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Pharmaceutical composition and application thereof in preparation of medicaments for treating tumors

A technology of tumor drugs and compositions, applied in the field of biomedicine, can solve the problems of unimproved survival of patients, poor effect of monoclonal antibodies, and limited effect of monoclonal antibodies, etc., to improve tumor cell metabolism, inhibit tumor cell proliferation, inhibit The effect of neovascularization

Active Publication Date: 2020-07-17
SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although sodium dichloroacetate and chloroquine have certain anti-malignant tumor effects, the effect of single use is limited. Clinical trials have shown that sodium dichloroacetate is ineffective against breast cancer and non-small cell lung cancer, and chloroquine alone is also ineffective in some cancer treatments. At present The two drugs can only be used as adjuvant drugs in cancer treatment, and the survival of patients has not been improved
However, simply blocking the effect of integrin often leads to the body's compensation and weakens the anticancer effect. The αvβ3 and αvβ5 inhibitor Cilengitide (Cilengitide) failed in phase 3 clinical trials alone, and the combination of cilengitide with radiotherapy and chemotherapy failed. The survival of patients has not been improved; monoclonal antibodies to integrins also face the same problem, and many monoclonal antibodies have terminated clinical trials or research and development due to poor results

Method used

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  • Pharmaceutical composition and application thereof in preparation of medicaments for treating tumors
  • Pharmaceutical composition and application thereof in preparation of medicaments for treating tumors
  • Pharmaceutical composition and application thereof in preparation of medicaments for treating tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] To verify the toxic effect of sodium dichloroacetate and chloroquine on tumor cells, the test is as follows: Human colon cancer HCT116, human breast cancer MCF7, and human liver cancer HepG2 cells derived from ATCC in the United States were cultured in DMEM containing 10% fetal bovine serum to 90% Digest and subculture with 0.25% trypsin when confluent, and subculture once every 3-5 days. 20,000 cells were planted in wells of 96-well cell culture plates and cultured overnight at 37°C. Different concentrations of sodium dichloroacetate and chloroquine were added to culture for 5 days (renewed once a day). On the 6th day, the cell viability was detected according to the MTS kit (Promega Company). As a result, it can be seen that with the increase of the concentration, sodium dichloroacetate and chloroquine are used in combination on HCT116 ( figure 1 ), MCF7 ( figure 2 ) and HepG2 ( image 3 ) produced a significant toxic effect, and the two drugs had a significant s...

Embodiment 2

[0041] To verify the significant cytotoxic effect of sodium dichloroacetate, chloroquine and integrin siRNA on HepG2 cells, the test is as follows: 40,000 human liver cancer HepG2 cells were planted in 96-well cell culture plate wells, and cultured overnight at 37°C. Then, Lipofectamine RNAiMAX was used to transfect integrin β5 (ITGB5) and β3 (ITGB3) siRNA (0.3nmol / well) for 48 hours, then added different concentrations of sodium dichloroacetate and chloroquine and cultured for 3 days (renewed once a day). On the 6th day, the cell viability was detected according to the MTS kit (Promega Company). In this embodiment, the cell seeding density was doubled compared to Example 1, and it can be seen that the three combined use of HepG2 cells ( Figure 4 ) produced significant toxic effects, and with the increase of sodium dichloroacetate and chloroquine concentrations, the cytotoxic effects were strengthened.

Embodiment 3

[0043] Sodium dichloroacetate and chloroquine combined inhibit HepG2 cell colony formation test, the method is as follows: HepG2 cells in the logarithmic growth phase were digested and counted, and 2500 cells / well were drawn and inoculated into a 6-well cell culture plate. After culturing for 24 hours, add 10 mM sodium dichloroacetate, 10 μM chloroquine or 10 mM sodium dichloroacetate / 10 μM chloroquine for 24 hours, and then replace with a new drug-free medium to continue culturing for 7 to 10 days. Cells were washed twice with PBS, fixed with cold 100% methanol for 15 minutes, and incubated with 0.5% crystal violet for 1 hour at room temperature. The results showed that the combination of sodium dichloroacetate and chloroquine significantly reduced the colony formation of HepG2 cells ( Figure 5 ).

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Abstract

The invention belongs to the field of biological medicines and discloses a pharmaceutical composition and application thereof in preparation of medicaments for treating tumors. The pharmaceutical composition is a group of compositions containing chemical drugs and / or containing siRNA or recombinant viruses expressing shRNA, wherein the pharmaceutical composition containingthe chemical drugs comprises (i) sodium dichloroacetate or analogues thereof and (ii) chloroquine or analogues thereof, and the pharmaceutical composition containing the siRNA or the recombinant viruses expressing the shRNAcomprises a) siRNA and / or shRNA of an integrin subunit, or an inhibitor thereof, or an antibody, or b) an expression vector constructed based on a target sequence of the siRNA or the shRNA of the integrin subunit. The pharmaceutical composition has anti-cancer effects of inhibiting tumor cell proliferation, improving tumor cell metabolism, inhibiting autophagy and generation of neovascularizationin tumor microenvironment.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to the use of a group of chemical medicines and / or pharmaceutical compositions containing siRNA or recombinant viruses expressing shRNA in the preparation of medicines for treating tumors. Background technique [0002] Cancer, also known as malignant tumor, is a serious threat to human life and health. It involves abnormal cell growth and can invade or spread to other parts of the body. The occurrence and development mechanism of cancer is complex, involving gene mutation, abnormal regulation of signaling pathways, metabolic disorders and other aspects. Although various therapeutic drugs and methods are emerging, problems such as treatment sensitivity and drug resistance have prompted continuous research and development of new drugs. anticancer drugs and treatments. [0003] Sodium dichloroacetate (dichloroacetate, DCA) is clinically used to treat lactic acidosis. In recent ye...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/19A61K31/4706A61K31/713A61K31/7105A61K39/39A61K38/12A61K45/00A61K48/00A61K35/76A61P35/00A61P35/02
CPCA61K31/19A61K31/4706A61K31/713A61K31/7105A61K39/39558A61K38/12A61K45/00A61K35/76A61P35/00A61P35/02A61K2300/00Y02A50/30
Inventor 邱瑜郑理陈红专李佳冰黄燕王宏英
Owner SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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