H),1.16(s,6H).

[0151] 10. Synthesis of Compound Ⅰ-11

[0152]

[0153] Compound 26 is used to replace the compound 2,2'-thiodiacetic acid in Example 1, X can be selected from Se, Te, and the remaining reagents and preparation methods are the same as steps 1-9 of Example 1 to prepare compound I-11;

[0154] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.52 (t, 1H), 8.36 (d, 1H), 8.23 ​​(s, 2H), 8.12 (s, 1H), 8.05(d,1H),7.72(d,2H),7.45(m,3H),7.30(m,4H),7.13(t,1H),7.00(t,4H),6.84 (d,2H),6.21(d,2H),5.26(s,2H),4.42(m,4H),4.11(t,2H),3.78(s,3H),3.72(s, 3H),3.45(t,2H),3.28(s,4H),2.62(m,4H),1.80(m,2H),1.63(s,6H),1.60(s,6H).

[0155] 11. Synthesis of Compound I-12

[0156]

[0157] Compound 26 is substituted for the compound 2,2'-thiodiacetic acid in Example 1, and compound 17 is substituted for compound 11 in Example 1, X can be selected from Se and Te, and the remaining reagents and preparation methods are the same as steps 1-9 of Example 1) to prepare compound I-12;

[0158] 1 HNMR (400MHz, CDCl3) δ (ppm): 8.81 (s, 1H), 8.64 (s, 2H), 7.84 (d, 2H), 7.55 (d, 4H), 7.34 (d, 2H), 7.22(d,2H),7.06(t,1H),7.03(d,4H),6.84(d,2H),6.72(t,1H),6.64(s,1H),6.51(s,2H),6.36 (d,1H),6.23(s,1H),5.79(s,2H),5.64(s,1H),4.48(t,2H),4.37(s,1H),4.16(t,2H),3.81(s, 6H),3.39(t,2H),3.34(s,4H),3.16(t,2H),2.84(m,1H),2.10(d,2H),1.79(s,6H),1.16(s,6H).

[0159] 12. Synthesis of Compound I-13

[0160]

[0161] Compound 26 is used to replace the compound 2,2'-thiodiacetic acid in Example 1, and compound 19 is used to replace compound 11 in Example 1. X can be selected from Se and Te. The remaining reagents and preparation methods are the same as steps 1-9 of Example 1 to prepare compound I-13;

[0162] 1H NMR (400MHz, CDCl3): δ (ppm): 8.71 (s, 1H), 8.64 (s, 2H), 8.33 (s, 1H), 7.96 (d, 2H), 7.84 (d ,2H),7.55(d,4H),7.42(d,1H),7.37(d,1H),7.34(d,2H),7.30(d,1H),7.03(d,4H),6.91 (d,1H),6.51(s,2H),5.79(t,2H),5.64(s,1H),4.48(t,2H),4.16(t,2H),3.81(s,6H),3. 39(t,2H),3.34(s,4H),3.16(t,2H),2.81(t,4H),1.85(s,6H),1.47(m,2H),1.16(s,6H).

[0163] 13. Synthesis of Compound I-14

[0164]

[0165] Compound 26 is substituted for the compound 2,2'-thiodiacetic acid in Example 1, and compound 21 is substituted for the compound 11 in Example 1, X can be selected from Se and Te, and the remaining reagents and preparation methods are the same as steps 1-9 of Example 1) to prepare compound I-14;

[0166] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.71 (s, 1H), 8.64 (s, 2H), 8.33 (s, 1H), 7.88 (d, 1H), 7.8 4(d,2H),7.56(d,1H),7.55(d,4H),7.48(t,1H),7.34(d,2H),7.29(t,1H),7.03(d,4H ),6.51(s,2H),6.23(s,1H),5.79(s,2H),5.46(s,1H),4.48(t,2H),4.16(t,2H),3.81 (s,6H),3.39(t,2H),3.34(s,4H),3.16(t,2H),2.81(t,4H),1.47(m,2H),1.16(s,6H).

[0167] 14. Synthesis of Compound I-15

[0168]

[0169] Compound 26 is substituted for the compound 2,2'-thiodiacetic acid in Example 1, and compound 23 is substituted for compound 11 in Example 1, X can be selected from Se, Te, and the remaining reagents and preparation methods are the same as steps 1-9 of Example 1) to prepare compound I-15;

[0170] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.71 (s, 1H), 8.64 (s, 2H), 8.33 (s, 1H), 7.96 (d, 1H), 7.84 (d ,2H),7.82(d,1H),7.64(t,1H),7.62(d,1H),7.55(d,4H),7.45(t,1H),7.34(d,2H),7.03 (d,4H),6.51(s,2H),6.23(s,1H),5.89(s,1H),5.79(s,2H),4.48(t,2H),4.16(t,2H),3. 81(s,6H),3.39(t,2H),3.34(s,4H),3.16(t,2H),2.81(t,4H),1.47(m,2H),1.16(s,6H).

[0171] 15. Synthesis of Compound I-16

[0172]

[0173] Compound 27 was used to replace the compound 2,2'-thiodiacetic acid in Example 1. The remaining reagents and preparation methods were the same as steps 1-9 of Example 1 to prepare compound I-16;

[0174] 1 H NMR (400MHz, CDCl3): δ (ppm): 8.71 (s, 1H), 8.64 (s, 2H), 8.33 (s, 1H), 7.96 (d, 1H), 7.84 (d, 2 H),7.82(d,1H),7.64(t,1H),7.62(d,1H),7.55(d,4H),7.45(t,1H),7.34(d,2H),7.03(d,4H ),6.51(s,2H),5.89(s,1H),5.79(s,2H),4.48(t,2H),4.16(t,2H),3.81(s,6H),3.39(t,2H) ,3.34(s,4H),3.16(t,2H),2.81(t,4H),1.79(s,6H),1.59(s,6H),1.47(m,2H),1.16(s,6H).

[0175] Example 3 Preparation method of micro-nano structure

[0176] Taking the self-assembled micro-nanostructure of compound I-1 as an example, I-1 was dissolved in DMSO (or an organic solvent such as ethanol) to prepare a 2mM storage solution. A small amount of the storage solution was added to 2mL of deionized water to prepare nanoparticles. 10μL was added dropwise to a copper grid and observed and photographed under a transmission electron microscope (TEM). The micro-nanostructure with the morphology of vesicles was clearly observed. Figure 4 That is the transmission electron microscopy result, Figure 5 The particle size distribution of the DLS was found to be about 60-140 nm in size.

[0177] Experimental Example 1 In vitro photothermal effect and photothermal stability of compound Ⅰ-1

[0178] Take 3 mL of each of the 4 groups of samples and add them to the cuvette, then seal it.

[0179] Sample No. 1 was 3 mL of deionized water;

[0180] Sample No. 2 is 10 μM Ⅰ-1, and the specific preparation method is to add 15 μL Ⅰ-1 stock solution (2 mM, dissolved in DMSO) to 3 mL of deionized water;

[0181] Sample No. 3 is 20 μM Ⅰ-1, and the specific preparation method is to add 30 μL Ⅰ-1 stock solution (2 mM, dissolved in DMSO) to 3 mL of deionized water;

[0182] Sample No. 4 is 25 μM Ⅰ-1, and the specific preparation method is 3 mL deionized water plus 45 μL Ⅰ-1 stock solution (2 mM, dissolved in DMSO).

[0183] Irradiate each sample with 808nm laser for 5 minutes, and record the temperature data every 10 seconds with a thermal imager. Plot the temperature corresponding to the time in Origin. Figure 6 The temperature of sample No. 1 remained almost unchanged within 5 minutes, rising only 0.5°C; the temperature of sample No. 2 rose from room temperature 24°C to 38°C, a temperature increase of 14°C; the temperature of sample No. 3 rose from room temperature 22.3°C to 45.9°C, a temperature increase of 23.6°C; the temperature of sample No. 4 rose from room temperature 22.5°C to 50.1°C, a temperature increase of 27.6°C.

[0184] This indicates that compound I-1 has an excellent photothermal effect. At the same time, we calculated the photothermal conversion efficiency of compound I-1 and found that its photothermal conversion efficiency is 41.7%, which also indicates that compound I-1 has an extremely excellent photothermal effect.

[0185] Experimental Example 2 Comparison of in vitro photothermal effect and photothermal stability of compound I-1 before and after H2O2 and GSH response

[0186] The working concentrations of the compounds after the response of H2O2 and GSH were prepared at the same concentrations, and sample No. 3 was selected to test the photothermal stability experiment under the same conditions. Figure 7 As shown, the two samples were irradiated with an 808nm laser for 10 minutes, then heated from room temperature and allowed to cool naturally to room temperature. They were then irradiated with an 808nm laser for 10 minutes, followed by a natural cooling cycle, and repeated five times. The results showed that the compound reacting with H2O2 and GSH exhibited better photothermal effects, superior photothermal conversion efficiency, and better photothermal stability than the original compound.

[0187] This demonstrates that Compound I-1 not only exhibits excellent photothermal effects, but also exhibits enhanced photothermal effects, superior photothermal conversion efficiency, and improved photothermal stability compared to the original compound after responsiveness to H₂O₂ and GSH, demonstrating the potential application of stimuli-responsiveness. Other compounds of the present invention exhibit similar properties.

[0188] Experimental Example 3 Cell Imaging Experiment

[0189] The nuclear dye Hoechst33342 (100 nM), lysosomal dye Lyso-Green (75 nM) and I-1 (8 μM) were added to the cell culture medium for 30 minutes of cell staining. After staining, the cells were rinsed twice with PBS and observed and photographed under a confocal fluorescence microscope. Figure 8 As shown, it shows that compound I-1 can be effectively taken up by cells.

[0190] Experimental Example 4: Intracellular Photothermal Effect Detection Experiment

[0191] HeLa cells were cultured in 96-well plates, with 10 cells per well. 4 After 24 hours, different concentrations of I-1 (0.1 μM to 100 μM) were added to the cells. After the plates were placed in an incubator for 24 hours, the cells were stained with the live cell dye Calcein-AM and the dead cell dye EthD-I for 20 minutes. Subsequent observation under a fluorescence microscope revealed that almost all cells were alive, demonstrating that compound I-1 itself has minimal toxicity.

[0192] like Figure 9 As shown, the cells in the cell well plate for phototoxicity detection were irradiated with an 808nm laser for 6 minutes and observed and photographed under a fluorescence microscope. It was found that when the concentration of Ⅰ-1 was greater than 15μM, 100% of the cells were dead, proving that compound Ⅰ-1 had a strong photothermal killing ability on cancer cells under laser irradiation and had an excellent photothermal effect.

[0193] Combining the results of the laser irradiation group and the dark toxicity group shows that the compound itself has minimal toxicity, but its photothermal effect under mild conditions has a significant killing effect on tumor cells, demonstrating excellent anti-tumor efficacy. Other compounds of the present invention also have similar photothermal therapeutic effects under mild conditions.

[0194] Experimental Example 5 Photoacoustic Imaging Test in Mice

[0195] First, a mouse tumor model was constructed. 10 7 HeLa cells, allowing tumors to grow to a volume of 60 mm 3 200 μL of Ⅰ-1 (200 μg) was injected into mice via the tail vein. The three-dimensional photoacoustic tomography system was used to monitor the mice at different times. Figure 10 As shown in Figure 2, the fluorescence of the mouse tumor site gradually increased over time within 2-8 hours after injection. Figure 11 As shown in the histogram, photoacoustic signals were consistently present at the tumor site over time, up to 24 hours. This example demonstrates the excellent tumor targeting properties of Compound I-1 and its excellent photoacoustic signal. Furthermore, the nude mice experienced no seizures or convulsions within 24 hours, demonstrating the near-total toxicity and high safety of Compound I-1.

[0196] Experimental Example 6: Photothermal Imaging Experiment in Photothermal Therapy in Mice

[0197] The experimental group of mice were injected with 200 μL of Ⅰ-1 (200 μg) through the tail vein. The tumor site of the mice was irradiated with 808 nm laser for 10 minutes. At the same time, the photothermal imager was used to continuously take pictures. The low-power laser was used to irradiate the tumor site to keep the temperature below 45°C. Under the irradiation of the laser, the tumor site was heated to 43°C. Figure 12 It can be seen that the temperature of the tissue around the tumor did not increase, indicating that the use of Ⅰ-1 for mild photothermal therapy can avoid the damage to surrounding tissues caused by high temperature, and is safer than traditional photothermal therapy.

[0198] Experimental Example 7: Photothermal therapy experiment in mice

[0199] Nude mice were divided into five groups. Group 1 received saline injection without laser irradiation; Group 2 received saline injection and laser irradiation for 10 minutes; Group 3 received 200 μL of Ⅰ-1 (200 μg) without laser irradiation; Group 4 received 200 μL of Ⅰ-1 (200 μg) via the tail vein and irradiated the tumor site with an 808 nm laser for 10 minutes. Group 5 received APO and photosensitizer coated with F127 and laser irradiated. Tumor volume in each group was measured daily with a vernier caliper for 22 days.

[0200] like Figure 13 , Group 4 nude mice after photothermal treatment, the tumor volume before photothermal treatment was 40mm 3 After photothermal treatment, the tumor ruptured slightly on the second day. As time went by, no obvious tumor growth was observed. The ruptured part of the tumor began to heal. On the 18th day, the ruptured part was completely healed with a small scar. Figure 14 The tumors of mice in the experimental group (Group 4) were eliminated after laser irradiation, while the tumor volumes of mice in the control group (Groups 1, 2, 3, and 5) continued to increase. Figure 15 There was no abnormal change in the body weight of mice in both the experimental and control groups, and no obvious side effects of Ⅰ-1 were observed. Figure 17 Twenty-two days after the experiment, mice in the experimental group were dissected, and the hearts, livers, spleens, lungs, and kidneys were sectioned and stained with H&E. No significant damage was observed in major tissues and organs. This demonstrates that I-1 possesses excellent, gentle photothermal therapeutic capabilities, does not damage internal organs, has minimal side effects, and is relatively safe and reliable.

[0201] These experiments demonstrate that compound I-1 exhibits excellent photothermal tumor-killing efficacy under mild conditions under 808nm laser irradiation, with high safety, and has broad application prospects in clinical photothermal therapy for cancer. Other compounds of the present invention have also been shown to exhibit similar photothermal therapeutic effects.

[0202] Test Example 8 Safety test of compound Ⅰ-1 in mice

[0203] Ten female Kunming mice were selected, 5 of which were injected with 200 μL of Ⅰ-1 (200 μg) through the tail vein, and 5 were injected with normal saline. After 24 hours, blood samples were collected from the mice for blood routine and liver function tests. Figure 16 As shown, routine blood tests, including mean corpuscular hemoglobin, red blood cell volume distribution width, hematocrit, and mean platelet volume, were all within normal ranges. Liver function tests, including albumin, transaminases, alkaline phosphatase, and blood glucose, were also within normal ranges. These results demonstrate that Compound I-1 has a high safety profile, does not cause liver damage in the short term, and is relatively safe and reliable.

[0204] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art may still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modifications, equivalent replacements, and modifications made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A compound for achieving mild photothermal therapy of tumors, characterized in that: The compound is compound I-1, 2. A pharmaceutical composition, characterized in that The invention comprises the compound according to claim 1, and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 and the pharmaceutical composition according to claim 2 in the preparation of tumor photothermal therapy drugs, heat shock protein inhibitors, and stimulus-responsive release drugs.

4. The use according to claim 3, characterized in that The phototherapy drug is a photothermal therapy drug, a photodynamic therapy drug or a photoacoustic therapy drug; the stimulus-responsive release is an oxidation-reduction response, an active oxygen response, a pH response, a temperature response, an enzyme response, an oxygen deficiency response, a light response and a magnetic response.

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