D-A type asymmetric non-conjugated polymer based on ATQ electron withdrawing unit and preparation method and application thereof

Abstract

The invention provides a D-A type asymmetric non-conjugated polymer based on an ATQ electron withdrawing unit, in which stereo conformation (asymmetric + non-conjugated) PATQ-DPP breaks the planarity of a polymer main chain, and an absorption peak is expanded to an NIR-II window region, so that the photoacoustic signal intensity is effectively improved. The PATQ-DPP is used as a core and is blended with a phospholipid compound through an ultrasonic precipitation method to obtain the water-soluble nano-particles, and the photoacoustic and photothermal properties of the three-dimensional conformation PATQ-DPP-NPs are obviously superior to those of two conjugate plane structures. The ATQ unit is subjected to three-dimensional conformation (asymmetric + non-conjugate) modification, compared with a polymer with a conjugate plane and a main chain structure, the polymer has better brightness and signal-to-noise ratio, PATQ-DPP has a narrower band gap, and therefore the photoacoustic signal intensity is effectively improved, and the photoelectric conversion efficiency is improved. And the nanoparticles prepared by taking the PATQ-DPP as the core for wrapping have higher photothermal conversion efficiency and photoacoustic imaging signals.

Description

Technical Field

[0001] The present invention relates to the field of biochemical materials, and in particular to a DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit, a preparation method and applications thereof. Background Art

[0002] Photoacoustic imaging (PAI) is a noninvasive biomedical imaging technique that combines the high contrast of optical imaging with the deep tissue resolution of ultrasound imaging. By detecting ultrasound signals generated by laser pulse excitation, it enables high-contrast visualization of tissue functional information and anatomical structures. While conventional PAI in the near-infrared (NIR-I) region (700-900 nm) has achieved clinical application, its tissue penetration depth is limited by photon scattering and the strong light attenuation of endogenous absorbers such as hemoglobin, making it difficult to achieve high-resolution imaging of deep tissue depths at the centimeter level. The recently developed near-infrared (NIR-II) region (900-1700 nm) offers the potential to achieve even higher penetration depths due to its significantly reduced tissue scattering coefficient and background absorption. Therefore, NIR-II PAI presents broad potential applications, providing effective and safe diagnosis and treatment of tumors. The choice of contrast agent is crucial to the performance of PAI. In addition to advanced laser technology, the choice of contrast agent is crucial to PAI performance. Currently, commonly used PAI contrast agents include inorganic nanomaterials, organic small molecules, and semiconductor polymers. Among them, semiconductor polymers have received widespread attention due to their strong extinction ability, good biocompatibility, excellent photostability and tunable optical properties.

[0003] Semiconducting polymers are a type of DA-type conjugated polymer materials formed by the alternating polymerization of electron-donating donors (Donor) and electron-deficient acceptors (Acceptor). The strong DA interaction within the molecule leads to effective intramolecular charge transfer (ICT), giving the material a high molar absorption coefficient and wide-spectrum absorption characteristics. By regulating the electron push-pull ability of the donor / acceptor unit, the absorption range of the polymer can be effectively controlled, thereby improving the PA signal. However, the current DA-type conjugated polymer materials have a strong planarity of the polymer main chain, and their photoacoustic and photothermal properties are difficult to meet the needs of practical applications. In order to promote the practical application of near-infrared contrast agents in biological imaging, the design strategy of photoacoustic imaging contrast agents that can amplify the brightness of PA still faces challenges, and a new catalyst is urgently needed to solve the above challenges.

[0004] In summary, a new technical solution is urgently needed to solve the problems existing in the existing technology. Summary of the Invention

[0005] Based on this, the present invention provides a DA-type asymmetric non-conjugated polymer based on ATQ electron-withdrawing units, whose stereo conformation breaks the planarity of the polymer main chain, extends the absorption peak to the NIR-II window region, and enhances the photoacoustic signal intensity.

[0006] PATQ-DPP was blended with phospholipids and prepared via ultrasonic precipitation to form water-soluble nanoparticles (PATQ-DPP@NPs). Their photoacoustic and photothermal performance surpassed that of conjugated planar structures. PATQ-DPP with stereomodified ATQ units exhibited improved brightness, signal-to-noise ratio, and a narrower band gap compared to conjugated planar polymers with the same backbone structure. Nanoparticles prepared with this core exhibited higher photothermal conversion efficiency and photoacoustic imaging signals.

[0007] One object of the present invention is to provide a DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit, wherein the DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit is represented by the following general structural formula:

[0008]

[0009] in,

[0010] n is a natural number from 1 to 10000;

[0011] Ar is independently one or more selected from aromatic hydrocarbon derivatives having 6 to 60 carbon atoms and heterocyclic derivatives having 1 to 60 carbon atoms;

[0012] in,

[0013] The aromatic hydrocarbon derivative is selected from a group containing one or more aromatic ring structures, wherein the hydrogen atoms on all aromatic ring structures are unsubstituted.

[0014] or

[0015] One or more hydrogen atoms at any position on one or more aromatic ring structures are replaced by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups;

[0016] The heterocyclic derivative is selected from a group containing one or more heterocyclic structures, wherein the hydrogen atoms on all heterocyclic structures are not substituted.

[0017] or

[0018] One or more hydrogen atoms at any position on one or more heterocyclic structures are replaced by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups;

[0019] Said R1 is selected from electron-rich groups;

[0020] The ATQ electron-withdrawing unit has a stereo conformation.

[0021] Furthermore, the ATQ electron-withdrawing unit is a [1,2,5]thiadiazolo[3,4-g]quinoxaline unit.

[0022] Furthermore, the R1 is selected from the following structures:

[0023]

[0024] Wherein, R2-R4 are independently selected from one or more of hydrogen atoms, aryl derivatives, and alkyl derivatives;

[0025] in,

[0026] All hydrogen atoms on the alkyl derivative are unsubstituted,

[0027] or

[0028] One or more hydrogen atoms at any position on the alkyl derivative are substituted by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups;

[0029] The aryl derivative is selected from a group containing one or more aromatic ring structures, wherein the hydrogen atoms on all aromatic ring structures are not substituted,

[0030] or

[0031] One or more hydrogen atoms at any position on one or more aromatic ring structures are substituted by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups.

[0032] Furthermore, the Ar is selected from different groups.

[0033] Furthermore, the ATQ electron-withdrawing unit Selected from the following structures:

[0034]

[0035] Said R5, R6, R7, R8, and R9 are independently selected from one or more of hydrogen atoms, halogen atoms, aryl derivatives, and alkyl derivatives;

[0036] All hydrogen atoms on the alkyl derivative are unsubstituted,

[0037] or

[0038] One or more hydrogen atoms at any position on the alkyl derivative are substituted by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups;

[0039] The aryl derivative is selected from a group containing one or more aromatic ring structures, wherein the hydrogen atoms on all aromatic ring structures are not substituted,

[0040] or

[0041] One or more hydrogen atoms at any position on one or more aromatic ring structures are substituted by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups.

[0042] Another object of the present invention is to provide a method for preparing the above-mentioned DA-type asymmetric non-conjugated polymer based on the ATQ electron-withdrawing unit, comprising the following steps:

[0043] S1. Under the protection of an inert gas, a nitro-containing benzothiadiazole or a derivative thereof and acetic acid are mixed, heated, a reducing agent is added, reacted, and purified to obtain an intermediate product 1;

[0044] S2, dissolving the intermediate product and a diketone derivative in acetic acid, heating the mixture under the protection of an inert gas, and purifying the mixture to obtain an intermediate product 2;

[0045] S3. Under the protection of inert gas, the intermediate product 2 and the R1 monomer treated with trimethyltin are dissolved in a solvent, heated to react in the presence of a catalyst, and purified to obtain a DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit.

[0046] Furthermore, in step S3, the heating temperature is 130-150°C.

[0047] Another object of the present invention is to provide a water-soluble nanoparticle comprising the above-mentioned DA-type asymmetric non-conjugated polymer based on ATQ electron-withdrawing units as a core structure and a phospholipid compound as a shell structure.

[0048] Furthermore, the phospholipid compound is N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-SN-glycerol-3-phosphoethanolamine, sodium salt; its CAS number is 147867-65-0.

[0049] Furthermore, the particle size of the water-soluble nanoparticles is 100-140 nm.

[0050] The mass ratio of the core structure to the shell structure is 1:(1-5).

[0051] Another object of the present invention is to provide the use of the above-mentioned water-soluble nanoparticles as a near-infrared second-region photoacoustic contrast agent.

[0052] The present invention has the following beneficial effects:

[0053] (1) The present invention discloses a DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit, wherein the stereo conformation (asymmetric + non-conjugated) PATQ-DPP breaks the planarity of the polymer backbone, extending the absorption peak to the NIR-II window region, thereby effectively enhancing the photoacoustic signal intensity. Water-soluble nanoparticles were obtained by ultrasonic precipitation using PATQ-DPP as the core and blending it with a phospholipid compound. Under 1064nm pulse excitation, the photoacoustic and photothermal performance of the stereo conformation PATQ-DPP@NPs was significantly superior to that of the two conjugated planar structures.

[0054] (2) By modifying the ATQ unit in a stereo conformation (asymmetric + non-conjugated), the present invention achieves better brightness and signal-to-noise ratio compared to conjugated planar polymers with the same main chain structure. CV testing shows that the stereo conformation of PATQ-DPP has a narrower band gap, thereby effectively improving the photoacoustic signal intensity. Nanoparticles prepared with PATQ-DPP as the core have higher photothermal conversion efficiency and photoacoustic imaging signal. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 Shown are the H NMR spectrum and high-resolution mass spectrum (HRMS) of ATQ;

[0056] in,

[0057] Figure 1 (a) shows the H NMR spectrum of ATQ;

[0058] Figure 1 (b) shows the high resolution mass spectrum (HRMS) of ATQ.

[0059] Figure 2 The H NMR spectrum of PATQ-DPP is shown.

[0060] Figure 3 Shown are the H NMR spectrum and high-resolution mass spectrum (HRMS) of BTTQ;

[0061] in,

[0062] Figure 3 (a) shows the H NMR spectrum of BTTQ;

[0063] Figure 3 (b) shows the high resolution mass spectrum (HRMS) of BTTQ.

[0064] Figure 4 The H NMR spectrum of PBTTQ-DPP is shown.

[0065] Figure 5 Shown are the nuclear magnetic hydrogen spectrum and high resolution mass spectrum (HRMS) of PhTQ;

[0066] in,

[0067] Figure 5 (a) shows the H NMR spectrum of PhTQ;

[0068] Figure 5 (b) shows the high resolution mass spectrum (HRMS) of PhTQ.

[0069] Figure 6 The H NMR spectrum of PPhTQ-DPP is shown.

[0070] Figure 7 The synthetic routes of Examples and Comparative Examples 1-2 are shown;

[0071] in,

[0072] Figure 7 (a) shows the synthetic route of the intermediate product 2 of Examples and Comparative Examples 1-2;

[0073] Figure 7 (b) shows the synthesis routes of the polymers of Examples and Comparative Examples 1-2.

[0074] Figure 8 The overall design concept of the present invention and the chemical structures of the embodiments and comparative examples 1-2 are shown;

[0075] in,

[0076] Figure 8 (a) shows the overall design concept of the present invention;

[0077] Figure 8 (b) shows the chemical structures of PBTTQ-DPP, PPhTQ-DPP, and PATQ-DPP.

[0078] Figure 9 shows the UV-Vis-NIR absorption spectrum of the polymer in THF;

[0079] in,

[0080] Figure 9 (a) shows the UV-Vis-NIR absorption spectrum of PBTTQ-DPP of Comparative Example 1 in THF; Figure 9 (b) shows the UV-Vis-NIR absorption spectrum of PPhTQ-DPP of Comparative Example 2 in THF;

[0081] Figure 9 (c) shows the UV-Vis-NIR absorption spectrum of the PATQ-DPP of the example in THF.

[0082] Figure 10shows the UV-Vis-NIR absorption spectra of water-soluble nanoparticles in aqueous solution;

[0083] in,

[0084] Figure 10 (a) shows the UV-Vis-NIR absorption spectrum of the water-soluble nanoparticles PBTTQ-DPP@NPs in aqueous solution of comparative application example 1;

[0085] Figure 10 (b) shows the UV-Vis-NIR absorption spectrum of the water-soluble nanoparticles PPhTQ-DPP@NPs in aqueous solution of comparative application example 2;

[0086] Figure 10 (c) shows the UV-Vis-NIR absorption spectrum of the water-soluble nanoparticles PATQ-DPP@NPs in aqueous solution.

[0087] Figure 11 The photothermal performance of the application example and comparative application examples 1-2 under laser irradiation is shown;

[0088] in,

[0089] Figure 11 (a) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the condition of temperature variation of water-soluble nanoparticles of application example and comparative application example 1-2 with illumination time;

[0090] Figure 11 (b) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ), the water-soluble nanoparticles PBTTQ-DPP@NPs of comparative application example 1 were -1 The relationship between the irradiation time and -ln(θ) at different concentrations, where θ represents the driving force temperature and the fitting slope represents the system time constant (τ s );

[0091] Figure 11 (c) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ), the water-soluble nanoparticles PPhTQ-DPP@NPs of comparative application example 2 were -1 The relationship between the irradiation time and -ln(θ) at different concentrations, where θ represents the driving force temperature and the fitting slope represents the system time constant (τ s );

[0092] Figure 11(d) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ), the water-soluble nanoparticles PATQ-DPP@NPs of the application example were at 50 μg mL -1 The relationship between the irradiation time and -ln(θ) at different concentrations, where θ represents the driving force temperature and the fitting slope represents the system time constant (τ s );

[0093] Figure 11 (e) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the condition of the temperature of the water-soluble nanoparticles PATQ-DPP@NPs of the application example changes with the power density;

[0094] Figure 11 (f) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ), the temperature of the water-soluble nanoparticles PATQ-DPP@NPs of the application example changes with the concentration.

[0095] Figure 12 The photothermal cycle stability of the application example and comparative application examples 1-2 under laser irradiation is shown;

[0096] in,

[0097] Figure 12 (a) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the conditions of heating and cooling curves of the water-soluble nanoparticles of Application Example and Comparative Application Example 1-2 within 5 laser on / off cycles;

[0098] Figure 12 (b) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the conditions of comparing the sizes of the water-soluble nanoparticles PBTTQ-DPP@NPs before and after laser irradiation in Application Example 1;

[0099] Figure 12 (c) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the conditions of comparing the sizes of the water-soluble nanoparticles PPhTQ-DPP@NPs of Application Example 2 before and after laser irradiation;

[0100] Figure 12 (d) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2) under the conditions of the application example, the size of the water-soluble nanoparticles PATQ-DPP@NPs before and after laser irradiation.

[0101] Figure 13 shows the concentration-dependent photoacoustic imaging signal diagram of water-soluble nanoparticles and the photoacoustic signal intensity at different concentrations;

[0102] in,

[0103] Figure 13 (a) shows the laser energy density of 18 mJ·cm -2 Concentration-dependent photoacoustic imaging signal diagram of water-soluble nanoparticles PBTTQ-DPP@NPs of comparative application example 1 under Nd:YAG laser irradiation (wavelength 1064 nm);

[0104] Figure 13 (b) shows the laser energy density of 18 mJ·cm -2 Concentration-dependent photoacoustic imaging signal diagram of water-soluble nanoparticles PPhTQ-DPP@NPs of comparative application example 2 under Nd:YAG laser irradiation (wavelength 1064nm);

[0105] Figure 13 (c) shows the laser energy density of 18 mJ·cm -2 Concentration-dependent photoacoustic imaging signal of water-soluble nanoparticles PATQ-DPP@NPs in the application example under Nd:YAG laser irradiation (wavelength 1064 nm);

[0106] Figure 13 (d) shows the laser energy density of 18 mJ·cm -2 The photoacoustic signal intensity of the water-soluble nanoparticles of Application Example and Comparative Application Example 1-2 at different concentrations under Nd:YAG laser irradiation (wavelength 1064 nm).

[0107] Figure 14 shows the depth-dependent photoacoustic imaging signal diagram of water-soluble nanoparticles and the photoacoustic signal intensity at different depths;

[0108] in,

[0109] Figure 14 (a) shows the depth-dependent photoacoustic imaging signal of the water-soluble nanoparticles PBTTQ-DPP@NPs of comparative application example 1;

[0110] Figure 14 (b) shows the depth-dependent photoacoustic imaging signal of the water-soluble nanoparticles PPhTQ-DPP@NPs of comparative application example 2;

[0111] Figure 14(c) shows the depth-dependent photoacoustic imaging signal of the water-soluble nanoparticles PATQ-DPP@NPs of the application example;

[0112] Figure 14 (d) shows the photoacoustic signal intensity of the water-soluble nanoparticles PBTTQ-DPP@NPs at different depths of comparative application example 1;

[0113] Figure 14 (e) shows the photoacoustic signal intensity of the water-soluble nanoparticles PPhTQ-DPP@NPs of comparative application example 2 at different depths;

[0114] Figure 14 (f) shows the photoacoustic signal intensity of the water-soluble nanoparticles PATQ-DPP@NPs at different depths.

[0115] Figure 15 The cytotoxicity test graph and hemolysis experiment of the water-soluble nanoparticles of the application example and comparative application example 1-2 are shown;

[0116] in,

[0117] Figure 15 (a) shows the cytotoxicity test graph of the water-soluble nanoparticles of Application Example and Comparative Application Example 1-2;

[0118] Figure 15 (b) shows the hemolysis experiment of water-soluble nanoparticles PBTTQ-DPP@NPs of comparative application example 1 at different concentrations;

[0119] Figure 15 (c) shows the hemolysis experiment of water-soluble nanoparticles PPhTQ-DPP@NPs of comparative application example 2 at different concentrations;

[0120] Figure 15 (d) shows the hemolysis experiment of water-soluble nanoparticles PATQ-DPP@NPs of the application example at different concentrations. DETAILED DESCRIPTION

[0121] In order to more clearly illustrate the technical solution of the present invention, the following examples are given. Unless otherwise stated, the raw materials, reactions and post-treatment methods shown in the examples are common raw materials on the market and technical methods well known to those skilled in the art.

[0122] The terms "preferred," "preferably," "more preferred," and the like, used herein, refer to embodiments of the invention that may provide certain benefits under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.

[0123] It should be understood that, except in any operating examples, or where otherwise indicated, all numbers expressing, for example, quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending upon the desired properties to be obtained by the present invention.

[0124] The present invention uses the following raw materials:

[0125] N-(Carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-SN-glycero-3-phosphoethanolamine, sodium salt (DSPE-mPEG2000): CAS number 147867-65-0, purchased from Avituo Shanghai Pharmaceutical Technology Co., Ltd.

[0126] DPP-C8-C 12 -2Sn: 2,5-bis(2-octyldodecyl)-3,6-bis(5-(trimethyltinyl)thiophen-2-yl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione.

[0127] Example

[0128] Synthesis of PATQ-DPP.

[0129] A DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit, wherein the preparation method comprises the following steps:

[0130] S1. Under nitrogen protection, add 60 mL of acetic acid and 4 g of 4,7-dibromo-5,6-dinitrobenzothiadiazole to a round-bottom flask equipped with a stirrer, heat to 100°C, add 8 g of Fe, react for 4 h, cool to room temperature after the reaction, filter, and Soxhlet extract the solid with ethyl acetate for 12 h. Evaporate the solvent to obtain intermediate 1.

[0131] S2, the intermediate product 1 (2g, 6.17mmol) and DL-camphorquinone (1.0775g, 6.48mmol) were dissolved in 50mL of acetic acid, under nitrogen protection, heated to 80 ° C, stirred for 29h, cooled to room temperature, and the reaction mixture was added to ultrapure water, then filtered using a Buchner funnel to isolate the solid product, and then washed sequentially with ultrapure water, ethanol and dichloromethane. The crude product was recrystallized using methanol and tetrahydrofuran as recrystallization solvents to obtain intermediate product 2 (ATQ, 0.9419g);

[0132] S3. Under the protection of nitrogen, the intermediate product 2 (45.4 mg, 0.1 mmol) was reacted with DPP-C8-C 12 -2Sn (118.8 mg, 0.1 mmol) and Pd(PPh3)4 (13 mg) were dissolved in 5 mL of ultra-dry chlorobenzene, heated to 140 ° C, refluxed for 78 h, cooled to room temperature, and then dropped into 150 mL of 99.5 wt% (analytical grade) methanol solution for precipitation. After filtration, the solid was added to a Soxhlet extractor and extracted with methanol, n-hexane, and tetrahydrofuran in sequence. The solvent was evaporated and washed with 1 mL of tetrahydrofuran, precipitated in methanol, filtered, and vacuum dried to obtain a DA-type asymmetric non-conjugated polymer based on ATQ electron-withdrawing unit (PATQ-DPP, 78.6 mg).

[0133] Figure 1 Shown are the H NMR spectrum and high-resolution mass spectrum (HRMS) of ATQ;

[0134] in,

[0135] Figure 1 (a) shows the H NMR spectrum of ATQ;

[0136] Figure 1 (b) shows the high resolution mass spectrum (HRMS) of ATQ.

[0137] 1 H NMR (400MHz, CDCl3)δ=3.19(d,J=4.0,1H),2.36–2.27(m,1H),2.12–2.03(m,1H),1.51-1.25(m,2H),1.22–1.10(m,6H),0.65(s,3H).HRMS(ESI):calcd for C 16 H 14 N4Br2S[M+H] + :452.9379; found,492.9380.

[0138] Figure 2The H NMR spectrum of PATQ-DPP is shown.

[0139] Depend on Figure 2 It can be seen that 1 H NMR (600MHz, CDCl3) δ1.22 (d, J = 36.0, 4H), 0.80 (s, 1H).

[0140] Comparative Example 1

[0141] Synthesis of PBTTQ-DPP.

[0142] A DA-type conjugated polymer based on an ATQ electron-withdrawing unit, wherein the preparation method comprises the following steps:

[0143] S1. Under nitrogen protection, add 60 mL of acetic acid and 4 g of 4,7-dibromo-5,6-dinitrobenzothiadiazole to a round-bottom flask equipped with a stirrer, heat to 100°C, add 8 g of Fe, react for 4 h, cool to room temperature after the reaction, filter, and Soxhlet extract the solid with ethyl acetate for 12 h. Evaporate the solvent to obtain intermediate 1.

[0144] S2, the intermediate product 1 (1.3825g, 4.26mmol) and 1,2-indandione (0.6239g, 4.26mmol) were dissolved in 50mL of acetic acid, heated to 80°C under nitrogen protection, stirred for 43h, and cooled to room temperature. The reaction mixture was added to ultrapure water, and then filtered using a Buchner funnel to separate the solid product, which was then washed with ultrapure water, ethanol, and dichloromethane in sequence. The crude product was recrystallized using petroleum ether and dichloromethane as recrystallization solvents to obtain intermediate product 2 (BTTQ, 0.6719g);

[0145] S3. Under the protection of nitrogen, the intermediate product 2 (21.7 mg, 0.05 mmol), DPP-C8-C 12 -2Sn (54.9 mg, 0.05 mmol) and Pd(PPh3)4 (13 mg) were dissolved in 5 mL of ultra-dry chlorobenzene, heated to 140 ° C, and the reaction was refluxed for 51 hours. After cooling to room temperature, it was dropped into 150 mL of 99.5 wt% (analytical grade) methanol solution for precipitation. After filtration, the solid was added to a Soxhlet extractor and extracted with methanol, n-hexane, and tetrahydrofuran in sequence. The solvent was evaporated and washed with 1 mL of tetrahydrofuran. It was precipitated in methanol, filtered, and vacuum dried to obtain a DA-type conjugated polymer based on ATQ electron-withdrawing unit (PBTTQ-DPP, 40.1 mg).

[0146] Figure 3 Shown are the H NMR spectrum and high-resolution mass spectrum (HRMS) of BTTQ;

[0147] in,

[0148] Figure 3 (a) shows the H NMR spectrum of BTTQ;

[0149] Figure 3 (b) shows the high resolution mass spectrum (HRMS) of BTTQ.

[0150] 1 H NMR (400MHz, CDCl3) δ7.93(d,J=8.0,1H),7.77(t,J=8.0,1H),7.59(d,J=8.0,1H),7.52(d,J=8.0,1H),3.66(s,2H).HRMS(ESI):calcd for C 15 H6N4Br2S[M+H] + :432.8753,found,432.8785.

[0151] Figure 4 The H NMR spectrum of PBTTQ-DPP is shown.

[0152] Depend on Figure 4 It can be seen that 1 H NMR (600MHz, CDCl3) δ1.38 (d, J = 6.0, 2H), 1.33 (s, 2H), 1.28 (s, 3H), 1.25 (s, 9H), 1.21 (s, 9H), 0.90-0.73 (m, 14H),

[0153] Comparative Example 2

[0154] Synthesis of PPhTQ-DPP.

[0155] A DA-type conjugated polymer based on an ATQ electron-withdrawing unit, wherein the preparation method comprises the following steps:

[0156] S1. Under nitrogen protection, add 60 mL of acetic acid and 4 g of 4,7-dibromo-5,6-dinitrobenzothiadiazole to a round-bottom flask equipped with a stirrer, heat to 100°C, add 8 g of Fe, react for 4 h, cool to room temperature after the reaction, filter, and Soxhlet extract the solid with ethyl acetate for 12 h. Evaporate the solvent to obtain intermediate 1.

[0157] S2, the intermediate product 1 (1g, 3.08mmol) and 9,10-phenanthrene dione (0.7139g, 3.42mmol) were dissolved in 60mL of acetic acid, heated to 80°C under nitrogen protection, stirred for 16h, and cooled to room temperature. The reaction mixture was added to ultrapure water, and then filtered using a Buchner funnel to separate the solid product, which was then washed with ultrapure water, ethanol, and n-hexane in sequence. The crude product was recrystallized using methanol and tetrahydrofuran as recrystallization solvents to obtain intermediate product 2 (PhTQ, 0.8193g);

[0158] S3. Under the protection of nitrogen, the intermediate product 2 (26.1 mg, 0.05 mmol) was reacted with DPP-C8-C 12 -2Sn (54.9 mg, 0.05 mmol) and Pd(PPh3)4 (13 mg) were dissolved in 5 mL of ultra-dry chlorobenzene, heated to 140 ° C, and the reaction was refluxed for 52 h. After cooling to room temperature, it was dropped into 150 mL of 99.5 wt% (analytical grade) methanol solution for precipitation. After filtration, the solid was added to a Soxhlet extractor and extracted with methanol, n-hexane, and tetrahydrofuran in sequence. The solvent was evaporated and washed with 1 mL of tetrahydrofuran. It was precipitated in methanol, filtered, and vacuum dried to obtain a DA-type conjugated polymer based on ATQ electron-withdrawing unit (PPhTQ-DPP, 43.8 mg).

[0159] Figure 5 Shown are the nuclear magnetic hydrogen spectrum and high resolution mass spectrum (HRMS) of PhTQ;

[0160] in,

[0161] Figure 5 (a) shows the H NMR spectrum of PhTQ;

[0162] Figure 5 (b) shows the high resolution mass spectrum (HRMS) of PhTQ.

[0163] 1 H NMR (400MHz, DMSO) δ=8.31(d,J=8.0,2H),8.03(d,J=8.0,2H),7.79(t,J=8.0,8.0,2H),7.54(t,J=8.0,8.0,2H).HRMS(ESI):calcd for C20H8N4Br2S[M+H] + :494.8836; found,494.8900.

[0164] Figure 6 The H NMR spectrum of PPhTQ-DPP is shown.

[0165] Depend on Figure 6 It can be seen that 1 H NMR (600MHz, CDCl3) δ1.43(s,2H),1.25(s,7H),0.69(s,31H).

[0166] Figure 7 The synthetic routes of Examples and Comparative Examples 1-2 are shown;

[0167] in,

[0168] Figure 7 (a) shows the synthetic route of the intermediate product 2 of Examples and Comparative Examples 1-2;

[0169] Figure 7 (b) shows the synthesis routes of the polymers of Examples and Comparative Examples 1-2; wherein, n in PBTTQ-DPP is 190, ranging from 1-200; n in PPhTQ-DPP is 193, ranging from 1-200; and n in PATQ-DPP is 185, ranging from 1-200.

[0170] Figure 8 The overall design concept of the present invention and the chemical structures of the embodiments and comparative examples 1-2 are shown;

[0171] in,

[0172] Figure 8 (a) shows the overall design concept of the present invention;

[0173] Figure 8 (b) shows the chemical structures of PBTTQ-DPP, PPhTQ-DPP, and PATQ-DPP.

[0174] Application Examples

[0175] A water-soluble nanoparticle, using DSPE-mPEG2000 as a shell structure and coating PATQ-DPP prepared in an embodiment as a core structure.

[0176] The preparation method of the water-soluble nanoparticles comprises the following steps:

[0177] 1 mg of PATQ-DPP of the example and 3 mg of DSPE-mPEG2000 were dissolved in 1 mL of THF, respectively, and then water-soluble nanoparticles (PATQ-DPP@NPs) were obtained by ultrasonic coprecipitation.

[0178] Comparative Application Example 1

[0179] A water-soluble nanoparticle, using DSPE-mPEG2000 as a shell structure and coating the PBTTQ-DPP prepared in Comparative Example 1 as a core structure.

[0180] The preparation method of the water-soluble nanoparticles comprises the following steps:

[0181] 1 mg of PBTTQ-DPP of Comparative Example 1 and 3 mg of DSPE-mPEG2000 were dissolved in 1 mL of THF, respectively, and then water-soluble nanoparticles (PBTTQ-DPP@NPs) were obtained by ultrasonic coprecipitation.

[0182] Comparative Application Example 2

[0183] A water-soluble nanoparticle, using DSPE-mPEG2000 as a shell structure and coating the PPhTQ-DPP prepared in Comparative Example 2 as a core structure.

[0184] The preparation method of the water-soluble nanoparticles comprises the following steps:

[0185] 1 mg of PPhTQ-DPP of Comparative Example 2 and 3 mg of DSPE-mPEG2000 were dissolved in 1 mL of THF, respectively, and then water-soluble nanoparticles (PPhTQ-DPP@NPs) were obtained by ultrasonic coprecipitation.

[0186] Test Example 1

[0187] In order to test the optical absorption ability of the DA-type asymmetric non-conjugated polymer based on the ATQ electron-withdrawing unit, the UV-visible absorption spectra of the polymers of Examples and Comparative Examples 1-2 in THF solution were tested;

[0188] Test method:

[0189] 1 mg of PBTTQ-DPP of Comparative Example 1, PPhTQ-DPP of Comparative Example 2, and PATQ-DPP of Example 1 were added to 50 mL of THF and subjected to UV-visible-near infrared absorption test. The test results are as follows: Figure 9 As shown;

[0190] Figure 9 shows the UV-Vis-NIR absorption spectrum of the polymer in THF;

[0191] in,

[0192] Figure 9 (a) shows the UV-Vis-NIR absorption spectrum of PBTTQ-DPP of Comparative Example 1 in THF;

[0193] Figure 9 (b) shows the UV-Vis-NIR absorption spectrum of PPhTQ-DPP of Comparative Example 2 in THF;

[0194] Figure 9 (c) shows the UV-Vis-NIR absorption spectrum of the PATQ-DPP of the example in THF.

[0195] Depend on Figure 9 It can be seen that the absorption range of PBTTQ-DPP, PPhTQ-DPP and PATQ-DPP is all in the NIR-II region, among which the highest ICT peak of PBTTQ-DPP in Comparative Example 1 is 836 nm, the highest ICT peak of PPhTQ-DPP in Comparative Example 2 is 1184 nm, and the highest ICT peak of PATQ-DPP in Example 1 is 1133 nm.

[0196] It can be seen that the absorption of the polymers in the embodiment and comparative examples 1-2 reaches the near-infrared region II, and has the potential to be used as near-infrared region II photoacoustic contrast agents.

[0197] Test Example 2

[0198] Since the PBTTQ-DPP of Comparative Example 1, the PPhTQ-DPP of Comparative Example 2, and the PATQ-DPP of the embodiment all have near-infrared absorption capabilities in the second region, in order to further explore their optical imaging capabilities in the nanoparticle state, the absorption spectra of the water-soluble nanoparticles PBTTQ-DPP@NPs of Comparative Application Example 1, the water-soluble nanoparticles PPhTQ-DPP@NPs of Comparative Application Example 2, and the water-soluble nanoparticles PATQ-DPP@NPs of the application example were tested;

[0199] Test method:

[0200] 1 mg of the prepared water-soluble nanoparticles of the application examples and comparative application examples 1-2 were respectively dissolved in 20 mL of ultrapure water to prepare a 0.05 mg / mL test solution, and the absorption spectrum was tested using a UV-visible absorption spectrometer, collecting wavelengths in the range of 300-2000 nm;

[0201] The test results are as follows Figure 10 As shown;

[0202] Figure 10 shows the UV-Vis-NIR absorption spectra of water-soluble nanoparticles in aqueous solution;

[0203] in,

[0204] Figure 10 (a) shows the UV-Vis-NIR absorption spectrum of the water-soluble nanoparticles PBTTQ-DPP@NPs in aqueous solution of comparative application example 1;

[0205] Figure 10(b) shows the UV-Vis-NIR absorption spectrum of the water-soluble nanoparticles PPhTQ-DPP@NPs in aqueous solution of comparative application example 2;

[0206] Figure 10 (c) shows the UV-Vis-NIR absorption spectrum of the water-soluble nanoparticles PATQ-DPP@NPs in aqueous solution.

[0207] Depend on Figure 10 It can be seen that the absorption range displayed by the water-soluble nanoparticles of Application Example and Comparative Application Example 1-2 is close to the absorption range of the previous conjugated polymer, and the highest absorption peaks are 850nm, 1081nm and 1029nm, respectively. This indicates that the nanoparticles of Application Example and Comparative Application Example 1-2 still have the potential to be used as near-infrared second-zone photoacoustic contrast agents.

[0208] Test Example 3

[0209] Based on the long wavelength and excellent light absorption properties of water-soluble nanoparticles, we systematically studied the photothermal properties of PBTTQ-DPP@NPs in comparative application example 1, PPhTQ-DPP@NPs in comparative application example 2, and PATQ-DPP@NPs in application example 3.

[0210] Test method: Using 1064nm (1W cm -2 ) The laser irradiation concentration is 0.05 mg mL -1 (600 μL) nanoparticle solution for 6 min, use an infrared thermal imaging camera to record the temperature change of the solution until the solution temperature reaches a stable state, then turn off the laser and cool to room temperature. During the experiment, the solution temperature is recorded every 30 s, and the photothermal conversion efficiency of the nanoparticles is calculated according to formula (1);

[0211] Calculation formula for photothermal conversion efficiency:

[0212] Where h and S are the heat transfer coefficient and the container surface area respectively. Max and T Sur are the maximum steady-state temperature and the ambient temperature respectively. Dis is the heat dissipated by the laser through the solvent and the container. I is the laser power; A is the absorbance intensity of the sample at λ. The value of hS is calculated by formula (2):

[0213]

[0214] Where m and Cp are the mass (0.6 g) and heat capacity (4.2 J / g) of water, τ s is the time constant of system heat transfer, which can be obtained from formula (3):

[0215] t = τ S ×(-lnθ) (3)

[0216] Where t is the cooling time, and θ is a dimensionless parameter based on temperature, which can be determined by formula (4):

[0217]

[0218] Where T is the cooling process temperature.

[0219] The test results are as follows Figure 11 shown.

[0220] Figure 11 The photothermal performance of the application example and comparative application examples 1-2 under laser irradiation is shown;

[0221] in,

[0222] Figure 11 (a) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the condition of temperature variation of water-soluble nanoparticles of application example and comparative application example 1-2 with illumination time;

[0223] Figure 11 (b) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ), the water-soluble nanoparticles PBTTQ-DPP@NPs of comparative application example 1 were -1 The relationship between the irradiation time and -ln(θ) at different concentrations, where θ represents the driving force temperature and the fitting slope represents the system time constant (τ s );

[0224] Figure 11 (c) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ), the water-soluble nanoparticles PPhTQ-DPP@NPs of comparative application example 2 were -1 The relationship between the irradiation time and -ln(θ) at different concentrations, where θ represents the driving force temperature and the fitting slope represents the system time constant (τ s );

[0225] Figure 11 (d) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ), the water-soluble nanoparticles PATQ-DPP@NPs of the application example were at 50 μg mL -1The relationship between the irradiation time and -ln(θ) at different concentrations, where θ represents the driving force temperature and the fitting slope represents the system time constant (τ s );

[0226] Figure 11 (e) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the condition of the temperature of the water-soluble nanoparticles PATQ-DPP@NPs of the application example changes with the power density;

[0227] Figure 11 (f) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ), the temperature of the water-soluble nanoparticles PATQ-DPP@NPs of the application example changes with the concentration.

[0228] from Figure 11 (a) It can be seen that under the same experimental conditions, no obvious temperature change was observed in the ultrapure water solution as the experimental control group, while the three nanoparticles showed a gradient temperature increase phenomenon: the temperature of PBTTQ-DPP@NPs rose to 57.8℃, PPhTQ-DPP@NPs reached 66.1℃, and PATQ-DPP@NPs rose to 82.5℃. Further calculations showed that the photothermal conversion efficiency of PBTTQ-DPP@NPs, PPhTQ-DPP@NPs and PATQ-DPP@NPs was 50.21%, 53.06% and 66.3%, respectively. Figure 11 (b)-11(d). Experimental data show that PATQ-DPP@NPs with a stereo conformation significantly outperform the other two nanoparticles in terms of photothermal performance, demonstrating the most outstanding photothermal performance.

[0229] We then evaluated the relationship between the photothermal conversion efficiency of PATQ-DPP@NPs and the concentration and power of the application example. Figure 11 (e) Figure 11 As shown in (f), the photothermal conversion efficiency increases with the increase of nanoparticle concentration and power, which is beneficial for its application in photoacoustic imaging and photothermal therapy.

[0230] To evaluate the photothermal stability of the three nanoparticles, we used five intermittent on / off cycles of a 1064 nm laser (1 W cm -2 ) to conduct photothermal cycle stability test.

[0231] The results are as follows Figure 12 shown.

[0232] Figure 12The photothermal cycle stability of the application example and comparative application examples 1-2 under laser irradiation is shown;

[0233] in,

[0234] Figure 12 (a) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the conditions of heating and cooling curves of the water-soluble nanoparticles of Application Example and Comparative Application Example 1-2 within 5 laser on / off cycles;

[0235] Figure 12 (b) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the conditions of comparing the sizes of the water-soluble nanoparticles PBTTQ-DPP@NPs before and after laser irradiation in Application Example 1;

[0236] Figure 12 (c) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the conditions of comparing the sizes of the water-soluble nanoparticles PPhTQ-DPP@NPs of Application Example 2 before and after laser irradiation;

[0237] Figure 12 (d) shows the Nd:YAG laser irradiation (wavelength 1064 nm, power 1.0 W cm -2 ) under the conditions of the application example, the size of the water-soluble nanoparticles PATQ-DPP@NPs before and after laser irradiation.

[0238] like Figure 12 As shown in (a), after five laser heating-cooling cycles, the heating-cooling curves of the three nanoparticles remained stable and no significant changes were observed. In addition, we also studied the effects of repeated laser heating (1064 nm, 1 W cm -2 ) particle size stability of nanoparticles under irradiation. Figure 12 As shown in Figures (b)-12(d), the particle sizes of the three nanoparticles did not change significantly. In summary, these results show that the three nanoparticles have good photothermal stability.

[0239] Test Example 4

[0240] In order to evaluate the feasibility of using the water-soluble nanoparticles of Application Examples and Comparative Application Examples 1-2 as PA imaging contrast agents, we evaluated the relationship between the PA imaging signal intensity and concentration of the water-soluble nanoparticles of Application Examples and Comparative Application Examples 1-2. Therefore, a solid model (the solid model contains 2wt% agar, 1wt% lipid, and the remainder is water) was used to simulate in vitro conditions, and then the PA signal intensity of the water-soluble nanoparticles of Application Examples and Comparative Application Examples 1-2 at different concentrations was measured.

[0241] Testing Method: For in vitro experiments, a solid model was prepared containing agar (2 wt%), lipids (1 wt%), and the balance water. The water-soluble nanoparticle solutions from the Application Examples and Comparative Application Examples 1-2 were injected into a 0.9 mm diameter transparent quartz tube. The tube was then sealed at both ends, encapsulating the solid model.

[0242] Subsequently, the solid model was placed on the experimental platform and the energy density was 18 mJ·cm -2 The PA imaging system was used to detect the PA images under laser irradiation. The scanning length was 8 mm.

[0243] The test results are as follows Figure 13 shown.

[0244] Figure 13 shows the concentration-dependent photoacoustic imaging signal diagram of water-soluble nanoparticles and the photoacoustic signal intensity at different concentrations;

[0245] in,

[0246] Figure 13 (a) shows the laser energy density of 18 mJ·cm -2 Concentration-dependent photoacoustic imaging signal diagram of water-soluble nanoparticles PBTTQ-DPP@NPs of comparative application example 1 under Nd:YAG laser irradiation (wavelength 1064 nm);

[0247] Figure 13 (b) shows the laser energy density of 18 mJ·cm -2 Concentration-dependent photoacoustic imaging signal diagram of water-soluble nanoparticles PPhTQ-DPP@NPs of comparative application example 2 under Nd:YAG laser irradiation (wavelength 1064nm);

[0248] Figure 13 (c) shows the laser energy density of 18 mJ·cm -2 Concentration-dependent photoacoustic imaging signal of water-soluble nanoparticles PATQ-DPP@NPs in the application example under Nd:YAG laser irradiation (wavelength 1064 nm);

[0249] Figure 13 (d) shows the laser energy density of 18 mJ·cm -2 The photoacoustic signal intensity of the water-soluble nanoparticles of Application Example and Comparative Application Example 1-2 at different concentrations under Nd:YAG laser irradiation (wavelength 1064 nm).

[0250] from Figure 13 It can be seen that the water-soluble nanoparticles of the present invention exhibit excellent photoacoustic signals. -1 Within the equivalent concentration range of the three water-soluble nanoparticles, the photoacoustic signals increased with increasing concentration. The stereo conformation PATQ-DPP@NPs exhibited a higher signal-to-noise ratio (88.3) than the asymmetric coplanar conformation PBTTQ-DPP@NPs (35.3) and coplanar conformation PPhTQ-DPP@NPs (70.6), representing increases of 150% and 25%, respectively. This indicates that the PATQ-DPP@NPs used in this study are superior contrast agents.

[0251] The performance of water-soluble nanoparticles in photoacoustic imaging is closely linked to their detection depth and signal strength. To further explore this characteristic, we further investigated the relationship between detection depth and PA signal strength.

[0252] The results are as follows Figure 14 shown.

[0253] Figure 14 shows the depth-dependent photoacoustic imaging signal diagram of water-soluble nanoparticles and the photoacoustic signal intensity at different depths;

[0254] in,

[0255] Figure 14 (a) shows the depth-dependent photoacoustic imaging signal of the water-soluble nanoparticles PBTTQ-DPP@NPs of comparative application example 1;

[0256] Figure 14 (b) shows the depth-dependent photoacoustic imaging signal of the water-soluble nanoparticles PPhTQ-DPP@NPs of comparative application example 2;

[0257] Figure 14 (c) shows the depth-dependent photoacoustic imaging signal of the water-soluble nanoparticles PATQ-DPP@NPs of the application example;

[0258] Figure 14 (d) shows the photoacoustic signal intensity of the water-soluble nanoparticles PBTTQ-DPP@NPs at different depths of comparative application example 1;

[0259] Figure 14(e) shows the photoacoustic signal intensity of the water-soluble nanoparticles PPhTQ-DPP@NPs of comparative application example 2 at different depths;

[0260] Figure 14 (f) shows the photoacoustic signal intensity of the water-soluble nanoparticles PATQ-DPP@NPs at different depths.

[0261] like Figure 14 As shown in the figure, under 1064nm laser pulse excitation, the three water-soluble nanoparticles can still clearly generate photoacoustic signals even at a depth of 5400μm. At the same time, the photoacoustic signal-to-noise ratio shows a gradually weakening trend with increasing depth. It is worth noting that regardless of how the detection depth changes, the photoacoustic signal-to-noise ratio of PATQ-DPP@NPs is always better than that of PBTTQ-DPP@NPs and PPhTQ-DPP@NPs. Specifically, when the maximum imaging depth reaches 5400μm, the signal-to-noise ratio of PATQ-DPP@NPs is 27, which is significantly higher than that of PBTTQ-DPP@NPs (21) and PPhTQ-DPP@NPs (19).

[0262] Test Example 5

[0263] The in vivo biocompatibility of water-soluble nanoparticles is one of the important prerequisites for potential clinical translation. To evaluate the biocompatibility of water-soluble nanoparticles, we performed in vitro cytotoxicity and hemolysis experiments.

[0264] In the in vitro cytotoxicity experiment, A549 cells (donated by Gannan Medical College) were treated with PBTTQ-DPP@NPs, PPhTQ-DPP@NPs and PATQ-DPP@NPs at concentrations of 0-100 μg / mL for 24 h, and the cell viability was evaluated by CCK-8 assay. Figure 15 As shown in (a), after 24 h of culture, cell viability showed a downward trend with increasing nanoparticle concentration. However, even at the highest concentration of 100 μg / mL, cell viability remained above 85%.

[0265] In order to further evaluate the biocompatibility of the three water-soluble nanoparticles, a hemolysis experiment was conducted. We used 4% BALB / C mouse red blood cell suspension (mice purchased from Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.) and mixed it with different concentrations of nanoparticles to form mixed solutions of different concentrations. After incubation at 37°C for 3 hours, the hemolysis rate was calculated. Figure 15 (b)-15(d) shows that even at a concentration of up to 240 μg mL -1The supernatants of the three water-soluble nanoparticles were clear and transparent, with no significant hemolysis, and the hemolysis rates were significantly lower than the biomaterial safety threshold of 5%. These results indicate that the three water-soluble nanoparticles have good blood compatibility.

[0266] Figure 15 The cytotoxicity test graph and hemolysis experiment of the water-soluble nanoparticles of the application example and comparative application example 1-2 are shown;

[0267] in,

[0268] Figure 15 (a) shows the cytotoxicity test graph of the water-soluble nanoparticles of Application Example and Comparative Application Example 1-2;

[0269] Figure 15 (b) shows the hemolysis experiment of water-soluble nanoparticles PBTTQ-DPP@NPs of comparative application example 1 at different concentrations;

[0270] Figure 15 (c) shows the hemolysis experiment of water-soluble nanoparticles PPhTQ-DPP@NPs of comparative application example 2 at different concentrations;

[0271] Figure 15 (d) shows the hemolysis experiment of water-soluble nanoparticles PATQ-DPP@NPs of the application example at different concentrations.

[0272] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations that come within the meaning and range of equivalents of the claims be embraced therein.

[0273] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit, characterized in that: The DA-type asymmetric non-conjugated polymer based on the ATQ electron-withdrawing unit is represented by the following general structural formula: in, n is a natural number from 1 to 10000; Ar is independently one or more selected from aromatic hydrocarbon derivatives having 6 to 60 carbon atoms and heterocyclic derivatives having 1 to 60 carbon atoms; in, The aromatic hydrocarbon derivative is selected from a group containing one or more aromatic ring structures, wherein the hydrogen atoms on all aromatic ring structures are unsubstituted. or One or more hydrogen atoms at any position on one or more aromatic ring structures are replaced by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups; The heterocyclic derivative is selected from a group containing one or more heterocyclic structures, wherein the hydrogen atoms on all heterocyclic structures are not substituted. or One or more hydrogen atoms at any position on one or more heterocyclic structures are replaced by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups; Said R1 is selected from electron-rich groups; The ATQ electron-withdrawing unit has a stereo conformation.

2. The DA-type asymmetric non-conjugated polymer based on the ATQ electron-withdrawing unit according to claim 1, characterized in that: The R1 is selected from the following structures: Wherein, R2-R4 are independently selected from one or more of hydrogen atoms, aryl derivatives, and alkyl derivatives; in, All hydrogen atoms on the alkyl derivative are unsubstituted, or One or more hydrogen atoms at any position on the alkyl derivative are substituted by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups; The aryl derivative is selected from a group containing one or more aromatic ring structures, wherein the hydrogen atoms on all aromatic ring structures are not substituted, or One or more hydrogen atoms at any position on one or more aromatic ring structures are replaced by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups.

3. The DA-type asymmetric non-conjugated polymer based on ATQ electron-withdrawing unit according to claim 1, characterized in that: The Ar is selected from different groups.

4. The DA-type asymmetric non-conjugated polymer based on ATQ electron-withdrawing unit according to claim 1, characterized in that: The ATQ electron-withdrawing unit Selected from the following structures: Said R5, R6, R7, R8, and R9 are independently selected from one or more of hydrogen atoms, halogen atoms, aryl derivatives, and alkyl derivatives; All hydrogen atoms on the alkyl derivative are unsubstituted, or One or more hydrogen atoms at any position on the alkyl derivative are substituted by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups; The aryl derivative is selected from a group containing one or more aromatic ring structures, wherein the hydrogen atoms on all aromatic ring structures are not substituted, or One or more hydrogen atoms at any position on one or more aromatic ring structures are replaced by one or more of halogen, hydroxy, amino, aryl, alkene, alkyne, carboxyl, ester, cyano or nitro groups.

5. The method for preparing a DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit according to any one of claims 1 to 4, characterized in that: The steps include: S1. Under the protection of an inert gas, a nitro-containing benzothiadiazole or a derivative thereof and acetic acid are mixed, heated, a reducing agent is added, reacted, and purified to obtain an intermediate product 1; S2, dissolving the intermediate product and a diketone derivative in acetic acid, heating the mixture under the protection of an inert gas, and purifying the mixture to obtain an intermediate product 2; S3. Under the protection of inert gas, the intermediate product 2 and the R1 monomer treated with trimethyltin are dissolved in a solvent, heated to react in the presence of a catalyst, and purified to obtain a DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit.

6. The method for preparing a DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit according to claim 5, characterized in that: In step S3, the heating temperature is 130-150°C.

7. A water-soluble nanoparticle, characterized in that: The invention comprises a DA-type asymmetric non-conjugated polymer based on an ATQ electron-withdrawing unit as described in any one of claims 1 to 4 as a core structure, and a phospholipid compound as a shell structure.

8. The water-soluble nanoparticles according to claim 7, characterized in that: The particle size of the water-soluble nanoparticles is 100-140 nm.

9. The water-soluble nanoparticles according to claim 7, characterized in that: The mass ratio of the core structure to the shell structure is 1:(1-5).

10. Use of the water-soluble nanoparticles according to any one of claims 7 to 9 as a near-infrared second-region photoacoustic contrast agent.

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