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Targeted fluorescent probe for two prostate-specific membrane antigens as well as preparation method and application of targeted fluorescent probe

A technology for fluorescent probes and prostate cancer, which is applied in the fields of biotechnology and pharmaceutical preparation, can solve problems such as difficulty in assessing the invasion degree of prostate cancer, poor sensitivity and specificity of fluorescent probes, and the difference between tumors and surrounding tissues. Accurate diagnosis and treatment, improved specificity and sensitivity, and low toxicity

Pending Publication Date: 2022-01-28
CANCER INST & HOSPITAL CHINESE ACADEMY OF MEDICAL SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

One is the problem of surgical margins. Because it is difficult to assess the extent of prostate cancer invasion during surgery, it is still difficult to completely resect the tumor with negative margins (Yossepowitch O, Briganti A, Eastham JA, Epstein J, Graefen M, Montironi R , et al. Positive surgical margins after radical prostatectomy: a systematic review and contemporary update. Eur Urol.2014,65:303-13)
The second major problem is the problem of lymph node metastasis
There are many reports about the use of fluorescent probes in the surgical treatment of prostate cancer, but the results are not very satisfactory, mainly reflected in the poor sensitivity and specificity of fluorescent probes, and the poor contrast between tumor and surrounding tissue (Tumor-to-background ratio, TBR), affecting the surgical effect of the prostate

Method used

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  • Targeted fluorescent probe for two prostate-specific membrane antigens as well as preparation method and application of targeted fluorescent probe
  • Targeted fluorescent probe for two prostate-specific membrane antigens as well as preparation method and application of targeted fluorescent probe
  • Targeted fluorescent probe for two prostate-specific membrane antigens as well as preparation method and application of targeted fluorescent probe

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Preparation of Compound 2

[0079] Substrate 1 (10g, 62.8mmol) and bromoethane (6.84g, 62.8mmol) were dissolved in toluene solvent (32mL). After the reaction was complete, the reaction system was distilled off the solvent under reduced pressure, washed, dried under vacuum, and directly for the next step. Finally, 4.8 g of reddish-brown solid product 2 was obtained with a yield of 28.5%. 1 H NMR (500MHz, DMSO-d 6 )δ8.04(d, J=6.8Hz, 1H), 7.90(d, J=6.4Hz, 1H), 7.69–7.60(m, 2H), 4.56(q, J=7.5Hz, 2H), 2.91( s,3H),1.57(s,6H),1.47(t,J=8.1Hz,4H); 13 C NMR (125MHz, DMSO-d 6 )δ196.60, 142.41, 141.18, 129.77, 129.38, 124.04, 115.81, 54.57, 43.56, 22.33, 14.46, 13.17.

[0080] Preparation of Compound 4

[0081] Substrate 1 (10g, 62.8mmol) and 6-bromohexanoic acid (12.2g, 62.8mmol) were dissolved in toluene solvent (32mL). After the reaction was complete, rotary evaporation, washing, and drying under vacuum were used directly in the following step. Finally, 9.7 g of white so...

Embodiment 2

[0097] Embodiment 2, probe 1, the measurement of the absorption emission spectrum of 2

[0098] Take 5 mM probe1 and 1.0 μL of probe2 prepared in Example 1, add 499 μL of Tris-HCl buffer solution, and then detect the absorption and emission spectra of the fluorescent probe on a microplate reader. See figure 2 .

Embodiment 3

[0099] Embodiment 3, probe 1, 2 are to prostate cancer cell (C4-2) cytotoxic experiment

[0100] Cell viability was determined by MTS method. One experimental group and nine control groups were set up. The adherent cells (C4-2 cells) in the 96-well plate were sequentially treated with probe 2 at concentrations of 0.2 μM, 0.4 μM, 0.8 μM, 1.6 μM, 3.2 μM, 6.25 μM, 12.5 μM and 25 μM, at 37° C. After culturing for 24 hours under 5% CO2 and 5% CO2 conditions, 20 μL MTS was added to each well, and then cultured at 37 °C and 5% CO2 for 4 hours. The absorbance OD value of each group was measured on a microplate reader, and the wavelength was set at 490 nm. According to the OD value of each well, the cell viability was calculated by the formula. The formula is as follows: cell survival rate (%)=(OD of experimental group / OD of control group)×100%. Probes 1 and 2 did not exhibit cytotoxicity to C4-2 at a concentration of 25 μM, indicating that probes 1 and 2 had low cytotoxicity. See ...

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Abstract

The invention provides a targeted fluorescent probe for two prostate specific membrane antigens as well as a preparation method and application of the targeted fluorescent probe. The probe has high affinity and specificity for prostate cancer cells expressing PSMA. In small animal living body imaging, fluorescence signals can be increased, background signals can be reduced, and high stability, time resolution and spatial resolution can be achieved within a certain time. The novel specific targeting prostate cancer fluorescent probe molecule is designed and synthesized, the specificity and sensitivity of prostate cancer detection are greatly improved, the probe can be used for detection of prostate cancer clinical samples, high-precision and high-sensitivity real-time imaging navigation is provided for individualized precise operation, and precise diagnosis and treatment of prostate cancer are achieved.

Description

Technical field [0001] The invention relates to two prostate-specific membrane antigen-targeted fluorescent probes and their preparation methods and their applications, and belongs to the fields of biotechnology and pharmaceutical preparation. Background technique [0002] The incidence rate of prostate cancer (PCa) ranks first among male malignancies in European and American countries and is the second cause of cancer mortality (Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CACancer J Clin. 2019, 69(1):7-34). In my country, with the improvement of people's living standards, aging of the population structure and changes in dietary structure, the incidence of prostate cancer is on the rise and has become a major factor threatening men's health (ChenW, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016, 66: 115-132.). [0003] Currently, radical prostatectomy and / or pelvic lymph node dissection is one of the m...

Claims

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Application Information

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IPC IPC(8): C07D209/10C09K11/06G01N21/64
CPCC07D209/10C09K11/06G01N21/6428C09K2211/1029
Inventor 邢念增胡海宇武岭岭赵钦欣王庆华张青扬
Owner CANCER INST & HOSPITAL CHINESE ACADEMY OF MEDICAL SCI