Affinity peptide targeting FGFR4 and its application

Abstract

The present invention discloses an affinity peptide targeting FGFR4 and its application. Tumor targeting peptides include 6 polypeptides such as YQGF-1: Ac-IIe-Asp-Pro-Asp-Gly-Tyr-Asn-His-NH2. The present invention has developed a series of new high-affinity polypeptides that simulate FGF19 (fibroblast growth factor 19), which can be used to target fibroblast growth factor receptor 4 (FGFR4). Taking advantage of the high expression of FGFR4 receptor in tumors, based on the principle of specific binding of YQGF-X (X=1-6) polypeptide to FGFR4 receptor, it can be used for early diagnosis of tumors with high FGFR4 expression. YQGF-X (X=1-6) series polypeptides can specifically bind to tumor cells, and have been confirmed by in vivo optical imaging and results to have excellent imaging effects on a variety of tumors, including liver cancer, breast cancer, cervical cancer and colorectal cancer.

Description

[0001] Description of the case

[0002] This application is a divisional application of the following Chinese invention patent application:

[0003] Parent case application number: 2021111097710

[0004] Parent case application date: 2021-09-18

[0005] Name of the invention of the parent case: A kind of affinity peptide targeting FGFR4 and its application Technical Field

[0006] The invention belongs to the field of biomedical engineering, and in particular relates to an affinity peptide targeting FGFR4 and an application thereof. Background Art

[0007] Malignant tumors pose a serious threat to human health. Early diagnosis and treatment of tumors are the key to improving their cure rate and the quality of life of patients. For tumors, the current conventional imaging diagnostic technologies are mainly B-ultrasound, CT and MRI. These imaging diagnostic technologies achieve diagnostic results by showing functional changes in tissues and have good application value. However, with the continuous improvement of clinical requirements for tumor diagnosis, these traditional detection methods are gradually unable to meet the detection needs in differential diagnosis, systemic staging and early efficacy evaluation. Among the many detection methods, molecular probes, as powerful tools for analytical sensing and optical imaging, can directly visualize biological analytes at the molecular level and provide useful information for complex biological structures and processes. The basic imaging principle of molecular probes is to introduce prepared fluorescent probes into living tissues, allow the labeled molecular probes to interact with target molecules, and then use a suitable imaging system to detect the information emitted by the molecular probes. Therefore, screening and optimizing tumor-targeting peptides can develop new molecular imaging drugs for tumor diagnosis, staging and surgical guidance, which can detect smaller lesions and achieve the purpose of early diagnosis.

[0008] The FGFR (fibroblast growth factor receptor) tyrosine kinase family includes FGFR1, FGFR2, FGFR3 and FGFR4, which are composed of an extracellular variable region, a conserved region that binds heparan sulfate proteoglycans, an FGF binding region, a single transmembrane region and an intracellular tyrosine kinase region. Most FGFs form a complex with FGFRs and heparin with the help of the co-receptor Klotho, resulting in autophosphorylation of the conformationally changed FGFR intracellular kinase region and activation of the STAT3 signaling pathway. Autophosphorylated FGFR can also phosphorylate its adaptor protein FRS2α, activate the Grb2 / Sos1 complex and initiate downstream MAPK and PI3K / AKT signaling, which is mainly related to cell motility and survival. Among FGFRs, FGFR4 has limited expression in normal human tissues and organs, but has a higher expression level in positive tumors. Therefore, the FGFR4 receptor can become a target for tumor-specific imaging.

[0009] FGF (fibroblast growth factor) signaling molecules are not only essential for the growth, survival, differentiation and vascularization of normal cells, but also play an important role in the occurrence and development of tumors. Among the more than 20 FGF members discovered so far, 10 can bind to FGFR4, and only FGF19 specifically binds to FGFR4. FGF19 is an endocrine growth factor. Its binding to the specific receptor FGFR4 requires the formation of a complex with βKlotho in the Klotho family protein to activate multiple downstream signaling pathways, such as continuous activation of PI3K / AKT, PLCγ / DAG / PKC, RAS / RAF / MAPK and GSK / β-catenin, mediating cancer cell proliferation, anti-apoptosis, angiogenesis, drug resistance and epithelial-mesenchymal transition (EMT) and metastasis. Therefore, the FGF19-FGFR4 signaling pathway is considered to be closely related to a variety of tumors and is an ideal target for specific tumor imaging. Summary of the invention

[0010] The primary purpose of the present invention is to provide a polypeptide and sequence that can target fibroblast growth factor receptor 4 (FGFR4), so that it can perform in vivo diagnosis of tumors with high expression of FGFR4 receptors, and can be used to prepare a new type of targeted drug carrier.

[0011] The present invention also aims to provide several tumor-specific targeted fluorescent probes.

[0012] Another object of the present invention is to provide applications of the above polypeptides and probes.

[0013] The purpose of the present invention can be achieved through the following technical solutions:

[0014] Tumor targeting peptide, selected from any of the following peptides:

[0015] YQGF-1: Ac-IIe-Asp-Pro-Asp-Gly-Tyr-Asn-His-NH2;

[0016] YQGF-2:Ac-IIe-Arg-Pro-Asp-Gly-Tyr-Asn-Val-NH2;

[0017] YQGF-3: Ac-Phe-Glu-Glu-Glu-Ile-Arg-Pro-Asp-Gly-Tyr-Asn-Val-Tyr-Arg-Ser-Glu-NH2;

[0018] YQGF-4: Ac-IIe-homoArg-Pro-Asp-Gly-Tyr-Asn-Val-NH2;

[0019] YQGF-5: Ac-IIe-Arg-Pro-Asp-Gly-Tyr-Asn-Nva-NH2;

[0020] YQGF-6: Ac-IIe-D-Asp-Pro-Asp-Gly-Tyr-Asn-His-NH2;

[0021] Among them, homoArg is homoarginine, Nva is norvaline, and D-Asp is D-aspartic acid.

[0022] The tumor targeting peptide of the present invention is used in preparing reagents for tumor diagnosis, treatment or tracing.

[0023] As a preferred embodiment of the present invention, the tumor targeting peptide of the present invention is used in the preparation of tumor diagnostic imaging agents; preferably in the preparation of imaging agents for accurate positioning of tumor boundaries and intraoperative image navigation or in the preparation of radionuclide imaging agents.

[0024] A tumor-targeting probe having the following general formula:

[0025] ML-YQGF-X, or M-YQGF-X,

[0026] Wherein, M represents photolabeling or radionuclide labeling;

[0027] L is a linking group;

[0028] YQGF-X is any polypeptide described in the present invention.

[0029] The optical label is selected from the group consisting of compounds containing organic chromophores, organic fluorophores, light absorbing compounds, light reflecting compounds, light scattering compounds and bioluminescent molecules.

[0030] As a further preferred embodiment of the present invention, the organic fluorophore is a near-infrared fluorescent dye, preferably selected from the group consisting of near-infrared fluorescent dyes MPA, IRDye800, Cy7.5, and Cy5.5; MPA is further preferred.

[0031] The radionuclide is selected from 99m Tc, 68 Ga, 64 Cu, 67 Ga, 90 Y, 111 In or 177 Lu, 125 I.

[0032] As a further preferred embodiment of the present invention, the L is selected from azidopentanoic acid, propiolic acid, polyethylene glycol, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 7-[(4-hydroxypropyl)methylene]-1,4,7-triazanonane-1,4-diacetic acid, 1,4,7,10-tetraazacyclotetraazacyclododecane-1,4,7,10-tetraacetic acid, mercaptoacetyl triglycine, MAG2, N3S, N2S2 ligands, diethyltriaminepentaacetic acid, 1,4-succinic acid, 5-aminopentanoic acid, polyethyleneimine, 6-hydrazinopyridine-3-carboxylic acid, benzyl bromoformate, N-(2-aminoacetic acid)maleimide or a combination thereof.

[0033] The L is further preferably any one or more of 6-aminocaproic acid, PEG 4, PEG 6, HYNIC-PEG4 or HYNIC.

[0034] The tumor-targeting probe of the present invention is used in the preparation of tumor diagnostic reagents; preferably, it is used in the preparation of tumor diagnostic imaging agents; further preferably, it is used in the preparation of precise positioning of tumor boundaries and intraoperative image navigation imaging agents or in the preparation of radionuclide imaging agents.

[0035] Application of the tumor targeting peptide of the present invention in the preparation of tumor targeting drug carriers.

[0036] The polypeptide described in the present invention can highly simulate the tumor targeting of FGF19 (fibroblast growth factor 19), efficiently bind to fibroblast growth factor receptor 4 (FGFR4) to the tumor site, and has good aggregation and retention at the tumor site, has a high target and 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.

[0037] The beneficial effects of the present invention are:

[0038] 1. The present invention has developed a series of novel high-affinity peptides that simulate FGF19 (fibroblast growth factor 19), which can be used to target fibroblast growth factor receptor 4 (FGFR4). Based on the principle that the FGFR4 receptor is highly expressed in tumors and the specific binding of the YQGF-X (X=1-6) peptide to the FGFR4 receptor, the peptides can be used for the early diagnosis of tumors with high FGFR4 expression.

[0039] 2. These peptides are all low molecular weight peptides with low synthesis cost, and this series of short peptides introduces non-natural amino acids for modification, which greatly improves the stability of the peptides in vivo. By extending the half-life of the peptides to increase their circulation time in the body, the imaging probes are promoted to concentrate and stay in the tumor site, thereby obtaining better tumor imaging effects and making it more conducive to clinical promotion and application.

[0040] 3. These peptides are reported for the first time, with simple preparation methods and convenient acquisition channels.

[0041] 4. YQGF-X (X=1-6) series peptides can specifically bind to tumor cells. In vivo optical imaging and results have confirmed that they have excellent imaging effects on a variety of tumors, including liver cancer, breast cancer, cervical cancer and colorectal cancer.

[0042] 5. The present invention utilizes the advantages of the near-infrared fluorescent dye MPA, which has a deeper penetration depth and weaker background tissue autofluorescence, and has good application prospects in fluorescence imaging and fluorescence-guided surgery.

[0043] 6. YQGF-X (X=1-6) polypeptide radioactive drugs can be used for the screening and early diagnosis of tumors, and can also be used for real-time non-destructive in-situ monitoring and treatment of early malignant tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The structure (A), HPLC analysis (B) and MS (C) of the targeting compound YQGF-1.

[0045] Figure 2 Flow cytometry was used to detect the affinity of different fluorescent targeting compounds in HepG2 cells.

[0046] Figure 3 This is the optical imaging of the fluorescent targeting compound MPA-YQGF-1 in HepG-2 liver cancer tumor-bearing mice.

[0047] Figure 4 This is the optical imaging of the fluorescent targeting compound MPA-YQGF-2 in mice bearing liver cancer SMMC-7721.

[0048] Figure 5This is the optical imaging of the fluorescent targeting compound MPA-YQGF-3 in colorectal adenocarcinoma HCT116 tumor-bearing mice.

[0049] Figure 6 This is the optical imaging of the fluorescent targeting compound MPA-YQGF-4 in colorectal adenocarcinoma HT29 tumor-bearing mice.

[0050] Figure 7 This is the optical imaging of the fluorescent targeting compound MPA-YQGF-5 in breast cancer MCF-7 tumor-bearing mice.

[0051] Figure 8 This is the optical imaging of the fluorescent targeting compound MPA-YQGF-6 in cervical cancer Hela tumor-bearing mice. DETAILED DESCRIPTION

[0052] The present invention is further described below by specific examples and application examples: the chemical substances used in the synthesis steps are all existing substances or commercially available products. The polypeptides involved in each example were commissioned to Hangzhou Gutuo Biotechnology Co., Ltd. for synthesis.

[0053] Example 1 takes polypeptide YQGF-1 as an example, comprising the following steps:

[0054] (1) Resin swelling

[0055] Add a certain amount of Rink Amide MBHA resin to the reaction column, then add an appropriate amount of dichloromethane (DCM), and gently blow nitrogen for 10-30 minutes to allow the resin to fully swell. Drain the dichloromethane solution, then wash with dimethylformamide (DMF) three times and drain.

[0056] (2) Removal of Fmoc

[0057] Add 20% hexahydropyridine in DMF solution to the reaction column and perform deprotection once every 5 minutes and once every 8 minutes. After the reaction is completed, wash the resin three times with DMF, DCM, and DMF, respectively.

[0058] (3) Coupling

[0059] Accurately weigh 3 times the molar number of the feed resin Fmoc-IIe-OH and O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), completely dissolve in DMF, add N, N-diisopropylethylamine (DIPEA) to activate the carboxyl group, add the solution to the reaction column for reaction, react for 30 minutes, wash with DMF, DCM, and DMF three times respectively, then drain the solvent, take a small amount of resin and add one drop of 6% ninhydrin / ethanol solution and 80% phenol / ethanol solution for detection. If the condensation is complete and there is no free amino group, the solution will be colorless or light yellow; otherwise, the resin or solution will turn blue or reddish brown, indicating that the reaction is incomplete. After the reaction is completed, wash with DMF, DCM, and DMF three times respectively. Repeat the above operation, and couple other amino acids in turn until the last amino acid Fmoc-His-OH is coupled, wash the obtained peptidyl resin with methanol, and dry it in a vacuum drying oven.

[0060] (4) Cracking

[0061] Take 120mL lysate (87.5% trifluoroacetic acid + 5% thioanisole + 2.5% ethanedithiol + 2.5% phenol + 2.5% water) and add to resin, shake 2h under low temperature, then separate lysate from resin with sand core funnel, retain filtrate. Slowly add filtrate dropwise to ice anhydrous ether, after dropwise addition, naturally settle for 30min. Then centrifuge to obtain solid, wash solid three times with ether, after gained precipitation is dried, obtain dry powder crude product.

[0062] (5) Purification

[0063] The purification was carried out by high performance liquid chromatography, the chromatographic filler for purification was a 10 μm C18 preparative column, the mobile phase system was 0.1% TFA / water solution-0.1% TFA / acetonitrile solution, gradient elution and cyclic injection purification were adopted, the crude product solution was loaded on the chromatographic column, the mobile phase elution was started, the main peak was collected and the acetonitrile was evaporated to obtain the target polypeptide concentrate, which was then freeze-dried to obtain the target polypeptide, and finally the mass-to-charge ratio was measured to determine the molecular weight [MH] - =930.

[0064] Example 2 Preparation of polypeptide YQGF-X (X = 2-6)

[0065] The tumor targeting peptide YQGF-2 was prepared according to the method of Example 1. The sequence of the peptide was the polypeptide shown in SEQ ID NO: 2. The mass spectrometry confirmed that [MH] - =933. Tumor targeting peptide YQGF-3, the sequence of which is the polypeptide shown in SEQ ID NO:3, mass spectrometry confirmed [MH] -=1953. Tumor targeting peptide YQGF-4, the sequence of which is the polypeptide shown in SEQ ID NO:4, mass spectrometry confirmed [MH] - =943. Tumor targeting peptide YQGF-5, the sequence of which is the polypeptide shown in SEQ ID NO:5, [MH] - =933. Tumor targeting peptide YQGF-6, the sequence of which is the polypeptide shown in SEQ ID NO:6, [MH] - =933.

[0066] Example 3 Preparation of fluorescent targeting compound MPA-YQGF-1

[0067] MPA comes from an invention patent applied for by our research group in the early stage, and the authorized patent number is: CN101440282.

[0068] (1) 0.02 mmol MPA was dissolved in 200 μL ultra-dry DMSO, and 3.7 mg 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 2.2 mg N-hydroxysuccinimide (EDCI / NHS) (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.

[0069] (2) 0.02 mmol of the solid phase synthesized peptide YQGF-1 (X=1-6), 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 solution in the above reaction (1) was added to the reaction solution in (2), and the reaction was stirred at room temperature for 12 h;

[0070] (3) After the reaction, the reaction solution was concentrated by freeze drying, then diluted with distilled water, and separated and purified by preparative liquid phase. The preparative liquid phase conditions were as follows: Agilent 1220 Infinity II series HPLC system equipped with Agilent ZORBAX SB-C18 semi-preparative column (9.4×250 mm, 5 um) was used, gradient elution was 60 minutes, flow rate was 2 mL / min, and mobile phase A was ultrapure water (0.01% TFA), and mobile phase B was acetonitrile (0.01% TFA). The elution gradient was set as: 95% A and 5% B at 0-5 minutes, 85% A and 15% B at 15 minutes, 70% A and 30% B at 30 minutes, 50% A and 50% B at 45 minutes, and 10% A and 90% B at 60 minutes. The green product finally obtained was confirmed to be the expected product MPA-YQGF-1 by analytical HPLC and ESI-MS mass spectrometry analysis, see Figure 1In the above preparation process, the YQGF-1 polypeptide used in the step is replaced by the solid-phase synthesized YQGF-X (X=2, 3, 4, 5, 6) polypeptide to obtain various other polypeptide compounds MPA-YQGF-2, MPA-YQGF-3, MPA-YQGF-4, MPA-YQGF-5, and MPA-YQGF-6 with tumor-targeting optical imaging function.

[0071] Affinity of the compound MPA-YQGF-X (X=1-6) prepared in Example 4 to HepG2 cells.

[0072] The cultured human liver cancer HepG2 cells were washed from the 12-well plate and resuspended in PBS solution, and incubated with MPA-YQGF-X (X=1-6) (10umol / L) prepared in the example for 2 hours, and the average fluorescence intensity was detected by flow cytometry. The stronger the fluorescence intensity, the stronger the affinity for the cells. When the probe has a strong affinity with the receptor on the cell, the average fluorescence intensity of the cell detected by the flow cytometer is high, see Figure 2 The results of in vitro affinity experiments showed that after the probes of MPA-YQGF-X (X=1-6) with the same concentration were incubated with HepG2 cells with high expression of FGFR4, the YQGF-1 of the present invention had the strongest affinity with HepG2, but YQGF-2, YQGF-3, YQGF-4, YQGF-5, and YQGF-6 also had obvious affinity compared with the blank control group.

[0073] Optical imaging of the compound MPA-YQGF-1 prepared in Example 5 in mice bearing HepG2 liver cancer.

[0074] The compound MPA-YQGF-1 prepared in Example 3 was formulated into a physiological saline solution (1 mg / mL), and 15 μL of the drug MPA-YQGF-1 solution was injected into three HepG2 liver cancer tumor-bearing nude mice (weighing about 20 grams) through the tail vein, and optical signal collection was performed at 0.5h, 1h, 2h, 4h, 6h and 12h after administration. The distribution of the probe in the mouse body and the enrichment in the tumor area were observed. The imaging results of the compound MPA-YQGF-2 in the three tumor-bearing nude mice were basically consistent. From the imaging image at 1h, it can be seen that the probe has been obviously aggregated in the tumor, and the outline of the tumor edge is clear. The probe is still retained in the tumor until 12h. The imaging results are as follows Figure 3 Among them, the probe was most enriched in the tumor site at 2 hours, while the uptake and clearance in other background organs was faster. From the signal of the bladder, it can be inferred that this probe is mainly metabolized by the kidney.

[0075] Optical imaging of the compound MPA-YQGF-2 prepared in Example 6 in mice bearing liver cancer SMMC-7721.

[0076] The compound MPA-YQGF-2 prepared in Example 3 was formulated into a physiological saline solution (1 mg / mL), and 15 μL of the drug MPA-YQGF-2 solution was injected into three nude mice bearing SMMC-7721 liver cancer (weighing about 20 grams) through the tail vein, and optical signal collection was performed at 0.5 h, 1 h, 2 h, 4 h, 6 h and 12 h after administration. The distribution of the probe in the mouse body and the enrichment in the tumor area were observed. The imaging results of the compound MPA-YQGF-2 in the three tumor-bearing nude mice were basically consistent. From the imaging image at 1 h, it can be seen that the probe has been clearly aggregated in the tumor, and the outline of the tumor edge is clear. The probe is still retained in the tumor until 12 h. The imaging results are as follows Figure 4 Among them, the probe was most enriched in the tumor site at 2 hours, while the uptake and clearance in other background organs was faster. From the signal of the bladder, it can be inferred that this probe is mainly metabolized by the kidney.

[0077] Optical imaging of the compound MPA-YQGF-3 prepared in Example 7 in mice bearing colorectal adenocarcinoma HCT116.

[0078] The compound MPA-YQGF-3 prepared in Example 3 was formulated into a physiological saline solution (1 mg / mL), and 15 μL of the drug MPA-YQGF-3 solution was injected into three nude mice bearing colorectal adenocarcinoma HCT116 (weighing about 20 grams) through the tail vein, and optical signal collection was performed at 0.5 h, 1 h, 2 h, 4 h, 6 h and 12 h after administration. The distribution of the probe in the mouse body and the enrichment in the tumor area were observed. The imaging results of the compound MPA-YQGF-3 in the three tumor-bearing nude mice were basically consistent. It can be seen from the imaging image at 1 h that the probe has been clearly aggregated in the tumor, and the outline of the tumor edge is clear. The probe is still retained in the tumor until 12 h. The imaging results are as follows Figure 5 Among them, the probe was most enriched in the tumor site at 2 hours, while the uptake and clearance in other background organs was faster. From the signal of the bladder, it can be inferred that this probe is mainly metabolized by the kidney.

[0079] Optical imaging of the compound MPA-YQGF-4 prepared in Example 8 in mice bearing colorectal adenocarcinoma HT29.

[0080] The compound MPA-YQGF-4 prepared in Example 3 was formulated into a physiological saline solution (1 mg / mL), and 15 μL of the drug MPA-YQGF-4 solution was injected into three colorectal adenocarcinoma HT29 tumor-bearing nude mice (weighing about 20 grams) through the tail vein, and optical signal collection was performed at 0.5h, 1h, 2h, 4h, 6h and 12h after administration. The distribution of the probe in the mouse body and the enrichment in the tumor area were observed. The imaging results of the compound MPA-YQGF-4 in the three tumor-bearing nude mice were basically consistent. From the imaging image at 1h, it can be seen that the probe has been obviously aggregated in the tumor, and the outline of the tumor edge is clear. The probe is still retained in the tumor until 12h. The imaging results are as follows Figure 6 Among them, the probe was most enriched in the tumor site at 2 hours, while the uptake and clearance in other background organs was faster. From the signal of the bladder, it can be inferred that this probe is mainly metabolized by the kidney.

[0081] Optical imaging of the compound MPA-YQGF-5 prepared in Example 9 in mice bearing breast cancer MCF-7 tumor.

[0082] The compound MPA-YQGF-5 prepared in Example 3 was formulated into a physiological saline solution (1 mg / mL), and 15 μL of the drug MPA-YQGF-5 solution was injected into three breast cancer MCF-7 tumor-bearing nude mice (weighing about 20 grams) through the tail vein, and optical signal collection was performed at 0.5h, 1h, 2h, 4h, 6h and 12h after administration. The distribution of the probe in the mouse body and the enrichment in the tumor area were observed. The imaging results of the compound MPA-YQGF-5 in the three tumor-bearing nude mice were basically consistent. From the imaging image at 1h, it can be seen that the probe has been obviously aggregated in the tumor, and the outline of the tumor edge is clear. The probe is still retained in the tumor until 12h. The imaging results are as follows Figure 7 Among them, the probe was most enriched in the tumor site at 2 hours, while the uptake and clearance in other background organs was faster. From the signal of the bladder, it can be inferred that this probe is mainly metabolized by the kidney.

[0083] Optical imaging of the compound MPA-YQGF-6 prepared in Example 10 in Hela cervical cancer-bearing mice.

[0084] The compound MPA-YQGF-6 prepared in Example 3 was formulated into a physiological saline solution (1 mg / mL), and 15 μL of the drug MPA-YQGF-6 solution was injected into three cervical cancer Hela tumor-bearing nude mice (weighing about 20 grams) through the tail vein, and optical signal collection was performed at 0.5h, 1h, 2h, 4h, 6h and 12h after administration. The distribution of the probe in the mouse body and the enrichment in the tumor area were observed. The imaging results of the compound MPA-YQGF-6 in the three tumor-bearing nude mice were basically consistent. From the imaging image at 1h, it can be seen that the probe has been obviously aggregated in the tumor, and the outline of the tumor edge is clear. The probe is still retained in the tumor until 12h. The imaging results are as follows Figure 8 Among them, the probe was most enriched in the tumor site at 2 hours, while the uptake and clearance in other background organs was faster. From the signal of the bladder, it can be inferred that this probe is mainly metabolized by the kidney.

Claims

1. A tumor-targeting probe, characterized in that With the following general formula: M-YQGF-3, Wherein, M represents the near-infrared fluorescent dye MPA; The sequence of YQGF-3 is: Ac-Phe-Glu-Glu-Glu-Ile-Arg-Pro-Asp-Gly-Tyr-Asn-Val-Tyr-Arg-Ser-Glu-NH2.

2. Use of the tumor-targeting probe according to claim 1 in the preparation of a diagnostic imaging agent for colorectal adenocarcinoma.

3. The use according to claim 2, characterized in that Use of the tumor-targeting probe described in claim 1 in the preparation of imaging agents for accurate positioning of the border of colorectal adenocarcinoma and intraoperative image navigation or in the preparation of radionuclide imaging agents.

Images