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Cyclic NGR polypeptide, radionuclide labeled molecular probe and application thereof

A radionuclide and molecular probe technology, applied in the fields of radioactive carrier, peptide, peptide preparation, etc., can solve the problems of kidney side effects, inability to achieve tumor treatment, etc., and achieve the effect of improving targeting and retention time

Active Publication Date: 2020-12-15
INST OF NUCLEAR PHYSICS & CHEM CHINA ACADEMY OF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because the structure of the NGR cyclic derivative c(NGR) is too small, it will be rapidly metabolized by the kidneys as a radiopharmaceutical in the body, especially when it is used for therapeutic radionuclides with long half-lives (such as 177 Lu) combined, the shortcoming of its rapid metabolism in the body will not be able to achieve tumor treatment and bring great side effects on metabolic organs such as the kidney

Method used

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  • Cyclic NGR polypeptide, radionuclide labeled molecular probe and application thereof
  • Cyclic NGR polypeptide, radionuclide labeled molecular probe and application thereof
  • Cyclic NGR polypeptide, radionuclide labeled molecular probe and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of a DOTA-NGR Cyclic Polypeptide DOTA-I

[0037] Its chemical structure is as figure 1 Shown:

[0038] The preparation method is as follows: take 10 μmol of NGR polypeptide I solution, dissolve it in 80 μL N,N-dimethylformamide (DMF), add 11 μmol of bifunctional chelating group (Mal-DOTA), 30 μmol of diisopropylethylamine Carry out coupling, stir and react at room temperature for 1 to 2 hours, use high performance liquid chromatography (HPLC) to separate and purify the obtained product, freeze-dry to obtain the coupling product, and test the chemical composition of the obtained coupling product by high performance liquid chromatography (HPLC). Purity>95%, recorded as DOTA-I.

[0039] The mass spectrogram of above-mentioned DOTA-I polypeptide is as follows figure 2 shown.

Embodiment 2

[0041] DOTA-I 177 Lu radiolabeled

[0042] experimental method:

[0043]1) Dissolving DOTA-I in sodium acetate (NaOAc) buffer solution (0.25M, pH=5.5) to prepare a solution with a concentration of 2nmol / μL;

[0044] 2) Take the known activity (100μCi / μL, 3.7MBq / μL) in the lead tank 177 LuCl 3 Solution 400 μCi (14.8 MBq), mixed well with 2 μL of DOTA-I solution, and 20 μl of NaOAc buffer was added to adjust the pH value, and then the reaction mixture was placed in a metal bath at 80° C. for 30 minutes.

[0045] 3) The radiochemical purity of the marker was determined by instant silica thin layer chromatography (iTLC-SG). Using 0.1M citric acid solution (pH=5.5) as a developing agent to develop, scan with a radiochromatographic scanner (TLC), and calculate the radiolabeling rate of the marker.

[0046] 177 Lu-DOTA-I all remain at the origin of the spectrum (Rf=0), where the free 177 Lu moved to the leading edge together with the developer (Rf=0.62), and the radiolabeling ...

Embodiment 3

[0049] 177 In Vitro Stability Test of Lu-DOTA-I Molecular Probe

[0050] Test method: Take 10μL (30μCi, 1.11MBq) 177 Lu-labeled DOTA-I samples were uniformly mixed with 290 μL of FBS or normal saline, placed in a metal bath at 37°C and 300 rpm, and incubated with shaking, and were analyzed by iTLC-SG at 1, 4, 24, 48, and 72 hours, respectively. The radiochemical purity of the markers was tested to assess the in vitro stability of the prodrugs.

[0051] the above 177 The in vitro stability results of Lu-DOTA-I molecular probe are as follows: Figure 4 shown. The results show that the stability of the molecular probe in physiological saline and FBS solution is greater than 90% within 24 hours, and its stability in physiological saline for 72 hours is still greater than 90%. However, the stability of the molecular probe in FBS solution for 72 hours is greater than 65%. Considering that the serum (FBS) content in the in vivo environment is mostly about 10% during actual use,...

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Abstract

The invention provides a cyclic NGR polypeptide, a radionuclide-labeled aminopeptidase targeting molecular probe and application thereof. The molecular probe is obtained by labeling the cyclic NGR polypeptide with radionuclide, or coupling the cyclic NGR polypeptide with a bifunctional chelating group, and then labeling the coupled product with radionuclide. The radionuclide-labeled aminopeptidasetargeting molecular probe can be used for preparing a developing agent for diagnosing aminopeptidase N (CD13) high-expression tumors or preparing a drug for biological targeting treatment of aminopeptidase N (CD13) high-expression tumors. The integrin receptor can be accurately positioned in vivo, the aim of tumor molecular imaging is achieved through nuclear medicine imaging, and the in-vivo targeting property and the retention time thereof can be remarkably improved. And the aminopeptidase N (CD13) tumor can be accurately positioned as a carrier of radioactive therapy nuclide, so that the aim of treating tumors is fulfilled. The structural formula of the cyclic NGR polypeptide is shown in the specification.

Description

technical field [0001] The invention belongs to the technical fields of aminopeptidase targeting polypeptide, radiopharmaceutical-labeled molecular probe and nuclear medicine, and specifically relates to a cyclic NGR polypeptide, radionuclide-labeled molecular probe and applications thereof. Background technique [0002] Aminopeptidase N (CD13) is a metalloprotease called a tumor marker. It is not only overexpressed in the rapidly growing part of tumor blood vessels, but also highly expressed on the membrane surface of malignant tumors such as breast cancer, lung cancer, and liver cancer. , play an important role in tumor invasion and metastasis and angiogenesis. [0003] NGR (a tripeptide consisting of aspartic acid-glycine-arginine) can specifically bind to aminopeptidase N (CD13). NGR-hTNF (recombinant human tumor necrosis factor)-combined drug targeting tumor angiogenesis has completed Phase III clinical trials and has submitted an application to EMA. Cyclic NGR (GG-CN...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/13C07K1/02C07K1/20A61K51/08A61P35/00A61K103/30
CPCC07K7/06A61K51/08A61P35/00
Inventor 王静杨宇川彭述明杨夏卓连刚廖伟赵鹏王关全阚文涛
Owner INST OF NUCLEAR PHYSICS & CHEM CHINA ACADEMY OF
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