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Radioactive complex targeting HER2 and preparation method and application of radioactive complex

A complex and radiolabeling technology, applied in the directions of radioactive physical shape, radioactive carrier, drug delivery, etc., can solve the problems of long retention time and high concentration, and achieve the effect of reducing radioactive concentration and retention and good HER2 targeting.

Active Publication Date: 2019-09-20
SHANGHAI THERANOSTICS BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although 68 Ga-ABY-025 has an excellent tumor imaging effect, but because Affibody is mainly excreted by the kidney and the metabolites can be reabsorbed by the renal tubules, the concentration of radioactivity in the kidney is abnormally high and the residence time is particularly long

Method used

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  • Radioactive complex targeting HER2 and preparation method and application of radioactive complex
  • Radioactive complex targeting HER2 and preparation method and application of radioactive complex
  • Radioactive complex targeting HER2 and preparation method and application of radioactive complex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Prepare a polypeptide compound with HER2 targeting function, and its synthetic route is as follows:

[0059]

[0060] Concrete preparation process comprises the following steps:

[0061] 1. Synthesis of compound 1:

[0062] Add 0.5g Fmoc-Lys(Dde)-Resin (the amount of substance of Fmoc-Lys(Dde)-OH is 0.4mmol, 1 equivalent) in solid-phase synthesizer, take DMF as reaction solvent, with 0.8M DIPEA / DMF and 0.4M HBTU / DMF were used as activators, and 20% piperidine in DMF was used as the eluent of Fmoc. According to the sequence of the polypeptide, Fmaoc-Val-OH (0.543g, 4 equivalents) and Boc-Met were added sequentially. -OH (0.399 g, 4 equivalents) to extend the peptide chain. After the solid-phase synthesis, the crude polypeptide product attached to the resin was placed in 3 mL of 2% hydrazine hydrate in DMF, stirred at room temperature for 1.5 h, filtered with suction, and the resin was washed with dichloromethane, methanol and DMF in sequence. The resin was then pl...

Embodiment 2

[0070] Prepare another polypeptide compound with HER2 targeting function, and its synthetic route is as follows:

[0071]

[0072] Concrete preparation process comprises the following steps:

[0073] 1. Synthesis of compound 1:

[0074]Add 0.5g Fmoc-Lys(Dde)-Resin (the amount of substance of Fmoc-Lys(Dde)-OH is 0.4mmol, 1 equivalent) in solid-phase synthesizer, take DMF as reaction solvent, with 0.8M DIPEA / DMF and 0.4M HBTU / DMF were used as activators, and 20% piperidine in DMF was used as the eluent of Fmoc. According to the sequence of the polypeptide, Fmaoc-Val-OH (0.543g, 4 equivalents) and Boc-Met were added sequentially. -OH (0.399 g, 4 equivalents) to extend the peptide chain. After the solid-phase synthesis, the crude polypeptide product attached to the resin was placed in 3 mL of 2% hydrazine hydrate in DMF, stirred at room temperature for 1.5 h, filtered with suction, and the resin was washed with dichloromethane, methanol and DMF in sequence. The resin was th...

Embodiment 3

[0082] Preparation of lyophilized kits for radiolabeling

[0083] 1) Preparation of lyophilized kits for radioactive Ga-68 and Cu-64 labeling (take the preparation of 100 tubes as an example)

[0084] Weigh 4 mg of compound 4 prepared in Example 1 and dissolve it in 10 mL of 0.5 mol / L acetic acid-sodium acetate buffer solution (pH=4). After sterile filtration, it is divided into 100 cryopreservation tubes, and then placed in the freezer. Freeze-dry in a desiccant for 24 hours, and seal with a stopper to obtain a freeze-dried medicine box I. According to the formation of the freeze-dried powder injection of the kit, excipients such as mannitol and ascorbic acid can be added to the kit, and the dosage of compound 4 and excipients can be adjusted to optimize the molding of the kit.

[0085] 2) Preparation of freeze-dried kits for radioactive F-18 labeling (taking the preparation of 100 tubes as an example)

[0086] Weigh 4 mg of the compound 4 prepared in Example 1 and dissolve...

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Abstract

The invention provides a polypeptide compound with a HER2 targeting function. The polypeptide compound with the HER2 targeting function is formed by connecting a HER2 affinity with a bifunctional chelating agent through a polypeptide sequence; the polypeptide sequence is Met-Val-Lys; the general structural formula of the polypeptide compound is shown in formula (I) as shown in specification, wherein R is a HER2 affinity molecule and X is a bifunctional chelator group. The invention also provides a radiolabelled complex targeting HER2 by taking the polypeptide compound as a ligand. The radiolabeled complex provided by the invention can be used as a radioactive diagnostic probe for evaluating the HER2 receptor of breast cancer, and the probe can reduce the concentration of the kidney under the condition of keeping the uptake of the tumor unchanged, so that the target-to-non-target ratio of the tumor is improved, and the radiation dose to the kidney is reduced. The invention also provides a preparation method of the polypeptide compound and the radiolabelled complex, and application of the polypeptide compound and the radiolabelled complex in preparation of a HER2 positive breast cancer radioactive diagnosis and treatment probe for humans or animals.

Description

technical field [0001] The invention relates to a radioactive complex, in particular to a radioactive complex targeting HER2, its preparation method and its application as a diagnosis and treatment probe. Background technique [0002] According to data from the International Cancer Research Center, the age-standardized incidence rate of breast cancer in the world (43.1 / 100,000 people) ranked first among female cancers in 2012, far ahead of the second-ranked colorectal cancer (14.3 / 100,000 people) human), accounted for 35.3% of new tumors in women, and accounted for 20.8% of all cancer deaths in women. According to data from the National Cancer Center of China, in 2015 breast cancer was still the cancer with the highest incidence rate among women, and it was also the second leading cause of cancer death among women after lung cancer. Breast cancer has become a major public health problem in the current society, and the key to improving the efficacy of breast cancer lies in e...

Claims

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Application Information

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IPC IPC(8): A61K51/08A61K51/12
CPCA61K51/08A61K51/1241A61K51/121
Inventor 陈小元张明如
Owner SHANGHAI THERANOSTICS BIOTECH CO LTD
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