Preparation method and application of conjugated microporous polymer type sound-sensitive agent
By designing triphenylamine-based conjugated microporous polymers, the problems of low ROS production and poor biocompatibility of sonosensitizers in sonodynamic therapy were solved, efficient and safe targeted therapy effects were achieved, and the drug enrichment and ROS production capabilities in the lesion area were enhanced.
Patent Information
- Application Number
- CN202510920964.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-04
- Publication Date
- 2025-10-28
AI Technical Summary
Existing sonosensitizers have low ROS production, poor biocompatibility, and difficulty in targeted delivery in sonodynamic therapy, resulting in limited therapeutic effects and increased side effects.
A conjugated microporous polymer based on triphenylamine was designed and synthesized, and a three-dimensional conjugated network was formed by linking thiophene units to improve drug loading capacity and biocompatibility, enhance ROS production ability, and construct targeted delivery function.
It improves the efficiency and safety of sonodynamic therapy, enhances the drug enrichment effect in the lesion area, reduces systemic toxicity, and expands the molecular design space to optimize sonosensitive performance.
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Figure CN120842545A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing a conjugated microporous polymer-type sonosensitive agent and its application in sonodynamic therapy (SDT), belonging to the interdisciplinary field of organic optoelectronic materials and biomedicine. Background Technology
[0002] Sonodynamic therapy (SDT) is an emerging non-invasive cancer treatment technology that utilizes ultrasound to activate specific sonosensitive agents to generate reactive oxygen species (ROS), inducing tumor cell apoptosis. Traditional sonosensitive agents (such as porphyrins) suffer from low ROS yields, poor biocompatibility, and difficulty in targeted delivery. Conjugated microporous polymers (CMPs), due to their high specific surface area, tunable pore structure, and excellent photoelectric properties, have wide applications in drug loading and energy conversion. However, the application of existing CMPs in sonodynamic therapy is not yet fully explored, and molecular design targeting sonosensitive properties is lacking. Therefore, designing and synthesizing novel CMP-type sonosensitive agents to improve the therapeutic effect of SDT is of significant research value. Summary of the Invention
[0003] Based on the above analysis, this invention designs a conjugated microporous polymer with triphenylamine as the main component and molecules of different lengths as connectors. The three-dimensional microporous structure improves drug loading and the generation of ultrasonic cavitation effects, and its application in SDT is explored. This invention is achieved through the following technical solution:
[0004] This invention first discloses a conjugated microporous polymer-type sound-sensitive agent, which uses triphenylamine units as the main structure and thiophene units as linking molecules to form a three-dimensional conjugated network through covalent bonds. Its general chemical structure is shown in formula (I):
[0005]
[0006] In this system, triphenylamine is the main unit, Th is the thiophene unit, n is the number of thiophene links (1≤n≤3), and m is the degree of polymerization.
[0007] This invention also discloses a method for preparing the conjugated microporous polymeric acoustic sensor described in Formula I above, comprising the following steps:
[0008] (1) Dissolve tris(4-bromophenyl)amine and thiophene tin derivatives in toluene at a molar ratio of 1:1.5, and add the catalyst bis(triphenylphosphine)palladium(II) dichloride;
[0009] (2) Under inert gas protection, carry out the oxidative coupling reaction at 85°C for 10-12 hours;
[0010] (3) After the reaction is complete, the solution is dissolved in dichloromethane and then added dropwise to anhydrous methanol under stirring. The settled solution is centrifuged, the supernatant is removed after centrifugation, and the solid obtained is dried under vacuum overnight to obtain the target polymer.
[0011] This invention also discloses a conjugated microporous polymer type sound-sensitive agent, which uses triphenylamine units as the main structure and 4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)dithiophen-2,6-diyl)bistrimethyltin (TT) as the linking molecule, forming a three-dimensional conjugated network through covalent bonds. Its chemical structural formula is shown in formula (II):
[0012]
[0013] In this system, triphenylamine is the main unit, TT is the connecting unit, and m is the degree of polymerization.
[0014] This invention also discloses a method for preparing the conjugated microporous polymer type sound-sensing agent described in Formula II above, comprising the following steps:
[0015] (1) Tri(4-bromophenyl)amine and 8-bis(5-(2-ethylhexyl)thiophen-2-yl)dithiophen-2,6-diyl)bistrimethyltin were dissolved in toluene at a molar ratio of 1:1.5, and the catalyst bis(triphenylphosphine)palladium(II) chloride was added;
[0016] (2) Under inert gas protection, carry out the oxidative coupling reaction at 85°C for 10-12 hours;
[0017] (3) After the reaction is complete, the solution is dissolved in dichloromethane and then added dropwise to anhydrous methanol under stirring. The settled solution is centrifuged, the supernatant is removed after centrifugation, and the solid obtained is dried under vacuum overnight to obtain the target polymer.
[0018] This invention discloses a conjugated microporous polymer type acoustic sensor prepared according to any of the above preparation methods.
[0019] The present invention also discloses the application of any of the above-described conjugated microporous polymer type sonosensitive agents in sonodynamic therapy.
[0020] The beneficial effects of this invention are as follows:
[0021] Currently widely used traditional sonosensitive agents, such as porphyrins and phthalocyanines, have many limitations in sonodynamic therapy (SDT). First, their reactive oxygen species (ROS) yields are generally low, resulting in limited therapeutic efficacy. Second, these traditional sonosensitive agents generally suffer from poor water solubility and biocompatibility, limiting their stability and safety in vivo. Furthermore, traditional sonosensitive agents typically lack targeted delivery capabilities, are easily absorbed by non-target tissues, leading to increased side effects and reduced treatment efficiency. In summary, existing sonosensitive agents are insufficient to meet the clinical needs for efficient, safe, and targeted therapy, necessitating breakthroughs with new technological solutions. The improvements and technical effects of this invention...
[0022] This invention provides a novel sound-sensing agent based on conjugated microporous polymers (CMPs). Through rational molecular design and structural regulation, it effectively solves the problems existing in traditional sound-sensing agents. CMPs materials have the following significant advantages:
[0023] High specific surface area and tunable pore structure: help enhance drug loading capacity and improve dispersion and stability in complex physiological environments; excellent photoelectric properties: can efficiently generate ROS under ultrasonic excitation, significantly improving the efficacy of SDT treatment; good biocompatibility and structural modifiability: help construct targeted delivery functional units, enhance enrichment effect in lesion areas, and reduce systemic toxicity; scalable molecular design space: through fine control of electron donor-acceptor units in the CMP backbone structure, the band structure and acoustic sensitivity can be further optimized, achieving effective enhancement of acoustic dynamic response. Attached Figure Description
[0024] Figure 1 Images representing the surface morphology of a material obtained using transmission electron microscopy (TEM);
[0025] Figure 2 Images representing the surface morphology of a material obtained using scanning electron microscopy (SEM);
[0026] Figure 3 To obtain the nitrogen adsorption-desorption curves of the material using a specific surface area and pore size analyzer (BET);
[0027] Figure 4 Normalized absorption spectra of TPA-Th, TPA-DTh, TPA-TTh, and TPA-TT in water;
[0028] Figure 5 Normalized emission spectra of TPA-Th, TPA-DTh, TPA-TTh, and TPA-TT in water;
[0029] Figure 6The TPA-Th 1H NMR spectrum;
[0030] Figure 7 The TPA-DTh 1H NMR spectrum;
[0031] Figure 8 The TPA-TTh 1H NMR spectrum;
[0032] Figure 9 The hydrogen NMR spectrum of TPA-TT;
[0033] Figure 10 The instrument parameters were set to a frequency of 3.0 MHz, a duty cycle of 50%, and a power of 1 W / cm². 2 Under the condition that the solvent is EtOH:H2O=1:1, the absorption decrease curve of DPBF after 10 minutes of ultrasonic treatment after the addition of TPA-Th.
[0034] Figure 11 The instrument parameters were set to a frequency of 3.0 MHz, a duty cycle of 50%, and a power of 1 W / cm². 2 Under the condition that the solvent is EtOH:H2O=1:1, after adding TPA-DTh, the absorption decrease curve of DPBF after 10 minutes of ultrasonic treatment.
[0035] Figure 12 The instrument parameters were set to a frequency of 3.0 MHz, a duty cycle of 50%, and a power of 1 W / cm². 2 Under the condition that the solvent is EtOH:H2O=1:1, after adding TPA-TTh, the absorption decrease curve of DPBF after 10 minutes of ultrasonic treatment.
[0036] Figure 13 The instrument parameters were set to a frequency of 3.0 MHz, a duty cycle of 50%, and a power of 1 W / cm². 2 Under the condition that the solvent is EtOH:H2O=1:1, after adding TPA-TTh, the absorption decrease curve of DPBF after 10 minutes of ultrasonic treatment.
[0037] Figure 14 The instrument parameters were set to a frequency of 3.0 MHz, a duty cycle of 50%, and a power of 1 W / cm². 2 Under the condition that the solvent is EtOH:H2O=1:1, the absorption decrease curve of DPBF after continuous ultrasonic treatment after adding different concentrations of TPA-TT.
[0038] Figure 15The absorption decrease curves of DPBF after ultrasonic treatment with different power were obtained under the conditions of instrument parameters set to frequency 3.0MHz, duty cycle 50%, and solvent EtOH:H2O=1:1, after adding the same concentration of TPA-TT. Detailed Implementation
[0039] To make the objectives, technical solutions, and advantages of this disclosure clearer, the following detailed description is provided in conjunction with specific embodiments and the accompanying drawings.
[0040] Example 1
[0041] In Equation I, when n = 1:
[0042]
[0043] 2,5-bis(trimethyltinyl)thiophene and tris(4-bromophenyl)amine were dissolved in toluene in a molar ratio of 1.5:1 in a 10 ml Schlenk tube equipped with a magnetic flux. The catalyst bis(triphenylphosphine)palladium(II) dichloride was added. After the addition was complete, the entire reaction system was sealed and evacuated, then purged with nitrogen. The reaction was carried out under a nitrogen atmosphere at 85°C for 10-12 hours for oxidative coupling. After the reaction was complete, the solution was dissolved in dichloromethane and added dropwise to anhydrous methanol with stirring. The settled solution was centrifuged, and the supernatant was discarded. The resulting solid was dried under vacuum overnight to obtain the target polymer TPA-Th.
[0044] Example 2
[0045] In Equation I, when n = 2:
[0046]
[0047] 5,5'-bis(trimethyltin)-2,2'-bithiophene and tris(4-bromophenyl)amine were added to a 10 ml Schlenk tube with a magnetic flux in a molar ratio of 1.5:1 and dissolved in toluene. The catalyst bis(triphenylphosphine)palladium(II) dichloride was added. After the addition was complete, the entire reaction system was sealed and evacuated, then purged with nitrogen. The reaction was carried out under a nitrogen atmosphere at 85°C for 10-12 hours for oxidative coupling. After the reaction was complete, the solution was dissolved in dichloromethane and added dropwise to anhydrous methanol with stirring. The settled solution was centrifuged, and the supernatant was discarded. The resulting solid was dried under vacuum overnight to obtain the target polymer TPA-DTh.
[0048] Example 3
[0049] In Equation I, when n = 3:
[0050]
[0051] 5,5”-bis(trimethyltinyl)-2,2':5',2”-trithiophene and tris(4-bromophenyl)amine were dissolved in toluene in a molar ratio of 1.5:1 in a 10 ml Schlenk tube equipped with a magnetic flux. The catalyst bis(triphenylphosphine)palladium(II) dichloride was added. After the addition was complete, the entire reaction system was sealed and evacuated, then purged with nitrogen. The reaction was carried out under a nitrogen atmosphere at 85 °C for 10-12 hours for oxidative coupling. After the reaction was complete, the solution was dissolved in dichloromethane and added dropwise to anhydrous methanol with stirring. The settled solution was centrifuged, and the supernatant was discarded. The resulting solid was dried under vacuum overnight to obtain the target polymer TPA-TTh.
[0052] Example 4
[0053] In Formula II:
[0054]
[0055] 8-bis(5-(2-ethylhexyl)thiophen-2-yl)dithiophen-2,6-diyl)bistrimethyltin and tri(4-bromophenyl)amine were dissolved in toluene in a molar ratio of 1.5:1 in a 10 ml Schlenk tube equipped with a magnetic flux. The catalyst bis(triphenylphosphine)palladium(II) dichloride was added. After the addition was complete, the entire reaction system was sealed and evacuated, then purged with nitrogen. The reaction was carried out under a nitrogen atmosphere at 85°C for 10-12 hours for oxidative coupling. After the reaction was complete, the solution was dissolved in dichloromethane and added dropwise to anhydrous methanol with stirring. The settled solution was centrifuged, and the supernatant was discarded. The resulting solid was dried under vacuum overnight to obtain the target polymer TPA-TT.
[0056] This invention provides the application of the conjugated microporous polymer material in sonodynamic therapy.
[0057] Experimental example:
[0058] The prepared products underwent the following material characterization and performance testing:
[0059] The prepared products were analyzed using transmission electron microscopy (TEM) (e.g.) Figure 1 ) and scanning electron microscope (SEM) (such as Figure 2 The material was characterized by its morphology, proving that it is a porous conjugated microporous polymer.
[0060] The prepared products were characterized by pore size analysis using a surface area and pore size analyzer (BET). The results are shown in Table 1, along with the nitrogen adsorption-desorption curves of each material (e.g., ...). Figure 3 This indicates that the obtained material is a conjugated microporous polymer with mesoporous structure.
[0061] Table 1
[0062]
[0063] The prepared products were characterized by photophysical properties and normalized representation (e.g.) Figures 4-5 As shown in Table 2:
[0064] Table 2
[0065]
[0066]
[0067] The prepared product was characterized by molecular structure using 1H NMR spectroscopy, and the results are as follows: Figures 6-9 As shown:
[0068] DPBF (1,3-diphenylisobenzofuran) is a commonly used ROS indicator. It can react with ROS, causing a decrease in its absorbance at 410 nm, thus indirectly reflecting the amount of ROS generated.
[0069] The ultrasonic physiotherapy device was set to a frequency of 3.0MHz, a duty cycle of 50%, and a power of 1W / cm². 2 Under conditions where the solvent was EtOH:H2O = 1:1, continuous sonication was performed for 10 minutes, and the decrease in DPBF was measured after the addition of different materials. The change in DPBF absorbance can indirectly assess the generation of ROS in sonodynamic therapy.
[0070] The preliminary in vitro acoustic dynamic test results of the prepared product are shown in Table 3:
[0071] Table 3
[0072] Material <![CDATA[DPBF decline rate (1 W / cm 2 , 3 MHz, 10 min)]]> TPA-Th 9.06％ TPA-DTh 11.65％ TPA-TTh 12.90％ TPA-TT 38.28％
[0073] As shown in Table 3, the synthesized products all exhibit good reactive oxygen generation, resulting in a significant improvement in acoustic dynamics.
[0074] according to Figure 10 The results show that the DPBF reduction rate of TPA-Th was 9.06%.
[0075] according to Figure 11 The results show that the DPBF reduction rate of TPA-DTh was 11.65%.
[0076] according to Figure 12 The results show that the DPBF reduction rate of TPA-TTh was 12.90%.
[0077] according to Figure 13 The results show that the DPBF reduction rate of TPA-TT was 38.28%.
[0078] Preliminary in vitro acoustic dynamics tests were conducted on the prepared products, with the TPA-TT showing the best performance being used for further testing. The ultrasonic physiotherapy device parameters were set to a frequency of 3.0MHz, a duty cycle of 50%, and a power of 1W / cm². 2 Under conditions where the solvent was EtOH:H2O = 1:1, continuous sonication was performed, and the decrease in DPBF after adding different concentrations of TPA-TT nanoparticles was tested. The change in DPBF absorbance can indirectly assess the generation of ROS in sonodynamic therapy.
[0079] The absorption decrease rate of DPBF was tested at different concentrations. Figure 14 As shown in Table 4:
[0080] Table 4
[0081]
[0082]
[0083] according to Figure 14 The results show that the acoustic-dynamic effect of TPA-TT increases with the increase of TPA-TT nanoparticle concentration.
[0084] Preliminary in vitro sonodynamic testing of the prepared products was conducted, with TPA-TT showing the best performance being used for further testing. The ultrasonic therapy instrument was set to a frequency of 3.0 MHz, a duty cycle of 50%, and a solvent of EtOH:H2O = 1:1 for continuous ultrasound. The decrease in DPBF absorbance was measured at different power levels after adding the same concentration of TPA-TT nanoparticles. Changes in DPBF absorbance can indirectly assess the generation of ROS during sonodynamic therapy.
[0085] The absorption descent rate of DPBF was tested at different power levels. Figure 15 As shown in Table 5:
[0086] Table 5
[0087] US time / min 5min 10min 15min 20min <![CDATA[0.5W / cm 2 ]]> 25.34％ 40.65％ 44.04％ 42.12％ <![CDATA[1.0W / cm 2 ]]> 34.34％ 47.74％ 72.53％ 74.93％ <![CDATA[1.5W / cm 2 ]]> 34.49％ 52.10％ 60.22％ 62.50％
[0088] according to Figure 15 The results show that the acoustic dynamics of TPA-TT improves with increasing instrument power.
[0089] The specific embodiments described above further illustrate the purpose, technical solutions, and beneficial effects of this disclosure. It should be understood that the above descriptions are merely specific embodiments of this disclosure and are not intended to limit this disclosure. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this disclosure should be included within the protection scope of this disclosure.
Claims
1. A conjugated microporous polymer-type sound-sensitive agent, comprising triphenylamine units as the main structure and thiophene units as linking molecules, forming a three-dimensional conjugated network through covalent bonds, the general chemical formula of which is shown in formula (I): in, Triphenylamine is the main unit, Th is the thiophene unit, n is the number of thiophene links (1≤n≤3), and m is the degree of polymerization.
2. A conjugated microporous polymer-type sound-sensitive agent, comprising a triphenylamine unit as the main structure and 4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)dithiophen-2,6-diyl)bistrimethyltin (TT) as the linking molecule, forming a three-dimensional conjugated network through covalent bonds, the chemical structural formula of which is shown in formula (II): in, Triphenylamine is the main unit, TT is the linking unit, and m is the degree of polymerization.
3. A method for preparing the conjugated microporous polymeric acoustic sensor as described in claim 1, comprising the following steps: (1) Dissolve tris(4-bromophenyl)amine and thiophene tin derivatives in toluene at a molar ratio of 1:1.5, and add the catalyst bis(triphenylphosphine)palladium(II) dichloride; (2) Under inert gas protection, carry out the oxidative coupling reaction at 85°C for 10-12 hours; (3) After the reaction is complete, the solution is dissolved in dichloromethane and then added dropwise to anhydrous methanol under stirring. The settled solution is centrifuged, the supernatant is removed after centrifugation, and the solid obtained is dried under vacuum overnight to obtain the target polymer.
4. A method for preparing the conjugated microporous polymeric acoustic sensor as described in claim 2, comprising the following steps: (1) Tri(4-bromophenyl)amine and 8-bis(5-(2-ethylhexyl)thiophen-2-yl)dithiophen-2,6-diyl)bistrimethyltin were dissolved in toluene at a molar ratio of 1:1.5, and the catalyst bis(triphenylphosphine)palladium(II) chloride was added; (2) Under inert gas protection, carry out the oxidative coupling reaction at 85°C for 10-12 hours; (3) After the reaction is complete, the solution is dissolved in dichloromethane and then added dropwise to anhydrous methanol under stirring. The settled solution is centrifuged, the supernatant is removed after centrifugation, and the solid obtained is dried under vacuum overnight to obtain the target polymer.
5. A conjugated microporous polymeric acoustic sensor prepared by the preparation method according to claim 3 or 4.