CN109091683A - A kind of ring type polypeptide radiopharmaceutical and preparation method thereof for αvβ6 Integrin targeting - Google Patents

A kind of ring type polypeptide radiopharmaceutical and preparation method thereof for αvβ6 Integrin targeting Download PDF

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CN109091683A
CN109091683A CN201810908853.3A CN201810908853A CN109091683A CN 109091683 A CN109091683 A CN 109091683A CN 201810908853 A CN201810908853 A CN 201810908853A CN 109091683 A CN109091683 A CN 109091683A
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polypeptide
cycratide
chelating agent
radiopharmaceutical
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CN109091683B (en
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刘昭飞
王凡
冯薰
杨志
李囡
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Peking University
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Abstract

The invention discloses a kind of ring type polypeptide radiopharmaceutical and preparation method thereof for αvβ6 Integrin targeting.The radiopharmaceutical is radionuclide-bifunctional chelating agent-cycratide polypeptide, and radionuclide marks cycratide polypeptide by bifunctional chelating agent, and cycratide polypeptide is the cyclic structure of 8 amino acid composition.The radiopharmaceutical passes through cycratide polypeptide in vivo and realizes specific nuclear medicine positron emission tomography (PET) localization diagnosis to αvβ6 Integrin positive tumor or αvβ6 Integrin positive lesion (such as wound healing, liver pulmonary fibrosis) to the specific recognition of αvβ6 Integrin.

Description

A kind of ring type polypeptide radiopharmaceutical and its preparation for αvβ6 Integrin targeting Method
Technical field
The present invention relates to the radiopharmaceutical technical fields for tumour or other lesion localization diagnosis, in particular to are used for αvβ6 Integrin positive tumor or other lesions (such as wound healing, liver pulmonary fibrosis) targeting nuclear medicine positron emission calculate The cyclized polypeptide radiopharmaceutical and preparation method thereof of machine tomography (PET) localization diagnosis.
Background technique
Integrin (integrin) is a kind of cell adhesion receptor family, is connected by α, β Liang Ge subunit by non-covalent bond The heterodimer transmembrane glycoprotein to be formed is connect, is the most important molecule of mediated cell and extracellular matrix interaction.Exist so far Mammal has found 18 kinds of α subunits and 8 kinds of β subunits, they, which are combined with each other, can form 24 kinds of different integrins of function point Son.As the member of integrin family, αvβ6 Integrin is found in a variety of different types of tumour (such as breast cancer, lung cancer, stomaches Cancer, colorectal cancer, cancer of pancreas, head and neck cancer etc.) in high expression, and do not expressed or low expression in normal tissue.αvβ6 Integrin It expresses closely related with the poor prognosis of the malignant characteristics such as invasion, progress, angiogenesis, the transfer of tumour and patient.
In addition to tumour, the high expression or expression up-regulation of αvβ6 Integrin also occur in the process of wound healing.In wound During epithelium regeneration, the significant up-regulation of αvβ6 Integrin expression of wound edge.In wound healing process, the integrin of up-regulation α v β 6 is usually along with increased TGF-β therewith.TGF-β adjusts epithelium regeneration in wound healing process, inhibits inflammatory reaction, Promote the deposition of extracellular matrix protein and the formation of cicatricial tissue.
Fibrosis is the abnormal response due to generating after organ damage, and feature is fibroblastic proliferation and is divided into flesh The generation and deposition of fibroblast, excess extracellular matrix, these processes are mediated by TGF-β.Fibrosis is eventually Lead to the failure of major organs.More and more evidences show that the interaction between integrin receptor and TGF-β is the hair of fibrosis The key of disease and development.Integrin α3β1, α v β 5, especially α v β 6 control the activation of TGF-β and signal transmission in fibrosis. αvβ6 Integrin is not expressed in normal epithelial cell, but is induced to express in many fibrotic diseases, such as kidney fibre Dimensionization disease (diabetic, progressivity fibrosis glomerulitis, Alport syndrome), liver fibrosis disease (acute biliary tract fiber Change), pulmonary fibrosis disease (sclerosis and idiopathic pulmonary fibrosis) etc..The Antybody therapy energy of the anti-αvβ6 Integrin of studies have shown that The mouse pulmonary fibrosis of radiation or bleomycin induction is enough prevented, and does not cause inflammatory reaction.
αvβ6 Integrin becomes localization diagnosis in the specificity overexpression of tumour and wound healing and fibrosis lesion Specific target spot.Radionuclide is confirmed in early-stage study99mThe RGDLATLRQLAQEDGVVGVRK polypeptide energy of Tc label Enough specific recognition αvβ6 Integrin (patent No.: ZL201410084065.9).Since RGDLATLRQLAQEDGVVGVRK is line Property polypeptide, unstable in vivo, tumor imaging is ineffective.For this reason, it is necessary to the αvβ6 Integrin targeted molecular of development of new, Improve its internal stability.In addition, knowing due in RGDLATLRQLAQEDGVVGVRK polypeptide with αvβ6 Integrin specificity Other primary amino acid sequence is RGDLATL, it is necessary to further shorten polypeptide length, keep αvβ6 Integrin targeting Meanwhile it reducing and being synthetically prepared cost.
Summary of the invention
The object of the present invention is to provide a kind of cyclic peptide radiopharmaceutical and its system for the imaging of αvβ6 Integrin specificity Preparation Method, the medicine preparation is at low cost, stability is strong in vivo, has good tumor imaging effect.
The purpose of the present invention is what is be achieved through the following technical solutions:
A kind of ring type polypeptide radiopharmaceutical for αvβ6 Integrin targeting is radionuclide-bifunctional chelating agent- Cycratide polypeptide, radionuclide mark cycratide polypeptide, the cycratide polypeptide knot by bifunctional chelating agent Structure such as formula (1):
Further, the cycratide is connected by linear peptides Arg-Gly-Asp-Leu-Ala-Thr-Leu-Lys head and the tail Cyclic peptide made of cyclisation is connect, the carboxyl of Lys and the amino of Arg are cyclized through amido bond condensation reaction and connect.
Further, the cycratide polypeptide is the molecule for realizing αvβ6 Integrin targeting.
Further, the radionuclide is68Ga or64Cu。
Further, the radiopharmaceutical is colourless transparent liquid injection.
Further, the bifunctional chelating agent is one of DOTA, NOTA or derivatives thereof.
The preparation method of the ring type polypeptide radiopharmaceutical for targeted integration element α v β 6, comprising the following steps:
A, the preparation of bifunctional chelating agent-cycratide polypeptide: cycratide polypeptide is dissolved in alkaline buffer, is added Bifunctional chelating agent reacts at room temperature 3~10h, reaction mixture is isolated and purified by chromatography after mixing, collect product peak White powder i.e. bifunctional chelating agent-cycratide polypeptide is lyophilized to obtain in product；
B, radionuclide-bifunctional chelating agent-cycratide polypeptide preparation: by the resulting difunctional chelating of step a In agent-cycratide polypeptide solution weak acidic buffer, addition radionuclide, 80~120 DEG C of 10~20min of heating water bath, Radionuclide-bifunctional chelating agent-cycratide polypeptide is made.
Further, bifunctional chelating agent-cycratide polypeptide is carried out using half preparation HPLC in the step a pure Change.
Drug of the present invention is by αvβ6 Integrin targeting ring type polypeptide cycratide, bifunctional chelating agent and radionuclide It constitutes.Wherein, cycratide polypeptide is one lysine of addition on the basis of αvβ6 Integrin specific polypeptide RGDLATL (K), it is cyclized and is connected through amido bond condensation reaction using the amino of the carboxyl of lysine (K) and arginine (R), form cyclisation RGDLATLK polypeptide, i.e. c (RGDLATLK), are named as cycratide polypeptide.Keeping αvβ6 Integrin binding specificity On the basis of, increase the internal stability of polypeptide by cyclisation, reaches preferably localization diagnosis effect in vivo.Cycratide is more Using them as bifunctional chelating agent by radionuclide after peptide and DOTA, NOTA or derivatives thereof coupling68Ga or64Cu label Onto the cyclic peptide molecule.To pass through the specific recognition of cycratide polypeptide and αvβ6 Integrin in vivo, by radioactive nucleus Element carrier band utilizes nuclear medicine positron emission meter to the diseased region (tumour, wound, fibrosis etc.) of high expression αvβ6 Integrin Calculation machine tomography (PET) technology carries out noninvasive localization diagnosis to lesion.
Beneficial effects of the present invention:
1, αvβ6 Integrin target polypeptide cycratide of the invention is by the RGDLATLK head that totally 8 amino acid forms The polypeptide that tail is cyclized through amido bond reduces the amino acid number of αvβ6 Integrin target polypeptide in this way, reduces synthesis cost, and And increase the internal stability of polypeptide by cyclisation, to reach better internal targeting.
2, using preparation method of the invention, by bifunctional chelating agent by radionuclide68Ga or64Cu is tagged to Cycratide cyclic peptide, by cycratide to the specific recognition of αvβ6 Integrin, by radionuclide carrier band to lesion Position (tumour, wound, fibrosis etc.), noninvasive, highly sensitive, high special, accurate quantitative analysis the nuclear medicine positron emission of utilization calculate Machine tomography (PET) technology carries out noninvasive real time dynamic diagnosis imaging to lesion.
The invention will be further described with reference to the accompanying drawings and embodiments.
Detailed description of the invention
Fig. 1 is the chemical structural formula of cycratide polypeptide.
Fig. 2 is68Ga or64Cu marks the chemical structure schematic diagram of the cycratide cyclic peptide of DOTA coupling.
Fig. 3 is68Ga or64Cu marks the chemical structure schematic diagram of the cycratide cyclic peptide of NOTA coupling.
Fig. 4 is injection68The lotus 4T1 tumour of 0.5,1 and 2h after Ga-DOTA-cycratide (αvβ6 Integrin is positive) The PET of BALB/c mouse images figure.
Specific embodiment:
Material employed in the embodiment of the present invention: αvβ6 Integrin specific polypeptide RGDLATLRQLAQEDGVVGVRK Polypeptide is purchased from credit Biotechnology Co., Ltd of middle Guoqiang；N,N-dimethylformamide(DMF；N,N-dimethylformamide) Purchased from Sigma-Aldrich；1,4,7,10-tetraazadodecane-N,N′,N″,N″′-tetraacetic Acid (DOTA), Isosorbide-5-Nitrae, 7,10-tetraazadodecane-N, N ', N ", N " '-tetraacetic acid-N- Hydroxysuccinimide (DOTA-NHS) and S-2- (4-Isothiocyanatobenzyl)-Isosorbide-5-Nitrae, 7- Triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) is public purchased from U.S. Macrocyclics Department；1-Ethyl-3- [3- (dimethylamino)-propyl] carbodiimide (EDC) and N- Hydroxysulfonosuccinimide (SNHS) is purchased from Sigma-Aldrich；Bleomycin purchased from China I Ding company；Thioacetamide is purchased from Sigma-Aldrich；Radionuclide64Cu originates in tumour hospital of Peking University Nuclear Medicine Dept；Radionuclide68Ga by68Ge-68The elution of Ga generator obtains.
Embodiment 1:
It is radionuclide-bifunctional chelating agent-for the ring type polypeptide radiopharmaceutical of αvβ6 Integrin targeting Cycratide polypeptide, radionuclide mark cycratide polypeptide, the cycratide polypeptide knot by bifunctional chelating agent Structure such as formula (1):
The preparation method of the compound:
The following steps are included:
A, the preparation of bifunctional chelating agent-cycratide polypeptide: cycratide polypeptide is dissolved in alkaline buffer, is added Bifunctional chelating agent reacts at room temperature 3~10h, reaction mixture is isolated and purified by chromatography after mixing, collect product peak White powder i.e. bifunctional chelating agent-cycratide polypeptide is lyophilized to obtain in product；
B, radionuclide-bifunctional chelating agent-cycratide polypeptide preparation: by the resulting difunctional chelating of step a In agent-cycratide polypeptide solution weak acidic buffer, addition radionuclide, 80~120 DEG C of 10~20min of heating water bath, Radionuclide-bifunctional chelating agent-cycratide polypeptide is made.
Wherein cycratide polypeptide is manually prepared, and is not limited to a kind of preparation method, the preparation used in the present embodiment Method are as follows:
First synthesizing linear peptide Arg-Gly-Asp-Leu-Ala-Thr-Leu-Lys, then by the carboxyl of linear peptides tail portion Lys with The amino of stem Arg is cyclized through amido bond condensation reaction and connects, and forms the polypeptide of annular, i.e. cycratide polypeptide.
Composition sequence is from the C-terminal of linear polypeptide to N-terminal.Steps are as follows:
A, it weighs n equivalent resin and is put into reactor, methylene chloride (DCM) is added and is swollen half an hour, is added first in sequence A amino acid 2n equivalent, adds the diisopropylethylamine (DIEA) of 2n equivalent, suitable dimethylformamide (DMF), and nitrogen is bubbled React 60min；Then about 5n equivalents of methanol is added, reacts 0.5~2h, takes out reaction solution, is cleaned with DMF, MEOH；
B, second amino acid of 2n equivalent in sequence, benzotriazole-tetramethylurea of 2n equivalent are added into reactor Hexafluorophosphoric acid ester (HBTU) and DIEA, nitrogen 0.5~2h of blistering reaction wash off liquid, then pyridine and second are used in ninhydrin detection Acid anhydrides sealing end；It finally cleans, suitable liquid removal Fmoc protecting group of raising one's hat is added, cleans, ninhydrin detection；
C, amino acid different in sequence is sequentially added according to the mode of step b and carry out various modifications；
D, resin is poured into flask with being removed after being dried with nitrogen from reactor, then into flask plus a certain amount of (is cut Cut liquid and resin about with the ratio of 10mL/g) cutting liquid (forming is 95%TFA, 2% dithioglycol, 2% triisopropyl silicon Alkane, 1% water), concussion filters resin；
E, filtrate is obtained, ether is then added into filtrate, crude product is precipitated, is then centrifuged for, sequence can be obtained in cleaning Crude product；
F, crude product is purified to HPLC and requires purity, purified liquid is put into freeze dryer and is concentrated, be lyophilized At white powder.
Embodiment 2:
For αvβ6 Integrin targeting ring type polypeptide radiopharmaceutical, in which: bifunctional chelating agent be DOTA-NHS or P-SCN-Bn-NOTA, radionuclide are68Ga or64The preparation method of Cu, cycratide polypeptide such as embodiment 1.
The preparation method of ring type polypeptide radiopharmaceutical for αvβ6 Integrin targeting:
In step a, bifunctional chelating agent is DOTA-NHS or p-SCN-Bn-NOTA, concrete operation step are as follows: take Cycratide polypeptide is dissolved in the NaHCO of the 0.1mol/L of 500 μ L3In buffer (pH=8.5~9.0), then it is added difunctional Chelating agent (is dissolved in DMF).It mixes postposition and reacts at room temperature 5h, then separate by half preparation HPLC of reaction mixture injection pure Change.Product peak is collected, after revolving removes acetonitrile, freeze-dried machine is lyophilized into white powder；
In step b, radionuclide is68Ga or64Cu, concrete operation step are as follows: by bifunctional chelating agent-cycratide Polypeptide is dissolved in the 0.1M NaOAc buffer of 500 μ L (pH=4.5~6.5), and the radiation of 4~10mCi is then added thereto Radionuclide-bifunctional chelating agent-cycratide polypeptide is made in property nucleic, 100 DEG C of 10~20min of heating water bath.
And half preparation HPLC method described in step a is to use polypeptide reversed-phase column (218TP510；5μm,250×10mm) Bifunctional chelating agent-cycratide polypeptide is purified, HPLC liquid phase flow rate is 4mL/min, uses Vydac 218TP54 Chromatographic column (5 μm, 250 × 4.6mm).Flow visualizing is from 95%A phase (0.1% trifluoracetic acid [TFA] is dissolved in pure water) and 5%B Phase (0.1%TFA is dissolved in acetonitrile, [ACN]) (0-2min) fades to 35%A phase and 65%B phase (32min).It is examined with PDA detector Ultraviolet (UV) surveyed at 218nm absorbs and determines product according to UV absorption peak.
Fig. 2 is68Ga-DOTA-cycratide polypeptide or64The chemical structure schematic diagram of Cu-DOTA-cycratide polypeptide.
Fig. 3 is68Ga-NOTA-cycratide polypeptide and64The chemical structure schematic diagram of Cu-NOTA-cycratide polypeptide.
Embodiment 3:
Ring type polypeptide radiopharmaceutical for αvβ6 Integrin targeting, in which: bifunctional chelating agent is DOTA or NOTA Or derivatives thereof, radionuclide is68Ga or64The preparation method of Cu, cycratide polypeptide such as embodiment 1.
The preparation method of ring type polypeptide radiopharmaceutical for αvβ6 Integrin targeting:
In step a, bifunctional chelating agent is DOTA or NOTA or derivatives thereof, concrete operation step are as follows: difunctional chelating After agent is mixed with EDC and SNHS with certain molar ratio, 4 DEG C of 0.5~2h of reaction activation.Cycratide polypeptide is taken to be dissolved in 500 μ L 0.1mol/L NaHCO3In buffer (pH=8.5~9.0), the bifunctional chelating agent after activation is then added.After mixing Room temperature reaction 5h is set, then isolates and purifies half preparation HPLC of reaction mixture injection.Product peak is collected, revolving removes After acetonitrile, freeze-dried machine is lyophilized into white powder；
In step b, radionuclide is68Ga or64Cu, concrete operation step are as follows: by bifunctional chelating agent-cycratide Polypeptide is dissolved in the 0.1M NaOAc buffer of 500 μ L (pH=4.5~6.5), and the radiation of 4~10mCi is then added thereto Radionuclide-bifunctional chelating agent-cycratide polypeptide is made in property nucleic, 100 DEG C of 10~20min of heating water bath.
And half preparation HPLC method described in step a is to use polypeptide reversed-phase column (218TP510；5μm,250×10mm) Bifunctional chelating agent-cycratide polypeptide is purified, HPLC liquid phase flow rate is 4mL/min, uses Vydac 218TP54 Chromatographic column (5 μm, 250 × 4.6mm).Flow visualizing is from 95%A phase (0.1% trifluoracetic acid [TFA] is dissolved in pure water) and 5%B Phase (0.1%TFA is dissolved in acetonitrile, [ACN]) (0-2min) fades to 35%A phase and 65%B phase (32min).It is examined with PDA detector Ultraviolet (UV) surveyed at 218nm absorbs and determines product according to UV absorption peak.
Embodiment 4:
The present embodiment is68The preparation of Ga-DOTA-cycratide polypeptide radiopharmaceutical and its specificity PET imaging are answered With.
68Ga-DOTA-cycratide polypeptide is by cycratide polypeptide, bifunctional chelating agent DOTA and radionuclide68Ga is constituted.Cycratide polypeptide production methods are referring to embodiment 1, and structure is referring to Fig. 1.
68The preparation method of Ga-DOTA-cycratide polypeptide the following steps are included:
A, the preparation of DOTA-cycratide polypeptide
The cycratide polypeptide for taking 2 μm of ol is dissolved in the NaHCO of the 0.1mol/L of 500 μ L3Buffer (pH=8.5 ~9.0) in, the DOTA-NHS (being dissolved in DMF) of 6 μm of ol is then added.It mixes postposition and reacts at room temperature 5h, then by reaction mixture Half preparation HPLC of injection is isolated and purified.Product peak is collected, after revolving removes acetonitrile, freeze-dried machine is lyophilized into white powder End.Obtain the total 1.5mg of product DOTA-cycratide.MALDI-TOF-MS mass spectrometry results are m/z=1241.8 [MH]+ (C53H92N16O18Theoretical value 1241.4).
B, DOTA-cycratide polypeptide68Ga radioactive label
In the 0.1M NaOAc buffer of 500 μ L (pH=5.5), then the DOTA-cycratide polypeptide of 20 μ g is dissolved in It is added 10mCi's thereto68GaCl3Leacheate, 100 DEG C of heating water bath 15min, is made of the invention68Ga-DOTA- Cycratide radiopharmaceutical.
68The internal nuclear medicine positron emission fault (PET) of Ga-DOTA-cycratide polypeptide images:
4T1 lotus mouse breast cancer BALB/c mouse is divided into 2 groups (experimental group and αvβ6 Integrin closed groups), every group 4. Under conditions of anesthesia, every tumor-bearing mice of experimental group is through tail vein injection 1mCi's68Ga-DOTA-cycratide polypeptide.It is right In closed group, every tumor-bearing mice injects the αvβ6 Integrin specific polypeptide of 300 μ g through tail vein simultaneously RGDLATLRQLAQEDGVVGVRK's and 1mCi68Ga-DOTA-cycratide.PET imaging is respectively after injection of radioactive substances 30min, 1h and 2h time point are obtained by small animal position emission tomography (PET) imager (Sedecal company, Spain) scanning collection.
Referring to fig. 4, Fig. 4 is68Ga-DOTA-cycratide radiopharmaceutical is in 4T1 lotus mouse breast cancer BALB/c mouse Specific PET imaging in model (arrow indicates αvβ6 Integrin positive tumor position).Excessive unlabelled integrin alpha v beta 6 specific polypeptides can be closed effectively68The tumor uptake of Ga-DOTA-cycratide, it was demonstrated that its tumour αvβ6 Integrin Imaging specificity.
In the present embodiment, αvβ6 Integrin targets cyclic peptide radiopharmaceutical68Ga-DOTA-cycratide is used for integrin alpha v The specific PET of 6 positive tumor of β is imaged.When other lesions (such as wound healing, liver that mouse model is the αvβ6 Integrin positive Fibrosis, pulmonary fibrosis etc.),68Ga-DOTA-cycratide can be used for its PET imaging.

Claims (8)

1. a kind of ring type polypeptide radiopharmaceutical for αvβ6 Integrin targeting, it is characterised in that: the drug is radioactivity Nucleic-bifunctional chelating agent-cycratide polypeptide, radionuclide mark cycratide polypeptide by bifunctional chelating agent, The cycratide polypeptide structure such as formula (1):
2. the ring type polypeptide radiopharmaceutical according to claim 1 for targeted integration element α v β 6, it is characterised in that: institute Stating cycratide is the cyclic peptide as made of linear peptides Arg-Gly-Asp-Leu-Ala-Thr-Leu-Lys head and the tail connection cyclisation, The carboxyl of Lys and the amino of Arg are cyclized through amido bond condensation reaction and connect.
3. the ring type polypeptide radiopharmaceutical according to claim 1 for targeted integration element α v β 6, it is characterised in that: institute Stating cycratide polypeptide is the molecule for realizing αvβ6 Integrin targeting.
4. the ring type polypeptide radiopharmaceutical according to claim 1 for targeted integration element α v β 6, it is characterised in that: institute Stating radionuclide is68Ga or64Cu。
5. the ring type polypeptide radiopharmaceutical according to claim 1 for targeted integration element α v β 6, it is characterised in that: institute Stating radiopharmaceutical is colourless transparent liquid injection.
6. the ring type polypeptide radiopharmaceutical according to claim 1 for targeted integration element α v β 6, it is characterised in that: institute Stating bifunctional chelating agent is any one in DOTA, NOTA or derivatives thereof.
7. the system described in any one of claim 1~6 for the ring type polypeptide radiopharmaceutical of targeted integration element α v β 6 Preparation Method, it is characterised in that: the following steps are included:
A, the preparation of bifunctional chelating agent-cycratide polypeptide: cycratide polypeptide is dissolved in alkaline buffer, and double function are added Energy chelating agent, reacts at room temperature 3~10h, reaction mixture is isolated and purified by chromatography after mixing, collect product peak and produce White powder i.e. bifunctional chelating agent-cycratide polypeptide is lyophilized to obtain in object；
B, radionuclide-bifunctional chelating agent-cycratide polypeptide preparation: by the resulting bifunctional chelating agent-of step a In cycratide polypeptide solution weak acidic buffer, radionuclide, 80~120 DEG C of 10~20min of heating water bath, system is added At radionuclide-bifunctional chelating agent-cycratide polypeptide.
8. the preparation method of the ring type polypeptide radiopharmaceutical of targeted integration element α v β 6 according to claim 7, feature It is: bifunctional chelating agent-cycratide polypeptide is purified using half preparation HPLC in the step a.
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CN110743017A (en) * 2019-10-22 2020-02-04 北京大学 Radiopharmaceutical targeting galectin-1 and preparation method thereof
CN114028590A (en) * 2021-11-18 2022-02-11 北京大学 Granzyme B targeting complex, radiopharmaceutical, preparation methods and applications thereof
WO2023087871A1 (en) * 2021-11-18 2023-05-25 北京大学 Granzyme b targeting complex, radiopharmaceutical, preparation method therefor, and use thereof
WO2024012157A1 (en) * 2022-07-11 2024-01-18 杭州禾泰健宇生物科技有限公司 Polypeptide compound, and complex and use thereof
CN115282299A (en) * 2022-07-20 2022-11-04 北京大学深圳研究生院 TGF (transforming growth factor) beta tracer, preparation method of antibody probe and application
CN115282299B (en) * 2022-07-20 2024-01-12 北京大学深圳研究生院 TGF beta tracer, antibody probe preparation method and application

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