An iridium (III) complex prodrug for sound sensitization and its preparation method and application
Patent Information
- Application Number
- CN202611145184.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-07-30
- Publication Date
- 2026-10-23
AI Technical Summary
[0005]然而目前SDT研究尚处于起步阶段，其关键瓶颈在于缺乏高效安全的声敏剂，迄今尚无获批临床的产品
[0025]（1）本发明提供了一种具有优异声动力活性的铱(III)配合物声敏前药Ir-Fc。该前药以铱(III)配合物为核心声敏剂，在超声辐照下能够高效产生多种活性氧物种，且同时兼具Ⅱ型能量转移和I型电子转移两种ROS产生途径，对氧气浓度依赖较低，在乏氧微环境中仍能保持较好的治疗效果，有效克服了现有声敏剂活性不足的缺陷。
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Abstract
Description
Technical Field
[0001] This invention relates to the field of medicinal chemistry, specifically to a hypochlorous acid-responsive iridium(III) complex sonosensitive prodrug, its preparation method, and its application. Background Technology
[0002] Malignant tumors are a major disease that seriously threatens human life and health. Their incidence and mortality rates continue to rise globally, making them a prominent public health issue. Current cancer treatments include surgical resection, chemotherapy, radiotherapy, and photodynamic therapy (PDT), but each has its own limitations, necessitating the development of novel treatment strategies.
[0003] PDT utilizes light of a specific wavelength to excite a photosensitizer and generate reactive oxygen species (ROS), thereby inducing apoptosis and necrosis of tumor cells. This therapy has gained widespread attention and entered clinical application due to its advantages such as being minimally invasive, highly spatiotemporally selective, and having few toxic side effects. However, the efficacy of PDT is highly dependent on the tissue penetration capability of the excitation light; visible light penetrates only a few millimeters, and near-infrared light only 5-15 millimeters, making it difficult to effectively target deep tumors, severely limiting its clinical applicability.
[0004] Sonodynamic therapy (SDT) is a novel non-invasive treatment technique developed from photodynamic therapy (PDT). Its excitation source typically uses low-intensity ultrasound. During propagation, ultrasound waves induce cavitation. The mechanical shear force and localized high temperature generated by this effect directly activate the sonosensitive agent. The excited-state sonosensitive agent generates reactive oxygen species (ROS) with strong cytotoxicity through electron transfer or energy transfer. Compared to PDT, the biggest advantage of SDT is that ultrasound can penetrate tissue to a depth of several centimeters to over ten centimeters, achieving effective treatment of deep lesions.
[0005] However, SDT research is still in its early stages, with a key bottleneck being the lack of highly effective and safe sonosensitive agents; to date, no products have been approved for clinical trials. Furthermore, traditional antitumor drugs and sonosensitive agents suffer from systemic toxicity due to non-specific distribution, severely limiting treatment safety. The inherently high ROS characteristics of the tumor microenvironment offer the possibility of designing smart, responsive prodrugs that can be specifically activated.
[0006] Iridium (III) complexes, a transition metal, have shown significant advantages in the development of sonodynamic therapeutic drugs. Iridium (III) complexes possess tunable structures, excellent biocompatibility, and high intersystem crossing ability, and can efficiently generate reactive oxygen species (ROS) upon ultrasonic excitation. More importantly, iridium complexes readily generate ROS via type I electron transfer pathways, exhibiting low dependence on oxygen concentration and maintaining good therapeutic efficacy even in hypoxic microenvironments.
[0007] Based on the above problems, the development of an iridium(III) complex sonodynamic prodrug that can be specifically activated under the action of high concentrations of ROS in the tumor microenvironment is expected to overcome multiple defects such as insufficient penetration depth and non-specific toxicity, and achieve precise sonodynamic therapy for deep tumors, providing a new candidate drug for tumor sonodynamic therapy.
[0008] The information disclosed in this background section is intended only to enhance the understanding of the overall background of the invention and should not be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art. Summary of the Invention
[0009] To address the aforementioned technical problems, embodiments of the present invention provide a hypochlorous acid-responsive iridium(III) complex acoustic prodrug, its preparation method, and its application, thereby resolving the issues raised in the background section.
[0010] A hypochlorous acid-responsive iridium(III) complex acoustic prodrug, the structural formula of which is as follows: Figure 1 As shown in Chinese formula I.
[0011] A method for preparing a hypochlorous acid-responsive iridium(III) complex acoustic prodrug, the synthetic route of which is described above. Figure 2 As shown.
[0012] Preferably, the preparation method of the hypochlorous acid-responsive iridium(III) complex acoustic prodrug according to the above description includes the following preparation steps:
[0013] (1) Compound 1 was reacted with thionyl chloride, and then condensed with compound 3 in the presence of anhydrous triethylamine to obtain compound 4;
[0014] (2) Compound 5 and compound 6 were coupled in toluene, ethanol and sodium carbonate solution in the presence of the catalyst tetra(triphenylphosphine)palladium, and purified to obtain compound 7;
[0015] (3) Compound 7 was reacted with iridium trichloride hydrate under reflux in a mixed solvent of ethylene glycol ethyl ether and water to obtain compound 8;
[0016] (4) Compound 8 and compound 4 were refluxed in a mixed solvent of dichloromethane and methanol, and then potassium hexafluorophosphate was added and stirred to purify the sound-sensitive prodrug Ir-Fc.
[0017] Preferably, compound 1 and thionyl chloride are refluxed and stirred at 80 °C for 4 h, evaporated to dryness, and then reacted with compound 3 in anhydrous dichloromethane with anhydrous triethylamine as a neutralizing agent at room temperature for 12 h.
[0018] Preferably, the Suzuki coupling reaction conditions in step (2) are: reflux and stirring at 106 °C for 5 h under nitrogen protection.
[0019] Preferably, in step (3), the volume ratio of ethylene glycol ethyl ether to deionized water in the mixed solvent is 3:1, the reaction temperature is 110 °C, and the reaction time is 24 h.
[0020] Preferably, in step (4), the volume ratio of dichloromethane to methanol is 1:1, the reaction temperature is 65 °C, and the reaction time is 9 h.
[0021] The application of an iridium(III) complex sonosensitive prodrug according to the above description in the preparation of a sonodynamic therapeutic drug.
[0022] Preferably, the acoustically sensitive prodrug Ir-Fc generates reactive oxygen species under ultrasonic excitation, the reactive oxygen species including ¹O2, •OH and O2. • ⁻.
[0023] A pharmaceutical composition for sonodynamic therapy of tumors, comprising the aforementioned iridium(III) complex sonosensitive prodrug and pharmaceutically acceptable excipients.
[0024] The present invention provides a hypochlorous acid-responsive iridium(III) complex acoustic prodrug, its preparation method, and its application, which have the following beneficial effects:
[0025] (1) This invention provides an iridium(III) complex sonosensitive prodrug Ir-Fc with excellent sonodynamic activity. The prodrug uses an iridium(III) complex as the core sonosensitive agent, which can efficiently generate a variety of reactive oxygen species under ultrasonic irradiation, and simultaneously possesses both type II energy transfer and type I electron transfer ROS generation pathways. It has low dependence on oxygen concentration and can still maintain good therapeutic effect in hypoxic microenvironments, effectively overcoming the shortcomings of insufficient activity of existing sonosensitive agents.
[0026] (2) This invention covalently links a ferrocene group to an iridium(III) complex via an acylhydrazine bond, constructing a smart prodrug with specific responsiveness to the tumor microenvironment. The ferrocene group effectively quenches the sonodynamic activity of the iridium complex through a photoinduced electron transfer mechanism, keeping the prodrug in an OFF state under normal physiological conditions. Upon reaching the tumor microenvironment, high-concentration hypochlorous acid specifically oxidizes and cleaves the acylhydrazine bond, releasing ferrocene carboxylic acid and restoring the sonodynamic function of the active sonosensitive agent Ir. This prodrug exhibits high detection sensitivity to hypochlorous acid, accurately distinguishing tumor tissue from normal tissue and significantly reducing non-specific damage to normal tissue.
[0027] (3) This invention uses ultrasound as an external excitation source. By utilizing the physical property of ultrasound to penetrate tissues deeply, it effectively overcomes the limitation of insufficient light penetration depth in traditional photodynamic therapy. It can penetrate deep tissues non-invasively and precisely activate the sonosensitive agent, generating a high concentration of cytotoxic ROS in situ in deep lesions, thereby achieving efficient and precise killing of deep tumors. Attached Figure Description
[0028] Figure 1 The chemical structural formula of the sonosensitive prodrug Ir-Fc.
[0029] Figure 2 Synthetic route diagram of the acoustic-sensitive prodrug Ir-Fc.
[0030] Figure 3 The proton NMR spectrum of compound 4.
[0031] Figure 4 Mass spectrum of compound 4.
[0032] Figure 5 The proton NMR spectrum of compound 7.
[0033] Figure 6 Mass spectrum of compound 7.
[0034] Figure 7 The proton NMR spectrum of the acoustic-sensitive prodrug Ir-Fc.
[0035] Figure 8 Mass spectrum of the sonosensitive prodrug Ir-Fc.
[0036] Figure 9 A schematic diagram of the reaction process between the acoustic prodrug Ir-Fc and HClO.
[0037] Figure 10 Excitation and emission spectra of Ir, Ir-Fc, and Ir-Fc after reaction with HClO.
[0038] Figure 11 Phosphorescence response of the acoustic prodrug Ir-Fc to HClO.
[0039] in, Figure 11 In Figure A, the phosphorescence emission spectra of Ir-Fc reacting with different concentrations of HClO are shown.
[0040] in, Figure 11 B is the standard curve of phosphorescence intensity at 668 nm versus HClO concentration.
[0041] Figure 12 High-resolution mass spectrum of the reaction products of Ir-Fc and HClO.
[0042] in, Figure 12A in the middle is a high-resolution mass spectrum in positive mode.
[0043] in, Figure 12 The B-mode high-resolution mass spectrum is shown in the image.
[0044] Figure 13 Detection of singlet oxygen generated by ultrasound after Ir-Fc reacts with HClO.
[0045] in, Figure 13 In the image, A represents the ultraviolet absorption spectrum of the DPBF probe at 410 nm as a function of ultrasonic time.
[0046] in, Figure 13 Figure B shows a comparison of ¹O2 generation in different control groups under the same ultrasound conditions.
[0047] Figure 14 Detection of hydroxyl radicals generated by ultrasound after Ir-Fc reacts with HClO.
[0048] in, Figure 14 In Figure A, the ultraviolet absorption spectrum of the TMB probe at 652 nm as a function of ultrasonic time is shown.
[0049] in, Figure 14 Figure B shows a comparison of •OH generation in different control groups under the same ultrasound conditions.
[0050] Figure 15 Detection of superoxide anions generated by ultrasound after Ir-Fc reacts with HClO.
[0051] in, Figure 15 In Figure A, the fluorescence spectrum of the DHR123 probe at 540 nm is shown as a function of sonication time.
[0052] in, Figure 15 B represents the O2 levels of different control groups under the same ultrasound conditions. • ⁻Comparison of generation scenarios. Detailed Implementation
[0053] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0054] To address the aforementioned technical problems, embodiments of the present invention provide a hypochlorous acid-responsive iridium(III) complex acoustic prodrug, its preparation method, and its application, thereby resolving the issues raised in the background section.
[0055] Example 1: Preparation of Ir-Fc, an iridium(III) complex acoustic sensitizer
[0056] The synthetic route of the iridium(III) complex acoustic sensitizer Ir-Fc is as follows: Figure 2 As shown, the structures of the synthetic intermediate and the target product were confirmed using 1H NMR spectroscopy and mass spectrometry.
[0057] Synthesis and characterization of compound 4: Compound 1 (107 mg, 0.5 mmol) was added to 9 mL of SOCl2, refluxed at 80 °C and stirred for 4 h. The product was evaporated to dryness and then vacuum dried for 2 h. Compound 3 (122 mg, 0.5 mmol) was then added, followed by 10 mL of anhydrous dichloromethane, and then 300 μL of anhydrous triethylamine was added dropwise. The reaction was carried out at room temperature for 12 h. The product was evaporated to dryness and purified by Al2O3 chromatography using DCM-MeOH to obtain compound 4 (structural characterization data are shown in the figure). Figure 3 and 4 ESI-MS (M+H) + , m / z): 441.495. 1 HNMR (600 MHZ, DMSO-d6), 10.75 (s, 1H), 9.88 (s, 1H), 8.84-8.82 (m, 2H), 8.56 (s, 1H), 8.26 (s, 1H), 7.85 (s, 1H), 7.31 (s, 1H), 4.86 (s, 2H), 4.39 (s, 2H), 4.30 (s, 5H), 2.41 (s, 3H).
[0058] Synthesis and characterization of compound 7: Compound 5 (852.12 mg, 4 mmol), compound 6 (688.82 mg, 4 mmol), and the catalyst tetrakis(triphenylphosphine)palladium (173.34 mg, 0.15 mmol) were dissolved in 8 mL toluene, 5 mL ethanol, and 10 mL Na₂CO₃ (2 M) solution. The mixture was refluxed at 106 °C for 5 h under nitrogen protection, cooled to room temperature, and extracted three times with DCM. The extract was dried over anhydrous magnesium sulfate, filtered, and the product was evaporated to dryness and purified by silica gel chromatography using a PE-DCM column to obtain compound 7 (structural characterization data are shown below). Figure 5 and 6 ESI-MS (M+H) + , m / z): 306.126. 1H NMR (600 MHZ, DMSO-d6), 8.98 (d, J=7.98HZ, 1H), 8.89-8.88 (dd, J1=8.28HZ, J2=1.62HZ, 1H), 8.29(s, 1H), 8.16-8.15 (dd, J1=8.22HZ, J2=1.50HZ, 1H), 8.14-8.11 (m, 2H), 8.10-8.06 (m, 2H), 8.01-7.98 (m, 1H), 7.88-7.86 (dd, J1=8.34HZ, J2=1.80HZ, 1H),7.85-7.82 (m, 1H), 7.79-7.74 (m, 2H).
[0059] Synthesis of Compound 8: Compound 7 (915.36 mg, 3 mmol) and IrCl3•H2O (447.87 mg, 1.5 mmol) were dissolved in 20 mL of ethylene glycol diethyl ether / deionized water (3:1, v:v). The mixture was refluxed at 110 °C for 24 h under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, filtered, and washed repeatedly with deionized water and ethanol until the filtrate was colorless. The resulting solid was dried under vacuum to obtain Compound 8.
[0060] Synthesis and characterization of the sonosensitive prodrug Ir-Fc: Compound 8 (167.6 mg, 0.1 mmol) and compound 4 (22 mg, 0.05 mmol) were dissolved in 30 mL (DCM:MeOH = 1:1, V:V). Under nitrogen protection, the mixture was refluxed at 65 °C with stirring for 9 h. After cooling to room temperature, potassium hexafluorophosphate (368 mg, 2 mmol) was added, and the mixture was stirred for 1 h. The product was evaporated to dryness and purified by silica gel chromatography using DCM-MeOH to obtain the sonosensitive prodrug Ir-Fc (structural characterization data are shown in Figure 1). Figure 7 and 8 ESI-MS ([M-PF6)) + , m / z):1241.283. 1H NMR (600 MHZ, CD3CN), 9.44 (t, J=6.73HZ, 3H), 9.02-8.98 (m, 3H), 8.71-8.68 (m, 3H), 8.52-8.48 (m, 2H), 8.20 (s, 1H), 8.04-7.99 (m, 7H), 7.95(d, J=8.82HZ, 1H), 7.89 (d, J=8.64HZ, 1H), 7.80 (s, 1H), 7.62 (d, J=5.94HZ,1H), 7.49-7.44 (m, 2H), 7.33-7.24 (m, 7H), 7.17-7.14 (m, 3H), 7.08 (t, J=7.50HZ, 2H), 4.62 (s, 2H), 4.31 (s, 2H), 4.21 (s, 5H), 2.12 (s, 3H).
[0061] Example 2: Response process of the acoustic prodrug Ir-Fc with HClO:
[0062] like Figure 9 As shown, after the acoustic sensitizing prodrug Ir-Fc designed in this invention reaches the tumor tissue, its hydrazide bond can be specifically oxidized and cleaved by HClO highly expressed in the microenvironment, thereby releasing ferroceneic acid and the active acoustic sensitizer Ir. Due to the release of ferroceneic acid, its PET quenching effect on the iridium complex is relieved, and the acoustic dynamic activity of Ir is restored.
[0063] Example 3: The response of the sonosensitive prodrug Ir-Fc to HClO was investigated by phosphorescence spectroscopy analysis:
[0064] The phosphorescence spectra of Ir-Fc before and after the reaction with ROS were tested in 10 mM PBS and 20% DMSO buffer solution at pH 7.4. Figure 10 As shown, the optimal excitation wavelength of Ir-Fc after reacting with 10 μM HClO and Ir is 400 nm, and the maximum emission wavelength is 668 nm. The phosphorescence intensity of Ir-Fc is very weak, but it has a high phosphorescence intensity after reacting with HClO. The sonosensitive prodrug Ir-Fc can react with HClO to generate a sonosensitive agent Ir with phosphorescent emission capability.
[0065] The phosphorescence response of Ir-Fc to different concentrations of HClO was investigated in a 10 mM PBS (containing 20% DMSO) buffer solution at pH 7.4. Figure 11 A and Figure 11As shown in Figure B, the luminescence intensity of Ir-Fc gradually increases with increasing HClO concentration. A standard curve was plotted to show the luminescence intensity of Ir-Fc at 668 nm for different HClO concentrations; the linear equation is y = 35.47x + 219.5 (R²). 2 =0.988). Based on LOD=3σ / k, the limit of detection is calculated to be 184 nM.
[0066] The results showed that Ir-Fc exhibited a sensitive phosphorescence response to HClO, with its limit of detection (184 nM) falling within the threshold window between normal tissue (<10 nM) and tumor tissue (30-100 μM) concentrations. This characteristic ensures that Ir-Fc is specifically activated only in the high-HClO microenvironment of tumors, while remaining inert in normal tissues, thus achieving efficient identification and differentiation of tumor tissues.
[0067] Example 4: The response mechanism of the sonosensitive prodrug Ir-Fc to HClO was investigated by high-resolution mass spectrometry analysis:
[0068] The reaction mechanism of the sonosensitive prodrug Ir-Fc reacting with HClO to generate the sonosensitive agents Ir and ferrocene carboxylic acid was verified by high-resolution mass spectrometry analysis. Figure 12 A and Figure 12 As shown in Figure B, a new mass spectrum signal (m / z = 1015.2590) appears in the positive mode mass spectrum of the reaction product of the sonosensitive prodrug Ir-Fc and HClO, which is similar to the [M-PF6] signal of the sonosensitive agent Ir. + The molecular ion peak corresponds to this, and a new mass spectral signal of m / z = 228.9957 appears in the negative mode mass spectrum, which corresponds to the M of ferrocene carboxylic acid. - The molecular ion peaks correspond to these peaks. This demonstrates that the sonosensitive prodrug Ir-Fc reacts with HClO to generate ferrocene carboxylic acid and the sonodynamically active product Ir. These results indicate that Ir-Fc is an HClO-responsive sonosensitive prodrug, releasing ferrocene carboxylic acid and the sonosensitive agent Ir from high concentrations of hypochlorous acid in the tumor microenvironment.
[0069] Example 5: Investigating the ability of the acoustic sensitizer Ir-Fc to generate ROS under ultrasound using a commercially available ROS probe.
[0070] Ir-Fc generation 1 The ability to generate O2 was evaluated using the probe DPBF. For example... Figure 13 As shown in Figure A, after Ir-Fc (10 μM) reacted with HClO (100 μM) for 10 min, the following was added: 1The absorbance of the O2 probe DPBF (50 μM) gradually decreased at 410 nm with sonication (1.5 W / cm², 5 min, duty cycle 50%) from 0 to 300 s, indicating that the reaction of Ir-Fc with HClO can effectively generate [the necessary components] under ultrasonic excitation. 1 O2. For example... Figure 13 As shown in Figure B, under ultrasonic irradiation, the absorbance at 410 nm of the DPBF group and the Ir-Fc and DPBF group did not change significantly at different time intervals. However, the absorbance at 410 nm of the Ir and DPBF group and the Ir-Fc and HClO reaction group decreased significantly. This is because the conjugated system is destroyed after the probe DPBF reacts with ¹O₂, thus reducing the absorbance at 410 nm. The results indicate that the reaction of Ir-Fc with HClO can produce [something] under ultrasonic irradiation. 1 O2.
[0071] The ability of Ir-Fc to generate •OH was evaluated using the probe TMB. For example... Figure 14 As shown in Figure A, after Ir-Fc (10 μM) reacted with HClO (100 μM) for 10 min, probe TMB (500 μM) was added. With sonication (1.5 W / cm², 5 min, duty cycle 50%) from 0 s to 300 s, the absorbance of TMB at 652 nm gradually increased, indicating that Ir-Fc reacts with HClO and can effectively generate •OH under ultrasonic excitation. Figure 14 As shown in Figure B, under ultrasonic treatment, the absorbance at 652 nm of the TMB group and the Ir-Fc and TMB group showed no significant change at the same time interval. However, the absorbance at 652 nm of the Ir and TMB group and the Ir-Fc and HClO reaction group increased significantly. This is because the probe TMB is oxidized after reacting with •OH, resulting in a characteristic peak at 652 nm, and the prepared solution changes from colorless to blue. The results indicate that •OH can be generated after the reaction of Ir-Fc with HClO under ultrasonic treatment.
[0072] Ir-Fc generates O2 •- The capability was evaluated using the DHR123 probe. For example... Figure 15 As shown in Figure A, after Ir-Fc (10 μM) reacted with HClO (100 μM) for 10 min, the probe DHR123 (10 μM) was added. With sonication (1.5 W / cm², 5 min, duty cycle 50%) from 0 s to 300 s, the fluorescence intensity at 540 nm gradually increased, indicating that Ir-Fc reacts with HClO and can effectively generate O2 under ultrasonic excitation. •- .like Figure 15As shown in Figure B, under ultrasonic treatment, the fluorescence intensity of the DHR123 group and the Ir-Fc and DHR123 group showed no significant change at 540 nm at different time intervals. However, the fluorescence intensity of the Ir and DHR123 group and the Ir-Fc and HClO reaction group showed a significant increase at 540 nm. The probe DHR123 reacts with O2... •- The material was oxidized after the reaction, and its fluorescence was enhanced at 540 nm. The results indicate that Ir-Fc reacts with HClO to generate O2 under ultrasonication. •- .
[0073] The above experimental results show that Ir-Fc can be specifically activated by HClO, and the activated sonosensitive agent can efficiently generate ROS under ultrasonic irradiation, such as... 1 O 2、 •OH and O2 •- This indicates that it has good sonodynamic therapeutic activity.
[0074] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.
Claims
1. A hypochlorous acid-responsive iridium(III) complex sonosensitive prodrug, characterized in that, Its structural formula is shown in Equation I below: 。 2. A method for preparing a hypochlorous acid-responsive iridium(III) complex acoustic prodrug according to claim 1, characterized in that, Its synthetic route is as follows: 。 3. The method for preparing the hypochlorous acid-responsive iridium(III) complex acoustic prodrug according to claim 2, characterized in that, The preparation steps include the following: (1) Compound 1 was reacted with thionyl chloride, and then condensed with compound 3 in the presence of anhydrous triethylamine to obtain compound 4; (2) Compound 5 and compound 6 were coupled in toluene, ethanol and sodium carbonate solution in the presence of the catalyst tetra(triphenylphosphine)palladium, and purified to obtain compound 7; (3) Compound 7 was reacted with iridium trichloride hydrate under reflux in a mixed solvent of ethylene glycol ethyl ether and water to obtain compound 8; (4) Compound 8 and compound 4 were refluxed in a mixed solvent of dichloromethane and methanol, and then potassium hexafluorophosphate was added and stirred to purify the sound-sensitive prodrug Ir-Fc.
4. The method for preparing the hypochlorous acid-responsive iridium(III) complex acoustic prodrug according to claim 3, characterized in that, The reaction conditions described in step (1) are as follows: Compound 1 and thionyl chloride are refluxed and stirred at 80 °C for 4 h, evaporated to dryness, and then reacted with Compound 3 in anhydrous dichloromethane with anhydrous triethylamine as a neutralizing agent at room temperature for 12 h.
5. The method for preparing the hypochlorous acid-responsive iridium(III) complex acoustic prodrug according to claim 3, characterized in that, The Suzuki coupling reaction conditions described in step (2) are: reflux and stirring at 106 °C for 5 h under nitrogen protection.
6. The method for preparing the hypochlorous acid-responsive iridium(III) complex acoustic prodrug according to claim 3, characterized in that, In step (3), the volume ratio of ethylene glycol ethyl ether to deionized water in the mixed solvent is 3:1, the reaction temperature is 110 °C, and the reaction time is 24 h.
7. The method for preparing the hypochlorous acid-responsive iridium(III) complex acoustic prodrug according to claim 3, characterized in that, In step (4), the volume ratio of dichloromethane to methanol is 1:1, the reaction temperature is 65 °C, and the reaction time is 9 h.
8. The use of an iridium(III) complex sonosensitive prodrug according to claim 1 in the preparation of a sonodynamic therapeutic drug.
9. The application according to claim 8, characterized in that, The acoustically sensitive prodrug Ir-Fc generates reactive oxygen species under ultrasonic excitation, including ¹O₂, •OH, and O₂. • ⁻.
10. A pharmaceutical composition for sonodynamic therapy of tumors, characterized in that, It includes the iridium(III) complex sonosensitive prodrug as described in claim 1 and pharmaceutically acceptable excipients.