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A kind of antineoplastic drug or drug carrier comprising cyclodextrin modified by glutamine

An anti-tumor drug, glutamine technology, applied in the field of anti-tumor drugs, can solve the problems of large batch-to-batch variation, difficulty in evaluating the safety of nano-carriers, limiting nano-carriers, etc., and achieve the effect of avoiding toxicity

Active Publication Date: 2022-04-19
GENERAL HOSPITAL OF TIANJIN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, factors such as difficulty in assessing the safety of nanocarriers, instability, and large batch-to-batch variability limit the possibility of nanocarriers for drug development

Method used

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  • A kind of antineoplastic drug or drug carrier comprising cyclodextrin modified by glutamine
  • A kind of antineoplastic drug or drug carrier comprising cyclodextrin modified by glutamine
  • A kind of antineoplastic drug or drug carrier comprising cyclodextrin modified by glutamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: Expression of glutamine transporter ASCT2 in various tumors.

[0059] The expression of ASCT2 in each tumor was obtained by querying the public database GEPIA, the search condition was "SLC1A5" (ASCT2 gene name), the sample size of each tumor was shown in Table 1, and the expression of ASCT2 in each tumor was as follows figure 1 Shown in bladder cancer, breast cancer, lung cancer, gastric cancer, hepatocellular carcinoma, melanoma, glioma, lymphoma, colorectal cancer, cervical cancer, bladder cancer, cholangiocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, In ovarian cancer, prostate cancer, sarcoma, thyroid cancer, thymus cancer, endometrioma, sarcoma and other tumors, the expression of ASCT2 in tumor tissues is much higher than that in normal tissues.

[0060] Table 1

[0061]

[0062]

Embodiment 2

[0063] Example 2: Synthesis of glutamine-cyclodextrin.

[0064] A preparation method of glutamine-modified cyclodextrin, which uses tert-butyl bromoacetate to replace the hydrogen of the α-hydroxyl group of β-cyclodextrin under sodium-hydrogen conditions, and then uses trifluoroacetic acid to remove the tert-butyl bromoacetate. The butyl group forms a free carboxyl group, and finally the free carboxyl group is linked to the amino group of L-glutamine under the action of the condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Form amide bonds to make glutamine-modified β-cyclodextrin, and the modification ratio of glutamine to β-cyclodextrin is 1:1 to 7:1, both of which can achieve the drug effect of this scheme. Now the modification ratio Taking 1:1 as an example, the synthesis method is described in detail as follows.

[0065] Specific steps:

[0066] 1) Add sodium hydrogen (4 g, 0.1 mol) and tert-butyl bromoacetate (19.5 g, 0.1 mol), heated to 80°...

Embodiment 3

[0070] Example 3: Glutamine-cyclodextrin and doxorubicin form inclusion complexes.

[0071] Dissolve 100mg GLN-CD (75.7μmol) in 6mL ultrapure water at 40°C, and dissolve 37.8, 50.5, 75.7 and 151.4μmol of doxorubicin (DOX) in 0.6mL DMSO respectively, and then separately Add dropwise to the GLN-CD solution, and continue stirring at 40°C for 8 hours. Precipitate with 80 mL of absolute ethanol and wash 3 times, collect the precipitate and dry it in vacuum to obtain doxorubicin-glutamine-cyclodextrin inclusion compound (DOX@GLN-CD). After doxorubicin enters the inner cavity of cyclodextrin, the fluorescence intensity increases, so the inclusion efficiency of doxorubicin is analyzed by fluorescence spectroscopy, and the test concentration of each inclusion complex is 9.2×10 -4 mol / L, the excitation wavelength is 495nm.

[0072] Such as Figure 5-6 As shown, as the ratio of DOX:GLN-CD increases, the fluorescence gradually increases, indicating that DOX and GLN-CD have successfully...

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Abstract

The present invention relates to an antitumor drug or a drug carrier comprising a glutamine-modified cyclodextrin, and its application in the preparation of an antitumor drug, wherein the glutamine-modified β-cyclodextrin can form an inclusion complex with a chemotherapeutic drug Drugs that transport chemotherapy drugs into tumor cells by targeting the abnormally high-expressed glutamine transporter ASCT2 in tumors, glutamine-modified cyclodextrin or glutamine-modified β-cyclodextrin combined with doxorubicin or paclitaxel The formed clathrate can target the glutamine transporter ASCT2, and be recognized by the transporter, transported into the tumor cells, and then kill the tumor cells; in the tumor-bearing body, the tumor is the largest glutamine uptake organ, while the liver, Kidneys, lungs, and muscles are all glutamine-secreting organs, so targeting glutamine transporters can reduce the toxic and side effects of chemotherapy drugs on liver, kidney, lungs and other major organs.

Description

technical field [0001] The invention belongs to the field of antitumor drugs, in particular to an antitumor drug containing glutamine-modified cyclodextrin. Background technique [0002] Cancer is a major problem that threatens public health. Despite the emergence of new technologies such as immunotherapy and anti-angiogenic agents in recent years, chemotherapy based on cytotoxic drugs remains the cornerstone of cancer treatment. However, the side effects of chemotherapy on normal organs are still the main factor limiting its clinical efficacy. Glutamine is the most abundant amino acid in the cytoplasm, and it participates in biological processes such as energy production, biomacromolecule synthesis, and redox in cells. Reliance on exogenous glutamine is a common feature of most tumor cell metabolism. Therefore, most tumor cells highly express glutamine transporter ASCT2, such as lung cancer, breast cancer, colorectal cancer, etc., and the expression of ASCT2 is closely r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/69A61K47/54A61K45/00A61P35/00A61K31/704A61K31/337
CPCA61K47/6951A61K47/542A61K45/00A61P35/00A61K31/704A61K31/337
Inventor 钟殿胜周平梁兴梅王树青
Owner GENERAL HOSPITAL OF TIANJIN MEDICAL UNIV
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