CN114177314A - Application of thymopentin and derivatives thereof in preparation of tumor diagnosis and/or treatment reagent - Google Patents

Application of thymopentin and derivatives thereof in preparation of tumor diagnosis and/or treatment reagent Download PDF

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CN114177314A
CN114177314A CN202111542305.1A CN202111542305A CN114177314A CN 114177314 A CN114177314 A CN 114177314A CN 202111542305 A CN202111542305 A CN 202111542305A CN 114177314 A CN114177314 A CN 114177314A
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tumor
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mpa
lys
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涂远彪
周坤城
辛苏玲
秦凯莉
陶添明
陈淑莹
韩平畴
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Jiangxi University of Traditional Chinese Medicine
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Abstract

The invention provides application of thymopentin and derivatives thereof in preparation of tumor diagnosis and/or treatment reagents, and belongs to the technical field of fluorescent contrast agents, radiopharmaceuticals and nuclear medicine. The molecular probe constructed by the thymopentin and the derivatives thereof can be specifically targeted to a tumor part, has good uptake and retention capacity at the tumor part, has a high target/non-target ratio, is suitable for preparing an image navigation reagent in a tumor operation and preparing a radiopharmaceutical, and is used for tumor nuclear medicine diagnosis and precise radiotherapy.

Description

Application of thymopentin and derivatives thereof in preparation of tumor diagnosis and/or treatment reagent
Technical Field
The invention belongs to the technical field of fluorescent contrast agents, radiopharmaceuticals and nuclear medicine, and particularly relates to application of thymopentin and derivatives thereof in preparation of tumor diagnosis and/or treatment reagents.
Background
Malignant tumors have become the "first killer" threatening human health and life, and the diagnosis and effective treatment of malignant tumors are undoubtedly urgent. It is well known that tumor-targeted molecular imaging probes are advantageous tools for tumor diagnosis, staging and intraoperative navigation. Among them, the ligand of tumor specific targeting is the key of the tumor targeting molecular probe. The existing method for designing and screening the target ligand mainly comprises computer-aided drug design, modification and transformation of a lead compound, discovery from metabolites, discovery from drug synthesis intermediates, combinatorial chemistry and high-throughput screening, separation and extraction from natural compounds, screening of a phage display library and 'new application of old drugs'. 1988 James Blake, who has acquired a physiological or medical reward for nobel, proposed that the best way for new drug discovery began with the older drug. "old drug" refers to a drug that is marketed or in the clinical setting with certain pharmacokinetic and toxicological information, and safety is the most obvious feature. The non-selective beta receptor antagonist propranolol developed by james beleke and the first histamine H2 receptor antagonist cimetidine are typical examples of "new use of old drugs". Propranolol is a classic drug for treating coronary heart disease and hypertension, and is now used for treating osteoporosis and melanoma; cimetidine is a revolutionary drug for treating peptic gastric ulcer, and is proved to be suitable for treating chronic obstructive pulmonary disease, HIV virus infection and the like; nature states that metformin, in combination with another "new drug for old use" heme, can be used for the treatment of triple-negative breast cancer; arsenic trioxide, also known as arsenic trioxide, is a highly toxic substance, and recent studies have found that it can be used for treating acute promyelocytic leukemia; therefore, the strategy of 'new application of old drug' has important guiding significance in drug development, so that the method for screening the target drug of the tumor by applying the strategy of 'new application of old drug' is a quick and effective method.
Thymopentin is an important bioactive substance in the body of mammals, and plays an important role in maintaining the balance of immune systems, resisting tumors, resisting microbial infection and the like. The thymopentin is an amino acid residue fragment of 32 th to 36 th positions in thymopoietin II, retains the biological activity of thymopoietin, and has the same physiological functions and drug effects as thymus extract thymosin and thymopoietin. Based on the strategy of 'new application of old medicine', the prior art does not report what effect thymopentin has.
Disclosure of Invention
In view of the above, the present invention aims to provide applications of thymopentin and derivatives thereof in preparing tumor diagnosis and/or treatment reagents, and to provide new uses of thymopentin.
In order to achieve the above purpose, the invention provides the following technical scheme:
the invention provides application of thymopentin and derivatives thereof in preparing a tumor diagnosis and/or treatment reagent, wherein the thymopentin is selected from one or more of the following polypeptides:
TP-1：L-Arg-L-Lys-L-Asp-L-Val-L-Tyr(Thymopentin)；
TP-2：L-homo-Arg-L-Lys-L-Asp-L-Nva-L-Tyr；
TP-3：D-Arg-L-Lys-L-Asp-L-Val-L-Tyr；
TP-4：D-Arg-D-Lys-L-Asp-L-Val-L-Tyr；
TP-5：D-Arg-L-Lys-L-Asp-L-Val-D-Tyr；
TP-6：D-Arg-L-Lys-L-Asp-L-Nva-D-Tyr；
TP-7: L-Cys-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Cys, wherein the Cys-Cys disulfide bond forms a ring;
TP-8: beta-Ala-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Asp, wherein the amino group at the N-terminus and the side chain carboxyl group at the Asp at the C-terminus form an amide ring;
TP-9: D-Lys-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Glu, wherein the N-terminal main chain amino group and the side chain carboxyl of the C-terminal Glu form an amide ring;
TP-10: D-Lys-L-Gly-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Asp, wherein the N-terminal main chain amino group and the C-terminal main chain carboxyl group of Asp form an amide ring;
wherein: d represents an unnatural D-type amino acid, and L represents an L-type natural amino acid; homoArg is homoarginine; nva is norvaline.
Preferably, the tumor comprises one or more of lung cancer, pancreatic cancer, colorectal cancer, liver cancer, gastric cancer and breast cancer.
Preferably, the thymopentin and derivatives thereof are coupled to an imaging group to provide the agent.
Preferably, the agent comprises a fluorescent imaging agent and/or a radioactive agent, and the fluorescent imaging agent comprises an optical imaging agent for accurate tumor boundary localization and/or intraoperative image navigation.
Preferably, the reagent has the general formula: M-L-G;
m represents a light label, a complex of a metal chelator and a metal radionuclide, a non-metal radionuclide18F and11any one of C;
l is a linking group;
g is thymopentin and derivatives thereof;
the optical label comprises one or more of an organic chromophore, an organic fluorophore, a light absorbing compound, a light reflecting compound, a light scattering compound, and a bioluminescent molecule;
the metal chelating agent is selected from hydrazine nicotinamide, 1,4, 7-triazacyclononane-1, 4, 7-triacetic acid, 7- [ (4-hydroxypropyl) methylene ] -1,4, 7-triazatenonane-1, 4-diacetic acid, 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid, mercaptoacetyltriglycine, diethyltriaminepentaacetic acid or a combination modification thereof.
Preferably, the optical marker comprises a near-infrared one-region fluorescent dye and/or a near-infrared two-region fluorescent dye, and the near-infrared one-region fluorescent dye comprises one or more of MPA, IRDye800, Cy7.5, ICG and Cy5.5.
Preferably, the linking group comprises 6-aminocaproic acid, NH2-PEG3-COOH、NH2-PEG4-COOH、NH2-PEG6-COOH and NH2-GGGGGG-COOH.
Preferably, the agent comprises one or more of thymopentin and derivatives thereof.
Preferably, the reagent comprises99mTc-HYNIC-PEG4-TP-1-NH2And/or99mTc-HYNIC-PEG4-TP-7。
Preferably, the reagent is99mTc-HYNIC-2Aca-E-(TP-1-NH2)2。
The invention provides application of thymopentin and derivatives thereof in preparation of tumor diagnosis and/or treatment reagents, wherein a molecular probe constructed by the thymopentin and the derivatives thereof can be specifically targeted to a tumor part, has good uptake and retention capacity at the tumor part, has a high target/non-target ratio, is suitable for preparing an image navigation reagent in a tumor operation and preparing a radiopharmaceutical, and is used for tumor nuclear medicine diagnosis and precise radiotherapy.
TP-1 is the original thymopentin, and the rest sequences are modified based on the original peptide modification. For example, two or more natural amino acids are replaced by unnatural amino acids, and the cyclic peptide is also based on the original thymopentin sequence, and two to three amino acids are added to form a cyclic loop, wherein the core skeleton in the 10 sequences is the sequence of thymopentin.
Compared with the prior art, the invention has the beneficial effects that:
1. the thymopentin has long history in clinical use, has determined pharmacokinetic information and toxicological information, and has high in vivo safety. Therefore, the in vivo molecular probe constructed based on the thymopentin and the derivatives thereof has unique advantages in safety, and can significantly reduce the research and development cost and risk of the drug.
2. By means of the property that the thymopentin can specifically target tumors, the thymopentin and derivatives thereof are coupled with fluorescent dye to construct a fluorescent probe, so that doctors can be assisted in accurately positioning tumor boundaries in an operation, and the purpose of accurately cutting off the tumors is achieved. In addition, the thymopentin and the derivatives thereof can be coupled with radionuclide with diagnosis/treatment functions to construct corresponding radiopharmaceuticals, so that the purposes of tumor diagnosis and precise radiotherapy can be achieved.
3. The molecular probe constructed based on the thymopentin and the derivatives thereof has excellent targeting effects on various tumors, including liver cancer, lung cancer, colorectal cancer, breast cancer, pancreatic cancer, gastric cancer and the like, proved by in vivo optics and radionuclide imaging results. The characteristic that the probe can be specifically targeted to the tumor part can realize the nuclear medicine diagnosis, treatment and optical surgical navigation of malignant tumors.
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FIG. 1 shows MPA-PEG3-TP-1-NH2Mass spectrogram of (1);
FIG. 2 shows the preparation of the monomeric fluorescent compound MPA-PEG3-TP-1-NH22h fluorescence imaging in tumor-bearing mice; wherein A is fluorescence imaging in a lung cancer A549 tumor-bearing mouse; b is fluorescence imaging in vivo in a pancreatic cancer AsPC-1 tumor-bearing mouse; c is fluorescence imaging in vivo in a pancreatic cancer CFPAC-1 tumor-bearing mouse; d is fluorescence imaging in lung cancer H1299 tumor-bearing mice; e is fluorescence imaging in colorectal cancer HCT116 tumor-bearing mice; f is fluorescence imaging in a liver cancer HepG2 tumor-bearing mouse; g is fluorescence imaging in colorectal cancer HT29 tumor-bearing mice; h is fluorescence imaging in breast cancer MAD-MB-231 tumor-bearing mice; i is fluorescence imaging in a gastric cancer MGC-803 tumor-bearing mouse; j is fluorescence imaging in stomach cancer SGC-7901 tumor-bearing mice; k is fluorescence imaging in a breast cancer MCF-7 tumor-bearing mouse; l is fluorescence imaging in vivo in a pancreatic cancer MiaPaPc-2 tumor-bearing mouse;
FIG. 3 shows the preparation of the monomeric fluorescent compound MPA-PEG4-TP-2、MPA-PEG4-TP-3、MPA-PEG4-TP-4、MPA-PEG4-TP-5、MPA-PEG4-TP-6、MPA-PEG4-TP-8、MPA-PEG4-2 h fluorescence imaging of TP-9 in tumor-bearing mice; wherein A is MPA-PEG4-fluorescence imaging of TP-2 in lung carcinoma a549 tumor-bearing mice; b is MPA-PEG4-fluorescence imaging of TP-3 in gastric cancer SGC-803 tumor bearing mice; c is MPA-PEG4-fluorescence imaging of TP-4 in breast cancer MDA-MB-468 tumor bearing mice; d is MPA-PEG4-fluorescence imaging of TP-5 in breast cancer MCF-7 tumor-bearing mice; e is MPA-PEG4-fluorescence imaging of TP-6 in pancreatic cancer AsPC-1 bearing mice; f is MPA-PEG4-fluorescence imaging of TP-8 in lung cancer H1299 tumor-bearing mice; g is MPA-PEG4Fluorescence imaging of TP-9 in Colon cancer HCT 116-bearing mice;
FIG. 4 shows the preparation of the monomeric fluorescent compound MPA-PEG4-2 h fluorescence imaging of TP-7 in tumor-bearing mice; wherein A is fluorescence imaging in a pancreatic cancer AsPC-1 tumor-bearing mouse; b is fluorescence imaging in colorectal cancer HCT116 tumor-bearing mice; c is fluorescence imaging in a breast cancer MDA-MB-231 tumor-bearing mouse; d is fluorescence imaging in vivo in mice bearing MiaPaCa-2 tumor of pancreatic cancer; e is fluorescence imaging in stomach cancer SGC-7901 tumor-bearing mice;
FIG. 5 shows the preparation of the monomeric fluorescent compound MPA-PEG4-2 h fluorescence imaging of TP-10 in tumor-bearing mice; wherein A is fluorescence imaging in a pancreatic cancer AsPC-1 tumor-bearing mouse; b is fluorescence imaging in colorectal cancer HCT116 tumor-bearing mice; c is fluorescence imaging in a breast cancer MDA-MB-231 tumor-bearing mouse; d is fluorescence imaging in vivo in mice bearing MiaPaCa-2 tumor of pancreatic cancer; e is fluorescence imaging in stomach cancer SGC-7901 tumor-bearing mice;
FIG. 6 shows the preparation of monomeric radioactive compounds99mTc-HYNIC-PEG4-TP-1-NH2SPECT-CT imaging in a tumor-bearing mouse for 1 h; wherein A is SPECT-CT imaging in a pancreatic cancer AsPC-1 tumor-bearing mouse; b is SPECT-CT imaging in stomach cancer SGC-7901 tumor-bearing mice; c is SPECT-CT imaging in a pancreatic cancer MiaPaPc-2 tumor-bearing mouse; d is SPECT-CT imaging in a breast cancer MCF-7 tumor-bearing mouse; e is SPECT-CT imaging in colorectal cancer HT29 tumor-bearing mice;
FIG. 7 shows the preparation of monomeric radioactive compounds99mTc-HYNIC-PEG4-SPECT-CT imaging of TP-7 in tumor-bearing mice for 1 h; wherein A is SPECT-CT imaging in a breast cancer MCF-7 tumor-bearing mouse; b is SPECT-CT imaging in a pancreatic cancer AsPC-1 tumor-bearing mouse; c is SPECT-CT imaging in a pancreatic cancer MiaPaPc-2 tumor-bearing mouse; d is SPECT-CT imaging in colorectal cancer HT29 tumor-bearing mice; e is SPECT-CT imaging in a gastric cancer MGC-803 tumor-bearing mouse; e is SPECT-CT imaging in stomach cancer SGC-7901 tumor-bearing mice;
FIG. 8 shows the preparation of dimeric radioactive compounds99mTc-HYNIC-2Aca-(TP-1-NH2)2SPECT-CT imaging in pancreatic cancer AsPC-1 and colorectal cancer HT29 tumor-bearing mice, respectively.
Detailed Description
The invention provides application of thymopentin and derivatives thereof in preparing a tumor diagnosis and/or treatment reagent, wherein the thymopentin is selected from one or more of the following polypeptides:
TP-1：L-Arg-L-Lys-L-Asp-L-Val-L-Tyr(Thymopentin)；
TP-2：L-homo-Arg-L-Lys-L-Asp-L-Nva-L-Tyr；
TP-3：D-Arg-L-Lys-L-Asp-L-Val-L-Tyr；
TP-4：D-Arg-D-Lys-L-Asp-L-Val-L-Tyr；
TP-5：D-Arg-L-Lys-L-Asp-L-Val-D-Tyr；
TP-6：D-Arg-L-Lys-L-Asp-L-Nva-D-Tyr；
TP-7: L-Cys-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Cys, wherein the Cys-Cys disulfide bond forms a ring;
TP-8: beta-Ala-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Asp, wherein the amino group at the N-terminus and the side chain carboxyl group at the Asp at the C-terminus form an amide ring;
TP-9: D-Lys-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Glu, wherein the N-terminal main chain amino group and the side chain carboxyl of the C-terminal Glu form an amide ring;
TP-10: D-Lys-L-Gly-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Asp, wherein the N-terminal main chain amino group and the C-terminal main chain carboxyl group of Asp form an amide ring;
wherein: d represents an unnatural D-type amino acid, and L represents an L-type natural amino acid; homoArg is homoarginine; nva is norvaline.
In the present invention, the tumor preferably includes one or more of lung cancer, pancreatic cancer, colorectal cancer, liver cancer, stomach cancer and breast cancer.
According to the invention, the thymopentin and the derivative thereof are preferably coupled with an imaging group to obtain the reagent. In the present invention, the agent preferably comprises a fluorescent imaging agent and/or a radioactive agent, and the fluorescent imaging agent preferably comprises an optical imaging agent for precise localization of tumor boundaries and/or intraoperative image navigation.
In the present invention, the reagent has the general formula: M-L-G; m represents a light label, a complex of a metal chelator and a metal radionuclide, a non-metal radionuclide18F and11any one of C; l is a linking group; g is thymopentin and its derivatives. In the present invention, the optical label preferably comprises one or more of an organic chromophore, an organic fluorophore, a light absorbing compound, a light reflecting compound, a light scattering compound and a bioluminescent molecule. In the present invention, the metal chelating agent is preferably selected from the group consisting of hydrazinium nicotinamide, 1,4, 7-triazacyclononane-1, 4, 7-triacetic acid, 7- [ (4-hydroxypropyl) methylene]-1,4, 7-triazatenonane-1, 4-diacetic acid, 1,4,7, 10-tetraazacyclotetraazacyclododecane-1, 4,7, 10-tetraacetic acid, mercaptoacetyltriglycine, diethyltriaminepentaacetic acid, or a combination thereof. In the present invention, the optical marker preferably comprises a near-infrared one-region fluorescent dye and/or a near-infrared two-region fluorescent dye, and the near-infrared one-region fluorescent dye comprises one or more of MPA, IRDye800, cy7.5, ICG, and cy5.5. In the present invention, the linking group preferably includes 6-aminocaproic acid, NH2-PEG3-COOH、NH2-PEG4-COOH、NH2-PEG6-COOH and NH2-GGGGGG-COOH.
In the invention, the thymopentin, the derivative thereof and the near-infrared fluorescent probe based on the thymopentin are synthesized by Hangzhou Gutou Biotech, Inc. through a solid phase method, and the method comprises the following steps:
1) synthesis of near-infrared fluorescent dye MPA
Glacial acetic acid, p-hydrazino benzenesulfonic acid, methyl isopropyl ketone and sodium acetate are mixed and reacted, and a product 2,2, 3-trimethyl [3H ] -indole-5-sulfonic acid is obtained after purification; and adding o-dichlorobenzene into the mixture of 2,2, 3-trimethyl [3H ] -indole-5-sulfonic acid and 1, 3-propane sulfonic lactone to prepare the 2,2, 3-trimethyl-5-sulfonic acid-1- (3-sulfonic acid-propyl) - [3H ] -indole. And then reacting the product with N- [ (3- (anilomethylene) -2-chloro-1-cyclohexen-1-yl) methyl ] -aniline monohydrochloride to obtain green carbocyanine dye, and finally reacting the carbocyanine dye with mercaptopropionic acid and triethylamine to prepare a liquid phase, and separating and purifying the liquid phase to obtain the water-soluble near-infrared dye MPA.
2) Synthesis of MPA-L-TP-X (X ═ 1-10)
Selecting Ramage Amide AM resin with Loading of 0.45mmol/g, and removing Fmoc protecting group after swelling. Coupling from the C end to the N end in sequence until Fmoc-L-carboxyl according to a polypeptide sequence, cutting a small sample, and detecting the molecular weight of the polypeptide by mass spectrometry, wherein the side chains of Tyr, Asp, Lys and Arg are respectively protected by tBu, OtBu, Boc and Arg. All amino acids are Fmoc protected alpha amino; determination of the polypeptide Fmoc-L-TP-X-NH2And (3) removing the Fmoc protecting group after the mass spectrum is correct, adding a near-infrared dye MPA with the molar multiple of 1.2 times to perform solid-phase reaction, and finishing the reaction after the ninhydrin detection shows negative. The cleavage solution (TFA: triisopropylsilane: water ═ 95:2.5:2.5) was reacted with a linear peptide resin to obtain MPA-L-TP-X-NH from which all side chain protecting groups were removed2(ii) a MPA-L-TP-X-NH2Dissolving in water, purifying by semi-preparative chromatography, separating out liquid with qualified purity, collecting, rotary-steaming, and lyophilizing to obtain the final product.
The radionuclide probe monomer form constructed based on the thymopentin and the derivative thereof is simpler to prepare than a dimer form, the dimer structure of the radionuclide probe monomer form contains thymopentin and the derivative thereof used for targeting tumors, bifunctional chelating agent hydrazine nicotinamide (HYNIC) used for radioactive labeling, and a connecting agent L which can increase the distance between the thymopentin or the analogue thereof and radionuclide ligands N-tri (hydroxymethyl) methylglycine (Tricine) and triphenylphosphine sodium tri-sulfonate (TPPTS) and adjust the in vivo pharmacokinetic characteristic, wherein the L is selected from 6-aminocaproic acid, NH and the like2-PEG3-COOH、NH2-PEG4-COOH、NH2-PEG6-COOH or NH2Any one or more of-GGGGGG-COOH.
The coupling of different radionuclides can be achieved by changing the bifunctional chelating agent. For example, the bihydrazinium nicotinamide is replaced by a bifunctional chelating agent 1,4, 7-triazacyclononane-1, 4, 7-triacetic acid, 7- [ (4-hydroxypropyl) methylene]Any one of-1, 4, 7-triazatenonane-1, 4-diacetic acid, 1,4,7, 10-tetraazacyclotetraazacyclododecane-1, 4,7, 10-tetraacetic acid, mercaptoacetyltriglycine or diethyltriaminepentaacetic acid, radionuclides99mTc may be replaced by68Ga、64Cu、67Ga、90Y、111In、89Zr or177Lu. Or a radionuclide124I、125I、131I is directly marked on Tyr in the structure of free peptide TP-X to realize the function of disease diagnosis/treatment.
In the present invention, the method for preparing the monomeric radionuclide probe comprises the following steps:
1) synthesis of bifunctional chelating agent HYNIC-L-NHS
Adding 6-chloronicotinic acid and 80% hydrazine hydrate into ethanol, heating and refluxing for reaction, performing rotary evaporation on the solvent under reduced pressure after the reaction is finished, adding the obtained viscous substance into distilled water, adjusting the pH value to 5.5, separating out a solid, performing suction filtration and drying to obtain a yellow solid, and determining the product as 6-hydrazinonicotinic acid through ESI-MS mass spectrum and nuclear magnetic hydrogen spectrum. Adding the obtained 6-hydrazinonicotinic acid and p-aminobenzaldehyde into dimethyl sulfoxide (DMSO), heating for reaction for 5-6 hours, adding into water for precipitation after the reaction is finished, performing suction filtration to obtain a solid, adding the dried solid, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and N-hydroxysuccinimide (NHS) into the DMSO for reaction at room temperature, adding into water for precipitation after the reaction is finished, purifying the solid through a silica gel column, determining the solid as an intermediate HYNIC-NHS through ESI-MS mass spectrometry and nuclear magnetic hydrogen spectrometry, reacting the intermediate with a linking agent L under an alkaline condition, finally activating with activating agents EDCI and NHS, and purifying to obtain a HYNIC-L-NHS solid for later use.
2) Synthesis of HYNIC-L-TP-X (X ═ 1-10)
Dissolving the purified intermediate HYNIC-L-NHS in DMSO, adding 1-1.5 molar amount of TP-X, then adding 2-3 molar amount of DIPEA, reacting at room temperature for 1-2 hours, and separating and purifying by a preparation liquid phase after the reaction is finished and confirming by mass spectrum.
3)99mSynthesis of Tc-HYNIC-L-TP-X (X ═ 1-10)
TPPTS (Triphenyl sodium Tri-metaphosphate) solution with the concentration of 100.0-120mg/mL, Tricine (trimethylglycine) with the concentration of 130.0-150mg/mL, succinic acid-sodium succinate buffer solution with the concentration of 102.4-110mg/mL (wherein the succinic acid is 77.0-88.8mg, and the sodium succinate is 25.4-29.3mg) are respectively prepared, 10.0uL of TPPTS solution, 10.0uL of Tricine solution, 10.0uL of succinic acid-sodium succinate buffer solution and 10.0uL (1.0mg/mL) of HYNIC-L-TP-X are respectively mixed in a penicillin bottle, and then 10mCi Na is added99mTcO4Heating in a metal bath at 100 ℃ for 20-30 minutes, cooling to room temperature after the reaction is finished, and analyzing and identifying the product by HPLC to obtain the product.
In the present invention, the method for preparing the dimer radionuclide probe preferably comprises:
1) synthesis of bifunctional chelating agent HYNIC-L-NHS
The method is the same as the preparation step 1) of the monomer radionuclide probe.
2) Synthesis of scaffold (2L-glutamic acid)
Dissolving a proper amount of Boc-glutamic acid in DMSO, adding EDCI with 2-3 times of molar weight and NHS60, heating for reaction at 0.5-1 hour, analyzing the generation of glutamic acid double-activated ester by HPLC, adding a 2-3 times of molar weight of a linker L and 2-3 times of molar weight of DIPEA into the solution, heating for reaction at 60 ℃ for 0.5-1 hour, analyzing the connection of the 2-molecule linker L by HPLC, adding an equal volume of TFA, reacting at room temperature overnight to remove Boc protection, and finally, carrying out preparative liquid phase separation on the crude product, and freeze-drying for later use.
3) Synthesis of intermediate 2L-E-HYNIC-NHS
Dissolving the prepared stent 2L-glutamic acid in DMSO, adding HYNIC-L-NHS with the same molar weight, adding 2-3 times of DIPEA, reacting at room temperature for 1-2 hours, separating and purifying a prepared liquid phase after the reaction is finished, confirming a target compound by mass spectrometry, activating the purified product by EDCI and NHS, and purifying to obtain 2L-E-HYNIC-NHS for later use.
4)(TP-X)2Synthesis of (E) -2L-HYNIC (X-1-10)
Dissolving the purified intermediate 2L-E-HYNIC-NHS in DMSO, adding 1-1.5 molar amount of TP-X, then adding 2-3 molar amount of DIPEA, reacting at room temperature for 1-2 hours, and after the reaction is finished, separating and purifying by a preparation liquid phase and confirming by mass spectrum.
5) Radioactive probe99mTc-HYNIC-2L-E-(TP-X)2Synthesis of (X-1-10)
TPPTS (Triphenyl sodium Tri-metaphosphate) solution with concentration of 100.0-120mg/mL, Tricine (trimethylglycine) with concentration of 130.0-150mg/mL, succinic acid-sodium succinate buffer solution with concentration of 102.4-110mg/mL (wherein succinic acid is 77.0-88.8mg, sodium succinate is 25.4-29.3mg) are respectively prepared, 10.0uL TPPTS solution, 10.0uL Tricine solution, 10.0uL succinic acid-sodium succinate buffer solution and 10.0uL (1.0mg/mL) HYNIC-2L-E- (TP-X) are respectively taken2Mixing in penicillin bottle, adding 10mCi Na99mTcO4Heating in a metal bath at 100 ℃ for 20-30 minutes, cooling to room temperature after the reaction is finished, and analyzing and identifying the product by HPLC.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
MPA-PEG3-TP-1-NH2Synthesis of (2)
Selecting Ramage Amide AM resin with Loading of 0.45mmol/g, and removing Fmoc protecting group after swelling. According to the thymopentin sequence: Arg-Lys-Asp-Val-Tyr, which are coupled from C end to N end in sequence until Fmoc-PEG3Propionic acid, wherein the side chains of Tyr, Asp, Lys and Arg are respectively protected by tBu, OtBu, Boc and Arg, and the amino acids are Fmoc protected alpha amino. Cutting a small sample, detecting the molecular weight of the polypeptide by mass spectrometry, determining that the mass spectrometry of the polypeptide Fmoc-PEG3-TP-X-NH2 is correct, removing the Fmoc protecting group, and adding near infrared with the molar multiple of 1.2The dye MPA is subjected to solid phase reaction, and the reaction is finished after ninhydrin detection is negative. The cleavage solution (TFA: triisopropylsilane: water ═ 95:2.5:2.5) was reacted with a linear peptide resin to obtain MPA-PEG from which all side chain protecting groups were removed3-TP-1-NH2MPA-PEG3-TP-1-NH2Dissolving in water, purifying with semi-preparative chromatography, separating to obtain liquid with qualified purity, collecting, rotary evaporating, lyophilizing, and ESI-MS mass spectrometry to obtain MPA-PEG as target compound3-TP-1-NH2，ESI-MS：[M-2H]2-895.96 and [ M-3H]3-597.26 (fig. 1).
Example 2
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in lung cancer a549 tumor bearing mice.
Taking the prepared fluorescent compound MPA-PEG3-TP-1-NH2And prepared into a normal saline solution (100nmol/mL), 0.1mL (about 10nmol) is respectively injected into tail veins of 3 nude mice (body weight is about 22 g) with lung cancer A549 tumor, and optical signal acquisition is carried out for 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. And observing the distribution of the fluorescent drug in the model mouse and the enrichment condition in the tumor area. The results are shown in A in FIG. 2, and indicate that the fluorescent probe MPA-PEG3-TP-1-NH2Can specifically target the lung cancer (A549) part.
Example 3
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in pancreatic cancer AsPC-1 bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting the three-dimensional cells into 3 pancreatic cancer AsPC-1 tumor-bearing nude mice, and carrying out fluorescence signal acquisition at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in B in FIG. 2, in which the visible fluorescent probe MPA-PEG3-TP-1-NH2Can be specifically targeted to pancreatic cancer (AspC-1) sites.
Example 4
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in pancreatic cancer CFPAC-1 bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting the three drugs into 3 nude mice with pancreatic cancer CFPAC-1 tumor, and collecting fluorescence signals at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 2 as C, visible fluorescent probe MPA-PEG3-TP-1-NH2Can be specifically targeted to pancreatic cancer (CFPAC-1) sites.
Example 5
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in lung cancer H1299 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting the mixture into 3 nude mice with lung cancer H1299 tumor, and collecting fluorescence signals at 1H, 2H, 4H, 6H, 8H, 10H and 12H after administration. The results are shown in D in FIG. 2, and the visible fluorescent probe MPA-PEG3-TP-1-NH2Can be used for specifically targeting lung cancer (H1299) part.
Example 6
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in colorectal cancer HCT 116-bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting the mixture into 3 colorectal cancer HCT116 tumor-bearing nude mice, and collecting fluorescence signals at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. And observing the distribution of the fluorescent drug in the model mouse and the enrichment condition in the tumor area. The results are shown in E in FIG. 2, and the visible fluorescent probe MPA-PEG3-TP-1-NH2Can specifically target colorectal cancer (HCT116) sites.
Example 7
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in hepatoma HepG2 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting the mixture into 3 nude mice with tumor of liver cancer HepG2, and collecting fluorescence signals at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 2 as F, visible fluorescent probe MPA-PEG3-TP-1-NH2Can specifically target liver cancer (HepG2) part.
Example 8
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in colorectal cancer HT29 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting the mixture into 3 colorectal cancer HT29 tumor-bearing nude mice, and collecting fluorescence signals at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 2 as G, visible fluorescent probe MPA-PEG3-TP-1-NH2Can be specifically targeted to colorectal cancer (HT29) site.
Example 9
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in breast cancer MAD-MB-231 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting the three drugs into 3 nude mice with breast cancer MAD-MB-231 tumor, and collecting fluorescence signals 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 2 as H, visible fluorescent probe MPA-PEG3-TP-1-NH2Can specifically target the breast cancer (MAD-MB-231) part.
Example 10
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in gastric carcinoma MGC-803 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting into 3 nude mice with gastric cancer MGC-803 tumor, and collecting fluorescence signals 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 2 as I, visible fluorescent probe MPA-PEG3-TP-1-NH2Can be specifically targeted to the part of gastric cancer (MGC-803).
Example 11
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in gastric cancer SGC-7901 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting the mixture into 3 gastric cancer SGC-7901 tumor-bearing nude mice, and collecting fluorescence signals 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in J in FIG. 2, and the visible fluorescent probe MPA-PEG3-TP-1-NH2Can be specifically targeted to the stomach cancer (SGC-7901) part.
Example 12
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in breast cancer MCF-7 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting the mixture into 3 breast cancer MCF-7 tumor-bearing nude mice, and collecting fluorescence signals 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 2 as K, visible fluorescence probe MPA-PEG3-TP-1-NH2Can specifically target the breast cancer (MCF-7) part.
Example 13
Monomeric fluorescent compound MPA-PEG prepared in example 13-TP-1-NH2Fluorescence imaging in pancreatic cancer MiaPaPc-2 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23-TP-1-NH2Respectively injecting the three drugs into 3 nude mice with pancreatic cancer MiaPaPc-2 tumor, and collecting fluorescence signals at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in L in FIG. 2, in which the visible fluorescent probe MPA-PEG3-TP-1-NH2Can be specifically targeted to the pancreatic cancer (MiaPaPc-2) site.
Example 14
Prepared monomer fluorescent compound MPA-PEG4-TP-2 (preparation method same as example 1, TP-1-NH)2Replacement with TP-2) in vivo fluorescence imaging of Lung cancer A549 tumor-bearing mice
MPA-PEG was added in the same manner as in example 24And (3) injecting TP-2 into 3 nude mice with lung cancer A549 tumor respectively, and collecting fluorescence signals at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in A in FIG. 3, and the visible fluorescent probe MPA-PEG4TP-2 can specifically target the lung cancer (A549) site.
Example 15
Prepared sheetFluorescent compound MPA-PEG4-TP-3 (preparation method same as example 1, TP-1-NH)2Replacement to TP-3) in vivo fluorescence imaging of gastric cancer SGC-803 tumor-bearing mice
MPA-PEG was added in the same manner as in example 24TP-3 was injected into 3 stomach cancer SGC-803 tumor-bearing nude mice, and fluorescence signal acquisition was performed at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in B in FIG. 3, in which the visible fluorescent probe MPA-PEG4TP-3 can be specifically targeted to the gastric cancer (SGC-803) site.
Example 16
Prepared monomer fluorescent compound MPA-PEG4-TP-4 (preparation method same as example 1, TP-1-NH)2Replacement with TP-4) in vivo fluorescence imaging of breast cancer MDA-MB-468 tumor-bearing mice
MPA-PEG was added in the same manner as in example 24TP-4 is respectively injected into 3 nude mice with breast cancer MDA-MB-468 tumor, and fluorescence signal collection is carried out for 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 3, C, visible fluorescent probe MPA-PEG4TP-4 specifically targets the breast cancer (MDA-MB-468) site.
Example 17
Prepared monomer fluorescent compound MPA-PEG4-TP-5 (preparation method same as example 1, TP-1-NH)2Replacement with TP-5) in vivo fluorescence imaging of breast cancer MCF-7 tumor-bearing mice
MPA-PEG was added in the same manner as in example 24And (3) injecting TP-5 into 3 breast cancer MCF-7 tumor-bearing nude mice respectively, and performing fluorescence signal acquisition at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in D in FIG. 3, and the visible fluorescent probe MPA-PEG4TP-5 is capable of specifically targeting the breast cancer (MCF-7) site.
Example 18
Prepared monomer fluorescent compound MPA-PEG4-TP-6 (preparation method same as example 1, TP-1-NH)2Replacement with TP-6) in vivo fluorescence imaging of pancreatic cancer AsPC-1 tumor-bearing mice
MPA-PEG was added in the same manner as in example 24-TP-6 was injected into 3 nude mice bearing tumor of pancreatic cancer AsPC-1, respectively, and after administrationFluorescence signal acquisition was performed for 1h, 2h, 4h, 6h, 8h, 10h and 12 h. The results are shown in E in FIG. 3, and the visible fluorescent probe MPA-PEG4TP-6 can specifically target pancreatic cancer (AsPC-1) sites.
Example 19
Prepared monomer fluorescent compound MPA-PEG4-TP-8 (preparation method same as example 1, TP-1-NH)2Replacement with TP-8) in vivo fluorescence imaging of Lung cancer H1299 tumor-bearing mice
MPA-PEG was added in the same manner as in example 24TP-8 was injected into 3 nude mice bearing lung cancer H1299 tumor respectively, and fluorescence signal acquisition was performed at 1H, 2H, 4H, 6H, 8H, 10H and 12H after administration. The results are shown in FIG. 3, F, visible fluorescent probe MPA-PEG4TP-8 can specifically target the lung cancer (H1299) site.
Example 20
Prepared monomer fluorescent compound MPA-PEG4-TP-9 (preparation method same as example 1, TP-1-NH)2Replacement with TP-9) in vivo fluorescence imaging of Colon cancer HCT116 tumor-bearing mice
MPA-PEG was added in the same manner as in example 24TP-8 was injected into 3 nude mice bearing colon cancer HCT116 tumor, and fluorescence signal acquisition was performed at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 3, G, visible fluorescence probe MPA-PEG4TP-9 specifically targets the colon cancer (HCT116) site.
Example 21
Prepared monomer fluorescent compound MPA-PEG3-TP-7 (preparation method same as example 1, TP-1-NH)2Replacement with TP-7) in vivo fluorescence imaging of pancreatic cancer AsPC-1 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23TP-7 was injected into 3 pancreatic cancer AsPC-1 tumor-bearing nude mice, and fluorescence signal acquisition was performed at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in A in FIG. 4, and the visible fluorescent probe MPA-PEG3TP-7 is capable of specifically targeting pancreatic cancer (AsPC-1) sites.
Example 22
Monomeric fluorescent compound MPA-PEG prepared in example 213-TP-7 is straight at knotFluorescence imaging in vivo in mice bearing HCT116 tumor of intestinal cancer
MPA-PEG was added in the same manner as in example 23TP-7 was injected into 3 colorectal cancer HCT116 tumor-bearing nude mice, and fluorescence signal acquisition was performed at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in B in FIG. 4, in which the visible fluorescent probe MPA-PEG3TP-7 specifically targets the site of colorectal cancer (HCT 116).
Example 23
Monomeric fluorescent compound MPA-PEG prepared in example 213Fluorescence imaging of TP-7 in Breast cancer MAD-MB-231 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23And (3) injecting TP-7 into 3 breast cancer MAD-MB-231 tumor-bearing nude mice respectively, and collecting fluorescence signals 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 4 as C, visible fluorescent probe MPA-PEG3TP-7 specifically targets the breast cancer (MAD-MB-231) site.
Example 24
Monomeric fluorescent compound MPA-PEG prepared in example 213Fluorescence imaging of TP-7 in mice bearing MiaPaPc-2 tumor of pancreatic cancer
MPA-PEG was added in the same manner as in example 23TP-7 was injected into 3 nude mice bearing tumor of MiaPaPc-2 pancreatic cancer respectively, and fluorescence signal acquisition was performed at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in D in FIG. 4, and the visible fluorescent probe MPA-PEG3TP-7 can specifically target pancreatic cancer (MiaPaPc-2) site.
Example 25
Monomeric fluorescent compound MPA-PEG prepared in example 213Fluorescence imaging of TP-7 in gastric carcinoma SGC-7901 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23TP-7 was injected into 3 stomach cancer SGC-7901 tumor-bearing nude mice respectively, and fluorescence signal acquisition was performed at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in E in FIG. 4, and the visible fluorescent probe MPA-PEG3TP-7 is capable of specifically targeting gastric cancer (SGC-7901) site.
Example 26
Prepared monomeric fluorescent compoundMPA-PEG3-TP-10 (preparation method same as example 1, TP-1-NH)2Replacement with TP-10) in vivo fluorescence imaging of pancreatic cancer AsPC-1 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23TP-10 was injected into 3 pancreatic cancer AsPC-1 tumor-bearing nude mice, and fluorescence signal acquisition was performed at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in A in FIG. 5, and the visible fluorescent probe MPA-PEG3TP-10 is able to specifically target pancreatic cancer (AsPC-1) sites.
Example 27
Prepared monomer fluorescent compound MPA-PEG3Fluorescence imaging of TP-10 in colorectal cancer HCT 116-bearing mice
MPA-PEG was added in the same manner as in example 23TP-10 was injected into 3 colorectal cancer HCT116 tumor-bearing nude mice, and fluorescence signal acquisition was performed at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in B in FIG. 5, in which the visible fluorescent probe MPA-PEG3TP-10 is able to specifically target the site of colorectal cancer (HCT 116).
Example 28
Prepared monomer fluorescent compound MPA-PEG3Fluorescence imaging of TP-10 in Breast cancer MAD-MB-231 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23TP-10 was injected into 3 breast cancer MAD-MB-231 tumor-bearing nude mice respectively, and fluorescence signal acquisition was carried out 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 5, C, visible fluorescent probe MPA-PEG3TP-10 is able to specifically target the breast cancer (MAD-MB-231) site.
Example 29
Prepared monomer fluorescent compound MPA-PEG3Fluorescence imaging of TP-10 in mice bearing MiaPaPc-2 tumor of pancreatic cancer
MPA-PEG was added in the same manner as in example 23TP-10 was injected into 3 nude mice bearing tumor of MiaPaPc-2 pancreatic cancer respectively, and fluorescence signal acquisition was performed at 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in FIG. 5, D, visible fluorescence probe MPA-PEG3TP-10 can specifically target the pancreatic cancer (MiaPaPc-2) site.
Example 30
Prepared monomer fluorescent compound MPA-PEG3Fluorescence imaging of TP-10 in gastric carcinoma SGC-7901 tumor-bearing mice
MPA-PEG was added in the same manner as in example 23TP-10 was injected into 3 stomach cancer SGC-7901 tumor-bearing nude mice, and fluorescence signal acquisition was performed 1h, 2h, 4h, 6h, 8h, 10h and 12h after administration. The results are shown in E in FIG. 5, in which the visible fluorescent probe MPA-PEG3TP-10 is able to specifically target gastric cancer (SGC-7901) site.
Example 31
Monomeric radioactive compounds99mTc-HYNIC-PEG4-TP-1-NH2SPECT-CT imaging in pancreatic cancer AspC-1 bearing mice
1) Bifunctional chelating agent HYNIC-PEG4Synthesis of-NHS
Adding 1g of 6-chloronicotinic acid and 2.0mL of 80% hydrazine hydrate into 10mL of ethanol, heating, refluxing and reacting for 4 hours, decompressing and rotary evaporating a solvent after the reaction is finished, adding the obtained sticky substance into distilled water, adjusting the pH value to be about 5.5, separating out a solid, carrying out suction filtration and drying to obtain 0.86g of a yellow solid, and determining the product to be 6-hydrazinonicotinic acid through ESI-MS mass spectrometry and nuclear magnetic hydrogen spectrometry. Adding 0.86g of the obtained 6-hydrazinonicotinic acid and 0.61g of p-aminobenzaldehyde into 3.0mL of dimethyl sulfoxide (DMSO), heating for reacting for 5-6 hours, adding into water after the reaction is finished, separating out, performing suction filtration, and drying to obtain 1.2g of solid. Adding the dried 1.2g of solid, 2.5g of EDCI and 1.5g of NHS into DMSO for reaction at room temperature, adding water to separate out the solid after the reaction is finished, purifying the solid by a silica gel column, drying, weighing 1.3g, and determining the solid as HYNIC-NHS and ESI-MS by ESI-MS mass spectrum and nuclear magnetic hydrogen spectrum: [ M + H ]]382.1508. This product was purified and added to PEG containing DIPEA4Reacting at room temperature for 2 hours, adding EDCI and NHS with 2 times of molar weight into the solution after the reaction is finished, separating and purifying the solution by preparing a liquid phase after the reaction is finished, and verifying the solution by mass spectrum to obtain a target product HYNIC-PEG4-NHS，ESI-MS：[M+H]630.3 and [ M + Na]+＝652.3。
2) Purified 5mg intermediate HYNIC-PEG4-NHS in 0.3mL DMSO, 3mg TP-1 and 5.6mg DIPEA were added to the mixture,the reaction was carried out at room temperature for 2 hours. After the reaction is finished, the product is separated and purified by preparing a liquid phase, and finally 2.8mg of yellow solid is obtained and confirmed to be a target product HYNIC-PEG by mass spectrum4-TP-1-NH2，ESI-MS：[M+2H]2+596.81 and [ M +3H ═]3+＝398.18。
3) Radioactive compound99mTc-HYNIC-PEG4-TP-1-NH2Synthesis of (2)
TPPTS (Triphenyl sodium Tri-metaphosphate) solution with the concentration of 100.0mg/mL, Tricine (trimethylglycine) with the concentration of 130.0mg/mL, succinic acid-sodium succinate buffer solution with the concentration of 102.4mg/mL (wherein the succinic acid is 77.0mg, and the sodium succinate is 25.4mg) are respectively prepared, 10.0uL TPPTS solution, 10.0uL Tricine solution, 10.0uL succinic acid-sodium succinate buffer solution, 10.0uL (1.0mg/mL) and HYNIC-PEG are respectively taken4-TP-1-NH2Mixing in penicillin bottle, adding 10mCi Na99mTcO4Heating in 100 deg.C metal bath for 20 min, cooling to room temperature after reaction to obtain radiopharmaceuticals99mTc-HYNIC-PEG4-TP-1-NH2And the product is analyzed and identified by HPLC.
Radioactive compound999mTc-HYNIC-PEG4-TP-1-NH2And preparing a physiological saline solution (3mCi/mL), respectively injecting 0.1mL (about 300 mu Ci) into tail veins of 3 nude mice with pancreatic cancer AsPC-1 tumor, and performing SPECT-CT signal acquisition at 0.5h, 1h, 2h, 3h and 4h after administration. And observing the distribution of the radionuclide probes in the mice and the enrichment condition of the radionuclide probes in the tumor regions. The result is shown in FIG. 6, A, where the nuclide probe is shown99mTc-HYNIC-PEG4-TP-1-NH2Can be specifically targeted to pancreatic cancer (AspC-1) sites.
Example 32
Monomeric radioactive compounds99mTc-HYNIC-PEG4-TP-1-NH2SPECT-CT imaging in gastric carcinoma SGC-7901 tumor-bearing mice
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-PEG4-TP-1-NH2Prepared into a physiological saline solution (3mCi/mL), 0.1mL (about 300 mu Ci) is respectively injected into 3 gastric cancers SGC-7901Tumor-bearing nude mice, and SPECT-CT signal acquisition is carried out at 0.5h, 1h, 2h and 4h after administration. The result is shown in FIG. 6, B, from which a nuclide probe is seen99mTc-HYNIC-PEG4-TP-1-NH2Can be specifically targeted to the stomach cancer (SGC-7901) part.
Example 33
Monomeric radioactive compounds99mTc-HYNIC-PEG4-TP-1-NH2SPECT-CT imaging in pancreatic cancer MiaPaPc-2 tumor-bearing mice
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-PEG4-TP-1-NH2Prepared into a physiological saline solution (3mCi/mL), 0.1mL (about 300 mu Ci) is respectively injected into 3 nude mice with the tumor of the pancreatic cancer MiaPaPc-2, and SPECT-CT signal acquisition is carried out at 0.5h, 1h, 2h and 4h after the administration. The result is shown in FIG. 6, C, where the nuclide probe is visible99mTc-HYNIC-PEG4-TP-1-NH2Can be specifically targeted to the pancreatic cancer (MiaPaPc-2) site.
Example 34
Monomeric radioactive compounds99mTc-HYNIC-PEG4-TP-1-NH2SPECT-CT imaging in vivo in breast cancer MCF-7 tumor-bearing mice
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-PEG4-TP-1-NH2Prepared into physiological saline solution (3mCi/mL), 0.1mL (about 300 mu Ci) is respectively injected into 3 nude mice with breast cancer MCF-7 tumor, and SPECT-CT signal acquisition is carried out at 0.5h, 1h, 2h and 4h after administration. The result is shown in FIG. 6, D, where the nuclide probe is shown99mTc-HYNIC-PEG4-TP-1-NH2Can specifically target the breast cancer (MCF-7) part.
Example 35
Monomeric radioactive compounds99mTc-HYNIC-PEG4-TP-1-NH2SPECT-CT imaging in colorectal cancer HT29 tumor-bearing mice
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-PEG4-TP-1-NH2Prepared into physiological saline solution (3mCi/mL), 0.1mL (about 300 mu Ci) is respectively injected into 3 colorectal cancer HT29 tumor-bearing nude mice and then injected into the miceSPECT-CT signal acquisition is carried out at 0.5h, 1h, 2h and 4h after administration. The result is shown in FIG. 6, E, where the nuclide probe is shown99mTc-HYNIC-PEG4-TP-1-NH2Can be specifically targeted to colorectal cancer (HT29) site.
Example 36
Monomeric radioactive compounds99mTc-HYNIC-PEG4-TP-7 (preparation method same as example 31, TP-1-NH)2Replacement with TP-7) SPECT-CT imaging in breast cancer MCF-7 tumor-bearing mice
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-PEG4TP-7 is prepared into a physiological saline solution (3mCi/mL), 0.1mL (about 300 mu Ci) is respectively injected into 3 breast cancer MCF-7 tumor-bearing nude mice, and SPECT-CT signal acquisition is carried out at 0.5h, 1h, 2h and 4h after administration. The results are shown in FIG. 7, A, where the nuclide probe is shown99mTc-HYNIC-PEG4TP-7 is capable of specifically targeting the breast cancer (MCF-7) site.
Example 37
Prepared monomeric radioactive compounds99mTc-HYNIC-PEG4SPECT-CT imaging of TP-7 in mice bearing AspC-1 tumor of pancreatic cancer
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-PEG4TP-7 was prepared as a physiological saline solution (3mCi/mL), 0.1mL (about 300. mu. Ci) was injected into 3 pancreatic cancer AsPC-1 tumor-bearing nude mice, respectively, and SPECT-CT signal acquisition was performed at 0.5h, 1h, 2h and 4h after administration. The result is shown in FIG. 7, B, from which a nuclide probe is seen99mTc-HYNIC-PEG4TP-7 is capable of specifically targeting pancreatic cancer (AsPC-1) sites.
Example 38
Prepared monomeric radioactive compounds99mTc-HYNIC-PEG4SPECT-CT imaging of TP-7 in mice bearing MiaPaPc-2 tumors of pancreatic cancer
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-PEG4TP-7 was prepared as a physiological saline solution (3mCi/mL), 0.1mL (about 300. mu. Ci) was injected into 3 nude mice bearing MiaPaPc-2 pancreatic cancer, respectively, and SPECT-CT signals were performed at 0.5h, 1h, 2h and 4h after administrationAnd (5) collecting. The result is shown in FIG. 7, C, from which a nuclide probe is seen99mTc-HYNIC-PEG4TP-7 can specifically target pancreatic cancer (MiaPaPc-2) site.
Example 39
Monomeric radioactive compounds99mTc-HYNIC-PEG4SPECT-CT imaging of TP-7 in colorectal cancer HT29 tumor-bearing mice
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-PEG4TP-7 was prepared as a physiological saline solution (3mCi/mL), 0.1mL (about 300. mu. Ci) was injected into 3 colorectal cancer HT29 tumor-bearing nude mice, respectively, and SPECT-CT signal acquisition was performed at 0.5h, 1h, 2h and 4h after administration. The result is shown in FIG. 7, D, where the nuclide probe is visible99mTc-HYNIC-PEG4TP-7 specifically targets the site of colorectal cancer (HT 29).
Example 40
Prepared monomeric radioactive compounds99mTc-HYNIC-PEG4SPECT-CT imaging of TP-7 in MGC-803 Gaster mouse of gastric carcinoma
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-PEG4TP-7 was prepared as a physiological saline solution (3mCi/mL), 0.1mL (about 300. mu. Ci) was injected into 3 stomach cancer MGC-803 tumor-bearing nude mice, and SPECT-CT signal acquisition was performed at 0.5h, 1h, 2h and 4h after administration. The result is shown in FIG. 7, E, where the nuclide probe is shown99mTc-HYNIC-PEG4TP-7 specifically targets the site of gastric cancer (MGC-803).
EXAMPLE 41
Prepared monomeric radioactive compounds99mTc-HYNIC-PEG4SPECT-CT imaging of TP-7 in gastric carcinoma SGC-7901 tumor-bearing mice
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-PEG4TP-7 was prepared as a physiological saline solution (3mCi/mL), 0.1mL (about 300. mu. Ci) was injected into 3 stomach cancer MGC-803 tumor-bearing nude mice, and SPECT-CT signal acquisition was performed at 0.5h, 1h, 2h and 4h after administration. The result is shown in FIG. 7, F, where the nuclide probe is visible99mTc-HYNIC-PEG4TP-7 can be specifically targeted to the gastric cancer (SGC-7901) site.
Example 42
Dimer99mTc-HYNIC-2Aca-E-(TP-1-NH2)2By radiosynthesis of
1) Synthesis of bifunctional chelating agent HYNIC-NHS
Adding 1g of 6-chloronicotinic acid and 2.0mL of 80% hydrazine hydrate into 10mL of ethanol, heating, refluxing and reacting for 4 hours, decompressing and rotary evaporating a solvent after the reaction is finished, adding the obtained sticky substance into distilled water, adjusting the pH value to be about 5.5, separating out a solid, carrying out suction filtration and drying to obtain 0.86g of a yellow solid, and determining the product to be 6-hydrazinonicotinic acid through ESI-MS mass spectrometry and nuclear magnetic hydrogen spectrometry. Adding 0.86g of the obtained 6-hydrazinonicotinic acid and 0.61g of p-aminobenzaldehyde into 3.0mL of dimethyl sulfoxide (DMSO), heating for reacting for 5-6 hours, adding into water after the reaction is finished, separating out, performing suction filtration, and drying to obtain 1.2g of solid. Adding the dried 1.2g of solid, 2.5g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1.5g N Hydroxysuccinimide (NHS) into DMSO for reaction at room temperature, adding water after the reaction is finished to separate out a solid, purifying the solid by a silica gel column, drying, weighing 1.3g, and determining a target product HYNIC-NHS through ESI-MS mass spectrum and nuclear magnetic hydrogen spectrum, ESI-MS: and M + H382.15.
2) Support (Aca)2Synthesis of (E)
Adding 5.0g of tert-butyloxycarbonyl (t-Butyloxy carbony) protected glutamic acid (E), 8.3g of Dicyclohexylcarbodiimide (DCC) and 4.6g of NHS into 100mL of Tetrahydrofuran (THF) as an organic solvent, stirring overnight at room temperature for activating the dicarboxyl group, after the reaction is completed, suction-filtering, washing the filtrate with THF, directly adding the filtrate into 50mL of DMSO without further purification after the washing is completed, dissolving, then adding 10g of aminocaproic acid (Aca), finally adding 14.6g of DIPEA, reacting at room temperature for 2 hours, after the detection reaction is completed, adding 3.0mL of trifluoroacetic acid (TEA) into the reaction to remove the Boc protecting group, after the reaction is completed, separating and purifying by a preparative liquid phase, and finally drying to obtain 7.8g of a thick solid, which is verified to be an expected target (Aca) by mass spectrometry2-E。
3) Intermediate HYNIC-E- (Aca)2Synthesis of-2 NHS
Will prepare 05g stand (Aca)2-E is dissolved in DMSO, then 0.28g HYNIC-NHS is added, then 0.32g DIPEA is added, the reaction is carried out for 2 hours at room temperature, then EDCI and NHS are added for activation, after the reaction is finished, the solution is separated and purified by a preparation liquid phase and is frozen and dried, 0.34g of yellow solid is obtained, and the expected target compound HYNIC-E- (Aca) is verified by mass spectrometry2-2NHS。
4)HYNIC-2Aca-E-(TP-1-NH2)2Synthesis of (2)
Purified 5mg intermediate HYNIC-E- (Aca)2-2NHS is dissolved in 0.3mL DMSO, 5mg TP-1 is added after the reaction is finished, then 5.6mg DIPEA is added for reaction at room temperature for 2 hours, separation and purification are carried out through a preparation liquid phase after the reaction is finished, and finally 3.5mg yellow solid is obtained and is confirmed to be a target product through mass spectrometry.
5)99mTc-HYNIC-2Aca-E-(TP-1-NH2)2Preparation of
TPPTS (Triphenyl sodium Tri-metaphosphate) solution with the concentration of 100.0mg/mL, Tricine (trimethylglycine) with the concentration of 130.0mg/mL, succinic acid-sodium succinate buffer solution with the concentration of 102.4mg/mL (wherein the succinic acid is 77.0mg, and the sodium succinate is 25.4mg) are respectively prepared, 10.0uL TPPTS solution, 10.0uL Tricine solution, 10.0uL succinic acid-sodium succinate buffer solution and 10.0uL (1.0mg/mL) and HYNIC-2Aca-E- (TP-1-NH) are respectively taken2)2Mixing in penicillin bottle, adding 10mCi Na99mTcO4Heating in 100 deg.C metal bath for 20 min, cooling to room temperature after reaction to obtain radiopharmaceuticals99mTc-HYNIC-2Aca-E-(TP-1-NH2)2And the product is analyzed and identified by HPLC.
Example 43
Dimer radioactive compound prepared in example 4299mTc-HYNIC-2Aca-E-(TP-1-NH2)2SPECT-CT imaging in pancreatic cancer AspC-1 bearing mice
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-2Aca-E-(TP-1-NH2)2Prepared into a physiological saline solution (3mCi/mL), 0.1mL (about 300 mu Ci) is respectively injected into 3 nude mice bearing the tumor of the pancreatic cancer AsPC-1 and is injected at 0.5h, 1h, 2h and 4h after the administrationAnd acquiring SPECT-CT signals. The results are shown in FIG. 8, A, where the nuclide probe is shown99mTc-HYNIC-2Aca-E-(TP-1-NH2)2Can be specifically targeted to pancreatic cancer (AspC-1) sites.
Example 44
Prepared dimer radioactive compound99mTc-HYNIC-2Aca-E-(TP-1-NH2)2SPECT-CT imaging in colorectal cancer HT29 tumor-bearing mice
The radioactive compound was prepared in the same manner as in example 3199mTc-HYNIC-2Aca-E-(TP-1-NH2)2Prepared into physiological saline solution (3mCi/mL), 0.1mL (about 300 mu Ci) is respectively injected into 3 nude mice bearing colorectal cancer HT29, and SPECT-CT signal acquisition is carried out at 0.5h, 1h, 2h and 4h after administration. The result is shown in FIG. 8, B, from which a nuclide probe is seen99mTc-HYNIC-2Aca-E-(TP-1-NH2)2Can be specifically targeted to colorectal cancer (HT29) site.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. The application of thymopentin and derivatives thereof in preparing tumor diagnosis and/or treatment reagents is disclosed, wherein the thymopentin is selected from one or more of the following polypeptides:
TP-1：L-Arg-L-Lys-L-Asp-L-Val-L-Tyr(Thymopentin)；
TP-2：L-homo-Arg-L-Lys-L-Asp-L-Nva-L-Tyr；
TP-3：D-Arg-L-Lys-L-Asp-L-Val-L-Tyr；
TP-4：D-Arg-D-Lys-L-Asp-L-Val-L-Tyr；
TP-5：D-Arg-L-Lys-L-Asp-L-Val-D-Tyr；
TP-6：D-Arg-L-Lys-L-Asp-L-Nva-D-Tyr；
TP-7: L-Cys-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Cys, wherein the Cys-Cys disulfide bond forms a ring;
TP-8: beta-Ala-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Asp, wherein the amino group at the N-terminus and the side chain carboxyl group at the Asp at the C-terminus form an amide ring;
TP-9: D-Lys-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Glu, wherein the N-terminal main chain amino group and the side chain carboxyl of the C-terminal Glu form an amide ring;
TP-10: D-Lys-L-Gly-L-Arg-L-Lys-L-Asp-L-Val-L-Tyr-L-Asp, wherein the N-terminal main chain amino group and the C-terminal main chain carboxyl group of Asp form an amide ring;
wherein: d represents an unnatural D-type amino acid, and L represents an L-type natural amino acid; homoArg is homoarginine; nva is norvaline.
2. The use of claim 1, wherein the tumor comprises one or more of lung cancer, pancreatic cancer, colorectal cancer, liver cancer, stomach cancer, and breast cancer.
3. The use according to claim 1, wherein the agent is obtained by coupling thymopentin and derivatives thereof to an imaging group.
4. The use of claim 3, wherein the agent comprises a fluorescent imaging agent and/or a radioactive agent, and wherein the fluorescent imaging agent comprises an optical imaging agent for precise localization of tumor boundaries and/or intra-operative image navigation.
5. Use according to claim 3, wherein the reagent has the general formula: M-L-G;
m represents a light label, a complex of a metal chelator and a metal radionuclide, a non-metal radionuclide18F and11any one of C;
l is a linking group;
g is thymopentin and derivatives thereof;
the optical label comprises one or more of an organic chromophore, an organic fluorophore, a light absorbing compound, a light reflecting compound, a light scattering compound, and a bioluminescent molecule;
the metal chelating agent is selected from hydrazine nicotinamide, 1,4, 7-triazacyclononane-1, 4, 7-triacetic acid, 7- [ (4-hydroxypropyl) methylene ] -1,4, 7-triazatenonane-1, 4-diacetic acid, 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid, mercaptoacetyltriglycine, diethyltriaminepentaacetic acid or a combination modification thereof.
6. The use of claim 5, wherein the optical marker comprises a near-infrared one-zone fluorescent dye and/or a near-infrared two-zone fluorescent dye, the near-infrared one-zone fluorescent dye comprising one or more of MPA, IRDye800, Cy7.5, ICG, and Cy5.5.
7. Use according to claim 5, wherein the linking group comprises 6-aminocaproic acid, NH2-PEG3-COOH、NH2-PEG4-COOH、NH2-PEG6-COOH and NH2-GGGGGG-COOH.
8. The use of any one of claims 5 to 7, wherein the agent comprises one or more thymopentin and/or derivative.
9. The use according to any one of claims 5 to 7, wherein the agent comprises99mTc-HYNIC-PEG4-TP-1-NH2And/or99mTc-HYNIC-PEG4-TP-7。
10. The use according to any one of claims 5 to 7, wherein the agent is99mTc-HYNIC-2Aca-E-(TP-1-NH2)2。
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