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A boron-doped tumor targeting drug and its preparation method and application

A tumor targeting and drug technology, applied in the field of biomedicine, can solve the problems of low drug load, strong systemic toxicity, unreachable, etc., and achieve the effect of high-efficiency accumulation capacity, good biocompatibility, and satisfying treatment needs.

Active Publication Date: 2022-05-17
THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] As an important member of BNCT therapy, boron-containing drugs have not performed satisfactorily in clinical applications, because BNCT requires drugs to target tumors and accumulate sufficient boron-containing drugs in tumor cells. The ratio of the concentration in normal tissue or blood should be greater than 3.0, entering the concentration of each gram of tumor 10 The average amount of B is required to be 20-35 μg, and corresponds to a tumor cell containing at least 10 9 indivual 10 B atoms, but existing technologies such as the two BNCT drugs currently approved by the FDA, BSH (mercapto polyhedral boron clathrate) and BPA (4-boron-L-phenylalanine), cannot reach this level, and various boron loadings Targeted drugs such as low molecular weight borides, boron-doped peptides, antibody fragments and various proteins, intact antibodies and antibody-based conjugates, and liposomes, etc., are also due to low drug loading, poor penetration, and systemic Problems such as strong toxicity are difficult to meet the treatment requirements of BNCT
[0004] CN106279231A discloses a boron-containing compound used in BNCT and its preparation method and application. The new boron-containing compound provided by the invention is obtained through condensation, ammonolysis and ring-forming reactions, and is easy to prepare, low in cost, and has good biological properties. Its performance is superior to BPA in the uptake, accumulation and retention of tumor cells, and it has good application prospects in BNCT. It is also expected to become a clinical potential positron emission tomography tumor imaging agent. The identification of diseases and the detection of metastatic lesions in the whole body have created favorable conditions, but the boron-containing compounds are still not ideal in terms of tumor cell targeting and accumulation
However, this preparation needs the help of an external magnetic field to target it to the tumor site, and there may be problems such as low drug loading and poor penetration.

Method used

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  • A boron-doped tumor targeting drug and its preparation method and application
  • A boron-doped tumor targeting drug and its preparation method and application
  • A boron-doped tumor targeting drug and its preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0074] This embodiment provides a boron-doped tumor targeting drug, which includes a polypeptide, a hydrophobic molecule 2-naphthylacetic acid located at the nitrogen terminal of the polypeptide, and BSH linked to lysine of the polypeptide; the polypeptide includes phosphorylated L-tyrosine , L-lysine and L-phenylalanine, the molecular structure of which is shown below:

[0075]

[0076] Its preparation method comprises the following steps:

[0077] (1) In a solid-phase synthesis tube, swell 1.0 g of 2-chloro-trityl chloride resin in 10 mL of dichloromethane for 30 min;

[0078] (2) Using phosphorylated L-tyrosine, L-phenylalanine, terminal amino group and side chain amino group protected by Fmoc and Boc respectively as raw materials, according to the above polypeptide Amino acid sequence, 1.0g Fmoc and Boc protected L-lysine and 992μL N,N-diisopropylethylamine were dissolved in 5mL N,N-dimethylformamide, then added to the carrier resin, and passed Nitrogen, react with th...

Embodiment 2

[0090] The boron-doped tumor targeting drug and BSH prepared in Example 1 were tested for cumulative performance in HeLa cells, the specific method is:

[0091] Select HeLa cells as model cells, and inoculate with 2×10 5 Add 2mL of DMEM medium containing 10-1000μM of the product of Example 1 or 2mL of DMEM medium containing 10-1000μM BSH to a 6-well plate containing 2 cells, and incubate at 37°C and 5% CO 2 Under conditions, incubate for 24h. The cells were digested with trypsin, counted, heated and digested by adding nitric acid, and finally the amount of accumulated boron was measured by ICP-MS. The statistical results were as follows: Figure 4 shown.

[0092] Depend on Figure 4 It can be seen that the accumulated boron amount of the boron-doped tumor targeting drug involved in the present invention in HeLa cells is significantly greater than that of the BSH group in HeLa cells, and with the prolongation of the administration concentration, this advantage becomes more a...

Embodiment 3

[0094] The boron-doped tumor targeting drug and BSH prepared in Example 1 were subjected to a cytotoxicity test, and the specific method was:

[0095] Select HeLa cells as model cells, add 0.1 mL of DMEM medium containing 10-1000 μM of the product of Example 1 or 0.1 mL of 10-1000 μM BSH into a 96-well plate inoculated with 5000 cells, and incubate at 37°C and 5 %CO 2 Under the conditions of 24h, and then use the MTT method to detect cytotoxicity, the statistical results are as follows Figure 5 shown.

[0096] Depend on Figure 5 It can be seen that the boron-doped tumor targeting drug involved in the present invention has almost no cytotoxicity to HeLa cells in the range of 10 μM-500 μM, indicating that the boron-containing drug has good biocompatibility and no systemic toxicity.

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Abstract

The present invention relates to a boron-doped tumor targeting drug and its preparation method and application. The boron-doped tumor targeting drug comprises a polypeptide, a hydrophobic molecule located at the nitrogen terminal of the polypeptide, and a mercaptododecaborane disulfide located on the lysine of the polypeptide. Sodium salt; amino acids comprising the polypeptide include phosphorylated L-tyrosine, L-lysine and L-phenylalanine. The drug can achieve specific enrichment in tumor cells, and the enrichment amount of each tumor cell can reach 37.3×10 9 B atoms, meeting the needs of boron neutron capture therapy. In addition, the boron-containing drug has good biocompatibility, low immunogenicity and low toxicity.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a boron-doped medicine and its preparation method and application, in particular to a boron-doped tumor targeting medicine and its preparation method and application. Background technique [0002] Boron neutron capture therapy (BNCT) is a treatment that destroys cancer cells through nuclear fission reactions within tumor cells. By injecting boron-containing compounds, it is concentrated in tumor cells, while the distribution in other tissues is small. When irradiated with an epithermal neutron ray, boron-10 in cancer cells can undergo neutron capture to form an unstable isotope, and then undergo nuclear fission reaction, releasing a very lethal ray, thus killing cancer cell. [0003] As an important member of BNCT therapy, boron-containing drugs have not performed satisfactorily in clinical applications, because BNCT requires drugs to target tumors and accumulat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K41/00A61K47/64A61P35/00
CPCA61K41/0095A61K47/64A61P35/00Y02P20/55
Inventor 姚庆鑫高远
Owner THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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