CN116444620B - Specific EGFR polypeptide-targeted radiopharmaceuticals, and preparation method and application thereof - Google Patents

Specific EGFR polypeptide-targeted radiopharmaceuticals, and preparation method and application thereof Download PDF

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CN116444620B
CN116444620B CN202211697220.5A CN202211697220A CN116444620B CN 116444620 B CN116444620 B CN 116444620B CN 202211697220 A CN202211697220 A CN 202211697220A CN 116444620 B CN116444620 B CN 116444620B
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CN116444620A (en
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黄顺
吴湖炳
白鹭
石大志
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Southern Hospital Southern Medical University
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
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    • A—HUMAN NECESSITIES
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Abstract

The application discloses a specific targeted EGFR polypeptide radiopharmaceuticals and a preparation method and application thereof; the radiopharmaceuticals are excellent novel pharmacokinetic probes, the structure of the radiopharmaceuticals comprises polypeptides, modification groups, metal chelating groups and radionuclides, and the D-type amino acid is used for replacing the L-type amino acid for the first time to prepare the GE11 variant polypeptide sequence radiopharmaceuticals targeting EGFR proteins, so that the stability of the radiopharmaceuticals is improved; the preparation method is simple, convenient and quick, the yield is high, the radioactive drug has good stability, strong water solubility and quick in vivo blood clearance, is mainly metabolized by kidneys, can specifically target EGFR and is ingested at tumor sites, and the radioactive drug can be widely applied to tumor PET imaging and tumor nuclide treatment.

Description

Specific EGFR polypeptide-targeted radiopharmaceuticals, and preparation method and application thereof
Technical Field
The application belongs to the field of pharmacy, and particularly relates to an EGFR-targeting polypeptide radiopharmaceuticals, and a preparation method and application thereof.
Background
Malignant tumor is one of the main diseases affecting human health, and has the characteristics of high morbidity, difficult treatment, high mortality rate and the like. The traditional cancer treatment methods such as surgery, chemotherapy, radiotherapy and the like cannot effectively treat non-solid tumors, cancers with extensive systemic metastasis and the like, and meanwhile, the traditional cancer treatment methods have the defects of large side effects, poor specificity, low curative effect and difficulty in meeting the clinical treatment requirements. With the continuous and deep research on pathogenesis of malignant tumor, the molecular targeted therapy and immunotherapy aiming at specific oncogene, protein or receptor achieve obvious effect, especially the targeted therapy, and the advantages of strong specificity, obvious curative effect, small side effect and the like are currently the main means of clinical tumor therapy.
The Epidermal Growth Factor Receptor (EGFR) is an expression product of the proto-oncogene c-erbB1, and overexpression and mutation of EGFR are commonly found in most epithelial tumors such as breast cancer, lung cancer, colorectal cancer, head and neck cancer, and the like. Wild-type EGFR is a cellular transmembrane protein consisting of 1210 amino acids, consisting of extracellular, transmembrane and intracellular structures. Is the receptor for the proliferation and signaling of Epidermal Growth Factor (EGF) cells, and belongs to the family of tyrosine kinase receptors. Numerous amino acid sequence deletions, mutations and insertions in the EGFR domain are closely related to tumor metastasis, invasion and prognosis. EGFR is the earliest target for developing tumor-targeted therapies. There are a number of related targeted drugs currently approved for clinical use. Mainly comprises small molecule tyrosine kinase inhibitors (EGFR-TKI such as gefitinib, erlotinib, afatinib, dacatinib, oritinib, amotinib, vomertinib and the like) and monoclonal antibodies (such as cetuximab, panitumumab, cetuximab and the like), which play an important role in clinic treatment of patients with non-small cell lung cancer, colorectal cancer and the like. However, EGFR-TKI related drugs require strict screening for patients with specific mutant genotypes, and most patients have acquired drug resistance with adverse reactions to the skin and digestive tract; monoclonal antibody titers are generally well tolerated in humans, but some of these substances may be recognized as foreign and may elicit immune responses with up to 81.4% of adverse skin reactions against EGFR monoclonal antibodies in 2018, national clinical studies. In contrast, the small molecular polypeptide has the characteristics of small molecular weight, high affinity, high blood clearance speed, low immunogenicity and the like, has obvious advantages, and the polypeptide-based targeting drug is gradually developed and enters clinic, so that the polypeptide drug targeting EGFR has great development potential.
In recent years, the diagnosis and treatment integrated radiopharmaceuticals carrying radioactive diagnosis/treatment nuclides rapidly develop by using specific polypeptides and analogues thereof as targeted tumor ligands, and a new treatment strategy is provided for targeted treatment of tumors (N.Jokar, I.Velikyan, H.Ahmadzadehfar, S.J.Rekabpour, E.Jafari, H.H.Ting, H.J.Biersack, M.Assadi, theranostic Approach in Breast Cancer ATreasured)Tailor for Future Oncology, clinical Nuclear Medicine,46 (2021) E410-E420.). There are a number of such drugs currently available for clinical use, such as PET imaging agents targeting somatostatin receptors (SSTR) 68 Ga-DOTATATE[10]And a neuroendocrine tumor therapeutic drug Lutathera 177 Lu-DOTATATE)[11]Approved by The FDA in 2016 and 2017 (U.Hennrich, K.Kopka, lutother (R): the First FDA-and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy, pharmaceuticals,12 (2019)), respectively; pluvicto of Nohua, 3.2022 @ 177 Lu-PSMA-617) is FDA approved for PSMA-positive prostate cancer treatment, with bulk as well 68 Ga-gozetotide as a diagnostic agent for PET imaging (S.J. Keam, lutetium Lu 177Vipivotide Tetraxetan:First Approval,Molecular Diagnosis)&Therapeutic, 26 (2022) 467-475.). The patient can use the diagnosis and treatment integrated radiopharmaceuticals to achieve the dual purposes of accurate diagnosis and accurate treatment, and can also monitor the treatment effect by utilizing imaging. Therefore, the development of novel EGFR-targeting polypeptide radiopharmaceuticals has important basic research significance and clinical application prospect.
Disclosure of Invention
The application aims to provide a novel polypeptide radiopharmaceuticals targeting EGFR and application thereof.
The technical scheme adopted by the application is as follows:
in a first aspect of the application, there is provided a polypeptide having the sequence ivnqptygywhyk and wherein the amino acid in the polypeptide is a D-type amino acid. Previously reported GE11 polypeptide sequences are L-type amino acids, which are found to be unstable in vivo in the research of the applicant, so in order to improve the in vivo stability, the applicant replaces the L-type amino acids with D-type amino acids, and changes the original GE11 polypeptide sequence (YHWYGYTPQNVI) to improve the stability, the modified design aiming at GE11 is the first time, the effect is consistent with the expected, the modified design exists stably in vivo for 2 hours, no decomposition is found, and the data of examples show that the D-type polypeptide has better stability and better in vivo biodistribution.
In a second aspect of the application, there is provided an EGFR-targeting complex comprising an EGFR-targeting polypeptide of the first aspect of the application.
Preferably, an imaging agent and/or a therapeutic agent is also included in the complex.
Preferably, the imaging agent comprises at least one of FB groups, diagnostic radionuclides, biotin, fluorophores, fluorescent proteins, antibodies, horseradish peroxidase and alkaline phosphatase.
Preferably, the therapeutic agent comprises at least one of a therapeutic radionuclide, a pro-apoptotic peptide, a nanoparticle, a chemotherapeutic agent, a nanodroplet, a liposomal drug, and a cytokine.
Preferably, the diagnostic radionuclide comprises 18 F、 44 Sc、 64 Cu、 67 Ga、 68 Ga、 89 Zr、 99 Tc、 111 In、 177 Lu and 188 at least one of Re.
Preferably, the therapeutic radionuclide comprises 51 Cr、 90 Y、 106 Ru、 149 Pm、 149 Tb、 153 Sm、 166 Ho、 169 Yb、 177 Lu、 186 Re、 188 Re、 203 Pb、 211 At、 212 Bi、 212 Pb、 213 Bi、 223 Ra、 225 Ac、 226 Th and 227 at least one of Th.
Preferably, the radionuclide labels the polypeptide by a chelator.
Preferably, the chelating agent comprises HYNIC, DOTA, DOTAGA, NOTA, NOTAGA, DTPA, NODA, DTPA, TETA, CB-TE2A, cyclam, DFO, MAG3, EC, EDTA, DADT, HYNIC, NS 3 At least one of 3,2-HOPO, macropa and derivatives thereof.
Preferably, the chelating agent is selected from structures represented by formulas (1) - (9):
preferably, the formula (1) is 1,4, 7-triazacyclononalkyl-4, 7-diacetoxy-1-acetyl (-NOTA).
Preferably, the formula (2) is 1- (4-isothiocyanatobenzyl) -1,4, 7-triazacyclononalkyl-4, 7-diacetic acid (p-SCN-Bn-NODA).
Preferably, the formula (3) is 2- (4-isothiocyanatobenzyl) -1,4, 7-triazacyclononane-1, 4, 7-triacetic acid (p-SCN-Bn-NOTA).
Preferably, the formula (4) is 1- (2- (2- (2, 5-dioxo-1-pyrrolidinyl) ethylamino) ethyl) -1,4, 7-tetraazacyclononane-4, 7-diacetic acid (MaI-NODA).
Preferably, the formula (5) is 1- (2, 5-dioxo-1-pyrrolidinyl) acyl ethyl) -1,4, 7-tetraazacyclononane-4, 7-diacetic acid.
Preferably, the formula (6) is 2- ((4, 7-dicarboxymethyl) -1,4,7 triazacyclononalkyl) glutaric acid.
Preferably, the formula (7) is 1,4,7, 10-tetraazacyclododecyl-4, 7, 10-triacetoxy-1-acetyl (-DOTA).
Preferably, the formula (8) is 1- (2- (2- (2, 5-dioxo-1-pyrrolidinyl) ethylamino) ethyl) -1,4,7, 10-tetraazacyclononane-4, 7, 10-triacetic acid (MaI-NODA).
Preferably, the formula (9) is 2- (4-isothiocyanatobenzyl) -1,4,7, 10-tetraazacyclododecane-1, 4,7, 10-tetraacetic acid (p-SCN-Bn-DOTA).
Preferably, the complex further comprises a modifying group.
Preferably, the modifying group is located at the C-terminus of the polypeptide. The modified group is added to regulate the biological half-life, water solubility and other properties of the medicine as required, and the modified group is introduced mainly to regulate the biological half-life of the medicine, so that the modified group is fast in vivo metabolism when being OH, is suitable for being used as an imaging medicine, and is prolonged in vivo half-life when being changed into other structures, and is suitable for being used as a therapeutic medicine.
The modifying group is selected from structures shown in the formulas (10) - (16):
preferably, the formula (10) is a hydroxyl group.
Preferably, the formula (11) is 2-amino-6-p-iodophenylacetylaminocaproic acid.
Preferably, the formula (12) is 2-amino-6-p-iodophenylpropionamido hexanoic acid.
Preferably, the formula (13) is 2-amino-6-tetrahydro-2-naphthacrylamidocaproic acid (PIB).
Preferably, the formula (14) is 2-amino-6-p-iodophenylpropionamido hexanoic acid.
Preferably, the formula (15) is 2-amino-6-p-bromophenylbutyrylaminohexanoic acid.
Preferably, the formula (16) is 4-amino-6- ((4 ' -amino-3, 3' dimethyl- [1,1' biphenyl ] -4-yl) diazenyl) -5-hydroxynaphthalene-1, 3-disulfonic acid.
Preferably, the structural formula of the complex is shown as a formula (I) or a formula (II):
in the formula (I), R 1 Represents a chelator, M represents a radionuclide, n is selected from positive integers; in the formula (II), R 3 Represents a chelator, A represents a radionuclide, b is selected from positive integers; r in the formulas (I), (II) 2 Represents a modifying group.
In a third aspect, the application provides the use of a polypeptide according to the first aspect of the application or a complex according to the second aspect of the application in the preparation of a product for targeted screening, diagnosis, treatment or prognosis of a disease.
Preferably, the disease comprises a disease that highly expresses EGFR.
Preferably, the disease comprises a tumor.
More preferably, the disease comprises breast cancer, lung cancer, colorectal cancer, head and neck cancer, non-small cell lung cancer, glioma, liver cancer, gastric cancer, pancreatic cancer, renal cancer, ovarian cancer, prostate cancer, cervical cancer, bladder cancer.
In a fourth aspect of the application there is provided a product comprising a polypeptide according to the first aspect of the application or a complex according to the second aspect of the application.
Preferably, the product comprises: drug and detection kit.
In a fifth aspect of the present application, there is provided a method for preparing the EGFR-targeting complex of the second aspect of the present application, comprising the steps of: the EGFR-targeting complex precursor is mixed with a radiometal nuclides for reaction.
Preferably, the EGFR-targeting complex precursor is reacted with the radiometal nuclides in a buffer.
Preferably, the buffer solution comprises at least one of sodium acetate, ammonium acetate, potassium acetate, hydrochloric acid, acetic acid.
More preferably, the buffer solution is sodium acetate.
Preferably, the concentration of the buffer solution is 0.05mol/L to 0.7mol/L.
More preferably, the concentration of the buffer solution is 0.1mol/L to 0.6mol/L.
Preferably, the pH of the reaction is 3.5-7.0.
More preferably, the pH of the reaction is in the range of 4.0 to 5.5.
Preferably, the temperature of the reaction is from 80 ℃ to 120 ℃.
More preferably, the temperature of the reaction is from 90 ℃ to 110 ℃.
Preferably, the reaction time is 8min-40min.
More preferably, the reaction time is from 10min to 30min.
Preferably, further purification can be performed after the reaction; the purification method comprises the following steps: reversed-phase high-pressure liquid chromatography, ion exchange chromatography, affinity chromatography, and solid-phase extraction.
Preferably, the purification comprises purification using a Sep-park Plus C-18, sep-park light C-18 or HLB column.
Preferably, the preparation method of the EGFR-targeting complex precursor comprises the following steps: the polypeptide targeting EGFR is synthesized by taking D-type amino acid as a raw material, and then a chelating agent and/or a modifying group are respectively coupled.
Preferably, the cysteine is modified at the C-terminus of the polypeptide and then the thiol side chain of the cysteine is coupled to a chelator and/or modification group.
The beneficial effects of the application are as follows:
the application discloses a targeted EGFR polypeptide radiopharmaceuticals, which is an excellent pharmacokinetic novel probe, the structure of the radiopharmaceuticals comprises polypeptides, modification groups, metal chelating groups and radionuclides, the application uses D-type amino acid to replace L-type amino acid for the first time to prepare the EGFR-targeted GE11 variant polypeptide sequence radiopharmaceuticals, and the stability of the radiopharmaceuticals is improved; the preparation method is simple, convenient and quick, the yield is high, the radioactive drug has good stability, strong water solubility and quick in vivo blood clearance, is mainly metabolized by kidneys, can specifically target EGFR to be ingested at tumor sites, and can be widely applied to tumor PET imaging and tumor nuclide treatment.
Drawings
FIG. 1 is an HPLC chromatogram of precursor DGE 11-NOTA.
FIG. 2 is a high resolution mass spectrum of precursor DGE 11-NOTA.
FIG. 3 is an HPLC chromatogram of precursor NOTA-PIB-DGE 11.
FIG. 4 is a high resolution mass spectrum of precursor NOTA-PIB-DGE 11.
FIG. 5 shows EGFR-targeting polypeptides as radiopharmaceuticals [ 18 F]Radioactive HPLC profile of AlF-NOTA-DGE 11.
FIG. 6 shows EGFR-targeting polypeptides as radiopharmaceuticals [ 18 F]Radioactive HPLC profile of AlF-NOTA-PIB-DGE 11.
FIG. 7 is [ 18 F]Radioactive HPLC profile of AlF-NOTA-DGE11 injection in vitro in FBS 2 h.
FIG. 8 is [ 18 F]Radioactive HPLC profile of AlF-NOTA-PIB-DGE11 injection in FBS 2 h.
FIG. 9 is [ 18 F]Plasma radioactivity HPLC profile of AlF-NOTA-DGE11 injection metabolized in vivo for 2 h.
FIG. 10 is [ 18 F]AlF-NOTA-DGE11 biodistribution in Kunming mice for 60 minutes.
FIG. 11 is [ 18 F]Biological profile of AlF-NOTA-PIB-DGE11 in Kunming mice for 12 h.
FIG. 12 is [ 18 F]AlF-NOTA-DGE11 images from Mico-PET/CT at various time points over 120 minutes in HCT116 tumor-bearing mice.
FIG. 13 is [ 18 F]AlF-NOTA-DGE 11% ID/g values at various time points of the viscera are plotted against time.
FIG. 14 is [ 18 F]AlF-NOTA-DGE11 in U87, huh-7, HCT116 tumor bearing mice in 60 minutes Mico-PET/CT image.
FIG. 15 is [ 18 F]AlF-NOTA-PIB-DGE11 in HCT116 tumor-bearing murine model 6h, 12hMico-PET/CT images.
Detailed Description
The conception and the technical effects produced by the present application will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present application. It is apparent that the described embodiments are only some embodiments of the present application, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present application based on the embodiments of the present application.
Example 1
The GE11 polypeptide sequence reported in the literature is L-type amino acid, and the applicant finds that the GE11 polypeptide is unstable in vivo in research, so that in order to improve the in vivo stability of the GE11 polypeptide, the applicant replaces the L-type amino acid with D-type amino acid and performs sequence inversion to improve the stability of the GE11 polypeptide, so that the DGE11 polypeptide is obtained, and the amino acid sequence of the DGE11 polypeptide is ivnqptywhyk.
Further uses DGE11 polypeptide structure as pharmacophore, connects with a metal ion chelating group to construct precursor, uses radioactive metal nuclide M n+ Marker constructs such as [ M ] n+ ]DGE11-NOTA or [ M ] n+ ]The structure of the DGE11-DOTA probe is shown as a formula (I) so as to obtain a specific targeted EGFR polypeptide radiopharmaceutical;
in the formula (I), R 1 Represents a metal ion chelating group, R 2 Represents a modifying group, M represents a radiometal nuclide, and n is selected from positive integers.
The embodiment of the application can also react the sulfhydryl side chain of cysteine with a metal ion chelating group (such as NOTA or DOTA analogue) to construct a precursor after the C-terminal lysine (Lys) branched chain of DGE11 polypeptide modifies a cysteine (Cys), and then react with a radioactive metal nuclide A b+ Reacting in buffer solution to obtain [ A ] b+ ]DGE11-NOTA or [ A ] b+ ]DGE11-DOTA, a targeted EGFR polypeptide radiopharmaceutical represented by formula (ii);
in the formula (II), R 3 Represents a metal ion chelating group, R 2 Represents a modifying group, A b+ And b represents a radionuclide, b being selected from positive integers.
Example 2
The precursor DGE11-NOTA is prepared as follows:
DGE11 (ivqptygywhyk) polypeptide is synthesized by adopting D-type amino acid as a raw material through a solid-phase polypeptide synthesis method, a metal ion chelating group is 1,4, 7-triazacyclononalkyl-4, 7-diacetoxy-1-acetyl (-NOTA), the side chain amino group of lysine (Lys) at the C end is connected with NOTA, and a modification group (R 2 Is hydroxyl). And separating, purifying and collecting product peaks by using preparative HPLC, and freeze-drying to obtain the DGE11-NOTA precursor.
FIG. 1 is an HPLC plot of precursor DGE 11-NOTA; FIG. 2 is a high resolution mass spectrum of precursor DGE 11-NOTA. HPLC profile retention time Rt is 11.575, mass spectrum MS (M/z) molecular weight [ M+2H]2H + The purity of the DGE11-NOTA precursor structure was greater than 98% by HPLC testing at 978.00 as determined by HPLC and high resolution mass spectrometry.
EGFR-targeting polypeptides radiopharmaceuticals 18 F]The preparation steps of AlF-NOTA-DGE11 are as follows:
by cyclotrons 18 O(p,n) 18 F nuclear reactionProduced by 18 F - Under helium loading, the enrichment was carried out in a Sep-Pak QMA anion column. The QMA column is filled with 0.3 mL-0.4 mL of physiological saline (the mass fraction is 0.9 percent) 18 F - Eluting into small bottle for use. In a reaction flask containing the prepared DGE11-NOTA (2. Mu.g/. Mu.L, 50. Mu.L), 2mmol/L AlCl was added sequentially 3 mu.L of the solution, 5. Mu.L of glacial acetic acid and 300. Mu.L of acetonitrile were mixed. 50 mu L of the above 18 F - Adding the eluent into a reaction bottle, stirring and uniformly mixing, and heating at 100 ℃ for reaction for 15min. Cooling, adding 6-8 mL of water for injection into a reaction bottle, uniformly mixing, and transferring to a Sep-pak C-18 column. The Sep-pak Plus C-18 column was then rinsed with 10mL×3 water for injection and blow dried. Finally, eluting the product with 1mL of ethanol, passing through a sterile filter membrane, collecting the product in a receiving bottle, diluting the product into a product solution containing 5% of ethanol by using physiological saline to obtain the product solution meeting the requirements 18 F]AlF-NOTA-DGE11 injection. Uncorrected radiochemical yields were 20.5% -52.0% with a total radiosynthesis time of 30min. FIG. 5 shows EGFR-targeting polypeptides as radiopharmaceuticals [ 18 F]The radioactive HPLC spectrum of AlF-NOTA-DGE11 shows the peak time of 9.419min for the target imaging agent, and the radiochemical purity of the product is more than 99%.
Example 3
EGFR-targeting polypeptides radiopharmaceuticals 18 F]The preparation steps of AlF-NOTA-DGE11 are as follows:
by cyclotrons 18 O(p,n) 18 Produced by F nuclear reaction 18 F - (100 mCi) was concentrated in a Sep-Pak QMA anion column under a helium carrier. The QMA column was subjected to a treatment with 450. Mu.L of 0.5M sodium acetate (pH 3.9 adjusted with acetic acid) 18 F - Eluting into small bottle for use. To 100. Mu.g DGE11-NOTA precursor, 350. Mu.L DMSO, 2mmol/L AlCl were added sequentially 3 The solution was mixed well at 30. Mu.L. Adding the precursor mixed solution to 18 F - Eluting, sealing in a small bottle, and heating at 105 ℃ for 15min. After the reaction, cooling and adding 9mL of water for injection, mixing evenly, transferring toHLB Plus column. The HLB column was rinsed with 20mL 2 water for injection and dried. Then, the mixture was eluted with 1mL (50% ethanol aqueous solution)The product is diluted into a product solution containing 5 percent of ethanol by normal saline to obtain the product meeting the requirements 18 F]AlF-NOTA-DGE11 injection. Uncorrected radiochemical yields were 75% to 92% with a total radiosynthesis time of 30min. FIG. 7 is [ 18 F]Radioactive HPLC profile of AlF-NOTA-DGE11 injection in vitro in FBS 2 h.
Example 4
EGFR-targeting polypeptides radiopharmaceuticals 68 Ga]The preparation procedure for DGE11-DOTA is as follows:
the precursor DGE11-DOTA is prepared as follows:
DGE11 (ivqptygywhyk) polypeptide is synthesized by using D-type amino acid as a raw material through a solid-phase polypeptide synthesis method, a metal ion chelating group is 1,4,7, 10-tetraazacyclododecyl-4, 7, 10-triacetoxy-1-acetyl (-DOTA), the side chain amino group of lysine (Lys) at the C end is connected with DOTA, and a modification group (R) is connected at the carbonyl of the C end 2 Is hydroxyl). And separating, purifying and collecting product peaks by using preparative HPLC, and freeze-drying to obtain the DGE11-DOTA precursor.
Into a reaction tube containing 50. Mu.L of the precursor DGE11-DOTA (2. Mu.g/. Mu.L) prepared in example 2 was added 900. Mu.L of a sodium acetate solution at a concentration of 0.25 mol/L. From the slave 68 Ge/ 68 The Ga generator is eluted with 4mL hydrochloric acid with the concentration of 0.05mol/L 68 GaCl 3 Mixing the materials in the reaction tube, and heating and reacting at 100 ℃ for 15min, wherein the pH of the solution is about 4.0. Cooled and added with 4mL of water for injection, mixed evenly and transferred to an HLB column. Rinse with 10mL x 2 water for injectionHLB Plus column and blow-dried. Then eluting the product with 1mL of ethanol and diluting it with physiological saline to a product solution containing 5% ethanol to obtain the desired product 68 Ga]DGE11-DOTA injection. [ 68 Ga]The uncorrected radiochemical yield of DGE11-DOTA is 70% -95% and the total radiosynthesis time is 30min.
Example 5
The precursor NOTA-PIB-DGE11 is prepared by the following steps:
DGE is synthesized by using D-type amino acid as raw material and solid-phase polypeptide synthesis method11 polypeptide, wherein the metal ion chelating group is 1,4, 7-triazacyclononalkyl-4, 7-diacetoxy-1-acetyl (-NOTA), the side chain amino group of C-terminal lysine (Lys) is linked to NOTA, and the C-terminal carbonyl group is linked to a modifying group (R 2 Is 2-amino-6-p-iodophenylbutyrylaminohexanoic acid (PIB), as shown in structural formula (13). Separating, purifying and collecting product peaks by using preparative HPLC, and freeze-drying to obtain a NOTA-PIB-DGE11 precursor. FIG. 3 is an HPLC plot of precursor DGE 11-NOTA; FIG. 4 is a high resolution mass spectrum of precursor DGE 11-NOTA. HPLC profile retention time Rt is 9.853, mass spectrum MS (M/z) molecular weight [ M+2H]2H + 1178.3, the purity of the HPLC test is greater than 95%.
EGFR-targeting polypeptides radiopharmaceuticals 18 F]The preparation steps of AlF-DGE11-PIB-NOTA are as follows:
by cyclotrons 18 O(p,n) 18 Produced by F nuclear reaction 18 F - (100 mCi) was concentrated in a Sep-Pak QMA anion column under a helium carrier. The QMA column was subjected to a treatment with 450. Mu.L of 0.5M sodium acetate (pH 3.9 adjusted with acetic acid) 18 F - Eluting into small bottle for use. To 100. Mu.g of NOTA-PIB-DGE11 precursor, 350. Mu.L of DMSO and 2mmol/L of AlCl were added sequentially 3 The solution was mixed well at 30. Mu.L. Adding the precursor mixed solution to 18 F - Eluting, sealing in a small bottle, and heating at 105 ℃ for 15min. After the reaction, cooling and adding 9mL of water for injection, mixing evenly, transferring toHLB Plus column. The HLB column was rinsed with 20mL 2 water for injection and dried. Then, the product was eluted with 1mL (50% aqueous ethanol) and diluted with physiological saline to a 5% ethanol-containing product solution to obtain a satisfactory [ 18 F]AlF-NOTA-PIB-DGE11 injection. Uncorrected radiochemical yields were 32.9% to 46.1% with a total radiosynthesis time of 30min. FIG. 6 shows EGFR-targeting polypeptides as radiopharmaceuticals [ 18 F]The radioactive HPLC spectrum of AlF-NOTA-PIB-DGE11 shows the peak time of the target imaging agent of 10.748min. FIG. 8 is [ 18 F]Radioactive HPLC profile of AlF-NOTA-PIB-DGE11 injection in vitro in FBS 2 h.
EXAMPLE 6 determination of the product radiochemical purity and stability
The radiochemical purity and stability of the drug injection were determined by High Performance Liquid Chromatography (HPLC). HPLC analysis conditions: the analytical column is ZORBAX Eclipse XDB-C18 column; mobile phase: phase a was 0.1% trifluoroacetic acid (TFA) in water and phase B was 0.1% TFA in acetonitrile. The leaching gradient is as follows: 0-2min, 90% of phase A, 10% of phase B and 1mL/min of flow rate; 2-10min, phase A is reduced to 20%, phase B is increased to 80%, and the flow rate is 1mL/min;10-14min, phase A is kept at 90%, phase B is kept at 10% and the flow rate is 1mL/min.
To examine the stability of the developer in vitro, respectively 18 F]AlF-NOTA-DGE11、[ 18 F]Stability of AlF-NOTA-PIB-DGE11 in Fetal Bovine Serum (FBS). 2mL of FBS was mixed thoroughly with 200. Mu. Ci imaging agent, incubated in incubator at 37℃for 2h, a small amount of solution was taken and the stability of the imaging agent was checked by HPLC, and the above experiment was repeated 4 times. Representative HPLC diagrams are shown in FIG. 7 and FIG. 8. Results discovery [ 18 F]AlF-NOTA-DGE11、[ 18 F]AlF-NOTA-PIB-DGE11 was found to be 100% stable in FBS as a prototype.
To detect imaging agent [ 18 F]Stability of AlF-NOTA-DGE11 in vivo [ taking 18 F]AlF-NOTA-DGE11 injection is about 200 μCi, enters into a Kunming mouse body through tail vein injection, is normally fed for 2 hours, is picked up for blood taking, is centrifuged at 10000 revolutions for 10 minutes to obtain supernatant, is centrifuged by an ultrafiltration membrane (12000 revolutions for 5 minutes), and is subjected to HPLC analysis, and the experiment is repeated for 4 times, wherein the representative in-vivo serum stability HPLC is shown in figure 9. Results discovery [ 18 F]AlF-NOTA-DGE11 is not decomposed in vivo for 2 hours, and 100% exists stably in a prototype.
Example 7 Water distribution coefficient determination experiment of ester
Prepared 10 mu L of each 18 F]AlF-NOTA-DGE11、[ 18 F]AlF-NOTA-PIB-DGE11 injection is put into a 2.5mL centrifuge tube filled with 1mL of n-octanol and 990 mu L of water, and is hermetically placed into a dry type thermostat to oscillate for 10min at normal temperature, and is kept stand for 10min to separate two phases, 500 mu L of each of the two phases is taken out of the two phases by a liquid transfer device and placed into a gamma counter tube, and the gamma counter is used for measuring and counting. Two experiments were performed in parallel, each repeated three times. The Log P value is calculated according to the following formula.
Determination by means of a radioactive technique [ 18 F]AlF-NOTA-DGE11 and [ 18 F]The lipid water distribution coefficients log P of AlF-NOTA-PIB-DGE11 are-1.690 +/-0.010 respectively, which shows that the imaging agent is a water-soluble substance and has good hydrophilic property, and the in vivo uptake and imaging are predicted to be mainly metabolized by kidneys, other soft tissues are likely to be lower in uptake, and the imaging background uptake is lower.
Example 8[ 18 F]AlF-NOTA-DGE11 in vivo biodistribution experiment
EGFR-targeting polypeptide PET imaging agent prepared as in example 2 18 F]After AlF-NOTA-DGE11, after 30 mu Ci imaging agent is respectively injected into 4 normal Kunming mice through tail veins, the mice are sacrificed after normal feeding and ingestion for 1h, main organs and tissues such as blood, brain, heart, lung, liver, kidney and the like are weighed and gamma counting is carried out, and the biodistribution of the imaging agent in the mice is studied. [ 18 F]AlF-DGE11-NOT is biodistribution in Kunming mice as shown in figure 10, and the result shows that the medicine is mainly metabolized by kidneys, the blood clearance speed is high, the radioactivity in bones is NOT high, and the medicine is NOT defluorinated in vivo.
EGFR-targeting polypeptide PET imaging agent prepared as in example 5 18 F]After AlF-NOTA-PIB-DGE11, after 30 mu Ci imaging agent is respectively injected into 4 normal Kunming mice through tail veins, the mice are sacrificed after normal feeding and ingestion for 12 hours, main organs and tissues such as blood, brain, heart, lung, liver, kidney and the like are weighed and gamma counting is carried out, and the biodistribution of the imaging agent in the mice is studied. [ 18 F]AlF-DGE11-NOT is biodistribution in Kunming mice as shown in figure 11, and the result shows that the detention time of the probe in the blood circulation system is prolonged, the radioactive counts of blood and lung are obviously increased, the probe is still mainly metabolized by kidneys, the radioactivity in bones is NOT high, the medicine is NOT defluorinated in the bodies, and NOTA-PIB-DGE11 has potential as a therapeutic radiopharmaceuticals precursor.
EXAMPLE 9Micro PET/CT imaging experiment
Micro-PET/CT displayFor example, the study utilized Siemens Inveon Micro-PET/CT with an acquisition workstation of Inveon Acquirision Workplace (IAW) 2.2 and a data analysis workstation of Inveon Research Workplace (IRW). EGFR positive expression brain glioma cell U87, human liver cancer cell Huh7 and human colon cancer cell HCT116 are taken to be 5 multiplied by 10 6 Density of nude mice was inoculated subcutaneously and when the tumor diameter had grown to 8-10mm, an imaging agent study was performed.
Dynamic imaging: taking HCT116 tumor-bearing mice, fixing on a scanning bed after being anesthetized by 10% pentobarbital, establishing a method to enable the bed to be positioned in a PET visual field, taking [ 18 F]AlF-NOTA-DGE11 injection is about 200 μCi, and is injected through tail vein, and the scanning is started at the same time of injection, and the scanning is continued for 120 minutes. The PET dynamic diagram and the main organ time-activity curve are shown in fig. 12 and 13.
Static imaging: fetch [ 18 F]About 200 μCi of AlF-NOTA-DGE11 injection is injected into U87, huh7 and HCT116 tumor-bearing mice via tail vein, and after 40min of routine intake, 0.1mL of 10% pentobarbital is injected, and then routine PET/CT imaging (PET acquisition for 10 min) is performed, and the PET/CT imaging result is shown in FIG. 14. Fetch [ 18 F]About 200 μCi of AlF-NOTA-PIB-DGE11 injection is injected into an HCT116 tumor-bearing mouse model through tail vein, and is taken for 6 hours and 12 hours conventionally, and then PET/CT scanning (PET acquisition for 30 minutes) is carried out, and the PET/CT imaging result is shown in figure 15.
Inhibition of development: other procedures were followed with "dynamic imaging" and "static imaging" with 300. Mu.g DGE11 polypeptide added to the injected drug.
PET imaging results show that: probe [ 18 F]AlF-NOTA-DGE11 has higher uptake in tumors of U87, huh7 and HCT116 tumor-bearing mice, and the uptake amount of tumor parts is obviously higher than that of organs or tissues such as muscles, lungs, livers, intestines and the like. The time dynamic diagram of each organ in dynamic imaging shows that the tumor/muscle ratio is higher at 60 minutes, so the optimal imaging time is selected to be 60 minutes, and the inhibition imaging result shows that the tumor/muscle ratio is obviously reduced by inhibition imaging and is specific uptake. Development results are compared with literature report 18 F]FP-Lys-GE11(Xueli Li,Kongzhen Hu,et al.Synthesis and evaluation of[18F]FP-Lys-GE11 as a new radiolabeled peptide probe for epidermal growth factor receptor(EGFR) imaging. Nuclear Medicine and Biology,2020,90-91:84-92.) has better tumor imaging effect, higher tumor/muscle ratio ([ the same ]) 18 F]AlF-NOTA-DGE11 Probe 1h HCT116 tumor/muscle ratio 8.75.+ -. 0.13 [ 18 F]FP-Lys-GE11 probe 2h U87 tumor/muscle 3.45.+ -. 0.43) while the peritoneal cavity is locally low (liver uptake significantly reduced). The imaging result shows that the imaging agent is specifically absorbed at the tumor part in a targeting way, and has better application prospect. [ 18 F]AlF-NOTA-PIB-DGE11 has obvious concentration of tumor sites in CHT116 tumor-bearing murine models (FIG. 15), and blood and lung radioactivity concentrations are obviously higher than those of [ 18 F]AlF-NOTA-DGE11 due to R 2 Similar substitution of hydroxy groups with p-iodophenylbutyric acid, resulting in an extended biological half-life of the probe, has shown the potential for NOTA-PIB-DGE11 precursors and analogs thereof to be ligands for nuclide treatment.
In summary, the radiopharmaceuticals obtained in this example have conditions that are useful tools for diagnosing malignant tumors, providing powerful imaging evidence for the determination of treatment regimens and efficacy monitoring; meanwhile, if the therapeutic nuclide is used to be provided with a therapeutic drug for treating malignant tumor, the malignant tumor can be targeted for treatment.
The present application has been described in detail in the above embodiments, but the present application is not limited to the above examples, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present application. Furthermore, embodiments of the application and features of the embodiments may be combined with each other without conflict.

Claims (16)

1. A polypeptide having the sequence ivnqptygywhyk, wherein the amino acid in the polypeptide is a D-type amino acid.
2. An EGFR-targeting complex, comprising the polypeptide of claim 1.
3. The complex of claim 2, further comprising an imaging agent and/or a therapeutic agent.
4. The complex of claim 3, wherein the imaging agent comprises at least one of FB groups, diagnostic radionuclides, biotin, fluorophores, fluorescent proteins, antibodies, horseradish peroxidase, and alkaline phosphatase.
5. The complex of claim 3, wherein the therapeutic agent comprises at least one of a therapeutic radionuclide, a pro-apoptotic peptide, a nanoparticle, a chemotherapeutic agent, a nanodroplet, a liposomal drug, and a cytokine.
6. The complex of claim 4, wherein the diagnostic radionuclide comprises 18 F、 44 Sc、 64 Cu、 67 Ga、 68 Ga、 89 Zr、 99 Tc、 111 In、 177 Lu and 188 at least one of Re.
7. The complex of claim 5, wherein the therapeutic radionuclide comprises 51 Cr、 90 Y、 106 Ru、 149 Pm、 149 Tb、 153 Sm、 166 Ho、 169 Yb、 177 Lu、 186 Re、 188 Re、 203 Pb、 211 At、 212 Bi、 212 Pb、 213 Bi、 223 Ra、 225 Ac、 226 Th and 227 at least one of Th.
8. The complex of claim 4 or 5, wherein the radionuclide labels the polypeptide by a chelator.
9. The complex of claim 8, wherein the chelating agent comprises HYNIC, DOTA, DOTAGA, NOTA, NOTAGA, DTPA, NODA, DTPA, TETA, CB-TE2A、Cyclam、DFO、MAG3、EC、EDTA、DADT、HYNIC、NS 3 At least one of 3,2-HOPO, macropa and derivatives thereof.
10. The complex of claim 9, wherein the chelating agent is selected from structures represented by formulas (1) - (9):
11. a complex according to claim 3, wherein the complex further comprises a modifying group.
12. The complex of claim 11, wherein the modifying group is selected from structures represented by formulas (10) - (16):
13. the complex according to any one of claims 2 to 5, wherein the structural formula of the complex is represented by formula (I) or formula (ii):
in the formula (I), R 1 Represents a chelator, M represents a radionuclide, n is selected from positive integers; (II)
Wherein R is 3 Represents a chelator, A represents a radionuclide, b is selected from positive integers; r in the formulas (I), (II) 2 Represents a modifying group.
14. A method of preparing an EGFR-targeting complex according to any one of claims 2-13, comprising the steps of: mixing and reacting the EGFR-targeting complex precursor with a radiometal nuclide; the preparation method of the EGFR-targeting complex precursor comprises the following steps: the polypeptide targeting EGFR is synthesized by taking D-type amino acid as a raw material, and then a chelating agent and/or a modifying group are respectively coupled.
15. Use of the polypeptide of claim 1 or the EGFR-targeting complex of any one of claims 2-13 for the preparation of a product for targeted screening, diagnosis, treatment or prognostic evaluation of a disease selected from diseases in which EGFR is highly expressed, selected from tumors selected from breast cancer, lung cancer, colorectal cancer, head and neck cancer, glioma, liver cancer, gastric cancer, pancreatic cancer, kidney cancer, ovarian cancer, prostate cancer, cervical cancer, bladder cancer.
16. A product comprising the polypeptide of claim 1 or the EGFR-targeting complex of any one of claims 2-13.
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