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CN-121991165-A - Targeting GRPR polypeptide nuclide ligand and preparation method and application thereof

CN121991165ACN 121991165 ACN121991165 ACN 121991165ACN-121991165-A

Abstract

The invention belongs to the technical field of biomedical materials, and particularly relates to a target GRPR polypeptide nuclide ligand, a preparation method and application thereof. The structural formula of the target GRPR polypeptide nuclide ligand is shown as formula (1) or formula (2): wherein L is a metal chelator, X is Any one of R is The target GRPR polypeptide nuclide ligand is prepared by coupling a metal chelating agent and polypeptide, so that the clearance dynamics of non-tumor tissues is obviously improved, the possibility is provided for realizing more accurate diagnosis and treatment of tumors, and the target GRPR polypeptide nuclide probe is obtained by coupling the metal chelating agent and the polypeptide, is suitable for guiding the anticancer drug treatment of GRPR positive tumor patients, and provides real-time curative effect monitoring for the GRPR positive tumor patients.

Inventors

  • SUN LI
  • WU AIGUO
  • LI JUAN

Assignees

  • 中国科学院宁波材料技术与工程研究所
  • 宁波慈溪生物医学工程研究所

Dates

Publication Date
20260508
Application Date
20241107

Claims (10)

  1. 1. The target GRPR polypeptide nuclide ligand is characterized in that the structural formula of the target GRPR polypeptide nuclide ligand is shown as formula (1) or formula (2): wherein L is a metal chelator, X is Any one of R is Any one of them.
  2. 2. The targeted GRPR polypeptide nuclide ligand of claim 1, wherein the metal chelator is one or more of 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetracarboxylic acid, 1,4, 7-triazacyclononane-N, N' -triacetic acid, N-hydroxysuccinimide carbohydrazide, (2S) - (1-tetrahydropyrimidin-2-one) -3-methylbutanoic acid, diethylenetriamine pentaacetic acid, 2- [1,4, 7-triazacyclononan-1-yl-4, 7-bis (t-Bu ester) ] -1, 5-pentanedioic acid, triethylenetetramine, cyclohexanedimethanol, and terephthalic acid copolymer, 1,4,7, 10-tetra (aminocarbonylmethyl) -1,4,7, 10-tetraazacyclododecane.
  3. 3. A method of preparing a targeted GRPR polypeptide nuclide ligand of claim 1, wherein when the structural formula of the targeted GRPR polypeptide nuclide ligand is formula (1), the method of preparing the targeted GRPR polypeptide nuclide ligand comprises the steps of: (1) Adding proline, an activating agent, a condensing agent and a solvent into RINK AMIDE MBHA Resin, reacting for 1-5 hours at room temperature, and grafting proline on RINK AMIDE MBHA Resin; (2) Adding leucine, an activating agent and a solvent, reacting for 1-5 hours at room temperature, grafting leucine, sequentially grafting histidine, sarcosine, valine, alanine, tryptophan, glutamine and phenylalanine according to the steps, deprotecting the obtained Resin, mixing with 2- (4-aminopiperidin-1-yl) acetic acid dihydrochloride or piperazine-1-formic acid for reaction, and finally grafting a metal chelating agent to obtain polypeptide Resin D-Phe-Gln-Trp-Ala-Val-Sar-His-Leu-Pro-RINK AMIDE MBHA Resin; (3) And adding the obtained polypeptide-resin into a mixed solution of trifluoroacetic acid, 1, 2-ethanedithiol, triisopropylsilane and water to react for 1-5 hours at room temperature.
  4. 4. A method of preparing a targeted GRPR polypeptide nuclide ligand of claim 1, wherein when the structural formula of the targeted GRPR polypeptide nuclide ligand is formula (2), the method of preparing the targeted GRPR polypeptide nuclide ligand comprises the steps of: (1) Adding histidine, an activating agent, a condensing agent and a solvent into RINK AMIDE MBHA Resin, reacting for 1-5 hours at room temperature, and grafting histidine on RINK AMIDE MBHA Resin; (2) Adding lysine, an activating agent and a solvent or arginine, the activating agent and the solvent, reacting for 1-5 hours at room temperature, grafting lysine or arginine, and sequentially grafting tryptophan, glutamine and a metal chelating agent according to the steps to obtain polypeptide Resin Gln-Trp-Lys-His-RINK AMIDE MBHA Resin or Gln-Trp-Arg-His-RINK AMIDE MBHA Resin; (3) And adding the obtained polypeptide-resin into a mixed solution of trifluoroacetic acid, 1, 2-ethanedithiol, triisopropylsilane and water to react for 1-5 hours at room temperature.
  5. 5. The method for preparing a target GRPR polypeptide nuclide ligand according to claim 3, wherein in the step (1), mass ratio of RINK AMIDE MBHA Resin, fluorene methoxycarbonyl protected proline, activating agent and condensing agent is 3.0-8.0:2.0-5.0:2.0-5.0:2.2-5.5.
  6. 6. The method of claim 4, wherein the mass ratio of RINK AMIDE MBHA Resin, fluorenylmethoxycarbonyl protected histidine, activator, condensing agent in step (1) is 3.0-8.0:2.0-5.0:2.0-5.0:2.2-5.5.
  7. 7. The method of claim 3 or 4, wherein the activator is one or more of N, N' -diisopropylcarbodiimide, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
  8. 8. The method of claim 3 or 4, wherein the condensing agent is one or both of 1-hydroxybenzotriazole and N-methylmorpholine.
  9. 9. The method of claim 3 or 4, wherein the mixed solution of trifluoroacetic acid, 1, 2-ethanedithiol, triisopropylsilane and water in step (2) comprises 80-90%, 1-5%, 5-10% and 5-10% by volume of trifluoroacetic acid, 1, 2-ethanedithiol, triisopropylsilane and water, respectively.
  10. 10. A targeted GRPR polypeptide nuclide probe comprising the targeted GRPR polypeptide nuclide ligand of claim 1 and a radionuclide.

Description

Targeting GRPR polypeptide nuclide ligand and preparation method and application thereof Technical Field The invention belongs to the technical field of biomedical materials, and particularly relates to a target GRPR polypeptide nuclide ligand, a preparation method and application thereof. Background Cancer has become a major health problem worldwide, with a continual rise in morbidity and mortality, which has attracted widespread attention. Common medical diagnostic techniques are nuclear medicine imaging techniques, particularly Positron Emission Tomography (PET) and single photon emission tomography (SPECT), which show great potential with their unique advantages in early detection and therapy monitoring of cancer. The Gastrin Releasing Peptide Receptor (GRPR) is an autocrine growth factor in many tumors, is used as a key participant in various physiological and pathological processes, is overexpressed in various cancers such as breast cancer, prostatic cancer, lung cancer, colorectal cancer and the like, and provides a new view for diagnosis and treatment of the cancers. GRPR is a G protein coupled receptor, is widely distributed in the central nervous system and peripheral tissues, plays an important role in regulating appetite, energy metabolism, stress response, emotion treatment and the like, and in cancers, the expression level change of GRPR is closely related to the invasiveness of tumors, metastatic potential and prognosis of patients. Among them, the precursor structure of GRPR, gastrin releasing peptide precursor (ProGRP), has been used as a biomarker for Small Cell Lung Cancer (SCLC). The detection of serum ProGRP level is not only helpful for the auxiliary diagnosis of SCLC, but also can be used for the differential diagnosis of SCLC and non-small cell lung cancer (NSCLC), and the curative effect monitoring and recurrence monitoring of SCLC. Although no targeted drug against GRPR is currently approved by the FDA, many studies are focusing on the utilization of GRPR as a target for cancer treatment and the evaluation of stability of GRPR targeted imaging drugs. For example, studies have reported the development of drug conjugates targeting GRPR that selectively deliver drugs to cancer cells overexpressing GRPR in vitro and in vivo. However, the pharmacokinetics, in vivo residence time, targeting, safety, efficacy and applicability of these drugs remain to be improved. Disclosure of Invention The invention aims to solve the technical problems, provides a target GRPR polypeptide nuclide ligand, adopts metal chelating agent to couple with polypeptide, aims to realize imaging diagnosis of GRPR positive tumors, and is particularly suitable for guiding anticancer drug treatment of GRPR positive tumor patients and providing real-time curative effect monitoring for GRPR positive tumor patients by coupling with radionuclides. The structural formula of the target GRPR polypeptide nuclide ligand in the technical scheme is shown as formula (1) or formula (2): wherein L is a metal chelator, X is Any one of R isAny one of them. Further, the metal chelator is one or more of 1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetracarboxylic acid (DOTA), 1,4, 7-triazacyclononane-N, N' -triacetic acid (NOTA), N-hydroxysuccinimide carbohydrazide (HYNIC), (2S) - (1-tetrahydropyrimidin-2-one) -3-methylbutanoic acid (TPA), diethylenetriamine pentaacetic acid (DTPA), 2- [1,4, 7-triazacyclononan-1-yl-4, 7-bis (t-Bu ester) ] -1, 5-pentanedioic acid (NODAGA), triethylenetetramine (TETA), cyclohexanedimethanol and terephthalic acid copolymer (PCTA), 1,4,7, 10-tetrakis (aminocarbolmethyl) -1,4,7, 10-tetraazacyclododecane (DOTAM). When the structural formula of the target GRPR polypeptide nuclide ligand is shown as the formula (1), the preparation method of the target GRPR polypeptide nuclide ligand comprises the following steps: (1) Adding proline, an activating agent, a condensing agent and a solvent into RINK AMIDE MBHA Resin, reacting for 1-5 hours at room temperature, and grafting proline on RINK AMIDE MBHA Resin; (2) Adding leucine, an activating agent and a solvent, reacting for 1-5 hours at room temperature, grafting leucine, sequentially grafting histidine, sarcosine, valine, alanine, tryptophan, glutamine and phenylalanine according to the steps, deprotecting the obtained Resin, mixing with 2- (4-aminopiperidin-1-yl) acetic acid dihydrochloride or piperazine-1-formic acid for reaction, and finally grafting a metal chelating agent to obtain polypeptide Resin D-Phe-Gln-Trp-Ala-Val-Sar-His-Leu-Pro-RINK AMIDE MBHA Resin; (3) And adding the obtained polypeptide-resin into a mixed solution of trifluoroacetic acid, 1, 2-ethanedithiol, triisopropylsilane and water to react for 1-5 hours at room temperature. Further, in the step (1), the mass ratio of RINK AMIDE MBHA Resin, fluorene methoxycarbonyl protected proline, an activating agent and a condensing agent is 3.0-8.0:2.0-5.0:2.0-5.0:2.2-5.5. Further, the molar ratio of the r