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Application of phenylboronic acid in preparing nuclear-targeted boron capture agent

A technology for coupling boron phenylboronic acid and phenylboronic acid, which is applied in the direction of active ingredients of boron compounds, medical preparations of non-active ingredients, antineoplastic drugs, etc., can solve the problem of unsatisfactory tumor targeting effect and achieve biocompatibility good effect

Active Publication Date: 2019-10-15
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the tumor targeting effect of BPA and BSH is not ideal, and it is necessary to develop new boron capture agents

Method used

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  • Application of phenylboronic acid in preparing nuclear-targeted boron capture agent
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  • Application of phenylboronic acid in preparing nuclear-targeted boron capture agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1 Cytotoxicity experiment of small molecule phenylboronic acid (PBA) boron capture agent on B16F10 cells

[0036] The B16F10 cells in the logarithmic growth phase were inoculated in a 96-well plate, and the number of cells per well was 5×10 3 , at 37°C, 5% CO 2 After culturing in the cell incubator for 24 hours, remove the culture medium, add 200 μL of culture medium containing PBA or 4-boron-L-phenylalanine (BPA) to each well, set up 7 equal concentration gradients, and place in the cell incubator to continue incubation Remove the culture medium after 48 hours, add 100 μL of culture medium containing 10% CCK8 to each well, continue to cultivate for 4 hours, shake on the shaker for 2 minutes, use a microplate reader to measure the OD value at a wavelength of 450 nm, and use the formula to calculate the cell survival rate to evaluate the cells toxicity:

[0037]

[0038] Such as figure 1 As shown, BPA is a safe boron capture agent that has been clinically u...

Embodiment 2

[0039] Embodiment 2 small molecule phenylboronic acid (PBA) boron capture agent in B16F10 nucleoplasm fluorescence distribution

[0040] Amino-modified phenylboronic acid (4-aminophenylboronic acid) was dissolved in water, added with 1 equivalent of rhodamine B and EDCI catalyst to react overnight, and then dialyzed for 12 hours to obtain rhodamine (RHB) fluorescently labeled PBA (PBA-RHB). B16F10 cells were incubated with RHB and PBA-RHB solutions (both at a concentration of 5 μg / ml) for 2 hours, 6 hours, and 12 hours, respectively. After washing, the cells were fixed. DAPI staining marked the nuclei, and the fluorescence distribution of nuclei and cytoplasm was evaluated under a confocal microscope. Condition.

[0041] Such as figure 2As shown, the PBA-RHB red fluorescence was obviously distributed in the nucleus after 2 hours of incubation, and part of the PBA-RHB red fluorescence was still in the nucleus after 6 hours ( image 3 ), but after 12 hours there was little PB...

Embodiment 3

[0042] Embodiment 3 Small molecule phenylboronic acid (PBA) boron capture agent is distributed in B16F10 cell nucleoplasm

[0043] Prepare PBA with a boron concentration of 1 μg / mL and incubate B16F10 cells for 4 hours, and then use ICP-MS to evaluate the amount of boron uptake per million cells (n=3). Methods Boron uptake per million nuclei was assessed (n=3).

[0044] Such as Figure 5 As shown, B16F10 cells have more than 20ng B / 10 to PBA preparation 6 Cells uptake, more than half of the boron is located in the nucleus, the effect of the preparation meets the expected design, and is suitable for further modification or encapsulation in nano preparations to achieve tumor-targeted delivery in vivo.

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Abstract

The invention discloses application of phenylboronic acid in preparing a nuclear-targeted boron capture agent and in preparing a boron neutron capture therapeutic drug. The phenylboronic acid moleculeitself can be used as the nuclear-targeted boron capture agent, can also be linked to an antibody to prepare an antibody drug-coupled phenylboronic acid boron capture agent, and can also be dissolvedin normal saline to obtain the boron capture agent of phenylboric solution. In addition, liposome can be used to wrap the phenylboronic acid to form a liposome boron capture agent. The phenylboronicacid can further enter the nucleus besides ingestion and distribution in the cell; and the prepared boron capture agent can exert greater therapeutic effect of boron neutron capture with the same intracellular boron content, and has good biocompatibility.

Description

technical field [0001] The invention relates to the technical field of research and development of boron neutron capture therapy drugs, in particular to the application of phenylboronic acid in the preparation of nucleus-targeted boron capture agents. Background technique [0002] Malignant tumors seriously threaten human health and bring a heavy burden to the whole society. At present, the main technical means of tumor treatment include radiotherapy, chemotherapy, surgical treatment and immunotherapy, etc., but a considerable number of tumor patients (such as metastatic tumors, recurrent tumors, invasive tumors, etc.) have not benefited from them. [0003] Boron neutron capture therapy (BNCT) is a precise radiation therapy mode based on nuclear capture and fission reactions, which can destroy cancer cells through nuclear reactions in tumor cells. Its working principle is: stable isotope 10 boron( 10 B) After targeted delivery to tumor cells, the application of epithermal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/69A61K47/68A61K9/127A61K47/24A61K47/28A61P35/00
CPCA61K31/69A61K47/68A61K9/127A61K47/24A61K47/28A61P35/00
Inventor 魏启春陈捷键杨琪瑶林梦婷王田田张振涛钟新程卢一莹韩旻高建青
Owner ZHEJIANG UNIV
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