1, 3-dithio heterocyclic fused naphthalene tetracarboxylic diimide derivative, near-infrared two-region photo-thermal molecule containing same, and preparation method and application of 1, 3-dithio heterocyclic fused naphthalene tetracarboxylic diimide derivative and near-infrared two-region photo-thermal molecule

Abstract

The invention discloses a 1, 3-disulfur heterocyclic ring fused naphthalene tetracarboxylic acid diimide derivative, a near-infrared two-region photo-thermal molecule containing the 1, 3-disulfur heterocyclic ring fused naphthalene tetracarboxylic acid diimide derivative as well as a preparation method and application of the 1, 3-disulfur heterocyclic ring fused naphthalene tetracarboxylic acid diimide derivative and the near-infrared two-region photo-thermal molecule, and belongs to the technical field of biomedicine. A sulfur heterocycle fused naphthalene tetracarboxylic acid diimide derivative and adriamycin are jointly encapsulated in a temperature / pH dual-response type nanogel matrix to form a PND core, and the surface of PND is coated with a nasopharyngeal carcinoma tumor cell membrane of a high-expression growth arrest specific gene 6, so that the nano bait with homologous targeting capability is constructed. The four functions of homologous targeted delivery, dual-mode imaging guidance, local chemotherapy-photo-thermal synergistic treatment and systematic metastasis inhibition are integrated on a single platform, and the dual problems of nasopharyngeal carcinoma in-situ treatment and lung cancer cell metastasis prevention and control are synchronously solved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biomedical technology, and particularly relates to 1,3-dithia-fused naphthalene tetracarboxylic diimide derivatives, near-infrared two-region photothermal molecules containing the same, and a preparation method and application thereof. BACKGROUND

[0002] Nasopharyngeal carcinoma (NPC) is a highly metastatic malignant tumor derived from nasopharyngeal epithelium, and its incidence is particularly significant in East Asia and Southeast Asia. Its occurrence is closely related to dietary habits, long-term smoking and chronic inflammatory stimulation. Early-stage NPC can cause distant metastasis to organs such as lung, bone and brain, leading to organ dysfunction and significantly increasing the risk of death. Current conventional radiotherapy and chemotherapy strategies face bottlenecks due to low treatment efficiency, high recurrence rate and poor prognosis, especially the lack of effective metastasis prevention means.

[0003] At the molecular mechanism level, the Gas6 / AXL signaling axis has been confirmed to be a key pathway driving nasopharyngeal carcinoma cell proliferation and migration. Current clinical interventions mainly rely on AXL inhibitors (such as Foretinib, Cabozantinib, Bemcentinib, etc.) to block this pathway, but there are limitations such as high off-target toxicity, low kinase selectivity, and unstable response rate of combined immunotherapy. Although nanodiagnosis and treatment science has attempted to develop new nanomaterials to improve the stability of AXL inhibitors or inhibit the Gas6 / AXL signaling axis, these designs still lack the ability to actively kill tumors. For example, covalent organic frameworks (COFs) carry osimertinib to improve drug resistance, and non-Aβ peptide derivative nanofibers inhibit Gas6 / AXL binding. Although these designs have improved the influence of the material on the Gas6 / AXL signaling axis, they do not have the ability to actively initiate tumor killing. SUMMARY

[0004] To solve the above technical problems, the present application provides 1,3-dithia-fused naphthalene tetracarboxylic diimide derivatives, near-infrared two-region photothermal molecules containing the same, and a preparation method and application thereof. The present application provides a four-function integrated (homologous targeting delivery, dual-mode imaging guidance, local chemotherapy-photothermal synergistic treatment, and systemic metastasis inhibition) dual-responsive near-infrared two-region (NIR-II) intelligent nanobait PND@Gas6(+): first, the cell membrane of nasopharyngeal carcinoma tumor cells (Gas6@5-8F) that highly express growth arrest-specific gene 6 is disguised to achieve homologous targeting delivery for precise accumulation of metastatic lesions; at the same time, NIR-II fluorescence / photothermal dual-mode imaging is integrated to monitor the lesions in real time; then, acid / pH dual-responsive release of chemotherapy drugs and activation of photothermal effect are used to synergistically kill primary tumors; finally, the "ligand decoy" strategy is used to competitively inhibit the Gas6 / AXL axis to block lung metastasis colonization, thereby simultaneously solving the dual problems of nasopharyngeal carcinoma in situ clearance and systemic metastasis prevention, and providing a revolutionary solution for cancer diagnosis and treatment integration.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] This invention provides a 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative, with the general structural formula shown in Formula I:

[0007]

[0008] Formula I

[0009] Among them, R1 is selected from C 14 Straight chain or C2-C 10 Branches; R1 is preferably , or -C 14 H 29 .

[0010] The present invention also provides a method for preparing the above-mentioned 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative, comprising the following steps: reacting sodium hydride and compound A under ice bath conditions, then adding carbon disulfide and continuing the reaction at room temperature, then adding N-alkylR1-substituted 2,3,6,7-tetrabromonaphthalenetetracarboxylic acid diimide for further reaction, stopping the reaction with saturated ammonium chloride solution after the reaction is completed, extracting with dichloromethane or ethyl acetate, drying the organic phase with anhydrous sodium sulfate and then evaporating to dryness, and separating the residue by column chromatography to obtain the 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative;

[0011] The structural formula of compound A is as follows: ;

[0012] The structural formula of the N-alkylR1-substituted 2,3,6,7-tetrabromonaphthalenetetracarboxylic acid diimide is: R1 is selected from C 14 Straight chain or C2-C 10 Branches; R1 is preferably , or -C 14 H 29 .

[0013] Further, in the method for preparing the 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative, the molar ratio of sodium hydride, compound A and carbon disulfide is 2:(1~2):(1~2).

[0014] The molar ratio of the N-alkylR1-substituted 2,3,6,7-tetrabromonaphthalenetetracarboxylic acid diimide to compound A is 1:(8~12).

[0015] Furthermore, the reaction time of sodium hydride and compound A under ice bath conditions (0°C) was 1 hour; after adding N-alkylR1-substituted 2,3,6,7-tetrabromonaphthalenetetracarboxylic acid diimide, the reaction time was 4 hours.

[0016] The present invention also provides a method for preparing the above-mentioned near-infrared II photothermal molecule, comprising the following steps: dissolving a 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative, compound B, a deprotonating agent, a ligand and a catalyst in an organic solvent, performing a reflux reaction, and performing post-treatment after the reaction to obtain the near-infrared II photothermal molecule;

[0017] The structural formula of compound B is as follows: , or .

[0018] The near-infrared II photothermal molecule provided by this invention is prepared from the above-mentioned 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative. This near-infrared II photothermal molecule is based on the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative and has a donor-acceptor-donor (DAD) configuration. It uses a thioheterocarboxylic acid diimide containing a long alkyl chain as an electron acceptor. Its highly conjugated backbone exhibits quinone-like electron delocalization characteristics, significantly reducing the molecular band gap and achieving long-wavelength near-infrared light absorption. Simultaneously, triphenylamine is used as an electron donor and flexible molecular rotor, forming a strongly twisted intramolecular structure through its electron-rich properties. The charge transfer (TICT) effect synergistically enhances the luminescence efficiency and photothermal conversion performance in the near-infrared II region. The long alkyl chain at the electron acceptor end effectively blocks excessive molecular stacking, completely eliminating the problems of decreased imaging signal-to-noise ratio and photostability degradation caused by aggregation-induced quenching (ACQ). Meanwhile, the alkyl chain at the donor end end gives triphenylamine greater rotational freedom, suppressing intermolecular interactions in aggregated states. Thus, under laser irradiation, near-infrared II fluorescence emission and efficient photothermal conversion are simultaneously achieved, exhibiting both high photostability and anti-quenching properties. This provides key support for the construction of dual-response near-infrared II smart nanodecoys PND@Gas6(+).

[0019] Chinese patent CN119708007A discloses a near-infrared emission aggregation-induced emission organic photothermal molecule and its preparation method. This patent employs a three-step reaction to prepare the near-infrared emission aggregation-induced emission organic photothermal molecule: the first step is an addition cyclization reaction, which yields... The second step involves adding a reducing agent (iron powder) to reduce the nitro group (-NO2) to an amino group (-NH2), thus preparing the desired product. The third step of the reaction is: adding... (R' is selected from H, methyl, and methoxy) A Buchwald-Hartwig carbon-nitrogen coupling reaction is performed to generate the final near-infrared emission aggregation-induced luminescence organic photothermal molecule, which is an infrared II photothermal molecule based on a thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative. Compared with that patent, the preparation method of the infrared II photothermal molecule based on the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative in this invention is reduced from three steps to two steps (first, a 1,3-dithiocyclic fused naphthalenetetracarboxylic acid diimide derivative is prepared, and then the infrared II photothermal molecule based on the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative is prepared using the 1,3-dithiocyclic fused naphthalenetetracarboxylic acid diimide derivative) and the reaction conditions are optimized, simplifying the reaction process and improving the conversion rate of the reaction raw materials to the final structure.

[0020] Furthermore, the structural formula of the near-infrared II photothermal molecule is shown in Formula II:

[0021]

[0022] Formula II

[0023] Among them, R1 is selected from C 14 Straight chain or C2-C 10 The branch chain, R1 is preferably , or -C 14 H 29 R2 is selected from one of diphenylamine, 4,4'-dimethoxydiphenylamine and 4,4'-dimethyldiphenylamine.

[0024] Furthermore, the near-infrared II photothermal molecules are selected from the following structures:

[0025] , , , or .

[0026] Furthermore, in the method for preparing the near-infrared II photothermal molecule, the molar ratio of the 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative, compound B, deprotonating agent, ligand and catalyst is 1:(3~4):(4~6):(0.3~0.8):(0.15~0.45).

[0027] Furthermore, in the method for preparing near-infrared II photothermal molecules, the deprotonating agent is selected from sodium tert-butoxide or potassium tert-butoxide.

[0028] The ligand is selected from tritert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl or 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl;

[0029] The organic solvent is toluene;

[0030] The catalyst is selected from tris(dibenzylacetone)dipalladium(O) or palladium acetate.

[0031] This invention also provides an application of the above-mentioned near-infrared II photothermal molecules in the preparation of dual-response near-infrared II smart nanodecoys. The preparation method of the dual-response near-infrared II smart nanodecoys includes the following steps:

[0032] N-isopropylacrylamide (NIPAM), acrylic acid, crosslinking agent and surfactant were mixed in water and heated under magnetic stirring to obtain a mixture. Oxygen in the mixture was removed, an initiator was added, and a polymerization reaction was carried out. After the polymerization reaction was completed, the mixture was purified by dialysis and dried to obtain temperature / pH dual-responsive (PNA) nanogels.

[0033] The above-mentioned near-infrared II region photothermal molecules were dissolved in tetrahydrofuran to obtain a solution;

[0034] The solution was added to a Tris buffer solution containing the temperature / pH dual-responsive nanogel, and allowed to stand overnight to obtain the nanogel, denoted as PN nanogel.

[0035] The antitumor drug solution was mixed with the dispersion of the nanogel, stirred, ultrafiltered, and washed with water to obtain the nanogel loaded with the antitumor drug.

[0036] The nanogel loaded with antitumor drugs was coated with the cell membrane of nasopharyngeal carcinoma tumors (Gas6@5-8F) that highly express the growth arrest-specific gene 6 to obtain the dual-response near-infrared II smart nanodecoy.

[0037] Furthermore, in the preparation method of the dual-response near-infrared II smart nanodecoy, the amount of acrylic acid added is 5% of the molar amount of N-isopropylacrylamide, the amount of crosslinking agent added is 5% of the molar amount of NIPAM, and the amount of surfactant added is 1.5% of the molar amount of NIPAM.

[0038] Furthermore, in the preparation method of the dual-response near-infrared II smart nanodecoy, the crosslinking agent is N,N'-methylenebisacrylamide, and the surfactant is sodium dodecyl sulfate.

[0039] Furthermore, in the preparation method of the dual-response near-infrared II smart nanodecoy, the antitumor drug is doxorubicin (Dox). When the antitumor drug is Dox, the resulting nanogel loaded with the antitumor drug is denoted as PND nanogel.

[0040] This invention also provides the application of the aforementioned dual-response near-infrared II-zone intelligent nanodecoy in the preparation of drugs for the diagnosis or treatment of in situ tumors and in situ metastatic tumors, as well as in preventing early tumor metastasis. That is, the dual-response near-infrared II-zone intelligent nanodecoy of this invention can diagnose or treat in situ tumors and in situ metastatic tumors, and prevent early tumor metastasis.

[0041] Compared with the prior art, the present invention has the following advantages and technical effects:

[0042] This invention provides a two-step method for preparing infrared II photothermal molecules based on thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivatives. The process is simple and efficient, and the resulting novel infrared II photothermal molecules possess near-infrared II luminescence properties and excellent photothermal performance. Furthermore, the preparation process of the dual-response near-infrared II smart nanodecoy PND@Gas6(+) in this invention is simple and exhibits excellent performance. Firstly, homologous targeted delivery is achieved through Gas6@5-8F cell membrane camouflage to precisely accumulate metastatic lesions; simultaneously, NIR-II fluorescence / photothermal dual-mode imaging is integrated to monitor lesions in real time; then, acid / pH dual-response release of chemotherapy drugs and activation of photothermal effect are utilized to synergistically kill the primary tumor; at the same time, the growth arrest-specific gene 6 (Gas6) protein overexpressed on the cell membrane surface plays the core function of "molecular decoy", competitively binding AXL with high affinity in the lung metastasis microenvironment, strongly blocking the activation pathway of the Gas6 / AXL signaling axis, and precisely inhibiting the migration, invasion and colonization of tumor cells from the molecular source. The four functions of homologous targeted delivery, dual-mode imaging guidance, local chemotherapy-photothermal synergistic therapy and systemic metastasis inhibition are integrated into a single platform, simultaneously tackling the dual challenges of nasopharyngeal carcinoma in situ treatment and lung cancer cell metastasis prevention and control, providing a solution for integrated cancer diagnosis and treatment. Attached Figure Description

[0043] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

[0044] Figure 1 Proton nuclear magnetic resonance spectroscopy characterization of the 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative 1 obtained in Example 1;

[0045] Figure 2 Proton nuclear magnetic resonance spectroscopy characterization of near-infrared II photothermal molecule 4 of the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative obtained in Example 5;

[0046] Figure 3 The near-infrared II region photothermal molecule 4 of the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative obtained in Example 5 was characterized by carbon-13 nuclear magnetic resonance spectroscopy.

[0047] Figure 4 Mass spectrometry characterization of near-infrared II photothermal molecule 4 of the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative obtained in Example 5.

[0048] Figure 5 The near-infrared II photothermal molecule 4 of the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative obtained in Example 5 is shown in tetrahydrofuran solvent as molecular absorption and fluorescence emission spectra.

[0049] Figure 6 This is a scanning electron microscope image of the dual-response near-infrared two-zone smart nanodecoy PND@Gas6(+) obtained in Example 11;

[0050] Figure 7 The image shows the photothermal heating and cooling test results of the dual-response near-infrared two-zone intelligent nano-decoy PND@Gas6(+) and its process products obtained in Example 11.

[0051] Figure 8 The pH / temperature time-release curve of the dual-response near-infrared two-zone smart nanodecoy PND@Gas6(+) obtained in Example 11 is shown.

[0052] Figure 9 This is a schematic diagram of the photothermal therapy (PTT) effect of the dual-response near-infrared two-zone intelligent nanodecoy PND@Gas6(+) obtained in Example 11 in a subcutaneous tumor model;

[0053] Figure 10 This is a diagram showing the therapeutic effect of the dual-response near-infrared two-zone intelligent nanodecoy PND@Gas6(+) obtained in Example 11 on a subcutaneous tumor model.

[0054] Figure 11 This image shows the therapeutic effect of the dual-response near-infrared two-zone intelligent nanodecoy PND@Gas6(+) obtained in Example 11 on a lung metastatic tumor model. Detailed Implementation

[0055] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0056] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0057] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0058] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0059] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0060] Compared to patent CN119708007A, the present invention reduces the preparation method of near-infrared II photothermal molecules based on thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivatives from three steps to two steps (first, preparing 1,3-dithiocyclic fused naphthalenetetracarboxylic acid diimide derivatives, then using 1,3-dithiocyclic fused naphthalenetetracarboxylic acid diimide derivatives to prepare near-infrared II photothermal molecules based on thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivatives) and optimizes the reaction conditions, simplifying the reaction process and improving the conversion rate (also known as the synthesis yield) of the reactants to the final structure. The synthesis yield is calculated as follows: Two-step synthesis yield (%) = First step yield A% × Second step yield B% × 100%; Three-step synthesis yield (%) = First step yield A% × Second step yield B% × Third step yield C% × 100%. For example, in patent CN119708007A, NDA-1 ( The synthesis yield of the original method was 52% × 76% × 46% = 18.1%, while the synthesis yield of the same method in this invention was 18.1%. The synthesis yield of the structure (i.e., the structure of Example 10) was 49% × 66% = 32.3%. The present invention uses a two-step method to improve the synthesis yield.

[0061] Compared to CN119708007A, the reaction conditions of this invention are optimized as follows:

[0062] The method in CN119708007A:

[0063] ,

[0064] The method of the present invention:

[0065] .

[0066] In the following embodiments of the present invention, doxorubicin (Dox) is used as an antitumor drug to prepare near-infrared II smart nanodecoys.

[0067] In this invention, PNA serves as a temperature / pH dual-responsive nanogel matrix, providing a basic responsive framework for constructing an intelligent drug delivery system. PN nanogels, based on PNA, introduce near-infrared II photothermal molecules, endowing the material with dual functions of near-infrared II imaging and photothermal conversion, achieving optical monitoring and energy conversion capabilities. PND (dox-loaded nanogel) further integrates the chemotherapeutic drug doxorubicin (Dox) to form a trifunctional core, simultaneously possessing environmentally responsive drug release, photothermal killing, and synergistic chemotherapy mechanisms. By coating the PND surface with Gas6@5-8F cell membranes, the nanosystem is endowed with crucial dual core capabilities: on the one hand, based on homology recognition proteins on the membrane surface, it achieves active targeting and precise accumulation of in situ tumors, significantly increasing drug concentration at the tumor site; on the other hand, it utilizes the membrane protein Gas6 as a "molecular decoy" to competitively bind to the Axl receptor in metastatic lesions, blocking the Gas6 / Axl signaling axis activation pathway, inhibiting tumor cell migration and colonization from the source, and ultimately synergistically overcoming the dual challenges of in situ clearance and metastasis control within a single platform.

[0068] In the following embodiments of the present invention, the doxorubicin solution is prepared by dissolving doxorubicin (Dox) in PBS to obtain a concentration of 1 mg·mL⁻¹. -1 The solution is doxorubicin solution; the preparation method of PN nanogel dispersion is as follows: dissolve PN nanogel in Tris buffer (15 mM, pH=8.5) and stir until homogeneous.

[0069] In the following embodiments of the present invention, the specific preparation process of Gas6@5-8F cell membrane protein is as follows: tumor cells expressing high levels of growth arrest-specific gene 6 are placed in 1 M Tris-HCl buffer (pH=7.4) and incubated at 4°C for 1 hour. Cell lysates are collected and centrifuged at 500×g for 10 minutes. The supernatant is then aspirated and sonicated for 10 minutes. After sonication, the sample is centrifuged at 10,000×g for 10 minutes to separate the supernatant and collect the fraction. The precipitate is then separated by ultracentrifugation at 100,000×g for 1 hour. The protein concentration in the supernatant is determined using a BCA kit. The sample is then resuspended in ultrapure water to a final concentration of 1 mg / mL. Finally, the Gas6@5-8F cell membrane protein is prepared by sonication for 30 seconds.

[0070] In the following embodiments of the present invention, regarding the membrane camouflage of Gas6@5-8F cell membranes: the obtained Gas6@5-8F cell membrane proteins were ultrasonically disrupted and fully dispersed in PBS, and then mixed with PND nanogel by ultrasonic treatment for 3 minutes to obtain a mixture. This mixture underwent at least five physical extrusion cycles of 400 nm polycarbonate membranes through an Avatar extruder, and was finally purified by ultrafiltration (molecular weight cutoff = 100 kDa).

[0071] In the following embodiments of the present invention compound It was prepared according to the method disclosed in Chinese Patent CN101885732A; compound It was prepared according to the method disclosed in Chinese Patent CN101885732A; compound It was prepared according to the method disclosed in Chinese Patent CN101885732A.

[0072] This invention first constructs a near-infrared II photothermal molecule (also known as a near-infrared II photothermal molecule) with a donor-acceptor-donor (DAD) configuration, consisting of a thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative. Using triphenylamine as a powerful electron donor and a flexible rotor, significant near-infrared II (NIR-II) fluorescence emission and excellent photothermal conversion efficiency are achieved. Subsequently, the near-infrared II photothermal molecule and doxorubicin (Dox) are co-encapsulated in a temperature / pH dual-responsive PNA nanogel matrix to form a PND core. Then, by coating the surface of the PND with the membrane of nasopharyngeal carcinoma cells that highly express the growth arrest-specific gene 6 (Gas6), a nanodecoy with homology targeting capability is constructed. This system, in a nasopharyngeal carcinoma model, precisely accumulates at the tumor site through homologous targeting. Its acidic microenvironment triggers Dox release for chemotherapy, while near-infrared irradiation activates a photothermal effect, directly killing tumors and enhancing drug release, forming a synergistic chemotherapy-photothermal therapy mechanism. Furthermore, relying on the dual-mode functionality of NIR-II fluorescence imaging and photothermal imaging, high-resolution real-time monitoring is achieved. A "decoy" strategy is employed to allow nano-decoys to competitively bind to AXL receptor tyrosine kinase (AXL), thereby blocking the Gas6 / Axl signaling axis to prevent metastasis and proliferation. This invention integrates four major functions—homogeneous targeted delivery, dual-mode imaging guidance, local chemotherapy-photothermal synergistic therapy, and systemic metastasis inhibition—into a single platform, simultaneously tackling the dual challenges of in situ treatment of nasopharyngeal carcinoma and prevention of lung cancer cell metastasis, providing a breakthrough solution for integrated precision cancer diagnosis and treatment.

[0073] Unless otherwise specified, the room temperature in this invention is 25±2℃.

[0074] All raw materials used in the embodiments of the present invention were obtained through commercial purchase.

[0075] The technical solution of the present invention will be further illustrated by the following examples. As an example, 5-8F tumor cells (human nasopharyngeal carcinoma cells) were purchased from the Cell Center of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (Beijing); Gas6 (highly expressing growth arrest-specific gene 6) was purchased from Wuhan Miaoling Biotechnology Co., Ltd.; nude mice were purchased from Guangdong Provincial Animal Center; BCA kit was purchased from Thermo Fisher Scientific; 4,5,9,10-tetrabromo-2,7-bis(2-octyldodecyl)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone was purchased from Guangzhou Yunshan Biochemical Technology Co., Ltd.; tris(dibenzylideneacetone)dipalladium(O) and palladium acetate were both purchased from Beijing Bailingwei Technology Co., Ltd.; toluene was purchased from Guangzhou Chemical Reagent Factory; 4-bromophenylacetonitrile, 4-iodophenylacetonitrile, diphenylamine, 4,4'-dimethoxydiphenylamine, 4,4'-dimethyldiphenylamine, sodium tert-butoxide and N,N-dimethylformamide were all purchased from Anaiji Chemical Co., Ltd.

[0076] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention. For example, the method of transfecting 5-8F cells with luciferase is performed using conventional methods.

[0077] Example 1

[0078] This embodiment provides a method for preparing a 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative 1, the synthetic route of which is as follows:

[0079]

[0080] The specific steps are as follows:

[0081] Under nitrogen protection, sodium hydride (210 mg, 5.24 mmol) was added to 10 mL of redistilled N,N-dimethylformamide (DMF), and stirred in an ice bath. Then, 2-(4-iodophenyl)acetonitrile (513 mg, 2.62 mmol) was added and reacted for 30 minutes. Next, carbon disulfide (300 mg, 3.93 mmol) was added, the ice bath was removed, and the reaction was continued at room temperature for 2 hours. The reaction solution changed from colorless to light green and then gradually turned brownish-red. Then, 4,5,9,10-tetrabromo-2,7-bis(2-octyldodecyl)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone (300 mg, 0.262 mmol) was added all at once. After stirring at room temperature for 1 hour, the reaction solution turned blackish-purple. The solution was then analyzed using 20... The reaction was quenched with mL of physiological saline, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was separated by dichloromethane / petroleum ether (2:1, volume ratio, the same below) column chromatography, and finally a dark green solid product was obtained, which is 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative 1, with a yield of 49%. 1 H NMR (500 MHz, CDCl3)7.88 (d, J = 8.0 Hz, 4H), 7.43 (d, J = 8.3 Hz, 4H), 4.21 – 4.11 (m, 4H), 2.01(s, 2H), 1.38 – 1.15 (m, 64H), 0.85 (d, J = 5.2 Hz, 12H). 13C NMR (126 MHz, CDCl3) 162.40, 162.25, 148.13, 147.62, 147.46, 144.63, 143.90, 143.61,143.38, 141.04, 140.49, 139.61, 132.45, 131.39, 128.08, 127.75, 127.67,126.56, 126.46, 125.63, 125.35, 124.29, 121.88, 117.31, 115.56, 115.28,101.64, 77.31, 77.05, 76.80, 46.05, 36.30, 31.98, 31.94, 31.90, 31.85, 31.57, 31.49, 31.40, 30.11, 29.74, 29.70, 29.67, 29.62, 29.56, 29.52, 29.39, 29.35, 29.31, 26.41, 22.72, 22.70, 22.68, 14.18, 0.04.

[0082] Example 2

[0083] This embodiment provides a method for preparing 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative 2, and the synthetic route is as follows:

[0084]

[0085] The specific steps are the same as in Example 1, the only difference being that... Converted to equimolar amounts In this embodiment, the yield of product 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative 2 was 31%.

[0086] Example 3

[0087] This embodiment provides a method for preparing a 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative 3, the synthetic route of which is as follows:

[0088]

[0089] The specific steps are the same as in Example 1, the only difference being that... Converted to equimolar amounts In this embodiment, the yield of product 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative 3 was 45%.

[0090] Example 4

[0091] This embodiment provides a method for preparing infrared II photothermal molecule 4 based on a thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative. The synthetic route is as follows:

[0092]

[0093] The specific steps are as follows:

[0094] Under nitrogen protection, the compound Compound i (100.0 mg, 0.07 mmol), 4,4'-dimethyldiphenylamine (41.4 mg, 0.21 mmol), sodium tert-butoxide (26.8 mg, 0.28 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (11.5 mg, 0.02 mmol), and tris(dibenzylacetone)dipalladium(0) (Pd2(dba)3, 9.2 mg, 0.01 mmol) were dissolved in toluene and refluxed at 120 °C for 12 hours. After the reaction was completed, the mixture was cooled, extracted with dichloromethane, and washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / petroleum ether = 2:1) to obtain a green powder product, which is infrared II photothermal molecule 4, with a yield of 48%. 1 H NMR (500 MHz, CDCl3) 7.40 (d, J = 8.4 Hz, 1H), 7.14(d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.7 Hz, 1H), 4.14(s, 1H), 2.35 (s, 3H), 2.03 (s, 1H), 0.82 (s, 4H). 13C NMR (126 MHz, CDCl3)162.27, 162.13, 152.63, 147.46, 146.30, 145.74, 132.16, 130.20, 129.81,128.01, 126.24, 125.83, 121.37, 115.46, 115.27, 115.14, 93.35, 46.02, 45.66,36.25, 32.82, 31.92, 31.87, 31.83, 31.50, 31.44, 31.09, 30.17, 30.11, 29.71,29.68, 29.64, 29.59, 29.56, 29.36, 29.33, 29.29, 28.46, 26.37, 23.91, 22.69,22.67, 22.17, 20.93, 15.18, 14.13, 12.66, -0.00, -9.57. MS (MALDI-TOF) [m / z]:calcd for C 72 H 94 N6O4S4, 1596.3220; found, 1596.0077.

[0095] Example 5

[0096]

[0097] The preparation method of the infrared II photothermal molecule 4 based on the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative in this embodiment is the same as that in Example 4, the only difference being that compound i ( The following were replaced with an equimolar amount of 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative 1 (0.07 mmol), the 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl was replaced with 2.5 times the molar amount of tritert-butylphosphine tetrafluoroborate (0.05 mmol), and the tris(dibenzylideneacetone)dipalladium(0) was increased to twice the molar amount in Example 4 (0.02 mmol).

[0098] In this embodiment, the yield of near-infrared II photothermal molecule 4 was 54%.

[0099] Example 6

[0100] The preparation method of the infrared II photothermal molecule 4 based on the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative in this embodiment is the same as that in Example 4, except that the deprotonating agent is potassium tert-butoxide (0.28 mmol) and the catalyst is palladium acetate (0.01 mmol).

[0101] In this embodiment, the yield of near-infrared II photothermal molecule 4 was 35%.

[0102] Example 7

[0103] This embodiment provides a method for preparing infrared II photothermal molecule 5 based on a thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative. The synthetic route is as follows:

[0104]

[0105] The specific steps are the same as in Example 4, except that compound i is replaced with an equimolar amount of compound ii. In this embodiment, the yield of near-infrared II photothermal molecule 5 was 33%.

[0106] Example 8

[0107] This embodiment provides a method for preparing infrared II photothermal molecule 6 based on a thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative. The synthetic route is as follows:

[0108]

[0109] The specific steps are the same as in Example 4, except that compound i is replaced with an equimolar amount of compound iii. In this embodiment, the yield of near-infrared II photothermal molecule 6 was 21%.

[0110] Example 9

[0111] This embodiment provides a method for preparing infrared II photothermal molecule 7 based on a thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative. The synthetic route is as follows:

[0112]

[0113] The specific steps are the same as in Example 5, the only difference being that... Converted to equimolar amounts In this embodiment, the yield of near-infrared II photothermal molecule 7 was 33%.

[0114] Example 10

[0115] This embodiment provides a method for preparing near-infrared II photothermal molecule 8 based on a thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative. The synthetic route is as follows:

[0116]

[0117] The specific steps are the same as in Example 5, except that compound i is replaced with an equimolar amount of compound 1 prepared in Example 1 (0.07 mmol). Converted to equimolar amounts In this embodiment, the yield of near-infrared II photothermal molecule 8 was 54%.

[0118] Figure 1 The proton nuclear magnetic resonance spectroscopy characterization of the 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative 1 obtained in Example 1. Figure 2 The proton nuclear magnetic resonance (NMR) spectrometry of the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative obtained in Example 5 is used for the infrared II region photothermal characterization of molecule 4. Figure 3 The carbon-13 NMR spectrum of the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative obtained in Example 4 was used for the infrared II photothermal characterization of molecule 4. Figure 4 The mass spectrometry characterization of the near-infrared II photothermal molecule 4, a thiocyclic fused naphthalenetetracarboxylic acid diimide derivative obtained in Example 4, confirms the correct structure of the near-infrared II photothermal molecule.

[0119] Figure 5 The infrared II photothermal molecule 4 of the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative obtained in Example 5 was tested in tetrahydrofuran solvent. It can be seen that its molecular absorption is located in the near-infrared region with a relatively long absorption wavelength; the molecular emission is in the near-infrared II region, indicating that the material has excellent near-infrared II imaging potential.

[0120] Example 11

[0121] A method for preparing a dual-response near-infrared II smart nanodecoy PND@Gas6(+) includes the following steps:

[0122] N-Isopropylacrylamide (NIPAM, 0.02 M, monomer), acrylic acid (5% of the molar amount of NIPAM, monomer), N,N'-methylenebisacrylamide (5% of the molar amount of NIPAM, crosslinking agent), and sodium dodecyl sulfate (1.5% of the molar amount of NIPAM, surfactant) were dissolved in deionized water and heated to 70°C with magnetic stirring to obtain a mixture. Nitrogen gas was bubbled into the mixture for 30 minutes to remove oxygen, and then potassium persulfate aqueous solution was quickly added to initiate the polymerization reaction. After 4 hours of polymerization, the product was analyzed by dialysis (molecular weight cutoff = 100). The responsive PNA nanogel was purified for one week and then freeze-dried for later use. The near-infrared II photothermal molecule prepared in Example 5 was dissolved in tetrahydrofuran (THF) to obtain a solution. This solution was then gradually added to Tris buffer (15 mM, pH=8.5) containing the responsive PNA nanogel under stirring. The mixture was allowed to stand overnight to allow the organic solvent THF to evaporate, thereby forming the PN nanogel. Subsequently, in order to load doxorubicin (Dox), a Dox solution (concentration of 1 mg·mL⁻¹) was prepared. -1 The gas was added to the dispersion of the obtained PN nanogel and stirred at 25°C for 12 hours. The PND nanogel was then separated by ultrafiltration (molecular weight cutoff = 100 kDa) and washed repeatedly with deionized water until pH = 7.4. To achieve the function of the nanodecoy, Gas6@5-8F cell membrane camouflage was used. 5-8F tumor cell membranes were sonicated in PBS to break down and fully disperse the membrane proteins. These membrane proteins were then mixed with the PND nanogel by sonication for 3 minutes to obtain a mixture. This mixture was physically extruded five times through a 400 nm polycarbonate membrane using an Avatar extruder, followed by ultrafiltration purification (molecular weight cutoff = 100 kDa) to finally obtain the dual-response near-infrared II smart nanodecoy PND@Gas6(+). Similarly, nanodecoys without Gas6 protein were designated as PND@Gas6(-).

[0123] Figure 6 The image shown is a scanning electron microscope image of the dual-response near-infrared II smart nanodecoy PND@Gas6(+) obtained in this embodiment. It can be seen that the dual-response near-infrared II smart nanodecoy PND@Gas6(+) has a uniform particle size and morphology, with a particle size of about 140 nanometers and a uniform morphology.

[0124] Performance testing:

[0125] 1. Photothermal heating and cooling test of dual-response near-infrared II smart nanodecoy PND@Gas6(+) and its process products

[0126] The photothermal properties of dual-response near-infrared II smart nanodecoys PND@Gas6(+), PN, PND, and PND@Gas6(-) were tested in aqueous solution (all at a concentration of 100 μM) at a power density of 0.8 W / cm². 2 Local temperature changes were monitored using a thermal imaging camera under 808 nm laser irradiation.

[0127] Figure 7 The graphs shown in Example 11 depict the photothermal heating and cooling of the dual-response near-infrared II smart nanodecoys PND@Gas6(+), PN, PND, and PND@Gas6(-). All materials exhibit highly efficient photothermal conversion, with a rapid temperature increase reaching approximately 76°C within 5 minutes. This rapid temperature rise is attributed to the free molecular movement of the infrared II photothermal molecules of the thioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative within the nanogel matrix, enhancing the dissipation of photothermal energy.

[0128] 2. pH / temperature time-release curve test of dual-response near-infrared II smart nanodecoy PND@Gas6(+) on the tumor drug Dox

[0129] To verify the pH / temperature dual-response performance of the dual-response near-infrared II smart nanodecoy PND@Gas6(+), experiments were conducted under both laser-free and laser-lased conditions (laser wavelength of 808 nm and power density of 0.3 W·cm⁻¹). -2 Or 0.6 W·cm -2 The release kinetics of dual-response near-infrared II smart nanodecoy PND@Gas6(+) were tested under different pH PBS buffers (pH=5.0 or 7.4) and different temperatures (0~90℃). The content of Dox in PND nanogel was quantified by measuring the absorbance at 480 nm and using the standard concentration curve of Dox. Subsequently, the release curve of Dox was analyzed and fitted using zero-order reaction, Higuchi model and Peppas-Sahlin model.

[0130] Figure 8The pH / temperature time-release curves of the dual-response near-infrared II smart nanodecoy PND@Gas6(+) obtained in Example 11 show that, regardless of the presence or absence of laser light, the cumulative release of Dox at pH=5.0 is significantly higher than that at pH=7.4, indicating that the drug exhibits pH-responsive release characteristics. This effect is attributed to the enhanced protonation under acidic conditions, which weakens the electrostatic interaction between Dox and PNA, thereby promoting drug dissociation. Furthermore, increasing the 808 nm laser power density further accelerates Dox release, mainly due to the disruption of hydrogen bonds between the nanogel and water molecules caused by the increased temperature. This thermal effect leads to nanogel contraction, thereby expelling Dox from the nanogel interior.

[0131] 3. Application of Dual-Response Near-Infrared II Smart Nanodecoy PND@Gas6(+) in the Diagnosis and Treatment of In Situ and Metastatic Tumors

[0132] The therapeutic effect was evaluated in a mouse model of subcutaneous xenograft tumors (5-8F tumor cells) on the back. Mice were randomly divided into six groups: PBS+L, Dox+L, PN+L, PND+L, PND@Gas6(-)+L, and PND@Gas6(+)+L. The PBS+L group served as the negative control group, in which mice were intravenously injected with PBS and subjected to an 808 nm laser. The Dox+L group was intravenously injected with the same dose of free Dox solution as the treatment group and subjected to an 808 nm laser. The PN+L group was intravenously injected with PN nanogel and subjected to an 808 nm laser. The PND+L group was intravenously injected with PND nanogel and subjected to an 808 nm laser. The PND@Gas6(-)+L group was intravenously injected with PND@Gas6(-) nanodecoys and subjected to an 808 nm laser. The PND@Gas6(+)+L group was intravenously injected with PND@Gas6(+) nanodecoys and subjected to an 808 nm laser. On day 1 of the experiment, the drug was administered intravenously at a concentration of 6 mg / mL in a volume of 200 μL. Twelve hours post-injection, the tumor region was irradiated with an 808 nm near-infrared laser (power density 0.8 W·cm²). -2 (For 12 minutes), and use a thermal imager to monitor local temperature changes in real time.

[0133] Figure 9 This is a schematic diagram illustrating the photothermal therapeutic (PTT) effect of the dual-response near-infrared two-zone intelligent nano-decoy PND@Gas6(+) obtained in Example 11 in a subcutaneous tumor model. Figure 10The image shows the therapeutic effect of the dual-response near-infrared dual-zone intelligent nanodecoy PND@Gas6(+) obtained in Example 11 on a subcutaneous tumor model. It can be seen that after 12 minutes of 808 nm laser irradiation, the tumor temperature in the PBS+L group only slightly increased to 36°C. In contrast, the tumor temperature in the PN+L and PND+L groups increased to approximately 45°C due to the high-penetration and long-retention effect. Benefiting from the targeting effect of the homologous tumor cell membrane, the tumor temperature in the PND@Gas6(-)+L group increased to 53°C. The highest temperature (60°C) appeared in the PND@Gas6(+)+L group, where the overexpression of Gas6 protein on the homologous tumor cell membrane significantly enhanced the targeting ability, thereby greatly improving the photothermal effect.

[0134] 4. Application of Dual-Response Near-Infrared II Smart Nanodecoy PND@Gas6(+) in Preventing Early Tumor Metastasis

[0135] After a week of acclimatization, nude mice were injected via tail vein with 5-8F tumor cells transfected with luciferase (5 × 10⁻⁶ cells per mouse). 6 A nasopharyngeal carcinoma lung metastasis model was established. Seven days after modeling, a fluorescein substrate was injected intraperitoneally, and tumor formation was confirmed by whole-body bioluminescence imaging. The mice were then randomly divided into five groups (n=5 / group): (a) PBS group, (b) Dox group, (c) PND group, (d) PND@Gas6(-) group, and (e) PND@Gas6(+) group. On day 1, each group received the corresponding drug intravenously, and treatment was repeated every other day. Fourteen days after treatment, the fluorescein substrate was injected intraperitoneally, and whole-body bioluminescence imaging (IVIS) was performed to analyze fluorescence intensity and assess the tumor metastasis inhibition effect.

[0136] Figure 11 The image shows the therapeutic effect of the dual-response near-infrared II-zone intelligent nanodecoy PND@Gas6(+) obtained in Example 11 on a lung metastatic tumor model. The results show that the PBS group exhibited the strongest tumor fluorescence signal, while the PND@Gas6(+) group showed the most significant therapeutic effect, with tumors in all five mice being almost completely eliminated. These results demonstrate that the dual-response near-infrared II-zone intelligent nanodecoy PND@Gas6(+) has excellent anti-tumor effects in a lung metastasis model, providing a promising therapeutic strategy for inhibiting tumor metastasis.

[0137] In summary, the near-infrared II photothermal molecules designed in this invention exhibit excellent 808nm excitation photothermal performance and near-infrared II imaging performance, making them particularly suitable for preparing nanodecoy materials for homologous targeted delivery, dual-mode imaging guidance, local chemotherapy-photothermal synergistic therapy, and systemic metastasis inhibition. The core of this invention lies in introducing controllable photothermal drug release into a nasopharyngeal carcinoma nanotherapy platform. The dual-response near-infrared II intelligent nanodecoy PND@Gas6(+) of this invention demonstrates excellent and efficient encapsulation efficiency and stability for various photothermal molecules. It provides a solution for integrating four major functions—homogeneous targeted delivery, dual-mode imaging guidance, local chemotherapy-photothermal synergistic therapy, and systemic metastasis inhibition—into a single platform, simultaneously overcoming the dual challenges of in situ nasopharyngeal carcinoma treatment and lung cancer cell metastasis control.

[0138] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative, characterized in that, The general structural formula is shown in Formula I: Formula I Among them, R1 is selected from C 14 Straight chain or C2-C 10 Branches.

2. A method for preparing the 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative of claim 1, characterized in that, Includes the following steps: Sodium hydride and compound A were reacted under ice bath conditions, and then carbon disulfide was added to continue the reaction at room temperature. Then, N-alkylR1-substituted 2,3,6,7-tetrabromonaphthalenetetracarboxylic acid diimide was added to carry out the reaction. After the reaction was completed, the reaction was terminated with saturated ammonium chloride solution, and the mixture was extracted with dichloromethane or ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was separated by column chromatography to obtain the 1,3-disulfide heterocyclic fused naphthalenetetracarboxylic acid diimide derivative. The structural formula of compound A is as follows: ; The structural formula of the N-alkylR1-substituted 2,3,6,7-tetrabromonaphthalenetetracarboxylic acid diimide is: R1 is selected from C 14 Straight chain or C2-C 10 Branches.

3. The method for preparing the 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative according to claim 2, characterized in that, The molar ratio of sodium hydride, compound A and carbon disulfide is 2:(1~2):(1~2); And / or, the molar ratio of the N-alkylR1-substituted 2,3,6,7-tetrabromonaphthalenetetracarboxylic acid diimide to compound A is 1:(8~12).

4. A method for preparing near-infrared II region photothermal molecules, characterized in that, The process includes the following steps: dissolving the 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative of claim 1, compound B, deprotonating agent, ligand and catalyst in an organic solvent, performing a reflux reaction, and performing post-treatment after the reaction to obtain the near-infrared II region photothermal molecule; The structural formula of compound B is as follows: , or .

5. The method for preparing near-infrared II photothermal molecules according to claim 4, characterized in that, The structural formula of the near-infrared II region photothermal molecule is shown in Formula II: Formula II Among them, R1 is selected from C 14 Straight chain or C2-C 10 The branched chain; R2 is selected from one of diphenylamine, 4,4'-dimethoxydiphenylamine and 4,4'-dimethyldiphenylamine.

6. The method for preparing near-infrared II photothermal molecules according to claim 5, characterized in that, The near-infrared II photothermal molecules are selected from the following structures: , , , or .

7. The method for preparing near-infrared II photothermal molecules according to claim 4, characterized in that, The molar ratio of the 1,3-dithioheterocyclic fused naphthalenetetracarboxylic acid diimide derivative, compound B, deprotonating agent, ligand and catalyst is 1:(3~4):(4~6):(0.3~0.8):(0.15~0.45).

8. The method for preparing near-infrared II photothermal molecules according to claim 7, characterized in that, The deprotonating agent is selected from sodium tert-butoxide or potassium tert-butoxide; And / or, the ligand is selected from tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl or 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl; And / or, the organic solvent is toluene; And / or, the catalyst is selected from tris(dibenzylacetone)dipalladium(O) or palladium acetate.

9. The application of a near-infrared II photothermal molecule in the preparation of dual-response near-infrared II smart nanodecoys, characterized in that, The near-infrared II photothermal molecule is the near-infrared II photothermal molecule according to any one of claims 4 to 8, and the preparation method of the dual-response near-infrared II smart nanodecoy includes the following steps: N-isopropylacrylamide, acrylic acid, crosslinking agent and surfactant were mixed in water and heated under magnetic stirring to obtain a mixture. Oxygen in the mixture was removed, and an initiator was added to carry out a polymerization reaction. After the polymerization reaction was completed, the mixture was purified by dialysis and dried to obtain a temperature / pH dual-responsive nanogel. Near-infrared II photothermal molecules are dissolved in tetrahydrofuran to obtain a solution; The solution was added to a tris(hydroxymethyl)aminomethane buffer containing the temperature / pH dual-responsive nanogel, and allowed to stand overnight to obtain the nanogel. The antitumor drug solution was mixed with the dispersion of the nanogel, stirred, ultrafiltered, and washed with water to obtain the nanogel loaded with the antitumor drug. The nanogel loaded with antitumor drugs was coated with the membrane of nasopharyngeal carcinoma tumor cells that highly express the growth arrest-specific gene 6 to obtain the dual-response near-infrared II smart nanodecoy.

10. The application of a dual-response near-infrared dual-zone intelligent nanodecoy in the preparation of drugs for the diagnosis or treatment of in situ tumors and in situ metastatic tumors, and in preventing early tumor metastasis, characterized in that, The dual-response near-infrared II smart nanodecoy is the dual-response near-infrared II smart nanodecoy as described in claim 9.

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