Application of STING agonist in preparation of medicine for enhancing lung cancer radiotherapy sensitivity

Abstract

The invention relates to application of an STING agonist in preparation of a medicine for enhancing lung cancer radiotherapy sensitivity. The STING agonist is found to be capable of increasing the radiotherapy sensitivity of the non-small cell lung cancer for the first time, a new treatment strategy is provided for treating the non-small cell lung cancer, and meanwhile, a new application of the STING agonist is provided.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to an application of a STING agonist in the preparation of a drug for enhancing the radiotherapy sensitivity of lung cancer. Background Art

[0002] Lung cancer is the malignant tumor with the highest incidence rate in the world, of which 80% to 85% is non-small cell lung cancer. Radiotherapy is one of the important means of comprehensive treatment of lung cancer, and about 2 / 3 of patients need to receive radiotherapy at a certain stage of their disease course. Radiosensitizers are a class of drugs used in radiotherapy, the purpose of which is to increase the sensitivity of tumor cells to radiation, thereby enhancing the effect of radiotherapy. Radiosensitizers can be small molecules, macromolecules or nanomaterials. Although a variety of radiosensitizers have been developed, related research still cannot fully meet the clinical needs of radiotherapy. Therefore, it is particularly important to find new, accurate and effective radiosensitization methods to improve the efficacy of radiotherapy for non-small cell lung cancer, reduce damage to normal tissues, and explore new treatment strategies. In view of this, the present invention provides a STING agonist for the preparation of a drug for enhancing the radiotherapy sensitivity of lung cancer. Summary of the invention

[0003] The technical problem to be solved by the present invention is to provide an application of a STING agonist in the preparation of a drug for enhancing the radiosensitivity of lung cancer. The purpose is to provide an accurate and effective radiosensitizing agent to improve the efficacy of radiotherapy for non-small cell lung cancer and reduce damage to normal tissues.

[0004] The technical solution of the present invention to solve the above technical problems is as follows:

[0005] In the first aspect, a STING agonist is used in the preparation of a drug for enhancing the radiosensitivity of lung cancer.

[0006] The beneficial effects of the present invention are: the present invention discovers for the first time that STING agonists can increase the radiotherapy sensitivity of non-small cell lung cancer, provides a new treatment strategy for the treatment of non-small cell lung cancer, and provides a new application of diABZI STINGagonist-1.

[0007] Furthermore, the STING agonist is diABZI STING agonist-1.

[0008] Among them, the STING agonist diABZI STING agonist-1 is artificially synthesized, and the structural formula of diABZI STINGagonist-1 is:

[0009]

[0010] Furthermore, the concentration of the STING agonist is 5 to 15 nM, preferably 10 nM.

[0011] Furthermore, the STING agonist is administered within 24 hours after the end of radiotherapy.

[0012] The STING agonist used in the present invention, such as diABZI STING agonist-1, is a selective interferon gene (STING) receptor agonist. Through the exploration of the timing of radiotherapy sensitivity, it is found that drug treatment within a certain period of time after radiotherapy has a sensitizing effect on radiotherapy.

[0013] Furthermore, the STING agonist increases the killing of lung cancer cells by radiotherapy.

[0014] Furthermore, the lung cancer is non-small cell lung cancer.

[0015] In the second aspect, a drug for enhancing the radiotherapy sensitivity of lung cancer includes a STING agonist, and the STING agonist includes diABZI STING agonist-1, but is not limited thereto, and may also be a synthetic STING agonist MSA-2 or STING agonist ADU-S100.

[0016] Furthermore, the drug also includes pharmaceutically acceptable excipients and / or carriers.

[0017] Furthermore, the dosage form of the drug includes at least one of an injection and an oral preparation.

[0018] Furthermore, the injection includes at least one of an intravenous injection, an arterial injection, an intramuscular injection, and a subcutaneous injection. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is a comparison chart of cell survival rates in Example 1;

[0020] Figure 2 This is a cell survival rate comparison chart of Comparative Example 1;

[0021] Figure 3 This is a cell survival rate comparison chart for Comparative Example 2. DETAILED DESCRIPTION

[0022] The principles and features of the present invention are described below, and the examples are only used to explain the present invention and are not used to limit the scope of the present invention. If no specific technology or conditions are specified in the embodiments, the technology or conditions described in the literature in this field or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased through regular channels.

[0023] Example 1

[0024] (1) Cell culture

[0025] Human non-small cell lung cancer cell line HCC827 (EGFR gene exon 19 deletion mutation) was purchased from the Chinese Academy of Sciences Cell Bank. HCC827 cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, 1% penicillin and streptomycin at 37°C and 5% CO. 2 Culture in an incubator.

[0026] (2) Immune cell culture

[0027] PBS and blood (3 mL heparin anticoagulant tube, the blood sample has obtained the patient's informed consent, and the design of this study has been approved by the Ethics Committee of Hangzhou Cancer Hospital, approval number: (HZCH-2024) Fast Review No. (022).) were diluted 1:1, and the resulting suspension was added with red blood cell sedimentation fluid (4:1) and shaken evenly. Take a new centrifuge tube and add Ficoll separation solution, and slowly add the supernatant to Ficoll. The final volume after addition should not exceed 45 ml, 2000 rpm, 20 min, room temperature (Note: adjust the centrifuge acceleration and deceleration process to the lowest, and the output speed of the electric pipette to the lowest). After centrifugation, carefully remove the centrifuge tube, and the cell stratification can be clearly seen. Use a Pasteur pipette to slowly extract the white film layer cells into a 50 ml centrifuge tube. Add PBS to 45 ml, mix well, 1500 rpm, 5 minutes. Discard the supernatant, add 45 mL of PBS again, wash once, and count. Use X-VIVO15 medium (brand: LONZA, catalog number: 04-418Q) to adjust the cell concentration to 1-2×10 6 / ml. Add IL-2, add 12ul per 1ml X-VIVO15 medium (1 million IU / tube, 2ml / tube). The final concentration of IL-2 is 6000IU / ml. Mix well and add to a 24-well plate or a 6-well plate according to the volume of the culture medium. After 3 days, transfer the suspended cells to a new culture bottle, add CD3 and CD28, add 0.5ul per 1ml X-VIVO15, and the final concentration of CD3 and CD28 is 500ng / ml. Culture horizontally in a 37°C, 5% carbon dioxide incubator.

[0028] (3) Co-culture model

[0029] 10W HCC827 cells were counted and inoculated in a 6-well plate. After 24 hours, they were mixed with immune cells at a ratio of 1:10, and culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin (RPMI1640 culture medium: X-VIVO15 culture medium = 1:1) was added, and IL-2 was added at a final concentration of 6000 IU / ml.

[0030] (4) Immediately after low-dose radiotherapy (1 Gy), diABZI STING agonist-1 (reagent brand: MCE, catalog number: HY-112921A) was added at a dose of 10 nM at 37°C and 5% CO 2 The cells were cultured in an incubator and the drugs were withdrawn and replaced with normal culture medium after 2 hours.

[0031] Blank control group (Ctrl): no treatment;

[0032] Control group diABZI: diABZI STING agonist-1 was added to make the final concentration 10nM;

[0033] Control group 1Gy: Organoids were irradiated with X-rays at a dose of 1Gy.

[0034] CCK8 was used to detect the OD value for 72 hours and the cell survival rate was calculated. The calculation formula was: survival rate (%) = (OD value of experimental group - OD value of blank control group) / (OD value of control group - OD value of blank control group) × 100%;

[0035] Among them, OD value refers to the optical density value. The OD value of the experimental group is the absorbance value of the treated cells, the OD value of the control group is the absorbance value of the untreated cells, and the OD value of the blank control group is the absorbance value of the culture medium.

[0036] Comparative Example 1

[0037] The difference between Comparative Example 1 and Example 1 is that diABZI STING agonist-1 (at a dose of 10 nM) was added 2 hours before radiotherapy for 2 hours, and the rest was the same as Example 1.

[0038] Comparative Example 2

[0039] The difference between Comparative Example 2 and Example 1 is that diABZI STING agonist-1 (at a dose of 10 nM) was added for 2 hours after radiotherapy for 24 hours, and the rest was the same as Example 1.

[0040] The cell survival rate of Example 1 is as follows Figure 1 As shown, the cell survival rate of Comparative Example 1 is as follows Figure 2 The cell survival rate of Comparative Example 2 is shown in Figure 3 The results showed that adding diABZI STING agonist-1 2 hours before radiotherapy and 24 hours after radiotherapy did not produce a sensitizing effect on radiotherapy. Adding diABZI STING agonist-1 immediately after radiotherapy increased the cell-killing effect of radiotherapy.

[0041] In summary, the present invention discovered for the first time that the STING agonist diABZI STING agonist-1 can increase the radiosensitivity of non-small cell lung cancer, providing a new treatment strategy for the treatment of non-small cell lung cancer, and at the same time providing a new application of diABZI STING agonist-1.

[0042] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. Use of a STING agonist in the preparation of a drug for enhancing the radiosensitivity of lung cancer.

2. The use according to claim 1, characterized in that: The STING agonist is the STING agonist diABZISTING agonist-1.

3. The use according to claim 2, characterized in that: The concentration of the STING agonist is 5-15 nM.

4. The use according to claim 2 or 3, characterized in that: The STING agonist diABZI STING agonist-1 is administered within 24 hours after the end of radiotherapy.

5. The use according to claim 1, characterized in that: The STING agonist increases the killing of lung cancer cells by radiotherapy.

6. The use according to claim 1, characterized in that: The lung cancer is non-small cell lung cancer.

7. A drug for enhancing the radiosensitivity of lung cancer, characterized in that: The drug includes a STING agonist, and the STING agonist includes diABZI STING agonist-1.

8. The drug for enhancing the radiotherapy sensitivity of lung cancer according to claim 7, characterized in that: The drug also includes pharmaceutically acceptable excipients and / or carriers.

9. The drug for enhancing the radiotherapy sensitivity of lung cancer according to claim 7, characterized in that: The dosage form of the drug includes at least one of an injection and an oral preparation.

10. A drug for enhancing the radiotherapy sensitivity of lung cancer according to claim 9, characterized in that: The injection includes at least one of intravenous injection, arterial injection, intramuscular injection and subcutaneous injection.

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