D-a-d type organic small molecules, nanoparticles comprising the same, and preparation methods and applications thereof

Abstract

The application discloses a D-A-D type organic small molecule, nanoparticles containing the same, and a preparation method and application thereof. The D-A-D type organic small molecule and the nanoparticles thereof are particularly suitable for precise photothermal treatment and real-time imaging guidance of hematological malignancies such as leukemia, lymphoma and multiple myeloma. The D-A-D type organic small molecule constructs a D-A-D type conjugated structure, realizes near-infrared absorption red shift to 685 nm through enhancing intramolecular charge transfer (ICT) effect, and promotes non-radiative transition by using high excited state reorganization energy (lambda=1.29eV), with a photothermal conversion efficiency of more than 35%. The small molecule does not contain metal and halogen, has a molecular weight of about 878 Da, and has good biocompatibility and metabolic potential. The small molecule is self-assembled into nanoparticles with a particle size of about 130 nm, and has good colloidal stability and passive targeting ability. Meanwhile, the high molar absorption coefficient and high-efficiency photothermal conversion characteristics of the small molecule endow the small molecule with strong photoacoustic imaging capability, and the small molecule can be used for real-time monitoring of drug distribution and realization of 'diagnosis and treatment integration'.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a DAD-type organic small molecule, nanoparticles containing it, and their preparation methods and applications. Background Technology

[0002] Photothermal therapy (PTT), a non-invasive cancer treatment strategy, has attracted considerable attention in recent years for its selective destruction of malignant tissue through localized high heat generated by photothermal conversion agents (PTCAs) under near-infrared (NIR) light irradiation. The core of PTT's efficacy lies in developing advanced PTCAs that operate efficiently within the near-infrared biological window (650-900 nm), which offers optimal light penetration depth due to minimal tissue absorption and scattering. Despite significant progress in nanomaterial-based PTT, its clinical translation still faces key challenges, including long-term biosafety concerns, unpredictable biodistribution, and unclear metabolic pathways. These issues are particularly prominent in inorganic or hybrid nanomaterials such as gold nanorods, carbon nanotubes, and metal chalcogenides.

[0003] In contrast, small organic molecule photothermal conversion agents (PTCAs) are considered a promising alternative due to their well-defined molecular structures, precisely tunable optical properties, good biocompatibility, and potential renal clearance capabilities. However, the development of high-performance small organic molecule PTCAs still faces significant bottlenecks: firstly, their absorption in the near-infrared II region above 800 nm is generally insufficient; secondly, competitive radiative decay or insufficient relaxation of the excited state in the aggregated state leads to low photothermal conversion efficiency (PCE); and finally, their photothermal stability in the aggregated or solid state is often poor, which is crucial for the accumulation of drugs in the form of nanoparticles at tumor sites and the exertion of therapeutic effects. Therefore, it is urgent to simultaneously enhance the near-infrared absorption capacity of materials, promote non-radiative decay processes, and ensure their performance stability in the aggregated state through rational molecular design strategies.

[0004] At the molecular design level, constructing a donor-receptor-receptor (DAD) conjugated framework is one of the effective strategies for regulating the near-infrared absorption of organic chromophores. In existing technologies, studies have used benzo[2,1-b:3,4-b′]dithiophene-4,5-dione as the acceptor unit to construct DA-type photothermal molecules and achieved some success. However, these molecules still have room for optimization in terms of absorption wavelength, photothermal efficiency, and stability. Especially for the treatment of hematologic malignancies requiring deep tissue penetration and highly efficient thermotherapy, their performance is not yet sufficient to fully meet clinical needs.

[0005] Currently, the material systems used in photothermal therapy for tumors suffer from the following main drawbacks: inorganic nanomaterials present difficulties in biological metabolism and long-term toxicity risks; traditional organic dyes such as indocyanine green (ICG) face problems of poor photostability and rapid decay of photothermal efficiency; and most reported conjugated polymers or small-molecule photothermal agents lack systematic and precise control of their molecular structures, making it difficult to simultaneously achieve strong near-infrared absorption and efficient non-radiative relaxation, resulting in generally low photothermal conversion efficiency (mostly below 30%) or absorption peaks deviating from the ideal therapeutic window. Furthermore, existing materials often have limited functionality, lack theatrical integration capabilities, cannot achieve real-time imaging monitoring during treatment, and are prone to aggregation or performance degradation in complex physiological environments such as blood, affecting their application efficacy in the treatment of systemic, diffusely distributed hematologic malignancies (such as leukemia and lymphoma).

[0006] Therefore, developing an organic small molecule photothermal formulation that combines efficient near-infrared photothermal conversion, excellent biocompatibility and metabolism, good colloidal stability, and integrated diagnostic and therapeutic functions is of great scientific significance and practical value for promoting the clinical application of PTT, especially in the treatment of hematologic malignancies. Summary of the Invention

[0007] Therefore, the purpose of this invention is to provide a DAD-type organic small molecule, nanoparticles containing it, and their preparation methods and applications. The DAD-type organic small molecule and nanoparticles containing it provided by this invention are particularly suitable for precise photothermal therapy and real-time imaging guidance for hematologic malignancies such as leukemia, lymphoma, and multiple myeloma. This addresses key technical problems in existing technologies, such as the long-term biotoxicity and non-metabolizable risks of inorganic materials, the poor photostability and low photothermal conversion efficiency of traditional organic dyes, insufficient molecular excited-state regulation leading to difficulties in simultaneously achieving light absorption and heat generation, the inability to visualize treatment due to separation of diagnostic and therapeutic functions, and poor colloidal stability in complex blood environments. Through molecular engineering strategies, a DAD-type conjugated small molecule is designed with benzodithiophene dione (BDTD) as a strong electron acceptor and N-alkylated triphenylamine derivatives (such as NPA) as a strong electron donor. Utilizing its significant intramolecular charge transfer effect and large excited-state recombination energy, it achieves near-infrared (650–700 nm) imaging. By combining strong absorption (nm) and efficient non-radiative energy dissipation, a photothermal conversion efficiency of over 35% can be achieved. Furthermore, through self-assembly to form water-dispersible nanoparticles, the biocompatibility, serum stability, and in vivo circulation performance are significantly improved. Ultimately, a novel organic photothermal diagnostic and therapeutic platform that is metal-free, biodegradable, and allows for real-time monitoring of the treatment process is constructed, providing a safe and effective new strategy with clear clinical translational potential for the non-invasive or minimally invasive precision treatment of hematological malignancies.

[0008] Specifically, the present invention provides a DAD-type organic small molecule, characterized in that it has the structure described in formula (I):

[0009] Where: R1, R2, R4, R5, R6, R7, R9, R 10 R 11 R 12 R 13 R 14， R 15 and R 16 The group consisting of hydrogen atoms, straight-chain or branched alkyl groups, is independently selected; and R1, R2, R4, R5, R6, R7, R9, R... 10 R 11 R 12 R 13 R 14， R 15 and R 16 They can be the same or different; R3 and R8 are L and M are each independently selected from the group consisting of hydrogen atoms, straight-chain or branched alkyl groups. L and M can be the same or different, and R3 and R8 can be the same or different.

[0010] In some specific embodiments of the present invention, R1, R2, R4, R5, R6, R7, R9, R 10 R 11 R 12 R 13 R 14， R 15 and R 16 All are hydrogen atoms; R3 and R8 are dimethylamino groups, with the structural formula shown in formula (II). .

[0011] This invention also provides a method for preparing DAD-type organic small molecules, which is carried out according to the following reaction route: ; Where: R1, R2, R4, R5, R6, R7, R9, R 10 R 11 R 12 R 13 R 14， R 15 and R 16 The group consisting of hydrogen atoms, straight-chain or branched alkyl groups, is independently selected; and R1, R2, R4, R5, R6, R7, R9, R... 10 R 11 R12 R 13 R 14， R 15 and R 16 They can be the same or different; R3 and R8 are L and M are each independently selected from the group consisting of hydrogen atoms, straight-chain or branched alkyl groups. L and M can be the same or different, and R3 and R8 can be the same or different.

[0012] In some specific embodiments of the present invention, the reaction is carried out according to the following reaction route: ; In some specific embodiments of the present invention, the molar ratio of compound (Ⅳ) to compound (Ⅲ) is 1:(2-10), and the molar ratio of Pd(PPH3)4) to compound (Ⅳ) is 1:(10-100).

[0013] In some specific embodiments of the present invention, the reaction is carried out according to the following reaction route: ; In some specific embodiments of the present invention, the reaction is carried out according to the following reaction route: ; The present invention also provides a DAD-type organic small molecule nanoparticle, characterized in that it is prepared by a nanoprecipitation method from a compound of formula (I) or formula (II).

[0014] In some specific embodiments of the present invention, the particle size of the DAD-type organic small molecule nanoparticles is 80-200 nm.

[0015] In some specific embodiments of the present invention, it is prepared from a compound of formula (I) or formula (II) and DSPE-PEG2000-COOH.

[0016] In some specific embodiments of the present invention, the preparation of the nanoparticles includes the following steps: dissolving the compound of formula (I) or formula (II) in an organic solvent, adding it dropwise to a solution of DSPE-PEG2000-COOH after ultrasonic dissolution, maintaining a high-speed rotation during the dropwise addition process, and continuing to stir at the same speed until the mixed solution becomes transparent, then removing the organic solvent by vacuum distillation, and lyophilizing the remaining aqueous solution, the lyophilized powder solid being the DAD type organic small molecule nanoparticles.

[0017] In some specific embodiments of the present invention, the mass ratio of compound of formula (I) or formula (II) to DSPE-PEG2000-COOH is 1:(1-5).

[0018] In some specific embodiments of the present invention, the preparation of the nanoparticles includes the following steps: dissolving the compound of formula (I) or formula (II) in tetrahydrofuran, and slowly adding the tetrahydrofuran solution of the compound of formula (I) or formula (II) dropwise to a PBS solution of DSPE-PEG2000-COOH with a concentration of 0.5 mg / mL-1 while stirring, continuing to stir the mixture until the mixed solution becomes transparent, then removing the organic solvent by vacuum distillation, and lyophilizing the remaining aqueous solution, and the lyophilized powder solid is the nanoparticles s.

[0019] The present invention also provides a drug or drug composition for photothermal therapy of tumors, comprising any of the DAD-type organic small molecules described above, or DAD-type organic small molecules prepared by the preparation method described above, or DAD-type organic small molecule nanoparticles described above.

[0020] In some specific embodiments of the present invention, the photothermal therapy is performed under 650–850 nm laser irradiation, preferably 808 nm.

[0021] The present invention also provides the application of the DAD-type organic small molecules described in any of the above-mentioned methods, or the DAD-type organic small molecules prepared by the above-mentioned methods, or the DAD-type organic small molecule nanoparticles described in any of the above-mentioned methods, in the preparation of drugs for hematologic malignancies.

[0022] In some specific embodiments of the present invention, the hematologic malignancy is diffuse large B-cell lymphoma.

[0023] The present invention has the following significant advantages and effects compared with the prior art: Firstly, regarding photothermal conversion performance, this invention employs a molecular engineering strategy, using BDTD as a strong electron acceptor and N-alkylated triphenylamine (NPA) as a strong electron donor, to design and synthesize a DAD-type conjugated small molecule. This significantly enhances intramolecular charge transfer (ICT) intensity, resulting in a significant upward shift of the HOMO energy level while maintaining relative stability of the LUMO energy level. Consequently, the optical band gap is reduced to 1.70 eV, and the absorption is red-shifted to the 685 nm NIR-I therapeutic window, perfectly matching the optical requirements of hematological malignancy diagnosis and treatment. Simultaneously, the N-alkyl / alkoxy donor induces a large geometric relaxation in the excited state, enabling the recombination energy to reach 1.29 eV (far higher than 0.83 eV for BDQ-TPA), significantly enhancing electron-phonon coupling, effectively promoting nonradiative internal conversion (IC) from S1 to S0, suppressing fluorescence radiation, achieving efficient conversion of light energy to heat energy, and maintaining high oscillator strength (f = (0.2555), without compromising conjugate planarity and transition dipole moment, ensuring a high molar extinction coefficient and strong light-capturing capability per unit concentration, ultimately achieving efficient photothermal conversion and providing core performance support for precise photothermal therapy.

[0024] Secondly, regarding biosafety and metabolic performance, the DAD-type conjugated small molecule designed in this invention has a fully organic structure, free of metals, halogens, or recalcitrant polymer backbones, and is composed only of common elements such as C, H, O, N, and S. Theoretically, it can be metabolized into small molecule products through the liver / kidneys, and the molecular weight is controlled below 1000 Da (BDQ-NPA molecular weight is approximately 878 Da), which meets the principle of "drug-likeness" and can effectively avoid long-term accumulation of materials in vivo. Compared with inorganic photothermal materials such as gold nanorods and CuS, the material of this invention completely eliminates the risk of heavy metal toxicity, and in vitro hemolysis experiments and cytotoxicity tests have demonstrated its good biocompatibility. Even at high concentrations, there is no obvious hemolysis or immune activation phenomenon, which is fully suitable for the application scenario of systemic circulation administration of hematologic malignancies and solves the key pain points of high biotoxicity and non-metabolizability of existing materials.

[0025] Thirdly, regarding its efficacy in vivo, this invention prepares self-assembled nanoparticles from DAD-type conjugated small molecules using a nanoprecipitation method. These nanoparticles have uniform particle size (approximately 130 nm) and an electrically neutral surface, which reduces opsonin adsorption. They remain stable for more than 7 days in culture media containing 50% serum and in whole blood without significant aggregation, effectively solving the problem of insufficient colloidal stability of existing materials in complex blood environments. Simultaneously, the nanoparticle size is within the effective range of the EPR effect (100-200 nm), allowing for passive retention in hematologic tumor-rich sites such as bone marrow, spleen, and lymph nodes, achieving passive targeting. Furthermore, it eliminates the need for surface modification with targeting ligands, simplifying the preparation process, reducing production costs and immunogenicity risks, and ensuring the material's circulation and targeting performance in vivo, thus laying the foundation for its efficacy in in vivo diagnosis and treatment.

[0026] Fourthly, regarding the integration of diagnosis and treatment and the precision of treatment, the DAD-type conjugated small molecules of this invention, with their high molar absorptivity and photothermal expansion effect, can generate strong photoacoustic signals under 685 nm laser excitation. This enables real-time imaging and monitoring of the enrichment of nanoparticles in the tumor area, achieving integrated diagnosis and treatment. Based on this imaging function, laser irradiation can be performed under imaging guidance, effectively avoiding accidental damage to healthy tissues and realizing a closed-loop diagnosis and treatment strategy of "seeing is treating". This solves the problem of existing materials having separate diagnosis and treatment functions and being unable to achieve visual monitoring of the treatment process, significantly improving the precision and safety of the treatment of hematological malignancies.

[0027] In summary, through the above-mentioned technical design, this invention has ultimately constructed a novel organic photothermal platform that is metal-free, has high photothermal conversion efficiency, is capable of photoacoustic imaging, is biodegradable, and has excellent biocompatibility. This platform effectively realizes precise photothermal therapy and real-time imaging guidance for hematologic malignancies, providing a safe, effective, and clinically promising new strategy for non-invasive / minimally invasive precision treatment of hematologic malignancies, thus successfully achieving the intended purpose of this invention. Attached Figure Description

[0028] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0029] Figure 1 The 1H NMR spectrum of BDQ-NPA, a DAD-type organic small molecule.

[0030] Figure 2 The carbon NMR spectrum of BDQ-NPA, a DAD-type organic small molecule.

[0031] Figure 3 This is the 1H NMR spectrum of NPA-Bpin.

[0032] Figure 4 This is a high-resolution mass spectrum of BDQ-NPA.

[0033] Figure 5 This is a high-resolution mass spectrum of NPA-Bpin.

[0034] Figure 6 The UV absorption spectra of BDQ-NPA and BDQ-NPA NPs are shown.

[0035] Figure 7The particle size distribution of BDQ-NPA NPs in PBS as measured by DLS.

[0036] Figure 8 To observe the morphology of BDQ-NPA NPs using transmission electron microscopy.

[0037] Figure 9 Thermal imaging of BDQ-NPA NPs at different concentrations was performed using a thermometer under 808 nm laser irradiation (1.0 W / cm²).

[0038] Figure 10 Temperature variation curves of BDQ-NPA NPs with different concentrations under 808nm laser irradiation (1.0 W / cm²).

[0039] Figure 11 The temperature change curves of BDQ-NPANPs under four ON / OFF irradiation cycles of 808 nm laser (1.0 W / cm², 100 μg / mL) are shown.

[0040] Figure 12 The heating / cooling temperature change curves of BDQ-NPA NPs under 808 nm laser irradiation (1.0 W / cm², 200 μg / mL) are shown.

[0041] Figure 13 To calculate the PCE of BDQ-NPA NPs under 808nm laser irradiation.

[0042] Figure 14 After different treatment groups, the viability of A20 cells was detected using the CCK-8 assay.

[0043] Figure 15 To determine cell viability after incubating HK-2 cells with BDQ-NPA NPs, the CCK-8 assay was used.

[0044] Figure 16 To capture fluorescence images of live A20 cells (green) and dead A20 cells (red) using CLSM after treatment in different groups (scale bar = 50 μm).

[0045] Figure 17 A20 cell apoptosis was detected by flow cytometry after different treatment groups.

[0046] Figure 18 Photoacoustic imaging at different time points after tail vein injection of BDQ-NPA-NPs.

[0047] Figure 19 To quantify the photoacoustic intensity at different time points in the tumor site.

[0048] Figure 20 Fluorescence imaging at different time points after tail vein injection of BDQ-NPA NPs.

[0049] Figure 21 To quantify the fluorescence intensity of tumor sites at different time points.

[0050] Figure 22 24 hours after injecting BDQ-NPA NPs into the tail vein, mice were dissected to obtain organs and tumors for fluorescence imaging.

[0051] Figure 23 Quantitative fluorescence of organs and tumors after dissection.

[0052] Figure 24 This is a curve showing the weight change of tumor-bearing mice during treatment.

[0053] Figure 25 The curves show the changes in tumor size in mice at different treatment stages.

[0054] Figure 26 After treatment, tumor photos of each group of mice were taken using a digital camera. Detailed Implementation

[0055] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are merely some embodiments of the present invention and should not be used to limit the scope of protection of the present invention. 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. Protection range.

[0056] Example 1: Synthesis and characterization of the DAD-type small organic molecule (BDQ-NPA) shown in formula (II) 1) Synthesis of BDQ-NPA Synthesize according to the following reaction route: ; The synthesis steps are as follows: The target molecule BDQ-NPA was synthesized via a palladium-catalyzed double Suzuki–Miyaura cross-coupling reaction: A triphenylamine derivative functionalized with N,N-dimethylamino pinacol boronic acid ester (D-Bpin, compound (V), 2.4 mmol), dibromobenzo[1,2-b:4,3-b′]dithiophene-4,5-dione (BDTD-Br2, 1 mmol), palladium catalyst (0.05 mmol), and KOAc (600 mg, 6 mmol) were mixed in 20 mL of THF and reacted at 80 °C for 12 hours. After cooling, THF was removed by vacuum distillation. The mixture was dissolved in CH2Cl2, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After solvent removal, the residue was purified by rapid column chromatography (silica gel, petroleum ether / ethyl acetate 5:1) to give compound (II).

[0057] 2) Characterization of the product The synthesized product was subjected to ¹H NMR and ¹³C NMR spectroscopy. The ¹H NMR spectrum is attached. Figure 1 In the BDTD-Br2 precursor (shown), the 2,7-proton signal at δ = 8.05 ppm completely disappeared after coupling, confirming quantitative substitution; all aromatic ring protons in the final product shifted below 8.0 ppm, indicating the formation of an extended π-conjugated system between the TPA donor and the BDTD acceptor. The ¹³C NMR spectrum of BDQ-NPA showed a sharp singlet at δ = 2.95 ppm, corresponding to the –N(CH3)2 proton of N,N-dimethylamino. This chemical shift is higher than that of aliphatic tertiary amines (δ ≈ 2.2–2.5 ppm), consistent with N,N-dimethylaniline derivatives in the literature (δ ≈ 2.7–3.2 ppm), confirming the successful introduction of the donor unit. ¹³C NMR spectrum (see attached) Figure 2 In the figure shown, the signal of the para-carbon (C4) of the TPA aromatic ring directly connected to BDTD shifted from δ ≈ 123 ppm in unmodified TPA to δ ≈ 127 ppm, a low-field shift of about 4 ppm, which is due to the electron-withdrawing conjugation effect of the BDTD core. This directly proves that there is effective electronic coupling between the donor and acceptor, and confirms the construction of the D–A–D conjugated framework.

[0058] To ensure the accuracy of the synthetic route for the target molecule BDQ-NPA, key intermediates and the final product were characterized by multinuclear NMR and high-resolution mass spectrometry (HRMS). As the core synthetic module, NPA-Bpin (a triphenylamine derivative substituted with bipinol borate) was prepared via a palladium-catalyzed borylation reaction. Its ¹H NMR (with attached...) Figure 3As shown, a characteristic singlet appears at δ = 1.31 ppm, corresponding to the methyl proton of the Bpin group (–O–C(CH3)2–O–), and there are no isomer or oxidation byproduct signals, indicating that the borylation step has high purity and regioselectivity.

[0059] Subsequently, NPA-Bpin was Suzuki–Miyaura cross-coupled with the dibromoBDTD acceptor nucleus to obtain the target D–A–D molecule BDQ-NPA. HRMS (positive ion mode, with...) Figure 4 As shown, the [M + H]⁺ main peak is located at m / z = 879.35, which is closer to the theoretical value of 879.34 (C). 54 H 51 The N6O2S2⁺ is completely identical, confirming the accuracy of the molecular formula and the success of the coupling reaction. HRMS of the intermediate NPA-Bpin (attached) Figure 5 The diagram also shows the [M + H]⁺ signal with m / z = 458.31, compared to the calculated value of 458.29 (C). 28 H 36 The deviation of BN3O2⁺ was only −2 ppm, which is within the allowable range of instrument error, further confirming the chemical structure of this key building block.

[0060] In summary, the dual verification by ¹H NMR and HRMS provides a solid basis for the high-purity preparation of BDQ-NPA and its precursors, and also lays a solid foundation for subsequent structure-performance studies such as optical absorption, energy level arrangement and photothermal properties.

[0061] Figure 1 Verification of aging in vivo and in vitro.

[0062] Example 2: Preparation and characterization of BDQ-NPA nanoparticles (BDQ-NPA NPS) 1) Preparation of BDQ-NPA NPS To prepare BDQ-NPA nanoparticles (NPs), 1 mg of BDQ-NPA was first dissolved in THF and sonicated in an ice bath for 15 min until completely dissolved. Then, 3 mg of DSPE-PEG2000-COOH was weighed and dissolved in 5 mL of PBS, also dissolved by sonication. Next, under magnetic stirring at 1200 rpm, the BDQ-NPA THF solution was added dropwise to 5 mL of DSPE-PEG2000-COOH solution, and stirring was continued for 1 h until the solution became clear. Finally, THF was removed using a rotary evaporator, and the solution was concentrated to 200 μg / mL. The remaining aqueous solution was lyophilized, and the lyophilized powder was the BDQ-NPA NPS.

[0063] 2) Solution characterization of BDQ-NPA NPs When BDQ-NPA was dissolved in chloroform, a significant absorption peak appeared at 685 nm in the UV-Vis spectrum (Figure 6). After being prepared into nanoparticles (NPs) by nanoprecipitation, the absorption peak red-shifted to approximately 698 nm (Figure 6), indicating an aggregation-induced bathochromic shift. Although the change was small, it suggests that the dye molecules may exhibit a certain degree of "head-to-tail" alignment, forming J-like aggregates, thereby prolonging the delocalization of π electrons and reducing the transition band gap. This aggregation enhances the absorption capacity in the near-infrared region, which is beneficial to the photothermal conversion efficiency under laser irradiation.

[0064] It is worth noting that although the main absorption band of BDQ-NPA NPs is located in the 600–700 nm region, significant residual absorption still exists in the near-infrared region. To quantitatively evaluate its feasibility for use in 808 nm laser-mediated photothermal therapy (PTT), the molar extinction coefficient at this wavelength was measured in this embodiment. Based on the UV–Vis–NIR spectrum and the known nanoparticle concentration, ε at 808 nm was calculated to be 1.88 × 10⁻⁶. 4 L mol⁻¹ cm⁻¹. This high value confirms that BDQ-NPA NPs possess sufficient near-infrared absorption capacity to achieve efficient photo-thermal conversion under 808 nm irradiation, meeting the practical application requirements of PTT.

[0065] The morphology and size distribution of the obtained BDQ-NPA NPs were systematically characterized. Dynamic light scattering (DLS) revealed an average hydrodynamic diameter of 130 nm and a polydispersity index (PDI) of only 0.19, indicating a narrow size distribution and high colloidal homogeneity (Figure 7). Transmission electron microscopy (TEM) images further verified the above results, showing that the particles were regular spherical and uniform in size (Figure 8).

[0066] Example 3: Photothermal properties and photostability tests of BDQ-NPA NPs To evaluate the potential of BDQ-NPA nanoparticles for photothermal therapy (PTT), we conducted a series of in vitro photothermal performance tests under physiologically relevant conditions. First, different concentrations (0–200 μg mL⁻¹) of BDQ-NPA nanoparticle aqueous dispersions were irradiated with an 808 nm near-infrared laser (1.0 W cm⁻²), and temperature changes were recorded in real time using an infrared thermal imager. Figure 9The thermal imaging showed that the temperature rise increased with time and concentration, with the highest concentration group experiencing a temperature increase of over 50 °C within 10 minutes. Quantitative temperature rise curves simultaneously acquired by the thermometer (shown in Figure 10) further verified the stable and reproducible thermal generation capability of BDQ-NPA nanoparticles.

[0067] To further investigate the photostability under repeated thermal stress, this embodiment subjected the same nanodispersion to five cycles of "laser on (10 minutes) - laser off (10 minutes)". Figure 11 shows that the maximum temperature of each cycle remained almost unchanged, and no photothermal performance degradation was observed, indicating that the nanoparticles hardly underwent photobleaching or structural damage during long-term irradiation—this provides a key guarantee for future clinical applications with continuous heating.

[0068] The Roper model was used to fit the heating-cooling transient temperature curves (shown in Figure 12), and the photothermal conversion efficiency (PCE) of BDQ-NPA nanoparticles was found to be 35.05% (shown in Figure 13). This value ranks among the top reported for organic semiconductor polymers and small molecule photothermal agents. Such high efficiency is attributed to the extended π-conjugation, strong donor-acceptor properties, and efficient exciton relaxation within the D–A–D framework.

[0070] Example 4: In vitro therapeutic experiment of BDQ-NPA NPs In vitro cell experiments evaluated the therapeutic effect of BDQ-NPA nanoparticles on tumors. Figure 14 shows that the cell survival rate in the laser-free group was still above 80% at a concentration of 25 μg mL⁻¹, indicating that this concentration is safe and has no significant toxicity; however, after irradiation with an 808 nm laser, the survival rate of A20 cells dropped to below 45%, confirming that 25 μg mL⁻¹ BDQ-NPA nanoparticles have the best photothermal therapeutic effect on A20 cells.

[0071] Regarding biosafety, Figure 15 The results showed that the survival rate of HK-2 cells was higher than 75% in the range of 0–50 μg mL⁻¹, indicating that BDQ-NPA nanoparticles have low toxicity to normal cells and have the potential to be used as biomaterials in vivo.

[0072] To directly observe cell viability after laser irradiation, confocal imaging was performed using a Calcein AM (live cells) / PI (dead cells) double staining kit (see attached image). Figure 16 As shown in the figure. Most cells in the control group (–L and +L) and the BDQ-NPA nanoparticle (–L) group survived, while large-area cell death occurred in the BDQ-NPA nanoparticle (+L) group, indicating that its photothermal therapy effect was significant.

[0073] Flow cytometry further validated the above conclusions (see appendix) Figure 16 (As shown). Annexin V-FITC / PI double staining results showed that the control group (–L and +L) and the BDQ-NPA nanoparticle (–L) group had almost no apoptosis, while the apoptosis rate of the BDQ-NPA nanoparticle (+L) group was as high as 54.78%, which is consistent with the above experimental results, fully demonstrating that BDQ-NPA nanoparticles have excellent photothermal therapeutic performance on tumor cells.

[0074] Example 5: In vivo targeting and in vivo therapeutic experiments of BDQ-NPA NPs To evaluate the photothermal therapeutic effect of BDQ-NPA nanoparticles in vivo, a mouse tumor-bearing model was constructed in this embodiment. First, photoacoustic imaging (PAI) was used to visually observe the accumulation of nanoparticles at the tumor site. As shown in Figure 18, with prolonged administration time, BDQ-NPA nanoparticles gradually accumulated at the tumor site, reaching a peak at 6 hours, and then began to be metabolized. Quantitative analysis of the photoacoustic signal in the tumor region was performed using ImageJ, and Figure 19 shows that the signal intensity changes were consistent with the above observations.

[0075] Fluorescence imaging further validated the temporal tumor enrichment of BDQ-NPA nanoparticles. Figure 20 shows fluorescence images of small animals, indicating that the nanoparticles were most significantly enriched at the tumor site 6 hours after injection, subsequently gradually decreasing over time; quantitative results of fluorescence intensity in the tumor region also confirmed this trend (see appendix). Figure 21 (As shown).

[0076] To investigate the metabolic distribution of BDQ-NPA nanoparticles in vivo, mice were dissected 24 hours after tail vein injection. Major organs (heart, liver, spleen, lung, and kidney) and tumors were removed for in vitro fluorescence imaging. Figure 22 shows that after 24 hours, the nanoparticles were mainly metabolized by the liver, with some residue remaining in the tumor site; corresponding quantitative data also confirmed this distribution characteristic (see attached figure). Figure 23 (As shown).

[0077] Using photoacoustic and fluorescence imaging, the time point at which BDQ-NPA nanoparticles reached maximum accumulation in mice was first determined, and subsequent tumor treatment experiments were conducted based on this. As shown in Figure 24, during the 10-day treatment period, the body weight of mice in each group did not fluctuate significantly, indicating that BDQ-NPA nanoparticles, as a photothermal therapeutic agent, have no obvious toxicity to the body and can be safely used in in vivo studies. More importantly, after 10 days of treatment, the tumors in the experimental group mice shrank significantly compared to the control group, almost disappearing (see appendix). Figure 25(As shown). After treatment, anatomical resection revealed that the tumor volume in the BDQ-NPA nanoparticle (+L) group was significantly smaller than that in the control group and the BDQ-NPA nanoparticle (-L) group (see attached). Figure 26 (As shown).

[0078] The above description is merely a preferred embodiment of this application and an explanation of the technical principles employed. Those skilled in the art should understand that the scope of the invention involved in this application is not limited to the technical solutions formed by specific combinations of the above-described technical features, but should also cover other technical solutions formed by arbitrary combinations of the above-described technical features or their equivalents without departing from the inventive concept. For example, the above-described features have similar functions to (but are not limited to) those disclosed in this application.

Claims

1. A DAD-type organic small molecule, characterized in that, It has the structure described in equation (Ⅰ): ； Where: R1, R2, R4, R5, R6, R7, R9, R 10 R 11 R 12 R 13 R 14， R 15 and R 16 The group consisting of hydrogen atoms, straight-chain or branched alkyl groups, is independently selected; and R1, R2, R4, R5, R6, R7, R9, R... 10 R 11 R 12 R 13 R 14， R 15 and R 16 They can be the same or different; R3 and R8 are L and M are each independently selected from the group consisting of straight-chain or branched alkyl groups. L and M may be the same or different, and R3 and R8 may be the same or different.

2. The DAD-type organic small molecule as described in claim 1, characterized in that, R1, R2, R4, R5, R6, R7, R9, R 10 R 11 R 12 R 13 R 14， R 15 and R 16 All are hydrogen atoms; R3 and R8 are dimethylamino.

3. A method for preparing a DAD-type organic small molecule, characterized in that, The reaction is carried out according to the following reaction route: Where: R1, R2, R4, R5, R6, R7, R9, R 10 R 11 R 12 R 13 R 14， R 15 and R 16 The group consisting of hydrogen atoms, straight-chain or branched alkyl groups, is independently selected; and R1, R2, R4, R5, R6, R7, R9, R... 10 R 11 R 12 R 13 R 14， R 15 and R 16 They can be the same or different; R3 and R8 are L and M are each independently selected from the group consisting of straight-chain or branched alkyl groups. L and M may be the same or different, and R3 and R8 may be the same or different.

4. A DAD-type organic small molecule nanoparticle, characterized in that, The compound described in any one of claims 1-2 is prepared by nanoprecipitation.

5. The DAD-type organic small molecule nanoparticles as described in claim 4, characterized in that, It is prepared from the compound described in any one of claims 1-2 and DSPE-PEG2000-COOH.

6. The DAD-type organic small molecule nanoparticles as described in claim 5, characterized in that, The preparation of the nanoparticles includes the following steps: dissolving the compound of any one of claims 1-2 in an organic solvent, ultrasonically dissolving it, and then adding it dropwise to a solution of DSPE-PEG2000-COOH. During the dropwise addition, the mixture is stirred at a high speed while maintaining the high speed. After the addition is complete, the mixture is stirred at the same speed until the mixed solution becomes transparent. Then, the organic solvent is removed by vacuum distillation, and the remaining aqueous solution is lyophilized. The lyophilized powder solid is the DAD type organic small molecule nanoparticle.

7. The DAD-type organic small molecule nanoparticles as described in any one of claims 5-6, characterized in that, The mass ratio of the compound according to any one of claims 1-2 to DSPE-PEG2000-COOH is 1:(1-5).

8. A drug or drug composition for photothermal therapy of tumors, characterized in that, It comprises the DAD-type organic small molecule as described in any one of claims 1-2, or the DAD-type organic small molecule prepared by the preparation method described in claim 3, or the DAD-type organic small molecule nanoparticles as described in any one of claims 4-7.

9. The use of the DAD-type organic small molecule as described in any one of claims 1-2, or the DAD-type organic small molecule prepared by the preparation method described in claim 3, or the DAD-type organic small molecule nanoparticles as described in any one of claims 4-7, in the preparation of drugs for hematologic malignancies.

10. The application as described in claim 9, characterized in that, The hematologic malignancy is diffuse large B-cell lymphoma.

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