DLL3 affinity peptide and application thereof

Abstract

The invention relates to the technical field of biological medicine, and particularly discloses a DLL3 affinity peptide and application thereof. The amino acid sequence of the DLL3 affinity peptide disclosed by the invention is as shown in SEQ ID No.3. The DLL3 affinity peptide can efficiently target tumor tissues with over-expressed DLL3, has a relatively high target / non-target ratio, has good uptake and retention effects at tumor parts, has good pharmacokinetic properties, and can be used as a specific target head of a molecular probe, so that in-vivo diagnosis of tumors is realized, and the application prospect is wide. A new choice is provided for early diagnosis of tumors, precise positioning of tumor boundaries or intraoperative image navigation.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a DLL3 affinity peptide and application thereof. Background Art

[0002] Cancer is currently a disease that seriously affects human life and health. Through accurate cancer diagnosis and timely intervention in the early stage of tumor development, the patient's survival rate can be greatly improved, or the patient's survival status can be improved. Commonly used cancer diagnostic technologies in clinical practice are mostly serum screening, combined with conventional screening and other metabolomics screening, ultrasound angiography and CT and other imaging technologies, which can directly observe the differences between lesions and normal tissues, but there are still problems such as false positives and limited sensitivity in cancer diagnosis. The overall identification ability of whole-body examination is poor, and some diagnostic technologies will cause open wounds, such as puncture, biopsy and other injuries. Therefore, it is particularly important to develop diagnostic methods that can reduce open injuries and accurately and sensitively observe tumor conditions in real time. In the past few decades, the focus of cancer molecular imaging has shifted from non-targeted imaging to targeted imaging. It has been widely accepted to perform sequential diagnosis and treatment of diseases based on the same highly expressed biomarker on tumor cells. SPECT and PET are the mainstays of nuclear medicine imaging. Various molecular imaging tracers have been used to accelerate personalized drug therapy, including tracers from small molecules, peptides, antibodies, antibody fragments and protein scaffolds, achieving non-invasive target annotation and tumor characterization at the molecular level.

[0003] In recent years, with the deepening of understanding and research on tumors and related disciplines, the focus of research has begun to shift to specific tumor diagnostic drugs targeting abnormally expressed targets in tumor tissues for early diagnosis of tumors. This type of targeted drug mainly binds specifically to tumor tissues and has no targeting to normal tissues, so it can achieve a highly selective and low-toxic diagnostic effect. It is currently believed that targeted peptides are an ideal means of tumor targeted therapy. Compared with antibodies and antibody fragments, small peptide targeting molecules have many advantages, including low molecular weight, small size, and higher tumor permeability; peptides usually accumulate rapidly in tumor tissue sites, and can be quickly cleared from the blood and non-target tissues, with good pharmacokinetic properties; peptides as molecular probes are generally non-immunogenic and non-toxic, which can avoid the shortcomings of monoclonal antibody therapy; the design and synthesis are simple, and peptide synthesizers can be used for rapid and automated synthesis; a wide range of chemical or molecular modifications can be performed to optimize their affinity for specific receptors and in vivo pharmacokinetic properties; various conventional and new chelating agent modifications can be easily performed to label radionuclides for application.

[0004] Delta-like Ligand 3 (DLL3) is a member of the Notch ligand family and a transmembrane protein attached to the cell membrane surface. It is usually expressed in neural and neuroendocrine tissues during embryonic development, but is absent or lowly expressed in healthy adult tissues, but exists on the surface of tumor cells such as small cell lung cancer. DLL3 binds to the Notch receptor to activate the Notch pathway, affecting the conduction of cell signals such as cell proliferation, epithelial-mesenchymal transition, and inhibition of neuroendocrine differentiation, thereby leading to cancer progression and deterioration. Due to the abnormal upregulation of DLL3 expression, the development of targeted molecular probes can guide the early diagnosis of cancer, determine the location of lesions, and help pathological staging and intraoperative navigation. However, similar to many targeted therapies, tumor cells with abnormal DLL3 expression may develop drug resistance mechanisms to escape the effects of DLL3 targeted probes. Therefore, it is necessary to continuously develop new DLL3 targeted probes to compensate for the problem that the existing DLL3 targeted probes may gradually reduce their effectiveness. Summary of the invention

[0005] One of the objectives of the present invention is to provide an affinity peptide that can effectively target DLL3 and its application.

[0006] The present invention provides a DLL3 affinity peptide, whose amino acid sequence is shown in SEQ ID No.3.

[0007] The present invention has discovered a novel small molecule polypeptide targeting DLL3, which can efficiently target tumor tissues overexpressing DLL3 (such as small cell lung cancer), has good uptake and retention effects at the tumor site, has a high target / non-target ratio, is suitable for use as a fluorescent tumor imaging agent, and can be used to prepare optical imaging drugs for intraoperative image navigation of tumors and precise positioning of tumor boundaries.

[0008] Those skilled in the art can synthesize the above-mentioned DLL3 affinity peptide according to common knowledge in the art, and the amino acids used to synthesize the affinity peptide can be L-type or D-type.

[0009] The present invention also provides a tumor-specific targeting molecular probe, which is a DLL3 affinity peptide, a dimer of a DLL3 affinity peptide, or a polymer of a DLL3 affinity peptide connected to a light label or a radionuclide label; the DLL3 affinity peptide is as described above, and DLL3 is overexpressed in the tumor.

[0010] The DLL3 affinity peptide of the present invention can be easily modified with various conventional and novel chelating agents to label radionuclides or connect optical markers, thereby serving as a diagnostic imaging agent for tumors with overexpression of DLL3, and is used for early diagnosis of tumors, precise positioning of tumor boundaries, or intraoperative image navigation. The molecular probe of the present invention can be rapidly cleared from non-target tissues and has good pharmacokinetic properties.

[0011] In the tumor-specific targeting molecular probe of the present invention, the optical label is selected from organic chromophores, organic fluorophores, light absorbing compounds, light reflecting compounds, light scattering compounds, photochromic compounds, phosphorescent compounds or bioluminescent molecules; the radionuclide label is a diagnostic radionuclide or a therapeutic radionuclide.

[0012] Those skilled in the art can select the specific type of label included in the molecular probe of the present invention according to the application target.

[0013] Preferably, the optical marker is a near-infrared fluorescent dye; the radionuclide is selected from 99m Tc, 68 Ga, 64 Cu, 67 Ga, 90 Y. 111 In, 177 Lu, 225 Ac or 125 I.

[0014] More preferably, the near-infrared fluorescent dye is MPA, IRDye800, Cy7.5 or Cy5.5.

[0015] Radioactively labeled modified peptides can be used for the screening and early diagnosis of tumors, and can also be used for real-time, non-destructive, in-situ monitoring of early malignant tumors and treatment.

[0016] The present invention also provides a method for preparing the above-mentioned tumor-specific targeting molecular probe, which comprises the step of connecting a photolabel or a radionuclide label to a DLL3 affinity peptide, a dimer of a DLL3 affinity peptide or a multimer of a DLL3 affinity peptide; the DLL3 affinity peptide is as described above.

[0017] The present invention also provides the use of DLL3 affinity peptides, dimers of DLL3 affinity peptides, polymers of DLL3 affinity peptides or tumor-specific targeting molecular probes in the preparation of tumor targeting drugs or tumor diagnostic reagents; the DLL3 affinity peptides are as described above, and DLL3 is overexpressed in the tumor.

[0018] The present invention also provides a drug, which includes a DLL3 affinity peptide, a dimer of a DLL3 affinity peptide, a polymer of a DLL3 affinity peptide or a tumor-specific targeting molecular probe and a pharmaceutically acceptable excipient; the DLL3 affinity peptide is as described above.

[0019] In the drug of the present invention, the above-mentioned DLL3 affinity peptide, dimer of DLL3 affinity peptide, polymer of DLL3 affinity peptide or tumor-specific targeting molecular probe is also coupled with an active substance; the active substance can inhibit and / or treat a disease characterized by overexpression of DLL3.

[0020] The above-mentioned DLL3 affinity peptide of the present invention has an excellent targeting effect and can be combined with a substance having pharmaceutical activity to accurately deliver the therapeutic agent to the lesion site, thereby improving the targeting of the drug, reducing side effects, and enhancing the therapeutic effect.

[0021] The present invention also provides the use of DLL3 affinity peptides, dimers of DLL3 affinity peptides, polymers of DLL3 affinity peptides or tumor-specific targeting molecular probes in the preparation of reagents or kits for diagnosing and / or treating diseases; the DLL3 affinity peptides are as described above, and the diseases are characterized by overexpression of DLL3.

[0022] The present invention also provides a diagnostic reagent or a kit, which comprises the above-mentioned tumor-specific targeting molecular probe.

[0023] The diagnostic reagent or kit of the present invention can effectively track tumors with overexpression of DLL3, and thus can be used to assist in tumor diagnosis or intraoperative navigation.

[0024] The beneficial effects of the present invention are at least: The present invention provides a new tumor tissue targeting polypeptide, which can be used for early diagnosis and imaging of tumor tissue after being constructed into an optical probe, and can realize preoperative and intraoperative image navigation with high imaging accuracy, which helps to improve surgical precision.

[0025] The DLL3 affinity peptide of the present invention can also be used to construct diagnostic and therapeutic agents, which helps to improve the targeting of drug carriers, can guide the precise release of drugs in tumor tissues, reduce the toxic and side effects caused by systemic release of drugs, and improve the therapeutic effect.

[0026] The DLL3 affinity peptide of the present invention has a low molecular weight, a simple preparation method, convenient acquisition channels, low synthesis cost, and is relatively stable in vivo. It can promote the concentration and retention of imaging probes at the tumor site, thereby obtaining better tumor imaging effects, which is beneficial to clinical promotion and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is the structural formula of tumor affinity peptide YQP-2.

[0028] Figure 2 Binding energy analysis diagram of tumor affinity peptide kinetic simulation.

[0029] Figure 3 This is the affinity analysis diagram of tumor affinity probe (fluorescent targeting probe) and DLL3. Represents P < 0.001.

[0030] Figure 4 Representative optical imaging of the fluorescent targeted probe MPA-YQP-2 in small cell lung cancer SHP-77 tumor-bearing mice.

[0031] Figure 5 For nuclear probe 99M SPECT / CT imaging of Tc-YQP-2 in mice bearing small cell lung cancer SHP-77. The red dotted box in the figure indicates the tumor. DETAILED DESCRIPTION

[0032] The preferred embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that the following examples are provided only for the purpose of illustration and are not intended to limit the scope of the present invention. Those skilled in the art may make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

[0033] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples are commercially available or prepared according to conventional methods in the art unless otherwise specified.

[0034] The amino acids used in the present invention were purchased from Jier Biochemical (Shanghai) Co., Ltd., RinkAmideMBHA resin was purchased from Jiangsu Jitai Peptide Co., Ltd. (JT-08-2235, 10 mg), the 1640 culture medium used was purchased from Jiangsu Keygen Biotechnology Co., Ltd., and SHP-77 cells were purchased from Wuhan Sean Biotechnology Co., Ltd.; DMSO, EDCI and NHS were all purchased from Shanghai Lingfeng Chemical Reagent Co., Ltd.

[0035] Example 1 Preparation of polypeptide In this example, multiple peptides (YQP-0, YQP-1, YQP-2, YQP-3, YQP-4) were synthesized: The amino acid sequence of YQP-0 is (SEQ ID No. 1): VCLKPGLSEEAAESPCALGAALSAR; The amino acid sequence of YQP-1 is (SEQ ID No. 2): AGAWELR; The amino acid sequence of YQP-2 is (SEQ ID No. 3): CEPPAVGTACTR; The amino acid sequence of YQP-3 is (SEQ ID No. 4): AGCSPEHGFCEQPGECR; The amino acid sequence of YQP-4 is (SEQ ID No. 5): NGGLCLDLGHALR.

[0036] Each peptide was synthesized by solid phase synthesis method, and the specific examples are as follows: (1) Resin swelling Weigh 1 mmol equivalent of Rink Amide MBHA resin into a peptide synthesis tube, add an appropriate amount of dichloromethane (DCM) to cover the resin, and swell for 30 minutes. Drain the DCM solution, wash with DMF, and drain.

[0037] (2) Removal of Fmoc Add a DMF solution with a volume fraction of 20% piperidine into the synthesis tube until the resin is submerged. The deprotection time is 5 minutes and repeated twice. After the reaction is completed, wash with DMF.

[0038] (3) Coupling Add 2 mmol equivalent of amino acid, 4 mmol equivalent of DIPEA, 2 mmol equivalent of HCTU and DMF to the synthesis tube, shake and react for 1 hour, remove the reaction solution and wash with DMF, then remove Fmoc according to step (2), wash and detect with ninhydrin.

[0039] (4) Add different amino acids in the sequence in sequence for coupling according to step (3), wherein the amino acid residues involved can be L-type or D-type. Proline (Pro) can also be replaced by hydroxyproline (Hyp), arginine (Arg) can be replaced by homoarginine (homo-Arg), and alanine can be replaced by β-alanine.

[0040] (5) Cracking The resin was blown dry with nitrogen, and a cutting solution (87.5% TFA + 5% thioanisole + 2.5% ethanedithiol + 2.5% phenol + 2.5% water) was added to the polypeptide synthesis tube. The ratio of the cutting solution volume to the resin was approximately 10 ml / g. After reacting for 2-3 hours, the filtrate was filtered to which a large amount of methyl tert-butyl ether was added, followed by centrifugation. The solid was washed three times with methyl tert-butyl ether to obtain a crude polypeptide.

[0041] (6) Separation and purification Reverse phase high performance liquid chromatography was used for purification, the chromatographic filler for purification was 10 μm reverse phase C18, the mobile phase system was 0.1% TFA / water solution and acetonitrile solution, the gradient system (see Example 3) was used for elution, and the ultraviolet absorption of the polypeptide was measured by ultraviolet spectrophotometry for quantification. The results showed that each polypeptide was successfully synthesized and the purity was above 95%. The collected eluate was placed in a freeze dryer for concentration and freeze-dried into a white powder.

[0042] The structural formula of YQP-2 is shown in Figure 1 , molecular weight is 1203.54.

[0043] Example 2 The present invention also uses AUTODOCK software to perform virtual docking between each peptide prepared in Example 1 and the receptor (DLL3), and uses gmx grompp, gmx trjconv, gmx mdrun and gmx energy commands to extract docking energy data. The energy data are shown in Figure 2 Among them, the peptide with the highest binding free energy shows stronger affinity.

[0044] Example 3 Preparation of fluorescent targeting probe MPA-YQP-2 The preparation method of the fluorescent targeting probe MPA-YQP-2 is as follows: (1) 0.02 mmol MPA was dissolved in 200 μL DMSO, and 3.7 mg 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 2.2 mg N-hydroxysuccinimide (molar ratio MPA:EDCI:NHS=1:1.5:1.5) were added. The mixture was reacted in the dark for 4 h to perform carboxyl activation reaction.

[0045] (2) 0.02 mmol of the peptide YQP-2 synthesized in the solid phase in Example 1, 0.1 mmol of triethylamine and 200 μL of ultra-dry DMSO were added to a 5 mL reaction bottle and reacted under nitrogen protection for 10 min; the reaction solution in the above step (1) was added to the reaction solution in step (2), and the reaction was stirred at room temperature for 12 h; (3) After the reaction is completed, the reaction solution is concentrated by freeze-drying, then diluted with distilled water, and separated and purified using a preparative liquid phase.

[0046] The preparation conditions of the liquid phase are as follows: An Agilent 1220 Infinity II series HPLC system equipped with an Agilent ZORBAX SB-C18 semi-preparative column (9.4×250 mm, 5 um) was used, with gradient elution for 60 minutes and a flow rate of 2 mL / min, wherein mobile phase A was ultrapure water (0.01% TFA / aqueous solution by volume) and mobile phase B was acetonitrile.

[0047] The elution gradient was set as follows: 95% A and 5% B at 0-5 min; 85% A and 15% B at 15 min; 70% A and 30% B at 30 min; 50% A and 50% B at 45 min; and 10% A and 90% B at 60 min.

[0048] The green product finally obtained was confirmed to be the expected product MPA-YQP-2 by analytical HPLC and ESI-MS mass spectrometry analysis.

[0049] Example 4 Nuclear probe 99M Preparation of Tc-YQP-2 Nuclear probe 99M The preparation method of Tc-YQP-2 is as follows: (1) 0.03 mmol HYNIC was dissolved in 200 μL DMSO, and 6.87 mg 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4.72 mg N-hydroxysuccinimide (molar ratio HYNIC:EDCI:NHS=1:1.2:1.2) were added. The mixture was reacted in the dark for 4 h to perform carboxyl activation reaction.

[0050] (2) 0.02 mmol of the peptide YQP-2 synthesized in the solid phase in Example 1, 0.1 mmol of triethylamine and 200 μL of ultra-dry DMSO were added to a 5 mL reaction bottle and reacted under nitrogen protection for 10 min; the reaction solution in the above step (1) was added to the reaction solution in step (2), and the reaction was stirred at room temperature for 12 h; (3) After the reaction is completed, the reaction solution is concentrated by freeze drying, then diluted with distilled water, and separated and purified using a preparative liquid phase.

[0051] The preparation liquid phase conditions are as follows: An Agilent 1220 Infinity II series HPLC system equipped with an Agilent ZORBAX SB-C18 semi-preparative column (9.4×250 mm, 5 um) was used, with gradient elution for 60 minutes and a flow rate of 2 mL / min, wherein mobile phase A was ultrapure water (0.01% TFA / aqueous solution by volume) and mobile phase B was acetonitrile.

[0052] The elution gradient was set as follows: 95% A and 5% B at 0-5 min; 85% A and 15% B at 15 min; 70% A and 30% B at 30 min; 50% A and 50% B at 45 min; and 10% A and 90% B at 60 min.

[0053] The green product finally obtained was confirmed to be the process product HYNIC-YQP-2 by analytical HPLC and ESI-MS mass spectrometry analysis.

[0054] 20 mg of triphenylphosphine tris(sulfonic acid) sodium salt (TPPtS) was dissolved in 200 μL of saline, and 26 mg of N-(tris(hydroxymethyl)methyl)glycine (Tricine) was dissolved in 200 μL of saline. 10 μL of each was taken. 10 μg of the process product HYNIC-YQP-2 was taken and put into a glass bottle reactor together with sodium pertechnetate with an activity value of 400 microcuries. It was heated at 100°C for 30 minutes.

[0055] The green product obtained was confirmed by analytical HPLC to be 99M Tc-YQP-2.

[0056] Example 5 In vitro affinity experiment of fluorescent targeting probe MPA-YQP-2 and other peptide fluorescent probes for SHP-77 cells According to the method described in Example 3, the peptides YQP-0, YQP-1, YQP-2, YQP-3, and YQP-4 described in Example 1 were prepared as fluorescent targeting probes, respectively named MPA-YQP-0, MPA-YQP-1, MPA-YQP-2, MPA-YQP-3, and MPA-YQP-4. And their in vitro affinity for SHP-77 cells was tested. The specific method is as follows: (1) First, prepare a 12-well plate, resuspend the SHP-77 cells that are in good growth condition and free of bacteria in fresh 1640 medium, and count them using the counting plate method. Add the same amount of cells to each well of the 12-well plate, and then culture it in a cell culture incubator at 37°C and 5% CO2 for 24 hours.

[0057] (2) After the cells had grown for 24 h, the culture medium in the 12-well plate was discarded and 500 μL of fresh 1640 culture medium without serum was added to set up different groups: blank group Control (CON), single dye group MPA, and peptide group. The peptide group was added with 5 μL of MPA and 5 μL of MPA-YQP-0, MPA-YQP-1, MPA-YQP-2, MPA-YQP-3, and MPA-YQP-4 fluorescent targeting probes, respectively. The initial concentration of the probes was 500 μM. The final concentration in the well plate was 5 μM, and then the cells were incubated in the incubator for 2 h.

[0058] (3) Sample treatment before flow cytometry: The cell suspension was transferred to a 1.5 mL EP tube, centrifuged at 1200 rpm for 5 min, washed three times with 500 μL PBS buffer (pH 7.2), and finally resuspended in 500 μL PBS buffer (pH 7.2) for later use.

[0059] (4) Determination of cell fluorescence intensity by flow cytometry: Set the flow cytometer parameters, the flow rate to medium flow rate, and the cell injection volume to 40,000 cells. Load the sample and measure the fluorescence intensity of each group, as well as the fluorescence intensity relative to the control group and the single dye group.

[0060] (5) Data processing: FlowJo 7.0 software was used to generate peak graphs of the raw data and calculate the mean fluorescence intensity (MFI). GraphPad Prism software was used to quantitatively plot the mean fluorescence intensity and perform data difference analysis.

[0061] When the probe has a strong affinity with the receptor on the cell, the average fluorescence intensity of the cell detected by flow cytometry is high. Figure 3 The results of in vitro affinity experiments showed that after the fluorescent targeting probes with the same concentration were incubated with SHP-77 cells with high expression of DLL3, the affinity strength of MPA-YQP-2 of the present invention to SHP-77 was the highest (27.94×10 3 ±1.5).

[0062] Example 6 Optical imaging of fluorescent targeted probe MPA-YQP-2 in mice bearing small cell lung cancer SHP-77 The fluorescent targeting probe MPA-YQP-2 prepared in Example 3 was dissolved in physiological saline solution to prepare a solution with a concentration of 1 mg / 1 mL. 15 μL of the probe MPA-YQP-2 solution was injected into three nude mice bearing small cell lung cancer SHP-77 tumors (weighing about 20 g) through the tail vein, and optical signal collection was performed at 0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h and 48 h after injection. The distribution of the MPA-YQP-2 fluorescent targeting probe in mice and its enrichment in the tumor area were observed.

[0063] The imaging results of the fluorescent targeted probe MPA-YQP-2 in the three tumor-bearing nude mice were basically consistent. The representative imaging results are shown in Figure 4 As shown in the figure, from the 1-hour imaging image, it can be seen that the probe has been significantly accumulated in the tumor, and the edge of the tumor is clear. The probe is still retained in the tumor until 48 hours. Among them, the probe is most enriched in the tumor site at 1 hour, while the uptake and clearance of other background organs is faster. From the signal of the bladder, it can be inferred that this probe is mainly metabolized by the kidneys.

[0064] The above pharmacodynamic experiments show that the polypeptide of the present invention has the ability to bind to small cell lung cancer cells with high specificity. The high affinity characteristics of the targeting peptide can be used for optical imaging of malignant tumors. These high affinity polypeptide monomers, polypeptide dimers or polypeptide polymers directly or indirectly coupled with fluorescent dyes can be used as tumor-specific targeting molecular probes, which are expected to achieve the effect of accurately locating the tumor boundary, can bring real-time performance to preoperative and intraoperative image navigation, and have the advantage of improving surgical accuracy.

[0065] Example 7 Nuclear probe 99M SPECT / CT imaging of Tc-YQP-2 in mice bearing small cell lung cancer SHP-77 The nuclide probe prepared in Example 4 99M Tc-YQP-2 was dissolved in physiological saline solution to prepare a solution with a concentration of 10 μg / 1 mL. The radionuclide probe was injected into SHP-77 tumor-bearing nude mice (weighing about 20 g) through the tail vein. 99M 100 μL of Tc-YQP-2 solution was injected, and the radiation signal was collected by SPECT at 1h, 2h, and 3h after injection. 99M Distribution of Tc-YQP-2 radionuclide targeted probe in mice and its enrichment in tumor areas.

[0066] The imaging results are as follows Figure 5 As shown in the 1h image, the radionuclide probe 99M Tc-YQP-2 has been clearly accumulated in the tumor, the tumor edge contour is clear, and the probe is most enriched in the tumor site at 1 hour, while the uptake and clearance in other background organs is relatively fast. From the signal of the bladder, it can be inferred that this probe is mainly metabolized by the kidneys.

[0067] The above pharmacodynamic experiments show that the polypeptide of the present invention has the ability to bind to small cell lung cancer cells with high specificity. The high affinity characteristics of the targeting peptide can be used for SPECT imaging of malignant tumors. These high affinity polypeptide monomers, polypeptide dimers or polypeptide polymers directly or indirectly chelate radionuclides and can be used as tumor-specific targeting molecular probes, which are expected to achieve the effect of accurately locating the tumor boundary. Replacing different radionuclides has different effects such as diagnosis and treatment.

[0068] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A DLL3 affinity peptide, characterized in that The amino acid sequence is shown in SEQ ID No.

3.

2. A tumor-specific targeting molecular probe, characterized in that: The tumor-specific targeting molecular probe is a DLL3 affinity peptide, a dimer of a DLL3 affinity peptide, or a polymer of a DLL3 affinity peptide connected with a light label or a radionuclide label; the DLL3 affinity peptide is as described in claim 1, and DLL3 is overexpressed in the tumor.

3. The tumor-specific targeting molecular probe according to claim 2, characterized in that: The optical label is selected from organic chromophores, organic fluorophores, light absorbing compounds, light reflecting compounds, light scattering compounds, photochromic compounds, phosphorescent compounds or bioluminescent molecules; the radionuclide label is a diagnostic radionuclide or a therapeutic radionuclide.

4. The tumor-specific targeting molecular probe according to claim 3, characterized in that: The radionuclide label is selected from 99m Tc, 68 Ga, 64 Cu, 67 Ga, 90 Y. 111 In, 177 Lu, 225 Ac or 125 I.

5. A method for preparing the tumor-specific targeting molecular probe according to any one of claims 2 to 4, characterized in that: The method comprises the step of attaching a photolabel or a radionuclide label to a DLL3 affinity peptide, a dimer of a DLL3 affinity peptide, or a multimer of a DLL3 affinity peptide; the DLL3 affinity peptide is as described in claim 1.

6. Use of a DLL3 affinity peptide, a dimer of a DLL3 affinity peptide, a polymer of a DLL3 affinity peptide, or a tumor-specific targeting molecular probe as described in any one of claims 2 to 4 in the preparation of tumor-targeted drugs or tumor diagnostic reagents; the DLL3 affinity peptide is as described in claim 1, and DLL3 is overexpressed in the tumor.

7. A drug, characterized in that It comprises a DLL3 affinity peptide, a dimer of a DLL3 affinity peptide, a polymer of a DLL3 affinity peptide, or a tumor-specific targeting molecular probe as described in any one of claims 2 to 4, and a pharmaceutically acceptable excipient; the DLL3 affinity peptide is as described in claim 1.

8. The drug according to claim 7, characterized in that The DLL3 affinity peptide, the dimer of the DLL3 affinity peptide, the polymer of the DLL3 affinity peptide or the tumor-specific targeting molecular probe according to any one of claims 2 to 4 is also coupled with an active substance; the active substance can inhibit and / or treat a disease characterized by overexpression of DLL3.

9. Use of a DLL3 affinity peptide, a dimer of a DLL3 affinity peptide, a polymer of a DLL3 affinity peptide, or a tumor-specific targeting molecular probe as described in any one of claims 2 to 4 in the preparation of a reagent or kit for diagnosing and / or treating a disease; the DLL3 affinity peptide is as described in claim 1, and the disease is characterized by overexpression of DLL3.

10. A diagnostic reagent or kit, characterized in that: It comprises the tumor-specific targeting molecular probe according to any one of claims 2 to 4.

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